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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Febrile neutropenia'.	Practical Issues in the Use of Atezolizumab for Patients with Non-Small Cell Lung Cancer: Case Reports and Literature Review. Atezolizumab is a monoclonal antibody targeting the programmed death ligand 1 (PD-L1) that was approved in 2017 in the USA and Europe for the second-line treatment of advanced or metastatic non-small cell lung cancer (NSCLC). This review article describes the practical clinical issues associated with atezolizumab treatment in NSCLC using a combination of four illustrative cases and a narrative literature review. The first two cases highlight the importance of tumor mutational status when making treatment decisions. A 62-year-old man with epidermal growth factor receptor (EGFR)-mutated, PD-L1-positive, stage IV lung adenocarcinoma received treatment with second-line atezolizumab + bevacizumab, carboplatin, and paclitaxel (BCP) after first-line osimertinib. In the second case, a 63-year-old man with stage IVb lung adenocarcinoma with anaplastic lymphoma kinase (ALK) translocation received sixth-line treatment with atezolizumab + BCP. The two final cases both had extensive metastases. A 55-year-old woman with EGFR-mutated lung adenocarcinoma received second-line treatment with atezolizumab + BCP after development of multiple metastases, followed by atezolizumab + bevacizumab until last follow-up. A 42-year-old man with PD-L1-positive pulmonary adenocarcinoma (negative for EGFR mutations) developed liver and brain metastases after several lines of therapy. He underwent holocranial radiation and received atezolizumab + BCP, which resulted in a decrease in all measurable and evaluable tumoral lesions. These illustrative cases indicate that the type and number of mutations may influence treatment response to atezolizumab, and that atezolizumab may provide clinical benefit in patients with high disease burden. Key Summary Points Why carry out this study? Targeted immunotherapies, such as atezolizumab, have improved overall survival in patients with advanced or metastatic non-small cell lung cancer (NSCLC) in clinical trials. Understanding how to treat patients on the basis of their targetable oncogenic mutations or those usually excluded from clinical trials (e.g., with treated brain metastases or high disease burden) is important for oncologists in the real-world clinical setting. Four cases of treatment with atezolizumab plus bevacizumab, carboplatin, and paclitaxel in patients with NSCLC after at least one previous line of targeted therapy are described to illustrate these clinical issues. What was learned from the study? The presented cases suggest that both the number and type of mutations may be relevant for guiding treatment decisions in NSCLC, and that patients with high disease burden or brain metastases may benefit from atezolizumab-containing therapy. Digital Features This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13521968. Introduction Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and has a high rate of mortality [1, 2]. According to global estimates, lung cancer was the most commonly diagnosed cancer in 2018 (11.6% of all new cases) and the leading cause of cancer-related mortality (18.4% of all cancer deaths) [3]. In a US analysis of patients with NSCLC, the median overall survival (OS) time after diagnosis was only 13 months, and the estimated 4-year survival rate was between 22% and 28% [1]. However, OS has been improving over recent decades as a result of novel treatments [1, 2], including targeted therapies and immunotherapies. One such novel treatment is atezolizumab, a monoclonal antibody targeting the programmed death ligand 1 (PD-L1) [4]. Atezolizumab was approved in the USA and Europe for the second-line treatment of advanced or metastatic NSCLC in 2017, based on the results of the phase II POPLAR study [5] and the phase III OAK study [6], in which atezolizumab was associated with significantly better survival compared with docetaxel. Since its approval, the IMpower150 study has demonstrated that atezolizumab in combination with bevacizumab, carboplatin, and paclitaxel (BCP) was more effective than BCP alone as first-line therapy in previously untreated patients with metastatic non-squamous NSCLC [7]. The current review describes the practical clinical issues associated with atezolizumab + BCP in patients with NSCLC, using a combination of illustrative case presentations and a narrative literature review. Cases Illustrating Role of Mutational Status Patient 1 A 62-year-old man with no relevant medical or surgical history was diagnosed with stage IIIC lung adenocarcinoma (cT3cN3cM0) in January 2018. He was a former smoker with a 15 pack-year history. Molecular testing showed an L858R point mutation in epidermal growth factor receptor (EGFR) exon 21 and a primary T790M mutation in EGFR exon 20. The tumor was PD-L1 positive, with a tumor proportion score (TPS) of 80% on immunohistochemistry (pharmDx 28–8; DAKO, Glostrup, Denmark). On February 1, 2018, he began first-line treatment with osimertinib; the 12-week assessment showed a partial response by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. Response continued until March 2019, when the disease progressed to stage IV with mediastinal and retroperitoneal involvement (Fig. 1a). At this time, the patient was asymptomatic and started second-line treatment with atezolizumab in combination with BCP, based on the results of the IMpower150 clinical trial [7]. After two cycles, a computed tomography (CT) scan showed partial response by RECIST 1.1 criteria (Fig. 1b), and the patient was able to receive six cycles without significant adverse events.Fig. 1 Patient 1: Computed tomography scan of chest on a March 25, 2019, showing mediastinal and retroperitoneal involvement, b June 6, 2019 after two cycles of atezolizumab + BCP, c October 5, 2019 indicating a maintained radiologic response, and d January 30, 2020 showing tumor progression after 13 weeks of maintenance atezolizumab + bevacizumab. BCP bevacizumab, carboplatin, and paclitaxel After confirming that the radiologic response was maintained (Fig. 1c), he continued maintenance treatment with atezolizumab + bevacizumab. In February 2020, after 13 cycles, tumor progression was noted (Fig. 1d) and treatment was discontinued. Biopsy showed amplification and overexpression of c-MET, so the patient initiated third-line treatment with telisotuzumab vedotin as part of a clinical trial (NCT03539536). Patient 2 A 63-year-old man was diagnosed with a stage IVb lung adenocarcinoma with a brain metastasis (T2N3M1b) in February 2013. He was a former smoker (20 pack-year history) with occupational exposure to oil and its derivatives. On June 13, 2013, he started induction chemotherapy with cisplatin + pemetrexed, undergoing radiosurgery for the brain lesion after the first cycle. He showed a partial radiologic and metabolic response after two cycles of cisplatin + pemetrexed, and a brain magnetic resonance imaging (MRI) revealed a reduction in the size of the brain metastasis. He received two cycles of cisplatin + pemetrexed from June 13 to June 24, 2013, followed by radical-intent chemoradiation between June 28 and September 6, 2013, consisting of a 60 Gy dose and two cycles of weekly paclitaxel + carboplatin; however, he was unable to continue this treatment because of sustained leukopenia. A follow-up assessment on October 6, 2014, found no signs of thoracoabdominal progression. Lesions consistent with metastases were identified in the cerebellar vermis and the right centrum semiovale; radiosurgery was administered using 20.7 Gy and 20.9 Gy, respectively, at these sites. A CT scan on January 12, 2015, showed hilar-mediastinal progression, and a biopsy of the left hilar adenopathy showed that the tumor had wild-type KRAS, was EGFR- and BRAF-mutation negative, and had an anaplastic lymphoma kinase (ALK) translocation. In February 2015, he started second-line treatment with crizotinib and had a partial response. A brain MRI performed on November 3, 2015, showed oligoprogression, for which he received radiosurgery. On April 4, 2016, he showed pulmonary progression, and 2 weeks later, he started third-line treatment with ceritinib as part of a clinical trial, with a best response of stable disease. A CT scan on January 30, 2018, showed an increase in the size of the space-occupying lesions in the brain. On March 6 of the same year, he initiated fourth-line treatment with alectinib for metastases, with a best response of stable disease. A further CT scan on July 23, 2018, showed left hilar adenopathy progression and left upper lobe atelectasis. He started fifth-line therapy for metastases with brigatinib on September 5, 2018, and stable disease was his best response. The patient developed left hemiparesis on January 16, 2019. A brain MRI on January 21 showed signs of radionecrosis, but an acute or subacute ischemic event could not be ruled out. Brain progression, with an increase in the size and number of lesions, was detected in March 2019 (Fig. 2a), and he received hippocampal-sparing whole brain radiation with focal boost (45 Gy dose) on the lesions.Fig. 2 Patient 2: brain magnetic resonance imaging scan results on a March 11, 2019, showing an increase in the size and number of brain lesions, and b March 22, 2020, after 4 cycles of atezolizumab + BCP followed by 13 cycles of maintenance atezolizumab + bevacizumab, and chest computed tomography scan results on c March 11, 2019, prior to, and d March 22, 2020, after atezolizumab-based treatment On May 8, 2019, he began sixth-line treatment with atezolizumab + BCP. After four cycles (ending on August 8, 2019), he started maintenance treatment with atezolizumab + bevacizumab, achieving a partial brain response. In March 2020, he had received 13 cycles of maintenance treatment, and he showed stable disease as assessed by brain MRI (Fig. 2b) and CT scans of the chest (Fig. 2c, d), abdomen, and pelvis. CASES Illustrating Management of High Disease Burden Patient 3 A 55-year-old non-smoking woman without known morbidity was diagnosed with a stage IIIB lung adenocarcinoma (cT4N2) in June 2016. She received treatment with external radiation therapy (dose administered, 66 Gy) concomitantly with cisplatin and vinorelbine (three cycles). A follow-up CT scan showed partial response and the multidisciplinary Committee on Thoracic Tumors recommended surgical intervention. She underwent video-assisted thoracic surgery consisting of an upper right pulmonary lobectomy with systematic hilar and mediastinal lymph node dissection on October 5, 2016. Molecular analysis of the excised tumor showed EGFR exon 19 deletion. In March 2018, disease progression was detected in lung, pleura, and bone, and in subcutaneous tissue and the lymphatic system. On March 27, she received palliative and decompressive radiation therapy of the lumbar spine (L5) at 8 Gy. Subsequently, in April 2018, she started treatment with afatinib at 40 mg/day, and had a partial response. Afatinib treatment continued until July 2019, when imaging identified disease progression in the liver and bone, and a sacral soft tissue mass (Fig. 3a). Analysis of liquid and sacral mass biopsy did not detect a resistant T790M mutation on EGFR exon 20.Fig. 3 Patient 3: Computed tomography of lumbosacral region on a July 4, 2019, before and b October 8, 2019, after three cycles of atezolizumab + BCP, showing partial response in the sacral soft tissue mass. BCP bevacizumab, carboplatin, and paclitaxel At this time, the patient’s Eastern Cooperative Oncology Group (ECOG) performance status was 2, and she was negative for PD-L1 (TPS 0%). On August 7, 2019, on the basis of the results of the IMpower150 clinical trial [7], she began second-line treatment with atezolizumab + BCP. After three cycles she showed a partial response (Fig. 3b), and was able to complete six cycles of treatment. However, the patient developed febrile neutropenia and sepsis due to central catheter-related infections in the second cycle leading to hospital admission; grade 2 sensory neuropathy that reverted to grade 1 after discontinuing paclitaxel and carboplatin; and grade 1 asthenia. She then continued treatment with atezolizumab + bevacizumab. By June 2020, she had completed 14 cycles of treatment without relevant toxicities, but treatment was interrupted at that time because a CT scan showed progression of the liver and bone metastases. Patient 4 A 42-year-old man was diagnosed with stage IIIB pulmonary adenocarcinoma (cT4N2M0) in June 2018; at this time, he had an ECOG performance status of 0. Molecular analysis showed the tumor was negative for EGFR mutations and ALK fusions, with PD-L1 expression on 30% of cancer cells. He was a smoker at the time of diagnosis, smoking one pack daily for 20 years (20 pack-years). On August 22, 2018, treatment with cisplatin, gemcitabine, and paclitaxel was started, for a total of four 21-day cycles. Treatment was well tolerated, with the exception of nausea and asthenia (both grade 1). Repeat CT scans performed in September 2018 after two treatment cycles, and again in November after four treatment cycles, revealed decreasing tumor volume, with mediastinal contact still present; at this time, results of a brain MRI were normal. In December 2018, the man underwent a right lower lobectomy; the right lower pulmonary lobe was found to have well-differentiated adenocarcinoma with an acinar pattern, without evidence of vascular invasion, and no visceral pleural infiltration. Surgical resection margins were not affected. TNM staging at this point was ypT1cN0M0. He subsequently received consolidative radiation therapy on the mediastinal bed; he had a performance status of 0 and no complications. In October 2019, a follow-up examination revealed a de novo pulmonary micronodule in the control CT scan, but this was not seen on a positron emission tomography–CT scan. In February 2020, repeat CT scans revealed a growth on the left perihilar pulmonary nodule and a new right-hand micronodule. Metastases were seen in several liver segments. As a result of mild dizziness, a central nervous system (CNS) MRI scan was performed in January 2020, revealing the presence of brain metastases (Fig. 4a).Fig. 4 Patient 4: Brain magnetic resonance imaging scan results in a January 2020 showing brain metastases and b April 2020 showing reduced lesion size after atezolizumab + BCP treatment. BCP bevacizumab, carboplatin, and paclitaxel Holocranial radiotherapy was administered, finishing at the beginning of February 2020. After 4 weeks, a repeat MRI did not show any significant changes in the size of the brain lesions. One month after discontinuing holocranial radiotherapy, in the second week of March 2020, he began treatment with four 21-day cycles of atezolizumab + BCP, followed by atezolizumab + bevacizumab until disease progression or toxicity. After two cycles, there were no notable toxicities, and an assessment performed at the end of April 2020 revealed a decrease in all measurable and evaluable tumoral lesions (Fig. 4b). By December 2020, 40 weeks after the start of atezolizumab + BCP, the patient was still in partial response and was being managed on chemotherapy-free maintenance treatment with atezolizumab + bevacizumab. Compliance with Ethics Guidelines Data on these patients were collected in accordance with the Helsinki Declaration of 1964 and its later amendments concerning human and animal rights. All patients provided written informed consent to all the diagnostic and therapeutic procedures, for the use of their medical images, and for inclusion in this manuscript. Ethical committee approval was not required, as per Spanish law. Discussion EGFR mutations are present in 10–20% of Caucasian patients and about 50% of Asian patients with NSCLC [8]. The L858R point mutation in EGFR exon 21 identified in patient 1 at diagnosis is one of the most common “classical” EGFR mutations, along with a deletion in exon 19 [8]. Together, these mutations represent 85% of EGFR mutations. These activating mutations make the tumor sensitive to tyrosine kinase inhibitors (TKIs) and are an indication for choosing a TKI agent as first-line therapy [9], as occurred in patient 1. Indeed, current NSCLC guidelines note the importance of molecular tumor analysis in determining first-line therapy [9, 10]. In Europe, testing for mutations or rearrangements of ALK, c-ros oncogene 1 (ROS1), and EGFR is considered mandatory, and testing for BRAF V600E mutations is important in countries where BRAF/MEK inhibitors are approved. Other tests include those for human epidermal growth factor receptor 2 (HER2) and MET exon mutations and for fusion genes in RET and NTRK1, which are all are considered evolving biomarkers [10]. The US National Comprehensive Cancer Network guidelines recommend the biomarker test panel for non-squamous NSCLC should, at a minimum, include EGFR mutations, BRAF mutations, ALK fusions, ROS1 fusions, and PD-L1 expression [9]. A primary T790M mutation in EGFR exon 20 is a resistance mutation and more likely to coexist with an L858R mutation than with an exon 19 deletion [11]. While osimertinib has been shown to be effective in patients with a primary T790M mutation, as shown in patient 1, most patients with such mutations progress within 1 year of starting osimertinib [11]. Patient 1 also had high expression of PD-L1 as shown by a TPS of 80%. This suggests that this patient is a good candidate for immunotherapy, but guidelines recommend the use of targeted therapy first-line (before immunotherapy) in patients with sensitizing mutations because the response rate is likely to be higher [9]. Once targeted therapy fails, immunotherapy is indicated. ALK rearrangements are the driving mutations responsible for the development of NSCLC in 3–7% of patients, and, as observed in patient 2, these patients have a higher risk of developing brain metastases than those with other NSCLC subtypes [12]. The first-generation ALK inhibitor crizotinib, used for second-line treatment in patient 2, has antitumor advantages over chemotherapy in this subtype of patients; however, all patients eventually progress because of drug resistance [10]. Furthermore, the amount of crizotinib that crosses the blood–brain barrier is negligible, which limits its use in patients with brain metastases [10]. In patients with crizotinib-resistant ALK-rearranged NSCLC, one strategy is sequential treatment with next-generation ALK inhibitors, such as ceritinib, alectinib, or brigatinib [12], as used in patient 2. In the IMpower150 study, most patients had wild-type EGFR and ALK, but 10% of patients were EGFR-mutation positive and 8.5% were ALK-rearrangement positive [7]. IMpower150 is the only trial that has shown positive results with immunotherapy in patients with EGFR- or ALK-positive NSCLC [10]. OS in the population that included patients with these mutations receiving the atezolizumab + BCP regimen was 19.8 months, which was similar to that in the population excluding patients with these mutations (19.5 months), and significantly longer than in the BCP group (15.0 months for the whole population and 14.7 months for the EGFR and ALK wild-type population) [13]. In patients with EGFR mutations, OS was 29.4 months in the atezolizumab + BCP group and 18.1 months in the BCP group [13]. Median progression-free survival (PFS) in patients with EGFR mutations receiving the atezolizumab + BCP regimen was 9.7 months, similar to the PFS in patients with wild-type EGFR (8.3 months), and significantly longer than in the BCP group irrespective of EGFR mutation status (6.1 months and 6.8 months, respectively, in the EGFR mutation and wild-type groups receiving BCP) [7]. Similarly, median PFS was significantly longer in the atezolizumab + BCP group than in the placebo + BCP group in patients with KRAS mutations (8.1 vs. 5.8 months, respectively), as well as in those with wild-type KRAS (9.7 vs. 5.8 months) [7]. The number of mutations, as well as the type, may be relevant to treatment response to atezolizumab. Data suggest that the survival (PFS and OS) benefit of PD-L1 or PD-1 inhibitors may be more marked in patients with a high tumor mutation burden (TMB) than in those with low TMB [14–16], although this result was not seen in some trials [17, 18]. Recent data from randomized trials show that a blood-based assay for TMB can be a useful and valid biomarker for atezolizumab [19]. The cases of patients 3 and 4 illustrated the use of atezolizumab in patients with high disease burden, which was characterized by extensive metastases, including in the liver. In the IMPower150 study, 13% of patients had liver metastases, and atezolizumab + BCP significantly prolonged PFS and OS compared with placebo + BCP in patients with or without liver metastases [7, 20]. However, the difference in PFS and OS between the atezolizumab + BCP group and the BCP group was more marked in the cohort with liver metastases [7]. In the group with liver metastases, the PFS hazard ratio was 0.42 (median PFS 7.4 vs. 4.9 months for atezolizumab + BCP vs. placebo + BCP), whereas in the group without liver metastases the PFS hazard ratio was 0.63 (median PFS 8.3 vs. 7.0 months, respectively) [7]; the OS hazard ratio was 0.52 in the group with liver metastases (median OS 13.3 vs. 9.4 months for atezolizumab + BCP vs. placebo + BCP), and in the group without liver metastases the OS hazard ratio was 0.82 (median OS 20.4 vs. 17.0 months, respectively) [20]. In addition to liver metastases, patient 3 also had bone metastases, which are associated with significantly reduced survival in patients with NSCLC [21, 22]. Moreover, bone metastases are associated with significant pain, fatigue, and disturbed sleep [23], which may negatively affect the patient’s performance status. Indeed, this patient had an ECOG performance status of 2. The IMpower150 study excluded patients with ECOG performance status of 2 or higher [7]; however, data indicate that between one-third and one-half of patients with NSCLC have poor performance status (e.g., ECOG PS of 2 or higher) [24]. It is encouraging that patient 3, who had multiple metastatic sites including in the appendicular skeleton, was able to benefit from treatment with atezolizumab over a prolonged period before disease progression. The last case presented (patient 4) had both liver and brain metastases at the time of starting treatment with atezolizumab. Adenocarcinomas are the most common tumor type to metastasize to the CNS, and 30–64% of patients with NSCLC have CNS metastases [9, 10]. Historically, patients with brain metastases have had a particularly poor prognosis [25], although this is starting to change with the increasing availability of novel agents. However, patients with untreated brain metastases are usually excluded from clinical trials, many of which also exclude patients with treated brain metastases. Indeed, both the POPLAR study and IMPower150 excluded patients with untreated CNS metastases [5, 7], with neither study reporting on patients with treated brain metastases. Patient 4 described here received treatment of brain metastases with holocranial radiotherapy, and subsequently derived benefit from atezolizumab treatment. The positive CNS responses in this patient is consistent with findings reported in the OAK trial [6]. In this trial, which specified inclusion of patients with treated, asymptomatic supratentorial CNS metastases, subgroup analysis demonstrated a survival benefit with atezolizumab compared with docetaxel in patients with treated CNS metastases at baseline, with a hazard ratio of 0.54 [95% confidence interval (CI) 0.31–0.94] [6]. These findings for atezolizumab in patients with brain metastases are also consistent with those of a phase II study of pembrolizumab in patients with NSCLC (n = 18) or melanoma and untreated brain metastases, in which pembrolizumab demonstrated activity in brain metastases, with a response rate for brain metastasis of 33% among patients with NSCLC [26]. Although this case series provides valuable information regarding the practical clinical issues associated with atezolizumab + BCP treatment, more well-designed studies are needed to develop evidence-based recommendations on immunotherapy to guide oncologists, immunologists, and other specialists in the management of patients with mutated NSCLC. Conclusion As more becomes known about the importance of the various genetic mutations, rearrangements, and expression profiles in NSCLC, testing for targetable oncogenic alterations and immuno-oncology therapy biomarkers is becoming more and more essential for treatment decisions [10]. The first two patients discussed here suggest that the number and type of mutations may be relevant for guiding treatment decisions in NSCLC. To our knowledge, atezolizumab + BCP is the only immunotherapy combination that has demonstrated efficacy in patients with mutated NSCLC [7, 27], and these cases show that the results of these studies have been transferred to clinical practice. Another factor that should be considered when deciding upon a course of therapy is a patient’s performance status. However, clinical trials often exclude patients with poor performance status; hence, the second two cases described here of patients with NSCLC and high disease burden (patients 3 and 4), who benefited from atezolizumab-containing therapy over a prolonged period, are particularly encouraging. Finally, the CNS responses reported here suggest that atezolizumab + bevacizumab may be an important option for the significant unmet need of treating brain metastases in NSCLC. These observations provide valuable insights into the practical clinical issues associated with atezolizumab + BCP treatment in patients with advanced or metastatic NSCLC. These illustrative clinical cases may also help clinicians to identify patients with NSCLC who will potentially gain the most benefit from the use of atezolizumab + BCP in routine clinical practice. We thank the patients who allowed us to report their clinical details. Funding Medical writing assistance and the Rapid Service Fee for this manuscript were funded by Roche. Medical Writing Assistance We would like to thank Catherine Rees of Springer Healthcare Communications, and Marie Cheeseman, on behalf of Springer Healthcare Communications, who wrote the outline and first draft, respectively. This medical writing assistance was funded by Roche. Authorship All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. Compliance with Ethics Guidelines Data from these patients were collected in accordance with the Helsinki Declaration of 1964 and its later amendments, concerning human and animal rights. All patients provided written informed consent to all the diagnostic-therapeutic procedures, for the use of their medical images, and for inclusion in this manuscript. Ethical committee approval was not required, as per Spanish law. Disclosures Dr Cobo reports receiving advisory or consultancy fees from Roche, Bristol Myers Squibb, AstraZeneca, Pfizer, and Boehringer, and travel and accommodation funding from Roche, Bristol Myers Squibb, and AstraZeneca outside of the submitted work. Dr Rodríguez-Abreu reports receiving advisory or consultancy fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Pfizer, Boehringer, and Takeda, speaker’s fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Boehringer, and Takeda, and travel and accommodation funding from Roche, Merck, Bristol Myers Squibb, and AstraZeneca outside of the submitted work. Diego Pérez Parente is an employee of Roche Farma, Spain. Pedro Ruiz Gracia is an employee of Roche Farma, Spain. Dr González reports receiving advisory or consultancy fees from Roche, Bristol Myers Squibb, AstraZeneca, Boehringer, and Sanofi, speaker’s fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Lilly, and Ipsen, and travel and accommodation funding from Roche, Merck, Bristol Myers Squibb, and Lilly outside of the submitted work. Data Availability Qualified researchers may request access to individual patient level data through the clinical study data request platform (https://vivli.org/). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).	ATEZOLIZUMAB, BEVACIZUMAB, CARBOPLATIN, PACLITAXEL	DrugsGivenReaction	CC BY-NC	33582978	18,969,138	2021-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Peripheral sensory neuropathy'.	Practical Issues in the Use of Atezolizumab for Patients with Non-Small Cell Lung Cancer: Case Reports and Literature Review. Atezolizumab is a monoclonal antibody targeting the programmed death ligand 1 (PD-L1) that was approved in 2017 in the USA and Europe for the second-line treatment of advanced or metastatic non-small cell lung cancer (NSCLC). This review article describes the practical clinical issues associated with atezolizumab treatment in NSCLC using a combination of four illustrative cases and a narrative literature review. The first two cases highlight the importance of tumor mutational status when making treatment decisions. A 62-year-old man with epidermal growth factor receptor (EGFR)-mutated, PD-L1-positive, stage IV lung adenocarcinoma received treatment with second-line atezolizumab + bevacizumab, carboplatin, and paclitaxel (BCP) after first-line osimertinib. In the second case, a 63-year-old man with stage IVb lung adenocarcinoma with anaplastic lymphoma kinase (ALK) translocation received sixth-line treatment with atezolizumab + BCP. The two final cases both had extensive metastases. A 55-year-old woman with EGFR-mutated lung adenocarcinoma received second-line treatment with atezolizumab + BCP after development of multiple metastases, followed by atezolizumab + bevacizumab until last follow-up. A 42-year-old man with PD-L1-positive pulmonary adenocarcinoma (negative for EGFR mutations) developed liver and brain metastases after several lines of therapy. He underwent holocranial radiation and received atezolizumab + BCP, which resulted in a decrease in all measurable and evaluable tumoral lesions. These illustrative cases indicate that the type and number of mutations may influence treatment response to atezolizumab, and that atezolizumab may provide clinical benefit in patients with high disease burden. Key Summary Points Why carry out this study? Targeted immunotherapies, such as atezolizumab, have improved overall survival in patients with advanced or metastatic non-small cell lung cancer (NSCLC) in clinical trials. Understanding how to treat patients on the basis of their targetable oncogenic mutations or those usually excluded from clinical trials (e.g., with treated brain metastases or high disease burden) is important for oncologists in the real-world clinical setting. Four cases of treatment with atezolizumab plus bevacizumab, carboplatin, and paclitaxel in patients with NSCLC after at least one previous line of targeted therapy are described to illustrate these clinical issues. What was learned from the study? The presented cases suggest that both the number and type of mutations may be relevant for guiding treatment decisions in NSCLC, and that patients with high disease burden or brain metastases may benefit from atezolizumab-containing therapy. Digital Features This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13521968. Introduction Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and has a high rate of mortality [1, 2]. According to global estimates, lung cancer was the most commonly diagnosed cancer in 2018 (11.6% of all new cases) and the leading cause of cancer-related mortality (18.4% of all cancer deaths) [3]. In a US analysis of patients with NSCLC, the median overall survival (OS) time after diagnosis was only 13 months, and the estimated 4-year survival rate was between 22% and 28% [1]. However, OS has been improving over recent decades as a result of novel treatments [1, 2], including targeted therapies and immunotherapies. One such novel treatment is atezolizumab, a monoclonal antibody targeting the programmed death ligand 1 (PD-L1) [4]. Atezolizumab was approved in the USA and Europe for the second-line treatment of advanced or metastatic NSCLC in 2017, based on the results of the phase II POPLAR study [5] and the phase III OAK study [6], in which atezolizumab was associated with significantly better survival compared with docetaxel. Since its approval, the IMpower150 study has demonstrated that atezolizumab in combination with bevacizumab, carboplatin, and paclitaxel (BCP) was more effective than BCP alone as first-line therapy in previously untreated patients with metastatic non-squamous NSCLC [7]. The current review describes the practical clinical issues associated with atezolizumab + BCP in patients with NSCLC, using a combination of illustrative case presentations and a narrative literature review. Cases Illustrating Role of Mutational Status Patient 1 A 62-year-old man with no relevant medical or surgical history was diagnosed with stage IIIC lung adenocarcinoma (cT3cN3cM0) in January 2018. He was a former smoker with a 15 pack-year history. Molecular testing showed an L858R point mutation in epidermal growth factor receptor (EGFR) exon 21 and a primary T790M mutation in EGFR exon 20. The tumor was PD-L1 positive, with a tumor proportion score (TPS) of 80% on immunohistochemistry (pharmDx 28–8; DAKO, Glostrup, Denmark). On February 1, 2018, he began first-line treatment with osimertinib; the 12-week assessment showed a partial response by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. Response continued until March 2019, when the disease progressed to stage IV with mediastinal and retroperitoneal involvement (Fig. 1a). At this time, the patient was asymptomatic and started second-line treatment with atezolizumab in combination with BCP, based on the results of the IMpower150 clinical trial [7]. After two cycles, a computed tomography (CT) scan showed partial response by RECIST 1.1 criteria (Fig. 1b), and the patient was able to receive six cycles without significant adverse events.Fig. 1 Patient 1: Computed tomography scan of chest on a March 25, 2019, showing mediastinal and retroperitoneal involvement, b June 6, 2019 after two cycles of atezolizumab + BCP, c October 5, 2019 indicating a maintained radiologic response, and d January 30, 2020 showing tumor progression after 13 weeks of maintenance atezolizumab + bevacizumab. BCP bevacizumab, carboplatin, and paclitaxel After confirming that the radiologic response was maintained (Fig. 1c), he continued maintenance treatment with atezolizumab + bevacizumab. In February 2020, after 13 cycles, tumor progression was noted (Fig. 1d) and treatment was discontinued. Biopsy showed amplification and overexpression of c-MET, so the patient initiated third-line treatment with telisotuzumab vedotin as part of a clinical trial (NCT03539536). Patient 2 A 63-year-old man was diagnosed with a stage IVb lung adenocarcinoma with a brain metastasis (T2N3M1b) in February 2013. He was a former smoker (20 pack-year history) with occupational exposure to oil and its derivatives. On June 13, 2013, he started induction chemotherapy with cisplatin + pemetrexed, undergoing radiosurgery for the brain lesion after the first cycle. He showed a partial radiologic and metabolic response after two cycles of cisplatin + pemetrexed, and a brain magnetic resonance imaging (MRI) revealed a reduction in the size of the brain metastasis. He received two cycles of cisplatin + pemetrexed from June 13 to June 24, 2013, followed by radical-intent chemoradiation between June 28 and September 6, 2013, consisting of a 60 Gy dose and two cycles of weekly paclitaxel + carboplatin; however, he was unable to continue this treatment because of sustained leukopenia. A follow-up assessment on October 6, 2014, found no signs of thoracoabdominal progression. Lesions consistent with metastases were identified in the cerebellar vermis and the right centrum semiovale; radiosurgery was administered using 20.7 Gy and 20.9 Gy, respectively, at these sites. A CT scan on January 12, 2015, showed hilar-mediastinal progression, and a biopsy of the left hilar adenopathy showed that the tumor had wild-type KRAS, was EGFR- and BRAF-mutation negative, and had an anaplastic lymphoma kinase (ALK) translocation. In February 2015, he started second-line treatment with crizotinib and had a partial response. A brain MRI performed on November 3, 2015, showed oligoprogression, for which he received radiosurgery. On April 4, 2016, he showed pulmonary progression, and 2 weeks later, he started third-line treatment with ceritinib as part of a clinical trial, with a best response of stable disease. A CT scan on January 30, 2018, showed an increase in the size of the space-occupying lesions in the brain. On March 6 of the same year, he initiated fourth-line treatment with alectinib for metastases, with a best response of stable disease. A further CT scan on July 23, 2018, showed left hilar adenopathy progression and left upper lobe atelectasis. He started fifth-line therapy for metastases with brigatinib on September 5, 2018, and stable disease was his best response. The patient developed left hemiparesis on January 16, 2019. A brain MRI on January 21 showed signs of radionecrosis, but an acute or subacute ischemic event could not be ruled out. Brain progression, with an increase in the size and number of lesions, was detected in March 2019 (Fig. 2a), and he received hippocampal-sparing whole brain radiation with focal boost (45 Gy dose) on the lesions.Fig. 2 Patient 2: brain magnetic resonance imaging scan results on a March 11, 2019, showing an increase in the size and number of brain lesions, and b March 22, 2020, after 4 cycles of atezolizumab + BCP followed by 13 cycles of maintenance atezolizumab + bevacizumab, and chest computed tomography scan results on c March 11, 2019, prior to, and d March 22, 2020, after atezolizumab-based treatment On May 8, 2019, he began sixth-line treatment with atezolizumab + BCP. After four cycles (ending on August 8, 2019), he started maintenance treatment with atezolizumab + bevacizumab, achieving a partial brain response. In March 2020, he had received 13 cycles of maintenance treatment, and he showed stable disease as assessed by brain MRI (Fig. 2b) and CT scans of the chest (Fig. 2c, d), abdomen, and pelvis. CASES Illustrating Management of High Disease Burden Patient 3 A 55-year-old non-smoking woman without known morbidity was diagnosed with a stage IIIB lung adenocarcinoma (cT4N2) in June 2016. She received treatment with external radiation therapy (dose administered, 66 Gy) concomitantly with cisplatin and vinorelbine (three cycles). A follow-up CT scan showed partial response and the multidisciplinary Committee on Thoracic Tumors recommended surgical intervention. She underwent video-assisted thoracic surgery consisting of an upper right pulmonary lobectomy with systematic hilar and mediastinal lymph node dissection on October 5, 2016. Molecular analysis of the excised tumor showed EGFR exon 19 deletion. In March 2018, disease progression was detected in lung, pleura, and bone, and in subcutaneous tissue and the lymphatic system. On March 27, she received palliative and decompressive radiation therapy of the lumbar spine (L5) at 8 Gy. Subsequently, in April 2018, she started treatment with afatinib at 40 mg/day, and had a partial response. Afatinib treatment continued until July 2019, when imaging identified disease progression in the liver and bone, and a sacral soft tissue mass (Fig. 3a). Analysis of liquid and sacral mass biopsy did not detect a resistant T790M mutation on EGFR exon 20.Fig. 3 Patient 3: Computed tomography of lumbosacral region on a July 4, 2019, before and b October 8, 2019, after three cycles of atezolizumab + BCP, showing partial response in the sacral soft tissue mass. BCP bevacizumab, carboplatin, and paclitaxel At this time, the patient’s Eastern Cooperative Oncology Group (ECOG) performance status was 2, and she was negative for PD-L1 (TPS 0%). On August 7, 2019, on the basis of the results of the IMpower150 clinical trial [7], she began second-line treatment with atezolizumab + BCP. After three cycles she showed a partial response (Fig. 3b), and was able to complete six cycles of treatment. However, the patient developed febrile neutropenia and sepsis due to central catheter-related infections in the second cycle leading to hospital admission; grade 2 sensory neuropathy that reverted to grade 1 after discontinuing paclitaxel and carboplatin; and grade 1 asthenia. She then continued treatment with atezolizumab + bevacizumab. By June 2020, she had completed 14 cycles of treatment without relevant toxicities, but treatment was interrupted at that time because a CT scan showed progression of the liver and bone metastases. Patient 4 A 42-year-old man was diagnosed with stage IIIB pulmonary adenocarcinoma (cT4N2M0) in June 2018; at this time, he had an ECOG performance status of 0. Molecular analysis showed the tumor was negative for EGFR mutations and ALK fusions, with PD-L1 expression on 30% of cancer cells. He was a smoker at the time of diagnosis, smoking one pack daily for 20 years (20 pack-years). On August 22, 2018, treatment with cisplatin, gemcitabine, and paclitaxel was started, for a total of four 21-day cycles. Treatment was well tolerated, with the exception of nausea and asthenia (both grade 1). Repeat CT scans performed in September 2018 after two treatment cycles, and again in November after four treatment cycles, revealed decreasing tumor volume, with mediastinal contact still present; at this time, results of a brain MRI were normal. In December 2018, the man underwent a right lower lobectomy; the right lower pulmonary lobe was found to have well-differentiated adenocarcinoma with an acinar pattern, without evidence of vascular invasion, and no visceral pleural infiltration. Surgical resection margins were not affected. TNM staging at this point was ypT1cN0M0. He subsequently received consolidative radiation therapy on the mediastinal bed; he had a performance status of 0 and no complications. In October 2019, a follow-up examination revealed a de novo pulmonary micronodule in the control CT scan, but this was not seen on a positron emission tomography–CT scan. In February 2020, repeat CT scans revealed a growth on the left perihilar pulmonary nodule and a new right-hand micronodule. Metastases were seen in several liver segments. As a result of mild dizziness, a central nervous system (CNS) MRI scan was performed in January 2020, revealing the presence of brain metastases (Fig. 4a).Fig. 4 Patient 4: Brain magnetic resonance imaging scan results in a January 2020 showing brain metastases and b April 2020 showing reduced lesion size after atezolizumab + BCP treatment. BCP bevacizumab, carboplatin, and paclitaxel Holocranial radiotherapy was administered, finishing at the beginning of February 2020. After 4 weeks, a repeat MRI did not show any significant changes in the size of the brain lesions. One month after discontinuing holocranial radiotherapy, in the second week of March 2020, he began treatment with four 21-day cycles of atezolizumab + BCP, followed by atezolizumab + bevacizumab until disease progression or toxicity. After two cycles, there were no notable toxicities, and an assessment performed at the end of April 2020 revealed a decrease in all measurable and evaluable tumoral lesions (Fig. 4b). By December 2020, 40 weeks after the start of atezolizumab + BCP, the patient was still in partial response and was being managed on chemotherapy-free maintenance treatment with atezolizumab + bevacizumab. Compliance with Ethics Guidelines Data on these patients were collected in accordance with the Helsinki Declaration of 1964 and its later amendments concerning human and animal rights. All patients provided written informed consent to all the diagnostic and therapeutic procedures, for the use of their medical images, and for inclusion in this manuscript. Ethical committee approval was not required, as per Spanish law. Discussion EGFR mutations are present in 10–20% of Caucasian patients and about 50% of Asian patients with NSCLC [8]. The L858R point mutation in EGFR exon 21 identified in patient 1 at diagnosis is one of the most common “classical” EGFR mutations, along with a deletion in exon 19 [8]. Together, these mutations represent 85% of EGFR mutations. These activating mutations make the tumor sensitive to tyrosine kinase inhibitors (TKIs) and are an indication for choosing a TKI agent as first-line therapy [9], as occurred in patient 1. Indeed, current NSCLC guidelines note the importance of molecular tumor analysis in determining first-line therapy [9, 10]. In Europe, testing for mutations or rearrangements of ALK, c-ros oncogene 1 (ROS1), and EGFR is considered mandatory, and testing for BRAF V600E mutations is important in countries where BRAF/MEK inhibitors are approved. Other tests include those for human epidermal growth factor receptor 2 (HER2) and MET exon mutations and for fusion genes in RET and NTRK1, which are all are considered evolving biomarkers [10]. The US National Comprehensive Cancer Network guidelines recommend the biomarker test panel for non-squamous NSCLC should, at a minimum, include EGFR mutations, BRAF mutations, ALK fusions, ROS1 fusions, and PD-L1 expression [9]. A primary T790M mutation in EGFR exon 20 is a resistance mutation and more likely to coexist with an L858R mutation than with an exon 19 deletion [11]. While osimertinib has been shown to be effective in patients with a primary T790M mutation, as shown in patient 1, most patients with such mutations progress within 1 year of starting osimertinib [11]. Patient 1 also had high expression of PD-L1 as shown by a TPS of 80%. This suggests that this patient is a good candidate for immunotherapy, but guidelines recommend the use of targeted therapy first-line (before immunotherapy) in patients with sensitizing mutations because the response rate is likely to be higher [9]. Once targeted therapy fails, immunotherapy is indicated. ALK rearrangements are the driving mutations responsible for the development of NSCLC in 3–7% of patients, and, as observed in patient 2, these patients have a higher risk of developing brain metastases than those with other NSCLC subtypes [12]. The first-generation ALK inhibitor crizotinib, used for second-line treatment in patient 2, has antitumor advantages over chemotherapy in this subtype of patients; however, all patients eventually progress because of drug resistance [10]. Furthermore, the amount of crizotinib that crosses the blood–brain barrier is negligible, which limits its use in patients with brain metastases [10]. In patients with crizotinib-resistant ALK-rearranged NSCLC, one strategy is sequential treatment with next-generation ALK inhibitors, such as ceritinib, alectinib, or brigatinib [12], as used in patient 2. In the IMpower150 study, most patients had wild-type EGFR and ALK, but 10% of patients were EGFR-mutation positive and 8.5% were ALK-rearrangement positive [7]. IMpower150 is the only trial that has shown positive results with immunotherapy in patients with EGFR- or ALK-positive NSCLC [10]. OS in the population that included patients with these mutations receiving the atezolizumab + BCP regimen was 19.8 months, which was similar to that in the population excluding patients with these mutations (19.5 months), and significantly longer than in the BCP group (15.0 months for the whole population and 14.7 months for the EGFR and ALK wild-type population) [13]. In patients with EGFR mutations, OS was 29.4 months in the atezolizumab + BCP group and 18.1 months in the BCP group [13]. Median progression-free survival (PFS) in patients with EGFR mutations receiving the atezolizumab + BCP regimen was 9.7 months, similar to the PFS in patients with wild-type EGFR (8.3 months), and significantly longer than in the BCP group irrespective of EGFR mutation status (6.1 months and 6.8 months, respectively, in the EGFR mutation and wild-type groups receiving BCP) [7]. Similarly, median PFS was significantly longer in the atezolizumab + BCP group than in the placebo + BCP group in patients with KRAS mutations (8.1 vs. 5.8 months, respectively), as well as in those with wild-type KRAS (9.7 vs. 5.8 months) [7]. The number of mutations, as well as the type, may be relevant to treatment response to atezolizumab. Data suggest that the survival (PFS and OS) benefit of PD-L1 or PD-1 inhibitors may be more marked in patients with a high tumor mutation burden (TMB) than in those with low TMB [14–16], although this result was not seen in some trials [17, 18]. Recent data from randomized trials show that a blood-based assay for TMB can be a useful and valid biomarker for atezolizumab [19]. The cases of patients 3 and 4 illustrated the use of atezolizumab in patients with high disease burden, which was characterized by extensive metastases, including in the liver. In the IMPower150 study, 13% of patients had liver metastases, and atezolizumab + BCP significantly prolonged PFS and OS compared with placebo + BCP in patients with or without liver metastases [7, 20]. However, the difference in PFS and OS between the atezolizumab + BCP group and the BCP group was more marked in the cohort with liver metastases [7]. In the group with liver metastases, the PFS hazard ratio was 0.42 (median PFS 7.4 vs. 4.9 months for atezolizumab + BCP vs. placebo + BCP), whereas in the group without liver metastases the PFS hazard ratio was 0.63 (median PFS 8.3 vs. 7.0 months, respectively) [7]; the OS hazard ratio was 0.52 in the group with liver metastases (median OS 13.3 vs. 9.4 months for atezolizumab + BCP vs. placebo + BCP), and in the group without liver metastases the OS hazard ratio was 0.82 (median OS 20.4 vs. 17.0 months, respectively) [20]. In addition to liver metastases, patient 3 also had bone metastases, which are associated with significantly reduced survival in patients with NSCLC [21, 22]. Moreover, bone metastases are associated with significant pain, fatigue, and disturbed sleep [23], which may negatively affect the patient’s performance status. Indeed, this patient had an ECOG performance status of 2. The IMpower150 study excluded patients with ECOG performance status of 2 or higher [7]; however, data indicate that between one-third and one-half of patients with NSCLC have poor performance status (e.g., ECOG PS of 2 or higher) [24]. It is encouraging that patient 3, who had multiple metastatic sites including in the appendicular skeleton, was able to benefit from treatment with atezolizumab over a prolonged period before disease progression. The last case presented (patient 4) had both liver and brain metastases at the time of starting treatment with atezolizumab. Adenocarcinomas are the most common tumor type to metastasize to the CNS, and 30–64% of patients with NSCLC have CNS metastases [9, 10]. Historically, patients with brain metastases have had a particularly poor prognosis [25], although this is starting to change with the increasing availability of novel agents. However, patients with untreated brain metastases are usually excluded from clinical trials, many of which also exclude patients with treated brain metastases. Indeed, both the POPLAR study and IMPower150 excluded patients with untreated CNS metastases [5, 7], with neither study reporting on patients with treated brain metastases. Patient 4 described here received treatment of brain metastases with holocranial radiotherapy, and subsequently derived benefit from atezolizumab treatment. The positive CNS responses in this patient is consistent with findings reported in the OAK trial [6]. In this trial, which specified inclusion of patients with treated, asymptomatic supratentorial CNS metastases, subgroup analysis demonstrated a survival benefit with atezolizumab compared with docetaxel in patients with treated CNS metastases at baseline, with a hazard ratio of 0.54 [95% confidence interval (CI) 0.31–0.94] [6]. These findings for atezolizumab in patients with brain metastases are also consistent with those of a phase II study of pembrolizumab in patients with NSCLC (n = 18) or melanoma and untreated brain metastases, in which pembrolizumab demonstrated activity in brain metastases, with a response rate for brain metastasis of 33% among patients with NSCLC [26]. Although this case series provides valuable information regarding the practical clinical issues associated with atezolizumab + BCP treatment, more well-designed studies are needed to develop evidence-based recommendations on immunotherapy to guide oncologists, immunologists, and other specialists in the management of patients with mutated NSCLC. Conclusion As more becomes known about the importance of the various genetic mutations, rearrangements, and expression profiles in NSCLC, testing for targetable oncogenic alterations and immuno-oncology therapy biomarkers is becoming more and more essential for treatment decisions [10]. The first two patients discussed here suggest that the number and type of mutations may be relevant for guiding treatment decisions in NSCLC. To our knowledge, atezolizumab + BCP is the only immunotherapy combination that has demonstrated efficacy in patients with mutated NSCLC [7, 27], and these cases show that the results of these studies have been transferred to clinical practice. Another factor that should be considered when deciding upon a course of therapy is a patient’s performance status. However, clinical trials often exclude patients with poor performance status; hence, the second two cases described here of patients with NSCLC and high disease burden (patients 3 and 4), who benefited from atezolizumab-containing therapy over a prolonged period, are particularly encouraging. Finally, the CNS responses reported here suggest that atezolizumab + bevacizumab may be an important option for the significant unmet need of treating brain metastases in NSCLC. These observations provide valuable insights into the practical clinical issues associated with atezolizumab + BCP treatment in patients with advanced or metastatic NSCLC. These illustrative clinical cases may also help clinicians to identify patients with NSCLC who will potentially gain the most benefit from the use of atezolizumab + BCP in routine clinical practice. We thank the patients who allowed us to report their clinical details. Funding Medical writing assistance and the Rapid Service Fee for this manuscript were funded by Roche. Medical Writing Assistance We would like to thank Catherine Rees of Springer Healthcare Communications, and Marie Cheeseman, on behalf of Springer Healthcare Communications, who wrote the outline and first draft, respectively. This medical writing assistance was funded by Roche. Authorship All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. Compliance with Ethics Guidelines Data from these patients were collected in accordance with the Helsinki Declaration of 1964 and its later amendments, concerning human and animal rights. All patients provided written informed consent to all the diagnostic-therapeutic procedures, for the use of their medical images, and for inclusion in this manuscript. Ethical committee approval was not required, as per Spanish law. Disclosures Dr Cobo reports receiving advisory or consultancy fees from Roche, Bristol Myers Squibb, AstraZeneca, Pfizer, and Boehringer, and travel and accommodation funding from Roche, Bristol Myers Squibb, and AstraZeneca outside of the submitted work. Dr Rodríguez-Abreu reports receiving advisory or consultancy fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Pfizer, Boehringer, and Takeda, speaker’s fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Boehringer, and Takeda, and travel and accommodation funding from Roche, Merck, Bristol Myers Squibb, and AstraZeneca outside of the submitted work. Diego Pérez Parente is an employee of Roche Farma, Spain. Pedro Ruiz Gracia is an employee of Roche Farma, Spain. Dr González reports receiving advisory or consultancy fees from Roche, Bristol Myers Squibb, AstraZeneca, Boehringer, and Sanofi, speaker’s fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Lilly, and Ipsen, and travel and accommodation funding from Roche, Merck, Bristol Myers Squibb, and Lilly outside of the submitted work. Data Availability Qualified researchers may request access to individual patient level data through the clinical study data request platform (https://vivli.org/). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).	ATEZOLIZUMAB, BEVACIZUMAB, CARBOPLATIN, PACLITAXEL	DrugsGivenReaction	CC BY-NC	33582978	18,969,138	2021-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sepsis'.	Practical Issues in the Use of Atezolizumab for Patients with Non-Small Cell Lung Cancer: Case Reports and Literature Review. Atezolizumab is a monoclonal antibody targeting the programmed death ligand 1 (PD-L1) that was approved in 2017 in the USA and Europe for the second-line treatment of advanced or metastatic non-small cell lung cancer (NSCLC). This review article describes the practical clinical issues associated with atezolizumab treatment in NSCLC using a combination of four illustrative cases and a narrative literature review. The first two cases highlight the importance of tumor mutational status when making treatment decisions. A 62-year-old man with epidermal growth factor receptor (EGFR)-mutated, PD-L1-positive, stage IV lung adenocarcinoma received treatment with second-line atezolizumab + bevacizumab, carboplatin, and paclitaxel (BCP) after first-line osimertinib. In the second case, a 63-year-old man with stage IVb lung adenocarcinoma with anaplastic lymphoma kinase (ALK) translocation received sixth-line treatment with atezolizumab + BCP. The two final cases both had extensive metastases. A 55-year-old woman with EGFR-mutated lung adenocarcinoma received second-line treatment with atezolizumab + BCP after development of multiple metastases, followed by atezolizumab + bevacizumab until last follow-up. A 42-year-old man with PD-L1-positive pulmonary adenocarcinoma (negative for EGFR mutations) developed liver and brain metastases after several lines of therapy. He underwent holocranial radiation and received atezolizumab + BCP, which resulted in a decrease in all measurable and evaluable tumoral lesions. These illustrative cases indicate that the type and number of mutations may influence treatment response to atezolizumab, and that atezolizumab may provide clinical benefit in patients with high disease burden. Key Summary Points Why carry out this study? Targeted immunotherapies, such as atezolizumab, have improved overall survival in patients with advanced or metastatic non-small cell lung cancer (NSCLC) in clinical trials. Understanding how to treat patients on the basis of their targetable oncogenic mutations or those usually excluded from clinical trials (e.g., with treated brain metastases or high disease burden) is important for oncologists in the real-world clinical setting. Four cases of treatment with atezolizumab plus bevacizumab, carboplatin, and paclitaxel in patients with NSCLC after at least one previous line of targeted therapy are described to illustrate these clinical issues. What was learned from the study? The presented cases suggest that both the number and type of mutations may be relevant for guiding treatment decisions in NSCLC, and that patients with high disease burden or brain metastases may benefit from atezolizumab-containing therapy. Digital Features This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13521968. Introduction Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and has a high rate of mortality [1, 2]. According to global estimates, lung cancer was the most commonly diagnosed cancer in 2018 (11.6% of all new cases) and the leading cause of cancer-related mortality (18.4% of all cancer deaths) [3]. In a US analysis of patients with NSCLC, the median overall survival (OS) time after diagnosis was only 13 months, and the estimated 4-year survival rate was between 22% and 28% [1]. However, OS has been improving over recent decades as a result of novel treatments [1, 2], including targeted therapies and immunotherapies. One such novel treatment is atezolizumab, a monoclonal antibody targeting the programmed death ligand 1 (PD-L1) [4]. Atezolizumab was approved in the USA and Europe for the second-line treatment of advanced or metastatic NSCLC in 2017, based on the results of the phase II POPLAR study [5] and the phase III OAK study [6], in which atezolizumab was associated with significantly better survival compared with docetaxel. Since its approval, the IMpower150 study has demonstrated that atezolizumab in combination with bevacizumab, carboplatin, and paclitaxel (BCP) was more effective than BCP alone as first-line therapy in previously untreated patients with metastatic non-squamous NSCLC [7]. The current review describes the practical clinical issues associated with atezolizumab + BCP in patients with NSCLC, using a combination of illustrative case presentations and a narrative literature review. Cases Illustrating Role of Mutational Status Patient 1 A 62-year-old man with no relevant medical or surgical history was diagnosed with stage IIIC lung adenocarcinoma (cT3cN3cM0) in January 2018. He was a former smoker with a 15 pack-year history. Molecular testing showed an L858R point mutation in epidermal growth factor receptor (EGFR) exon 21 and a primary T790M mutation in EGFR exon 20. The tumor was PD-L1 positive, with a tumor proportion score (TPS) of 80% on immunohistochemistry (pharmDx 28–8; DAKO, Glostrup, Denmark). On February 1, 2018, he began first-line treatment with osimertinib; the 12-week assessment showed a partial response by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. Response continued until March 2019, when the disease progressed to stage IV with mediastinal and retroperitoneal involvement (Fig. 1a). At this time, the patient was asymptomatic and started second-line treatment with atezolizumab in combination with BCP, based on the results of the IMpower150 clinical trial [7]. After two cycles, a computed tomography (CT) scan showed partial response by RECIST 1.1 criteria (Fig. 1b), and the patient was able to receive six cycles without significant adverse events.Fig. 1 Patient 1: Computed tomography scan of chest on a March 25, 2019, showing mediastinal and retroperitoneal involvement, b June 6, 2019 after two cycles of atezolizumab + BCP, c October 5, 2019 indicating a maintained radiologic response, and d January 30, 2020 showing tumor progression after 13 weeks of maintenance atezolizumab + bevacizumab. BCP bevacizumab, carboplatin, and paclitaxel After confirming that the radiologic response was maintained (Fig. 1c), he continued maintenance treatment with atezolizumab + bevacizumab. In February 2020, after 13 cycles, tumor progression was noted (Fig. 1d) and treatment was discontinued. Biopsy showed amplification and overexpression of c-MET, so the patient initiated third-line treatment with telisotuzumab vedotin as part of a clinical trial (NCT03539536). Patient 2 A 63-year-old man was diagnosed with a stage IVb lung adenocarcinoma with a brain metastasis (T2N3M1b) in February 2013. He was a former smoker (20 pack-year history) with occupational exposure to oil and its derivatives. On June 13, 2013, he started induction chemotherapy with cisplatin + pemetrexed, undergoing radiosurgery for the brain lesion after the first cycle. He showed a partial radiologic and metabolic response after two cycles of cisplatin + pemetrexed, and a brain magnetic resonance imaging (MRI) revealed a reduction in the size of the brain metastasis. He received two cycles of cisplatin + pemetrexed from June 13 to June 24, 2013, followed by radical-intent chemoradiation between June 28 and September 6, 2013, consisting of a 60 Gy dose and two cycles of weekly paclitaxel + carboplatin; however, he was unable to continue this treatment because of sustained leukopenia. A follow-up assessment on October 6, 2014, found no signs of thoracoabdominal progression. Lesions consistent with metastases were identified in the cerebellar vermis and the right centrum semiovale; radiosurgery was administered using 20.7 Gy and 20.9 Gy, respectively, at these sites. A CT scan on January 12, 2015, showed hilar-mediastinal progression, and a biopsy of the left hilar adenopathy showed that the tumor had wild-type KRAS, was EGFR- and BRAF-mutation negative, and had an anaplastic lymphoma kinase (ALK) translocation. In February 2015, he started second-line treatment with crizotinib and had a partial response. A brain MRI performed on November 3, 2015, showed oligoprogression, for which he received radiosurgery. On April 4, 2016, he showed pulmonary progression, and 2 weeks later, he started third-line treatment with ceritinib as part of a clinical trial, with a best response of stable disease. A CT scan on January 30, 2018, showed an increase in the size of the space-occupying lesions in the brain. On March 6 of the same year, he initiated fourth-line treatment with alectinib for metastases, with a best response of stable disease. A further CT scan on July 23, 2018, showed left hilar adenopathy progression and left upper lobe atelectasis. He started fifth-line therapy for metastases with brigatinib on September 5, 2018, and stable disease was his best response. The patient developed left hemiparesis on January 16, 2019. A brain MRI on January 21 showed signs of radionecrosis, but an acute or subacute ischemic event could not be ruled out. Brain progression, with an increase in the size and number of lesions, was detected in March 2019 (Fig. 2a), and he received hippocampal-sparing whole brain radiation with focal boost (45 Gy dose) on the lesions.Fig. 2 Patient 2: brain magnetic resonance imaging scan results on a March 11, 2019, showing an increase in the size and number of brain lesions, and b March 22, 2020, after 4 cycles of atezolizumab + BCP followed by 13 cycles of maintenance atezolizumab + bevacizumab, and chest computed tomography scan results on c March 11, 2019, prior to, and d March 22, 2020, after atezolizumab-based treatment On May 8, 2019, he began sixth-line treatment with atezolizumab + BCP. After four cycles (ending on August 8, 2019), he started maintenance treatment with atezolizumab + bevacizumab, achieving a partial brain response. In March 2020, he had received 13 cycles of maintenance treatment, and he showed stable disease as assessed by brain MRI (Fig. 2b) and CT scans of the chest (Fig. 2c, d), abdomen, and pelvis. CASES Illustrating Management of High Disease Burden Patient 3 A 55-year-old non-smoking woman without known morbidity was diagnosed with a stage IIIB lung adenocarcinoma (cT4N2) in June 2016. She received treatment with external radiation therapy (dose administered, 66 Gy) concomitantly with cisplatin and vinorelbine (three cycles). A follow-up CT scan showed partial response and the multidisciplinary Committee on Thoracic Tumors recommended surgical intervention. She underwent video-assisted thoracic surgery consisting of an upper right pulmonary lobectomy with systematic hilar and mediastinal lymph node dissection on October 5, 2016. Molecular analysis of the excised tumor showed EGFR exon 19 deletion. In March 2018, disease progression was detected in lung, pleura, and bone, and in subcutaneous tissue and the lymphatic system. On March 27, she received palliative and decompressive radiation therapy of the lumbar spine (L5) at 8 Gy. Subsequently, in April 2018, she started treatment with afatinib at 40 mg/day, and had a partial response. Afatinib treatment continued until July 2019, when imaging identified disease progression in the liver and bone, and a sacral soft tissue mass (Fig. 3a). Analysis of liquid and sacral mass biopsy did not detect a resistant T790M mutation on EGFR exon 20.Fig. 3 Patient 3: Computed tomography of lumbosacral region on a July 4, 2019, before and b October 8, 2019, after three cycles of atezolizumab + BCP, showing partial response in the sacral soft tissue mass. BCP bevacizumab, carboplatin, and paclitaxel At this time, the patient’s Eastern Cooperative Oncology Group (ECOG) performance status was 2, and she was negative for PD-L1 (TPS 0%). On August 7, 2019, on the basis of the results of the IMpower150 clinical trial [7], she began second-line treatment with atezolizumab + BCP. After three cycles she showed a partial response (Fig. 3b), and was able to complete six cycles of treatment. However, the patient developed febrile neutropenia and sepsis due to central catheter-related infections in the second cycle leading to hospital admission; grade 2 sensory neuropathy that reverted to grade 1 after discontinuing paclitaxel and carboplatin; and grade 1 asthenia. She then continued treatment with atezolizumab + bevacizumab. By June 2020, she had completed 14 cycles of treatment without relevant toxicities, but treatment was interrupted at that time because a CT scan showed progression of the liver and bone metastases. Patient 4 A 42-year-old man was diagnosed with stage IIIB pulmonary adenocarcinoma (cT4N2M0) in June 2018; at this time, he had an ECOG performance status of 0. Molecular analysis showed the tumor was negative for EGFR mutations and ALK fusions, with PD-L1 expression on 30% of cancer cells. He was a smoker at the time of diagnosis, smoking one pack daily for 20 years (20 pack-years). On August 22, 2018, treatment with cisplatin, gemcitabine, and paclitaxel was started, for a total of four 21-day cycles. Treatment was well tolerated, with the exception of nausea and asthenia (both grade 1). Repeat CT scans performed in September 2018 after two treatment cycles, and again in November after four treatment cycles, revealed decreasing tumor volume, with mediastinal contact still present; at this time, results of a brain MRI were normal. In December 2018, the man underwent a right lower lobectomy; the right lower pulmonary lobe was found to have well-differentiated adenocarcinoma with an acinar pattern, without evidence of vascular invasion, and no visceral pleural infiltration. Surgical resection margins were not affected. TNM staging at this point was ypT1cN0M0. He subsequently received consolidative radiation therapy on the mediastinal bed; he had a performance status of 0 and no complications. In October 2019, a follow-up examination revealed a de novo pulmonary micronodule in the control CT scan, but this was not seen on a positron emission tomography–CT scan. In February 2020, repeat CT scans revealed a growth on the left perihilar pulmonary nodule and a new right-hand micronodule. Metastases were seen in several liver segments. As a result of mild dizziness, a central nervous system (CNS) MRI scan was performed in January 2020, revealing the presence of brain metastases (Fig. 4a).Fig. 4 Patient 4: Brain magnetic resonance imaging scan results in a January 2020 showing brain metastases and b April 2020 showing reduced lesion size after atezolizumab + BCP treatment. BCP bevacizumab, carboplatin, and paclitaxel Holocranial radiotherapy was administered, finishing at the beginning of February 2020. After 4 weeks, a repeat MRI did not show any significant changes in the size of the brain lesions. One month after discontinuing holocranial radiotherapy, in the second week of March 2020, he began treatment with four 21-day cycles of atezolizumab + BCP, followed by atezolizumab + bevacizumab until disease progression or toxicity. After two cycles, there were no notable toxicities, and an assessment performed at the end of April 2020 revealed a decrease in all measurable and evaluable tumoral lesions (Fig. 4b). By December 2020, 40 weeks after the start of atezolizumab + BCP, the patient was still in partial response and was being managed on chemotherapy-free maintenance treatment with atezolizumab + bevacizumab. Compliance with Ethics Guidelines Data on these patients were collected in accordance with the Helsinki Declaration of 1964 and its later amendments concerning human and animal rights. All patients provided written informed consent to all the diagnostic and therapeutic procedures, for the use of their medical images, and for inclusion in this manuscript. Ethical committee approval was not required, as per Spanish law. Discussion EGFR mutations are present in 10–20% of Caucasian patients and about 50% of Asian patients with NSCLC [8]. The L858R point mutation in EGFR exon 21 identified in patient 1 at diagnosis is one of the most common “classical” EGFR mutations, along with a deletion in exon 19 [8]. Together, these mutations represent 85% of EGFR mutations. These activating mutations make the tumor sensitive to tyrosine kinase inhibitors (TKIs) and are an indication for choosing a TKI agent as first-line therapy [9], as occurred in patient 1. Indeed, current NSCLC guidelines note the importance of molecular tumor analysis in determining first-line therapy [9, 10]. In Europe, testing for mutations or rearrangements of ALK, c-ros oncogene 1 (ROS1), and EGFR is considered mandatory, and testing for BRAF V600E mutations is important in countries where BRAF/MEK inhibitors are approved. Other tests include those for human epidermal growth factor receptor 2 (HER2) and MET exon mutations and for fusion genes in RET and NTRK1, which are all are considered evolving biomarkers [10]. The US National Comprehensive Cancer Network guidelines recommend the biomarker test panel for non-squamous NSCLC should, at a minimum, include EGFR mutations, BRAF mutations, ALK fusions, ROS1 fusions, and PD-L1 expression [9]. A primary T790M mutation in EGFR exon 20 is a resistance mutation and more likely to coexist with an L858R mutation than with an exon 19 deletion [11]. While osimertinib has been shown to be effective in patients with a primary T790M mutation, as shown in patient 1, most patients with such mutations progress within 1 year of starting osimertinib [11]. Patient 1 also had high expression of PD-L1 as shown by a TPS of 80%. This suggests that this patient is a good candidate for immunotherapy, but guidelines recommend the use of targeted therapy first-line (before immunotherapy) in patients with sensitizing mutations because the response rate is likely to be higher [9]. Once targeted therapy fails, immunotherapy is indicated. ALK rearrangements are the driving mutations responsible for the development of NSCLC in 3–7% of patients, and, as observed in patient 2, these patients have a higher risk of developing brain metastases than those with other NSCLC subtypes [12]. The first-generation ALK inhibitor crizotinib, used for second-line treatment in patient 2, has antitumor advantages over chemotherapy in this subtype of patients; however, all patients eventually progress because of drug resistance [10]. Furthermore, the amount of crizotinib that crosses the blood–brain barrier is negligible, which limits its use in patients with brain metastases [10]. In patients with crizotinib-resistant ALK-rearranged NSCLC, one strategy is sequential treatment with next-generation ALK inhibitors, such as ceritinib, alectinib, or brigatinib [12], as used in patient 2. In the IMpower150 study, most patients had wild-type EGFR and ALK, but 10% of patients were EGFR-mutation positive and 8.5% were ALK-rearrangement positive [7]. IMpower150 is the only trial that has shown positive results with immunotherapy in patients with EGFR- or ALK-positive NSCLC [10]. OS in the population that included patients with these mutations receiving the atezolizumab + BCP regimen was 19.8 months, which was similar to that in the population excluding patients with these mutations (19.5 months), and significantly longer than in the BCP group (15.0 months for the whole population and 14.7 months for the EGFR and ALK wild-type population) [13]. In patients with EGFR mutations, OS was 29.4 months in the atezolizumab + BCP group and 18.1 months in the BCP group [13]. Median progression-free survival (PFS) in patients with EGFR mutations receiving the atezolizumab + BCP regimen was 9.7 months, similar to the PFS in patients with wild-type EGFR (8.3 months), and significantly longer than in the BCP group irrespective of EGFR mutation status (6.1 months and 6.8 months, respectively, in the EGFR mutation and wild-type groups receiving BCP) [7]. Similarly, median PFS was significantly longer in the atezolizumab + BCP group than in the placebo + BCP group in patients with KRAS mutations (8.1 vs. 5.8 months, respectively), as well as in those with wild-type KRAS (9.7 vs. 5.8 months) [7]. The number of mutations, as well as the type, may be relevant to treatment response to atezolizumab. Data suggest that the survival (PFS and OS) benefit of PD-L1 or PD-1 inhibitors may be more marked in patients with a high tumor mutation burden (TMB) than in those with low TMB [14–16], although this result was not seen in some trials [17, 18]. Recent data from randomized trials show that a blood-based assay for TMB can be a useful and valid biomarker for atezolizumab [19]. The cases of patients 3 and 4 illustrated the use of atezolizumab in patients with high disease burden, which was characterized by extensive metastases, including in the liver. In the IMPower150 study, 13% of patients had liver metastases, and atezolizumab + BCP significantly prolonged PFS and OS compared with placebo + BCP in patients with or without liver metastases [7, 20]. However, the difference in PFS and OS between the atezolizumab + BCP group and the BCP group was more marked in the cohort with liver metastases [7]. In the group with liver metastases, the PFS hazard ratio was 0.42 (median PFS 7.4 vs. 4.9 months for atezolizumab + BCP vs. placebo + BCP), whereas in the group without liver metastases the PFS hazard ratio was 0.63 (median PFS 8.3 vs. 7.0 months, respectively) [7]; the OS hazard ratio was 0.52 in the group with liver metastases (median OS 13.3 vs. 9.4 months for atezolizumab + BCP vs. placebo + BCP), and in the group without liver metastases the OS hazard ratio was 0.82 (median OS 20.4 vs. 17.0 months, respectively) [20]. In addition to liver metastases, patient 3 also had bone metastases, which are associated with significantly reduced survival in patients with NSCLC [21, 22]. Moreover, bone metastases are associated with significant pain, fatigue, and disturbed sleep [23], which may negatively affect the patient’s performance status. Indeed, this patient had an ECOG performance status of 2. The IMpower150 study excluded patients with ECOG performance status of 2 or higher [7]; however, data indicate that between one-third and one-half of patients with NSCLC have poor performance status (e.g., ECOG PS of 2 or higher) [24]. It is encouraging that patient 3, who had multiple metastatic sites including in the appendicular skeleton, was able to benefit from treatment with atezolizumab over a prolonged period before disease progression. The last case presented (patient 4) had both liver and brain metastases at the time of starting treatment with atezolizumab. Adenocarcinomas are the most common tumor type to metastasize to the CNS, and 30–64% of patients with NSCLC have CNS metastases [9, 10]. Historically, patients with brain metastases have had a particularly poor prognosis [25], although this is starting to change with the increasing availability of novel agents. However, patients with untreated brain metastases are usually excluded from clinical trials, many of which also exclude patients with treated brain metastases. Indeed, both the POPLAR study and IMPower150 excluded patients with untreated CNS metastases [5, 7], with neither study reporting on patients with treated brain metastases. Patient 4 described here received treatment of brain metastases with holocranial radiotherapy, and subsequently derived benefit from atezolizumab treatment. The positive CNS responses in this patient is consistent with findings reported in the OAK trial [6]. In this trial, which specified inclusion of patients with treated, asymptomatic supratentorial CNS metastases, subgroup analysis demonstrated a survival benefit with atezolizumab compared with docetaxel in patients with treated CNS metastases at baseline, with a hazard ratio of 0.54 [95% confidence interval (CI) 0.31–0.94] [6]. These findings for atezolizumab in patients with brain metastases are also consistent with those of a phase II study of pembrolizumab in patients with NSCLC (n = 18) or melanoma and untreated brain metastases, in which pembrolizumab demonstrated activity in brain metastases, with a response rate for brain metastasis of 33% among patients with NSCLC [26]. Although this case series provides valuable information regarding the practical clinical issues associated with atezolizumab + BCP treatment, more well-designed studies are needed to develop evidence-based recommendations on immunotherapy to guide oncologists, immunologists, and other specialists in the management of patients with mutated NSCLC. Conclusion As more becomes known about the importance of the various genetic mutations, rearrangements, and expression profiles in NSCLC, testing for targetable oncogenic alterations and immuno-oncology therapy biomarkers is becoming more and more essential for treatment decisions [10]. The first two patients discussed here suggest that the number and type of mutations may be relevant for guiding treatment decisions in NSCLC. To our knowledge, atezolizumab + BCP is the only immunotherapy combination that has demonstrated efficacy in patients with mutated NSCLC [7, 27], and these cases show that the results of these studies have been transferred to clinical practice. Another factor that should be considered when deciding upon a course of therapy is a patient’s performance status. However, clinical trials often exclude patients with poor performance status; hence, the second two cases described here of patients with NSCLC and high disease burden (patients 3 and 4), who benefited from atezolizumab-containing therapy over a prolonged period, are particularly encouraging. Finally, the CNS responses reported here suggest that atezolizumab + bevacizumab may be an important option for the significant unmet need of treating brain metastases in NSCLC. These observations provide valuable insights into the practical clinical issues associated with atezolizumab + BCP treatment in patients with advanced or metastatic NSCLC. These illustrative clinical cases may also help clinicians to identify patients with NSCLC who will potentially gain the most benefit from the use of atezolizumab + BCP in routine clinical practice. We thank the patients who allowed us to report their clinical details. Funding Medical writing assistance and the Rapid Service Fee for this manuscript were funded by Roche. Medical Writing Assistance We would like to thank Catherine Rees of Springer Healthcare Communications, and Marie Cheeseman, on behalf of Springer Healthcare Communications, who wrote the outline and first draft, respectively. This medical writing assistance was funded by Roche. Authorship All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. Compliance with Ethics Guidelines Data from these patients were collected in accordance with the Helsinki Declaration of 1964 and its later amendments, concerning human and animal rights. All patients provided written informed consent to all the diagnostic-therapeutic procedures, for the use of their medical images, and for inclusion in this manuscript. Ethical committee approval was not required, as per Spanish law. Disclosures Dr Cobo reports receiving advisory or consultancy fees from Roche, Bristol Myers Squibb, AstraZeneca, Pfizer, and Boehringer, and travel and accommodation funding from Roche, Bristol Myers Squibb, and AstraZeneca outside of the submitted work. Dr Rodríguez-Abreu reports receiving advisory or consultancy fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Pfizer, Boehringer, and Takeda, speaker’s fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Boehringer, and Takeda, and travel and accommodation funding from Roche, Merck, Bristol Myers Squibb, and AstraZeneca outside of the submitted work. Diego Pérez Parente is an employee of Roche Farma, Spain. Pedro Ruiz Gracia is an employee of Roche Farma, Spain. Dr González reports receiving advisory or consultancy fees from Roche, Bristol Myers Squibb, AstraZeneca, Boehringer, and Sanofi, speaker’s fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Lilly, and Ipsen, and travel and accommodation funding from Roche, Merck, Bristol Myers Squibb, and Lilly outside of the submitted work. Data Availability Qualified researchers may request access to individual patient level data through the clinical study data request platform (https://vivli.org/). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).	ATEZOLIZUMAB, BEVACIZUMAB, CARBOPLATIN, PACLITAXEL	DrugsGivenReaction	CC BY-NC	33582978	18,969,138	2021-06
What was the dosage of drug 'BEVACIZUMAB'?	Practical Issues in the Use of Atezolizumab for Patients with Non-Small Cell Lung Cancer: Case Reports and Literature Review. Atezolizumab is a monoclonal antibody targeting the programmed death ligand 1 (PD-L1) that was approved in 2017 in the USA and Europe for the second-line treatment of advanced or metastatic non-small cell lung cancer (NSCLC). This review article describes the practical clinical issues associated with atezolizumab treatment in NSCLC using a combination of four illustrative cases and a narrative literature review. The first two cases highlight the importance of tumor mutational status when making treatment decisions. A 62-year-old man with epidermal growth factor receptor (EGFR)-mutated, PD-L1-positive, stage IV lung adenocarcinoma received treatment with second-line atezolizumab + bevacizumab, carboplatin, and paclitaxel (BCP) after first-line osimertinib. In the second case, a 63-year-old man with stage IVb lung adenocarcinoma with anaplastic lymphoma kinase (ALK) translocation received sixth-line treatment with atezolizumab + BCP. The two final cases both had extensive metastases. A 55-year-old woman with EGFR-mutated lung adenocarcinoma received second-line treatment with atezolizumab + BCP after development of multiple metastases, followed by atezolizumab + bevacizumab until last follow-up. A 42-year-old man with PD-L1-positive pulmonary adenocarcinoma (negative for EGFR mutations) developed liver and brain metastases after several lines of therapy. He underwent holocranial radiation and received atezolizumab + BCP, which resulted in a decrease in all measurable and evaluable tumoral lesions. These illustrative cases indicate that the type and number of mutations may influence treatment response to atezolizumab, and that atezolizumab may provide clinical benefit in patients with high disease burden. Key Summary Points Why carry out this study? Targeted immunotherapies, such as atezolizumab, have improved overall survival in patients with advanced or metastatic non-small cell lung cancer (NSCLC) in clinical trials. Understanding how to treat patients on the basis of their targetable oncogenic mutations or those usually excluded from clinical trials (e.g., with treated brain metastases or high disease burden) is important for oncologists in the real-world clinical setting. Four cases of treatment with atezolizumab plus bevacizumab, carboplatin, and paclitaxel in patients with NSCLC after at least one previous line of targeted therapy are described to illustrate these clinical issues. What was learned from the study? The presented cases suggest that both the number and type of mutations may be relevant for guiding treatment decisions in NSCLC, and that patients with high disease burden or brain metastases may benefit from atezolizumab-containing therapy. Digital Features This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13521968. Introduction Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and has a high rate of mortality [1, 2]. According to global estimates, lung cancer was the most commonly diagnosed cancer in 2018 (11.6% of all new cases) and the leading cause of cancer-related mortality (18.4% of all cancer deaths) [3]. In a US analysis of patients with NSCLC, the median overall survival (OS) time after diagnosis was only 13 months, and the estimated 4-year survival rate was between 22% and 28% [1]. However, OS has been improving over recent decades as a result of novel treatments [1, 2], including targeted therapies and immunotherapies. One such novel treatment is atezolizumab, a monoclonal antibody targeting the programmed death ligand 1 (PD-L1) [4]. Atezolizumab was approved in the USA and Europe for the second-line treatment of advanced or metastatic NSCLC in 2017, based on the results of the phase II POPLAR study [5] and the phase III OAK study [6], in which atezolizumab was associated with significantly better survival compared with docetaxel. Since its approval, the IMpower150 study has demonstrated that atezolizumab in combination with bevacizumab, carboplatin, and paclitaxel (BCP) was more effective than BCP alone as first-line therapy in previously untreated patients with metastatic non-squamous NSCLC [7]. The current review describes the practical clinical issues associated with atezolizumab + BCP in patients with NSCLC, using a combination of illustrative case presentations and a narrative literature review. Cases Illustrating Role of Mutational Status Patient 1 A 62-year-old man with no relevant medical or surgical history was diagnosed with stage IIIC lung adenocarcinoma (cT3cN3cM0) in January 2018. He was a former smoker with a 15 pack-year history. Molecular testing showed an L858R point mutation in epidermal growth factor receptor (EGFR) exon 21 and a primary T790M mutation in EGFR exon 20. The tumor was PD-L1 positive, with a tumor proportion score (TPS) of 80% on immunohistochemistry (pharmDx 28–8; DAKO, Glostrup, Denmark). On February 1, 2018, he began first-line treatment with osimertinib; the 12-week assessment showed a partial response by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. Response continued until March 2019, when the disease progressed to stage IV with mediastinal and retroperitoneal involvement (Fig. 1a). At this time, the patient was asymptomatic and started second-line treatment with atezolizumab in combination with BCP, based on the results of the IMpower150 clinical trial [7]. After two cycles, a computed tomography (CT) scan showed partial response by RECIST 1.1 criteria (Fig. 1b), and the patient was able to receive six cycles without significant adverse events.Fig. 1 Patient 1: Computed tomography scan of chest on a March 25, 2019, showing mediastinal and retroperitoneal involvement, b June 6, 2019 after two cycles of atezolizumab + BCP, c October 5, 2019 indicating a maintained radiologic response, and d January 30, 2020 showing tumor progression after 13 weeks of maintenance atezolizumab + bevacizumab. BCP bevacizumab, carboplatin, and paclitaxel After confirming that the radiologic response was maintained (Fig. 1c), he continued maintenance treatment with atezolizumab + bevacizumab. In February 2020, after 13 cycles, tumor progression was noted (Fig. 1d) and treatment was discontinued. Biopsy showed amplification and overexpression of c-MET, so the patient initiated third-line treatment with telisotuzumab vedotin as part of a clinical trial (NCT03539536). Patient 2 A 63-year-old man was diagnosed with a stage IVb lung adenocarcinoma with a brain metastasis (T2N3M1b) in February 2013. He was a former smoker (20 pack-year history) with occupational exposure to oil and its derivatives. On June 13, 2013, he started induction chemotherapy with cisplatin + pemetrexed, undergoing radiosurgery for the brain lesion after the first cycle. He showed a partial radiologic and metabolic response after two cycles of cisplatin + pemetrexed, and a brain magnetic resonance imaging (MRI) revealed a reduction in the size of the brain metastasis. He received two cycles of cisplatin + pemetrexed from June 13 to June 24, 2013, followed by radical-intent chemoradiation between June 28 and September 6, 2013, consisting of a 60 Gy dose and two cycles of weekly paclitaxel + carboplatin; however, he was unable to continue this treatment because of sustained leukopenia. A follow-up assessment on October 6, 2014, found no signs of thoracoabdominal progression. Lesions consistent with metastases were identified in the cerebellar vermis and the right centrum semiovale; radiosurgery was administered using 20.7 Gy and 20.9 Gy, respectively, at these sites. A CT scan on January 12, 2015, showed hilar-mediastinal progression, and a biopsy of the left hilar adenopathy showed that the tumor had wild-type KRAS, was EGFR- and BRAF-mutation negative, and had an anaplastic lymphoma kinase (ALK) translocation. In February 2015, he started second-line treatment with crizotinib and had a partial response. A brain MRI performed on November 3, 2015, showed oligoprogression, for which he received radiosurgery. On April 4, 2016, he showed pulmonary progression, and 2 weeks later, he started third-line treatment with ceritinib as part of a clinical trial, with a best response of stable disease. A CT scan on January 30, 2018, showed an increase in the size of the space-occupying lesions in the brain. On March 6 of the same year, he initiated fourth-line treatment with alectinib for metastases, with a best response of stable disease. A further CT scan on July 23, 2018, showed left hilar adenopathy progression and left upper lobe atelectasis. He started fifth-line therapy for metastases with brigatinib on September 5, 2018, and stable disease was his best response. The patient developed left hemiparesis on January 16, 2019. A brain MRI on January 21 showed signs of radionecrosis, but an acute or subacute ischemic event could not be ruled out. Brain progression, with an increase in the size and number of lesions, was detected in March 2019 (Fig. 2a), and he received hippocampal-sparing whole brain radiation with focal boost (45 Gy dose) on the lesions.Fig. 2 Patient 2: brain magnetic resonance imaging scan results on a March 11, 2019, showing an increase in the size and number of brain lesions, and b March 22, 2020, after 4 cycles of atezolizumab + BCP followed by 13 cycles of maintenance atezolizumab + bevacizumab, and chest computed tomography scan results on c March 11, 2019, prior to, and d March 22, 2020, after atezolizumab-based treatment On May 8, 2019, he began sixth-line treatment with atezolizumab + BCP. After four cycles (ending on August 8, 2019), he started maintenance treatment with atezolizumab + bevacizumab, achieving a partial brain response. In March 2020, he had received 13 cycles of maintenance treatment, and he showed stable disease as assessed by brain MRI (Fig. 2b) and CT scans of the chest (Fig. 2c, d), abdomen, and pelvis. CASES Illustrating Management of High Disease Burden Patient 3 A 55-year-old non-smoking woman without known morbidity was diagnosed with a stage IIIB lung adenocarcinoma (cT4N2) in June 2016. She received treatment with external radiation therapy (dose administered, 66 Gy) concomitantly with cisplatin and vinorelbine (three cycles). A follow-up CT scan showed partial response and the multidisciplinary Committee on Thoracic Tumors recommended surgical intervention. She underwent video-assisted thoracic surgery consisting of an upper right pulmonary lobectomy with systematic hilar and mediastinal lymph node dissection on October 5, 2016. Molecular analysis of the excised tumor showed EGFR exon 19 deletion. In March 2018, disease progression was detected in lung, pleura, and bone, and in subcutaneous tissue and the lymphatic system. On March 27, she received palliative and decompressive radiation therapy of the lumbar spine (L5) at 8 Gy. Subsequently, in April 2018, she started treatment with afatinib at 40 mg/day, and had a partial response. Afatinib treatment continued until July 2019, when imaging identified disease progression in the liver and bone, and a sacral soft tissue mass (Fig. 3a). Analysis of liquid and sacral mass biopsy did not detect a resistant T790M mutation on EGFR exon 20.Fig. 3 Patient 3: Computed tomography of lumbosacral region on a July 4, 2019, before and b October 8, 2019, after three cycles of atezolizumab + BCP, showing partial response in the sacral soft tissue mass. BCP bevacizumab, carboplatin, and paclitaxel At this time, the patient’s Eastern Cooperative Oncology Group (ECOG) performance status was 2, and she was negative for PD-L1 (TPS 0%). On August 7, 2019, on the basis of the results of the IMpower150 clinical trial [7], she began second-line treatment with atezolizumab + BCP. After three cycles she showed a partial response (Fig. 3b), and was able to complete six cycles of treatment. However, the patient developed febrile neutropenia and sepsis due to central catheter-related infections in the second cycle leading to hospital admission; grade 2 sensory neuropathy that reverted to grade 1 after discontinuing paclitaxel and carboplatin; and grade 1 asthenia. She then continued treatment with atezolizumab + bevacizumab. By June 2020, she had completed 14 cycles of treatment without relevant toxicities, but treatment was interrupted at that time because a CT scan showed progression of the liver and bone metastases. Patient 4 A 42-year-old man was diagnosed with stage IIIB pulmonary adenocarcinoma (cT4N2M0) in June 2018; at this time, he had an ECOG performance status of 0. Molecular analysis showed the tumor was negative for EGFR mutations and ALK fusions, with PD-L1 expression on 30% of cancer cells. He was a smoker at the time of diagnosis, smoking one pack daily for 20 years (20 pack-years). On August 22, 2018, treatment with cisplatin, gemcitabine, and paclitaxel was started, for a total of four 21-day cycles. Treatment was well tolerated, with the exception of nausea and asthenia (both grade 1). Repeat CT scans performed in September 2018 after two treatment cycles, and again in November after four treatment cycles, revealed decreasing tumor volume, with mediastinal contact still present; at this time, results of a brain MRI were normal. In December 2018, the man underwent a right lower lobectomy; the right lower pulmonary lobe was found to have well-differentiated adenocarcinoma with an acinar pattern, without evidence of vascular invasion, and no visceral pleural infiltration. Surgical resection margins were not affected. TNM staging at this point was ypT1cN0M0. He subsequently received consolidative radiation therapy on the mediastinal bed; he had a performance status of 0 and no complications. In October 2019, a follow-up examination revealed a de novo pulmonary micronodule in the control CT scan, but this was not seen on a positron emission tomography–CT scan. In February 2020, repeat CT scans revealed a growth on the left perihilar pulmonary nodule and a new right-hand micronodule. Metastases were seen in several liver segments. As a result of mild dizziness, a central nervous system (CNS) MRI scan was performed in January 2020, revealing the presence of brain metastases (Fig. 4a).Fig. 4 Patient 4: Brain magnetic resonance imaging scan results in a January 2020 showing brain metastases and b April 2020 showing reduced lesion size after atezolizumab + BCP treatment. BCP bevacizumab, carboplatin, and paclitaxel Holocranial radiotherapy was administered, finishing at the beginning of February 2020. After 4 weeks, a repeat MRI did not show any significant changes in the size of the brain lesions. One month after discontinuing holocranial radiotherapy, in the second week of March 2020, he began treatment with four 21-day cycles of atezolizumab + BCP, followed by atezolizumab + bevacizumab until disease progression or toxicity. After two cycles, there were no notable toxicities, and an assessment performed at the end of April 2020 revealed a decrease in all measurable and evaluable tumoral lesions (Fig. 4b). By December 2020, 40 weeks after the start of atezolizumab + BCP, the patient was still in partial response and was being managed on chemotherapy-free maintenance treatment with atezolizumab + bevacizumab. Compliance with Ethics Guidelines Data on these patients were collected in accordance with the Helsinki Declaration of 1964 and its later amendments concerning human and animal rights. All patients provided written informed consent to all the diagnostic and therapeutic procedures, for the use of their medical images, and for inclusion in this manuscript. Ethical committee approval was not required, as per Spanish law. Discussion EGFR mutations are present in 10–20% of Caucasian patients and about 50% of Asian patients with NSCLC [8]. The L858R point mutation in EGFR exon 21 identified in patient 1 at diagnosis is one of the most common “classical” EGFR mutations, along with a deletion in exon 19 [8]. Together, these mutations represent 85% of EGFR mutations. These activating mutations make the tumor sensitive to tyrosine kinase inhibitors (TKIs) and are an indication for choosing a TKI agent as first-line therapy [9], as occurred in patient 1. Indeed, current NSCLC guidelines note the importance of molecular tumor analysis in determining first-line therapy [9, 10]. In Europe, testing for mutations or rearrangements of ALK, c-ros oncogene 1 (ROS1), and EGFR is considered mandatory, and testing for BRAF V600E mutations is important in countries where BRAF/MEK inhibitors are approved. Other tests include those for human epidermal growth factor receptor 2 (HER2) and MET exon mutations and for fusion genes in RET and NTRK1, which are all are considered evolving biomarkers [10]. The US National Comprehensive Cancer Network guidelines recommend the biomarker test panel for non-squamous NSCLC should, at a minimum, include EGFR mutations, BRAF mutations, ALK fusions, ROS1 fusions, and PD-L1 expression [9]. A primary T790M mutation in EGFR exon 20 is a resistance mutation and more likely to coexist with an L858R mutation than with an exon 19 deletion [11]. While osimertinib has been shown to be effective in patients with a primary T790M mutation, as shown in patient 1, most patients with such mutations progress within 1 year of starting osimertinib [11]. Patient 1 also had high expression of PD-L1 as shown by a TPS of 80%. This suggests that this patient is a good candidate for immunotherapy, but guidelines recommend the use of targeted therapy first-line (before immunotherapy) in patients with sensitizing mutations because the response rate is likely to be higher [9]. Once targeted therapy fails, immunotherapy is indicated. ALK rearrangements are the driving mutations responsible for the development of NSCLC in 3–7% of patients, and, as observed in patient 2, these patients have a higher risk of developing brain metastases than those with other NSCLC subtypes [12]. The first-generation ALK inhibitor crizotinib, used for second-line treatment in patient 2, has antitumor advantages over chemotherapy in this subtype of patients; however, all patients eventually progress because of drug resistance [10]. Furthermore, the amount of crizotinib that crosses the blood–brain barrier is negligible, which limits its use in patients with brain metastases [10]. In patients with crizotinib-resistant ALK-rearranged NSCLC, one strategy is sequential treatment with next-generation ALK inhibitors, such as ceritinib, alectinib, or brigatinib [12], as used in patient 2. In the IMpower150 study, most patients had wild-type EGFR and ALK, but 10% of patients were EGFR-mutation positive and 8.5% were ALK-rearrangement positive [7]. IMpower150 is the only trial that has shown positive results with immunotherapy in patients with EGFR- or ALK-positive NSCLC [10]. OS in the population that included patients with these mutations receiving the atezolizumab + BCP regimen was 19.8 months, which was similar to that in the population excluding patients with these mutations (19.5 months), and significantly longer than in the BCP group (15.0 months for the whole population and 14.7 months for the EGFR and ALK wild-type population) [13]. In patients with EGFR mutations, OS was 29.4 months in the atezolizumab + BCP group and 18.1 months in the BCP group [13]. Median progression-free survival (PFS) in patients with EGFR mutations receiving the atezolizumab + BCP regimen was 9.7 months, similar to the PFS in patients with wild-type EGFR (8.3 months), and significantly longer than in the BCP group irrespective of EGFR mutation status (6.1 months and 6.8 months, respectively, in the EGFR mutation and wild-type groups receiving BCP) [7]. Similarly, median PFS was significantly longer in the atezolizumab + BCP group than in the placebo + BCP group in patients with KRAS mutations (8.1 vs. 5.8 months, respectively), as well as in those with wild-type KRAS (9.7 vs. 5.8 months) [7]. The number of mutations, as well as the type, may be relevant to treatment response to atezolizumab. Data suggest that the survival (PFS and OS) benefit of PD-L1 or PD-1 inhibitors may be more marked in patients with a high tumor mutation burden (TMB) than in those with low TMB [14–16], although this result was not seen in some trials [17, 18]. Recent data from randomized trials show that a blood-based assay for TMB can be a useful and valid biomarker for atezolizumab [19]. The cases of patients 3 and 4 illustrated the use of atezolizumab in patients with high disease burden, which was characterized by extensive metastases, including in the liver. In the IMPower150 study, 13% of patients had liver metastases, and atezolizumab + BCP significantly prolonged PFS and OS compared with placebo + BCP in patients with or without liver metastases [7, 20]. However, the difference in PFS and OS between the atezolizumab + BCP group and the BCP group was more marked in the cohort with liver metastases [7]. In the group with liver metastases, the PFS hazard ratio was 0.42 (median PFS 7.4 vs. 4.9 months for atezolizumab + BCP vs. placebo + BCP), whereas in the group without liver metastases the PFS hazard ratio was 0.63 (median PFS 8.3 vs. 7.0 months, respectively) [7]; the OS hazard ratio was 0.52 in the group with liver metastases (median OS 13.3 vs. 9.4 months for atezolizumab + BCP vs. placebo + BCP), and in the group without liver metastases the OS hazard ratio was 0.82 (median OS 20.4 vs. 17.0 months, respectively) [20]. In addition to liver metastases, patient 3 also had bone metastases, which are associated with significantly reduced survival in patients with NSCLC [21, 22]. Moreover, bone metastases are associated with significant pain, fatigue, and disturbed sleep [23], which may negatively affect the patient’s performance status. Indeed, this patient had an ECOG performance status of 2. The IMpower150 study excluded patients with ECOG performance status of 2 or higher [7]; however, data indicate that between one-third and one-half of patients with NSCLC have poor performance status (e.g., ECOG PS of 2 or higher) [24]. It is encouraging that patient 3, who had multiple metastatic sites including in the appendicular skeleton, was able to benefit from treatment with atezolizumab over a prolonged period before disease progression. The last case presented (patient 4) had both liver and brain metastases at the time of starting treatment with atezolizumab. Adenocarcinomas are the most common tumor type to metastasize to the CNS, and 30–64% of patients with NSCLC have CNS metastases [9, 10]. Historically, patients with brain metastases have had a particularly poor prognosis [25], although this is starting to change with the increasing availability of novel agents. However, patients with untreated brain metastases are usually excluded from clinical trials, many of which also exclude patients with treated brain metastases. Indeed, both the POPLAR study and IMPower150 excluded patients with untreated CNS metastases [5, 7], with neither study reporting on patients with treated brain metastases. Patient 4 described here received treatment of brain metastases with holocranial radiotherapy, and subsequently derived benefit from atezolizumab treatment. The positive CNS responses in this patient is consistent with findings reported in the OAK trial [6]. In this trial, which specified inclusion of patients with treated, asymptomatic supratentorial CNS metastases, subgroup analysis demonstrated a survival benefit with atezolizumab compared with docetaxel in patients with treated CNS metastases at baseline, with a hazard ratio of 0.54 [95% confidence interval (CI) 0.31–0.94] [6]. These findings for atezolizumab in patients with brain metastases are also consistent with those of a phase II study of pembrolizumab in patients with NSCLC (n = 18) or melanoma and untreated brain metastases, in which pembrolizumab demonstrated activity in brain metastases, with a response rate for brain metastasis of 33% among patients with NSCLC [26]. Although this case series provides valuable information regarding the practical clinical issues associated with atezolizumab + BCP treatment, more well-designed studies are needed to develop evidence-based recommendations on immunotherapy to guide oncologists, immunologists, and other specialists in the management of patients with mutated NSCLC. Conclusion As more becomes known about the importance of the various genetic mutations, rearrangements, and expression profiles in NSCLC, testing for targetable oncogenic alterations and immuno-oncology therapy biomarkers is becoming more and more essential for treatment decisions [10]. The first two patients discussed here suggest that the number and type of mutations may be relevant for guiding treatment decisions in NSCLC. To our knowledge, atezolizumab + BCP is the only immunotherapy combination that has demonstrated efficacy in patients with mutated NSCLC [7, 27], and these cases show that the results of these studies have been transferred to clinical practice. Another factor that should be considered when deciding upon a course of therapy is a patient’s performance status. However, clinical trials often exclude patients with poor performance status; hence, the second two cases described here of patients with NSCLC and high disease burden (patients 3 and 4), who benefited from atezolizumab-containing therapy over a prolonged period, are particularly encouraging. Finally, the CNS responses reported here suggest that atezolizumab + bevacizumab may be an important option for the significant unmet need of treating brain metastases in NSCLC. These observations provide valuable insights into the practical clinical issues associated with atezolizumab + BCP treatment in patients with advanced or metastatic NSCLC. These illustrative clinical cases may also help clinicians to identify patients with NSCLC who will potentially gain the most benefit from the use of atezolizumab + BCP in routine clinical practice. We thank the patients who allowed us to report their clinical details. Funding Medical writing assistance and the Rapid Service Fee for this manuscript were funded by Roche. Medical Writing Assistance We would like to thank Catherine Rees of Springer Healthcare Communications, and Marie Cheeseman, on behalf of Springer Healthcare Communications, who wrote the outline and first draft, respectively. This medical writing assistance was funded by Roche. Authorship All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. Compliance with Ethics Guidelines Data from these patients were collected in accordance with the Helsinki Declaration of 1964 and its later amendments, concerning human and animal rights. All patients provided written informed consent to all the diagnostic-therapeutic procedures, for the use of their medical images, and for inclusion in this manuscript. Ethical committee approval was not required, as per Spanish law. Disclosures Dr Cobo reports receiving advisory or consultancy fees from Roche, Bristol Myers Squibb, AstraZeneca, Pfizer, and Boehringer, and travel and accommodation funding from Roche, Bristol Myers Squibb, and AstraZeneca outside of the submitted work. Dr Rodríguez-Abreu reports receiving advisory or consultancy fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Pfizer, Boehringer, and Takeda, speaker’s fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Boehringer, and Takeda, and travel and accommodation funding from Roche, Merck, Bristol Myers Squibb, and AstraZeneca outside of the submitted work. Diego Pérez Parente is an employee of Roche Farma, Spain. Pedro Ruiz Gracia is an employee of Roche Farma, Spain. Dr González reports receiving advisory or consultancy fees from Roche, Bristol Myers Squibb, AstraZeneca, Boehringer, and Sanofi, speaker’s fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Lilly, and Ipsen, and travel and accommodation funding from Roche, Merck, Bristol Myers Squibb, and Lilly outside of the submitted work. Data Availability Qualified researchers may request access to individual patient level data through the clinical study data request platform (https://vivli.org/). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).	UNK UNK, 2 CYCLIC	DrugDosageText	CC BY-NC	33582978	18,610,802	2021-06
What was the dosage of drug 'CARBOPLATIN'?	Practical Issues in the Use of Atezolizumab for Patients with Non-Small Cell Lung Cancer: Case Reports and Literature Review. Atezolizumab is a monoclonal antibody targeting the programmed death ligand 1 (PD-L1) that was approved in 2017 in the USA and Europe for the second-line treatment of advanced or metastatic non-small cell lung cancer (NSCLC). This review article describes the practical clinical issues associated with atezolizumab treatment in NSCLC using a combination of four illustrative cases and a narrative literature review. The first two cases highlight the importance of tumor mutational status when making treatment decisions. A 62-year-old man with epidermal growth factor receptor (EGFR)-mutated, PD-L1-positive, stage IV lung adenocarcinoma received treatment with second-line atezolizumab + bevacizumab, carboplatin, and paclitaxel (BCP) after first-line osimertinib. In the second case, a 63-year-old man with stage IVb lung adenocarcinoma with anaplastic lymphoma kinase (ALK) translocation received sixth-line treatment with atezolizumab + BCP. The two final cases both had extensive metastases. A 55-year-old woman with EGFR-mutated lung adenocarcinoma received second-line treatment with atezolizumab + BCP after development of multiple metastases, followed by atezolizumab + bevacizumab until last follow-up. A 42-year-old man with PD-L1-positive pulmonary adenocarcinoma (negative for EGFR mutations) developed liver and brain metastases after several lines of therapy. He underwent holocranial radiation and received atezolizumab + BCP, which resulted in a decrease in all measurable and evaluable tumoral lesions. These illustrative cases indicate that the type and number of mutations may influence treatment response to atezolizumab, and that atezolizumab may provide clinical benefit in patients with high disease burden. Key Summary Points Why carry out this study? Targeted immunotherapies, such as atezolizumab, have improved overall survival in patients with advanced or metastatic non-small cell lung cancer (NSCLC) in clinical trials. Understanding how to treat patients on the basis of their targetable oncogenic mutations or those usually excluded from clinical trials (e.g., with treated brain metastases or high disease burden) is important for oncologists in the real-world clinical setting. Four cases of treatment with atezolizumab plus bevacizumab, carboplatin, and paclitaxel in patients with NSCLC after at least one previous line of targeted therapy are described to illustrate these clinical issues. What was learned from the study? The presented cases suggest that both the number and type of mutations may be relevant for guiding treatment decisions in NSCLC, and that patients with high disease burden or brain metastases may benefit from atezolizumab-containing therapy. Digital Features This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13521968. Introduction Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and has a high rate of mortality [1, 2]. According to global estimates, lung cancer was the most commonly diagnosed cancer in 2018 (11.6% of all new cases) and the leading cause of cancer-related mortality (18.4% of all cancer deaths) [3]. In a US analysis of patients with NSCLC, the median overall survival (OS) time after diagnosis was only 13 months, and the estimated 4-year survival rate was between 22% and 28% [1]. However, OS has been improving over recent decades as a result of novel treatments [1, 2], including targeted therapies and immunotherapies. One such novel treatment is atezolizumab, a monoclonal antibody targeting the programmed death ligand 1 (PD-L1) [4]. Atezolizumab was approved in the USA and Europe for the second-line treatment of advanced or metastatic NSCLC in 2017, based on the results of the phase II POPLAR study [5] and the phase III OAK study [6], in which atezolizumab was associated with significantly better survival compared with docetaxel. Since its approval, the IMpower150 study has demonstrated that atezolizumab in combination with bevacizumab, carboplatin, and paclitaxel (BCP) was more effective than BCP alone as first-line therapy in previously untreated patients with metastatic non-squamous NSCLC [7]. The current review describes the practical clinical issues associated with atezolizumab + BCP in patients with NSCLC, using a combination of illustrative case presentations and a narrative literature review. Cases Illustrating Role of Mutational Status Patient 1 A 62-year-old man with no relevant medical or surgical history was diagnosed with stage IIIC lung adenocarcinoma (cT3cN3cM0) in January 2018. He was a former smoker with a 15 pack-year history. Molecular testing showed an L858R point mutation in epidermal growth factor receptor (EGFR) exon 21 and a primary T790M mutation in EGFR exon 20. The tumor was PD-L1 positive, with a tumor proportion score (TPS) of 80% on immunohistochemistry (pharmDx 28–8; DAKO, Glostrup, Denmark). On February 1, 2018, he began first-line treatment with osimertinib; the 12-week assessment showed a partial response by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. Response continued until March 2019, when the disease progressed to stage IV with mediastinal and retroperitoneal involvement (Fig. 1a). At this time, the patient was asymptomatic and started second-line treatment with atezolizumab in combination with BCP, based on the results of the IMpower150 clinical trial [7]. After two cycles, a computed tomography (CT) scan showed partial response by RECIST 1.1 criteria (Fig. 1b), and the patient was able to receive six cycles without significant adverse events.Fig. 1 Patient 1: Computed tomography scan of chest on a March 25, 2019, showing mediastinal and retroperitoneal involvement, b June 6, 2019 after two cycles of atezolizumab + BCP, c October 5, 2019 indicating a maintained radiologic response, and d January 30, 2020 showing tumor progression after 13 weeks of maintenance atezolizumab + bevacizumab. BCP bevacizumab, carboplatin, and paclitaxel After confirming that the radiologic response was maintained (Fig. 1c), he continued maintenance treatment with atezolizumab + bevacizumab. In February 2020, after 13 cycles, tumor progression was noted (Fig. 1d) and treatment was discontinued. Biopsy showed amplification and overexpression of c-MET, so the patient initiated third-line treatment with telisotuzumab vedotin as part of a clinical trial (NCT03539536). Patient 2 A 63-year-old man was diagnosed with a stage IVb lung adenocarcinoma with a brain metastasis (T2N3M1b) in February 2013. He was a former smoker (20 pack-year history) with occupational exposure to oil and its derivatives. On June 13, 2013, he started induction chemotherapy with cisplatin + pemetrexed, undergoing radiosurgery for the brain lesion after the first cycle. He showed a partial radiologic and metabolic response after two cycles of cisplatin + pemetrexed, and a brain magnetic resonance imaging (MRI) revealed a reduction in the size of the brain metastasis. He received two cycles of cisplatin + pemetrexed from June 13 to June 24, 2013, followed by radical-intent chemoradiation between June 28 and September 6, 2013, consisting of a 60 Gy dose and two cycles of weekly paclitaxel + carboplatin; however, he was unable to continue this treatment because of sustained leukopenia. A follow-up assessment on October 6, 2014, found no signs of thoracoabdominal progression. Lesions consistent with metastases were identified in the cerebellar vermis and the right centrum semiovale; radiosurgery was administered using 20.7 Gy and 20.9 Gy, respectively, at these sites. A CT scan on January 12, 2015, showed hilar-mediastinal progression, and a biopsy of the left hilar adenopathy showed that the tumor had wild-type KRAS, was EGFR- and BRAF-mutation negative, and had an anaplastic lymphoma kinase (ALK) translocation. In February 2015, he started second-line treatment with crizotinib and had a partial response. A brain MRI performed on November 3, 2015, showed oligoprogression, for which he received radiosurgery. On April 4, 2016, he showed pulmonary progression, and 2 weeks later, he started third-line treatment with ceritinib as part of a clinical trial, with a best response of stable disease. A CT scan on January 30, 2018, showed an increase in the size of the space-occupying lesions in the brain. On March 6 of the same year, he initiated fourth-line treatment with alectinib for metastases, with a best response of stable disease. A further CT scan on July 23, 2018, showed left hilar adenopathy progression and left upper lobe atelectasis. He started fifth-line therapy for metastases with brigatinib on September 5, 2018, and stable disease was his best response. The patient developed left hemiparesis on January 16, 2019. A brain MRI on January 21 showed signs of radionecrosis, but an acute or subacute ischemic event could not be ruled out. Brain progression, with an increase in the size and number of lesions, was detected in March 2019 (Fig. 2a), and he received hippocampal-sparing whole brain radiation with focal boost (45 Gy dose) on the lesions.Fig. 2 Patient 2: brain magnetic resonance imaging scan results on a March 11, 2019, showing an increase in the size and number of brain lesions, and b March 22, 2020, after 4 cycles of atezolizumab + BCP followed by 13 cycles of maintenance atezolizumab + bevacizumab, and chest computed tomography scan results on c March 11, 2019, prior to, and d March 22, 2020, after atezolizumab-based treatment On May 8, 2019, he began sixth-line treatment with atezolizumab + BCP. After four cycles (ending on August 8, 2019), he started maintenance treatment with atezolizumab + bevacizumab, achieving a partial brain response. In March 2020, he had received 13 cycles of maintenance treatment, and he showed stable disease as assessed by brain MRI (Fig. 2b) and CT scans of the chest (Fig. 2c, d), abdomen, and pelvis. CASES Illustrating Management of High Disease Burden Patient 3 A 55-year-old non-smoking woman without known morbidity was diagnosed with a stage IIIB lung adenocarcinoma (cT4N2) in June 2016. She received treatment with external radiation therapy (dose administered, 66 Gy) concomitantly with cisplatin and vinorelbine (three cycles). A follow-up CT scan showed partial response and the multidisciplinary Committee on Thoracic Tumors recommended surgical intervention. She underwent video-assisted thoracic surgery consisting of an upper right pulmonary lobectomy with systematic hilar and mediastinal lymph node dissection on October 5, 2016. Molecular analysis of the excised tumor showed EGFR exon 19 deletion. In March 2018, disease progression was detected in lung, pleura, and bone, and in subcutaneous tissue and the lymphatic system. On March 27, she received palliative and decompressive radiation therapy of the lumbar spine (L5) at 8 Gy. Subsequently, in April 2018, she started treatment with afatinib at 40 mg/day, and had a partial response. Afatinib treatment continued until July 2019, when imaging identified disease progression in the liver and bone, and a sacral soft tissue mass (Fig. 3a). Analysis of liquid and sacral mass biopsy did not detect a resistant T790M mutation on EGFR exon 20.Fig. 3 Patient 3: Computed tomography of lumbosacral region on a July 4, 2019, before and b October 8, 2019, after three cycles of atezolizumab + BCP, showing partial response in the sacral soft tissue mass. BCP bevacizumab, carboplatin, and paclitaxel At this time, the patient’s Eastern Cooperative Oncology Group (ECOG) performance status was 2, and she was negative for PD-L1 (TPS 0%). On August 7, 2019, on the basis of the results of the IMpower150 clinical trial [7], she began second-line treatment with atezolizumab + BCP. After three cycles she showed a partial response (Fig. 3b), and was able to complete six cycles of treatment. However, the patient developed febrile neutropenia and sepsis due to central catheter-related infections in the second cycle leading to hospital admission; grade 2 sensory neuropathy that reverted to grade 1 after discontinuing paclitaxel and carboplatin; and grade 1 asthenia. She then continued treatment with atezolizumab + bevacizumab. By June 2020, she had completed 14 cycles of treatment without relevant toxicities, but treatment was interrupted at that time because a CT scan showed progression of the liver and bone metastases. Patient 4 A 42-year-old man was diagnosed with stage IIIB pulmonary adenocarcinoma (cT4N2M0) in June 2018; at this time, he had an ECOG performance status of 0. Molecular analysis showed the tumor was negative for EGFR mutations and ALK fusions, with PD-L1 expression on 30% of cancer cells. He was a smoker at the time of diagnosis, smoking one pack daily for 20 years (20 pack-years). On August 22, 2018, treatment with cisplatin, gemcitabine, and paclitaxel was started, for a total of four 21-day cycles. Treatment was well tolerated, with the exception of nausea and asthenia (both grade 1). Repeat CT scans performed in September 2018 after two treatment cycles, and again in November after four treatment cycles, revealed decreasing tumor volume, with mediastinal contact still present; at this time, results of a brain MRI were normal. In December 2018, the man underwent a right lower lobectomy; the right lower pulmonary lobe was found to have well-differentiated adenocarcinoma with an acinar pattern, without evidence of vascular invasion, and no visceral pleural infiltration. Surgical resection margins were not affected. TNM staging at this point was ypT1cN0M0. He subsequently received consolidative radiation therapy on the mediastinal bed; he had a performance status of 0 and no complications. In October 2019, a follow-up examination revealed a de novo pulmonary micronodule in the control CT scan, but this was not seen on a positron emission tomography–CT scan. In February 2020, repeat CT scans revealed a growth on the left perihilar pulmonary nodule and a new right-hand micronodule. Metastases were seen in several liver segments. As a result of mild dizziness, a central nervous system (CNS) MRI scan was performed in January 2020, revealing the presence of brain metastases (Fig. 4a).Fig. 4 Patient 4: Brain magnetic resonance imaging scan results in a January 2020 showing brain metastases and b April 2020 showing reduced lesion size after atezolizumab + BCP treatment. BCP bevacizumab, carboplatin, and paclitaxel Holocranial radiotherapy was administered, finishing at the beginning of February 2020. After 4 weeks, a repeat MRI did not show any significant changes in the size of the brain lesions. One month after discontinuing holocranial radiotherapy, in the second week of March 2020, he began treatment with four 21-day cycles of atezolizumab + BCP, followed by atezolizumab + bevacizumab until disease progression or toxicity. After two cycles, there were no notable toxicities, and an assessment performed at the end of April 2020 revealed a decrease in all measurable and evaluable tumoral lesions (Fig. 4b). By December 2020, 40 weeks after the start of atezolizumab + BCP, the patient was still in partial response and was being managed on chemotherapy-free maintenance treatment with atezolizumab + bevacizumab. Compliance with Ethics Guidelines Data on these patients were collected in accordance with the Helsinki Declaration of 1964 and its later amendments concerning human and animal rights. All patients provided written informed consent to all the diagnostic and therapeutic procedures, for the use of their medical images, and for inclusion in this manuscript. Ethical committee approval was not required, as per Spanish law. Discussion EGFR mutations are present in 10–20% of Caucasian patients and about 50% of Asian patients with NSCLC [8]. The L858R point mutation in EGFR exon 21 identified in patient 1 at diagnosis is one of the most common “classical” EGFR mutations, along with a deletion in exon 19 [8]. Together, these mutations represent 85% of EGFR mutations. These activating mutations make the tumor sensitive to tyrosine kinase inhibitors (TKIs) and are an indication for choosing a TKI agent as first-line therapy [9], as occurred in patient 1. Indeed, current NSCLC guidelines note the importance of molecular tumor analysis in determining first-line therapy [9, 10]. In Europe, testing for mutations or rearrangements of ALK, c-ros oncogene 1 (ROS1), and EGFR is considered mandatory, and testing for BRAF V600E mutations is important in countries where BRAF/MEK inhibitors are approved. Other tests include those for human epidermal growth factor receptor 2 (HER2) and MET exon mutations and for fusion genes in RET and NTRK1, which are all are considered evolving biomarkers [10]. The US National Comprehensive Cancer Network guidelines recommend the biomarker test panel for non-squamous NSCLC should, at a minimum, include EGFR mutations, BRAF mutations, ALK fusions, ROS1 fusions, and PD-L1 expression [9]. A primary T790M mutation in EGFR exon 20 is a resistance mutation and more likely to coexist with an L858R mutation than with an exon 19 deletion [11]. While osimertinib has been shown to be effective in patients with a primary T790M mutation, as shown in patient 1, most patients with such mutations progress within 1 year of starting osimertinib [11]. Patient 1 also had high expression of PD-L1 as shown by a TPS of 80%. This suggests that this patient is a good candidate for immunotherapy, but guidelines recommend the use of targeted therapy first-line (before immunotherapy) in patients with sensitizing mutations because the response rate is likely to be higher [9]. Once targeted therapy fails, immunotherapy is indicated. ALK rearrangements are the driving mutations responsible for the development of NSCLC in 3–7% of patients, and, as observed in patient 2, these patients have a higher risk of developing brain metastases than those with other NSCLC subtypes [12]. The first-generation ALK inhibitor crizotinib, used for second-line treatment in patient 2, has antitumor advantages over chemotherapy in this subtype of patients; however, all patients eventually progress because of drug resistance [10]. Furthermore, the amount of crizotinib that crosses the blood–brain barrier is negligible, which limits its use in patients with brain metastases [10]. In patients with crizotinib-resistant ALK-rearranged NSCLC, one strategy is sequential treatment with next-generation ALK inhibitors, such as ceritinib, alectinib, or brigatinib [12], as used in patient 2. In the IMpower150 study, most patients had wild-type EGFR and ALK, but 10% of patients were EGFR-mutation positive and 8.5% were ALK-rearrangement positive [7]. IMpower150 is the only trial that has shown positive results with immunotherapy in patients with EGFR- or ALK-positive NSCLC [10]. OS in the population that included patients with these mutations receiving the atezolizumab + BCP regimen was 19.8 months, which was similar to that in the population excluding patients with these mutations (19.5 months), and significantly longer than in the BCP group (15.0 months for the whole population and 14.7 months for the EGFR and ALK wild-type population) [13]. In patients with EGFR mutations, OS was 29.4 months in the atezolizumab + BCP group and 18.1 months in the BCP group [13]. Median progression-free survival (PFS) in patients with EGFR mutations receiving the atezolizumab + BCP regimen was 9.7 months, similar to the PFS in patients with wild-type EGFR (8.3 months), and significantly longer than in the BCP group irrespective of EGFR mutation status (6.1 months and 6.8 months, respectively, in the EGFR mutation and wild-type groups receiving BCP) [7]. Similarly, median PFS was significantly longer in the atezolizumab + BCP group than in the placebo + BCP group in patients with KRAS mutations (8.1 vs. 5.8 months, respectively), as well as in those with wild-type KRAS (9.7 vs. 5.8 months) [7]. The number of mutations, as well as the type, may be relevant to treatment response to atezolizumab. Data suggest that the survival (PFS and OS) benefit of PD-L1 or PD-1 inhibitors may be more marked in patients with a high tumor mutation burden (TMB) than in those with low TMB [14–16], although this result was not seen in some trials [17, 18]. Recent data from randomized trials show that a blood-based assay for TMB can be a useful and valid biomarker for atezolizumab [19]. The cases of patients 3 and 4 illustrated the use of atezolizumab in patients with high disease burden, which was characterized by extensive metastases, including in the liver. In the IMPower150 study, 13% of patients had liver metastases, and atezolizumab + BCP significantly prolonged PFS and OS compared with placebo + BCP in patients with or without liver metastases [7, 20]. However, the difference in PFS and OS between the atezolizumab + BCP group and the BCP group was more marked in the cohort with liver metastases [7]. In the group with liver metastases, the PFS hazard ratio was 0.42 (median PFS 7.4 vs. 4.9 months for atezolizumab + BCP vs. placebo + BCP), whereas in the group without liver metastases the PFS hazard ratio was 0.63 (median PFS 8.3 vs. 7.0 months, respectively) [7]; the OS hazard ratio was 0.52 in the group with liver metastases (median OS 13.3 vs. 9.4 months for atezolizumab + BCP vs. placebo + BCP), and in the group without liver metastases the OS hazard ratio was 0.82 (median OS 20.4 vs. 17.0 months, respectively) [20]. In addition to liver metastases, patient 3 also had bone metastases, which are associated with significantly reduced survival in patients with NSCLC [21, 22]. Moreover, bone metastases are associated with significant pain, fatigue, and disturbed sleep [23], which may negatively affect the patient’s performance status. Indeed, this patient had an ECOG performance status of 2. The IMpower150 study excluded patients with ECOG performance status of 2 or higher [7]; however, data indicate that between one-third and one-half of patients with NSCLC have poor performance status (e.g., ECOG PS of 2 or higher) [24]. It is encouraging that patient 3, who had multiple metastatic sites including in the appendicular skeleton, was able to benefit from treatment with atezolizumab over a prolonged period before disease progression. The last case presented (patient 4) had both liver and brain metastases at the time of starting treatment with atezolizumab. Adenocarcinomas are the most common tumor type to metastasize to the CNS, and 30–64% of patients with NSCLC have CNS metastases [9, 10]. Historically, patients with brain metastases have had a particularly poor prognosis [25], although this is starting to change with the increasing availability of novel agents. However, patients with untreated brain metastases are usually excluded from clinical trials, many of which also exclude patients with treated brain metastases. Indeed, both the POPLAR study and IMPower150 excluded patients with untreated CNS metastases [5, 7], with neither study reporting on patients with treated brain metastases. Patient 4 described here received treatment of brain metastases with holocranial radiotherapy, and subsequently derived benefit from atezolizumab treatment. The positive CNS responses in this patient is consistent with findings reported in the OAK trial [6]. In this trial, which specified inclusion of patients with treated, asymptomatic supratentorial CNS metastases, subgroup analysis demonstrated a survival benefit with atezolizumab compared with docetaxel in patients with treated CNS metastases at baseline, with a hazard ratio of 0.54 [95% confidence interval (CI) 0.31–0.94] [6]. These findings for atezolizumab in patients with brain metastases are also consistent with those of a phase II study of pembrolizumab in patients with NSCLC (n = 18) or melanoma and untreated brain metastases, in which pembrolizumab demonstrated activity in brain metastases, with a response rate for brain metastasis of 33% among patients with NSCLC [26]. Although this case series provides valuable information regarding the practical clinical issues associated with atezolizumab + BCP treatment, more well-designed studies are needed to develop evidence-based recommendations on immunotherapy to guide oncologists, immunologists, and other specialists in the management of patients with mutated NSCLC. Conclusion As more becomes known about the importance of the various genetic mutations, rearrangements, and expression profiles in NSCLC, testing for targetable oncogenic alterations and immuno-oncology therapy biomarkers is becoming more and more essential for treatment decisions [10]. The first two patients discussed here suggest that the number and type of mutations may be relevant for guiding treatment decisions in NSCLC. To our knowledge, atezolizumab + BCP is the only immunotherapy combination that has demonstrated efficacy in patients with mutated NSCLC [7, 27], and these cases show that the results of these studies have been transferred to clinical practice. Another factor that should be considered when deciding upon a course of therapy is a patient’s performance status. However, clinical trials often exclude patients with poor performance status; hence, the second two cases described here of patients with NSCLC and high disease burden (patients 3 and 4), who benefited from atezolizumab-containing therapy over a prolonged period, are particularly encouraging. Finally, the CNS responses reported here suggest that atezolizumab + bevacizumab may be an important option for the significant unmet need of treating brain metastases in NSCLC. These observations provide valuable insights into the practical clinical issues associated with atezolizumab + BCP treatment in patients with advanced or metastatic NSCLC. These illustrative clinical cases may also help clinicians to identify patients with NSCLC who will potentially gain the most benefit from the use of atezolizumab + BCP in routine clinical practice. We thank the patients who allowed us to report their clinical details. Funding Medical writing assistance and the Rapid Service Fee for this manuscript were funded by Roche. Medical Writing Assistance We would like to thank Catherine Rees of Springer Healthcare Communications, and Marie Cheeseman, on behalf of Springer Healthcare Communications, who wrote the outline and first draft, respectively. This medical writing assistance was funded by Roche. Authorship All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. Compliance with Ethics Guidelines Data from these patients were collected in accordance with the Helsinki Declaration of 1964 and its later amendments, concerning human and animal rights. All patients provided written informed consent to all the diagnostic-therapeutic procedures, for the use of their medical images, and for inclusion in this manuscript. Ethical committee approval was not required, as per Spanish law. Disclosures Dr Cobo reports receiving advisory or consultancy fees from Roche, Bristol Myers Squibb, AstraZeneca, Pfizer, and Boehringer, and travel and accommodation funding from Roche, Bristol Myers Squibb, and AstraZeneca outside of the submitted work. Dr Rodríguez-Abreu reports receiving advisory or consultancy fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Pfizer, Boehringer, and Takeda, speaker’s fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Boehringer, and Takeda, and travel and accommodation funding from Roche, Merck, Bristol Myers Squibb, and AstraZeneca outside of the submitted work. Diego Pérez Parente is an employee of Roche Farma, Spain. Pedro Ruiz Gracia is an employee of Roche Farma, Spain. Dr González reports receiving advisory or consultancy fees from Roche, Bristol Myers Squibb, AstraZeneca, Boehringer, and Sanofi, speaker’s fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Lilly, and Ipsen, and travel and accommodation funding from Roche, Merck, Bristol Myers Squibb, and Lilly outside of the submitted work. Data Availability Qualified researchers may request access to individual patient level data through the clinical study data request platform (https://vivli.org/). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).	UNK UNK, 2 CYCLIC	DrugDosageText	CC BY-NC	33582978	18,610,802	2021-06
What was the dosage of drug 'PACLITAXEL'?	Practical Issues in the Use of Atezolizumab for Patients with Non-Small Cell Lung Cancer: Case Reports and Literature Review. Atezolizumab is a monoclonal antibody targeting the programmed death ligand 1 (PD-L1) that was approved in 2017 in the USA and Europe for the second-line treatment of advanced or metastatic non-small cell lung cancer (NSCLC). This review article describes the practical clinical issues associated with atezolizumab treatment in NSCLC using a combination of four illustrative cases and a narrative literature review. The first two cases highlight the importance of tumor mutational status when making treatment decisions. A 62-year-old man with epidermal growth factor receptor (EGFR)-mutated, PD-L1-positive, stage IV lung adenocarcinoma received treatment with second-line atezolizumab + bevacizumab, carboplatin, and paclitaxel (BCP) after first-line osimertinib. In the second case, a 63-year-old man with stage IVb lung adenocarcinoma with anaplastic lymphoma kinase (ALK) translocation received sixth-line treatment with atezolizumab + BCP. The two final cases both had extensive metastases. A 55-year-old woman with EGFR-mutated lung adenocarcinoma received second-line treatment with atezolizumab + BCP after development of multiple metastases, followed by atezolizumab + bevacizumab until last follow-up. A 42-year-old man with PD-L1-positive pulmonary adenocarcinoma (negative for EGFR mutations) developed liver and brain metastases after several lines of therapy. He underwent holocranial radiation and received atezolizumab + BCP, which resulted in a decrease in all measurable and evaluable tumoral lesions. These illustrative cases indicate that the type and number of mutations may influence treatment response to atezolizumab, and that atezolizumab may provide clinical benefit in patients with high disease burden. Key Summary Points Why carry out this study? Targeted immunotherapies, such as atezolizumab, have improved overall survival in patients with advanced or metastatic non-small cell lung cancer (NSCLC) in clinical trials. Understanding how to treat patients on the basis of their targetable oncogenic mutations or those usually excluded from clinical trials (e.g., with treated brain metastases or high disease burden) is important for oncologists in the real-world clinical setting. Four cases of treatment with atezolizumab plus bevacizumab, carboplatin, and paclitaxel in patients with NSCLC after at least one previous line of targeted therapy are described to illustrate these clinical issues. What was learned from the study? The presented cases suggest that both the number and type of mutations may be relevant for guiding treatment decisions in NSCLC, and that patients with high disease burden or brain metastases may benefit from atezolizumab-containing therapy. Digital Features This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13521968. Introduction Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and has a high rate of mortality [1, 2]. According to global estimates, lung cancer was the most commonly diagnosed cancer in 2018 (11.6% of all new cases) and the leading cause of cancer-related mortality (18.4% of all cancer deaths) [3]. In a US analysis of patients with NSCLC, the median overall survival (OS) time after diagnosis was only 13 months, and the estimated 4-year survival rate was between 22% and 28% [1]. However, OS has been improving over recent decades as a result of novel treatments [1, 2], including targeted therapies and immunotherapies. One such novel treatment is atezolizumab, a monoclonal antibody targeting the programmed death ligand 1 (PD-L1) [4]. Atezolizumab was approved in the USA and Europe for the second-line treatment of advanced or metastatic NSCLC in 2017, based on the results of the phase II POPLAR study [5] and the phase III OAK study [6], in which atezolizumab was associated with significantly better survival compared with docetaxel. Since its approval, the IMpower150 study has demonstrated that atezolizumab in combination with bevacizumab, carboplatin, and paclitaxel (BCP) was more effective than BCP alone as first-line therapy in previously untreated patients with metastatic non-squamous NSCLC [7]. The current review describes the practical clinical issues associated with atezolizumab + BCP in patients with NSCLC, using a combination of illustrative case presentations and a narrative literature review. Cases Illustrating Role of Mutational Status Patient 1 A 62-year-old man with no relevant medical or surgical history was diagnosed with stage IIIC lung adenocarcinoma (cT3cN3cM0) in January 2018. He was a former smoker with a 15 pack-year history. Molecular testing showed an L858R point mutation in epidermal growth factor receptor (EGFR) exon 21 and a primary T790M mutation in EGFR exon 20. The tumor was PD-L1 positive, with a tumor proportion score (TPS) of 80% on immunohistochemistry (pharmDx 28–8; DAKO, Glostrup, Denmark). On February 1, 2018, he began first-line treatment with osimertinib; the 12-week assessment showed a partial response by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. Response continued until March 2019, when the disease progressed to stage IV with mediastinal and retroperitoneal involvement (Fig. 1a). At this time, the patient was asymptomatic and started second-line treatment with atezolizumab in combination with BCP, based on the results of the IMpower150 clinical trial [7]. After two cycles, a computed tomography (CT) scan showed partial response by RECIST 1.1 criteria (Fig. 1b), and the patient was able to receive six cycles without significant adverse events.Fig. 1 Patient 1: Computed tomography scan of chest on a March 25, 2019, showing mediastinal and retroperitoneal involvement, b June 6, 2019 after two cycles of atezolizumab + BCP, c October 5, 2019 indicating a maintained radiologic response, and d January 30, 2020 showing tumor progression after 13 weeks of maintenance atezolizumab + bevacizumab. BCP bevacizumab, carboplatin, and paclitaxel After confirming that the radiologic response was maintained (Fig. 1c), he continued maintenance treatment with atezolizumab + bevacizumab. In February 2020, after 13 cycles, tumor progression was noted (Fig. 1d) and treatment was discontinued. Biopsy showed amplification and overexpression of c-MET, so the patient initiated third-line treatment with telisotuzumab vedotin as part of a clinical trial (NCT03539536). Patient 2 A 63-year-old man was diagnosed with a stage IVb lung adenocarcinoma with a brain metastasis (T2N3M1b) in February 2013. He was a former smoker (20 pack-year history) with occupational exposure to oil and its derivatives. On June 13, 2013, he started induction chemotherapy with cisplatin + pemetrexed, undergoing radiosurgery for the brain lesion after the first cycle. He showed a partial radiologic and metabolic response after two cycles of cisplatin + pemetrexed, and a brain magnetic resonance imaging (MRI) revealed a reduction in the size of the brain metastasis. He received two cycles of cisplatin + pemetrexed from June 13 to June 24, 2013, followed by radical-intent chemoradiation between June 28 and September 6, 2013, consisting of a 60 Gy dose and two cycles of weekly paclitaxel + carboplatin; however, he was unable to continue this treatment because of sustained leukopenia. A follow-up assessment on October 6, 2014, found no signs of thoracoabdominal progression. Lesions consistent with metastases were identified in the cerebellar vermis and the right centrum semiovale; radiosurgery was administered using 20.7 Gy and 20.9 Gy, respectively, at these sites. A CT scan on January 12, 2015, showed hilar-mediastinal progression, and a biopsy of the left hilar adenopathy showed that the tumor had wild-type KRAS, was EGFR- and BRAF-mutation negative, and had an anaplastic lymphoma kinase (ALK) translocation. In February 2015, he started second-line treatment with crizotinib and had a partial response. A brain MRI performed on November 3, 2015, showed oligoprogression, for which he received radiosurgery. On April 4, 2016, he showed pulmonary progression, and 2 weeks later, he started third-line treatment with ceritinib as part of a clinical trial, with a best response of stable disease. A CT scan on January 30, 2018, showed an increase in the size of the space-occupying lesions in the brain. On March 6 of the same year, he initiated fourth-line treatment with alectinib for metastases, with a best response of stable disease. A further CT scan on July 23, 2018, showed left hilar adenopathy progression and left upper lobe atelectasis. He started fifth-line therapy for metastases with brigatinib on September 5, 2018, and stable disease was his best response. The patient developed left hemiparesis on January 16, 2019. A brain MRI on January 21 showed signs of radionecrosis, but an acute or subacute ischemic event could not be ruled out. Brain progression, with an increase in the size and number of lesions, was detected in March 2019 (Fig. 2a), and he received hippocampal-sparing whole brain radiation with focal boost (45 Gy dose) on the lesions.Fig. 2 Patient 2: brain magnetic resonance imaging scan results on a March 11, 2019, showing an increase in the size and number of brain lesions, and b March 22, 2020, after 4 cycles of atezolizumab + BCP followed by 13 cycles of maintenance atezolizumab + bevacizumab, and chest computed tomography scan results on c March 11, 2019, prior to, and d March 22, 2020, after atezolizumab-based treatment On May 8, 2019, he began sixth-line treatment with atezolizumab + BCP. After four cycles (ending on August 8, 2019), he started maintenance treatment with atezolizumab + bevacizumab, achieving a partial brain response. In March 2020, he had received 13 cycles of maintenance treatment, and he showed stable disease as assessed by brain MRI (Fig. 2b) and CT scans of the chest (Fig. 2c, d), abdomen, and pelvis. CASES Illustrating Management of High Disease Burden Patient 3 A 55-year-old non-smoking woman without known morbidity was diagnosed with a stage IIIB lung adenocarcinoma (cT4N2) in June 2016. She received treatment with external radiation therapy (dose administered, 66 Gy) concomitantly with cisplatin and vinorelbine (three cycles). A follow-up CT scan showed partial response and the multidisciplinary Committee on Thoracic Tumors recommended surgical intervention. She underwent video-assisted thoracic surgery consisting of an upper right pulmonary lobectomy with systematic hilar and mediastinal lymph node dissection on October 5, 2016. Molecular analysis of the excised tumor showed EGFR exon 19 deletion. In March 2018, disease progression was detected in lung, pleura, and bone, and in subcutaneous tissue and the lymphatic system. On March 27, she received palliative and decompressive radiation therapy of the lumbar spine (L5) at 8 Gy. Subsequently, in April 2018, she started treatment with afatinib at 40 mg/day, and had a partial response. Afatinib treatment continued until July 2019, when imaging identified disease progression in the liver and bone, and a sacral soft tissue mass (Fig. 3a). Analysis of liquid and sacral mass biopsy did not detect a resistant T790M mutation on EGFR exon 20.Fig. 3 Patient 3: Computed tomography of lumbosacral region on a July 4, 2019, before and b October 8, 2019, after three cycles of atezolizumab + BCP, showing partial response in the sacral soft tissue mass. BCP bevacizumab, carboplatin, and paclitaxel At this time, the patient’s Eastern Cooperative Oncology Group (ECOG) performance status was 2, and she was negative for PD-L1 (TPS 0%). On August 7, 2019, on the basis of the results of the IMpower150 clinical trial [7], she began second-line treatment with atezolizumab + BCP. After three cycles she showed a partial response (Fig. 3b), and was able to complete six cycles of treatment. However, the patient developed febrile neutropenia and sepsis due to central catheter-related infections in the second cycle leading to hospital admission; grade 2 sensory neuropathy that reverted to grade 1 after discontinuing paclitaxel and carboplatin; and grade 1 asthenia. She then continued treatment with atezolizumab + bevacizumab. By June 2020, she had completed 14 cycles of treatment without relevant toxicities, but treatment was interrupted at that time because a CT scan showed progression of the liver and bone metastases. Patient 4 A 42-year-old man was diagnosed with stage IIIB pulmonary adenocarcinoma (cT4N2M0) in June 2018; at this time, he had an ECOG performance status of 0. Molecular analysis showed the tumor was negative for EGFR mutations and ALK fusions, with PD-L1 expression on 30% of cancer cells. He was a smoker at the time of diagnosis, smoking one pack daily for 20 years (20 pack-years). On August 22, 2018, treatment with cisplatin, gemcitabine, and paclitaxel was started, for a total of four 21-day cycles. Treatment was well tolerated, with the exception of nausea and asthenia (both grade 1). Repeat CT scans performed in September 2018 after two treatment cycles, and again in November after four treatment cycles, revealed decreasing tumor volume, with mediastinal contact still present; at this time, results of a brain MRI were normal. In December 2018, the man underwent a right lower lobectomy; the right lower pulmonary lobe was found to have well-differentiated adenocarcinoma with an acinar pattern, without evidence of vascular invasion, and no visceral pleural infiltration. Surgical resection margins were not affected. TNM staging at this point was ypT1cN0M0. He subsequently received consolidative radiation therapy on the mediastinal bed; he had a performance status of 0 and no complications. In October 2019, a follow-up examination revealed a de novo pulmonary micronodule in the control CT scan, but this was not seen on a positron emission tomography–CT scan. In February 2020, repeat CT scans revealed a growth on the left perihilar pulmonary nodule and a new right-hand micronodule. Metastases were seen in several liver segments. As a result of mild dizziness, a central nervous system (CNS) MRI scan was performed in January 2020, revealing the presence of brain metastases (Fig. 4a).Fig. 4 Patient 4: Brain magnetic resonance imaging scan results in a January 2020 showing brain metastases and b April 2020 showing reduced lesion size after atezolizumab + BCP treatment. BCP bevacizumab, carboplatin, and paclitaxel Holocranial radiotherapy was administered, finishing at the beginning of February 2020. After 4 weeks, a repeat MRI did not show any significant changes in the size of the brain lesions. One month after discontinuing holocranial radiotherapy, in the second week of March 2020, he began treatment with four 21-day cycles of atezolizumab + BCP, followed by atezolizumab + bevacizumab until disease progression or toxicity. After two cycles, there were no notable toxicities, and an assessment performed at the end of April 2020 revealed a decrease in all measurable and evaluable tumoral lesions (Fig. 4b). By December 2020, 40 weeks after the start of atezolizumab + BCP, the patient was still in partial response and was being managed on chemotherapy-free maintenance treatment with atezolizumab + bevacizumab. Compliance with Ethics Guidelines Data on these patients were collected in accordance with the Helsinki Declaration of 1964 and its later amendments concerning human and animal rights. All patients provided written informed consent to all the diagnostic and therapeutic procedures, for the use of their medical images, and for inclusion in this manuscript. Ethical committee approval was not required, as per Spanish law. Discussion EGFR mutations are present in 10–20% of Caucasian patients and about 50% of Asian patients with NSCLC [8]. The L858R point mutation in EGFR exon 21 identified in patient 1 at diagnosis is one of the most common “classical” EGFR mutations, along with a deletion in exon 19 [8]. Together, these mutations represent 85% of EGFR mutations. These activating mutations make the tumor sensitive to tyrosine kinase inhibitors (TKIs) and are an indication for choosing a TKI agent as first-line therapy [9], as occurred in patient 1. Indeed, current NSCLC guidelines note the importance of molecular tumor analysis in determining first-line therapy [9, 10]. In Europe, testing for mutations or rearrangements of ALK, c-ros oncogene 1 (ROS1), and EGFR is considered mandatory, and testing for BRAF V600E mutations is important in countries where BRAF/MEK inhibitors are approved. Other tests include those for human epidermal growth factor receptor 2 (HER2) and MET exon mutations and for fusion genes in RET and NTRK1, which are all are considered evolving biomarkers [10]. The US National Comprehensive Cancer Network guidelines recommend the biomarker test panel for non-squamous NSCLC should, at a minimum, include EGFR mutations, BRAF mutations, ALK fusions, ROS1 fusions, and PD-L1 expression [9]. A primary T790M mutation in EGFR exon 20 is a resistance mutation and more likely to coexist with an L858R mutation than with an exon 19 deletion [11]. While osimertinib has been shown to be effective in patients with a primary T790M mutation, as shown in patient 1, most patients with such mutations progress within 1 year of starting osimertinib [11]. Patient 1 also had high expression of PD-L1 as shown by a TPS of 80%. This suggests that this patient is a good candidate for immunotherapy, but guidelines recommend the use of targeted therapy first-line (before immunotherapy) in patients with sensitizing mutations because the response rate is likely to be higher [9]. Once targeted therapy fails, immunotherapy is indicated. ALK rearrangements are the driving mutations responsible for the development of NSCLC in 3–7% of patients, and, as observed in patient 2, these patients have a higher risk of developing brain metastases than those with other NSCLC subtypes [12]. The first-generation ALK inhibitor crizotinib, used for second-line treatment in patient 2, has antitumor advantages over chemotherapy in this subtype of patients; however, all patients eventually progress because of drug resistance [10]. Furthermore, the amount of crizotinib that crosses the blood–brain barrier is negligible, which limits its use in patients with brain metastases [10]. In patients with crizotinib-resistant ALK-rearranged NSCLC, one strategy is sequential treatment with next-generation ALK inhibitors, such as ceritinib, alectinib, or brigatinib [12], as used in patient 2. In the IMpower150 study, most patients had wild-type EGFR and ALK, but 10% of patients were EGFR-mutation positive and 8.5% were ALK-rearrangement positive [7]. IMpower150 is the only trial that has shown positive results with immunotherapy in patients with EGFR- or ALK-positive NSCLC [10]. OS in the population that included patients with these mutations receiving the atezolizumab + BCP regimen was 19.8 months, which was similar to that in the population excluding patients with these mutations (19.5 months), and significantly longer than in the BCP group (15.0 months for the whole population and 14.7 months for the EGFR and ALK wild-type population) [13]. In patients with EGFR mutations, OS was 29.4 months in the atezolizumab + BCP group and 18.1 months in the BCP group [13]. Median progression-free survival (PFS) in patients with EGFR mutations receiving the atezolizumab + BCP regimen was 9.7 months, similar to the PFS in patients with wild-type EGFR (8.3 months), and significantly longer than in the BCP group irrespective of EGFR mutation status (6.1 months and 6.8 months, respectively, in the EGFR mutation and wild-type groups receiving BCP) [7]. Similarly, median PFS was significantly longer in the atezolizumab + BCP group than in the placebo + BCP group in patients with KRAS mutations (8.1 vs. 5.8 months, respectively), as well as in those with wild-type KRAS (9.7 vs. 5.8 months) [7]. The number of mutations, as well as the type, may be relevant to treatment response to atezolizumab. Data suggest that the survival (PFS and OS) benefit of PD-L1 or PD-1 inhibitors may be more marked in patients with a high tumor mutation burden (TMB) than in those with low TMB [14–16], although this result was not seen in some trials [17, 18]. Recent data from randomized trials show that a blood-based assay for TMB can be a useful and valid biomarker for atezolizumab [19]. The cases of patients 3 and 4 illustrated the use of atezolizumab in patients with high disease burden, which was characterized by extensive metastases, including in the liver. In the IMPower150 study, 13% of patients had liver metastases, and atezolizumab + BCP significantly prolonged PFS and OS compared with placebo + BCP in patients with or without liver metastases [7, 20]. However, the difference in PFS and OS between the atezolizumab + BCP group and the BCP group was more marked in the cohort with liver metastases [7]. In the group with liver metastases, the PFS hazard ratio was 0.42 (median PFS 7.4 vs. 4.9 months for atezolizumab + BCP vs. placebo + BCP), whereas in the group without liver metastases the PFS hazard ratio was 0.63 (median PFS 8.3 vs. 7.0 months, respectively) [7]; the OS hazard ratio was 0.52 in the group with liver metastases (median OS 13.3 vs. 9.4 months for atezolizumab + BCP vs. placebo + BCP), and in the group without liver metastases the OS hazard ratio was 0.82 (median OS 20.4 vs. 17.0 months, respectively) [20]. In addition to liver metastases, patient 3 also had bone metastases, which are associated with significantly reduced survival in patients with NSCLC [21, 22]. Moreover, bone metastases are associated with significant pain, fatigue, and disturbed sleep [23], which may negatively affect the patient’s performance status. Indeed, this patient had an ECOG performance status of 2. The IMpower150 study excluded patients with ECOG performance status of 2 or higher [7]; however, data indicate that between one-third and one-half of patients with NSCLC have poor performance status (e.g., ECOG PS of 2 or higher) [24]. It is encouraging that patient 3, who had multiple metastatic sites including in the appendicular skeleton, was able to benefit from treatment with atezolizumab over a prolonged period before disease progression. The last case presented (patient 4) had both liver and brain metastases at the time of starting treatment with atezolizumab. Adenocarcinomas are the most common tumor type to metastasize to the CNS, and 30–64% of patients with NSCLC have CNS metastases [9, 10]. Historically, patients with brain metastases have had a particularly poor prognosis [25], although this is starting to change with the increasing availability of novel agents. However, patients with untreated brain metastases are usually excluded from clinical trials, many of which also exclude patients with treated brain metastases. Indeed, both the POPLAR study and IMPower150 excluded patients with untreated CNS metastases [5, 7], with neither study reporting on patients with treated brain metastases. Patient 4 described here received treatment of brain metastases with holocranial radiotherapy, and subsequently derived benefit from atezolizumab treatment. The positive CNS responses in this patient is consistent with findings reported in the OAK trial [6]. In this trial, which specified inclusion of patients with treated, asymptomatic supratentorial CNS metastases, subgroup analysis demonstrated a survival benefit with atezolizumab compared with docetaxel in patients with treated CNS metastases at baseline, with a hazard ratio of 0.54 [95% confidence interval (CI) 0.31–0.94] [6]. These findings for atezolizumab in patients with brain metastases are also consistent with those of a phase II study of pembrolizumab in patients with NSCLC (n = 18) or melanoma and untreated brain metastases, in which pembrolizumab demonstrated activity in brain metastases, with a response rate for brain metastasis of 33% among patients with NSCLC [26]. Although this case series provides valuable information regarding the practical clinical issues associated with atezolizumab + BCP treatment, more well-designed studies are needed to develop evidence-based recommendations on immunotherapy to guide oncologists, immunologists, and other specialists in the management of patients with mutated NSCLC. Conclusion As more becomes known about the importance of the various genetic mutations, rearrangements, and expression profiles in NSCLC, testing for targetable oncogenic alterations and immuno-oncology therapy biomarkers is becoming more and more essential for treatment decisions [10]. The first two patients discussed here suggest that the number and type of mutations may be relevant for guiding treatment decisions in NSCLC. To our knowledge, atezolizumab + BCP is the only immunotherapy combination that has demonstrated efficacy in patients with mutated NSCLC [7, 27], and these cases show that the results of these studies have been transferred to clinical practice. Another factor that should be considered when deciding upon a course of therapy is a patient’s performance status. However, clinical trials often exclude patients with poor performance status; hence, the second two cases described here of patients with NSCLC and high disease burden (patients 3 and 4), who benefited from atezolizumab-containing therapy over a prolonged period, are particularly encouraging. Finally, the CNS responses reported here suggest that atezolizumab + bevacizumab may be an important option for the significant unmet need of treating brain metastases in NSCLC. These observations provide valuable insights into the practical clinical issues associated with atezolizumab + BCP treatment in patients with advanced or metastatic NSCLC. These illustrative clinical cases may also help clinicians to identify patients with NSCLC who will potentially gain the most benefit from the use of atezolizumab + BCP in routine clinical practice. We thank the patients who allowed us to report their clinical details. Funding Medical writing assistance and the Rapid Service Fee for this manuscript were funded by Roche. Medical Writing Assistance We would like to thank Catherine Rees of Springer Healthcare Communications, and Marie Cheeseman, on behalf of Springer Healthcare Communications, who wrote the outline and first draft, respectively. This medical writing assistance was funded by Roche. Authorship All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. Compliance with Ethics Guidelines Data from these patients were collected in accordance with the Helsinki Declaration of 1964 and its later amendments, concerning human and animal rights. All patients provided written informed consent to all the diagnostic-therapeutic procedures, for the use of their medical images, and for inclusion in this manuscript. Ethical committee approval was not required, as per Spanish law. Disclosures Dr Cobo reports receiving advisory or consultancy fees from Roche, Bristol Myers Squibb, AstraZeneca, Pfizer, and Boehringer, and travel and accommodation funding from Roche, Bristol Myers Squibb, and AstraZeneca outside of the submitted work. Dr Rodríguez-Abreu reports receiving advisory or consultancy fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Pfizer, Boehringer, and Takeda, speaker’s fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Boehringer, and Takeda, and travel and accommodation funding from Roche, Merck, Bristol Myers Squibb, and AstraZeneca outside of the submitted work. Diego Pérez Parente is an employee of Roche Farma, Spain. Pedro Ruiz Gracia is an employee of Roche Farma, Spain. Dr González reports receiving advisory or consultancy fees from Roche, Bristol Myers Squibb, AstraZeneca, Boehringer, and Sanofi, speaker’s fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Lilly, and Ipsen, and travel and accommodation funding from Roche, Merck, Bristol Myers Squibb, and Lilly outside of the submitted work. Data Availability Qualified researchers may request access to individual patient level data through the clinical study data request platform (https://vivli.org/). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).	UNK UNK,2 CYCLIC	DrugDosageText	CC BY-NC	33582978	18,610,802	2021-06
What was the outcome of reaction 'Peripheral sensory neuropathy'?	Practical Issues in the Use of Atezolizumab for Patients with Non-Small Cell Lung Cancer: Case Reports and Literature Review. Atezolizumab is a monoclonal antibody targeting the programmed death ligand 1 (PD-L1) that was approved in 2017 in the USA and Europe for the second-line treatment of advanced or metastatic non-small cell lung cancer (NSCLC). This review article describes the practical clinical issues associated with atezolizumab treatment in NSCLC using a combination of four illustrative cases and a narrative literature review. The first two cases highlight the importance of tumor mutational status when making treatment decisions. A 62-year-old man with epidermal growth factor receptor (EGFR)-mutated, PD-L1-positive, stage IV lung adenocarcinoma received treatment with second-line atezolizumab + bevacizumab, carboplatin, and paclitaxel (BCP) after first-line osimertinib. In the second case, a 63-year-old man with stage IVb lung adenocarcinoma with anaplastic lymphoma kinase (ALK) translocation received sixth-line treatment with atezolizumab + BCP. The two final cases both had extensive metastases. A 55-year-old woman with EGFR-mutated lung adenocarcinoma received second-line treatment with atezolizumab + BCP after development of multiple metastases, followed by atezolizumab + bevacizumab until last follow-up. A 42-year-old man with PD-L1-positive pulmonary adenocarcinoma (negative for EGFR mutations) developed liver and brain metastases after several lines of therapy. He underwent holocranial radiation and received atezolizumab + BCP, which resulted in a decrease in all measurable and evaluable tumoral lesions. These illustrative cases indicate that the type and number of mutations may influence treatment response to atezolizumab, and that atezolizumab may provide clinical benefit in patients with high disease burden. Key Summary Points Why carry out this study? Targeted immunotherapies, such as atezolizumab, have improved overall survival in patients with advanced or metastatic non-small cell lung cancer (NSCLC) in clinical trials. Understanding how to treat patients on the basis of their targetable oncogenic mutations or those usually excluded from clinical trials (e.g., with treated brain metastases or high disease burden) is important for oncologists in the real-world clinical setting. Four cases of treatment with atezolizumab plus bevacizumab, carboplatin, and paclitaxel in patients with NSCLC after at least one previous line of targeted therapy are described to illustrate these clinical issues. What was learned from the study? The presented cases suggest that both the number and type of mutations may be relevant for guiding treatment decisions in NSCLC, and that patients with high disease burden or brain metastases may benefit from atezolizumab-containing therapy. Digital Features This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13521968. Introduction Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and has a high rate of mortality [1, 2]. According to global estimates, lung cancer was the most commonly diagnosed cancer in 2018 (11.6% of all new cases) and the leading cause of cancer-related mortality (18.4% of all cancer deaths) [3]. In a US analysis of patients with NSCLC, the median overall survival (OS) time after diagnosis was only 13 months, and the estimated 4-year survival rate was between 22% and 28% [1]. However, OS has been improving over recent decades as a result of novel treatments [1, 2], including targeted therapies and immunotherapies. One such novel treatment is atezolizumab, a monoclonal antibody targeting the programmed death ligand 1 (PD-L1) [4]. Atezolizumab was approved in the USA and Europe for the second-line treatment of advanced or metastatic NSCLC in 2017, based on the results of the phase II POPLAR study [5] and the phase III OAK study [6], in which atezolizumab was associated with significantly better survival compared with docetaxel. Since its approval, the IMpower150 study has demonstrated that atezolizumab in combination with bevacizumab, carboplatin, and paclitaxel (BCP) was more effective than BCP alone as first-line therapy in previously untreated patients with metastatic non-squamous NSCLC [7]. The current review describes the practical clinical issues associated with atezolizumab + BCP in patients with NSCLC, using a combination of illustrative case presentations and a narrative literature review. Cases Illustrating Role of Mutational Status Patient 1 A 62-year-old man with no relevant medical or surgical history was diagnosed with stage IIIC lung adenocarcinoma (cT3cN3cM0) in January 2018. He was a former smoker with a 15 pack-year history. Molecular testing showed an L858R point mutation in epidermal growth factor receptor (EGFR) exon 21 and a primary T790M mutation in EGFR exon 20. The tumor was PD-L1 positive, with a tumor proportion score (TPS) of 80% on immunohistochemistry (pharmDx 28–8; DAKO, Glostrup, Denmark). On February 1, 2018, he began first-line treatment with osimertinib; the 12-week assessment showed a partial response by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. Response continued until March 2019, when the disease progressed to stage IV with mediastinal and retroperitoneal involvement (Fig. 1a). At this time, the patient was asymptomatic and started second-line treatment with atezolizumab in combination with BCP, based on the results of the IMpower150 clinical trial [7]. After two cycles, a computed tomography (CT) scan showed partial response by RECIST 1.1 criteria (Fig. 1b), and the patient was able to receive six cycles without significant adverse events.Fig. 1 Patient 1: Computed tomography scan of chest on a March 25, 2019, showing mediastinal and retroperitoneal involvement, b June 6, 2019 after two cycles of atezolizumab + BCP, c October 5, 2019 indicating a maintained radiologic response, and d January 30, 2020 showing tumor progression after 13 weeks of maintenance atezolizumab + bevacizumab. BCP bevacizumab, carboplatin, and paclitaxel After confirming that the radiologic response was maintained (Fig. 1c), he continued maintenance treatment with atezolizumab + bevacizumab. In February 2020, after 13 cycles, tumor progression was noted (Fig. 1d) and treatment was discontinued. Biopsy showed amplification and overexpression of c-MET, so the patient initiated third-line treatment with telisotuzumab vedotin as part of a clinical trial (NCT03539536). Patient 2 A 63-year-old man was diagnosed with a stage IVb lung adenocarcinoma with a brain metastasis (T2N3M1b) in February 2013. He was a former smoker (20 pack-year history) with occupational exposure to oil and its derivatives. On June 13, 2013, he started induction chemotherapy with cisplatin + pemetrexed, undergoing radiosurgery for the brain lesion after the first cycle. He showed a partial radiologic and metabolic response after two cycles of cisplatin + pemetrexed, and a brain magnetic resonance imaging (MRI) revealed a reduction in the size of the brain metastasis. He received two cycles of cisplatin + pemetrexed from June 13 to June 24, 2013, followed by radical-intent chemoradiation between June 28 and September 6, 2013, consisting of a 60 Gy dose and two cycles of weekly paclitaxel + carboplatin; however, he was unable to continue this treatment because of sustained leukopenia. A follow-up assessment on October 6, 2014, found no signs of thoracoabdominal progression. Lesions consistent with metastases were identified in the cerebellar vermis and the right centrum semiovale; radiosurgery was administered using 20.7 Gy and 20.9 Gy, respectively, at these sites. A CT scan on January 12, 2015, showed hilar-mediastinal progression, and a biopsy of the left hilar adenopathy showed that the tumor had wild-type KRAS, was EGFR- and BRAF-mutation negative, and had an anaplastic lymphoma kinase (ALK) translocation. In February 2015, he started second-line treatment with crizotinib and had a partial response. A brain MRI performed on November 3, 2015, showed oligoprogression, for which he received radiosurgery. On April 4, 2016, he showed pulmonary progression, and 2 weeks later, he started third-line treatment with ceritinib as part of a clinical trial, with a best response of stable disease. A CT scan on January 30, 2018, showed an increase in the size of the space-occupying lesions in the brain. On March 6 of the same year, he initiated fourth-line treatment with alectinib for metastases, with a best response of stable disease. A further CT scan on July 23, 2018, showed left hilar adenopathy progression and left upper lobe atelectasis. He started fifth-line therapy for metastases with brigatinib on September 5, 2018, and stable disease was his best response. The patient developed left hemiparesis on January 16, 2019. A brain MRI on January 21 showed signs of radionecrosis, but an acute or subacute ischemic event could not be ruled out. Brain progression, with an increase in the size and number of lesions, was detected in March 2019 (Fig. 2a), and he received hippocampal-sparing whole brain radiation with focal boost (45 Gy dose) on the lesions.Fig. 2 Patient 2: brain magnetic resonance imaging scan results on a March 11, 2019, showing an increase in the size and number of brain lesions, and b March 22, 2020, after 4 cycles of atezolizumab + BCP followed by 13 cycles of maintenance atezolizumab + bevacizumab, and chest computed tomography scan results on c March 11, 2019, prior to, and d March 22, 2020, after atezolizumab-based treatment On May 8, 2019, he began sixth-line treatment with atezolizumab + BCP. After four cycles (ending on August 8, 2019), he started maintenance treatment with atezolizumab + bevacizumab, achieving a partial brain response. In March 2020, he had received 13 cycles of maintenance treatment, and he showed stable disease as assessed by brain MRI (Fig. 2b) and CT scans of the chest (Fig. 2c, d), abdomen, and pelvis. CASES Illustrating Management of High Disease Burden Patient 3 A 55-year-old non-smoking woman without known morbidity was diagnosed with a stage IIIB lung adenocarcinoma (cT4N2) in June 2016. She received treatment with external radiation therapy (dose administered, 66 Gy) concomitantly with cisplatin and vinorelbine (three cycles). A follow-up CT scan showed partial response and the multidisciplinary Committee on Thoracic Tumors recommended surgical intervention. She underwent video-assisted thoracic surgery consisting of an upper right pulmonary lobectomy with systematic hilar and mediastinal lymph node dissection on October 5, 2016. Molecular analysis of the excised tumor showed EGFR exon 19 deletion. In March 2018, disease progression was detected in lung, pleura, and bone, and in subcutaneous tissue and the lymphatic system. On March 27, she received palliative and decompressive radiation therapy of the lumbar spine (L5) at 8 Gy. Subsequently, in April 2018, she started treatment with afatinib at 40 mg/day, and had a partial response. Afatinib treatment continued until July 2019, when imaging identified disease progression in the liver and bone, and a sacral soft tissue mass (Fig. 3a). Analysis of liquid and sacral mass biopsy did not detect a resistant T790M mutation on EGFR exon 20.Fig. 3 Patient 3: Computed tomography of lumbosacral region on a July 4, 2019, before and b October 8, 2019, after three cycles of atezolizumab + BCP, showing partial response in the sacral soft tissue mass. BCP bevacizumab, carboplatin, and paclitaxel At this time, the patient’s Eastern Cooperative Oncology Group (ECOG) performance status was 2, and she was negative for PD-L1 (TPS 0%). On August 7, 2019, on the basis of the results of the IMpower150 clinical trial [7], she began second-line treatment with atezolizumab + BCP. After three cycles she showed a partial response (Fig. 3b), and was able to complete six cycles of treatment. However, the patient developed febrile neutropenia and sepsis due to central catheter-related infections in the second cycle leading to hospital admission; grade 2 sensory neuropathy that reverted to grade 1 after discontinuing paclitaxel and carboplatin; and grade 1 asthenia. She then continued treatment with atezolizumab + bevacizumab. By June 2020, she had completed 14 cycles of treatment without relevant toxicities, but treatment was interrupted at that time because a CT scan showed progression of the liver and bone metastases. Patient 4 A 42-year-old man was diagnosed with stage IIIB pulmonary adenocarcinoma (cT4N2M0) in June 2018; at this time, he had an ECOG performance status of 0. Molecular analysis showed the tumor was negative for EGFR mutations and ALK fusions, with PD-L1 expression on 30% of cancer cells. He was a smoker at the time of diagnosis, smoking one pack daily for 20 years (20 pack-years). On August 22, 2018, treatment with cisplatin, gemcitabine, and paclitaxel was started, for a total of four 21-day cycles. Treatment was well tolerated, with the exception of nausea and asthenia (both grade 1). Repeat CT scans performed in September 2018 after two treatment cycles, and again in November after four treatment cycles, revealed decreasing tumor volume, with mediastinal contact still present; at this time, results of a brain MRI were normal. In December 2018, the man underwent a right lower lobectomy; the right lower pulmonary lobe was found to have well-differentiated adenocarcinoma with an acinar pattern, without evidence of vascular invasion, and no visceral pleural infiltration. Surgical resection margins were not affected. TNM staging at this point was ypT1cN0M0. He subsequently received consolidative radiation therapy on the mediastinal bed; he had a performance status of 0 and no complications. In October 2019, a follow-up examination revealed a de novo pulmonary micronodule in the control CT scan, but this was not seen on a positron emission tomography–CT scan. In February 2020, repeat CT scans revealed a growth on the left perihilar pulmonary nodule and a new right-hand micronodule. Metastases were seen in several liver segments. As a result of mild dizziness, a central nervous system (CNS) MRI scan was performed in January 2020, revealing the presence of brain metastases (Fig. 4a).Fig. 4 Patient 4: Brain magnetic resonance imaging scan results in a January 2020 showing brain metastases and b April 2020 showing reduced lesion size after atezolizumab + BCP treatment. BCP bevacizumab, carboplatin, and paclitaxel Holocranial radiotherapy was administered, finishing at the beginning of February 2020. After 4 weeks, a repeat MRI did not show any significant changes in the size of the brain lesions. One month after discontinuing holocranial radiotherapy, in the second week of March 2020, he began treatment with four 21-day cycles of atezolizumab + BCP, followed by atezolizumab + bevacizumab until disease progression or toxicity. After two cycles, there were no notable toxicities, and an assessment performed at the end of April 2020 revealed a decrease in all measurable and evaluable tumoral lesions (Fig. 4b). By December 2020, 40 weeks after the start of atezolizumab + BCP, the patient was still in partial response and was being managed on chemotherapy-free maintenance treatment with atezolizumab + bevacizumab. Compliance with Ethics Guidelines Data on these patients were collected in accordance with the Helsinki Declaration of 1964 and its later amendments concerning human and animal rights. All patients provided written informed consent to all the diagnostic and therapeutic procedures, for the use of their medical images, and for inclusion in this manuscript. Ethical committee approval was not required, as per Spanish law. Discussion EGFR mutations are present in 10–20% of Caucasian patients and about 50% of Asian patients with NSCLC [8]. The L858R point mutation in EGFR exon 21 identified in patient 1 at diagnosis is one of the most common “classical” EGFR mutations, along with a deletion in exon 19 [8]. Together, these mutations represent 85% of EGFR mutations. These activating mutations make the tumor sensitive to tyrosine kinase inhibitors (TKIs) and are an indication for choosing a TKI agent as first-line therapy [9], as occurred in patient 1. Indeed, current NSCLC guidelines note the importance of molecular tumor analysis in determining first-line therapy [9, 10]. In Europe, testing for mutations or rearrangements of ALK, c-ros oncogene 1 (ROS1), and EGFR is considered mandatory, and testing for BRAF V600E mutations is important in countries where BRAF/MEK inhibitors are approved. Other tests include those for human epidermal growth factor receptor 2 (HER2) and MET exon mutations and for fusion genes in RET and NTRK1, which are all are considered evolving biomarkers [10]. The US National Comprehensive Cancer Network guidelines recommend the biomarker test panel for non-squamous NSCLC should, at a minimum, include EGFR mutations, BRAF mutations, ALK fusions, ROS1 fusions, and PD-L1 expression [9]. A primary T790M mutation in EGFR exon 20 is a resistance mutation and more likely to coexist with an L858R mutation than with an exon 19 deletion [11]. While osimertinib has been shown to be effective in patients with a primary T790M mutation, as shown in patient 1, most patients with such mutations progress within 1 year of starting osimertinib [11]. Patient 1 also had high expression of PD-L1 as shown by a TPS of 80%. This suggests that this patient is a good candidate for immunotherapy, but guidelines recommend the use of targeted therapy first-line (before immunotherapy) in patients with sensitizing mutations because the response rate is likely to be higher [9]. Once targeted therapy fails, immunotherapy is indicated. ALK rearrangements are the driving mutations responsible for the development of NSCLC in 3–7% of patients, and, as observed in patient 2, these patients have a higher risk of developing brain metastases than those with other NSCLC subtypes [12]. The first-generation ALK inhibitor crizotinib, used for second-line treatment in patient 2, has antitumor advantages over chemotherapy in this subtype of patients; however, all patients eventually progress because of drug resistance [10]. Furthermore, the amount of crizotinib that crosses the blood–brain barrier is negligible, which limits its use in patients with brain metastases [10]. In patients with crizotinib-resistant ALK-rearranged NSCLC, one strategy is sequential treatment with next-generation ALK inhibitors, such as ceritinib, alectinib, or brigatinib [12], as used in patient 2. In the IMpower150 study, most patients had wild-type EGFR and ALK, but 10% of patients were EGFR-mutation positive and 8.5% were ALK-rearrangement positive [7]. IMpower150 is the only trial that has shown positive results with immunotherapy in patients with EGFR- or ALK-positive NSCLC [10]. OS in the population that included patients with these mutations receiving the atezolizumab + BCP regimen was 19.8 months, which was similar to that in the population excluding patients with these mutations (19.5 months), and significantly longer than in the BCP group (15.0 months for the whole population and 14.7 months for the EGFR and ALK wild-type population) [13]. In patients with EGFR mutations, OS was 29.4 months in the atezolizumab + BCP group and 18.1 months in the BCP group [13]. Median progression-free survival (PFS) in patients with EGFR mutations receiving the atezolizumab + BCP regimen was 9.7 months, similar to the PFS in patients with wild-type EGFR (8.3 months), and significantly longer than in the BCP group irrespective of EGFR mutation status (6.1 months and 6.8 months, respectively, in the EGFR mutation and wild-type groups receiving BCP) [7]. Similarly, median PFS was significantly longer in the atezolizumab + BCP group than in the placebo + BCP group in patients with KRAS mutations (8.1 vs. 5.8 months, respectively), as well as in those with wild-type KRAS (9.7 vs. 5.8 months) [7]. The number of mutations, as well as the type, may be relevant to treatment response to atezolizumab. Data suggest that the survival (PFS and OS) benefit of PD-L1 or PD-1 inhibitors may be more marked in patients with a high tumor mutation burden (TMB) than in those with low TMB [14–16], although this result was not seen in some trials [17, 18]. Recent data from randomized trials show that a blood-based assay for TMB can be a useful and valid biomarker for atezolizumab [19]. The cases of patients 3 and 4 illustrated the use of atezolizumab in patients with high disease burden, which was characterized by extensive metastases, including in the liver. In the IMPower150 study, 13% of patients had liver metastases, and atezolizumab + BCP significantly prolonged PFS and OS compared with placebo + BCP in patients with or without liver metastases [7, 20]. However, the difference in PFS and OS between the atezolizumab + BCP group and the BCP group was more marked in the cohort with liver metastases [7]. In the group with liver metastases, the PFS hazard ratio was 0.42 (median PFS 7.4 vs. 4.9 months for atezolizumab + BCP vs. placebo + BCP), whereas in the group without liver metastases the PFS hazard ratio was 0.63 (median PFS 8.3 vs. 7.0 months, respectively) [7]; the OS hazard ratio was 0.52 in the group with liver metastases (median OS 13.3 vs. 9.4 months for atezolizumab + BCP vs. placebo + BCP), and in the group without liver metastases the OS hazard ratio was 0.82 (median OS 20.4 vs. 17.0 months, respectively) [20]. In addition to liver metastases, patient 3 also had bone metastases, which are associated with significantly reduced survival in patients with NSCLC [21, 22]. Moreover, bone metastases are associated with significant pain, fatigue, and disturbed sleep [23], which may negatively affect the patient’s performance status. Indeed, this patient had an ECOG performance status of 2. The IMpower150 study excluded patients with ECOG performance status of 2 or higher [7]; however, data indicate that between one-third and one-half of patients with NSCLC have poor performance status (e.g., ECOG PS of 2 or higher) [24]. It is encouraging that patient 3, who had multiple metastatic sites including in the appendicular skeleton, was able to benefit from treatment with atezolizumab over a prolonged period before disease progression. The last case presented (patient 4) had both liver and brain metastases at the time of starting treatment with atezolizumab. Adenocarcinomas are the most common tumor type to metastasize to the CNS, and 30–64% of patients with NSCLC have CNS metastases [9, 10]. Historically, patients with brain metastases have had a particularly poor prognosis [25], although this is starting to change with the increasing availability of novel agents. However, patients with untreated brain metastases are usually excluded from clinical trials, many of which also exclude patients with treated brain metastases. Indeed, both the POPLAR study and IMPower150 excluded patients with untreated CNS metastases [5, 7], with neither study reporting on patients with treated brain metastases. Patient 4 described here received treatment of brain metastases with holocranial radiotherapy, and subsequently derived benefit from atezolizumab treatment. The positive CNS responses in this patient is consistent with findings reported in the OAK trial [6]. In this trial, which specified inclusion of patients with treated, asymptomatic supratentorial CNS metastases, subgroup analysis demonstrated a survival benefit with atezolizumab compared with docetaxel in patients with treated CNS metastases at baseline, with a hazard ratio of 0.54 [95% confidence interval (CI) 0.31–0.94] [6]. These findings for atezolizumab in patients with brain metastases are also consistent with those of a phase II study of pembrolizumab in patients with NSCLC (n = 18) or melanoma and untreated brain metastases, in which pembrolizumab demonstrated activity in brain metastases, with a response rate for brain metastasis of 33% among patients with NSCLC [26]. Although this case series provides valuable information regarding the practical clinical issues associated with atezolizumab + BCP treatment, more well-designed studies are needed to develop evidence-based recommendations on immunotherapy to guide oncologists, immunologists, and other specialists in the management of patients with mutated NSCLC. Conclusion As more becomes known about the importance of the various genetic mutations, rearrangements, and expression profiles in NSCLC, testing for targetable oncogenic alterations and immuno-oncology therapy biomarkers is becoming more and more essential for treatment decisions [10]. The first two patients discussed here suggest that the number and type of mutations may be relevant for guiding treatment decisions in NSCLC. To our knowledge, atezolizumab + BCP is the only immunotherapy combination that has demonstrated efficacy in patients with mutated NSCLC [7, 27], and these cases show that the results of these studies have been transferred to clinical practice. Another factor that should be considered when deciding upon a course of therapy is a patient’s performance status. However, clinical trials often exclude patients with poor performance status; hence, the second two cases described here of patients with NSCLC and high disease burden (patients 3 and 4), who benefited from atezolizumab-containing therapy over a prolonged period, are particularly encouraging. Finally, the CNS responses reported here suggest that atezolizumab + bevacizumab may be an important option for the significant unmet need of treating brain metastases in NSCLC. These observations provide valuable insights into the practical clinical issues associated with atezolizumab + BCP treatment in patients with advanced or metastatic NSCLC. These illustrative clinical cases may also help clinicians to identify patients with NSCLC who will potentially gain the most benefit from the use of atezolizumab + BCP in routine clinical practice. We thank the patients who allowed us to report their clinical details. Funding Medical writing assistance and the Rapid Service Fee for this manuscript were funded by Roche. Medical Writing Assistance We would like to thank Catherine Rees of Springer Healthcare Communications, and Marie Cheeseman, on behalf of Springer Healthcare Communications, who wrote the outline and first draft, respectively. This medical writing assistance was funded by Roche. Authorship All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. Compliance with Ethics Guidelines Data from these patients were collected in accordance with the Helsinki Declaration of 1964 and its later amendments, concerning human and animal rights. All patients provided written informed consent to all the diagnostic-therapeutic procedures, for the use of their medical images, and for inclusion in this manuscript. Ethical committee approval was not required, as per Spanish law. Disclosures Dr Cobo reports receiving advisory or consultancy fees from Roche, Bristol Myers Squibb, AstraZeneca, Pfizer, and Boehringer, and travel and accommodation funding from Roche, Bristol Myers Squibb, and AstraZeneca outside of the submitted work. Dr Rodríguez-Abreu reports receiving advisory or consultancy fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Pfizer, Boehringer, and Takeda, speaker’s fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Boehringer, and Takeda, and travel and accommodation funding from Roche, Merck, Bristol Myers Squibb, and AstraZeneca outside of the submitted work. Diego Pérez Parente is an employee of Roche Farma, Spain. Pedro Ruiz Gracia is an employee of Roche Farma, Spain. Dr González reports receiving advisory or consultancy fees from Roche, Bristol Myers Squibb, AstraZeneca, Boehringer, and Sanofi, speaker’s fees from Roche, Merck, Bristol Myers Squibb, AstraZeneca, Lilly, and Ipsen, and travel and accommodation funding from Roche, Merck, Bristol Myers Squibb, and Lilly outside of the submitted work. Data Availability Qualified researchers may request access to individual patient level data through the clinical study data request platform (https://vivli.org/). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).	Recovering	ReactionOutcome	CC BY-NC	33582978	18,969,138	2021-06
What was the dosage of drug 'CHOLECALCIFEROL'?	Systemic Inflammatory Response Syndrome Secondary to Nitrofurantoin. Nitrofurantoin is considered optimal treatment for acute uncomplicated cystitis by the Infectious Diseases Society of America and is being increasingly recommended due to microbial resistance to sulfamethoxazole/trimethoprim and various fluoroquinolone antibiotics. Adverse effects of nitrofurantoin are generally considered mild, with gastrointestinal complaints being the most common. However, there have been isolated case reports describing a more severe systemic inflammatory response syndrome-like reaction, which leads to diagnostic challenges and treatment complications. We report the case of a patient with repeat episodes of systemic inflammatory response syndrome secondary to nitrofurantoin, which was initially attributed to recurrent urinary tract infections. Introduction Nitrofurantoin is considered optimal treatment for acute uncomplicated cystitis by the Infectious Diseases Society of America (IDSA) and is being increasingly recommended due to microbial resistance to sulfamethoxazole/trimethoprim and various fluoroquinolone antibiotics.1 Nitrofurantoin is also a commonly used medication for prophylaxis of acute urinary tract infections (UTIs). Gastrointestinal complaints, including nausea and vomiting, are the most commonly reported adverse events with nitrofurantoin.2 Although less common, more severe reactions including peripheral neuropathy, hemolytic anemia, hepatitis, cholestatic jaundice syndrome, interstitial lung disease, and pulmonary fibrosis have been described. Hypersensitivity reactions, including anaphylaxis and drug-induced fever, have also been documented after administration of nitrofurantoin.2,3 There have been isolated case reports describing systemic inflammatory response syndrome (SIRS) after nitrofurantoin administration with associated abrupt onset of fever, malaise, leukocytosis, and occasionally pleuritis.4-7 This often leads to a diagnostic challenge to determine if SIRS is due to transition to a more complicated UTI, such as acute pyelonephritis, or to a drug-associated adverse event. In this case report, the patient developed SIRS with abrupt onset of fever, leukocytosis, and hypotension in less than 24 hours after nitrofurantoin administration, which had been prescribed for uncomplicated urgency and frequency. Symptoms rapidly resolved after discontinuation of the medication. The patient developed similar symptoms of frequency and dysuria 2 months later, and was re-challenged with nitrofurantoin, which led to a similar episode of SIRS in less than 24 hours. Symptoms again rapidly resolved after discontinuing nitrofurantoin. All bacterial cultures were negative during both exposures to nitrofurantoin. Case Presentation This 58-year-old postmenopausal Caucasian female has a past medical history significant for hypothyroidism and cochlear hydrops and surgical history of partial thyroidectomy, cholecystectomy, benign breast nodule removal, adenoidectomy, and tonsillectomy. Home medications include levothyroxine 75 µg once daily, hydrochlorothiazide/triamterene 25 mg/37.5 mg once daily, a multivitamin once daily, and cholecalciferol 1000 units once daily. Her only known allergies are to yellowfin tuna and a possible reaction to shellfish. Family history was significant for type 2 diabetes mellitus and myocardial infarction in her mother and colon cancer in her father. The patient drinks alcohol socially, is a nonsmoker, and denies any illicit drug use. The patient reports that she had previously received sulfamethoxazole/trimethoprim for a previous uncomplicated UTI with no adverse events. After a hiking vacation in Yosemite National Park, the patient developed post-coital urgency and frequency, and was prescribed nitrofurantoin 100 mg twice daily for a UTI. The patient had no prior exposure to nitrofurantoin. In less than 24 hours after administration of the first dose of nitrofurantoin, the patient experienced an abrupt onset of fever, chills, lightheadedness, chest congestion, pleuritis, and generalized weakness. She presented to the emergency department at a local hospital and was found to be hypotensive with a blood pressure of 90/51 mm Hg, febrile with a temperature of 101.7 °F, but with normal oxygen saturations at 96% on room air. She required 2 L of normal saline solution to stabilize her blood pressure. Blood and urine cultures were drawn, and she was given 1 g of ceftriaxone IV (intravenous) and ondansetron 4 mg IV. The complete blood count (CBC) was remarkable for leukocytosis with white blood cell (WBC) count of 17.1 × 103/µL with 83% segs and 9% bands. The complete metabolic panel (CMP) was only remarkable for a potassium level of 3.4 mmol/L. Lactate was within normal limits at 1.4 mmol/L. Urinalysis showed 2+ blood, trace leukocyte esterase, 5 to 10 WBCs, 0 to 4 red blood cells, and 1+ bacteria. Blood and urine cultures were collected prior to administration of parenteral antibiotic and subsequently were negative. She was discharged from the local emergency department with a prescription for levofloxacin for suspected acute pyelonephritis. However, all symptoms improved within 24 hours of discharge. The patient completed the 7-day course of levofloxacin. On return home, an extensive workup was completed by her primary care physician due to her travel history and severity of symptoms. The CBC, CMP, C-reactive protein, and erythrocyte sedimentation rate were within normal limits. Lyme disease serology, Lyme immunoglobulin M (IgM), Lyme IgG, Borrelia burgdorferi C6 peptide antibody (Ab) total, and CD 57 for Lyme disease were all negative. Ehrlichia, Rocky Mountain spotted fever, and West Nile virus IgG and IgM antibodies were all negative. The symptoms at that time were attributed to a likely bacterial infection, presumably the UTI. Two months later, the patient experienced another episode of post-coital urinary frequency and urgency and took nitrofurantoin 100 mg twice daily over a 24-hour period. The next morning, the patient experienced an abrupt onset of fevers, chills, myalgia, pleuritis, and weakness, as well as nausea and vomiting. She presented to her primary care physician with a temperature of 102.6 °F, hypotension with a systolic blood pressure of 80 mm Hg, tachycardia with heart rate of 120 beats per minute, and was tilt test positive. She did not have a rash or urticaria and was fully alert and oriented. Her physical examination was unremarkable, except for generalized body aches. She received 2 L of normal saline to stabilize her blood pressure and was prescribed levofloxacin after blood and urine cultures were obtained. Her CBC was remarkable for a WBC count of 22 000 × 103/µL with 94% granulocytes. Urinalysis showed 500 leu/µL and 250 Ery/µL. CMP was only remarkable for a potassium level of 3.2 mmol/L. Within 24 hours, symptoms had resolved once again. The patient returned to her primary care provider and was afebrile and normotensive. A repeat CBC was performed, and her WBC had decreased to 8.5 × 103/µL, although the percentage of granulocytes was still elevated at 86.6%. Her hemoglobin had decreased from 12 g/dL to 10 g/dL and hematocrit had decreased from 38% to 34%. Platelets decreased from 138 × 103/µL to 128 × 103/µL. The patient’s D-dimer was slightly elevated at 0.6 (ref < 0.4). Partial thromboplastin time and international normalized ratio were unremarkable. Haptoglobin was also within normal limits at 191 mg/dL. Repeat CMP was only remarkable for a potassium level of 3.0 mmol/L. Within 48 hours, the patient’s WBC differential was within normal limits. The patient recognized that she had taken nitrofurantoin both times shortly before the onset of symptoms and reported this to her primary care provider when returning the second day for follow-up examination and blood work. Because all cultures drawn during these 2 occurrences were negative and her symptoms quickly resolved after discontinuation of nitrofurantoin, her SIRS symptoms were believed to be secondary to an adverse drug reaction to nitrofurantoin. Levofloxacin was discontinued. The patient was advised to avoid nitrofurantoin use in the future and nitrofurantoin was listed it as an adverse drug reaction (SIRS) in medical records to prevent recurrence of this reaction. The application of the Naranjo scale (Table 1) identifies this reaction to nitrofurantoin as a definite adverse drug reaction, with a score ≥9.8 Table 1. Naranjo ADR Probability Scalea,8. Yes No Do not know Case report patient score 1. Are there previous conclusive reports on this reaction? +1 0 0 +1 2. Did the adverse event appear after the suspected drug was administered? +2 −1 0 +2 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? +1 0 0 +1 4. Did the adverse reaction reappear when the drug was re-administered? +2 −1 0 +2 5. Are there alternative causes (other than the drug) that could on their own have caused the reaction? −1 +2 0 +2 6. Did the reaction reappear when a placebo was given? −1 +1 0 +1 7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? +1 0 0 0 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +1 0 0 0 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1 0 0 +1 10. Was the adverse event confirmed by any objective evidence? +1 0 0 +1 Total score 11 a Score interpretation8: ≥9, definite adverse drug reaction; 5-8, probable adverse drug reaction; 1-4, possible adverse drug reaction; 0, doubtful adverse drug reaction. Discussion Only a few other case reports could be found in the literature, which explicitly document a similar type of reaction to nitrofurantoin as the patient discussed in this case report. Forster and colleagues4 reported a 77-year-old male patient with bladder cancer status post-radical cystoprostatectomy and ileostomy who was treated with nitrofurantoin prophylaxis for recurrent UTIs. Two weeks after beginning nitrofurantoin therapy, the patient presented to the emergency room with fever, chills, and leukocytosis, which led to a broadening of antibiotic coverage to include tigecycline and aztreonam. The patient was restarted on nitrofurantoin 2 additional times and experienced SIRS each time, which resolved when the nitrofurantoin was discontinued, similar to our patient.4 In a report published by Gandotra and colleagues,5 a 74-year-old female was treated with nitrofurantoin for a UTI based on local antibiogram results and a urine culture positive for Escherichia coli and subsequently experienced chills, fever, tachypnea, and tachycardia. In this particular case report, the patient also developed a left bundle branch block and transaminitis. The patient was re-dosed with nitrofurantoin 2 different times during the same week and experienced SIRS each time, with resolution of symptoms after discontinuation of nitrofurantoin.5 Gohar and colleagues6 reported a case of SIRS due to nitrofurantoin use in an 83-year-old female with a history of recurrent UTIs. Within a few hours of receiving nitrofurantoin, the patient developed lethargy, chills, and fever and was treated with presumed sepsis secondary to UTI. After completing treatment with a cephalosporin antibiotic, the patient was restarted on nitrofurantoin for UTI prophylaxis, and developed recurrent malaise, chills, and fever. With no evidence of infection and return of hemodynamic stability after discontinuation of nitrofurantoin, the patient was discharged home and advised against the use of future use of nitrofurantoin.6 In one final case reported by Hospital Medicine, a 79-year-old woman with a history of recurrent UTIs presented with a 1-week history of fever, chills, nausea, vomiting, and abdominal discomfort after treatment with nitrofurantoin for a UTI. With negative cultures, no signs of infection, and symptomatic improvement after nitrofurantoin discontinuation, it was determined that nitrofurantoin was the likely cause of symptoms.7 Bäck and colleagues also discussed a similar clinical syndrome to our patient. In this study, 18 patients who received nitrofurantoin developed hypersensitivity including fever, cough, malaise, pleuritis, leukocytosis, and occasionally eosinophilia. They were analyzed for various antibodies and for lymphocyte transformation. This patient population was compared with a control group of 33 patients who received nitrofurantoin but did not develop hypersensitivity reactions. Ten of the hypersensitive patients were positive for the lymphocyte transformation test. IgE antibodies were negative in both groups; however, both groups developed IgG antibodies and the hypersensitive patients had higher titers. This study concluded that there seems to be an association between high IgG antibody titers and nitrofurantoin sensitivity.9 SIRS is one of several hypersensitivity reactions rarely reported with the use of nitrofurantoin. Anaphylaxis may also occur after administration of nitrofurantoin, which is a rare but severe allergic reaction which typically results in rash, swelling of tongue or throat, shortness of breath, and hypotension. Although the patient described in this case developed hypotension, she showed no other signs that would lead physicians to believe this was an anaphylactic reaction. The presence of fever in this case further distinguishes SIRS from an anaphylactic reaction, as fever is not a sign of anaphylaxis. Conclusion Nitrofurantoin is widely available and commonly prescribed for the prophylaxis and treatment of UTIs. With increased utilization of this medication, rare adverse reactions such as SIRS may occur more frequently. The exact mechanism leading to these rare adverse effects, including SIRS, is not completely understood. Understanding these pathways will help clinicians tailor antibiotic choices for patients and minimize adverse effects. SIRS like symptoms can easily complicate the clinical picture for a patient prescribed nitrofurantoin, especially in the inpatient setting where patients may have several medical comorbidities. A drug reaction of this type could easily be mistaken for a new-onset bacterial infection or worsening of a previous infection, leading to additional and unnecessary antibiotics. A better understanding of the immunologic reactions to nitrofurantoin is needed in order to properly identify these drug reactions and avoid unnecessary tests and therapies. Few articles exist that document a SIRS type reaction to nitrofurantoin; however, it appears it may be a more common phenomenon than previously thought. More research is needed to better understand this phenomenon and bring awareness to this particular type of adverse reaction to nitrofurantoin. The patient gave informed consent for the case report to be written and submitted for publication. This material is the result of work supported with the resources and the use of facilities at the Veterans Affairs Medical Center, Memphis, TN. The contents do not represent the view of the US Department of Veterans Affairs or the US government. Authors’ Note: Prior abstract presentation: Wagner M, Wall BM. Systemic inflammatory response syndrome secondary to nitrofurantoin [abstract]. Southern Regional Meeting Program At-a-Glance. New Orleans, LA; February 18, 2016. Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series. Informed Consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article. ORCID iD: Molly R. McGarry https://orcid.org/0000-0003-0052-9222	1000 UNITS ONCE DAILY	DrugDosageText	CC BY-NC	33583214	19,138,340	2021
What was the outcome of reaction 'Systemic inflammatory response syndrome'?	Systemic Inflammatory Response Syndrome Secondary to Nitrofurantoin. Nitrofurantoin is considered optimal treatment for acute uncomplicated cystitis by the Infectious Diseases Society of America and is being increasingly recommended due to microbial resistance to sulfamethoxazole/trimethoprim and various fluoroquinolone antibiotics. Adverse effects of nitrofurantoin are generally considered mild, with gastrointestinal complaints being the most common. However, there have been isolated case reports describing a more severe systemic inflammatory response syndrome-like reaction, which leads to diagnostic challenges and treatment complications. We report the case of a patient with repeat episodes of systemic inflammatory response syndrome secondary to nitrofurantoin, which was initially attributed to recurrent urinary tract infections. Introduction Nitrofurantoin is considered optimal treatment for acute uncomplicated cystitis by the Infectious Diseases Society of America (IDSA) and is being increasingly recommended due to microbial resistance to sulfamethoxazole/trimethoprim and various fluoroquinolone antibiotics.1 Nitrofurantoin is also a commonly used medication for prophylaxis of acute urinary tract infections (UTIs). Gastrointestinal complaints, including nausea and vomiting, are the most commonly reported adverse events with nitrofurantoin.2 Although less common, more severe reactions including peripheral neuropathy, hemolytic anemia, hepatitis, cholestatic jaundice syndrome, interstitial lung disease, and pulmonary fibrosis have been described. Hypersensitivity reactions, including anaphylaxis and drug-induced fever, have also been documented after administration of nitrofurantoin.2,3 There have been isolated case reports describing systemic inflammatory response syndrome (SIRS) after nitrofurantoin administration with associated abrupt onset of fever, malaise, leukocytosis, and occasionally pleuritis.4-7 This often leads to a diagnostic challenge to determine if SIRS is due to transition to a more complicated UTI, such as acute pyelonephritis, or to a drug-associated adverse event. In this case report, the patient developed SIRS with abrupt onset of fever, leukocytosis, and hypotension in less than 24 hours after nitrofurantoin administration, which had been prescribed for uncomplicated urgency and frequency. Symptoms rapidly resolved after discontinuation of the medication. The patient developed similar symptoms of frequency and dysuria 2 months later, and was re-challenged with nitrofurantoin, which led to a similar episode of SIRS in less than 24 hours. Symptoms again rapidly resolved after discontinuing nitrofurantoin. All bacterial cultures were negative during both exposures to nitrofurantoin. Case Presentation This 58-year-old postmenopausal Caucasian female has a past medical history significant for hypothyroidism and cochlear hydrops and surgical history of partial thyroidectomy, cholecystectomy, benign breast nodule removal, adenoidectomy, and tonsillectomy. Home medications include levothyroxine 75 µg once daily, hydrochlorothiazide/triamterene 25 mg/37.5 mg once daily, a multivitamin once daily, and cholecalciferol 1000 units once daily. Her only known allergies are to yellowfin tuna and a possible reaction to shellfish. Family history was significant for type 2 diabetes mellitus and myocardial infarction in her mother and colon cancer in her father. The patient drinks alcohol socially, is a nonsmoker, and denies any illicit drug use. The patient reports that she had previously received sulfamethoxazole/trimethoprim for a previous uncomplicated UTI with no adverse events. After a hiking vacation in Yosemite National Park, the patient developed post-coital urgency and frequency, and was prescribed nitrofurantoin 100 mg twice daily for a UTI. The patient had no prior exposure to nitrofurantoin. In less than 24 hours after administration of the first dose of nitrofurantoin, the patient experienced an abrupt onset of fever, chills, lightheadedness, chest congestion, pleuritis, and generalized weakness. She presented to the emergency department at a local hospital and was found to be hypotensive with a blood pressure of 90/51 mm Hg, febrile with a temperature of 101.7 °F, but with normal oxygen saturations at 96% on room air. She required 2 L of normal saline solution to stabilize her blood pressure. Blood and urine cultures were drawn, and she was given 1 g of ceftriaxone IV (intravenous) and ondansetron 4 mg IV. The complete blood count (CBC) was remarkable for leukocytosis with white blood cell (WBC) count of 17.1 × 103/µL with 83% segs and 9% bands. The complete metabolic panel (CMP) was only remarkable for a potassium level of 3.4 mmol/L. Lactate was within normal limits at 1.4 mmol/L. Urinalysis showed 2+ blood, trace leukocyte esterase, 5 to 10 WBCs, 0 to 4 red blood cells, and 1+ bacteria. Blood and urine cultures were collected prior to administration of parenteral antibiotic and subsequently were negative. She was discharged from the local emergency department with a prescription for levofloxacin for suspected acute pyelonephritis. However, all symptoms improved within 24 hours of discharge. The patient completed the 7-day course of levofloxacin. On return home, an extensive workup was completed by her primary care physician due to her travel history and severity of symptoms. The CBC, CMP, C-reactive protein, and erythrocyte sedimentation rate were within normal limits. Lyme disease serology, Lyme immunoglobulin M (IgM), Lyme IgG, Borrelia burgdorferi C6 peptide antibody (Ab) total, and CD 57 for Lyme disease were all negative. Ehrlichia, Rocky Mountain spotted fever, and West Nile virus IgG and IgM antibodies were all negative. The symptoms at that time were attributed to a likely bacterial infection, presumably the UTI. Two months later, the patient experienced another episode of post-coital urinary frequency and urgency and took nitrofurantoin 100 mg twice daily over a 24-hour period. The next morning, the patient experienced an abrupt onset of fevers, chills, myalgia, pleuritis, and weakness, as well as nausea and vomiting. She presented to her primary care physician with a temperature of 102.6 °F, hypotension with a systolic blood pressure of 80 mm Hg, tachycardia with heart rate of 120 beats per minute, and was tilt test positive. She did not have a rash or urticaria and was fully alert and oriented. Her physical examination was unremarkable, except for generalized body aches. She received 2 L of normal saline to stabilize her blood pressure and was prescribed levofloxacin after blood and urine cultures were obtained. Her CBC was remarkable for a WBC count of 22 000 × 103/µL with 94% granulocytes. Urinalysis showed 500 leu/µL and 250 Ery/µL. CMP was only remarkable for a potassium level of 3.2 mmol/L. Within 24 hours, symptoms had resolved once again. The patient returned to her primary care provider and was afebrile and normotensive. A repeat CBC was performed, and her WBC had decreased to 8.5 × 103/µL, although the percentage of granulocytes was still elevated at 86.6%. Her hemoglobin had decreased from 12 g/dL to 10 g/dL and hematocrit had decreased from 38% to 34%. Platelets decreased from 138 × 103/µL to 128 × 103/µL. The patient’s D-dimer was slightly elevated at 0.6 (ref < 0.4). Partial thromboplastin time and international normalized ratio were unremarkable. Haptoglobin was also within normal limits at 191 mg/dL. Repeat CMP was only remarkable for a potassium level of 3.0 mmol/L. Within 48 hours, the patient’s WBC differential was within normal limits. The patient recognized that she had taken nitrofurantoin both times shortly before the onset of symptoms and reported this to her primary care provider when returning the second day for follow-up examination and blood work. Because all cultures drawn during these 2 occurrences were negative and her symptoms quickly resolved after discontinuation of nitrofurantoin, her SIRS symptoms were believed to be secondary to an adverse drug reaction to nitrofurantoin. Levofloxacin was discontinued. The patient was advised to avoid nitrofurantoin use in the future and nitrofurantoin was listed it as an adverse drug reaction (SIRS) in medical records to prevent recurrence of this reaction. The application of the Naranjo scale (Table 1) identifies this reaction to nitrofurantoin as a definite adverse drug reaction, with a score ≥9.8 Table 1. Naranjo ADR Probability Scalea,8. Yes No Do not know Case report patient score 1. Are there previous conclusive reports on this reaction? +1 0 0 +1 2. Did the adverse event appear after the suspected drug was administered? +2 −1 0 +2 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? +1 0 0 +1 4. Did the adverse reaction reappear when the drug was re-administered? +2 −1 0 +2 5. Are there alternative causes (other than the drug) that could on their own have caused the reaction? −1 +2 0 +2 6. Did the reaction reappear when a placebo was given? −1 +1 0 +1 7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? +1 0 0 0 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +1 0 0 0 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1 0 0 +1 10. Was the adverse event confirmed by any objective evidence? +1 0 0 +1 Total score 11 a Score interpretation8: ≥9, definite adverse drug reaction; 5-8, probable adverse drug reaction; 1-4, possible adverse drug reaction; 0, doubtful adverse drug reaction. Discussion Only a few other case reports could be found in the literature, which explicitly document a similar type of reaction to nitrofurantoin as the patient discussed in this case report. Forster and colleagues4 reported a 77-year-old male patient with bladder cancer status post-radical cystoprostatectomy and ileostomy who was treated with nitrofurantoin prophylaxis for recurrent UTIs. Two weeks after beginning nitrofurantoin therapy, the patient presented to the emergency room with fever, chills, and leukocytosis, which led to a broadening of antibiotic coverage to include tigecycline and aztreonam. The patient was restarted on nitrofurantoin 2 additional times and experienced SIRS each time, which resolved when the nitrofurantoin was discontinued, similar to our patient.4 In a report published by Gandotra and colleagues,5 a 74-year-old female was treated with nitrofurantoin for a UTI based on local antibiogram results and a urine culture positive for Escherichia coli and subsequently experienced chills, fever, tachypnea, and tachycardia. In this particular case report, the patient also developed a left bundle branch block and transaminitis. The patient was re-dosed with nitrofurantoin 2 different times during the same week and experienced SIRS each time, with resolution of symptoms after discontinuation of nitrofurantoin.5 Gohar and colleagues6 reported a case of SIRS due to nitrofurantoin use in an 83-year-old female with a history of recurrent UTIs. Within a few hours of receiving nitrofurantoin, the patient developed lethargy, chills, and fever and was treated with presumed sepsis secondary to UTI. After completing treatment with a cephalosporin antibiotic, the patient was restarted on nitrofurantoin for UTI prophylaxis, and developed recurrent malaise, chills, and fever. With no evidence of infection and return of hemodynamic stability after discontinuation of nitrofurantoin, the patient was discharged home and advised against the use of future use of nitrofurantoin.6 In one final case reported by Hospital Medicine, a 79-year-old woman with a history of recurrent UTIs presented with a 1-week history of fever, chills, nausea, vomiting, and abdominal discomfort after treatment with nitrofurantoin for a UTI. With negative cultures, no signs of infection, and symptomatic improvement after nitrofurantoin discontinuation, it was determined that nitrofurantoin was the likely cause of symptoms.7 Bäck and colleagues also discussed a similar clinical syndrome to our patient. In this study, 18 patients who received nitrofurantoin developed hypersensitivity including fever, cough, malaise, pleuritis, leukocytosis, and occasionally eosinophilia. They were analyzed for various antibodies and for lymphocyte transformation. This patient population was compared with a control group of 33 patients who received nitrofurantoin but did not develop hypersensitivity reactions. Ten of the hypersensitive patients were positive for the lymphocyte transformation test. IgE antibodies were negative in both groups; however, both groups developed IgG antibodies and the hypersensitive patients had higher titers. This study concluded that there seems to be an association between high IgG antibody titers and nitrofurantoin sensitivity.9 SIRS is one of several hypersensitivity reactions rarely reported with the use of nitrofurantoin. Anaphylaxis may also occur after administration of nitrofurantoin, which is a rare but severe allergic reaction which typically results in rash, swelling of tongue or throat, shortness of breath, and hypotension. Although the patient described in this case developed hypotension, she showed no other signs that would lead physicians to believe this was an anaphylactic reaction. The presence of fever in this case further distinguishes SIRS from an anaphylactic reaction, as fever is not a sign of anaphylaxis. Conclusion Nitrofurantoin is widely available and commonly prescribed for the prophylaxis and treatment of UTIs. With increased utilization of this medication, rare adverse reactions such as SIRS may occur more frequently. The exact mechanism leading to these rare adverse effects, including SIRS, is not completely understood. Understanding these pathways will help clinicians tailor antibiotic choices for patients and minimize adverse effects. SIRS like symptoms can easily complicate the clinical picture for a patient prescribed nitrofurantoin, especially in the inpatient setting where patients may have several medical comorbidities. A drug reaction of this type could easily be mistaken for a new-onset bacterial infection or worsening of a previous infection, leading to additional and unnecessary antibiotics. A better understanding of the immunologic reactions to nitrofurantoin is needed in order to properly identify these drug reactions and avoid unnecessary tests and therapies. Few articles exist that document a SIRS type reaction to nitrofurantoin; however, it appears it may be a more common phenomenon than previously thought. More research is needed to better understand this phenomenon and bring awareness to this particular type of adverse reaction to nitrofurantoin. The patient gave informed consent for the case report to be written and submitted for publication. This material is the result of work supported with the resources and the use of facilities at the Veterans Affairs Medical Center, Memphis, TN. The contents do not represent the view of the US Department of Veterans Affairs or the US government. Authors’ Note: Prior abstract presentation: Wagner M, Wall BM. Systemic inflammatory response syndrome secondary to nitrofurantoin [abstract]. Southern Regional Meeting Program At-a-Glance. New Orleans, LA; February 18, 2016. Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series. Informed Consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article. ORCID iD: Molly R. McGarry https://orcid.org/0000-0003-0052-9222	Recovered	ReactionOutcome	CC BY-NC	33583214	19,138,340	2021
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Selenium deficiency'.	Refractory Hypotension Caused by Selenium Deficiency in a Patient on Peritoneal Dialysis. Selenium is essential for human health; its deficiency leads to cardiac dysfunction. We herein report a 79-year-old man on peritoneal dialysis who presented with refractory hypotension caused by selenium deficiency. He was admitted to our hospital with bacterial pneumonia and hypotension and abnormal electrocardiogram (ECG) findings. Despite improvement of pneumonia, his hypotension continued, and intravenous noradrenalin could not be discontinued. His serum selenium level was extremely low, and he was started on intravenous selenium. His hypotension and ECG findings gradually improved, and noradrenalin was discontinued. Physicians should consider selenium deficiency when patients on peritoneal dialysis show refractory hypotension. Introduction Selenium is a trace element that is necessary for many bodily processes, including thyroid hormone metabolism, DNA synthesis, reproduction, and protection from oxidative damage and infection (1). Therefore, selenium is essential for human health, and its deficiency is related to diseases such as hypothyroidism, deforming arthritis, and cardiovascular diseases (2). We herein report a peritoneal dialysis patient who presented with refractory hypotension and abnormal electrocardiogram (ECG) findings caused by selenium deficiency. His refractory hypotension was successfully treated with intravenous selenium administration. Case Report A 79-year-old Japanese man on peritoneal dialysis (PD) was hospitalized because of bacterial pneumonia and hypotension. His medical history included hypertension, ischemic heart disease, aortic dissection, gout, cerebral infarction, chronic heart failure, and chronic kidney disease caused by nephrosclerosis. His blood pressure had been controlled at 110-130 mmHg. He had taken esomeprazole, pitavastatin, nicorandil, cilostazol, clopidogrel, carvedilol, and amiodarone. He had been on peritoneal dialysis for eight years and he had been repeatedly hospitalized for heart failure caused by left ventricular (LV) dysfunction due to ischemic heart disease. He had been treated with ultrafiltration by peritoneal dialysis every time. With the decline in physical strength, his food intake had gradually decreased over the past year. On admission, a physical examination showed blood pressure of 66/42 mmHg, heart rate of 89 beats/min, temperature of 37.3 °C, and SpO2 of 91% (room air). His body weight could not be measured because of deterioration of his general condition. He was conscious and had no edema. Right chest coarse crackles were identified. His laboratory findings were as follows: white blood cell (WBC) 5,900/μL, red blood cell (RBC) 2.84×104/μL, hemoglobin (Hb) 8.4 g/dL, hematocrit (Ht) 26.1%, platelet (Plt) 16.3×104/μL, albumin 1.9 g/dL, blood urea nitrogen 39.4 mg/dL, creatinine 4.86 mg/dL, brain natriuretic peptide (BNP) 1967.5 pg/mL, and C-reactive protein (CRP) 10.90 mg/dL. Chest X-ray showed infiltration on the right side. Computed tomography showed patchy shadows in the bilateral lungs, and pleural effusion and atelectasis were observed in the right lung. Echocardiography showed diffuse hypokinesis of the left ventricle and a left ventricular ejection fraction of 40%, as before (2014: 68.1%, 2015: 75.9%, 2017: 75%, 2018: 68%, 2019: 48%). Bronchial pneumonia and heart failure were diagnosed, and he was treated with intravenous tazobactam/piperacillin and intravenous noradrenalin. His sputum culture was positive for Klebsiella pneumoniae, and two sets of blood culture were negative. His PD menu was daily extraneal and APD (1.5% reguneal 3 times) at night. Three months before admission, his peritoneal equivalent test (PET) category had shown a low average. After admission, his APD menu was changed to 2.5% fluid intended to increase ultrafiltration to improve overhydration. Although his general condition improved gradually, his volume overload and hypotension persisted. To determine why his hypotension persisted, his serum vitamin B1 level was measured, and vitamin B1 was administered, but it did not improve his condition. Several days later, his serum vitamin B1 level was reported as being in the normal range (4.9 μg/dL). Based on these findings and his abnormal ECG findings (Fig. 1), we investigated the possibility of selenium deficiency. His serum selenium level (reference range: 10.6-17.4 μg/dL) was then checked and was found to be extremely low (7.0 μg/dL) (Fig. 2). Sodium selenite injection (Fujimoto Pharmaceutical Corporation, Matsubara, Japan) 100 μg/day was then given intravenously; his blood pressure gradually increased, and intravenous noradrenalin was able to be discontinued five days after selenium administration (Fig. 2). Interestingly, his fluid removal by PD ultrafiltration increased after selenium administration, and his pulmonary congestion and serum BNP level also improved (Fig. 2). Since we were unable to estimate the serum selenium level after selenium administration, and there was concern about overcorrection (3), selenium administration was stopped on day 35. Discontinuation for 1 week resulted in a significant decrease in the serum selenium concentration (9.8 to 8.5 μg/dL). Intravenous selenium was then re-started, and an elevated serum selenium level was confirmed 4 days after administration (8.5 to 10.0 μg/dL). Figure 1. Electrocardiogram findings two months before admission and before and after treatment with intravenous selenium. Figure 2. Clinical course of the present case. BNP: brain natriuretic peptide, dBP: diastolic blood pressure, sBP: systolic blood pressure Selenium deficiency often causes ECG changes (4), and this case also showed abnormal ECG findings that improved after selenium administration (Fig. 1). The patient's general condition improved, and he was transferred to another hospital for rehabilitation on day 48. Discussion A case of refractory hypotension with abnormal ECG findings that was diagnosed as selenium deficiency was described. The patient's hypotension and pulmonary congestion were successfully treated with intravenous selenium administration. Hypotension can be caused by vitamin B1 deficiency, anemia, hypoalbuminemia, infectious state, and myocarditis. However, the patient's hemoglobin, albumin, and CRP levels did not change markedly after the improvement of hypotension (Fig. 1), and two sets of blood culture were negative. His serum vitamin B1 levels were also normal. As we did not perform a myocardial biopsy, we were unable to exclude the possibility of acute or chronic myocarditis. However, hypotension and his ECG finding improved just after selenium supplementation without intervention of myocarditis. Based on these findings, we diagnosed the cause of his hypotension as selenium deficiency. Historically, selenium deficiency has been famous for causing Keshan disease, which can lead to cardiac dysfunction (4,5). Keshan disease is an endemic cardiomyopathy occurring in low-selenium areas of China (5). The main clinical features are cardiac dysfunction and electrocardiographic changes. The present patient showed refractory hypotension and abnormal electrocardiogram findings that improved after intravenous selenium administration. Based on this clinical course and the diagnostic criteria for selenium deficiency (6), his hemodynamic instability was attributed to selenium deficiency. The present patient had several risks for selenium deficiency, including receiving total parenteral nutrition (TPN) and chronic kidney disease (CKD). In addition, the PD also likely contributed to selenium deficiency. A previous study evaluated the nutritional status in end-stage kidney disease (ESKD) patients before and six months after renal replacement therapy (hemodialysis or peritoneal dialysis) or renal transplantation (7). Interestingly, the level of serum selenium was significantly increased in hemodialysis and renal transplant patients but not in PD patients. Furthermore, one cross-sectional study showed that the serum selenium level was significantly lower in PD patients than in hemodialysis patients (8). Although these papers did not mention the precise mechanism responsible for such a difference, it may have been due to selenium bonding to serum albumin that was being removed by peritoneal dialysate. Indeed, peritoneal dialysate from some patients contained selenium (8). Thus, PD should be considered a risk factor for selenium deficiency. Although one study reported that PD did not lead to a loss of selenium, peritoneal dialysate from some patients showed the loss of selenium (9). However, the factor responsible for the loss of selenium was not confirmed. Furthermore, this study did not focus on the total amount of selenium but rather its concentration (9), so it was unable to conclude that PD did or did not lead to the loss of selenium. As described above, the present patient had several risk factors for a low selenium level. Of these, we considered PD to have contributed the most for two reasons. First, in most reported cases of selenium deficiency in patients on TPN in Japan, the durations of treatment were much longer than in the present patient (6). Second, the serum selenium level in the present case decreased just four days after the discontinuation of intravenous selenium administration, although selenium could not have been excreted in the urine of the present patient, as he had anuria. Physician should evaluate the serum selenium level when patients on PD receiving TPN show refractory hypotension. While our patient had several risk factors associated with low selenium levels, patients with low selenium levels do not always have symptoms of selenium deficiency, and many of them are actually asymptomatic according to previous reports (10,11). Selenium deficiency may be crucial to maintaining stable hemodynamics in patients with a history of chronic heart failure and ischemic heart disease. Indeed, there have been several reports suggesting that selenium levels affect chronic heart failure or coronary heart disease (12-14). Another study showed the effects of selenium supplementation on reducing NT-proBNP levels and cardiovascular mortality (15). Conclusion In conclusion, patients on PD receiving parenteral nutrition are at risk of selenium deficiency. Physicians should consider selenium deficiency as a cause of refractory hypotension in patients undergoing PD, especially those with a history of heart disease. The authors state that they have no Conflict of Interest (COI).	AMIODARONE, CALCIUM CHLORIDE\DEXTROSE MONOHYDRATE\HYDROCHLORIC ACID\MAGNESIUM CHLORIDE\SODIUM BICARBONATE\SODIUM CHLORIDE\SODIUM HYDROXIDE\SODIUM LACTATE, CALCIUM CHLORIDE\ICODEXTRIN\MAGNESIUM CHLORIDE\SODIUM CHLORIDE\SODIUM LACTATE, CARVEDILOL, CILOSTAZOL, CLOPIDOGREL BISULFATE, ESOMEPRAZOLE MAGNESIUM, NICORANDIL, NOREPINEPHRINE\NOREPINEPHRINE BITARTRATE, PIPERACILLIN SODIUM\TAZOBACTAM SODIUM, PITAVASTATIN CALCIUM	DrugsGivenReaction	CC BY-NC-ND	33583900	19,785,285	2021-08-01
What was the administration route of drug 'CALCIUM CHLORIDE\DEXTROSE MONOHYDRATE\HYDROCHLORIC ACID\MAGNESIUM CHLORIDE\SODIUM BICARBONATE\SODIUM CHLORIDE\SODIUM HYDROXIDE\SODIUM LACTATE'?	Refractory Hypotension Caused by Selenium Deficiency in a Patient on Peritoneal Dialysis. Selenium is essential for human health; its deficiency leads to cardiac dysfunction. We herein report a 79-year-old man on peritoneal dialysis who presented with refractory hypotension caused by selenium deficiency. He was admitted to our hospital with bacterial pneumonia and hypotension and abnormal electrocardiogram (ECG) findings. Despite improvement of pneumonia, his hypotension continued, and intravenous noradrenalin could not be discontinued. His serum selenium level was extremely low, and he was started on intravenous selenium. His hypotension and ECG findings gradually improved, and noradrenalin was discontinued. Physicians should consider selenium deficiency when patients on peritoneal dialysis show refractory hypotension. Introduction Selenium is a trace element that is necessary for many bodily processes, including thyroid hormone metabolism, DNA synthesis, reproduction, and protection from oxidative damage and infection (1). Therefore, selenium is essential for human health, and its deficiency is related to diseases such as hypothyroidism, deforming arthritis, and cardiovascular diseases (2). We herein report a peritoneal dialysis patient who presented with refractory hypotension and abnormal electrocardiogram (ECG) findings caused by selenium deficiency. His refractory hypotension was successfully treated with intravenous selenium administration. Case Report A 79-year-old Japanese man on peritoneal dialysis (PD) was hospitalized because of bacterial pneumonia and hypotension. His medical history included hypertension, ischemic heart disease, aortic dissection, gout, cerebral infarction, chronic heart failure, and chronic kidney disease caused by nephrosclerosis. His blood pressure had been controlled at 110-130 mmHg. He had taken esomeprazole, pitavastatin, nicorandil, cilostazol, clopidogrel, carvedilol, and amiodarone. He had been on peritoneal dialysis for eight years and he had been repeatedly hospitalized for heart failure caused by left ventricular (LV) dysfunction due to ischemic heart disease. He had been treated with ultrafiltration by peritoneal dialysis every time. With the decline in physical strength, his food intake had gradually decreased over the past year. On admission, a physical examination showed blood pressure of 66/42 mmHg, heart rate of 89 beats/min, temperature of 37.3 °C, and SpO2 of 91% (room air). His body weight could not be measured because of deterioration of his general condition. He was conscious and had no edema. Right chest coarse crackles were identified. His laboratory findings were as follows: white blood cell (WBC) 5,900/μL, red blood cell (RBC) 2.84×104/μL, hemoglobin (Hb) 8.4 g/dL, hematocrit (Ht) 26.1%, platelet (Plt) 16.3×104/μL, albumin 1.9 g/dL, blood urea nitrogen 39.4 mg/dL, creatinine 4.86 mg/dL, brain natriuretic peptide (BNP) 1967.5 pg/mL, and C-reactive protein (CRP) 10.90 mg/dL. Chest X-ray showed infiltration on the right side. Computed tomography showed patchy shadows in the bilateral lungs, and pleural effusion and atelectasis were observed in the right lung. Echocardiography showed diffuse hypokinesis of the left ventricle and a left ventricular ejection fraction of 40%, as before (2014: 68.1%, 2015: 75.9%, 2017: 75%, 2018: 68%, 2019: 48%). Bronchial pneumonia and heart failure were diagnosed, and he was treated with intravenous tazobactam/piperacillin and intravenous noradrenalin. His sputum culture was positive for Klebsiella pneumoniae, and two sets of blood culture were negative. His PD menu was daily extraneal and APD (1.5% reguneal 3 times) at night. Three months before admission, his peritoneal equivalent test (PET) category had shown a low average. After admission, his APD menu was changed to 2.5% fluid intended to increase ultrafiltration to improve overhydration. Although his general condition improved gradually, his volume overload and hypotension persisted. To determine why his hypotension persisted, his serum vitamin B1 level was measured, and vitamin B1 was administered, but it did not improve his condition. Several days later, his serum vitamin B1 level was reported as being in the normal range (4.9 μg/dL). Based on these findings and his abnormal ECG findings (Fig. 1), we investigated the possibility of selenium deficiency. His serum selenium level (reference range: 10.6-17.4 μg/dL) was then checked and was found to be extremely low (7.0 μg/dL) (Fig. 2). Sodium selenite injection (Fujimoto Pharmaceutical Corporation, Matsubara, Japan) 100 μg/day was then given intravenously; his blood pressure gradually increased, and intravenous noradrenalin was able to be discontinued five days after selenium administration (Fig. 2). Interestingly, his fluid removal by PD ultrafiltration increased after selenium administration, and his pulmonary congestion and serum BNP level also improved (Fig. 2). Since we were unable to estimate the serum selenium level after selenium administration, and there was concern about overcorrection (3), selenium administration was stopped on day 35. Discontinuation for 1 week resulted in a significant decrease in the serum selenium concentration (9.8 to 8.5 μg/dL). Intravenous selenium was then re-started, and an elevated serum selenium level was confirmed 4 days after administration (8.5 to 10.0 μg/dL). Figure 1. Electrocardiogram findings two months before admission and before and after treatment with intravenous selenium. Figure 2. Clinical course of the present case. BNP: brain natriuretic peptide, dBP: diastolic blood pressure, sBP: systolic blood pressure Selenium deficiency often causes ECG changes (4), and this case also showed abnormal ECG findings that improved after selenium administration (Fig. 1). The patient's general condition improved, and he was transferred to another hospital for rehabilitation on day 48. Discussion A case of refractory hypotension with abnormal ECG findings that was diagnosed as selenium deficiency was described. The patient's hypotension and pulmonary congestion were successfully treated with intravenous selenium administration. Hypotension can be caused by vitamin B1 deficiency, anemia, hypoalbuminemia, infectious state, and myocarditis. However, the patient's hemoglobin, albumin, and CRP levels did not change markedly after the improvement of hypotension (Fig. 1), and two sets of blood culture were negative. His serum vitamin B1 levels were also normal. As we did not perform a myocardial biopsy, we were unable to exclude the possibility of acute or chronic myocarditis. However, hypotension and his ECG finding improved just after selenium supplementation without intervention of myocarditis. Based on these findings, we diagnosed the cause of his hypotension as selenium deficiency. Historically, selenium deficiency has been famous for causing Keshan disease, which can lead to cardiac dysfunction (4,5). Keshan disease is an endemic cardiomyopathy occurring in low-selenium areas of China (5). The main clinical features are cardiac dysfunction and electrocardiographic changes. The present patient showed refractory hypotension and abnormal electrocardiogram findings that improved after intravenous selenium administration. Based on this clinical course and the diagnostic criteria for selenium deficiency (6), his hemodynamic instability was attributed to selenium deficiency. The present patient had several risks for selenium deficiency, including receiving total parenteral nutrition (TPN) and chronic kidney disease (CKD). In addition, the PD also likely contributed to selenium deficiency. A previous study evaluated the nutritional status in end-stage kidney disease (ESKD) patients before and six months after renal replacement therapy (hemodialysis or peritoneal dialysis) or renal transplantation (7). Interestingly, the level of serum selenium was significantly increased in hemodialysis and renal transplant patients but not in PD patients. Furthermore, one cross-sectional study showed that the serum selenium level was significantly lower in PD patients than in hemodialysis patients (8). Although these papers did not mention the precise mechanism responsible for such a difference, it may have been due to selenium bonding to serum albumin that was being removed by peritoneal dialysate. Indeed, peritoneal dialysate from some patients contained selenium (8). Thus, PD should be considered a risk factor for selenium deficiency. Although one study reported that PD did not lead to a loss of selenium, peritoneal dialysate from some patients showed the loss of selenium (9). However, the factor responsible for the loss of selenium was not confirmed. Furthermore, this study did not focus on the total amount of selenium but rather its concentration (9), so it was unable to conclude that PD did or did not lead to the loss of selenium. As described above, the present patient had several risk factors for a low selenium level. Of these, we considered PD to have contributed the most for two reasons. First, in most reported cases of selenium deficiency in patients on TPN in Japan, the durations of treatment were much longer than in the present patient (6). Second, the serum selenium level in the present case decreased just four days after the discontinuation of intravenous selenium administration, although selenium could not have been excreted in the urine of the present patient, as he had anuria. Physician should evaluate the serum selenium level when patients on PD receiving TPN show refractory hypotension. While our patient had several risk factors associated with low selenium levels, patients with low selenium levels do not always have symptoms of selenium deficiency, and many of them are actually asymptomatic according to previous reports (10,11). Selenium deficiency may be crucial to maintaining stable hemodynamics in patients with a history of chronic heart failure and ischemic heart disease. Indeed, there have been several reports suggesting that selenium levels affect chronic heart failure or coronary heart disease (12-14). Another study showed the effects of selenium supplementation on reducing NT-proBNP levels and cardiovascular mortality (15). Conclusion In conclusion, patients on PD receiving parenteral nutrition are at risk of selenium deficiency. Physicians should consider selenium deficiency as a cause of refractory hypotension in patients undergoing PD, especially those with a history of heart disease. The authors state that they have no Conflict of Interest (COI).	Intraperitoneal	DrugAdministrationRoute	CC BY-NC-ND	33583900	19,785,285	2021-08-01
What was the administration route of drug 'CALCIUM CHLORIDE\ICODEXTRIN\MAGNESIUM CHLORIDE\SODIUM CHLORIDE\SODIUM LACTATE'?	Refractory Hypotension Caused by Selenium Deficiency in a Patient on Peritoneal Dialysis. Selenium is essential for human health; its deficiency leads to cardiac dysfunction. We herein report a 79-year-old man on peritoneal dialysis who presented with refractory hypotension caused by selenium deficiency. He was admitted to our hospital with bacterial pneumonia and hypotension and abnormal electrocardiogram (ECG) findings. Despite improvement of pneumonia, his hypotension continued, and intravenous noradrenalin could not be discontinued. His serum selenium level was extremely low, and he was started on intravenous selenium. His hypotension and ECG findings gradually improved, and noradrenalin was discontinued. Physicians should consider selenium deficiency when patients on peritoneal dialysis show refractory hypotension. Introduction Selenium is a trace element that is necessary for many bodily processes, including thyroid hormone metabolism, DNA synthesis, reproduction, and protection from oxidative damage and infection (1). Therefore, selenium is essential for human health, and its deficiency is related to diseases such as hypothyroidism, deforming arthritis, and cardiovascular diseases (2). We herein report a peritoneal dialysis patient who presented with refractory hypotension and abnormal electrocardiogram (ECG) findings caused by selenium deficiency. His refractory hypotension was successfully treated with intravenous selenium administration. Case Report A 79-year-old Japanese man on peritoneal dialysis (PD) was hospitalized because of bacterial pneumonia and hypotension. His medical history included hypertension, ischemic heart disease, aortic dissection, gout, cerebral infarction, chronic heart failure, and chronic kidney disease caused by nephrosclerosis. His blood pressure had been controlled at 110-130 mmHg. He had taken esomeprazole, pitavastatin, nicorandil, cilostazol, clopidogrel, carvedilol, and amiodarone. He had been on peritoneal dialysis for eight years and he had been repeatedly hospitalized for heart failure caused by left ventricular (LV) dysfunction due to ischemic heart disease. He had been treated with ultrafiltration by peritoneal dialysis every time. With the decline in physical strength, his food intake had gradually decreased over the past year. On admission, a physical examination showed blood pressure of 66/42 mmHg, heart rate of 89 beats/min, temperature of 37.3 °C, and SpO2 of 91% (room air). His body weight could not be measured because of deterioration of his general condition. He was conscious and had no edema. Right chest coarse crackles were identified. His laboratory findings were as follows: white blood cell (WBC) 5,900/μL, red blood cell (RBC) 2.84×104/μL, hemoglobin (Hb) 8.4 g/dL, hematocrit (Ht) 26.1%, platelet (Plt) 16.3×104/μL, albumin 1.9 g/dL, blood urea nitrogen 39.4 mg/dL, creatinine 4.86 mg/dL, brain natriuretic peptide (BNP) 1967.5 pg/mL, and C-reactive protein (CRP) 10.90 mg/dL. Chest X-ray showed infiltration on the right side. Computed tomography showed patchy shadows in the bilateral lungs, and pleural effusion and atelectasis were observed in the right lung. Echocardiography showed diffuse hypokinesis of the left ventricle and a left ventricular ejection fraction of 40%, as before (2014: 68.1%, 2015: 75.9%, 2017: 75%, 2018: 68%, 2019: 48%). Bronchial pneumonia and heart failure were diagnosed, and he was treated with intravenous tazobactam/piperacillin and intravenous noradrenalin. His sputum culture was positive for Klebsiella pneumoniae, and two sets of blood culture were negative. His PD menu was daily extraneal and APD (1.5% reguneal 3 times) at night. Three months before admission, his peritoneal equivalent test (PET) category had shown a low average. After admission, his APD menu was changed to 2.5% fluid intended to increase ultrafiltration to improve overhydration. Although his general condition improved gradually, his volume overload and hypotension persisted. To determine why his hypotension persisted, his serum vitamin B1 level was measured, and vitamin B1 was administered, but it did not improve his condition. Several days later, his serum vitamin B1 level was reported as being in the normal range (4.9 μg/dL). Based on these findings and his abnormal ECG findings (Fig. 1), we investigated the possibility of selenium deficiency. His serum selenium level (reference range: 10.6-17.4 μg/dL) was then checked and was found to be extremely low (7.0 μg/dL) (Fig. 2). Sodium selenite injection (Fujimoto Pharmaceutical Corporation, Matsubara, Japan) 100 μg/day was then given intravenously; his blood pressure gradually increased, and intravenous noradrenalin was able to be discontinued five days after selenium administration (Fig. 2). Interestingly, his fluid removal by PD ultrafiltration increased after selenium administration, and his pulmonary congestion and serum BNP level also improved (Fig. 2). Since we were unable to estimate the serum selenium level after selenium administration, and there was concern about overcorrection (3), selenium administration was stopped on day 35. Discontinuation for 1 week resulted in a significant decrease in the serum selenium concentration (9.8 to 8.5 μg/dL). Intravenous selenium was then re-started, and an elevated serum selenium level was confirmed 4 days after administration (8.5 to 10.0 μg/dL). Figure 1. Electrocardiogram findings two months before admission and before and after treatment with intravenous selenium. Figure 2. Clinical course of the present case. BNP: brain natriuretic peptide, dBP: diastolic blood pressure, sBP: systolic blood pressure Selenium deficiency often causes ECG changes (4), and this case also showed abnormal ECG findings that improved after selenium administration (Fig. 1). The patient's general condition improved, and he was transferred to another hospital for rehabilitation on day 48. Discussion A case of refractory hypotension with abnormal ECG findings that was diagnosed as selenium deficiency was described. The patient's hypotension and pulmonary congestion were successfully treated with intravenous selenium administration. Hypotension can be caused by vitamin B1 deficiency, anemia, hypoalbuminemia, infectious state, and myocarditis. However, the patient's hemoglobin, albumin, and CRP levels did not change markedly after the improvement of hypotension (Fig. 1), and two sets of blood culture were negative. His serum vitamin B1 levels were also normal. As we did not perform a myocardial biopsy, we were unable to exclude the possibility of acute or chronic myocarditis. However, hypotension and his ECG finding improved just after selenium supplementation without intervention of myocarditis. Based on these findings, we diagnosed the cause of his hypotension as selenium deficiency. Historically, selenium deficiency has been famous for causing Keshan disease, which can lead to cardiac dysfunction (4,5). Keshan disease is an endemic cardiomyopathy occurring in low-selenium areas of China (5). The main clinical features are cardiac dysfunction and electrocardiographic changes. The present patient showed refractory hypotension and abnormal electrocardiogram findings that improved after intravenous selenium administration. Based on this clinical course and the diagnostic criteria for selenium deficiency (6), his hemodynamic instability was attributed to selenium deficiency. The present patient had several risks for selenium deficiency, including receiving total parenteral nutrition (TPN) and chronic kidney disease (CKD). In addition, the PD also likely contributed to selenium deficiency. A previous study evaluated the nutritional status in end-stage kidney disease (ESKD) patients before and six months after renal replacement therapy (hemodialysis or peritoneal dialysis) or renal transplantation (7). Interestingly, the level of serum selenium was significantly increased in hemodialysis and renal transplant patients but not in PD patients. Furthermore, one cross-sectional study showed that the serum selenium level was significantly lower in PD patients than in hemodialysis patients (8). Although these papers did not mention the precise mechanism responsible for such a difference, it may have been due to selenium bonding to serum albumin that was being removed by peritoneal dialysate. Indeed, peritoneal dialysate from some patients contained selenium (8). Thus, PD should be considered a risk factor for selenium deficiency. Although one study reported that PD did not lead to a loss of selenium, peritoneal dialysate from some patients showed the loss of selenium (9). However, the factor responsible for the loss of selenium was not confirmed. Furthermore, this study did not focus on the total amount of selenium but rather its concentration (9), so it was unable to conclude that PD did or did not lead to the loss of selenium. As described above, the present patient had several risk factors for a low selenium level. Of these, we considered PD to have contributed the most for two reasons. First, in most reported cases of selenium deficiency in patients on TPN in Japan, the durations of treatment were much longer than in the present patient (6). Second, the serum selenium level in the present case decreased just four days after the discontinuation of intravenous selenium administration, although selenium could not have been excreted in the urine of the present patient, as he had anuria. Physician should evaluate the serum selenium level when patients on PD receiving TPN show refractory hypotension. While our patient had several risk factors associated with low selenium levels, patients with low selenium levels do not always have symptoms of selenium deficiency, and many of them are actually asymptomatic according to previous reports (10,11). Selenium deficiency may be crucial to maintaining stable hemodynamics in patients with a history of chronic heart failure and ischemic heart disease. Indeed, there have been several reports suggesting that selenium levels affect chronic heart failure or coronary heart disease (12-14). Another study showed the effects of selenium supplementation on reducing NT-proBNP levels and cardiovascular mortality (15). Conclusion In conclusion, patients on PD receiving parenteral nutrition are at risk of selenium deficiency. Physicians should consider selenium deficiency as a cause of refractory hypotension in patients undergoing PD, especially those with a history of heart disease. The authors state that they have no Conflict of Interest (COI).	Intraperitoneal	DrugAdministrationRoute	CC BY-NC-ND	33583900	19,785,285	2021-08-01
What was the administration route of drug 'PIPERACILLIN SODIUM\TAZOBACTAM SODIUM'?	Refractory Hypotension Caused by Selenium Deficiency in a Patient on Peritoneal Dialysis. Selenium is essential for human health; its deficiency leads to cardiac dysfunction. We herein report a 79-year-old man on peritoneal dialysis who presented with refractory hypotension caused by selenium deficiency. He was admitted to our hospital with bacterial pneumonia and hypotension and abnormal electrocardiogram (ECG) findings. Despite improvement of pneumonia, his hypotension continued, and intravenous noradrenalin could not be discontinued. His serum selenium level was extremely low, and he was started on intravenous selenium. His hypotension and ECG findings gradually improved, and noradrenalin was discontinued. Physicians should consider selenium deficiency when patients on peritoneal dialysis show refractory hypotension. Introduction Selenium is a trace element that is necessary for many bodily processes, including thyroid hormone metabolism, DNA synthesis, reproduction, and protection from oxidative damage and infection (1). Therefore, selenium is essential for human health, and its deficiency is related to diseases such as hypothyroidism, deforming arthritis, and cardiovascular diseases (2). We herein report a peritoneal dialysis patient who presented with refractory hypotension and abnormal electrocardiogram (ECG) findings caused by selenium deficiency. His refractory hypotension was successfully treated with intravenous selenium administration. Case Report A 79-year-old Japanese man on peritoneal dialysis (PD) was hospitalized because of bacterial pneumonia and hypotension. His medical history included hypertension, ischemic heart disease, aortic dissection, gout, cerebral infarction, chronic heart failure, and chronic kidney disease caused by nephrosclerosis. His blood pressure had been controlled at 110-130 mmHg. He had taken esomeprazole, pitavastatin, nicorandil, cilostazol, clopidogrel, carvedilol, and amiodarone. He had been on peritoneal dialysis for eight years and he had been repeatedly hospitalized for heart failure caused by left ventricular (LV) dysfunction due to ischemic heart disease. He had been treated with ultrafiltration by peritoneal dialysis every time. With the decline in physical strength, his food intake had gradually decreased over the past year. On admission, a physical examination showed blood pressure of 66/42 mmHg, heart rate of 89 beats/min, temperature of 37.3 °C, and SpO2 of 91% (room air). His body weight could not be measured because of deterioration of his general condition. He was conscious and had no edema. Right chest coarse crackles were identified. His laboratory findings were as follows: white blood cell (WBC) 5,900/μL, red blood cell (RBC) 2.84×104/μL, hemoglobin (Hb) 8.4 g/dL, hematocrit (Ht) 26.1%, platelet (Plt) 16.3×104/μL, albumin 1.9 g/dL, blood urea nitrogen 39.4 mg/dL, creatinine 4.86 mg/dL, brain natriuretic peptide (BNP) 1967.5 pg/mL, and C-reactive protein (CRP) 10.90 mg/dL. Chest X-ray showed infiltration on the right side. Computed tomography showed patchy shadows in the bilateral lungs, and pleural effusion and atelectasis were observed in the right lung. Echocardiography showed diffuse hypokinesis of the left ventricle and a left ventricular ejection fraction of 40%, as before (2014: 68.1%, 2015: 75.9%, 2017: 75%, 2018: 68%, 2019: 48%). Bronchial pneumonia and heart failure were diagnosed, and he was treated with intravenous tazobactam/piperacillin and intravenous noradrenalin. His sputum culture was positive for Klebsiella pneumoniae, and two sets of blood culture were negative. His PD menu was daily extraneal and APD (1.5% reguneal 3 times) at night. Three months before admission, his peritoneal equivalent test (PET) category had shown a low average. After admission, his APD menu was changed to 2.5% fluid intended to increase ultrafiltration to improve overhydration. Although his general condition improved gradually, his volume overload and hypotension persisted. To determine why his hypotension persisted, his serum vitamin B1 level was measured, and vitamin B1 was administered, but it did not improve his condition. Several days later, his serum vitamin B1 level was reported as being in the normal range (4.9 μg/dL). Based on these findings and his abnormal ECG findings (Fig. 1), we investigated the possibility of selenium deficiency. His serum selenium level (reference range: 10.6-17.4 μg/dL) was then checked and was found to be extremely low (7.0 μg/dL) (Fig. 2). Sodium selenite injection (Fujimoto Pharmaceutical Corporation, Matsubara, Japan) 100 μg/day was then given intravenously; his blood pressure gradually increased, and intravenous noradrenalin was able to be discontinued five days after selenium administration (Fig. 2). Interestingly, his fluid removal by PD ultrafiltration increased after selenium administration, and his pulmonary congestion and serum BNP level also improved (Fig. 2). Since we were unable to estimate the serum selenium level after selenium administration, and there was concern about overcorrection (3), selenium administration was stopped on day 35. Discontinuation for 1 week resulted in a significant decrease in the serum selenium concentration (9.8 to 8.5 μg/dL). Intravenous selenium was then re-started, and an elevated serum selenium level was confirmed 4 days after administration (8.5 to 10.0 μg/dL). Figure 1. Electrocardiogram findings two months before admission and before and after treatment with intravenous selenium. Figure 2. Clinical course of the present case. BNP: brain natriuretic peptide, dBP: diastolic blood pressure, sBP: systolic blood pressure Selenium deficiency often causes ECG changes (4), and this case also showed abnormal ECG findings that improved after selenium administration (Fig. 1). The patient's general condition improved, and he was transferred to another hospital for rehabilitation on day 48. Discussion A case of refractory hypotension with abnormal ECG findings that was diagnosed as selenium deficiency was described. The patient's hypotension and pulmonary congestion were successfully treated with intravenous selenium administration. Hypotension can be caused by vitamin B1 deficiency, anemia, hypoalbuminemia, infectious state, and myocarditis. However, the patient's hemoglobin, albumin, and CRP levels did not change markedly after the improvement of hypotension (Fig. 1), and two sets of blood culture were negative. His serum vitamin B1 levels were also normal. As we did not perform a myocardial biopsy, we were unable to exclude the possibility of acute or chronic myocarditis. However, hypotension and his ECG finding improved just after selenium supplementation without intervention of myocarditis. Based on these findings, we diagnosed the cause of his hypotension as selenium deficiency. Historically, selenium deficiency has been famous for causing Keshan disease, which can lead to cardiac dysfunction (4,5). Keshan disease is an endemic cardiomyopathy occurring in low-selenium areas of China (5). The main clinical features are cardiac dysfunction and electrocardiographic changes. The present patient showed refractory hypotension and abnormal electrocardiogram findings that improved after intravenous selenium administration. Based on this clinical course and the diagnostic criteria for selenium deficiency (6), his hemodynamic instability was attributed to selenium deficiency. The present patient had several risks for selenium deficiency, including receiving total parenteral nutrition (TPN) and chronic kidney disease (CKD). In addition, the PD also likely contributed to selenium deficiency. A previous study evaluated the nutritional status in end-stage kidney disease (ESKD) patients before and six months after renal replacement therapy (hemodialysis or peritoneal dialysis) or renal transplantation (7). Interestingly, the level of serum selenium was significantly increased in hemodialysis and renal transplant patients but not in PD patients. Furthermore, one cross-sectional study showed that the serum selenium level was significantly lower in PD patients than in hemodialysis patients (8). Although these papers did not mention the precise mechanism responsible for such a difference, it may have been due to selenium bonding to serum albumin that was being removed by peritoneal dialysate. Indeed, peritoneal dialysate from some patients contained selenium (8). Thus, PD should be considered a risk factor for selenium deficiency. Although one study reported that PD did not lead to a loss of selenium, peritoneal dialysate from some patients showed the loss of selenium (9). However, the factor responsible for the loss of selenium was not confirmed. Furthermore, this study did not focus on the total amount of selenium but rather its concentration (9), so it was unable to conclude that PD did or did not lead to the loss of selenium. As described above, the present patient had several risk factors for a low selenium level. Of these, we considered PD to have contributed the most for two reasons. First, in most reported cases of selenium deficiency in patients on TPN in Japan, the durations of treatment were much longer than in the present patient (6). Second, the serum selenium level in the present case decreased just four days after the discontinuation of intravenous selenium administration, although selenium could not have been excreted in the urine of the present patient, as he had anuria. Physician should evaluate the serum selenium level when patients on PD receiving TPN show refractory hypotension. While our patient had several risk factors associated with low selenium levels, patients with low selenium levels do not always have symptoms of selenium deficiency, and many of them are actually asymptomatic according to previous reports (10,11). Selenium deficiency may be crucial to maintaining stable hemodynamics in patients with a history of chronic heart failure and ischemic heart disease. Indeed, there have been several reports suggesting that selenium levels affect chronic heart failure or coronary heart disease (12-14). Another study showed the effects of selenium supplementation on reducing NT-proBNP levels and cardiovascular mortality (15). Conclusion In conclusion, patients on PD receiving parenteral nutrition are at risk of selenium deficiency. Physicians should consider selenium deficiency as a cause of refractory hypotension in patients undergoing PD, especially those with a history of heart disease. The authors state that they have no Conflict of Interest (COI).	Intravenous (not otherwise specified)	DrugAdministrationRoute	CC BY-NC-ND	33583900	19,785,285	2021-08-01
What was the dosage of drug 'CALCIUM CHLORIDE\DEXTROSE MONOHYDRATE\HYDROCHLORIC ACID\MAGNESIUM CHLORIDE\SODIUM BICARBONATE\SODIUM CHLORIDE\SODIUM HYDROXIDE\SODIUM LACTATE'?	Refractory Hypotension Caused by Selenium Deficiency in a Patient on Peritoneal Dialysis. Selenium is essential for human health; its deficiency leads to cardiac dysfunction. We herein report a 79-year-old man on peritoneal dialysis who presented with refractory hypotension caused by selenium deficiency. He was admitted to our hospital with bacterial pneumonia and hypotension and abnormal electrocardiogram (ECG) findings. Despite improvement of pneumonia, his hypotension continued, and intravenous noradrenalin could not be discontinued. His serum selenium level was extremely low, and he was started on intravenous selenium. His hypotension and ECG findings gradually improved, and noradrenalin was discontinued. Physicians should consider selenium deficiency when patients on peritoneal dialysis show refractory hypotension. Introduction Selenium is a trace element that is necessary for many bodily processes, including thyroid hormone metabolism, DNA synthesis, reproduction, and protection from oxidative damage and infection (1). Therefore, selenium is essential for human health, and its deficiency is related to diseases such as hypothyroidism, deforming arthritis, and cardiovascular diseases (2). We herein report a peritoneal dialysis patient who presented with refractory hypotension and abnormal electrocardiogram (ECG) findings caused by selenium deficiency. His refractory hypotension was successfully treated with intravenous selenium administration. Case Report A 79-year-old Japanese man on peritoneal dialysis (PD) was hospitalized because of bacterial pneumonia and hypotension. His medical history included hypertension, ischemic heart disease, aortic dissection, gout, cerebral infarction, chronic heart failure, and chronic kidney disease caused by nephrosclerosis. His blood pressure had been controlled at 110-130 mmHg. He had taken esomeprazole, pitavastatin, nicorandil, cilostazol, clopidogrel, carvedilol, and amiodarone. He had been on peritoneal dialysis for eight years and he had been repeatedly hospitalized for heart failure caused by left ventricular (LV) dysfunction due to ischemic heart disease. He had been treated with ultrafiltration by peritoneal dialysis every time. With the decline in physical strength, his food intake had gradually decreased over the past year. On admission, a physical examination showed blood pressure of 66/42 mmHg, heart rate of 89 beats/min, temperature of 37.3 °C, and SpO2 of 91% (room air). His body weight could not be measured because of deterioration of his general condition. He was conscious and had no edema. Right chest coarse crackles were identified. His laboratory findings were as follows: white blood cell (WBC) 5,900/μL, red blood cell (RBC) 2.84×104/μL, hemoglobin (Hb) 8.4 g/dL, hematocrit (Ht) 26.1%, platelet (Plt) 16.3×104/μL, albumin 1.9 g/dL, blood urea nitrogen 39.4 mg/dL, creatinine 4.86 mg/dL, brain natriuretic peptide (BNP) 1967.5 pg/mL, and C-reactive protein (CRP) 10.90 mg/dL. Chest X-ray showed infiltration on the right side. Computed tomography showed patchy shadows in the bilateral lungs, and pleural effusion and atelectasis were observed in the right lung. Echocardiography showed diffuse hypokinesis of the left ventricle and a left ventricular ejection fraction of 40%, as before (2014: 68.1%, 2015: 75.9%, 2017: 75%, 2018: 68%, 2019: 48%). Bronchial pneumonia and heart failure were diagnosed, and he was treated with intravenous tazobactam/piperacillin and intravenous noradrenalin. His sputum culture was positive for Klebsiella pneumoniae, and two sets of blood culture were negative. His PD menu was daily extraneal and APD (1.5% reguneal 3 times) at night. Three months before admission, his peritoneal equivalent test (PET) category had shown a low average. After admission, his APD menu was changed to 2.5% fluid intended to increase ultrafiltration to improve overhydration. Although his general condition improved gradually, his volume overload and hypotension persisted. To determine why his hypotension persisted, his serum vitamin B1 level was measured, and vitamin B1 was administered, but it did not improve his condition. Several days later, his serum vitamin B1 level was reported as being in the normal range (4.9 μg/dL). Based on these findings and his abnormal ECG findings (Fig. 1), we investigated the possibility of selenium deficiency. His serum selenium level (reference range: 10.6-17.4 μg/dL) was then checked and was found to be extremely low (7.0 μg/dL) (Fig. 2). Sodium selenite injection (Fujimoto Pharmaceutical Corporation, Matsubara, Japan) 100 μg/day was then given intravenously; his blood pressure gradually increased, and intravenous noradrenalin was able to be discontinued five days after selenium administration (Fig. 2). Interestingly, his fluid removal by PD ultrafiltration increased after selenium administration, and his pulmonary congestion and serum BNP level also improved (Fig. 2). Since we were unable to estimate the serum selenium level after selenium administration, and there was concern about overcorrection (3), selenium administration was stopped on day 35. Discontinuation for 1 week resulted in a significant decrease in the serum selenium concentration (9.8 to 8.5 μg/dL). Intravenous selenium was then re-started, and an elevated serum selenium level was confirmed 4 days after administration (8.5 to 10.0 μg/dL). Figure 1. Electrocardiogram findings two months before admission and before and after treatment with intravenous selenium. Figure 2. Clinical course of the present case. BNP: brain natriuretic peptide, dBP: diastolic blood pressure, sBP: systolic blood pressure Selenium deficiency often causes ECG changes (4), and this case also showed abnormal ECG findings that improved after selenium administration (Fig. 1). The patient's general condition improved, and he was transferred to another hospital for rehabilitation on day 48. Discussion A case of refractory hypotension with abnormal ECG findings that was diagnosed as selenium deficiency was described. The patient's hypotension and pulmonary congestion were successfully treated with intravenous selenium administration. Hypotension can be caused by vitamin B1 deficiency, anemia, hypoalbuminemia, infectious state, and myocarditis. However, the patient's hemoglobin, albumin, and CRP levels did not change markedly after the improvement of hypotension (Fig. 1), and two sets of blood culture were negative. His serum vitamin B1 levels were also normal. As we did not perform a myocardial biopsy, we were unable to exclude the possibility of acute or chronic myocarditis. However, hypotension and his ECG finding improved just after selenium supplementation without intervention of myocarditis. Based on these findings, we diagnosed the cause of his hypotension as selenium deficiency. Historically, selenium deficiency has been famous for causing Keshan disease, which can lead to cardiac dysfunction (4,5). Keshan disease is an endemic cardiomyopathy occurring in low-selenium areas of China (5). The main clinical features are cardiac dysfunction and electrocardiographic changes. The present patient showed refractory hypotension and abnormal electrocardiogram findings that improved after intravenous selenium administration. Based on this clinical course and the diagnostic criteria for selenium deficiency (6), his hemodynamic instability was attributed to selenium deficiency. The present patient had several risks for selenium deficiency, including receiving total parenteral nutrition (TPN) and chronic kidney disease (CKD). In addition, the PD also likely contributed to selenium deficiency. A previous study evaluated the nutritional status in end-stage kidney disease (ESKD) patients before and six months after renal replacement therapy (hemodialysis or peritoneal dialysis) or renal transplantation (7). Interestingly, the level of serum selenium was significantly increased in hemodialysis and renal transplant patients but not in PD patients. Furthermore, one cross-sectional study showed that the serum selenium level was significantly lower in PD patients than in hemodialysis patients (8). Although these papers did not mention the precise mechanism responsible for such a difference, it may have been due to selenium bonding to serum albumin that was being removed by peritoneal dialysate. Indeed, peritoneal dialysate from some patients contained selenium (8). Thus, PD should be considered a risk factor for selenium deficiency. Although one study reported that PD did not lead to a loss of selenium, peritoneal dialysate from some patients showed the loss of selenium (9). However, the factor responsible for the loss of selenium was not confirmed. Furthermore, this study did not focus on the total amount of selenium but rather its concentration (9), so it was unable to conclude that PD did or did not lead to the loss of selenium. As described above, the present patient had several risk factors for a low selenium level. Of these, we considered PD to have contributed the most for two reasons. First, in most reported cases of selenium deficiency in patients on TPN in Japan, the durations of treatment were much longer than in the present patient (6). Second, the serum selenium level in the present case decreased just four days after the discontinuation of intravenous selenium administration, although selenium could not have been excreted in the urine of the present patient, as he had anuria. Physician should evaluate the serum selenium level when patients on PD receiving TPN show refractory hypotension. While our patient had several risk factors associated with low selenium levels, patients with low selenium levels do not always have symptoms of selenium deficiency, and many of them are actually asymptomatic according to previous reports (10,11). Selenium deficiency may be crucial to maintaining stable hemodynamics in patients with a history of chronic heart failure and ischemic heart disease. Indeed, there have been several reports suggesting that selenium levels affect chronic heart failure or coronary heart disease (12-14). Another study showed the effects of selenium supplementation on reducing NT-proBNP levels and cardiovascular mortality (15). Conclusion In conclusion, patients on PD receiving parenteral nutrition are at risk of selenium deficiency. Physicians should consider selenium deficiency as a cause of refractory hypotension in patients undergoing PD, especially those with a history of heart disease. The authors state that they have no Conflict of Interest (COI).	1.5 % REGUNEAL 3 TIMES	DrugDosageText	CC BY-NC-ND	33583900	19,785,285	2021-08-01
What was the outcome of reaction 'Selenium deficiency'?	Refractory Hypotension Caused by Selenium Deficiency in a Patient on Peritoneal Dialysis. Selenium is essential for human health; its deficiency leads to cardiac dysfunction. We herein report a 79-year-old man on peritoneal dialysis who presented with refractory hypotension caused by selenium deficiency. He was admitted to our hospital with bacterial pneumonia and hypotension and abnormal electrocardiogram (ECG) findings. Despite improvement of pneumonia, his hypotension continued, and intravenous noradrenalin could not be discontinued. His serum selenium level was extremely low, and he was started on intravenous selenium. His hypotension and ECG findings gradually improved, and noradrenalin was discontinued. Physicians should consider selenium deficiency when patients on peritoneal dialysis show refractory hypotension. Introduction Selenium is a trace element that is necessary for many bodily processes, including thyroid hormone metabolism, DNA synthesis, reproduction, and protection from oxidative damage and infection (1). Therefore, selenium is essential for human health, and its deficiency is related to diseases such as hypothyroidism, deforming arthritis, and cardiovascular diseases (2). We herein report a peritoneal dialysis patient who presented with refractory hypotension and abnormal electrocardiogram (ECG) findings caused by selenium deficiency. His refractory hypotension was successfully treated with intravenous selenium administration. Case Report A 79-year-old Japanese man on peritoneal dialysis (PD) was hospitalized because of bacterial pneumonia and hypotension. His medical history included hypertension, ischemic heart disease, aortic dissection, gout, cerebral infarction, chronic heart failure, and chronic kidney disease caused by nephrosclerosis. His blood pressure had been controlled at 110-130 mmHg. He had taken esomeprazole, pitavastatin, nicorandil, cilostazol, clopidogrel, carvedilol, and amiodarone. He had been on peritoneal dialysis for eight years and he had been repeatedly hospitalized for heart failure caused by left ventricular (LV) dysfunction due to ischemic heart disease. He had been treated with ultrafiltration by peritoneal dialysis every time. With the decline in physical strength, his food intake had gradually decreased over the past year. On admission, a physical examination showed blood pressure of 66/42 mmHg, heart rate of 89 beats/min, temperature of 37.3 °C, and SpO2 of 91% (room air). His body weight could not be measured because of deterioration of his general condition. He was conscious and had no edema. Right chest coarse crackles were identified. His laboratory findings were as follows: white blood cell (WBC) 5,900/μL, red blood cell (RBC) 2.84×104/μL, hemoglobin (Hb) 8.4 g/dL, hematocrit (Ht) 26.1%, platelet (Plt) 16.3×104/μL, albumin 1.9 g/dL, blood urea nitrogen 39.4 mg/dL, creatinine 4.86 mg/dL, brain natriuretic peptide (BNP) 1967.5 pg/mL, and C-reactive protein (CRP) 10.90 mg/dL. Chest X-ray showed infiltration on the right side. Computed tomography showed patchy shadows in the bilateral lungs, and pleural effusion and atelectasis were observed in the right lung. Echocardiography showed diffuse hypokinesis of the left ventricle and a left ventricular ejection fraction of 40%, as before (2014: 68.1%, 2015: 75.9%, 2017: 75%, 2018: 68%, 2019: 48%). Bronchial pneumonia and heart failure were diagnosed, and he was treated with intravenous tazobactam/piperacillin and intravenous noradrenalin. His sputum culture was positive for Klebsiella pneumoniae, and two sets of blood culture were negative. His PD menu was daily extraneal and APD (1.5% reguneal 3 times) at night. Three months before admission, his peritoneal equivalent test (PET) category had shown a low average. After admission, his APD menu was changed to 2.5% fluid intended to increase ultrafiltration to improve overhydration. Although his general condition improved gradually, his volume overload and hypotension persisted. To determine why his hypotension persisted, his serum vitamin B1 level was measured, and vitamin B1 was administered, but it did not improve his condition. Several days later, his serum vitamin B1 level was reported as being in the normal range (4.9 μg/dL). Based on these findings and his abnormal ECG findings (Fig. 1), we investigated the possibility of selenium deficiency. His serum selenium level (reference range: 10.6-17.4 μg/dL) was then checked and was found to be extremely low (7.0 μg/dL) (Fig. 2). Sodium selenite injection (Fujimoto Pharmaceutical Corporation, Matsubara, Japan) 100 μg/day was then given intravenously; his blood pressure gradually increased, and intravenous noradrenalin was able to be discontinued five days after selenium administration (Fig. 2). Interestingly, his fluid removal by PD ultrafiltration increased after selenium administration, and his pulmonary congestion and serum BNP level also improved (Fig. 2). Since we were unable to estimate the serum selenium level after selenium administration, and there was concern about overcorrection (3), selenium administration was stopped on day 35. Discontinuation for 1 week resulted in a significant decrease in the serum selenium concentration (9.8 to 8.5 μg/dL). Intravenous selenium was then re-started, and an elevated serum selenium level was confirmed 4 days after administration (8.5 to 10.0 μg/dL). Figure 1. Electrocardiogram findings two months before admission and before and after treatment with intravenous selenium. Figure 2. Clinical course of the present case. BNP: brain natriuretic peptide, dBP: diastolic blood pressure, sBP: systolic blood pressure Selenium deficiency often causes ECG changes (4), and this case also showed abnormal ECG findings that improved after selenium administration (Fig. 1). The patient's general condition improved, and he was transferred to another hospital for rehabilitation on day 48. Discussion A case of refractory hypotension with abnormal ECG findings that was diagnosed as selenium deficiency was described. The patient's hypotension and pulmonary congestion were successfully treated with intravenous selenium administration. Hypotension can be caused by vitamin B1 deficiency, anemia, hypoalbuminemia, infectious state, and myocarditis. However, the patient's hemoglobin, albumin, and CRP levels did not change markedly after the improvement of hypotension (Fig. 1), and two sets of blood culture were negative. His serum vitamin B1 levels were also normal. As we did not perform a myocardial biopsy, we were unable to exclude the possibility of acute or chronic myocarditis. However, hypotension and his ECG finding improved just after selenium supplementation without intervention of myocarditis. Based on these findings, we diagnosed the cause of his hypotension as selenium deficiency. Historically, selenium deficiency has been famous for causing Keshan disease, which can lead to cardiac dysfunction (4,5). Keshan disease is an endemic cardiomyopathy occurring in low-selenium areas of China (5). The main clinical features are cardiac dysfunction and electrocardiographic changes. The present patient showed refractory hypotension and abnormal electrocardiogram findings that improved after intravenous selenium administration. Based on this clinical course and the diagnostic criteria for selenium deficiency (6), his hemodynamic instability was attributed to selenium deficiency. The present patient had several risks for selenium deficiency, including receiving total parenteral nutrition (TPN) and chronic kidney disease (CKD). In addition, the PD also likely contributed to selenium deficiency. A previous study evaluated the nutritional status in end-stage kidney disease (ESKD) patients before and six months after renal replacement therapy (hemodialysis or peritoneal dialysis) or renal transplantation (7). Interestingly, the level of serum selenium was significantly increased in hemodialysis and renal transplant patients but not in PD patients. Furthermore, one cross-sectional study showed that the serum selenium level was significantly lower in PD patients than in hemodialysis patients (8). Although these papers did not mention the precise mechanism responsible for such a difference, it may have been due to selenium bonding to serum albumin that was being removed by peritoneal dialysate. Indeed, peritoneal dialysate from some patients contained selenium (8). Thus, PD should be considered a risk factor for selenium deficiency. Although one study reported that PD did not lead to a loss of selenium, peritoneal dialysate from some patients showed the loss of selenium (9). However, the factor responsible for the loss of selenium was not confirmed. Furthermore, this study did not focus on the total amount of selenium but rather its concentration (9), so it was unable to conclude that PD did or did not lead to the loss of selenium. As described above, the present patient had several risk factors for a low selenium level. Of these, we considered PD to have contributed the most for two reasons. First, in most reported cases of selenium deficiency in patients on TPN in Japan, the durations of treatment were much longer than in the present patient (6). Second, the serum selenium level in the present case decreased just four days after the discontinuation of intravenous selenium administration, although selenium could not have been excreted in the urine of the present patient, as he had anuria. Physician should evaluate the serum selenium level when patients on PD receiving TPN show refractory hypotension. While our patient had several risk factors associated with low selenium levels, patients with low selenium levels do not always have symptoms of selenium deficiency, and many of them are actually asymptomatic according to previous reports (10,11). Selenium deficiency may be crucial to maintaining stable hemodynamics in patients with a history of chronic heart failure and ischemic heart disease. Indeed, there have been several reports suggesting that selenium levels affect chronic heart failure or coronary heart disease (12-14). Another study showed the effects of selenium supplementation on reducing NT-proBNP levels and cardiovascular mortality (15). Conclusion In conclusion, patients on PD receiving parenteral nutrition are at risk of selenium deficiency. Physicians should consider selenium deficiency as a cause of refractory hypotension in patients undergoing PD, especially those with a history of heart disease. The authors state that they have no Conflict of Interest (COI).	Recovered	ReactionOutcome	CC BY-NC-ND	33583900	19,785,285	2021-08-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Glomerulonephritis membranoproliferative'.	Immune Thrombocytopenic Purpura Complicated by Hepatitis C Virus-related Membranoproliferative Glomerulonephritis after Rituximab Therapy. We herein report the case of a 54-year-old Japanese man with hepatitis C virus (HCV)-related membranoproliferative glomerulonephritis (MPGN), which developed at the time of relapse of immune thrombocytopenic purpura (ITP) after rituximab therapy. Antiviral therapy for HCV led to the improvement of both MPGN and ITP. Rituximab therapy may have contributed to the exacerbation of HCV infection and induced the development of HCV-related MPGN and the relapse of ITP. Our case suggested that HCV treatment should be prioritized over rituximab therapy for HCV-positive patients with ITP and that antiviral therapy for HCV may be effective for treating ITP itself. Introduction Immune thrombocytopenic purpura (ITP) is an immune-mediated acquired disease that is characterized by a transient or persistent decrease in the platelet count and an increased risk of bleeding (1,2). According to the Japanese guidelines for adult ITP (3), ITP treatment includes Helicobacter pylori eradication therapy and corticosteroid therapy as the first choice, and thrombopoietin receptor agonist, splenectomy, and rituximab therapy as the second choice. Rituximab is a chimeric monoclonal antibody against the CD20 antigen, which specifically eliminates CD20-positive B lymphocytes and reduces antibody production. In Japan, rituximab has been approved for the treatment of ITP since 2017 (4) and it is now used on a daily basis. It is widely known that the reactivation of hepatitis B virus (HBV) may occur in patients treated with rituximab-containing regimens, and there are guidelines aimed at its prevention (5). In contrast, with regard to hepatitis C virus (HCV), the onset of fulminant hepatitis is extremely rare, and there are no guidelines for its prevention (6). However, there are also some reports on the exacerbation of HCV infection by rituximab-containing regimens (7,8). We herein report a case of refractory ITP complicated by HCV-related membranoproliferative glomerulonephritis (MPGN) that developed after the initiation of rituximab therapy. Case Report A 54-year-old Japanese man was diagnosed with ITP at 25 years of age. He was treated with prednisolone (PSL), cyclosporin, azathioprine, high-dose intravenous immunoglobulin therapy, and eltrombopag. The effects of these treatments were all limited. Romiplostim (10 μg/kg) and PSL (10 mg) were continued for a long time. However, the dose of PSL often needed to be increased because the patient's platelet count dropped to <10.0×109/L with bleeding symptoms. The platelet-associated IgG value was in the range of 200-300 ng/107 cells. Due to long-term steroid therapy, he developed thin skin and obesity (body mass index, 30.2 kg/m2). Voglibose, linagliptin, olmesartan medoxomil/azelnidipine, enalapril maleate, and febuxostat were continued as treatments for hypertension, diabetes mellitus and hyperuricemia. Diabetic retinopathy was never noted. The estimated glomerular filtration rate remained at just over 60 mL/min/1.73 m2. Although HCV antibody positivity was pointed out, he was followed up without any treatment because there was no liver disorder. In November 2017, rituximab (375 mg/m2 per week) was administered four times. His platelet count increased and the PSL dosage could be decreased to 4 mg. In March 2018, however, his platelet count dropped in 8.0×109/L. 40 mg dexamethasone for 4 days was performed and the platelet count increased. Renal dysfunction appeared during the same period and it also worsened. Severe edema was noted on both lower legs and diuretics were required. No joint pain, swelling, Raynaud's symptoms, or numbness of the fingers or toes was observed. In April 2018, the serum creatinine concentration rose to 7.81 mg/dL and he was urgently hospitalized. A physical examination on admission revealed the following: body temperature, 35.8℃; heart rate, 84 bpm; blood pressure, 147/80 mmHg; and respiratory rate, 19 breaths/min. His oxygen saturation was 99% while breathing room air. A physical examination revealed purpura on his hand and breast. No edema was found in either of the lower limbs on admission. The laboratory findings are shown in Table. The patient's platelet count had increased due to the administration of high-dose dexamethasone therapy just before admission. He presented with mild liver dysfunction, severe renal dysfunction, and hyperkalemia due to renal dysfunction. The levels of complement proteins were low. A cryoglobulin test was positive, and IgG and IgM cryoglobulins were detected. Because M-protein was not found by immunoelectrophoresis, Type III cryoglobulinemia was thus diagnosed. A urinalysis revealed protein, occult blood, and various urinary casts. Abdominal echography showed normally sized kidneys, increased echogenicity of the renal parenchyma, and renal cysts. There were moderate to large amount of ascites without findings suggestive of cirrhosis. A renal biopsy revealed an enlargement of the glomeruli with mesangial proliferation, lobulation of the glomeruli (Fig. 1a, b), and double contours in the basement membranes (Fig. 1c, arrow). Microtubule-like deposits were diffusely observed in the subendothelial basement membrane and paramesagiual area on electron microscopy (Fig. 1c, d). Immunofluorescence staining showed IgM positivity in the basement membrane in the form of small granules (Fig. 1e), while IgG and C3 were negative (Fig. 1f, g). There was no marked difference between kappa and lambda staining. Exudative lesions in the capillaries were observed in some glomeruli (Fig. 1h, arrow). Table. Laboratory Examination at the Admission. Complete blood cell count Blood chemistry Serological test White blood cell 9.0 ×109/L Total protein 5.3 g/dL C-reactive protein 0.77 mg/dL Neutrophil 87.4 % Albumin 3.5 g/dL IgG/IgA/IgM 990/89/49 mg/dL Lymphocyte 10.2 % Aspartate transaminase 69 U/L M-protein negative Eosinophil 0.1 % Alanine aminotransferase 64 U/L C3 61 mg/dL (73-138) Hemoglobin 11.4 g/dL Lactate dehydrogenase 364 U/L C4 14 mg/dL (86-138) Hematocrit 35.1 % Alkaline phosphatase 400 U/L CH50 28.0 U/mL (31.6-57.6) Platelet count 136.0 ×109/L Total bilirubin 0.5 mg/dL Cryoglobulin positive Urea nitrogen 75 mg/dL Antinuclear antibody ×80 Coagulation test Creatinin 7.81 mg/mL Rheumatoid factor <5.0 IU/mL PT-INR 1.04 Sodium 137 mEq/L ds-DNA antibody <0.5 U/mL APTT 45.3 sec Potassium 5.8 mEq/L MPO/PR3-ANCA <1.0/<1.0 U/mL Fibrinogen 273 mg/dL Corrected calcium 8.4 mg/dL Anti-SS-A/B antibody <1.0/<1.0 U/mL D-dimer 0.7 μg/mL eGFR 6.7 mL/min/1.73m2 Anti-GBM antibody <2.0 U/mL Urine test Virological examination Protein 3+ White blood cell <0-1 /HPF Hepatitis B surface antigen (-) Glucose 1+ Red blood cell 1-4 / HPF HCV-antibody (+) Occult blood 1+ Oval fat body + Granular cast + HCV-genotype 2a Protein 6.20 g/gCre Hyalin cast + Fatty cast + HCV-RNA 6.5 log IU/mL Waxy cast + Epithelial cast + PT-INR: international normalized ratio, APTT: activated partial thromboplastin, HCV: hepatitis C virus, Cre: creatinine, Ig: immunoglobulin, MPO: myeloperoxidase, PR3: proteinase 3, ANCA: anti-neutrophil cytoplasmic antibody, SS: Sjogren’s syndrome, GBM: glomerular basement membrane, HPF: high power field. The numbers in parentheses after the C3, C4, and CH50 values are the normal range at the time of measurement Figure 1. Renal biopsy revealed enlargement of the glomeruli with mesangial proliferation, lobulation of the glomeruli (a, b), and double contours in the basement membranes (c, arrow). Microtubule-like deposits are diffusely observed in the subendothelial basement membrane and paramesagiual area on electron microscopy. (c, d) Immunofluorescence staining revealed IgM positivity in the basement membrane in the form of small granules (e), while IgG and C3 were negative (f, g). Exudative lesions in capillaries were observed in some glomeruli (h, arrow). The main cause of renal failure was diagnosed as HCV-related MPGN, which is classified as immune complex-mediated MPGN, and diabetic nephropathy was also considered to be present. The administration of glecaprevir hydrate/pibrentasvir for 12 weeks was initiated and the dose of PSL was increased to 30 mg for 2 weeks. At two weeks after the start of the antiviral therapy, HCV-RNA was no longer detected. The serum creatinine levels tended to improve, and the urinary occult blood disappeared, although mild proteinuria remained. The dose of PSL was gradually reduced to 3 mg, and the dose of romiplostim was reduced to 5 μg/kg. Because the platelet count decreased again, the dose of romiplostim was returned to 10 μg/kg. More than one year has passed since the dose of PSL was reduced to 2 mg. Although the patient's platelet count has fluctuated, no clear bleeding tendency has been observed (Fig. 2). With the reduction of the PSL dose, the patient's body mass index improved to 23.1 kg/m2, and voglibose and linagliptin could be discontinued. The levels of complement protein improved to 13 (normal range, 11-31) mg/dL for C3, 56 (73-138) mg/dL for C4, and 36.6 (25.0-48.0) U/mL for CH50. The elevated serum creatinine level and mild proteinuria persisted, a finding that was attributed to the diabetic nephropathy, and the management of chronic kidney disease was continued with a focus on antihypertensive therapy. Figure 2. The clinical course. HD-DEX: high dose dexamethasone, eGFR: estimated glomerular filtration rate, HCV: hepatitis C virus Discussion MPGN is a type of glomerulonephritis that is characterized by mesangial proliferation and basement membrane duplication. The clinical presentation and course are extremely variable (9). MPGN occurs as a primary or secondary condition. Secondary MPGN is most often due to hepatitis C and other infections (10). Patients with HCV-related MPGN have a higher incidence of liver dysfunction, cryoglobulinemia, rheumatoid factor, and hypocomplementemia (11,12). In our case, after rituximab therapy HCV-related MPGN developed with a relapse of ITP and both improved with antiviral therapy for HCV. HCV-RNA elevation due to rituximab therapy may have contributed to the development of MPGN and the relapse of ITP. Unfortunately, however, the patient's HCV-RNA levels were not measured until the onset of MPGN, as there was no liver disorder nor any indication for antiviral therapy. This clinical course may have been due to an iatrogenic cause. At the very least, the HCV-RNA levels should have been monitored before the initiation of rituximab therapy. Several reports have described the successful treatment of MPGN with rituximab therapy. The addition of rituximab therapy to antiviral therapy for HCV-related MPGN is well tolerated and it has been reported to be more effective than antiviral therapy alone (13,14). Mak et al. described the successful treatment of thrombotic thrombocytopenic purpura and MPGN with rituximab therapy in a case associated with HCV infection (15). In that case, the MPGN improved, but liver dysfunction and HCV-RNA elevation were transiently observed. In contrast to the present case, neither a blood examination nor a renal biopsy showed cryoglobulin. There is no doubt that rituximab is effective as a treatment for MPGN itself. However, it may not be possible to prevent the onset of MPGN, and in our case, it was considered that rituximab indirectly induced MPGN. In individuals who are infected with HCV, the incidence of ITP is increased in comparison individuals without HCV infection (16). Several reports have suggested that HCV infection is involved in the development of ITP through various mechanisms (16-18). Johia et al. described the case of an HCV-positive patient with refractory ITP in whom the eradication of HCV was effective for ITP (18). In this case, although rituximab therapy seemed to improve the responsiveness of ITP to steroid therapy, the reduced dose of PSL (4 mg) caused a relapse of ITP. Although the combined use of romiplostim was still necessary after antiviral therapy for HCV, the dosage of PSL could be reduced to 2 mg, suggesting that antiviral therapy for HCV was also effective against ITP. Thrombocytopenia is no longer a major problem in the treatment of chronic HCV infection because of the recent change in direct antiviral agents without interferon (19). The US guidelines for ITP recommend that testing for HCV be considered in all patients with acute ITP and that antiviral therapy be considered in HCV-positive patients with ITP in the absence of contraindications (20). Although whether or not all HCV-positive patients with ITP should be treated remains controversial in Japan, antiviral therapy for HCV should be actively performed as a treatment for refractory ITP. At least, it is certain that antiviral therapy for HCV should be given before rituximab therapy. In conclusion, we experienced a case in which HCV-related MPGN that developed with a relapse of ITP after rituximab therapy, in which both conditions were improved by antiviral therapy for HCV. Rituximab therapy may have contributed to the exacerbation of HCV infection and induced the development of HCV-related MPGN and relapse of ITP. Our case suggested that HCV treatment should be prioritized over rituximab therapy for HCV-positive patients with ITP and that antiviral therapy for HCV may be effective for ITP itself. The authors state that they have no Conflict of Interest (COI). Acknowledgement The authors would like to thank Yoshitaka Miyakawa of Department of General Internal Medicine, Saitama Medical University for his advice on the treatment of ITP in the present case.	AZELNIDIPINE, DEXAMETHASONE, ENALAPRIL MALEATE, FEBUXOSTAT, LINAGLIPTIN, OLMESARTAN MEDOXOMIL, PREDNISOLONE, RITUXIMAB, ROMIPLOSTIM, VOGLIBOSE	DrugsGivenReaction	CC BY-NC-ND	33583904	18,544,239	2021-08-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatic function abnormal'.	Immune Thrombocytopenic Purpura Complicated by Hepatitis C Virus-related Membranoproliferative Glomerulonephritis after Rituximab Therapy. We herein report the case of a 54-year-old Japanese man with hepatitis C virus (HCV)-related membranoproliferative glomerulonephritis (MPGN), which developed at the time of relapse of immune thrombocytopenic purpura (ITP) after rituximab therapy. Antiviral therapy for HCV led to the improvement of both MPGN and ITP. Rituximab therapy may have contributed to the exacerbation of HCV infection and induced the development of HCV-related MPGN and the relapse of ITP. Our case suggested that HCV treatment should be prioritized over rituximab therapy for HCV-positive patients with ITP and that antiviral therapy for HCV may be effective for treating ITP itself. Introduction Immune thrombocytopenic purpura (ITP) is an immune-mediated acquired disease that is characterized by a transient or persistent decrease in the platelet count and an increased risk of bleeding (1,2). According to the Japanese guidelines for adult ITP (3), ITP treatment includes Helicobacter pylori eradication therapy and corticosteroid therapy as the first choice, and thrombopoietin receptor agonist, splenectomy, and rituximab therapy as the second choice. Rituximab is a chimeric monoclonal antibody against the CD20 antigen, which specifically eliminates CD20-positive B lymphocytes and reduces antibody production. In Japan, rituximab has been approved for the treatment of ITP since 2017 (4) and it is now used on a daily basis. It is widely known that the reactivation of hepatitis B virus (HBV) may occur in patients treated with rituximab-containing regimens, and there are guidelines aimed at its prevention (5). In contrast, with regard to hepatitis C virus (HCV), the onset of fulminant hepatitis is extremely rare, and there are no guidelines for its prevention (6). However, there are also some reports on the exacerbation of HCV infection by rituximab-containing regimens (7,8). We herein report a case of refractory ITP complicated by HCV-related membranoproliferative glomerulonephritis (MPGN) that developed after the initiation of rituximab therapy. Case Report A 54-year-old Japanese man was diagnosed with ITP at 25 years of age. He was treated with prednisolone (PSL), cyclosporin, azathioprine, high-dose intravenous immunoglobulin therapy, and eltrombopag. The effects of these treatments were all limited. Romiplostim (10 μg/kg) and PSL (10 mg) were continued for a long time. However, the dose of PSL often needed to be increased because the patient's platelet count dropped to <10.0×109/L with bleeding symptoms. The platelet-associated IgG value was in the range of 200-300 ng/107 cells. Due to long-term steroid therapy, he developed thin skin and obesity (body mass index, 30.2 kg/m2). Voglibose, linagliptin, olmesartan medoxomil/azelnidipine, enalapril maleate, and febuxostat were continued as treatments for hypertension, diabetes mellitus and hyperuricemia. Diabetic retinopathy was never noted. The estimated glomerular filtration rate remained at just over 60 mL/min/1.73 m2. Although HCV antibody positivity was pointed out, he was followed up without any treatment because there was no liver disorder. In November 2017, rituximab (375 mg/m2 per week) was administered four times. His platelet count increased and the PSL dosage could be decreased to 4 mg. In March 2018, however, his platelet count dropped in 8.0×109/L. 40 mg dexamethasone for 4 days was performed and the platelet count increased. Renal dysfunction appeared during the same period and it also worsened. Severe edema was noted on both lower legs and diuretics were required. No joint pain, swelling, Raynaud's symptoms, or numbness of the fingers or toes was observed. In April 2018, the serum creatinine concentration rose to 7.81 mg/dL and he was urgently hospitalized. A physical examination on admission revealed the following: body temperature, 35.8℃; heart rate, 84 bpm; blood pressure, 147/80 mmHg; and respiratory rate, 19 breaths/min. His oxygen saturation was 99% while breathing room air. A physical examination revealed purpura on his hand and breast. No edema was found in either of the lower limbs on admission. The laboratory findings are shown in Table. The patient's platelet count had increased due to the administration of high-dose dexamethasone therapy just before admission. He presented with mild liver dysfunction, severe renal dysfunction, and hyperkalemia due to renal dysfunction. The levels of complement proteins were low. A cryoglobulin test was positive, and IgG and IgM cryoglobulins were detected. Because M-protein was not found by immunoelectrophoresis, Type III cryoglobulinemia was thus diagnosed. A urinalysis revealed protein, occult blood, and various urinary casts. Abdominal echography showed normally sized kidneys, increased echogenicity of the renal parenchyma, and renal cysts. There were moderate to large amount of ascites without findings suggestive of cirrhosis. A renal biopsy revealed an enlargement of the glomeruli with mesangial proliferation, lobulation of the glomeruli (Fig. 1a, b), and double contours in the basement membranes (Fig. 1c, arrow). Microtubule-like deposits were diffusely observed in the subendothelial basement membrane and paramesagiual area on electron microscopy (Fig. 1c, d). Immunofluorescence staining showed IgM positivity in the basement membrane in the form of small granules (Fig. 1e), while IgG and C3 were negative (Fig. 1f, g). There was no marked difference between kappa and lambda staining. Exudative lesions in the capillaries were observed in some glomeruli (Fig. 1h, arrow). Table. Laboratory Examination at the Admission. Complete blood cell count Blood chemistry Serological test White blood cell 9.0 ×109/L Total protein 5.3 g/dL C-reactive protein 0.77 mg/dL Neutrophil 87.4 % Albumin 3.5 g/dL IgG/IgA/IgM 990/89/49 mg/dL Lymphocyte 10.2 % Aspartate transaminase 69 U/L M-protein negative Eosinophil 0.1 % Alanine aminotransferase 64 U/L C3 61 mg/dL (73-138) Hemoglobin 11.4 g/dL Lactate dehydrogenase 364 U/L C4 14 mg/dL (86-138) Hematocrit 35.1 % Alkaline phosphatase 400 U/L CH50 28.0 U/mL (31.6-57.6) Platelet count 136.0 ×109/L Total bilirubin 0.5 mg/dL Cryoglobulin positive Urea nitrogen 75 mg/dL Antinuclear antibody ×80 Coagulation test Creatinin 7.81 mg/mL Rheumatoid factor <5.0 IU/mL PT-INR 1.04 Sodium 137 mEq/L ds-DNA antibody <0.5 U/mL APTT 45.3 sec Potassium 5.8 mEq/L MPO/PR3-ANCA <1.0/<1.0 U/mL Fibrinogen 273 mg/dL Corrected calcium 8.4 mg/dL Anti-SS-A/B antibody <1.0/<1.0 U/mL D-dimer 0.7 μg/mL eGFR 6.7 mL/min/1.73m2 Anti-GBM antibody <2.0 U/mL Urine test Virological examination Protein 3+ White blood cell <0-1 /HPF Hepatitis B surface antigen (-) Glucose 1+ Red blood cell 1-4 / HPF HCV-antibody (+) Occult blood 1+ Oval fat body + Granular cast + HCV-genotype 2a Protein 6.20 g/gCre Hyalin cast + Fatty cast + HCV-RNA 6.5 log IU/mL Waxy cast + Epithelial cast + PT-INR: international normalized ratio, APTT: activated partial thromboplastin, HCV: hepatitis C virus, Cre: creatinine, Ig: immunoglobulin, MPO: myeloperoxidase, PR3: proteinase 3, ANCA: anti-neutrophil cytoplasmic antibody, SS: Sjogren’s syndrome, GBM: glomerular basement membrane, HPF: high power field. The numbers in parentheses after the C3, C4, and CH50 values are the normal range at the time of measurement Figure 1. Renal biopsy revealed enlargement of the glomeruli with mesangial proliferation, lobulation of the glomeruli (a, b), and double contours in the basement membranes (c, arrow). Microtubule-like deposits are diffusely observed in the subendothelial basement membrane and paramesagiual area on electron microscopy. (c, d) Immunofluorescence staining revealed IgM positivity in the basement membrane in the form of small granules (e), while IgG and C3 were negative (f, g). Exudative lesions in capillaries were observed in some glomeruli (h, arrow). The main cause of renal failure was diagnosed as HCV-related MPGN, which is classified as immune complex-mediated MPGN, and diabetic nephropathy was also considered to be present. The administration of glecaprevir hydrate/pibrentasvir for 12 weeks was initiated and the dose of PSL was increased to 30 mg for 2 weeks. At two weeks after the start of the antiviral therapy, HCV-RNA was no longer detected. The serum creatinine levels tended to improve, and the urinary occult blood disappeared, although mild proteinuria remained. The dose of PSL was gradually reduced to 3 mg, and the dose of romiplostim was reduced to 5 μg/kg. Because the platelet count decreased again, the dose of romiplostim was returned to 10 μg/kg. More than one year has passed since the dose of PSL was reduced to 2 mg. Although the patient's platelet count has fluctuated, no clear bleeding tendency has been observed (Fig. 2). With the reduction of the PSL dose, the patient's body mass index improved to 23.1 kg/m2, and voglibose and linagliptin could be discontinued. The levels of complement protein improved to 13 (normal range, 11-31) mg/dL for C3, 56 (73-138) mg/dL for C4, and 36.6 (25.0-48.0) U/mL for CH50. The elevated serum creatinine level and mild proteinuria persisted, a finding that was attributed to the diabetic nephropathy, and the management of chronic kidney disease was continued with a focus on antihypertensive therapy. Figure 2. The clinical course. HD-DEX: high dose dexamethasone, eGFR: estimated glomerular filtration rate, HCV: hepatitis C virus Discussion MPGN is a type of glomerulonephritis that is characterized by mesangial proliferation and basement membrane duplication. The clinical presentation and course are extremely variable (9). MPGN occurs as a primary or secondary condition. Secondary MPGN is most often due to hepatitis C and other infections (10). Patients with HCV-related MPGN have a higher incidence of liver dysfunction, cryoglobulinemia, rheumatoid factor, and hypocomplementemia (11,12). In our case, after rituximab therapy HCV-related MPGN developed with a relapse of ITP and both improved with antiviral therapy for HCV. HCV-RNA elevation due to rituximab therapy may have contributed to the development of MPGN and the relapse of ITP. Unfortunately, however, the patient's HCV-RNA levels were not measured until the onset of MPGN, as there was no liver disorder nor any indication for antiviral therapy. This clinical course may have been due to an iatrogenic cause. At the very least, the HCV-RNA levels should have been monitored before the initiation of rituximab therapy. Several reports have described the successful treatment of MPGN with rituximab therapy. The addition of rituximab therapy to antiviral therapy for HCV-related MPGN is well tolerated and it has been reported to be more effective than antiviral therapy alone (13,14). Mak et al. described the successful treatment of thrombotic thrombocytopenic purpura and MPGN with rituximab therapy in a case associated with HCV infection (15). In that case, the MPGN improved, but liver dysfunction and HCV-RNA elevation were transiently observed. In contrast to the present case, neither a blood examination nor a renal biopsy showed cryoglobulin. There is no doubt that rituximab is effective as a treatment for MPGN itself. However, it may not be possible to prevent the onset of MPGN, and in our case, it was considered that rituximab indirectly induced MPGN. In individuals who are infected with HCV, the incidence of ITP is increased in comparison individuals without HCV infection (16). Several reports have suggested that HCV infection is involved in the development of ITP through various mechanisms (16-18). Johia et al. described the case of an HCV-positive patient with refractory ITP in whom the eradication of HCV was effective for ITP (18). In this case, although rituximab therapy seemed to improve the responsiveness of ITP to steroid therapy, the reduced dose of PSL (4 mg) caused a relapse of ITP. Although the combined use of romiplostim was still necessary after antiviral therapy for HCV, the dosage of PSL could be reduced to 2 mg, suggesting that antiviral therapy for HCV was also effective against ITP. Thrombocytopenia is no longer a major problem in the treatment of chronic HCV infection because of the recent change in direct antiviral agents without interferon (19). The US guidelines for ITP recommend that testing for HCV be considered in all patients with acute ITP and that antiviral therapy be considered in HCV-positive patients with ITP in the absence of contraindications (20). Although whether or not all HCV-positive patients with ITP should be treated remains controversial in Japan, antiviral therapy for HCV should be actively performed as a treatment for refractory ITP. At least, it is certain that antiviral therapy for HCV should be given before rituximab therapy. In conclusion, we experienced a case in which HCV-related MPGN that developed with a relapse of ITP after rituximab therapy, in which both conditions were improved by antiviral therapy for HCV. Rituximab therapy may have contributed to the exacerbation of HCV infection and induced the development of HCV-related MPGN and relapse of ITP. Our case suggested that HCV treatment should be prioritized over rituximab therapy for HCV-positive patients with ITP and that antiviral therapy for HCV may be effective for ITP itself. The authors state that they have no Conflict of Interest (COI). Acknowledgement The authors would like to thank Yoshitaka Miyakawa of Department of General Internal Medicine, Saitama Medical University for his advice on the treatment of ITP in the present case.	AZELNIDIPINE, DEXAMETHASONE, ENALAPRIL MALEATE, FEBUXOSTAT, LINAGLIPTIN, OLMESARTAN MEDOXOMIL, PREDNISOLONE, RITUXIMAB, ROMIPLOSTIM, VOGLIBOSE	DrugsGivenReaction	CC BY-NC-ND	33583904	18,544,239	2021-08-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatitis C'.	Immune Thrombocytopenic Purpura Complicated by Hepatitis C Virus-related Membranoproliferative Glomerulonephritis after Rituximab Therapy. We herein report the case of a 54-year-old Japanese man with hepatitis C virus (HCV)-related membranoproliferative glomerulonephritis (MPGN), which developed at the time of relapse of immune thrombocytopenic purpura (ITP) after rituximab therapy. Antiviral therapy for HCV led to the improvement of both MPGN and ITP. Rituximab therapy may have contributed to the exacerbation of HCV infection and induced the development of HCV-related MPGN and the relapse of ITP. Our case suggested that HCV treatment should be prioritized over rituximab therapy for HCV-positive patients with ITP and that antiviral therapy for HCV may be effective for treating ITP itself. Introduction Immune thrombocytopenic purpura (ITP) is an immune-mediated acquired disease that is characterized by a transient or persistent decrease in the platelet count and an increased risk of bleeding (1,2). According to the Japanese guidelines for adult ITP (3), ITP treatment includes Helicobacter pylori eradication therapy and corticosteroid therapy as the first choice, and thrombopoietin receptor agonist, splenectomy, and rituximab therapy as the second choice. Rituximab is a chimeric monoclonal antibody against the CD20 antigen, which specifically eliminates CD20-positive B lymphocytes and reduces antibody production. In Japan, rituximab has been approved for the treatment of ITP since 2017 (4) and it is now used on a daily basis. It is widely known that the reactivation of hepatitis B virus (HBV) may occur in patients treated with rituximab-containing regimens, and there are guidelines aimed at its prevention (5). In contrast, with regard to hepatitis C virus (HCV), the onset of fulminant hepatitis is extremely rare, and there are no guidelines for its prevention (6). However, there are also some reports on the exacerbation of HCV infection by rituximab-containing regimens (7,8). We herein report a case of refractory ITP complicated by HCV-related membranoproliferative glomerulonephritis (MPGN) that developed after the initiation of rituximab therapy. Case Report A 54-year-old Japanese man was diagnosed with ITP at 25 years of age. He was treated with prednisolone (PSL), cyclosporin, azathioprine, high-dose intravenous immunoglobulin therapy, and eltrombopag. The effects of these treatments were all limited. Romiplostim (10 μg/kg) and PSL (10 mg) were continued for a long time. However, the dose of PSL often needed to be increased because the patient's platelet count dropped to <10.0×109/L with bleeding symptoms. The platelet-associated IgG value was in the range of 200-300 ng/107 cells. Due to long-term steroid therapy, he developed thin skin and obesity (body mass index, 30.2 kg/m2). Voglibose, linagliptin, olmesartan medoxomil/azelnidipine, enalapril maleate, and febuxostat were continued as treatments for hypertension, diabetes mellitus and hyperuricemia. Diabetic retinopathy was never noted. The estimated glomerular filtration rate remained at just over 60 mL/min/1.73 m2. Although HCV antibody positivity was pointed out, he was followed up without any treatment because there was no liver disorder. In November 2017, rituximab (375 mg/m2 per week) was administered four times. His platelet count increased and the PSL dosage could be decreased to 4 mg. In March 2018, however, his platelet count dropped in 8.0×109/L. 40 mg dexamethasone for 4 days was performed and the platelet count increased. Renal dysfunction appeared during the same period and it also worsened. Severe edema was noted on both lower legs and diuretics were required. No joint pain, swelling, Raynaud's symptoms, or numbness of the fingers or toes was observed. In April 2018, the serum creatinine concentration rose to 7.81 mg/dL and he was urgently hospitalized. A physical examination on admission revealed the following: body temperature, 35.8℃; heart rate, 84 bpm; blood pressure, 147/80 mmHg; and respiratory rate, 19 breaths/min. His oxygen saturation was 99% while breathing room air. A physical examination revealed purpura on his hand and breast. No edema was found in either of the lower limbs on admission. The laboratory findings are shown in Table. The patient's platelet count had increased due to the administration of high-dose dexamethasone therapy just before admission. He presented with mild liver dysfunction, severe renal dysfunction, and hyperkalemia due to renal dysfunction. The levels of complement proteins were low. A cryoglobulin test was positive, and IgG and IgM cryoglobulins were detected. Because M-protein was not found by immunoelectrophoresis, Type III cryoglobulinemia was thus diagnosed. A urinalysis revealed protein, occult blood, and various urinary casts. Abdominal echography showed normally sized kidneys, increased echogenicity of the renal parenchyma, and renal cysts. There were moderate to large amount of ascites without findings suggestive of cirrhosis. A renal biopsy revealed an enlargement of the glomeruli with mesangial proliferation, lobulation of the glomeruli (Fig. 1a, b), and double contours in the basement membranes (Fig. 1c, arrow). Microtubule-like deposits were diffusely observed in the subendothelial basement membrane and paramesagiual area on electron microscopy (Fig. 1c, d). Immunofluorescence staining showed IgM positivity in the basement membrane in the form of small granules (Fig. 1e), while IgG and C3 were negative (Fig. 1f, g). There was no marked difference between kappa and lambda staining. Exudative lesions in the capillaries were observed in some glomeruli (Fig. 1h, arrow). Table. Laboratory Examination at the Admission. Complete blood cell count Blood chemistry Serological test White blood cell 9.0 ×109/L Total protein 5.3 g/dL C-reactive protein 0.77 mg/dL Neutrophil 87.4 % Albumin 3.5 g/dL IgG/IgA/IgM 990/89/49 mg/dL Lymphocyte 10.2 % Aspartate transaminase 69 U/L M-protein negative Eosinophil 0.1 % Alanine aminotransferase 64 U/L C3 61 mg/dL (73-138) Hemoglobin 11.4 g/dL Lactate dehydrogenase 364 U/L C4 14 mg/dL (86-138) Hematocrit 35.1 % Alkaline phosphatase 400 U/L CH50 28.0 U/mL (31.6-57.6) Platelet count 136.0 ×109/L Total bilirubin 0.5 mg/dL Cryoglobulin positive Urea nitrogen 75 mg/dL Antinuclear antibody ×80 Coagulation test Creatinin 7.81 mg/mL Rheumatoid factor <5.0 IU/mL PT-INR 1.04 Sodium 137 mEq/L ds-DNA antibody <0.5 U/mL APTT 45.3 sec Potassium 5.8 mEq/L MPO/PR3-ANCA <1.0/<1.0 U/mL Fibrinogen 273 mg/dL Corrected calcium 8.4 mg/dL Anti-SS-A/B antibody <1.0/<1.0 U/mL D-dimer 0.7 μg/mL eGFR 6.7 mL/min/1.73m2 Anti-GBM antibody <2.0 U/mL Urine test Virological examination Protein 3+ White blood cell <0-1 /HPF Hepatitis B surface antigen (-) Glucose 1+ Red blood cell 1-4 / HPF HCV-antibody (+) Occult blood 1+ Oval fat body + Granular cast + HCV-genotype 2a Protein 6.20 g/gCre Hyalin cast + Fatty cast + HCV-RNA 6.5 log IU/mL Waxy cast + Epithelial cast + PT-INR: international normalized ratio, APTT: activated partial thromboplastin, HCV: hepatitis C virus, Cre: creatinine, Ig: immunoglobulin, MPO: myeloperoxidase, PR3: proteinase 3, ANCA: anti-neutrophil cytoplasmic antibody, SS: Sjogren’s syndrome, GBM: glomerular basement membrane, HPF: high power field. The numbers in parentheses after the C3, C4, and CH50 values are the normal range at the time of measurement Figure 1. Renal biopsy revealed enlargement of the glomeruli with mesangial proliferation, lobulation of the glomeruli (a, b), and double contours in the basement membranes (c, arrow). Microtubule-like deposits are diffusely observed in the subendothelial basement membrane and paramesagiual area on electron microscopy. (c, d) Immunofluorescence staining revealed IgM positivity in the basement membrane in the form of small granules (e), while IgG and C3 were negative (f, g). Exudative lesions in capillaries were observed in some glomeruli (h, arrow). The main cause of renal failure was diagnosed as HCV-related MPGN, which is classified as immune complex-mediated MPGN, and diabetic nephropathy was also considered to be present. The administration of glecaprevir hydrate/pibrentasvir for 12 weeks was initiated and the dose of PSL was increased to 30 mg for 2 weeks. At two weeks after the start of the antiviral therapy, HCV-RNA was no longer detected. The serum creatinine levels tended to improve, and the urinary occult blood disappeared, although mild proteinuria remained. The dose of PSL was gradually reduced to 3 mg, and the dose of romiplostim was reduced to 5 μg/kg. Because the platelet count decreased again, the dose of romiplostim was returned to 10 μg/kg. More than one year has passed since the dose of PSL was reduced to 2 mg. Although the patient's platelet count has fluctuated, no clear bleeding tendency has been observed (Fig. 2). With the reduction of the PSL dose, the patient's body mass index improved to 23.1 kg/m2, and voglibose and linagliptin could be discontinued. The levels of complement protein improved to 13 (normal range, 11-31) mg/dL for C3, 56 (73-138) mg/dL for C4, and 36.6 (25.0-48.0) U/mL for CH50. The elevated serum creatinine level and mild proteinuria persisted, a finding that was attributed to the diabetic nephropathy, and the management of chronic kidney disease was continued with a focus on antihypertensive therapy. Figure 2. The clinical course. HD-DEX: high dose dexamethasone, eGFR: estimated glomerular filtration rate, HCV: hepatitis C virus Discussion MPGN is a type of glomerulonephritis that is characterized by mesangial proliferation and basement membrane duplication. The clinical presentation and course are extremely variable (9). MPGN occurs as a primary or secondary condition. Secondary MPGN is most often due to hepatitis C and other infections (10). Patients with HCV-related MPGN have a higher incidence of liver dysfunction, cryoglobulinemia, rheumatoid factor, and hypocomplementemia (11,12). In our case, after rituximab therapy HCV-related MPGN developed with a relapse of ITP and both improved with antiviral therapy for HCV. HCV-RNA elevation due to rituximab therapy may have contributed to the development of MPGN and the relapse of ITP. Unfortunately, however, the patient's HCV-RNA levels were not measured until the onset of MPGN, as there was no liver disorder nor any indication for antiviral therapy. This clinical course may have been due to an iatrogenic cause. At the very least, the HCV-RNA levels should have been monitored before the initiation of rituximab therapy. Several reports have described the successful treatment of MPGN with rituximab therapy. The addition of rituximab therapy to antiviral therapy for HCV-related MPGN is well tolerated and it has been reported to be more effective than antiviral therapy alone (13,14). Mak et al. described the successful treatment of thrombotic thrombocytopenic purpura and MPGN with rituximab therapy in a case associated with HCV infection (15). In that case, the MPGN improved, but liver dysfunction and HCV-RNA elevation were transiently observed. In contrast to the present case, neither a blood examination nor a renal biopsy showed cryoglobulin. There is no doubt that rituximab is effective as a treatment for MPGN itself. However, it may not be possible to prevent the onset of MPGN, and in our case, it was considered that rituximab indirectly induced MPGN. In individuals who are infected with HCV, the incidence of ITP is increased in comparison individuals without HCV infection (16). Several reports have suggested that HCV infection is involved in the development of ITP through various mechanisms (16-18). Johia et al. described the case of an HCV-positive patient with refractory ITP in whom the eradication of HCV was effective for ITP (18). In this case, although rituximab therapy seemed to improve the responsiveness of ITP to steroid therapy, the reduced dose of PSL (4 mg) caused a relapse of ITP. Although the combined use of romiplostim was still necessary after antiviral therapy for HCV, the dosage of PSL could be reduced to 2 mg, suggesting that antiviral therapy for HCV was also effective against ITP. Thrombocytopenia is no longer a major problem in the treatment of chronic HCV infection because of the recent change in direct antiviral agents without interferon (19). The US guidelines for ITP recommend that testing for HCV be considered in all patients with acute ITP and that antiviral therapy be considered in HCV-positive patients with ITP in the absence of contraindications (20). Although whether or not all HCV-positive patients with ITP should be treated remains controversial in Japan, antiviral therapy for HCV should be actively performed as a treatment for refractory ITP. At least, it is certain that antiviral therapy for HCV should be given before rituximab therapy. In conclusion, we experienced a case in which HCV-related MPGN that developed with a relapse of ITP after rituximab therapy, in which both conditions were improved by antiviral therapy for HCV. Rituximab therapy may have contributed to the exacerbation of HCV infection and induced the development of HCV-related MPGN and relapse of ITP. Our case suggested that HCV treatment should be prioritized over rituximab therapy for HCV-positive patients with ITP and that antiviral therapy for HCV may be effective for ITP itself. The authors state that they have no Conflict of Interest (COI). Acknowledgement The authors would like to thank Yoshitaka Miyakawa of Department of General Internal Medicine, Saitama Medical University for his advice on the treatment of ITP in the present case.	AZELNIDIPINE, DEXAMETHASONE, ENALAPRIL MALEATE, FEBUXOSTAT, LINAGLIPTIN, OLMESARTAN MEDOXOMIL, PREDNISOLONE, RITUXIMAB, ROMIPLOSTIM, VOGLIBOSE	DrugsGivenReaction	CC BY-NC-ND	33583904	18,544,239	2021-08-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal failure'.	Immune Thrombocytopenic Purpura Complicated by Hepatitis C Virus-related Membranoproliferative Glomerulonephritis after Rituximab Therapy. We herein report the case of a 54-year-old Japanese man with hepatitis C virus (HCV)-related membranoproliferative glomerulonephritis (MPGN), which developed at the time of relapse of immune thrombocytopenic purpura (ITP) after rituximab therapy. Antiviral therapy for HCV led to the improvement of both MPGN and ITP. Rituximab therapy may have contributed to the exacerbation of HCV infection and induced the development of HCV-related MPGN and the relapse of ITP. Our case suggested that HCV treatment should be prioritized over rituximab therapy for HCV-positive patients with ITP and that antiviral therapy for HCV may be effective for treating ITP itself. Introduction Immune thrombocytopenic purpura (ITP) is an immune-mediated acquired disease that is characterized by a transient or persistent decrease in the platelet count and an increased risk of bleeding (1,2). According to the Japanese guidelines for adult ITP (3), ITP treatment includes Helicobacter pylori eradication therapy and corticosteroid therapy as the first choice, and thrombopoietin receptor agonist, splenectomy, and rituximab therapy as the second choice. Rituximab is a chimeric monoclonal antibody against the CD20 antigen, which specifically eliminates CD20-positive B lymphocytes and reduces antibody production. In Japan, rituximab has been approved for the treatment of ITP since 2017 (4) and it is now used on a daily basis. It is widely known that the reactivation of hepatitis B virus (HBV) may occur in patients treated with rituximab-containing regimens, and there are guidelines aimed at its prevention (5). In contrast, with regard to hepatitis C virus (HCV), the onset of fulminant hepatitis is extremely rare, and there are no guidelines for its prevention (6). However, there are also some reports on the exacerbation of HCV infection by rituximab-containing regimens (7,8). We herein report a case of refractory ITP complicated by HCV-related membranoproliferative glomerulonephritis (MPGN) that developed after the initiation of rituximab therapy. Case Report A 54-year-old Japanese man was diagnosed with ITP at 25 years of age. He was treated with prednisolone (PSL), cyclosporin, azathioprine, high-dose intravenous immunoglobulin therapy, and eltrombopag. The effects of these treatments were all limited. Romiplostim (10 μg/kg) and PSL (10 mg) were continued for a long time. However, the dose of PSL often needed to be increased because the patient's platelet count dropped to <10.0×109/L with bleeding symptoms. The platelet-associated IgG value was in the range of 200-300 ng/107 cells. Due to long-term steroid therapy, he developed thin skin and obesity (body mass index, 30.2 kg/m2). Voglibose, linagliptin, olmesartan medoxomil/azelnidipine, enalapril maleate, and febuxostat were continued as treatments for hypertension, diabetes mellitus and hyperuricemia. Diabetic retinopathy was never noted. The estimated glomerular filtration rate remained at just over 60 mL/min/1.73 m2. Although HCV antibody positivity was pointed out, he was followed up without any treatment because there was no liver disorder. In November 2017, rituximab (375 mg/m2 per week) was administered four times. His platelet count increased and the PSL dosage could be decreased to 4 mg. In March 2018, however, his platelet count dropped in 8.0×109/L. 40 mg dexamethasone for 4 days was performed and the platelet count increased. Renal dysfunction appeared during the same period and it also worsened. Severe edema was noted on both lower legs and diuretics were required. No joint pain, swelling, Raynaud's symptoms, or numbness of the fingers or toes was observed. In April 2018, the serum creatinine concentration rose to 7.81 mg/dL and he was urgently hospitalized. A physical examination on admission revealed the following: body temperature, 35.8℃; heart rate, 84 bpm; blood pressure, 147/80 mmHg; and respiratory rate, 19 breaths/min. His oxygen saturation was 99% while breathing room air. A physical examination revealed purpura on his hand and breast. No edema was found in either of the lower limbs on admission. The laboratory findings are shown in Table. The patient's platelet count had increased due to the administration of high-dose dexamethasone therapy just before admission. He presented with mild liver dysfunction, severe renal dysfunction, and hyperkalemia due to renal dysfunction. The levels of complement proteins were low. A cryoglobulin test was positive, and IgG and IgM cryoglobulins were detected. Because M-protein was not found by immunoelectrophoresis, Type III cryoglobulinemia was thus diagnosed. A urinalysis revealed protein, occult blood, and various urinary casts. Abdominal echography showed normally sized kidneys, increased echogenicity of the renal parenchyma, and renal cysts. There were moderate to large amount of ascites without findings suggestive of cirrhosis. A renal biopsy revealed an enlargement of the glomeruli with mesangial proliferation, lobulation of the glomeruli (Fig. 1a, b), and double contours in the basement membranes (Fig. 1c, arrow). Microtubule-like deposits were diffusely observed in the subendothelial basement membrane and paramesagiual area on electron microscopy (Fig. 1c, d). Immunofluorescence staining showed IgM positivity in the basement membrane in the form of small granules (Fig. 1e), while IgG and C3 were negative (Fig. 1f, g). There was no marked difference between kappa and lambda staining. Exudative lesions in the capillaries were observed in some glomeruli (Fig. 1h, arrow). Table. Laboratory Examination at the Admission. Complete blood cell count Blood chemistry Serological test White blood cell 9.0 ×109/L Total protein 5.3 g/dL C-reactive protein 0.77 mg/dL Neutrophil 87.4 % Albumin 3.5 g/dL IgG/IgA/IgM 990/89/49 mg/dL Lymphocyte 10.2 % Aspartate transaminase 69 U/L M-protein negative Eosinophil 0.1 % Alanine aminotransferase 64 U/L C3 61 mg/dL (73-138) Hemoglobin 11.4 g/dL Lactate dehydrogenase 364 U/L C4 14 mg/dL (86-138) Hematocrit 35.1 % Alkaline phosphatase 400 U/L CH50 28.0 U/mL (31.6-57.6) Platelet count 136.0 ×109/L Total bilirubin 0.5 mg/dL Cryoglobulin positive Urea nitrogen 75 mg/dL Antinuclear antibody ×80 Coagulation test Creatinin 7.81 mg/mL Rheumatoid factor <5.0 IU/mL PT-INR 1.04 Sodium 137 mEq/L ds-DNA antibody <0.5 U/mL APTT 45.3 sec Potassium 5.8 mEq/L MPO/PR3-ANCA <1.0/<1.0 U/mL Fibrinogen 273 mg/dL Corrected calcium 8.4 mg/dL Anti-SS-A/B antibody <1.0/<1.0 U/mL D-dimer 0.7 μg/mL eGFR 6.7 mL/min/1.73m2 Anti-GBM antibody <2.0 U/mL Urine test Virological examination Protein 3+ White blood cell <0-1 /HPF Hepatitis B surface antigen (-) Glucose 1+ Red blood cell 1-4 / HPF HCV-antibody (+) Occult blood 1+ Oval fat body + Granular cast + HCV-genotype 2a Protein 6.20 g/gCre Hyalin cast + Fatty cast + HCV-RNA 6.5 log IU/mL Waxy cast + Epithelial cast + PT-INR: international normalized ratio, APTT: activated partial thromboplastin, HCV: hepatitis C virus, Cre: creatinine, Ig: immunoglobulin, MPO: myeloperoxidase, PR3: proteinase 3, ANCA: anti-neutrophil cytoplasmic antibody, SS: Sjogren’s syndrome, GBM: glomerular basement membrane, HPF: high power field. The numbers in parentheses after the C3, C4, and CH50 values are the normal range at the time of measurement Figure 1. Renal biopsy revealed enlargement of the glomeruli with mesangial proliferation, lobulation of the glomeruli (a, b), and double contours in the basement membranes (c, arrow). Microtubule-like deposits are diffusely observed in the subendothelial basement membrane and paramesagiual area on electron microscopy. (c, d) Immunofluorescence staining revealed IgM positivity in the basement membrane in the form of small granules (e), while IgG and C3 were negative (f, g). Exudative lesions in capillaries were observed in some glomeruli (h, arrow). The main cause of renal failure was diagnosed as HCV-related MPGN, which is classified as immune complex-mediated MPGN, and diabetic nephropathy was also considered to be present. The administration of glecaprevir hydrate/pibrentasvir for 12 weeks was initiated and the dose of PSL was increased to 30 mg for 2 weeks. At two weeks after the start of the antiviral therapy, HCV-RNA was no longer detected. The serum creatinine levels tended to improve, and the urinary occult blood disappeared, although mild proteinuria remained. The dose of PSL was gradually reduced to 3 mg, and the dose of romiplostim was reduced to 5 μg/kg. Because the platelet count decreased again, the dose of romiplostim was returned to 10 μg/kg. More than one year has passed since the dose of PSL was reduced to 2 mg. Although the patient's platelet count has fluctuated, no clear bleeding tendency has been observed (Fig. 2). With the reduction of the PSL dose, the patient's body mass index improved to 23.1 kg/m2, and voglibose and linagliptin could be discontinued. The levels of complement protein improved to 13 (normal range, 11-31) mg/dL for C3, 56 (73-138) mg/dL for C4, and 36.6 (25.0-48.0) U/mL for CH50. The elevated serum creatinine level and mild proteinuria persisted, a finding that was attributed to the diabetic nephropathy, and the management of chronic kidney disease was continued with a focus on antihypertensive therapy. Figure 2. The clinical course. HD-DEX: high dose dexamethasone, eGFR: estimated glomerular filtration rate, HCV: hepatitis C virus Discussion MPGN is a type of glomerulonephritis that is characterized by mesangial proliferation and basement membrane duplication. The clinical presentation and course are extremely variable (9). MPGN occurs as a primary or secondary condition. Secondary MPGN is most often due to hepatitis C and other infections (10). Patients with HCV-related MPGN have a higher incidence of liver dysfunction, cryoglobulinemia, rheumatoid factor, and hypocomplementemia (11,12). In our case, after rituximab therapy HCV-related MPGN developed with a relapse of ITP and both improved with antiviral therapy for HCV. HCV-RNA elevation due to rituximab therapy may have contributed to the development of MPGN and the relapse of ITP. Unfortunately, however, the patient's HCV-RNA levels were not measured until the onset of MPGN, as there was no liver disorder nor any indication for antiviral therapy. This clinical course may have been due to an iatrogenic cause. At the very least, the HCV-RNA levels should have been monitored before the initiation of rituximab therapy. Several reports have described the successful treatment of MPGN with rituximab therapy. The addition of rituximab therapy to antiviral therapy for HCV-related MPGN is well tolerated and it has been reported to be more effective than antiviral therapy alone (13,14). Mak et al. described the successful treatment of thrombotic thrombocytopenic purpura and MPGN with rituximab therapy in a case associated with HCV infection (15). In that case, the MPGN improved, but liver dysfunction and HCV-RNA elevation were transiently observed. In contrast to the present case, neither a blood examination nor a renal biopsy showed cryoglobulin. There is no doubt that rituximab is effective as a treatment for MPGN itself. However, it may not be possible to prevent the onset of MPGN, and in our case, it was considered that rituximab indirectly induced MPGN. In individuals who are infected with HCV, the incidence of ITP is increased in comparison individuals without HCV infection (16). Several reports have suggested that HCV infection is involved in the development of ITP through various mechanisms (16-18). Johia et al. described the case of an HCV-positive patient with refractory ITP in whom the eradication of HCV was effective for ITP (18). In this case, although rituximab therapy seemed to improve the responsiveness of ITP to steroid therapy, the reduced dose of PSL (4 mg) caused a relapse of ITP. Although the combined use of romiplostim was still necessary after antiviral therapy for HCV, the dosage of PSL could be reduced to 2 mg, suggesting that antiviral therapy for HCV was also effective against ITP. Thrombocytopenia is no longer a major problem in the treatment of chronic HCV infection because of the recent change in direct antiviral agents without interferon (19). The US guidelines for ITP recommend that testing for HCV be considered in all patients with acute ITP and that antiviral therapy be considered in HCV-positive patients with ITP in the absence of contraindications (20). Although whether or not all HCV-positive patients with ITP should be treated remains controversial in Japan, antiviral therapy for HCV should be actively performed as a treatment for refractory ITP. At least, it is certain that antiviral therapy for HCV should be given before rituximab therapy. In conclusion, we experienced a case in which HCV-related MPGN that developed with a relapse of ITP after rituximab therapy, in which both conditions were improved by antiviral therapy for HCV. Rituximab therapy may have contributed to the exacerbation of HCV infection and induced the development of HCV-related MPGN and relapse of ITP. Our case suggested that HCV treatment should be prioritized over rituximab therapy for HCV-positive patients with ITP and that antiviral therapy for HCV may be effective for ITP itself. The authors state that they have no Conflict of Interest (COI). Acknowledgement The authors would like to thank Yoshitaka Miyakawa of Department of General Internal Medicine, Saitama Medical University for his advice on the treatment of ITP in the present case.	AZELNIDIPINE, DEXAMETHASONE, ENALAPRIL MALEATE, FEBUXOSTAT, LINAGLIPTIN, OLMESARTAN MEDOXOMIL, PREDNISOLONE, RITUXIMAB, ROMIPLOSTIM, VOGLIBOSE	DrugsGivenReaction	CC BY-NC-ND	33583904	18,544,239	2021-08-01
What was the administration route of drug 'RITUXIMAB'?	Immune Thrombocytopenic Purpura Complicated by Hepatitis C Virus-related Membranoproliferative Glomerulonephritis after Rituximab Therapy. We herein report the case of a 54-year-old Japanese man with hepatitis C virus (HCV)-related membranoproliferative glomerulonephritis (MPGN), which developed at the time of relapse of immune thrombocytopenic purpura (ITP) after rituximab therapy. Antiviral therapy for HCV led to the improvement of both MPGN and ITP. Rituximab therapy may have contributed to the exacerbation of HCV infection and induced the development of HCV-related MPGN and the relapse of ITP. Our case suggested that HCV treatment should be prioritized over rituximab therapy for HCV-positive patients with ITP and that antiviral therapy for HCV may be effective for treating ITP itself. Introduction Immune thrombocytopenic purpura (ITP) is an immune-mediated acquired disease that is characterized by a transient or persistent decrease in the platelet count and an increased risk of bleeding (1,2). According to the Japanese guidelines for adult ITP (3), ITP treatment includes Helicobacter pylori eradication therapy and corticosteroid therapy as the first choice, and thrombopoietin receptor agonist, splenectomy, and rituximab therapy as the second choice. Rituximab is a chimeric monoclonal antibody against the CD20 antigen, which specifically eliminates CD20-positive B lymphocytes and reduces antibody production. In Japan, rituximab has been approved for the treatment of ITP since 2017 (4) and it is now used on a daily basis. It is widely known that the reactivation of hepatitis B virus (HBV) may occur in patients treated with rituximab-containing regimens, and there are guidelines aimed at its prevention (5). In contrast, with regard to hepatitis C virus (HCV), the onset of fulminant hepatitis is extremely rare, and there are no guidelines for its prevention (6). However, there are also some reports on the exacerbation of HCV infection by rituximab-containing regimens (7,8). We herein report a case of refractory ITP complicated by HCV-related membranoproliferative glomerulonephritis (MPGN) that developed after the initiation of rituximab therapy. Case Report A 54-year-old Japanese man was diagnosed with ITP at 25 years of age. He was treated with prednisolone (PSL), cyclosporin, azathioprine, high-dose intravenous immunoglobulin therapy, and eltrombopag. The effects of these treatments were all limited. Romiplostim (10 μg/kg) and PSL (10 mg) were continued for a long time. However, the dose of PSL often needed to be increased because the patient's platelet count dropped to <10.0×109/L with bleeding symptoms. The platelet-associated IgG value was in the range of 200-300 ng/107 cells. Due to long-term steroid therapy, he developed thin skin and obesity (body mass index, 30.2 kg/m2). Voglibose, linagliptin, olmesartan medoxomil/azelnidipine, enalapril maleate, and febuxostat were continued as treatments for hypertension, diabetes mellitus and hyperuricemia. Diabetic retinopathy was never noted. The estimated glomerular filtration rate remained at just over 60 mL/min/1.73 m2. Although HCV antibody positivity was pointed out, he was followed up without any treatment because there was no liver disorder. In November 2017, rituximab (375 mg/m2 per week) was administered four times. His platelet count increased and the PSL dosage could be decreased to 4 mg. In March 2018, however, his platelet count dropped in 8.0×109/L. 40 mg dexamethasone for 4 days was performed and the platelet count increased. Renal dysfunction appeared during the same period and it also worsened. Severe edema was noted on both lower legs and diuretics were required. No joint pain, swelling, Raynaud's symptoms, or numbness of the fingers or toes was observed. In April 2018, the serum creatinine concentration rose to 7.81 mg/dL and he was urgently hospitalized. A physical examination on admission revealed the following: body temperature, 35.8℃; heart rate, 84 bpm; blood pressure, 147/80 mmHg; and respiratory rate, 19 breaths/min. His oxygen saturation was 99% while breathing room air. A physical examination revealed purpura on his hand and breast. No edema was found in either of the lower limbs on admission. The laboratory findings are shown in Table. The patient's platelet count had increased due to the administration of high-dose dexamethasone therapy just before admission. He presented with mild liver dysfunction, severe renal dysfunction, and hyperkalemia due to renal dysfunction. The levels of complement proteins were low. A cryoglobulin test was positive, and IgG and IgM cryoglobulins were detected. Because M-protein was not found by immunoelectrophoresis, Type III cryoglobulinemia was thus diagnosed. A urinalysis revealed protein, occult blood, and various urinary casts. Abdominal echography showed normally sized kidneys, increased echogenicity of the renal parenchyma, and renal cysts. There were moderate to large amount of ascites without findings suggestive of cirrhosis. A renal biopsy revealed an enlargement of the glomeruli with mesangial proliferation, lobulation of the glomeruli (Fig. 1a, b), and double contours in the basement membranes (Fig. 1c, arrow). Microtubule-like deposits were diffusely observed in the subendothelial basement membrane and paramesagiual area on electron microscopy (Fig. 1c, d). Immunofluorescence staining showed IgM positivity in the basement membrane in the form of small granules (Fig. 1e), while IgG and C3 were negative (Fig. 1f, g). There was no marked difference between kappa and lambda staining. Exudative lesions in the capillaries were observed in some glomeruli (Fig. 1h, arrow). Table. Laboratory Examination at the Admission. Complete blood cell count Blood chemistry Serological test White blood cell 9.0 ×109/L Total protein 5.3 g/dL C-reactive protein 0.77 mg/dL Neutrophil 87.4 % Albumin 3.5 g/dL IgG/IgA/IgM 990/89/49 mg/dL Lymphocyte 10.2 % Aspartate transaminase 69 U/L M-protein negative Eosinophil 0.1 % Alanine aminotransferase 64 U/L C3 61 mg/dL (73-138) Hemoglobin 11.4 g/dL Lactate dehydrogenase 364 U/L C4 14 mg/dL (86-138) Hematocrit 35.1 % Alkaline phosphatase 400 U/L CH50 28.0 U/mL (31.6-57.6) Platelet count 136.0 ×109/L Total bilirubin 0.5 mg/dL Cryoglobulin positive Urea nitrogen 75 mg/dL Antinuclear antibody ×80 Coagulation test Creatinin 7.81 mg/mL Rheumatoid factor <5.0 IU/mL PT-INR 1.04 Sodium 137 mEq/L ds-DNA antibody <0.5 U/mL APTT 45.3 sec Potassium 5.8 mEq/L MPO/PR3-ANCA <1.0/<1.0 U/mL Fibrinogen 273 mg/dL Corrected calcium 8.4 mg/dL Anti-SS-A/B antibody <1.0/<1.0 U/mL D-dimer 0.7 μg/mL eGFR 6.7 mL/min/1.73m2 Anti-GBM antibody <2.0 U/mL Urine test Virological examination Protein 3+ White blood cell <0-1 /HPF Hepatitis B surface antigen (-) Glucose 1+ Red blood cell 1-4 / HPF HCV-antibody (+) Occult blood 1+ Oval fat body + Granular cast + HCV-genotype 2a Protein 6.20 g/gCre Hyalin cast + Fatty cast + HCV-RNA 6.5 log IU/mL Waxy cast + Epithelial cast + PT-INR: international normalized ratio, APTT: activated partial thromboplastin, HCV: hepatitis C virus, Cre: creatinine, Ig: immunoglobulin, MPO: myeloperoxidase, PR3: proteinase 3, ANCA: anti-neutrophil cytoplasmic antibody, SS: Sjogren’s syndrome, GBM: glomerular basement membrane, HPF: high power field. The numbers in parentheses after the C3, C4, and CH50 values are the normal range at the time of measurement Figure 1. Renal biopsy revealed enlargement of the glomeruli with mesangial proliferation, lobulation of the glomeruli (a, b), and double contours in the basement membranes (c, arrow). Microtubule-like deposits are diffusely observed in the subendothelial basement membrane and paramesagiual area on electron microscopy. (c, d) Immunofluorescence staining revealed IgM positivity in the basement membrane in the form of small granules (e), while IgG and C3 were negative (f, g). Exudative lesions in capillaries were observed in some glomeruli (h, arrow). The main cause of renal failure was diagnosed as HCV-related MPGN, which is classified as immune complex-mediated MPGN, and diabetic nephropathy was also considered to be present. The administration of glecaprevir hydrate/pibrentasvir for 12 weeks was initiated and the dose of PSL was increased to 30 mg for 2 weeks. At two weeks after the start of the antiviral therapy, HCV-RNA was no longer detected. The serum creatinine levels tended to improve, and the urinary occult blood disappeared, although mild proteinuria remained. The dose of PSL was gradually reduced to 3 mg, and the dose of romiplostim was reduced to 5 μg/kg. Because the platelet count decreased again, the dose of romiplostim was returned to 10 μg/kg. More than one year has passed since the dose of PSL was reduced to 2 mg. Although the patient's platelet count has fluctuated, no clear bleeding tendency has been observed (Fig. 2). With the reduction of the PSL dose, the patient's body mass index improved to 23.1 kg/m2, and voglibose and linagliptin could be discontinued. The levels of complement protein improved to 13 (normal range, 11-31) mg/dL for C3, 56 (73-138) mg/dL for C4, and 36.6 (25.0-48.0) U/mL for CH50. The elevated serum creatinine level and mild proteinuria persisted, a finding that was attributed to the diabetic nephropathy, and the management of chronic kidney disease was continued with a focus on antihypertensive therapy. Figure 2. The clinical course. HD-DEX: high dose dexamethasone, eGFR: estimated glomerular filtration rate, HCV: hepatitis C virus Discussion MPGN is a type of glomerulonephritis that is characterized by mesangial proliferation and basement membrane duplication. The clinical presentation and course are extremely variable (9). MPGN occurs as a primary or secondary condition. Secondary MPGN is most often due to hepatitis C and other infections (10). Patients with HCV-related MPGN have a higher incidence of liver dysfunction, cryoglobulinemia, rheumatoid factor, and hypocomplementemia (11,12). In our case, after rituximab therapy HCV-related MPGN developed with a relapse of ITP and both improved with antiviral therapy for HCV. HCV-RNA elevation due to rituximab therapy may have contributed to the development of MPGN and the relapse of ITP. Unfortunately, however, the patient's HCV-RNA levels were not measured until the onset of MPGN, as there was no liver disorder nor any indication for antiviral therapy. This clinical course may have been due to an iatrogenic cause. At the very least, the HCV-RNA levels should have been monitored before the initiation of rituximab therapy. Several reports have described the successful treatment of MPGN with rituximab therapy. The addition of rituximab therapy to antiviral therapy for HCV-related MPGN is well tolerated and it has been reported to be more effective than antiviral therapy alone (13,14). Mak et al. described the successful treatment of thrombotic thrombocytopenic purpura and MPGN with rituximab therapy in a case associated with HCV infection (15). In that case, the MPGN improved, but liver dysfunction and HCV-RNA elevation were transiently observed. In contrast to the present case, neither a blood examination nor a renal biopsy showed cryoglobulin. There is no doubt that rituximab is effective as a treatment for MPGN itself. However, it may not be possible to prevent the onset of MPGN, and in our case, it was considered that rituximab indirectly induced MPGN. In individuals who are infected with HCV, the incidence of ITP is increased in comparison individuals without HCV infection (16). Several reports have suggested that HCV infection is involved in the development of ITP through various mechanisms (16-18). Johia et al. described the case of an HCV-positive patient with refractory ITP in whom the eradication of HCV was effective for ITP (18). In this case, although rituximab therapy seemed to improve the responsiveness of ITP to steroid therapy, the reduced dose of PSL (4 mg) caused a relapse of ITP. Although the combined use of romiplostim was still necessary after antiviral therapy for HCV, the dosage of PSL could be reduced to 2 mg, suggesting that antiviral therapy for HCV was also effective against ITP. Thrombocytopenia is no longer a major problem in the treatment of chronic HCV infection because of the recent change in direct antiviral agents without interferon (19). The US guidelines for ITP recommend that testing for HCV be considered in all patients with acute ITP and that antiviral therapy be considered in HCV-positive patients with ITP in the absence of contraindications (20). Although whether or not all HCV-positive patients with ITP should be treated remains controversial in Japan, antiviral therapy for HCV should be actively performed as a treatment for refractory ITP. At least, it is certain that antiviral therapy for HCV should be given before rituximab therapy. In conclusion, we experienced a case in which HCV-related MPGN that developed with a relapse of ITP after rituximab therapy, in which both conditions were improved by antiviral therapy for HCV. Rituximab therapy may have contributed to the exacerbation of HCV infection and induced the development of HCV-related MPGN and relapse of ITP. Our case suggested that HCV treatment should be prioritized over rituximab therapy for HCV-positive patients with ITP and that antiviral therapy for HCV may be effective for ITP itself. The authors state that they have no Conflict of Interest (COI). Acknowledgement The authors would like to thank Yoshitaka Miyakawa of Department of General Internal Medicine, Saitama Medical University for his advice on the treatment of ITP in the present case.	Intravenous drip	DrugAdministrationRoute	CC BY-NC-ND	33583904	18,544,239	2021-08-01
What was the dosage of drug 'DEXAMETHASONE'?	Immune Thrombocytopenic Purpura Complicated by Hepatitis C Virus-related Membranoproliferative Glomerulonephritis after Rituximab Therapy. We herein report the case of a 54-year-old Japanese man with hepatitis C virus (HCV)-related membranoproliferative glomerulonephritis (MPGN), which developed at the time of relapse of immune thrombocytopenic purpura (ITP) after rituximab therapy. Antiviral therapy for HCV led to the improvement of both MPGN and ITP. Rituximab therapy may have contributed to the exacerbation of HCV infection and induced the development of HCV-related MPGN and the relapse of ITP. Our case suggested that HCV treatment should be prioritized over rituximab therapy for HCV-positive patients with ITP and that antiviral therapy for HCV may be effective for treating ITP itself. Introduction Immune thrombocytopenic purpura (ITP) is an immune-mediated acquired disease that is characterized by a transient or persistent decrease in the platelet count and an increased risk of bleeding (1,2). According to the Japanese guidelines for adult ITP (3), ITP treatment includes Helicobacter pylori eradication therapy and corticosteroid therapy as the first choice, and thrombopoietin receptor agonist, splenectomy, and rituximab therapy as the second choice. Rituximab is a chimeric monoclonal antibody against the CD20 antigen, which specifically eliminates CD20-positive B lymphocytes and reduces antibody production. In Japan, rituximab has been approved for the treatment of ITP since 2017 (4) and it is now used on a daily basis. It is widely known that the reactivation of hepatitis B virus (HBV) may occur in patients treated with rituximab-containing regimens, and there are guidelines aimed at its prevention (5). In contrast, with regard to hepatitis C virus (HCV), the onset of fulminant hepatitis is extremely rare, and there are no guidelines for its prevention (6). However, there are also some reports on the exacerbation of HCV infection by rituximab-containing regimens (7,8). We herein report a case of refractory ITP complicated by HCV-related membranoproliferative glomerulonephritis (MPGN) that developed after the initiation of rituximab therapy. Case Report A 54-year-old Japanese man was diagnosed with ITP at 25 years of age. He was treated with prednisolone (PSL), cyclosporin, azathioprine, high-dose intravenous immunoglobulin therapy, and eltrombopag. The effects of these treatments were all limited. Romiplostim (10 μg/kg) and PSL (10 mg) were continued for a long time. However, the dose of PSL often needed to be increased because the patient's platelet count dropped to <10.0×109/L with bleeding symptoms. The platelet-associated IgG value was in the range of 200-300 ng/107 cells. Due to long-term steroid therapy, he developed thin skin and obesity (body mass index, 30.2 kg/m2). Voglibose, linagliptin, olmesartan medoxomil/azelnidipine, enalapril maleate, and febuxostat were continued as treatments for hypertension, diabetes mellitus and hyperuricemia. Diabetic retinopathy was never noted. The estimated glomerular filtration rate remained at just over 60 mL/min/1.73 m2. Although HCV antibody positivity was pointed out, he was followed up without any treatment because there was no liver disorder. In November 2017, rituximab (375 mg/m2 per week) was administered four times. His platelet count increased and the PSL dosage could be decreased to 4 mg. In March 2018, however, his platelet count dropped in 8.0×109/L. 40 mg dexamethasone for 4 days was performed and the platelet count increased. Renal dysfunction appeared during the same period and it also worsened. Severe edema was noted on both lower legs and diuretics were required. No joint pain, swelling, Raynaud's symptoms, or numbness of the fingers or toes was observed. In April 2018, the serum creatinine concentration rose to 7.81 mg/dL and he was urgently hospitalized. A physical examination on admission revealed the following: body temperature, 35.8℃; heart rate, 84 bpm; blood pressure, 147/80 mmHg; and respiratory rate, 19 breaths/min. His oxygen saturation was 99% while breathing room air. A physical examination revealed purpura on his hand and breast. No edema was found in either of the lower limbs on admission. The laboratory findings are shown in Table. The patient's platelet count had increased due to the administration of high-dose dexamethasone therapy just before admission. He presented with mild liver dysfunction, severe renal dysfunction, and hyperkalemia due to renal dysfunction. The levels of complement proteins were low. A cryoglobulin test was positive, and IgG and IgM cryoglobulins were detected. Because M-protein was not found by immunoelectrophoresis, Type III cryoglobulinemia was thus diagnosed. A urinalysis revealed protein, occult blood, and various urinary casts. Abdominal echography showed normally sized kidneys, increased echogenicity of the renal parenchyma, and renal cysts. There were moderate to large amount of ascites without findings suggestive of cirrhosis. A renal biopsy revealed an enlargement of the glomeruli with mesangial proliferation, lobulation of the glomeruli (Fig. 1a, b), and double contours in the basement membranes (Fig. 1c, arrow). Microtubule-like deposits were diffusely observed in the subendothelial basement membrane and paramesagiual area on electron microscopy (Fig. 1c, d). Immunofluorescence staining showed IgM positivity in the basement membrane in the form of small granules (Fig. 1e), while IgG and C3 were negative (Fig. 1f, g). There was no marked difference between kappa and lambda staining. Exudative lesions in the capillaries were observed in some glomeruli (Fig. 1h, arrow). Table. Laboratory Examination at the Admission. Complete blood cell count Blood chemistry Serological test White blood cell 9.0 ×109/L Total protein 5.3 g/dL C-reactive protein 0.77 mg/dL Neutrophil 87.4 % Albumin 3.5 g/dL IgG/IgA/IgM 990/89/49 mg/dL Lymphocyte 10.2 % Aspartate transaminase 69 U/L M-protein negative Eosinophil 0.1 % Alanine aminotransferase 64 U/L C3 61 mg/dL (73-138) Hemoglobin 11.4 g/dL Lactate dehydrogenase 364 U/L C4 14 mg/dL (86-138) Hematocrit 35.1 % Alkaline phosphatase 400 U/L CH50 28.0 U/mL (31.6-57.6) Platelet count 136.0 ×109/L Total bilirubin 0.5 mg/dL Cryoglobulin positive Urea nitrogen 75 mg/dL Antinuclear antibody ×80 Coagulation test Creatinin 7.81 mg/mL Rheumatoid factor <5.0 IU/mL PT-INR 1.04 Sodium 137 mEq/L ds-DNA antibody <0.5 U/mL APTT 45.3 sec Potassium 5.8 mEq/L MPO/PR3-ANCA <1.0/<1.0 U/mL Fibrinogen 273 mg/dL Corrected calcium 8.4 mg/dL Anti-SS-A/B antibody <1.0/<1.0 U/mL D-dimer 0.7 μg/mL eGFR 6.7 mL/min/1.73m2 Anti-GBM antibody <2.0 U/mL Urine test Virological examination Protein 3+ White blood cell <0-1 /HPF Hepatitis B surface antigen (-) Glucose 1+ Red blood cell 1-4 / HPF HCV-antibody (+) Occult blood 1+ Oval fat body + Granular cast + HCV-genotype 2a Protein 6.20 g/gCre Hyalin cast + Fatty cast + HCV-RNA 6.5 log IU/mL Waxy cast + Epithelial cast + PT-INR: international normalized ratio, APTT: activated partial thromboplastin, HCV: hepatitis C virus, Cre: creatinine, Ig: immunoglobulin, MPO: myeloperoxidase, PR3: proteinase 3, ANCA: anti-neutrophil cytoplasmic antibody, SS: Sjogren’s syndrome, GBM: glomerular basement membrane, HPF: high power field. The numbers in parentheses after the C3, C4, and CH50 values are the normal range at the time of measurement Figure 1. Renal biopsy revealed enlargement of the glomeruli with mesangial proliferation, lobulation of the glomeruli (a, b), and double contours in the basement membranes (c, arrow). Microtubule-like deposits are diffusely observed in the subendothelial basement membrane and paramesagiual area on electron microscopy. (c, d) Immunofluorescence staining revealed IgM positivity in the basement membrane in the form of small granules (e), while IgG and C3 were negative (f, g). Exudative lesions in capillaries were observed in some glomeruli (h, arrow). The main cause of renal failure was diagnosed as HCV-related MPGN, which is classified as immune complex-mediated MPGN, and diabetic nephropathy was also considered to be present. The administration of glecaprevir hydrate/pibrentasvir for 12 weeks was initiated and the dose of PSL was increased to 30 mg for 2 weeks. At two weeks after the start of the antiviral therapy, HCV-RNA was no longer detected. The serum creatinine levels tended to improve, and the urinary occult blood disappeared, although mild proteinuria remained. The dose of PSL was gradually reduced to 3 mg, and the dose of romiplostim was reduced to 5 μg/kg. Because the platelet count decreased again, the dose of romiplostim was returned to 10 μg/kg. More than one year has passed since the dose of PSL was reduced to 2 mg. Although the patient's platelet count has fluctuated, no clear bleeding tendency has been observed (Fig. 2). With the reduction of the PSL dose, the patient's body mass index improved to 23.1 kg/m2, and voglibose and linagliptin could be discontinued. The levels of complement protein improved to 13 (normal range, 11-31) mg/dL for C3, 56 (73-138) mg/dL for C4, and 36.6 (25.0-48.0) U/mL for CH50. The elevated serum creatinine level and mild proteinuria persisted, a finding that was attributed to the diabetic nephropathy, and the management of chronic kidney disease was continued with a focus on antihypertensive therapy. Figure 2. The clinical course. HD-DEX: high dose dexamethasone, eGFR: estimated glomerular filtration rate, HCV: hepatitis C virus Discussion MPGN is a type of glomerulonephritis that is characterized by mesangial proliferation and basement membrane duplication. The clinical presentation and course are extremely variable (9). MPGN occurs as a primary or secondary condition. Secondary MPGN is most often due to hepatitis C and other infections (10). Patients with HCV-related MPGN have a higher incidence of liver dysfunction, cryoglobulinemia, rheumatoid factor, and hypocomplementemia (11,12). In our case, after rituximab therapy HCV-related MPGN developed with a relapse of ITP and both improved with antiviral therapy for HCV. HCV-RNA elevation due to rituximab therapy may have contributed to the development of MPGN and the relapse of ITP. Unfortunately, however, the patient's HCV-RNA levels were not measured until the onset of MPGN, as there was no liver disorder nor any indication for antiviral therapy. This clinical course may have been due to an iatrogenic cause. At the very least, the HCV-RNA levels should have been monitored before the initiation of rituximab therapy. Several reports have described the successful treatment of MPGN with rituximab therapy. The addition of rituximab therapy to antiviral therapy for HCV-related MPGN is well tolerated and it has been reported to be more effective than antiviral therapy alone (13,14). Mak et al. described the successful treatment of thrombotic thrombocytopenic purpura and MPGN with rituximab therapy in a case associated with HCV infection (15). In that case, the MPGN improved, but liver dysfunction and HCV-RNA elevation were transiently observed. In contrast to the present case, neither a blood examination nor a renal biopsy showed cryoglobulin. There is no doubt that rituximab is effective as a treatment for MPGN itself. However, it may not be possible to prevent the onset of MPGN, and in our case, it was considered that rituximab indirectly induced MPGN. In individuals who are infected with HCV, the incidence of ITP is increased in comparison individuals without HCV infection (16). Several reports have suggested that HCV infection is involved in the development of ITP through various mechanisms (16-18). Johia et al. described the case of an HCV-positive patient with refractory ITP in whom the eradication of HCV was effective for ITP (18). In this case, although rituximab therapy seemed to improve the responsiveness of ITP to steroid therapy, the reduced dose of PSL (4 mg) caused a relapse of ITP. Although the combined use of romiplostim was still necessary after antiviral therapy for HCV, the dosage of PSL could be reduced to 2 mg, suggesting that antiviral therapy for HCV was also effective against ITP. Thrombocytopenia is no longer a major problem in the treatment of chronic HCV infection because of the recent change in direct antiviral agents without interferon (19). The US guidelines for ITP recommend that testing for HCV be considered in all patients with acute ITP and that antiviral therapy be considered in HCV-positive patients with ITP in the absence of contraindications (20). Although whether or not all HCV-positive patients with ITP should be treated remains controversial in Japan, antiviral therapy for HCV should be actively performed as a treatment for refractory ITP. At least, it is certain that antiviral therapy for HCV should be given before rituximab therapy. In conclusion, we experienced a case in which HCV-related MPGN that developed with a relapse of ITP after rituximab therapy, in which both conditions were improved by antiviral therapy for HCV. Rituximab therapy may have contributed to the exacerbation of HCV infection and induced the development of HCV-related MPGN and relapse of ITP. Our case suggested that HCV treatment should be prioritized over rituximab therapy for HCV-positive patients with ITP and that antiviral therapy for HCV may be effective for ITP itself. The authors state that they have no Conflict of Interest (COI). Acknowledgement The authors would like to thank Yoshitaka Miyakawa of Department of General Internal Medicine, Saitama Medical University for his advice on the treatment of ITP in the present case.	FOR 4 DAYS	DrugDosageText	CC BY-NC-ND	33583904	18,544,239	2021-08-01
What was the outcome of reaction 'Glomerulonephritis membranoproliferative'?	Immune Thrombocytopenic Purpura Complicated by Hepatitis C Virus-related Membranoproliferative Glomerulonephritis after Rituximab Therapy. We herein report the case of a 54-year-old Japanese man with hepatitis C virus (HCV)-related membranoproliferative glomerulonephritis (MPGN), which developed at the time of relapse of immune thrombocytopenic purpura (ITP) after rituximab therapy. Antiviral therapy for HCV led to the improvement of both MPGN and ITP. Rituximab therapy may have contributed to the exacerbation of HCV infection and induced the development of HCV-related MPGN and the relapse of ITP. Our case suggested that HCV treatment should be prioritized over rituximab therapy for HCV-positive patients with ITP and that antiviral therapy for HCV may be effective for treating ITP itself. Introduction Immune thrombocytopenic purpura (ITP) is an immune-mediated acquired disease that is characterized by a transient or persistent decrease in the platelet count and an increased risk of bleeding (1,2). According to the Japanese guidelines for adult ITP (3), ITP treatment includes Helicobacter pylori eradication therapy and corticosteroid therapy as the first choice, and thrombopoietin receptor agonist, splenectomy, and rituximab therapy as the second choice. Rituximab is a chimeric monoclonal antibody against the CD20 antigen, which specifically eliminates CD20-positive B lymphocytes and reduces antibody production. In Japan, rituximab has been approved for the treatment of ITP since 2017 (4) and it is now used on a daily basis. It is widely known that the reactivation of hepatitis B virus (HBV) may occur in patients treated with rituximab-containing regimens, and there are guidelines aimed at its prevention (5). In contrast, with regard to hepatitis C virus (HCV), the onset of fulminant hepatitis is extremely rare, and there are no guidelines for its prevention (6). However, there are also some reports on the exacerbation of HCV infection by rituximab-containing regimens (7,8). We herein report a case of refractory ITP complicated by HCV-related membranoproliferative glomerulonephritis (MPGN) that developed after the initiation of rituximab therapy. Case Report A 54-year-old Japanese man was diagnosed with ITP at 25 years of age. He was treated with prednisolone (PSL), cyclosporin, azathioprine, high-dose intravenous immunoglobulin therapy, and eltrombopag. The effects of these treatments were all limited. Romiplostim (10 μg/kg) and PSL (10 mg) were continued for a long time. However, the dose of PSL often needed to be increased because the patient's platelet count dropped to <10.0×109/L with bleeding symptoms. The platelet-associated IgG value was in the range of 200-300 ng/107 cells. Due to long-term steroid therapy, he developed thin skin and obesity (body mass index, 30.2 kg/m2). Voglibose, linagliptin, olmesartan medoxomil/azelnidipine, enalapril maleate, and febuxostat were continued as treatments for hypertension, diabetes mellitus and hyperuricemia. Diabetic retinopathy was never noted. The estimated glomerular filtration rate remained at just over 60 mL/min/1.73 m2. Although HCV antibody positivity was pointed out, he was followed up without any treatment because there was no liver disorder. In November 2017, rituximab (375 mg/m2 per week) was administered four times. His platelet count increased and the PSL dosage could be decreased to 4 mg. In March 2018, however, his platelet count dropped in 8.0×109/L. 40 mg dexamethasone for 4 days was performed and the platelet count increased. Renal dysfunction appeared during the same period and it also worsened. Severe edema was noted on both lower legs and diuretics were required. No joint pain, swelling, Raynaud's symptoms, or numbness of the fingers or toes was observed. In April 2018, the serum creatinine concentration rose to 7.81 mg/dL and he was urgently hospitalized. A physical examination on admission revealed the following: body temperature, 35.8℃; heart rate, 84 bpm; blood pressure, 147/80 mmHg; and respiratory rate, 19 breaths/min. His oxygen saturation was 99% while breathing room air. A physical examination revealed purpura on his hand and breast. No edema was found in either of the lower limbs on admission. The laboratory findings are shown in Table. The patient's platelet count had increased due to the administration of high-dose dexamethasone therapy just before admission. He presented with mild liver dysfunction, severe renal dysfunction, and hyperkalemia due to renal dysfunction. The levels of complement proteins were low. A cryoglobulin test was positive, and IgG and IgM cryoglobulins were detected. Because M-protein was not found by immunoelectrophoresis, Type III cryoglobulinemia was thus diagnosed. A urinalysis revealed protein, occult blood, and various urinary casts. Abdominal echography showed normally sized kidneys, increased echogenicity of the renal parenchyma, and renal cysts. There were moderate to large amount of ascites without findings suggestive of cirrhosis. A renal biopsy revealed an enlargement of the glomeruli with mesangial proliferation, lobulation of the glomeruli (Fig. 1a, b), and double contours in the basement membranes (Fig. 1c, arrow). Microtubule-like deposits were diffusely observed in the subendothelial basement membrane and paramesagiual area on electron microscopy (Fig. 1c, d). Immunofluorescence staining showed IgM positivity in the basement membrane in the form of small granules (Fig. 1e), while IgG and C3 were negative (Fig. 1f, g). There was no marked difference between kappa and lambda staining. Exudative lesions in the capillaries were observed in some glomeruli (Fig. 1h, arrow). Table. Laboratory Examination at the Admission. Complete blood cell count Blood chemistry Serological test White blood cell 9.0 ×109/L Total protein 5.3 g/dL C-reactive protein 0.77 mg/dL Neutrophil 87.4 % Albumin 3.5 g/dL IgG/IgA/IgM 990/89/49 mg/dL Lymphocyte 10.2 % Aspartate transaminase 69 U/L M-protein negative Eosinophil 0.1 % Alanine aminotransferase 64 U/L C3 61 mg/dL (73-138) Hemoglobin 11.4 g/dL Lactate dehydrogenase 364 U/L C4 14 mg/dL (86-138) Hematocrit 35.1 % Alkaline phosphatase 400 U/L CH50 28.0 U/mL (31.6-57.6) Platelet count 136.0 ×109/L Total bilirubin 0.5 mg/dL Cryoglobulin positive Urea nitrogen 75 mg/dL Antinuclear antibody ×80 Coagulation test Creatinin 7.81 mg/mL Rheumatoid factor <5.0 IU/mL PT-INR 1.04 Sodium 137 mEq/L ds-DNA antibody <0.5 U/mL APTT 45.3 sec Potassium 5.8 mEq/L MPO/PR3-ANCA <1.0/<1.0 U/mL Fibrinogen 273 mg/dL Corrected calcium 8.4 mg/dL Anti-SS-A/B antibody <1.0/<1.0 U/mL D-dimer 0.7 μg/mL eGFR 6.7 mL/min/1.73m2 Anti-GBM antibody <2.0 U/mL Urine test Virological examination Protein 3+ White blood cell <0-1 /HPF Hepatitis B surface antigen (-) Glucose 1+ Red blood cell 1-4 / HPF HCV-antibody (+) Occult blood 1+ Oval fat body + Granular cast + HCV-genotype 2a Protein 6.20 g/gCre Hyalin cast + Fatty cast + HCV-RNA 6.5 log IU/mL Waxy cast + Epithelial cast + PT-INR: international normalized ratio, APTT: activated partial thromboplastin, HCV: hepatitis C virus, Cre: creatinine, Ig: immunoglobulin, MPO: myeloperoxidase, PR3: proteinase 3, ANCA: anti-neutrophil cytoplasmic antibody, SS: Sjogren’s syndrome, GBM: glomerular basement membrane, HPF: high power field. The numbers in parentheses after the C3, C4, and CH50 values are the normal range at the time of measurement Figure 1. Renal biopsy revealed enlargement of the glomeruli with mesangial proliferation, lobulation of the glomeruli (a, b), and double contours in the basement membranes (c, arrow). Microtubule-like deposits are diffusely observed in the subendothelial basement membrane and paramesagiual area on electron microscopy. (c, d) Immunofluorescence staining revealed IgM positivity in the basement membrane in the form of small granules (e), while IgG and C3 were negative (f, g). Exudative lesions in capillaries were observed in some glomeruli (h, arrow). The main cause of renal failure was diagnosed as HCV-related MPGN, which is classified as immune complex-mediated MPGN, and diabetic nephropathy was also considered to be present. The administration of glecaprevir hydrate/pibrentasvir for 12 weeks was initiated and the dose of PSL was increased to 30 mg for 2 weeks. At two weeks after the start of the antiviral therapy, HCV-RNA was no longer detected. The serum creatinine levels tended to improve, and the urinary occult blood disappeared, although mild proteinuria remained. The dose of PSL was gradually reduced to 3 mg, and the dose of romiplostim was reduced to 5 μg/kg. Because the platelet count decreased again, the dose of romiplostim was returned to 10 μg/kg. More than one year has passed since the dose of PSL was reduced to 2 mg. Although the patient's platelet count has fluctuated, no clear bleeding tendency has been observed (Fig. 2). With the reduction of the PSL dose, the patient's body mass index improved to 23.1 kg/m2, and voglibose and linagliptin could be discontinued. The levels of complement protein improved to 13 (normal range, 11-31) mg/dL for C3, 56 (73-138) mg/dL for C4, and 36.6 (25.0-48.0) U/mL for CH50. The elevated serum creatinine level and mild proteinuria persisted, a finding that was attributed to the diabetic nephropathy, and the management of chronic kidney disease was continued with a focus on antihypertensive therapy. Figure 2. The clinical course. HD-DEX: high dose dexamethasone, eGFR: estimated glomerular filtration rate, HCV: hepatitis C virus Discussion MPGN is a type of glomerulonephritis that is characterized by mesangial proliferation and basement membrane duplication. The clinical presentation and course are extremely variable (9). MPGN occurs as a primary or secondary condition. Secondary MPGN is most often due to hepatitis C and other infections (10). Patients with HCV-related MPGN have a higher incidence of liver dysfunction, cryoglobulinemia, rheumatoid factor, and hypocomplementemia (11,12). In our case, after rituximab therapy HCV-related MPGN developed with a relapse of ITP and both improved with antiviral therapy for HCV. HCV-RNA elevation due to rituximab therapy may have contributed to the development of MPGN and the relapse of ITP. Unfortunately, however, the patient's HCV-RNA levels were not measured until the onset of MPGN, as there was no liver disorder nor any indication for antiviral therapy. This clinical course may have been due to an iatrogenic cause. At the very least, the HCV-RNA levels should have been monitored before the initiation of rituximab therapy. Several reports have described the successful treatment of MPGN with rituximab therapy. The addition of rituximab therapy to antiviral therapy for HCV-related MPGN is well tolerated and it has been reported to be more effective than antiviral therapy alone (13,14). Mak et al. described the successful treatment of thrombotic thrombocytopenic purpura and MPGN with rituximab therapy in a case associated with HCV infection (15). In that case, the MPGN improved, but liver dysfunction and HCV-RNA elevation were transiently observed. In contrast to the present case, neither a blood examination nor a renal biopsy showed cryoglobulin. There is no doubt that rituximab is effective as a treatment for MPGN itself. However, it may not be possible to prevent the onset of MPGN, and in our case, it was considered that rituximab indirectly induced MPGN. In individuals who are infected with HCV, the incidence of ITP is increased in comparison individuals without HCV infection (16). Several reports have suggested that HCV infection is involved in the development of ITP through various mechanisms (16-18). Johia et al. described the case of an HCV-positive patient with refractory ITP in whom the eradication of HCV was effective for ITP (18). In this case, although rituximab therapy seemed to improve the responsiveness of ITP to steroid therapy, the reduced dose of PSL (4 mg) caused a relapse of ITP. Although the combined use of romiplostim was still necessary after antiviral therapy for HCV, the dosage of PSL could be reduced to 2 mg, suggesting that antiviral therapy for HCV was also effective against ITP. Thrombocytopenia is no longer a major problem in the treatment of chronic HCV infection because of the recent change in direct antiviral agents without interferon (19). The US guidelines for ITP recommend that testing for HCV be considered in all patients with acute ITP and that antiviral therapy be considered in HCV-positive patients with ITP in the absence of contraindications (20). Although whether or not all HCV-positive patients with ITP should be treated remains controversial in Japan, antiviral therapy for HCV should be actively performed as a treatment for refractory ITP. At least, it is certain that antiviral therapy for HCV should be given before rituximab therapy. In conclusion, we experienced a case in which HCV-related MPGN that developed with a relapse of ITP after rituximab therapy, in which both conditions were improved by antiviral therapy for HCV. Rituximab therapy may have contributed to the exacerbation of HCV infection and induced the development of HCV-related MPGN and relapse of ITP. Our case suggested that HCV treatment should be prioritized over rituximab therapy for HCV-positive patients with ITP and that antiviral therapy for HCV may be effective for ITP itself. The authors state that they have no Conflict of Interest (COI). Acknowledgement The authors would like to thank Yoshitaka Miyakawa of Department of General Internal Medicine, Saitama Medical University for his advice on the treatment of ITP in the present case.	Recovering	ReactionOutcome	CC BY-NC-ND	33583904	18,544,239	2021-08-01
What was the outcome of reaction 'Hepatitis C'?	Immune Thrombocytopenic Purpura Complicated by Hepatitis C Virus-related Membranoproliferative Glomerulonephritis after Rituximab Therapy. We herein report the case of a 54-year-old Japanese man with hepatitis C virus (HCV)-related membranoproliferative glomerulonephritis (MPGN), which developed at the time of relapse of immune thrombocytopenic purpura (ITP) after rituximab therapy. Antiviral therapy for HCV led to the improvement of both MPGN and ITP. Rituximab therapy may have contributed to the exacerbation of HCV infection and induced the development of HCV-related MPGN and the relapse of ITP. Our case suggested that HCV treatment should be prioritized over rituximab therapy for HCV-positive patients with ITP and that antiviral therapy for HCV may be effective for treating ITP itself. Introduction Immune thrombocytopenic purpura (ITP) is an immune-mediated acquired disease that is characterized by a transient or persistent decrease in the platelet count and an increased risk of bleeding (1,2). According to the Japanese guidelines for adult ITP (3), ITP treatment includes Helicobacter pylori eradication therapy and corticosteroid therapy as the first choice, and thrombopoietin receptor agonist, splenectomy, and rituximab therapy as the second choice. Rituximab is a chimeric monoclonal antibody against the CD20 antigen, which specifically eliminates CD20-positive B lymphocytes and reduces antibody production. In Japan, rituximab has been approved for the treatment of ITP since 2017 (4) and it is now used on a daily basis. It is widely known that the reactivation of hepatitis B virus (HBV) may occur in patients treated with rituximab-containing regimens, and there are guidelines aimed at its prevention (5). In contrast, with regard to hepatitis C virus (HCV), the onset of fulminant hepatitis is extremely rare, and there are no guidelines for its prevention (6). However, there are also some reports on the exacerbation of HCV infection by rituximab-containing regimens (7,8). We herein report a case of refractory ITP complicated by HCV-related membranoproliferative glomerulonephritis (MPGN) that developed after the initiation of rituximab therapy. Case Report A 54-year-old Japanese man was diagnosed with ITP at 25 years of age. He was treated with prednisolone (PSL), cyclosporin, azathioprine, high-dose intravenous immunoglobulin therapy, and eltrombopag. The effects of these treatments were all limited. Romiplostim (10 μg/kg) and PSL (10 mg) were continued for a long time. However, the dose of PSL often needed to be increased because the patient's platelet count dropped to <10.0×109/L with bleeding symptoms. The platelet-associated IgG value was in the range of 200-300 ng/107 cells. Due to long-term steroid therapy, he developed thin skin and obesity (body mass index, 30.2 kg/m2). Voglibose, linagliptin, olmesartan medoxomil/azelnidipine, enalapril maleate, and febuxostat were continued as treatments for hypertension, diabetes mellitus and hyperuricemia. Diabetic retinopathy was never noted. The estimated glomerular filtration rate remained at just over 60 mL/min/1.73 m2. Although HCV antibody positivity was pointed out, he was followed up without any treatment because there was no liver disorder. In November 2017, rituximab (375 mg/m2 per week) was administered four times. His platelet count increased and the PSL dosage could be decreased to 4 mg. In March 2018, however, his platelet count dropped in 8.0×109/L. 40 mg dexamethasone for 4 days was performed and the platelet count increased. Renal dysfunction appeared during the same period and it also worsened. Severe edema was noted on both lower legs and diuretics were required. No joint pain, swelling, Raynaud's symptoms, or numbness of the fingers or toes was observed. In April 2018, the serum creatinine concentration rose to 7.81 mg/dL and he was urgently hospitalized. A physical examination on admission revealed the following: body temperature, 35.8℃; heart rate, 84 bpm; blood pressure, 147/80 mmHg; and respiratory rate, 19 breaths/min. His oxygen saturation was 99% while breathing room air. A physical examination revealed purpura on his hand and breast. No edema was found in either of the lower limbs on admission. The laboratory findings are shown in Table. The patient's platelet count had increased due to the administration of high-dose dexamethasone therapy just before admission. He presented with mild liver dysfunction, severe renal dysfunction, and hyperkalemia due to renal dysfunction. The levels of complement proteins were low. A cryoglobulin test was positive, and IgG and IgM cryoglobulins were detected. Because M-protein was not found by immunoelectrophoresis, Type III cryoglobulinemia was thus diagnosed. A urinalysis revealed protein, occult blood, and various urinary casts. Abdominal echography showed normally sized kidneys, increased echogenicity of the renal parenchyma, and renal cysts. There were moderate to large amount of ascites without findings suggestive of cirrhosis. A renal biopsy revealed an enlargement of the glomeruli with mesangial proliferation, lobulation of the glomeruli (Fig. 1a, b), and double contours in the basement membranes (Fig. 1c, arrow). Microtubule-like deposits were diffusely observed in the subendothelial basement membrane and paramesagiual area on electron microscopy (Fig. 1c, d). Immunofluorescence staining showed IgM positivity in the basement membrane in the form of small granules (Fig. 1e), while IgG and C3 were negative (Fig. 1f, g). There was no marked difference between kappa and lambda staining. Exudative lesions in the capillaries were observed in some glomeruli (Fig. 1h, arrow). Table. Laboratory Examination at the Admission. Complete blood cell count Blood chemistry Serological test White blood cell 9.0 ×109/L Total protein 5.3 g/dL C-reactive protein 0.77 mg/dL Neutrophil 87.4 % Albumin 3.5 g/dL IgG/IgA/IgM 990/89/49 mg/dL Lymphocyte 10.2 % Aspartate transaminase 69 U/L M-protein negative Eosinophil 0.1 % Alanine aminotransferase 64 U/L C3 61 mg/dL (73-138) Hemoglobin 11.4 g/dL Lactate dehydrogenase 364 U/L C4 14 mg/dL (86-138) Hematocrit 35.1 % Alkaline phosphatase 400 U/L CH50 28.0 U/mL (31.6-57.6) Platelet count 136.0 ×109/L Total bilirubin 0.5 mg/dL Cryoglobulin positive Urea nitrogen 75 mg/dL Antinuclear antibody ×80 Coagulation test Creatinin 7.81 mg/mL Rheumatoid factor <5.0 IU/mL PT-INR 1.04 Sodium 137 mEq/L ds-DNA antibody <0.5 U/mL APTT 45.3 sec Potassium 5.8 mEq/L MPO/PR3-ANCA <1.0/<1.0 U/mL Fibrinogen 273 mg/dL Corrected calcium 8.4 mg/dL Anti-SS-A/B antibody <1.0/<1.0 U/mL D-dimer 0.7 μg/mL eGFR 6.7 mL/min/1.73m2 Anti-GBM antibody <2.0 U/mL Urine test Virological examination Protein 3+ White blood cell <0-1 /HPF Hepatitis B surface antigen (-) Glucose 1+ Red blood cell 1-4 / HPF HCV-antibody (+) Occult blood 1+ Oval fat body + Granular cast + HCV-genotype 2a Protein 6.20 g/gCre Hyalin cast + Fatty cast + HCV-RNA 6.5 log IU/mL Waxy cast + Epithelial cast + PT-INR: international normalized ratio, APTT: activated partial thromboplastin, HCV: hepatitis C virus, Cre: creatinine, Ig: immunoglobulin, MPO: myeloperoxidase, PR3: proteinase 3, ANCA: anti-neutrophil cytoplasmic antibody, SS: Sjogren’s syndrome, GBM: glomerular basement membrane, HPF: high power field. The numbers in parentheses after the C3, C4, and CH50 values are the normal range at the time of measurement Figure 1. Renal biopsy revealed enlargement of the glomeruli with mesangial proliferation, lobulation of the glomeruli (a, b), and double contours in the basement membranes (c, arrow). Microtubule-like deposits are diffusely observed in the subendothelial basement membrane and paramesagiual area on electron microscopy. (c, d) Immunofluorescence staining revealed IgM positivity in the basement membrane in the form of small granules (e), while IgG and C3 were negative (f, g). Exudative lesions in capillaries were observed in some glomeruli (h, arrow). The main cause of renal failure was diagnosed as HCV-related MPGN, which is classified as immune complex-mediated MPGN, and diabetic nephropathy was also considered to be present. The administration of glecaprevir hydrate/pibrentasvir for 12 weeks was initiated and the dose of PSL was increased to 30 mg for 2 weeks. At two weeks after the start of the antiviral therapy, HCV-RNA was no longer detected. The serum creatinine levels tended to improve, and the urinary occult blood disappeared, although mild proteinuria remained. The dose of PSL was gradually reduced to 3 mg, and the dose of romiplostim was reduced to 5 μg/kg. Because the platelet count decreased again, the dose of romiplostim was returned to 10 μg/kg. More than one year has passed since the dose of PSL was reduced to 2 mg. Although the patient's platelet count has fluctuated, no clear bleeding tendency has been observed (Fig. 2). With the reduction of the PSL dose, the patient's body mass index improved to 23.1 kg/m2, and voglibose and linagliptin could be discontinued. The levels of complement protein improved to 13 (normal range, 11-31) mg/dL for C3, 56 (73-138) mg/dL for C4, and 36.6 (25.0-48.0) U/mL for CH50. The elevated serum creatinine level and mild proteinuria persisted, a finding that was attributed to the diabetic nephropathy, and the management of chronic kidney disease was continued with a focus on antihypertensive therapy. Figure 2. The clinical course. HD-DEX: high dose dexamethasone, eGFR: estimated glomerular filtration rate, HCV: hepatitis C virus Discussion MPGN is a type of glomerulonephritis that is characterized by mesangial proliferation and basement membrane duplication. The clinical presentation and course are extremely variable (9). MPGN occurs as a primary or secondary condition. Secondary MPGN is most often due to hepatitis C and other infections (10). Patients with HCV-related MPGN have a higher incidence of liver dysfunction, cryoglobulinemia, rheumatoid factor, and hypocomplementemia (11,12). In our case, after rituximab therapy HCV-related MPGN developed with a relapse of ITP and both improved with antiviral therapy for HCV. HCV-RNA elevation due to rituximab therapy may have contributed to the development of MPGN and the relapse of ITP. Unfortunately, however, the patient's HCV-RNA levels were not measured until the onset of MPGN, as there was no liver disorder nor any indication for antiviral therapy. This clinical course may have been due to an iatrogenic cause. At the very least, the HCV-RNA levels should have been monitored before the initiation of rituximab therapy. Several reports have described the successful treatment of MPGN with rituximab therapy. The addition of rituximab therapy to antiviral therapy for HCV-related MPGN is well tolerated and it has been reported to be more effective than antiviral therapy alone (13,14). Mak et al. described the successful treatment of thrombotic thrombocytopenic purpura and MPGN with rituximab therapy in a case associated with HCV infection (15). In that case, the MPGN improved, but liver dysfunction and HCV-RNA elevation were transiently observed. In contrast to the present case, neither a blood examination nor a renal biopsy showed cryoglobulin. There is no doubt that rituximab is effective as a treatment for MPGN itself. However, it may not be possible to prevent the onset of MPGN, and in our case, it was considered that rituximab indirectly induced MPGN. In individuals who are infected with HCV, the incidence of ITP is increased in comparison individuals without HCV infection (16). Several reports have suggested that HCV infection is involved in the development of ITP through various mechanisms (16-18). Johia et al. described the case of an HCV-positive patient with refractory ITP in whom the eradication of HCV was effective for ITP (18). In this case, although rituximab therapy seemed to improve the responsiveness of ITP to steroid therapy, the reduced dose of PSL (4 mg) caused a relapse of ITP. Although the combined use of romiplostim was still necessary after antiviral therapy for HCV, the dosage of PSL could be reduced to 2 mg, suggesting that antiviral therapy for HCV was also effective against ITP. Thrombocytopenia is no longer a major problem in the treatment of chronic HCV infection because of the recent change in direct antiviral agents without interferon (19). The US guidelines for ITP recommend that testing for HCV be considered in all patients with acute ITP and that antiviral therapy be considered in HCV-positive patients with ITP in the absence of contraindications (20). Although whether or not all HCV-positive patients with ITP should be treated remains controversial in Japan, antiviral therapy for HCV should be actively performed as a treatment for refractory ITP. At least, it is certain that antiviral therapy for HCV should be given before rituximab therapy. In conclusion, we experienced a case in which HCV-related MPGN that developed with a relapse of ITP after rituximab therapy, in which both conditions were improved by antiviral therapy for HCV. Rituximab therapy may have contributed to the exacerbation of HCV infection and induced the development of HCV-related MPGN and relapse of ITP. Our case suggested that HCV treatment should be prioritized over rituximab therapy for HCV-positive patients with ITP and that antiviral therapy for HCV may be effective for ITP itself. The authors state that they have no Conflict of Interest (COI). Acknowledgement The authors would like to thank Yoshitaka Miyakawa of Department of General Internal Medicine, Saitama Medical University for his advice on the treatment of ITP in the present case.	Recovered	ReactionOutcome	CC BY-NC-ND	33583904	18,544,239	2021-08-01
What was the outcome of reaction 'Renal failure'?	Immune Thrombocytopenic Purpura Complicated by Hepatitis C Virus-related Membranoproliferative Glomerulonephritis after Rituximab Therapy. We herein report the case of a 54-year-old Japanese man with hepatitis C virus (HCV)-related membranoproliferative glomerulonephritis (MPGN), which developed at the time of relapse of immune thrombocytopenic purpura (ITP) after rituximab therapy. Antiviral therapy for HCV led to the improvement of both MPGN and ITP. Rituximab therapy may have contributed to the exacerbation of HCV infection and induced the development of HCV-related MPGN and the relapse of ITP. Our case suggested that HCV treatment should be prioritized over rituximab therapy for HCV-positive patients with ITP and that antiviral therapy for HCV may be effective for treating ITP itself. Introduction Immune thrombocytopenic purpura (ITP) is an immune-mediated acquired disease that is characterized by a transient or persistent decrease in the platelet count and an increased risk of bleeding (1,2). According to the Japanese guidelines for adult ITP (3), ITP treatment includes Helicobacter pylori eradication therapy and corticosteroid therapy as the first choice, and thrombopoietin receptor agonist, splenectomy, and rituximab therapy as the second choice. Rituximab is a chimeric monoclonal antibody against the CD20 antigen, which specifically eliminates CD20-positive B lymphocytes and reduces antibody production. In Japan, rituximab has been approved for the treatment of ITP since 2017 (4) and it is now used on a daily basis. It is widely known that the reactivation of hepatitis B virus (HBV) may occur in patients treated with rituximab-containing regimens, and there are guidelines aimed at its prevention (5). In contrast, with regard to hepatitis C virus (HCV), the onset of fulminant hepatitis is extremely rare, and there are no guidelines for its prevention (6). However, there are also some reports on the exacerbation of HCV infection by rituximab-containing regimens (7,8). We herein report a case of refractory ITP complicated by HCV-related membranoproliferative glomerulonephritis (MPGN) that developed after the initiation of rituximab therapy. Case Report A 54-year-old Japanese man was diagnosed with ITP at 25 years of age. He was treated with prednisolone (PSL), cyclosporin, azathioprine, high-dose intravenous immunoglobulin therapy, and eltrombopag. The effects of these treatments were all limited. Romiplostim (10 μg/kg) and PSL (10 mg) were continued for a long time. However, the dose of PSL often needed to be increased because the patient's platelet count dropped to <10.0×109/L with bleeding symptoms. The platelet-associated IgG value was in the range of 200-300 ng/107 cells. Due to long-term steroid therapy, he developed thin skin and obesity (body mass index, 30.2 kg/m2). Voglibose, linagliptin, olmesartan medoxomil/azelnidipine, enalapril maleate, and febuxostat were continued as treatments for hypertension, diabetes mellitus and hyperuricemia. Diabetic retinopathy was never noted. The estimated glomerular filtration rate remained at just over 60 mL/min/1.73 m2. Although HCV antibody positivity was pointed out, he was followed up without any treatment because there was no liver disorder. In November 2017, rituximab (375 mg/m2 per week) was administered four times. His platelet count increased and the PSL dosage could be decreased to 4 mg. In March 2018, however, his platelet count dropped in 8.0×109/L. 40 mg dexamethasone for 4 days was performed and the platelet count increased. Renal dysfunction appeared during the same period and it also worsened. Severe edema was noted on both lower legs and diuretics were required. No joint pain, swelling, Raynaud's symptoms, or numbness of the fingers or toes was observed. In April 2018, the serum creatinine concentration rose to 7.81 mg/dL and he was urgently hospitalized. A physical examination on admission revealed the following: body temperature, 35.8℃; heart rate, 84 bpm; blood pressure, 147/80 mmHg; and respiratory rate, 19 breaths/min. His oxygen saturation was 99% while breathing room air. A physical examination revealed purpura on his hand and breast. No edema was found in either of the lower limbs on admission. The laboratory findings are shown in Table. The patient's platelet count had increased due to the administration of high-dose dexamethasone therapy just before admission. He presented with mild liver dysfunction, severe renal dysfunction, and hyperkalemia due to renal dysfunction. The levels of complement proteins were low. A cryoglobulin test was positive, and IgG and IgM cryoglobulins were detected. Because M-protein was not found by immunoelectrophoresis, Type III cryoglobulinemia was thus diagnosed. A urinalysis revealed protein, occult blood, and various urinary casts. Abdominal echography showed normally sized kidneys, increased echogenicity of the renal parenchyma, and renal cysts. There were moderate to large amount of ascites without findings suggestive of cirrhosis. A renal biopsy revealed an enlargement of the glomeruli with mesangial proliferation, lobulation of the glomeruli (Fig. 1a, b), and double contours in the basement membranes (Fig. 1c, arrow). Microtubule-like deposits were diffusely observed in the subendothelial basement membrane and paramesagiual area on electron microscopy (Fig. 1c, d). Immunofluorescence staining showed IgM positivity in the basement membrane in the form of small granules (Fig. 1e), while IgG and C3 were negative (Fig. 1f, g). There was no marked difference between kappa and lambda staining. Exudative lesions in the capillaries were observed in some glomeruli (Fig. 1h, arrow). Table. Laboratory Examination at the Admission. Complete blood cell count Blood chemistry Serological test White blood cell 9.0 ×109/L Total protein 5.3 g/dL C-reactive protein 0.77 mg/dL Neutrophil 87.4 % Albumin 3.5 g/dL IgG/IgA/IgM 990/89/49 mg/dL Lymphocyte 10.2 % Aspartate transaminase 69 U/L M-protein negative Eosinophil 0.1 % Alanine aminotransferase 64 U/L C3 61 mg/dL (73-138) Hemoglobin 11.4 g/dL Lactate dehydrogenase 364 U/L C4 14 mg/dL (86-138) Hematocrit 35.1 % Alkaline phosphatase 400 U/L CH50 28.0 U/mL (31.6-57.6) Platelet count 136.0 ×109/L Total bilirubin 0.5 mg/dL Cryoglobulin positive Urea nitrogen 75 mg/dL Antinuclear antibody ×80 Coagulation test Creatinin 7.81 mg/mL Rheumatoid factor <5.0 IU/mL PT-INR 1.04 Sodium 137 mEq/L ds-DNA antibody <0.5 U/mL APTT 45.3 sec Potassium 5.8 mEq/L MPO/PR3-ANCA <1.0/<1.0 U/mL Fibrinogen 273 mg/dL Corrected calcium 8.4 mg/dL Anti-SS-A/B antibody <1.0/<1.0 U/mL D-dimer 0.7 μg/mL eGFR 6.7 mL/min/1.73m2 Anti-GBM antibody <2.0 U/mL Urine test Virological examination Protein 3+ White blood cell <0-1 /HPF Hepatitis B surface antigen (-) Glucose 1+ Red blood cell 1-4 / HPF HCV-antibody (+) Occult blood 1+ Oval fat body + Granular cast + HCV-genotype 2a Protein 6.20 g/gCre Hyalin cast + Fatty cast + HCV-RNA 6.5 log IU/mL Waxy cast + Epithelial cast + PT-INR: international normalized ratio, APTT: activated partial thromboplastin, HCV: hepatitis C virus, Cre: creatinine, Ig: immunoglobulin, MPO: myeloperoxidase, PR3: proteinase 3, ANCA: anti-neutrophil cytoplasmic antibody, SS: Sjogren’s syndrome, GBM: glomerular basement membrane, HPF: high power field. The numbers in parentheses after the C3, C4, and CH50 values are the normal range at the time of measurement Figure 1. Renal biopsy revealed enlargement of the glomeruli with mesangial proliferation, lobulation of the glomeruli (a, b), and double contours in the basement membranes (c, arrow). Microtubule-like deposits are diffusely observed in the subendothelial basement membrane and paramesagiual area on electron microscopy. (c, d) Immunofluorescence staining revealed IgM positivity in the basement membrane in the form of small granules (e), while IgG and C3 were negative (f, g). Exudative lesions in capillaries were observed in some glomeruli (h, arrow). The main cause of renal failure was diagnosed as HCV-related MPGN, which is classified as immune complex-mediated MPGN, and diabetic nephropathy was also considered to be present. The administration of glecaprevir hydrate/pibrentasvir for 12 weeks was initiated and the dose of PSL was increased to 30 mg for 2 weeks. At two weeks after the start of the antiviral therapy, HCV-RNA was no longer detected. The serum creatinine levels tended to improve, and the urinary occult blood disappeared, although mild proteinuria remained. The dose of PSL was gradually reduced to 3 mg, and the dose of romiplostim was reduced to 5 μg/kg. Because the platelet count decreased again, the dose of romiplostim was returned to 10 μg/kg. More than one year has passed since the dose of PSL was reduced to 2 mg. Although the patient's platelet count has fluctuated, no clear bleeding tendency has been observed (Fig. 2). With the reduction of the PSL dose, the patient's body mass index improved to 23.1 kg/m2, and voglibose and linagliptin could be discontinued. The levels of complement protein improved to 13 (normal range, 11-31) mg/dL for C3, 56 (73-138) mg/dL for C4, and 36.6 (25.0-48.0) U/mL for CH50. The elevated serum creatinine level and mild proteinuria persisted, a finding that was attributed to the diabetic nephropathy, and the management of chronic kidney disease was continued with a focus on antihypertensive therapy. Figure 2. The clinical course. HD-DEX: high dose dexamethasone, eGFR: estimated glomerular filtration rate, HCV: hepatitis C virus Discussion MPGN is a type of glomerulonephritis that is characterized by mesangial proliferation and basement membrane duplication. The clinical presentation and course are extremely variable (9). MPGN occurs as a primary or secondary condition. Secondary MPGN is most often due to hepatitis C and other infections (10). Patients with HCV-related MPGN have a higher incidence of liver dysfunction, cryoglobulinemia, rheumatoid factor, and hypocomplementemia (11,12). In our case, after rituximab therapy HCV-related MPGN developed with a relapse of ITP and both improved with antiviral therapy for HCV. HCV-RNA elevation due to rituximab therapy may have contributed to the development of MPGN and the relapse of ITP. Unfortunately, however, the patient's HCV-RNA levels were not measured until the onset of MPGN, as there was no liver disorder nor any indication for antiviral therapy. This clinical course may have been due to an iatrogenic cause. At the very least, the HCV-RNA levels should have been monitored before the initiation of rituximab therapy. Several reports have described the successful treatment of MPGN with rituximab therapy. The addition of rituximab therapy to antiviral therapy for HCV-related MPGN is well tolerated and it has been reported to be more effective than antiviral therapy alone (13,14). Mak et al. described the successful treatment of thrombotic thrombocytopenic purpura and MPGN with rituximab therapy in a case associated with HCV infection (15). In that case, the MPGN improved, but liver dysfunction and HCV-RNA elevation were transiently observed. In contrast to the present case, neither a blood examination nor a renal biopsy showed cryoglobulin. There is no doubt that rituximab is effective as a treatment for MPGN itself. However, it may not be possible to prevent the onset of MPGN, and in our case, it was considered that rituximab indirectly induced MPGN. In individuals who are infected with HCV, the incidence of ITP is increased in comparison individuals without HCV infection (16). Several reports have suggested that HCV infection is involved in the development of ITP through various mechanisms (16-18). Johia et al. described the case of an HCV-positive patient with refractory ITP in whom the eradication of HCV was effective for ITP (18). In this case, although rituximab therapy seemed to improve the responsiveness of ITP to steroid therapy, the reduced dose of PSL (4 mg) caused a relapse of ITP. Although the combined use of romiplostim was still necessary after antiviral therapy for HCV, the dosage of PSL could be reduced to 2 mg, suggesting that antiviral therapy for HCV was also effective against ITP. Thrombocytopenia is no longer a major problem in the treatment of chronic HCV infection because of the recent change in direct antiviral agents without interferon (19). The US guidelines for ITP recommend that testing for HCV be considered in all patients with acute ITP and that antiviral therapy be considered in HCV-positive patients with ITP in the absence of contraindications (20). Although whether or not all HCV-positive patients with ITP should be treated remains controversial in Japan, antiviral therapy for HCV should be actively performed as a treatment for refractory ITP. At least, it is certain that antiviral therapy for HCV should be given before rituximab therapy. In conclusion, we experienced a case in which HCV-related MPGN that developed with a relapse of ITP after rituximab therapy, in which both conditions were improved by antiviral therapy for HCV. Rituximab therapy may have contributed to the exacerbation of HCV infection and induced the development of HCV-related MPGN and relapse of ITP. Our case suggested that HCV treatment should be prioritized over rituximab therapy for HCV-positive patients with ITP and that antiviral therapy for HCV may be effective for ITP itself. The authors state that they have no Conflict of Interest (COI). Acknowledgement The authors would like to thank Yoshitaka Miyakawa of Department of General Internal Medicine, Saitama Medical University for his advice on the treatment of ITP in the present case.	Recovering	ReactionOutcome	CC BY-NC-ND	33583904	18,544,239	2021-08-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myopathy'.	Case Report: Myopathy in Critically Ill COVID-19 Patients: A Consequence of Hyperinflammation? Introduction: COVID-19-associated muscular complications may comprise myalgia, weakness, wasting, and rhabdomyolysis. Skeletal muscle damage in COVID-19 may be due to direct infection by the virus SARS-CoV-2 through interaction with the ACE2 receptor, systemic hyper-inflammatory state with cytokine release and homeostatic perturbation, an autoimmune process, or myotoxic drugs. Disclosing the cause of weakness in an individual patient is therefore difficult. Case Description: We report two patients, who survived typical COVID-19 pneumonia requiring intensive care treatment and who developed early on myalgia and severe proximal weakness in all four limbs. Laboratory exams revealed elevated serum creatine kinase and markedly increased C-reactive protein and interleukin 6, concurring with a systemic inflammatory response. On admission in neurorehabilitation (4 and 7 weeks after COVID-19 onset, respectively), the patients presented with proximal flaccid tetraparesis and limb-girdle muscle atrophy. Motor nerve conduction studies showed decreased amplitude and prolonged duration of compound muscle action potentials (CMAPs) with normal distal motor latencies and normal conduction velocities in median and ulnar nerves. Needle electromyography in proximal muscles revealed spontaneous activity in one and myopathic changes in both patients. Discussion: Clinical, laboratory, and electrodiagnostic findings in these patients were unequivocally consistent with myopathy. Interestingly, increased distal CMAP duration has been described in patients with critical illness myopathy (CIM) and reflects slow muscle fiber conduction velocity due to membrane hypo-excitability, possibly induced by inflammatory cytokines. By analogy with CIM, the pathogenesis of COVID-19-related myopathy might also depend on hyperinflammation and metabolic pathways that may affect muscles in a pathophysiological continuum from hypo-excitability to necrosis. Introduction Muscular complications in hospitalized coronavirus disease (COVID-19) patients may include myalgia, muscle weakness and wasting, elevated serum creatine kinase (CK), and rhabdomyolysis (1). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to cells through the angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed in skeletal muscle (2). However, SARS-CoV-2 particles, despite its broad organotropism beyond the respiratory tract, have not been demonstrated in muscle samples so far (3). Besides the possibility of direct skeletal muscle injury by SARS-CoV-2, other conceivable causes of myopathies in COVID-19 may comprise an autoimmune process, such as in necrotizing autoimmune myositis, consequence of the systemic hyperinflammatory state, and myotoxicity by medication (e.g., hydroxychloroquine, anti-retroviral agents) (2, 4, 5). Moreover, severely affected COVID-19 patients with systemic inflammatory response, prolonged intensive care treatment with ventilation, and immobilization are prone to develop critical illness myopathy (CIM). Hence, explaining the exact cause of weakness in an individual patient may be difficult. To date, CIM has been reported and at least electrodiagnostically confirmed in 20 patients with COVID-19 (6–9) (Table 1). Intensive care unit acquired muscle weakness was clinically diagnosed in 72% of COVID-19 patients at awakening (11). Compared to patients without muscle weakness, myopathic patients had longer ICU stays, prolonged duration of invasive mechanical ventilation, higher mean morning glycemia, higher exposure to corticosteroids, sedatives, analgesics, and neuromuscular blocking agents (11). Half of critically ill COVID-19 patients presented acute myopathy in a recent retrospective study (10). Table 1 Studies on COVID-19-patients with intensive care unit acquired myopathy. N of patients Age mean (range) [years] Sex ICU stay mean (range) [days] Medication Clinical feature NCS/EMG Muscle biopsy CK peak-level IL-6 peak-level (9) 7 NA NA NA Antiretrovirals, neuromuscular blockers, corticosteroids, antibiotics Generalized muscular weakness Myopathy Three patients (scattered necrotic and regenerative fibers, no inflammatory infiltrates) 181–3,228 μmol/l N/A (10) 5 N/A N/A N/A Antirheumatics, antiretrovirals, corticosteroids, antibiotics Generalized muscular weakness Myopathy ND 61–1,206 μg/l NA (8) 6 61 (51-72) 1 F 6-14 until NCS/EMG Antirheumatics, antiretrovirals, corticosteroids, antibiotics, anticoagulants Acute flaccid quadriplegia Myopathy; reduced CMAP amplitude with markedly prolonged duration ND 55–1,274 UI/L 18.4–5,402.2 ng/ml (6) 1 68 M 65 Antibiotics Severe symmetrical proximal and distal weakness and diffuse muscle wasting Myopathy and bilateral peroneal compression neuropathy. ND NA NA (7) 1 62 F 30 Antirheumatics, antiretrovirals, antibiotics, neuromuscular blockers, antifungal drugs, corticosteroids. Symmetrical muscle weakness predominant in lower limbs and proximal muscles. Myopathy ND Normal NA ICU, intensive care unit; NCS/EMG, nerve conduction studies/electromyography; CK, creatine kinase; IL-6, interleukine 6; F, female; M, male; CMAP, compound muscle action potential; ND not done; NA not available. Case Description Here, we report two patients who survived typical COVID-19 pneumonia, confirmed by RT-PCR test on nasopharyngeal swab and by chest computed tomography, which showed bilateral diffuse consolidations and ground-glass opacities. No personal or family medical history of rhabdomyolisis or myoglobinuria or any type of muscle pathology was known. Neither patient had ever received statin therapy or other potentially myotoxic agents. In general, the patients did not suffer from any previous relevant pathology. Table 2 summarizes demographic, clinical, laboratory, and electrophysiological data. Table 2 Demographic, clinical, laboratory, and electrodiagnostic data. Patient Age Sex ICU stay Clinical features Laboratory findings (peak levels) NCS/EMG: time since disease onset Sensory NCS Motor NCS EMG CK CRP IL-6 D-dimer WBC Lymphocyte SNAP amplitude sNCV CMAP amplitude CMAP duration DML mNCV Proximal muscles* [weeks] [U/l] [mg/l] [pg/ml] [mg/l] [×103/μl] [×103/μl] [weeks] [μV] [m/s] [mV] [ms] [ms] [m/s] 40–220 <0.8 <7.0 <0.5 3.6–10.5 1.1–4.5 1 77 M 6 Proximal weakness and muscle wasting in upper more than lower limbs; myalgia; fatigue 4,002 15.9 225.2 1.5 10.1 2.8 7 L median: 15.2 50 L median: 4.2 9.3 3.9 48 Myopathic R ulnar: 12.4 48 R ulnar: 5.7 13.7 2.9 55 R sural: 6.3 47 L peroneal: 2.1 7.3 3.1 40 R tibial: 2.4 4.2 4.0 41 2 58 M 3 Predominantly proximal weakness in four limbs; hyporeflexia; myalgia 6,732 17.1 343.6 2.1 9.9 4.6 4 L median: 22.5 49 L median: 3.9 9.0 3.8 48 Myopathic R ulnar: 25.8 51 R ulnar: 4.8 8.7 2.5 50 R sural: 9.5 48 L peroneal: 1.2 6.5 4.0 39 R tibial: 2.2 6.7 4.1 40 Laboratory data were obtained during intensive care. Clinical and electrodiagnostic data were obtained during neurorehabilitation. M, male; F, female; ICU, intensive care unit; CK, creatine kinase; CRP, C-reactive protein; WBC, white blood cell count; IL, interleukin; NCS, nerve conduction study; EMG, electromyography; SNAP, sensory nerve action potential; sNCV, sensory nerve conduction velocity; CMAP, compound muscle action potential; DML, distal motor latency; mNCV, motor nerve conduction velocity; R, right; L, left. The upper limits of normality (mean + 2 SD) for distal CMAP duration using a low frequency filter of 2 Hz are: median nerve = 7.3 ms, ulnar nerve = 7.5 ms, peroneal nerve = 7.3 ms, tibial nerve = 6.8 ms (12); abnormal values are marked in bold. * Left deltoid, right triceps brachii, left iliopsoas, and right rectus femoris muscles. Because of respiratory failure, both patients required intensive care treatment, including tracheostomy and ventilatory support for several weeks. Oral treatment with hydroxychloroquine 200 mg twice a day and lopinavir/ritonavir 400/100 mg twice a day was administered for 3 weeks. No antibiotics, corticosteroids or analgesics were administered. High serum levels of C-reactive protein (CRP) and interleukin 6 (IL-6) were documented during the acute phase (Table 2). After weaning from sedation (intravenous sufentanil/propofol together with rocuronium bromide as muscle relaxant) and ventilation, the patients suffered mild dyspnea requiring oxygen support (2 l/min), complained of myalgia and fatigue, and showed on examination severe proximal muscles weakness in in both upper and lower limbs (Medical Research Council scale 2/5). Strength in distal muscle was normal. Deep tendon reflexes were hypoactive. No deep or superficial sensory disturbance was noted. Cranial nerve examination was unremarkable; in particular, no bulbar muscles weakness was found. Laboratory examination revealed elevated creatine kinase (CK) (peak-levels 4,002 and 6,732 U/l, respectively) which progressively normalized in the following 3 weeks, but no myoglobinuria nor acute renal failure signs. Due to the Covid-19-related emergency situation in Italian Intensive Care Units, no further neuroradiological or histopathological muscle studies could be performed. On admission in the neurorehabilitation unit (4 and 7 weeks after onset of COVID-19, respectively), both patients presented with flaccid proximal tetraparesis and limb-girdle muscle atrophy. A timeline of the clinical course is presented in Figure 1. Figure 1 Timeline of key events related to COVID-19 and myopathy in patient 1 (green labels) and patient 2 (yellow labels). Motor nerve conduction studies showed normal distal latencies and normal conduction velocities. Distal compound muscle action potential (CMAP) amplitudes were decreased and CMAP durations were prolonged in median and ulnar nerves in both patients (Table 2, Figure 2). Sensory conduction velocities and sensory nerve action potential amplitudes were normal. Needle EMG showed spontaneous activity (fibrillation potentials) in patient 2 and a myopathic pattern with short duration motor unit action potentials, increased percentage of polyphasic potentials, and early recruitment at voluntary effort in proximal muscles in both patients. Distal muscles were unremarkable. Within 2 weeks from admission in neurorehabilitation, serum CK returned to normal values (23 and 201 U/l, respectively). Figure 2 Motor nerve conduction studies of patient 1 (A,B) compared to a healthy control subject (C,D). Amplitude and duration of the negative phase of compound muscle action potentials (CMAPs) were measured at a sensitivity of 0.5 mV with a 2 Hz low frequency filter. The cut-off values for distal CMAP duration are according to reported normal values + 2 SD (12). (A) median nerve: distal CMAP amplitude is reduced (4.2 mV), distal motor latency (DML) is normal (3.9 ms), distal CMAP duration is increased (9.3 ms, 127% of upper limit of normal = 7.3 ms), conduction velocity (CV) is 48 m/s. CMAP amplitude and duration did not change between proximal and distal stimulation. Note the broadening and smooth contour of the negative phase of the distal CMAP and the reduction of the ensuing positive phase compared to panel (C) (CMAP duration = 5.7 ms); (B) ulnar nerve: distal CMAP amplitude is slightly reduced (5.7 mV), DML is normal (2.9 ms), distal CMAP duration is increased (13.7 ms, 183% upper limit of normal = 7.5 ms), CV is 55 m/s. CMAP amplitude and duration did not change with proximal stimulation. Note the very prolonged negative phase of the distal CMAP with a long tail and the absence of the ensuing positive phase compared to panel (D) (CMAP duration = 6.3 ms). Clinical condition improved progressively in both patients, who were discharged home after 6–8 weeks of rehabilitation, with a muscle strength of 3/5 in proximal upper limb and 4/5 in proximal lower limb muscles, and normal walking capability. However, both complained of reduced endurance and increased fatigue during physical activity. Discussion In the presented patients, clinical, laboratory and electrodiagnostic findings were consistent with a myopathy except for increased distal CMAP duration that is usually considered a hallmark of acquired demyelination. However, prolonged duration of distal CMAPs that did not change between distal and proximal stimulation (Figure 2), together with normal distal motor latencies and conduction velocities, indicates that in these patients, temporal dispersion of distal CMAP is due to slow muscle fibers conduction velocity. Indeed, prolonged distal CMAP duration, besides reduced CMAP amplitude, has previously been reported in patients with CIM, who presented, as compared to healthy controls, with reduced mean muscle fiber conduction velocity, which was inversely related to CMAP duration (13, 14). Moreover, in an in vitro model, sera from patients with CIM applied to single muscle fibers induced depolarization of the resting membrane potential, reduced the action potential rise time, and increased inward sodium current peak amplitude (15). Evidence from human studies and animal models indicates that in CIM associated with sepsis (the so-called “SIM,” sepsis-induced myopathy), systemic inflammatory response, and cytokine release induce a depolarizing shift of the muscle cell membrane potential, sodium channel inactivation, slowing of muscle fiber conduction velocity until total membrane inexcitability, increase of membrane permeability for Ca2+, and eventually Ca2+-dependent muscle necrosis by proteasome activation (16). We hypothesize that in the reported patients, by analogy with SIM, myopathy was caused by the COVID-associated hyper-inflammatory state, as demonstrated by high initial serum levels of CRP and IL-6. Prolonged distal CMAP durations can be explained by muscle membrane hypo-excitability combined with slow muscle fiber conduction velocity in regenerating muscle fibers. Interestingly also six reported COVID-10 patients with acute quadriplegic myopathy (8), showed markedly prolonged CMAP durations without evidence of acute myonecrosis (CK were slightly elevated in half patients and decreased in few days) and, with exception of one patient who died due to sepsis, showed rapid improvement of weakness (14–20 days). This can concur with the proposed mechanism of muscular impairment in COVID-19, ranging from membrane excitability dysfunction (which reflects in reduced amplitude and increased duration of CMAPs) with possible prompt recovery to myonecrosis, CK elevation, consequent muscle atrophy, and poorer outcome. Serum IL-6 elevation is common in critically ill patients (16), but it also plays a central role in the COVID-19 inflammation cascade already at an early stage, preceding need for intensive care, and it correlates with disease severity (17). In conclusion, the same pathogenetic mechanism that causes interstitial pneumonia and damage to extrapulmonary tissues and organs in COVID-19, i.e., the inflammatory cytokine storm together with coagulopathy and macrophage activation, could contribute, in patients requiring prolonged critical care, to skeletal muscle damage (17). Further studies are necessary to elucidate the pathogenesis of COVID-19-associated myopathy and to differentiate among direct infection, autoimmune process, and CIM due to hyperinflammation; in particular, muscle biopsy with specific investigations would be of crucial importance. Data Availability Statement The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s. Ethics Statement Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. Written informed consent was obtained from the patients for the submission of their data and for the publication of any potentially identifiable images or data included in this article. Author Contributions Material preparation, data collection, and analysis were performed by VV, LSe, and DF. The first draft of the manuscript was written by VV and MK. AU contributed substantially to the interpretation of the results, provided critical feedback, and revised the manuscript. All authors contributed in review and editing of the manuscript and approved its final version. All authors contributed to the study conception and design. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.	HYDROXYCHLOROQUINE, LOPINAVIR\RITONAVIR	DrugsGivenReaction	CC BY	33584530	19,157,707	2021
What was the administration route of drug 'HYDROXYCHLOROQUINE'?	Case Report: Myopathy in Critically Ill COVID-19 Patients: A Consequence of Hyperinflammation? Introduction: COVID-19-associated muscular complications may comprise myalgia, weakness, wasting, and rhabdomyolysis. Skeletal muscle damage in COVID-19 may be due to direct infection by the virus SARS-CoV-2 through interaction with the ACE2 receptor, systemic hyper-inflammatory state with cytokine release and homeostatic perturbation, an autoimmune process, or myotoxic drugs. Disclosing the cause of weakness in an individual patient is therefore difficult. Case Description: We report two patients, who survived typical COVID-19 pneumonia requiring intensive care treatment and who developed early on myalgia and severe proximal weakness in all four limbs. Laboratory exams revealed elevated serum creatine kinase and markedly increased C-reactive protein and interleukin 6, concurring with a systemic inflammatory response. On admission in neurorehabilitation (4 and 7 weeks after COVID-19 onset, respectively), the patients presented with proximal flaccid tetraparesis and limb-girdle muscle atrophy. Motor nerve conduction studies showed decreased amplitude and prolonged duration of compound muscle action potentials (CMAPs) with normal distal motor latencies and normal conduction velocities in median and ulnar nerves. Needle electromyography in proximal muscles revealed spontaneous activity in one and myopathic changes in both patients. Discussion: Clinical, laboratory, and electrodiagnostic findings in these patients were unequivocally consistent with myopathy. Interestingly, increased distal CMAP duration has been described in patients with critical illness myopathy (CIM) and reflects slow muscle fiber conduction velocity due to membrane hypo-excitability, possibly induced by inflammatory cytokines. By analogy with CIM, the pathogenesis of COVID-19-related myopathy might also depend on hyperinflammation and metabolic pathways that may affect muscles in a pathophysiological continuum from hypo-excitability to necrosis. Introduction Muscular complications in hospitalized coronavirus disease (COVID-19) patients may include myalgia, muscle weakness and wasting, elevated serum creatine kinase (CK), and rhabdomyolysis (1). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to cells through the angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed in skeletal muscle (2). However, SARS-CoV-2 particles, despite its broad organotropism beyond the respiratory tract, have not been demonstrated in muscle samples so far (3). Besides the possibility of direct skeletal muscle injury by SARS-CoV-2, other conceivable causes of myopathies in COVID-19 may comprise an autoimmune process, such as in necrotizing autoimmune myositis, consequence of the systemic hyperinflammatory state, and myotoxicity by medication (e.g., hydroxychloroquine, anti-retroviral agents) (2, 4, 5). Moreover, severely affected COVID-19 patients with systemic inflammatory response, prolonged intensive care treatment with ventilation, and immobilization are prone to develop critical illness myopathy (CIM). Hence, explaining the exact cause of weakness in an individual patient may be difficult. To date, CIM has been reported and at least electrodiagnostically confirmed in 20 patients with COVID-19 (6–9) (Table 1). Intensive care unit acquired muscle weakness was clinically diagnosed in 72% of COVID-19 patients at awakening (11). Compared to patients without muscle weakness, myopathic patients had longer ICU stays, prolonged duration of invasive mechanical ventilation, higher mean morning glycemia, higher exposure to corticosteroids, sedatives, analgesics, and neuromuscular blocking agents (11). Half of critically ill COVID-19 patients presented acute myopathy in a recent retrospective study (10). Table 1 Studies on COVID-19-patients with intensive care unit acquired myopathy. N of patients Age mean (range) [years] Sex ICU stay mean (range) [days] Medication Clinical feature NCS/EMG Muscle biopsy CK peak-level IL-6 peak-level (9) 7 NA NA NA Antiretrovirals, neuromuscular blockers, corticosteroids, antibiotics Generalized muscular weakness Myopathy Three patients (scattered necrotic and regenerative fibers, no inflammatory infiltrates) 181–3,228 μmol/l N/A (10) 5 N/A N/A N/A Antirheumatics, antiretrovirals, corticosteroids, antibiotics Generalized muscular weakness Myopathy ND 61–1,206 μg/l NA (8) 6 61 (51-72) 1 F 6-14 until NCS/EMG Antirheumatics, antiretrovirals, corticosteroids, antibiotics, anticoagulants Acute flaccid quadriplegia Myopathy; reduced CMAP amplitude with markedly prolonged duration ND 55–1,274 UI/L 18.4–5,402.2 ng/ml (6) 1 68 M 65 Antibiotics Severe symmetrical proximal and distal weakness and diffuse muscle wasting Myopathy and bilateral peroneal compression neuropathy. ND NA NA (7) 1 62 F 30 Antirheumatics, antiretrovirals, antibiotics, neuromuscular blockers, antifungal drugs, corticosteroids. Symmetrical muscle weakness predominant in lower limbs and proximal muscles. Myopathy ND Normal NA ICU, intensive care unit; NCS/EMG, nerve conduction studies/electromyography; CK, creatine kinase; IL-6, interleukine 6; F, female; M, male; CMAP, compound muscle action potential; ND not done; NA not available. Case Description Here, we report two patients who survived typical COVID-19 pneumonia, confirmed by RT-PCR test on nasopharyngeal swab and by chest computed tomography, which showed bilateral diffuse consolidations and ground-glass opacities. No personal or family medical history of rhabdomyolisis or myoglobinuria or any type of muscle pathology was known. Neither patient had ever received statin therapy or other potentially myotoxic agents. In general, the patients did not suffer from any previous relevant pathology. Table 2 summarizes demographic, clinical, laboratory, and electrophysiological data. Table 2 Demographic, clinical, laboratory, and electrodiagnostic data. Patient Age Sex ICU stay Clinical features Laboratory findings (peak levels) NCS/EMG: time since disease onset Sensory NCS Motor NCS EMG CK CRP IL-6 D-dimer WBC Lymphocyte SNAP amplitude sNCV CMAP amplitude CMAP duration DML mNCV Proximal muscles* [weeks] [U/l] [mg/l] [pg/ml] [mg/l] [×103/μl] [×103/μl] [weeks] [μV] [m/s] [mV] [ms] [ms] [m/s] 40–220 <0.8 <7.0 <0.5 3.6–10.5 1.1–4.5 1 77 M 6 Proximal weakness and muscle wasting in upper more than lower limbs; myalgia; fatigue 4,002 15.9 225.2 1.5 10.1 2.8 7 L median: 15.2 50 L median: 4.2 9.3 3.9 48 Myopathic R ulnar: 12.4 48 R ulnar: 5.7 13.7 2.9 55 R sural: 6.3 47 L peroneal: 2.1 7.3 3.1 40 R tibial: 2.4 4.2 4.0 41 2 58 M 3 Predominantly proximal weakness in four limbs; hyporeflexia; myalgia 6,732 17.1 343.6 2.1 9.9 4.6 4 L median: 22.5 49 L median: 3.9 9.0 3.8 48 Myopathic R ulnar: 25.8 51 R ulnar: 4.8 8.7 2.5 50 R sural: 9.5 48 L peroneal: 1.2 6.5 4.0 39 R tibial: 2.2 6.7 4.1 40 Laboratory data were obtained during intensive care. Clinical and electrodiagnostic data were obtained during neurorehabilitation. M, male; F, female; ICU, intensive care unit; CK, creatine kinase; CRP, C-reactive protein; WBC, white blood cell count; IL, interleukin; NCS, nerve conduction study; EMG, electromyography; SNAP, sensory nerve action potential; sNCV, sensory nerve conduction velocity; CMAP, compound muscle action potential; DML, distal motor latency; mNCV, motor nerve conduction velocity; R, right; L, left. The upper limits of normality (mean + 2 SD) for distal CMAP duration using a low frequency filter of 2 Hz are: median nerve = 7.3 ms, ulnar nerve = 7.5 ms, peroneal nerve = 7.3 ms, tibial nerve = 6.8 ms (12); abnormal values are marked in bold. * Left deltoid, right triceps brachii, left iliopsoas, and right rectus femoris muscles. Because of respiratory failure, both patients required intensive care treatment, including tracheostomy and ventilatory support for several weeks. Oral treatment with hydroxychloroquine 200 mg twice a day and lopinavir/ritonavir 400/100 mg twice a day was administered for 3 weeks. No antibiotics, corticosteroids or analgesics were administered. High serum levels of C-reactive protein (CRP) and interleukin 6 (IL-6) were documented during the acute phase (Table 2). After weaning from sedation (intravenous sufentanil/propofol together with rocuronium bromide as muscle relaxant) and ventilation, the patients suffered mild dyspnea requiring oxygen support (2 l/min), complained of myalgia and fatigue, and showed on examination severe proximal muscles weakness in in both upper and lower limbs (Medical Research Council scale 2/5). Strength in distal muscle was normal. Deep tendon reflexes were hypoactive. No deep or superficial sensory disturbance was noted. Cranial nerve examination was unremarkable; in particular, no bulbar muscles weakness was found. Laboratory examination revealed elevated creatine kinase (CK) (peak-levels 4,002 and 6,732 U/l, respectively) which progressively normalized in the following 3 weeks, but no myoglobinuria nor acute renal failure signs. Due to the Covid-19-related emergency situation in Italian Intensive Care Units, no further neuroradiological or histopathological muscle studies could be performed. On admission in the neurorehabilitation unit (4 and 7 weeks after onset of COVID-19, respectively), both patients presented with flaccid proximal tetraparesis and limb-girdle muscle atrophy. A timeline of the clinical course is presented in Figure 1. Figure 1 Timeline of key events related to COVID-19 and myopathy in patient 1 (green labels) and patient 2 (yellow labels). Motor nerve conduction studies showed normal distal latencies and normal conduction velocities. Distal compound muscle action potential (CMAP) amplitudes were decreased and CMAP durations were prolonged in median and ulnar nerves in both patients (Table 2, Figure 2). Sensory conduction velocities and sensory nerve action potential amplitudes were normal. Needle EMG showed spontaneous activity (fibrillation potentials) in patient 2 and a myopathic pattern with short duration motor unit action potentials, increased percentage of polyphasic potentials, and early recruitment at voluntary effort in proximal muscles in both patients. Distal muscles were unremarkable. Within 2 weeks from admission in neurorehabilitation, serum CK returned to normal values (23 and 201 U/l, respectively). Figure 2 Motor nerve conduction studies of patient 1 (A,B) compared to a healthy control subject (C,D). Amplitude and duration of the negative phase of compound muscle action potentials (CMAPs) were measured at a sensitivity of 0.5 mV with a 2 Hz low frequency filter. The cut-off values for distal CMAP duration are according to reported normal values + 2 SD (12). (A) median nerve: distal CMAP amplitude is reduced (4.2 mV), distal motor latency (DML) is normal (3.9 ms), distal CMAP duration is increased (9.3 ms, 127% of upper limit of normal = 7.3 ms), conduction velocity (CV) is 48 m/s. CMAP amplitude and duration did not change between proximal and distal stimulation. Note the broadening and smooth contour of the negative phase of the distal CMAP and the reduction of the ensuing positive phase compared to panel (C) (CMAP duration = 5.7 ms); (B) ulnar nerve: distal CMAP amplitude is slightly reduced (5.7 mV), DML is normal (2.9 ms), distal CMAP duration is increased (13.7 ms, 183% upper limit of normal = 7.5 ms), CV is 55 m/s. CMAP amplitude and duration did not change with proximal stimulation. Note the very prolonged negative phase of the distal CMAP with a long tail and the absence of the ensuing positive phase compared to panel (D) (CMAP duration = 6.3 ms). Clinical condition improved progressively in both patients, who were discharged home after 6–8 weeks of rehabilitation, with a muscle strength of 3/5 in proximal upper limb and 4/5 in proximal lower limb muscles, and normal walking capability. However, both complained of reduced endurance and increased fatigue during physical activity. Discussion In the presented patients, clinical, laboratory and electrodiagnostic findings were consistent with a myopathy except for increased distal CMAP duration that is usually considered a hallmark of acquired demyelination. However, prolonged duration of distal CMAPs that did not change between distal and proximal stimulation (Figure 2), together with normal distal motor latencies and conduction velocities, indicates that in these patients, temporal dispersion of distal CMAP is due to slow muscle fibers conduction velocity. Indeed, prolonged distal CMAP duration, besides reduced CMAP amplitude, has previously been reported in patients with CIM, who presented, as compared to healthy controls, with reduced mean muscle fiber conduction velocity, which was inversely related to CMAP duration (13, 14). Moreover, in an in vitro model, sera from patients with CIM applied to single muscle fibers induced depolarization of the resting membrane potential, reduced the action potential rise time, and increased inward sodium current peak amplitude (15). Evidence from human studies and animal models indicates that in CIM associated with sepsis (the so-called “SIM,” sepsis-induced myopathy), systemic inflammatory response, and cytokine release induce a depolarizing shift of the muscle cell membrane potential, sodium channel inactivation, slowing of muscle fiber conduction velocity until total membrane inexcitability, increase of membrane permeability for Ca2+, and eventually Ca2+-dependent muscle necrosis by proteasome activation (16). We hypothesize that in the reported patients, by analogy with SIM, myopathy was caused by the COVID-associated hyper-inflammatory state, as demonstrated by high initial serum levels of CRP and IL-6. Prolonged distal CMAP durations can be explained by muscle membrane hypo-excitability combined with slow muscle fiber conduction velocity in regenerating muscle fibers. Interestingly also six reported COVID-10 patients with acute quadriplegic myopathy (8), showed markedly prolonged CMAP durations without evidence of acute myonecrosis (CK were slightly elevated in half patients and decreased in few days) and, with exception of one patient who died due to sepsis, showed rapid improvement of weakness (14–20 days). This can concur with the proposed mechanism of muscular impairment in COVID-19, ranging from membrane excitability dysfunction (which reflects in reduced amplitude and increased duration of CMAPs) with possible prompt recovery to myonecrosis, CK elevation, consequent muscle atrophy, and poorer outcome. Serum IL-6 elevation is common in critically ill patients (16), but it also plays a central role in the COVID-19 inflammation cascade already at an early stage, preceding need for intensive care, and it correlates with disease severity (17). In conclusion, the same pathogenetic mechanism that causes interstitial pneumonia and damage to extrapulmonary tissues and organs in COVID-19, i.e., the inflammatory cytokine storm together with coagulopathy and macrophage activation, could contribute, in patients requiring prolonged critical care, to skeletal muscle damage (17). Further studies are necessary to elucidate the pathogenesis of COVID-19-associated myopathy and to differentiate among direct infection, autoimmune process, and CIM due to hyperinflammation; in particular, muscle biopsy with specific investigations would be of crucial importance. Data Availability Statement The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s. Ethics Statement Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. Written informed consent was obtained from the patients for the submission of their data and for the publication of any potentially identifiable images or data included in this article. Author Contributions Material preparation, data collection, and analysis were performed by VV, LSe, and DF. The first draft of the manuscript was written by VV and MK. AU contributed substantially to the interpretation of the results, provided critical feedback, and revised the manuscript. All authors contributed in review and editing of the manuscript and approved its final version. All authors contributed to the study conception and design. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.	Oral	DrugAdministrationRoute	CC BY	33584530	19,157,707	2021
What was the outcome of reaction 'Myopathy'?	Case Report: Myopathy in Critically Ill COVID-19 Patients: A Consequence of Hyperinflammation? Introduction: COVID-19-associated muscular complications may comprise myalgia, weakness, wasting, and rhabdomyolysis. Skeletal muscle damage in COVID-19 may be due to direct infection by the virus SARS-CoV-2 through interaction with the ACE2 receptor, systemic hyper-inflammatory state with cytokine release and homeostatic perturbation, an autoimmune process, or myotoxic drugs. Disclosing the cause of weakness in an individual patient is therefore difficult. Case Description: We report two patients, who survived typical COVID-19 pneumonia requiring intensive care treatment and who developed early on myalgia and severe proximal weakness in all four limbs. Laboratory exams revealed elevated serum creatine kinase and markedly increased C-reactive protein and interleukin 6, concurring with a systemic inflammatory response. On admission in neurorehabilitation (4 and 7 weeks after COVID-19 onset, respectively), the patients presented with proximal flaccid tetraparesis and limb-girdle muscle atrophy. Motor nerve conduction studies showed decreased amplitude and prolonged duration of compound muscle action potentials (CMAPs) with normal distal motor latencies and normal conduction velocities in median and ulnar nerves. Needle electromyography in proximal muscles revealed spontaneous activity in one and myopathic changes in both patients. Discussion: Clinical, laboratory, and electrodiagnostic findings in these patients were unequivocally consistent with myopathy. Interestingly, increased distal CMAP duration has been described in patients with critical illness myopathy (CIM) and reflects slow muscle fiber conduction velocity due to membrane hypo-excitability, possibly induced by inflammatory cytokines. By analogy with CIM, the pathogenesis of COVID-19-related myopathy might also depend on hyperinflammation and metabolic pathways that may affect muscles in a pathophysiological continuum from hypo-excitability to necrosis. Introduction Muscular complications in hospitalized coronavirus disease (COVID-19) patients may include myalgia, muscle weakness and wasting, elevated serum creatine kinase (CK), and rhabdomyolysis (1). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to cells through the angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed in skeletal muscle (2). However, SARS-CoV-2 particles, despite its broad organotropism beyond the respiratory tract, have not been demonstrated in muscle samples so far (3). Besides the possibility of direct skeletal muscle injury by SARS-CoV-2, other conceivable causes of myopathies in COVID-19 may comprise an autoimmune process, such as in necrotizing autoimmune myositis, consequence of the systemic hyperinflammatory state, and myotoxicity by medication (e.g., hydroxychloroquine, anti-retroviral agents) (2, 4, 5). Moreover, severely affected COVID-19 patients with systemic inflammatory response, prolonged intensive care treatment with ventilation, and immobilization are prone to develop critical illness myopathy (CIM). Hence, explaining the exact cause of weakness in an individual patient may be difficult. To date, CIM has been reported and at least electrodiagnostically confirmed in 20 patients with COVID-19 (6–9) (Table 1). Intensive care unit acquired muscle weakness was clinically diagnosed in 72% of COVID-19 patients at awakening (11). Compared to patients without muscle weakness, myopathic patients had longer ICU stays, prolonged duration of invasive mechanical ventilation, higher mean morning glycemia, higher exposure to corticosteroids, sedatives, analgesics, and neuromuscular blocking agents (11). Half of critically ill COVID-19 patients presented acute myopathy in a recent retrospective study (10). Table 1 Studies on COVID-19-patients with intensive care unit acquired myopathy. N of patients Age mean (range) [years] Sex ICU stay mean (range) [days] Medication Clinical feature NCS/EMG Muscle biopsy CK peak-level IL-6 peak-level (9) 7 NA NA NA Antiretrovirals, neuromuscular blockers, corticosteroids, antibiotics Generalized muscular weakness Myopathy Three patients (scattered necrotic and regenerative fibers, no inflammatory infiltrates) 181–3,228 μmol/l N/A (10) 5 N/A N/A N/A Antirheumatics, antiretrovirals, corticosteroids, antibiotics Generalized muscular weakness Myopathy ND 61–1,206 μg/l NA (8) 6 61 (51-72) 1 F 6-14 until NCS/EMG Antirheumatics, antiretrovirals, corticosteroids, antibiotics, anticoagulants Acute flaccid quadriplegia Myopathy; reduced CMAP amplitude with markedly prolonged duration ND 55–1,274 UI/L 18.4–5,402.2 ng/ml (6) 1 68 M 65 Antibiotics Severe symmetrical proximal and distal weakness and diffuse muscle wasting Myopathy and bilateral peroneal compression neuropathy. ND NA NA (7) 1 62 F 30 Antirheumatics, antiretrovirals, antibiotics, neuromuscular blockers, antifungal drugs, corticosteroids. Symmetrical muscle weakness predominant in lower limbs and proximal muscles. Myopathy ND Normal NA ICU, intensive care unit; NCS/EMG, nerve conduction studies/electromyography; CK, creatine kinase; IL-6, interleukine 6; F, female; M, male; CMAP, compound muscle action potential; ND not done; NA not available. Case Description Here, we report two patients who survived typical COVID-19 pneumonia, confirmed by RT-PCR test on nasopharyngeal swab and by chest computed tomography, which showed bilateral diffuse consolidations and ground-glass opacities. No personal or family medical history of rhabdomyolisis or myoglobinuria or any type of muscle pathology was known. Neither patient had ever received statin therapy or other potentially myotoxic agents. In general, the patients did not suffer from any previous relevant pathology. Table 2 summarizes demographic, clinical, laboratory, and electrophysiological data. Table 2 Demographic, clinical, laboratory, and electrodiagnostic data. Patient Age Sex ICU stay Clinical features Laboratory findings (peak levels) NCS/EMG: time since disease onset Sensory NCS Motor NCS EMG CK CRP IL-6 D-dimer WBC Lymphocyte SNAP amplitude sNCV CMAP amplitude CMAP duration DML mNCV Proximal muscles* [weeks] [U/l] [mg/l] [pg/ml] [mg/l] [×103/μl] [×103/μl] [weeks] [μV] [m/s] [mV] [ms] [ms] [m/s] 40–220 <0.8 <7.0 <0.5 3.6–10.5 1.1–4.5 1 77 M 6 Proximal weakness and muscle wasting in upper more than lower limbs; myalgia; fatigue 4,002 15.9 225.2 1.5 10.1 2.8 7 L median: 15.2 50 L median: 4.2 9.3 3.9 48 Myopathic R ulnar: 12.4 48 R ulnar: 5.7 13.7 2.9 55 R sural: 6.3 47 L peroneal: 2.1 7.3 3.1 40 R tibial: 2.4 4.2 4.0 41 2 58 M 3 Predominantly proximal weakness in four limbs; hyporeflexia; myalgia 6,732 17.1 343.6 2.1 9.9 4.6 4 L median: 22.5 49 L median: 3.9 9.0 3.8 48 Myopathic R ulnar: 25.8 51 R ulnar: 4.8 8.7 2.5 50 R sural: 9.5 48 L peroneal: 1.2 6.5 4.0 39 R tibial: 2.2 6.7 4.1 40 Laboratory data were obtained during intensive care. Clinical and electrodiagnostic data were obtained during neurorehabilitation. M, male; F, female; ICU, intensive care unit; CK, creatine kinase; CRP, C-reactive protein; WBC, white blood cell count; IL, interleukin; NCS, nerve conduction study; EMG, electromyography; SNAP, sensory nerve action potential; sNCV, sensory nerve conduction velocity; CMAP, compound muscle action potential; DML, distal motor latency; mNCV, motor nerve conduction velocity; R, right; L, left. The upper limits of normality (mean + 2 SD) for distal CMAP duration using a low frequency filter of 2 Hz are: median nerve = 7.3 ms, ulnar nerve = 7.5 ms, peroneal nerve = 7.3 ms, tibial nerve = 6.8 ms (12); abnormal values are marked in bold. * Left deltoid, right triceps brachii, left iliopsoas, and right rectus femoris muscles. Because of respiratory failure, both patients required intensive care treatment, including tracheostomy and ventilatory support for several weeks. Oral treatment with hydroxychloroquine 200 mg twice a day and lopinavir/ritonavir 400/100 mg twice a day was administered for 3 weeks. No antibiotics, corticosteroids or analgesics were administered. High serum levels of C-reactive protein (CRP) and interleukin 6 (IL-6) were documented during the acute phase (Table 2). After weaning from sedation (intravenous sufentanil/propofol together with rocuronium bromide as muscle relaxant) and ventilation, the patients suffered mild dyspnea requiring oxygen support (2 l/min), complained of myalgia and fatigue, and showed on examination severe proximal muscles weakness in in both upper and lower limbs (Medical Research Council scale 2/5). Strength in distal muscle was normal. Deep tendon reflexes were hypoactive. No deep or superficial sensory disturbance was noted. Cranial nerve examination was unremarkable; in particular, no bulbar muscles weakness was found. Laboratory examination revealed elevated creatine kinase (CK) (peak-levels 4,002 and 6,732 U/l, respectively) which progressively normalized in the following 3 weeks, but no myoglobinuria nor acute renal failure signs. Due to the Covid-19-related emergency situation in Italian Intensive Care Units, no further neuroradiological or histopathological muscle studies could be performed. On admission in the neurorehabilitation unit (4 and 7 weeks after onset of COVID-19, respectively), both patients presented with flaccid proximal tetraparesis and limb-girdle muscle atrophy. A timeline of the clinical course is presented in Figure 1. Figure 1 Timeline of key events related to COVID-19 and myopathy in patient 1 (green labels) and patient 2 (yellow labels). Motor nerve conduction studies showed normal distal latencies and normal conduction velocities. Distal compound muscle action potential (CMAP) amplitudes were decreased and CMAP durations were prolonged in median and ulnar nerves in both patients (Table 2, Figure 2). Sensory conduction velocities and sensory nerve action potential amplitudes were normal. Needle EMG showed spontaneous activity (fibrillation potentials) in patient 2 and a myopathic pattern with short duration motor unit action potentials, increased percentage of polyphasic potentials, and early recruitment at voluntary effort in proximal muscles in both patients. Distal muscles were unremarkable. Within 2 weeks from admission in neurorehabilitation, serum CK returned to normal values (23 and 201 U/l, respectively). Figure 2 Motor nerve conduction studies of patient 1 (A,B) compared to a healthy control subject (C,D). Amplitude and duration of the negative phase of compound muscle action potentials (CMAPs) were measured at a sensitivity of 0.5 mV with a 2 Hz low frequency filter. The cut-off values for distal CMAP duration are according to reported normal values + 2 SD (12). (A) median nerve: distal CMAP amplitude is reduced (4.2 mV), distal motor latency (DML) is normal (3.9 ms), distal CMAP duration is increased (9.3 ms, 127% of upper limit of normal = 7.3 ms), conduction velocity (CV) is 48 m/s. CMAP amplitude and duration did not change between proximal and distal stimulation. Note the broadening and smooth contour of the negative phase of the distal CMAP and the reduction of the ensuing positive phase compared to panel (C) (CMAP duration = 5.7 ms); (B) ulnar nerve: distal CMAP amplitude is slightly reduced (5.7 mV), DML is normal (2.9 ms), distal CMAP duration is increased (13.7 ms, 183% upper limit of normal = 7.5 ms), CV is 55 m/s. CMAP amplitude and duration did not change with proximal stimulation. Note the very prolonged negative phase of the distal CMAP with a long tail and the absence of the ensuing positive phase compared to panel (D) (CMAP duration = 6.3 ms). Clinical condition improved progressively in both patients, who were discharged home after 6–8 weeks of rehabilitation, with a muscle strength of 3/5 in proximal upper limb and 4/5 in proximal lower limb muscles, and normal walking capability. However, both complained of reduced endurance and increased fatigue during physical activity. Discussion In the presented patients, clinical, laboratory and electrodiagnostic findings were consistent with a myopathy except for increased distal CMAP duration that is usually considered a hallmark of acquired demyelination. However, prolonged duration of distal CMAPs that did not change between distal and proximal stimulation (Figure 2), together with normal distal motor latencies and conduction velocities, indicates that in these patients, temporal dispersion of distal CMAP is due to slow muscle fibers conduction velocity. Indeed, prolonged distal CMAP duration, besides reduced CMAP amplitude, has previously been reported in patients with CIM, who presented, as compared to healthy controls, with reduced mean muscle fiber conduction velocity, which was inversely related to CMAP duration (13, 14). Moreover, in an in vitro model, sera from patients with CIM applied to single muscle fibers induced depolarization of the resting membrane potential, reduced the action potential rise time, and increased inward sodium current peak amplitude (15). Evidence from human studies and animal models indicates that in CIM associated with sepsis (the so-called “SIM,” sepsis-induced myopathy), systemic inflammatory response, and cytokine release induce a depolarizing shift of the muscle cell membrane potential, sodium channel inactivation, slowing of muscle fiber conduction velocity until total membrane inexcitability, increase of membrane permeability for Ca2+, and eventually Ca2+-dependent muscle necrosis by proteasome activation (16). We hypothesize that in the reported patients, by analogy with SIM, myopathy was caused by the COVID-associated hyper-inflammatory state, as demonstrated by high initial serum levels of CRP and IL-6. Prolonged distal CMAP durations can be explained by muscle membrane hypo-excitability combined with slow muscle fiber conduction velocity in regenerating muscle fibers. Interestingly also six reported COVID-10 patients with acute quadriplegic myopathy (8), showed markedly prolonged CMAP durations without evidence of acute myonecrosis (CK were slightly elevated in half patients and decreased in few days) and, with exception of one patient who died due to sepsis, showed rapid improvement of weakness (14–20 days). This can concur with the proposed mechanism of muscular impairment in COVID-19, ranging from membrane excitability dysfunction (which reflects in reduced amplitude and increased duration of CMAPs) with possible prompt recovery to myonecrosis, CK elevation, consequent muscle atrophy, and poorer outcome. Serum IL-6 elevation is common in critically ill patients (16), but it also plays a central role in the COVID-19 inflammation cascade already at an early stage, preceding need for intensive care, and it correlates with disease severity (17). In conclusion, the same pathogenetic mechanism that causes interstitial pneumonia and damage to extrapulmonary tissues and organs in COVID-19, i.e., the inflammatory cytokine storm together with coagulopathy and macrophage activation, could contribute, in patients requiring prolonged critical care, to skeletal muscle damage (17). Further studies are necessary to elucidate the pathogenesis of COVID-19-associated myopathy and to differentiate among direct infection, autoimmune process, and CIM due to hyperinflammation; in particular, muscle biopsy with specific investigations would be of crucial importance. Data Availability Statement The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s. Ethics Statement Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. Written informed consent was obtained from the patients for the submission of their data and for the publication of any potentially identifiable images or data included in this article. Author Contributions Material preparation, data collection, and analysis were performed by VV, LSe, and DF. The first draft of the manuscript was written by VV and MK. AU contributed substantially to the interpretation of the results, provided critical feedback, and revised the manuscript. All authors contributed in review and editing of the manuscript and approved its final version. All authors contributed to the study conception and design. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.	Recovering	ReactionOutcome	CC BY	33584530	19,157,707	2021
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute kidney injury'.	Atypical Neuroleptic Malignant Syndrome in the Setting of Quetiapine Overdose: A Case Report and Review of the Literature. Neuroleptic malignant syndrome (NMS) is a rare and life-threatening emergency. The condition is largely iatrogenic and is often precipitated by medications such as antipsychotics. First-generation antipsychotics are more likely to cause NMS than second-generation antipsychotics. The literature lacks an objective measure for NMS diagnosis. Instead, the diagnosis relies largely on the recognition of characteristic symptoms in the presence of an inciting medication. Additional challenges exist with concomitant disease processes and toxicities that may distort the clinical picture. Here, we report a case of a 44-year-old Caucasian man who presented with atypical NMS in the setting of quetiapine overdose. The patient remained uncharacteristically afebrile throughout his admission. Although the patient recovered, extended delays in identification and management can contribute to an increased risk of morbidity and mortality. Introduction Neuroleptic malignant syndrome (NMS) is a rare and potentially lethal constellation of symptoms [1-2]. Neuroleptic medications, particularly first-generation antipsychotics and certain antiemetics, have been shown to induce symptoms [3-5]. However, induction by second-generation antipsychotics, such as quetiapine, is less likely. Definitive diagnostic criteria do not exist for NMS, although hyperthermia, altered mental status, muscle rigidity, elevated creatine kinase (CK), and autonomic instability in the setting of newly introduced or increased doses of neuroleptic medications should prompt a high index of suspicion [3]. Unfortunately, not all cases of NMS present with hallmark signs and symptoms. NMS in the setting of alcohol or drug overdose can obfuscate the clinical picture. The risk of heightened morbidity and mortality requires prompt identification and persistent monitoring [3,5]. Here, we present a 44-year-old male with an atypical presentation of NMS in the setting of quetiapine overdose. Case presentation A 44-year-old Caucasian male with a past medical history pertinent for attention-deficit hyperactivity disorder and major depressive disorder with psychotic symptoms controlled with quetiapine (30 mg daily), fluoxetine (40 mg daily), and dextroamphetamine salts (30 mg daily) presented to the emergency department via ambulance after being found on the floor of his home. The patient has a known history of suicide attempts. Upon examination, the patient was obtunded, disheveled, speaking unintelligibly, and only responsive to tactile stimuli. The patient’s vital signs included a blood pressure of 119/83, pulse of 108, temperature of 96.6 F, respirations of 15, and oxygen saturation of 96% on room air. The patient was found in the presence of an empty bottle of quetiapine. His mother was unsure as to how long he had been on the floor. However, she advised that he might have consumed excessive amounts of alcohol the night before. Further workup revealed a urine toxicology screen positive for amphetamines and an elevated blood alcohol concentration (70 mg/dL; reference range 0-10 mg/dL). Acetaminophen and salicylate levels were within normal limits. Serology was remarkable for leukocytosis (15.8x10-3/uL; reference range 4.5-10.0x10-3/uL), a liver profile with slight elevation of aspartate transaminase (50 IU/uL; reference range 13-39 IU/L), and elevated lactate (8.04 mmol/L; reference range 0.90-1.70 mmol/L). Urinalysis was positive for a few bacteria and 2+ blood. A basic metabolic panel was impressive for hyperkalemia (l6.4 mEq/L; reference range 3.5-5.1 mEq/L) and elevated creatinine (2.6 mg/dL; reference range 0.60-1.30 mg/dL) in an otherwise healthy kidney. Phosphorus and phosphokinase were also elevated. Arterial blood gas revealed a high anion gap metabolic acidosis. A summary of the patient’s acute workup, with notable findings, can be found in Table 1. Table 1 Summary of Pertinent Laboratory Values at Time of Admission ABG = Arterial blood gas; CBC = Complete blood count; CMP = Comprehensive metabolic panel; UA = Urinalysis; S = Serology; T = Toxicology; H = Patient value above the upper limit of normal; N = Patient value within reference range; L = Patient value below the lower limit of normal Laboratory type Analyte Patient value Reference value T Amphetamines Positive Negative T Blood alcohol concentration 70.0 H 0.0-10.0 mg/dL CBC Leukocytes 15.8 x 10-3 H 4.5-10.0x10-3/uL CMP Aspartate transaminase (AST) 50 H 13-39 IU/L CMP Alanine aminotransferase (ALT) 22 N 7-52 IU/L CMP Lactate 8.04 H 0.90-1.70 mmol/L CMP Phosphorus 6.4 H 2.5-5.0 mg/dL CMP Creatinine 2.1 H 0.60-1.30 mg/dL ABG pH 7.452 H 7.350-7.450 ABG pCO2 25.0 L 35.0-45.0 mm Hg The patient was admitted to the internal medicine service with the working diagnosis of acute metabolic encephalopathy secondary to alcohol intoxication or amphetamine overdose with concomitant rhabdomyolysis. The patient was carefully monitored on an inpatient basis. By day two of admission, the patient's creatine kinase (CK) dramatically increased from 4,281 IU/L to 213,800 IU/L (reference range 30-223 IU/L). A longitudinal scatter plot of the patient’s CK over the course of admission is provided in Figure 1. Creatinine also increased despite fluid hydration. His mentation failed to improve, and he became aggressive, requiring physical restraints. The patient remained afebrile throughout his admission. He was persistently tachycardic with stable oxygen saturation (95%-100% on room air). Although the patient presented afebrile, all other signs and symptoms suggested NMS. The patient was transferred to the intensive care unit. Psychotropic medications were withheld, with the exception of lorazepam as needed for agitation. The patient’s normal basal temperature, mild muscle rigidity, and elevated liver enzymes precluded the use of dantrolene at that time. Figure 1 Longitudinal Creatine Kinase Levels During Admission Blue = Patient creatine kinase levels; Orange = Reference values Despite aggressive fluid resuscitation, the patient experienced acute renal failure with a creatinine increasing steadily from 2.10 mg/dL on admission to 7.2 mg/dL on day two (Figure 2). Other metabolic derangements were evident, including worsening metabolic acidosis and hyperkalemia. The patient underwent hemodialysis on post-admission day two and his clinical course improved without incident over the next 18 days. The patient was discharged requiring routine dialysis for the foreseeable future. Figure 2 Longitudinal Creatinine Levels During Admission Blue = Patient creatinine levels; Orange = Reference values Discussion Neuroleptic malignant syndrome (NMS) is a rare and life-threatening emergency leading to mortality in 30%-50% of unmanaged patients [3-4]. Prompt identification and continuous monitoring are necessary to reduce the risk of morbidity and mortality. Recognition can be challenging and complex, requiring careful consideration of symptoms that may overlap with a myriad of concomitant disease states. In this case, we report a middle-aged man presenting to the emergency department in an obtunded state. The patient had a prior history of suicide attempts and his past medical history was significant for depression with psychotic features controlled with more than one psychotropic medication. Although the totality of the circumstances suggested overdose toxicity, the patient’s symptoms were not fully characteristic of an overdose with any one of his prescription medications alone. Reports of quetiapine-induced NMS are limited, however, a case report analysis of 19 cases was conducted by Murri and colleagues, which revealed pooled clinical features with respect to quetiapine-induced NMS to include: 1) tachycardia, tachypnea, diaphoresis, and tremor in 100% of patients; 2) hyperpyrexia and rigidity in 92.3% of patients; 3) dysautonomia in 90% of patients; 4) mental status change in 85.7% of patients; and 5) fever in 78.9% patients [6]. Commensurate with this study, a set of diagnostic criteria proposed by Levenson in 1985 suggested similar features were characteristic of NMS and categorized them into major criteria (fever, rigidity, elevated creatine phosphokinase (CPK)) and minor criteria (tachycardia, abnormal arterial pressure, altered consciousness, diaphoresis, and leukocytosis) [2]. The presence of three major or two major and four minor signs suggests a high probability of NMS. In this case, the patient displayed moderate rigidity, elevated CPK, tachycardia, altered consciousness, leukocytosis, and abnormal arterial pressure, thereby satisfying two major and four minor criteria. However, these symptoms overlap with other more common conditions, such as malignant hyperthermia, in which full rigidity and mental status change are characteristic. Serotonin syndrome is also accompanied by similar symptoms, such as high fever, tachycardia, and confusion, while other well-reported entities, such as central nervous system (CNS) infections and toxins, can also be present in a similar manner and may complicate diagnosis and treatment [1,5]. Symptom onset and inciting medications can help identify or rule out NMS. For instance, NMS presents with an idiosyncratic onset, commonly developing between 24 hours and one month of newly introduced neuroleptic medication. Sixty-five percent of patients experience symptoms within one week, with a modicum of cases documenting symptoms within 24 hours [3]. First-generation antipsychotics (i.e., haloperidol, chlorpromazine, fluphenazine) are more commonly associated with NMS than second-generation antipsychotics [7]. Although, almost any medication that produces fulminant reductions in dopaminergic activity (either by blocking D2 receptors or abrupt withdrawal of D2 receptor stimulation) may cause suggestive symptoms [4-5]. Symptoms can arise from the initial introduction of antipsychotic therapy but have also been reported in patients with longstanding histories of neuroleptic use without incident [8]. Therefore, the duration of quetiapine therapy prior to the presentation should not be a deciding factor when considering NMS in a differential diagnosis. Quetiapine is commonly used off-label for sleep so even patients without known psychiatric histories may have the potential to develop the condition [9]. Coadministration of neuroleptics and selective serotonin reuptake inhibitors, such as in this patient suffering from depression with psychotic features, may increase the risk of developing NMS [10]. This calls particular attention to patients suffering from mixed depressive and psychotic disorders who may receive these medications concomitantly. At the same time, these patients are inherently predisposed to impulsivity and risk-taking behavior, such as suicide, by the virtue of their disease state [11-13]. Thus, patients with mixed depressive and psychotic disorders in the setting of overdose should prompt thorough medication reconciliation for NMS-inducing agents. The exact mechanism of NMS is not fully understood, but contemporary theories revolve around dopamine’s inhibitory effect on centrally and peripherally acting neuronal networks that may help explain presentations of NMS in the absence of fever and rigidity. The prevailing theory of NMS pathophysiology suggests a disruption of dopamine receptor antagonism, specifically within the hypothalamus, leading to hyperthermia and dysautonomia [14]. Similar involvement in the nigrostriatal pathways may explain rigidity and tremor associated with NMS considering this pathway is highly implicated with similar Parkinsonian manifestations [2,15]. Direct and indirect toxicity of offending agents to peripheral tissues, such as skeletal muscles, may influence mitochondrial function leading to hyperthermia secondary to muscle rigidity [16]. Lastly, dopamine’s regulatory influence on autonomic control may lead to heightened sympathetic activity impacting temperature control and muscle tone [16]. In each scenario, rigidity and hyperthermia seem to be directly correlated. This patient experienced moderate rigidity in the absence of fever, an atypical presentation, with a mild disease progression. Taken together, this information suggests that patients with NMS who are afebrile may also have the potential to lack significant muscle rigidity, further reducing a major symptom indicator for the presence of NMS. The timely diagnosis of NMS should be followed by the prompt discontinuation of inciting medication to prevent further symptom progression. The stage of NMS (mild, moderate, and severe) are used to inform the extent of supportive care and pharmacotherapy [17]. For instance, in this case, the patient’s symptoms were relatively mild, with acute renal failure that required close monitoring and muscle relaxers as needed, ultimately resolving over time. Progression to moderate or severe NMS in the presence of hyperpyrexia may warrant more intentional methods of cooling, with blankets or cooled saline. Severe cases may require direct muscle relaxers, such as dantrolene, or dopamine agonists such as bromocriptine. Monotherapy with dantrolene may actually increase mortality and should be avoided in patients with abnormal liver function due to increased risk of acute liver injury [18]. Once symptoms have resolved, approximately 30% of patients will experience a reoccurrence of symptoms [19]. Thus, it is important to slowly reintroduce an alternative antipsychotic medication in patients requiring therapy while remaining alert for signs and symptoms associated with this rare but serious condition. Conclusions Neuroleptic malignant syndrome (NMS) is a life-threatening condition requiring prompt identification and diagnosis with an array of potential presenting symptoms. Certain symptoms, such as fever and muscle rigidity, are highly characteristic of the condition, however, atypical presentations have occurred. This case serves to illustrate an attenuated and atypical presentation of NMS in the setting of overdose with the second-generation antipsychotic quetiapine. Future studies should examine whether a significant relationship exists between fever status and outcome in patients with NMS. The authors have declared that no competing interests exist. Human Ethics Consent was obtained by all participants in this study	AMPHETAMINE ASPARTATE\AMPHETAMINE SULFATE\DEXTROAMPHETAMINE SACCHARATE\DEXTROAMPHETAMINE SULFATE, FLUOXETINE HYDROCHLORIDE, QUETIAPINE	DrugsGivenReaction	CC BY	33585092	18,961,784	2021-01-10
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyperkalaemia'.	Atypical Neuroleptic Malignant Syndrome in the Setting of Quetiapine Overdose: A Case Report and Review of the Literature. Neuroleptic malignant syndrome (NMS) is a rare and life-threatening emergency. The condition is largely iatrogenic and is often precipitated by medications such as antipsychotics. First-generation antipsychotics are more likely to cause NMS than second-generation antipsychotics. The literature lacks an objective measure for NMS diagnosis. Instead, the diagnosis relies largely on the recognition of characteristic symptoms in the presence of an inciting medication. Additional challenges exist with concomitant disease processes and toxicities that may distort the clinical picture. Here, we report a case of a 44-year-old Caucasian man who presented with atypical NMS in the setting of quetiapine overdose. The patient remained uncharacteristically afebrile throughout his admission. Although the patient recovered, extended delays in identification and management can contribute to an increased risk of morbidity and mortality. Introduction Neuroleptic malignant syndrome (NMS) is a rare and potentially lethal constellation of symptoms [1-2]. Neuroleptic medications, particularly first-generation antipsychotics and certain antiemetics, have been shown to induce symptoms [3-5]. However, induction by second-generation antipsychotics, such as quetiapine, is less likely. Definitive diagnostic criteria do not exist for NMS, although hyperthermia, altered mental status, muscle rigidity, elevated creatine kinase (CK), and autonomic instability in the setting of newly introduced or increased doses of neuroleptic medications should prompt a high index of suspicion [3]. Unfortunately, not all cases of NMS present with hallmark signs and symptoms. NMS in the setting of alcohol or drug overdose can obfuscate the clinical picture. The risk of heightened morbidity and mortality requires prompt identification and persistent monitoring [3,5]. Here, we present a 44-year-old male with an atypical presentation of NMS in the setting of quetiapine overdose. Case presentation A 44-year-old Caucasian male with a past medical history pertinent for attention-deficit hyperactivity disorder and major depressive disorder with psychotic symptoms controlled with quetiapine (30 mg daily), fluoxetine (40 mg daily), and dextroamphetamine salts (30 mg daily) presented to the emergency department via ambulance after being found on the floor of his home. The patient has a known history of suicide attempts. Upon examination, the patient was obtunded, disheveled, speaking unintelligibly, and only responsive to tactile stimuli. The patient’s vital signs included a blood pressure of 119/83, pulse of 108, temperature of 96.6 F, respirations of 15, and oxygen saturation of 96% on room air. The patient was found in the presence of an empty bottle of quetiapine. His mother was unsure as to how long he had been on the floor. However, she advised that he might have consumed excessive amounts of alcohol the night before. Further workup revealed a urine toxicology screen positive for amphetamines and an elevated blood alcohol concentration (70 mg/dL; reference range 0-10 mg/dL). Acetaminophen and salicylate levels were within normal limits. Serology was remarkable for leukocytosis (15.8x10-3/uL; reference range 4.5-10.0x10-3/uL), a liver profile with slight elevation of aspartate transaminase (50 IU/uL; reference range 13-39 IU/L), and elevated lactate (8.04 mmol/L; reference range 0.90-1.70 mmol/L). Urinalysis was positive for a few bacteria and 2+ blood. A basic metabolic panel was impressive for hyperkalemia (l6.4 mEq/L; reference range 3.5-5.1 mEq/L) and elevated creatinine (2.6 mg/dL; reference range 0.60-1.30 mg/dL) in an otherwise healthy kidney. Phosphorus and phosphokinase were also elevated. Arterial blood gas revealed a high anion gap metabolic acidosis. A summary of the patient’s acute workup, with notable findings, can be found in Table 1. Table 1 Summary of Pertinent Laboratory Values at Time of Admission ABG = Arterial blood gas; CBC = Complete blood count; CMP = Comprehensive metabolic panel; UA = Urinalysis; S = Serology; T = Toxicology; H = Patient value above the upper limit of normal; N = Patient value within reference range; L = Patient value below the lower limit of normal Laboratory type Analyte Patient value Reference value T Amphetamines Positive Negative T Blood alcohol concentration 70.0 H 0.0-10.0 mg/dL CBC Leukocytes 15.8 x 10-3 H 4.5-10.0x10-3/uL CMP Aspartate transaminase (AST) 50 H 13-39 IU/L CMP Alanine aminotransferase (ALT) 22 N 7-52 IU/L CMP Lactate 8.04 H 0.90-1.70 mmol/L CMP Phosphorus 6.4 H 2.5-5.0 mg/dL CMP Creatinine 2.1 H 0.60-1.30 mg/dL ABG pH 7.452 H 7.350-7.450 ABG pCO2 25.0 L 35.0-45.0 mm Hg The patient was admitted to the internal medicine service with the working diagnosis of acute metabolic encephalopathy secondary to alcohol intoxication or amphetamine overdose with concomitant rhabdomyolysis. The patient was carefully monitored on an inpatient basis. By day two of admission, the patient's creatine kinase (CK) dramatically increased from 4,281 IU/L to 213,800 IU/L (reference range 30-223 IU/L). A longitudinal scatter plot of the patient’s CK over the course of admission is provided in Figure 1. Creatinine also increased despite fluid hydration. His mentation failed to improve, and he became aggressive, requiring physical restraints. The patient remained afebrile throughout his admission. He was persistently tachycardic with stable oxygen saturation (95%-100% on room air). Although the patient presented afebrile, all other signs and symptoms suggested NMS. The patient was transferred to the intensive care unit. Psychotropic medications were withheld, with the exception of lorazepam as needed for agitation. The patient’s normal basal temperature, mild muscle rigidity, and elevated liver enzymes precluded the use of dantrolene at that time. Figure 1 Longitudinal Creatine Kinase Levels During Admission Blue = Patient creatine kinase levels; Orange = Reference values Despite aggressive fluid resuscitation, the patient experienced acute renal failure with a creatinine increasing steadily from 2.10 mg/dL on admission to 7.2 mg/dL on day two (Figure 2). Other metabolic derangements were evident, including worsening metabolic acidosis and hyperkalemia. The patient underwent hemodialysis on post-admission day two and his clinical course improved without incident over the next 18 days. The patient was discharged requiring routine dialysis for the foreseeable future. Figure 2 Longitudinal Creatinine Levels During Admission Blue = Patient creatinine levels; Orange = Reference values Discussion Neuroleptic malignant syndrome (NMS) is a rare and life-threatening emergency leading to mortality in 30%-50% of unmanaged patients [3-4]. Prompt identification and continuous monitoring are necessary to reduce the risk of morbidity and mortality. Recognition can be challenging and complex, requiring careful consideration of symptoms that may overlap with a myriad of concomitant disease states. In this case, we report a middle-aged man presenting to the emergency department in an obtunded state. The patient had a prior history of suicide attempts and his past medical history was significant for depression with psychotic features controlled with more than one psychotropic medication. Although the totality of the circumstances suggested overdose toxicity, the patient’s symptoms were not fully characteristic of an overdose with any one of his prescription medications alone. Reports of quetiapine-induced NMS are limited, however, a case report analysis of 19 cases was conducted by Murri and colleagues, which revealed pooled clinical features with respect to quetiapine-induced NMS to include: 1) tachycardia, tachypnea, diaphoresis, and tremor in 100% of patients; 2) hyperpyrexia and rigidity in 92.3% of patients; 3) dysautonomia in 90% of patients; 4) mental status change in 85.7% of patients; and 5) fever in 78.9% patients [6]. Commensurate with this study, a set of diagnostic criteria proposed by Levenson in 1985 suggested similar features were characteristic of NMS and categorized them into major criteria (fever, rigidity, elevated creatine phosphokinase (CPK)) and minor criteria (tachycardia, abnormal arterial pressure, altered consciousness, diaphoresis, and leukocytosis) [2]. The presence of three major or two major and four minor signs suggests a high probability of NMS. In this case, the patient displayed moderate rigidity, elevated CPK, tachycardia, altered consciousness, leukocytosis, and abnormal arterial pressure, thereby satisfying two major and four minor criteria. However, these symptoms overlap with other more common conditions, such as malignant hyperthermia, in which full rigidity and mental status change are characteristic. Serotonin syndrome is also accompanied by similar symptoms, such as high fever, tachycardia, and confusion, while other well-reported entities, such as central nervous system (CNS) infections and toxins, can also be present in a similar manner and may complicate diagnosis and treatment [1,5]. Symptom onset and inciting medications can help identify or rule out NMS. For instance, NMS presents with an idiosyncratic onset, commonly developing between 24 hours and one month of newly introduced neuroleptic medication. Sixty-five percent of patients experience symptoms within one week, with a modicum of cases documenting symptoms within 24 hours [3]. First-generation antipsychotics (i.e., haloperidol, chlorpromazine, fluphenazine) are more commonly associated with NMS than second-generation antipsychotics [7]. Although, almost any medication that produces fulminant reductions in dopaminergic activity (either by blocking D2 receptors or abrupt withdrawal of D2 receptor stimulation) may cause suggestive symptoms [4-5]. Symptoms can arise from the initial introduction of antipsychotic therapy but have also been reported in patients with longstanding histories of neuroleptic use without incident [8]. Therefore, the duration of quetiapine therapy prior to the presentation should not be a deciding factor when considering NMS in a differential diagnosis. Quetiapine is commonly used off-label for sleep so even patients without known psychiatric histories may have the potential to develop the condition [9]. Coadministration of neuroleptics and selective serotonin reuptake inhibitors, such as in this patient suffering from depression with psychotic features, may increase the risk of developing NMS [10]. This calls particular attention to patients suffering from mixed depressive and psychotic disorders who may receive these medications concomitantly. At the same time, these patients are inherently predisposed to impulsivity and risk-taking behavior, such as suicide, by the virtue of their disease state [11-13]. Thus, patients with mixed depressive and psychotic disorders in the setting of overdose should prompt thorough medication reconciliation for NMS-inducing agents. The exact mechanism of NMS is not fully understood, but contemporary theories revolve around dopamine’s inhibitory effect on centrally and peripherally acting neuronal networks that may help explain presentations of NMS in the absence of fever and rigidity. The prevailing theory of NMS pathophysiology suggests a disruption of dopamine receptor antagonism, specifically within the hypothalamus, leading to hyperthermia and dysautonomia [14]. Similar involvement in the nigrostriatal pathways may explain rigidity and tremor associated with NMS considering this pathway is highly implicated with similar Parkinsonian manifestations [2,15]. Direct and indirect toxicity of offending agents to peripheral tissues, such as skeletal muscles, may influence mitochondrial function leading to hyperthermia secondary to muscle rigidity [16]. Lastly, dopamine’s regulatory influence on autonomic control may lead to heightened sympathetic activity impacting temperature control and muscle tone [16]. In each scenario, rigidity and hyperthermia seem to be directly correlated. This patient experienced moderate rigidity in the absence of fever, an atypical presentation, with a mild disease progression. Taken together, this information suggests that patients with NMS who are afebrile may also have the potential to lack significant muscle rigidity, further reducing a major symptom indicator for the presence of NMS. The timely diagnosis of NMS should be followed by the prompt discontinuation of inciting medication to prevent further symptom progression. The stage of NMS (mild, moderate, and severe) are used to inform the extent of supportive care and pharmacotherapy [17]. For instance, in this case, the patient’s symptoms were relatively mild, with acute renal failure that required close monitoring and muscle relaxers as needed, ultimately resolving over time. Progression to moderate or severe NMS in the presence of hyperpyrexia may warrant more intentional methods of cooling, with blankets or cooled saline. Severe cases may require direct muscle relaxers, such as dantrolene, or dopamine agonists such as bromocriptine. Monotherapy with dantrolene may actually increase mortality and should be avoided in patients with abnormal liver function due to increased risk of acute liver injury [18]. Once symptoms have resolved, approximately 30% of patients will experience a reoccurrence of symptoms [19]. Thus, it is important to slowly reintroduce an alternative antipsychotic medication in patients requiring therapy while remaining alert for signs and symptoms associated with this rare but serious condition. Conclusions Neuroleptic malignant syndrome (NMS) is a life-threatening condition requiring prompt identification and diagnosis with an array of potential presenting symptoms. Certain symptoms, such as fever and muscle rigidity, are highly characteristic of the condition, however, atypical presentations have occurred. This case serves to illustrate an attenuated and atypical presentation of NMS in the setting of overdose with the second-generation antipsychotic quetiapine. Future studies should examine whether a significant relationship exists between fever status and outcome in patients with NMS. The authors have declared that no competing interests exist. Human Ethics Consent was obtained by all participants in this study	AMPHETAMINE ASPARTATE\AMPHETAMINE SULFATE\DEXTROAMPHETAMINE SACCHARATE\DEXTROAMPHETAMINE SULFATE, FLUOXETINE HYDROCHLORIDE, QUETIAPINE	DrugsGivenReaction	CC BY	33585092	18,961,784	2021-01-10
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metabolic acidosis'.	Atypical Neuroleptic Malignant Syndrome in the Setting of Quetiapine Overdose: A Case Report and Review of the Literature. Neuroleptic malignant syndrome (NMS) is a rare and life-threatening emergency. The condition is largely iatrogenic and is often precipitated by medications such as antipsychotics. First-generation antipsychotics are more likely to cause NMS than second-generation antipsychotics. The literature lacks an objective measure for NMS diagnosis. Instead, the diagnosis relies largely on the recognition of characteristic symptoms in the presence of an inciting medication. Additional challenges exist with concomitant disease processes and toxicities that may distort the clinical picture. Here, we report a case of a 44-year-old Caucasian man who presented with atypical NMS in the setting of quetiapine overdose. The patient remained uncharacteristically afebrile throughout his admission. Although the patient recovered, extended delays in identification and management can contribute to an increased risk of morbidity and mortality. Introduction Neuroleptic malignant syndrome (NMS) is a rare and potentially lethal constellation of symptoms [1-2]. Neuroleptic medications, particularly first-generation antipsychotics and certain antiemetics, have been shown to induce symptoms [3-5]. However, induction by second-generation antipsychotics, such as quetiapine, is less likely. Definitive diagnostic criteria do not exist for NMS, although hyperthermia, altered mental status, muscle rigidity, elevated creatine kinase (CK), and autonomic instability in the setting of newly introduced or increased doses of neuroleptic medications should prompt a high index of suspicion [3]. Unfortunately, not all cases of NMS present with hallmark signs and symptoms. NMS in the setting of alcohol or drug overdose can obfuscate the clinical picture. The risk of heightened morbidity and mortality requires prompt identification and persistent monitoring [3,5]. Here, we present a 44-year-old male with an atypical presentation of NMS in the setting of quetiapine overdose. Case presentation A 44-year-old Caucasian male with a past medical history pertinent for attention-deficit hyperactivity disorder and major depressive disorder with psychotic symptoms controlled with quetiapine (30 mg daily), fluoxetine (40 mg daily), and dextroamphetamine salts (30 mg daily) presented to the emergency department via ambulance after being found on the floor of his home. The patient has a known history of suicide attempts. Upon examination, the patient was obtunded, disheveled, speaking unintelligibly, and only responsive to tactile stimuli. The patient’s vital signs included a blood pressure of 119/83, pulse of 108, temperature of 96.6 F, respirations of 15, and oxygen saturation of 96% on room air. The patient was found in the presence of an empty bottle of quetiapine. His mother was unsure as to how long he had been on the floor. However, she advised that he might have consumed excessive amounts of alcohol the night before. Further workup revealed a urine toxicology screen positive for amphetamines and an elevated blood alcohol concentration (70 mg/dL; reference range 0-10 mg/dL). Acetaminophen and salicylate levels were within normal limits. Serology was remarkable for leukocytosis (15.8x10-3/uL; reference range 4.5-10.0x10-3/uL), a liver profile with slight elevation of aspartate transaminase (50 IU/uL; reference range 13-39 IU/L), and elevated lactate (8.04 mmol/L; reference range 0.90-1.70 mmol/L). Urinalysis was positive for a few bacteria and 2+ blood. A basic metabolic panel was impressive for hyperkalemia (l6.4 mEq/L; reference range 3.5-5.1 mEq/L) and elevated creatinine (2.6 mg/dL; reference range 0.60-1.30 mg/dL) in an otherwise healthy kidney. Phosphorus and phosphokinase were also elevated. Arterial blood gas revealed a high anion gap metabolic acidosis. A summary of the patient’s acute workup, with notable findings, can be found in Table 1. Table 1 Summary of Pertinent Laboratory Values at Time of Admission ABG = Arterial blood gas; CBC = Complete blood count; CMP = Comprehensive metabolic panel; UA = Urinalysis; S = Serology; T = Toxicology; H = Patient value above the upper limit of normal; N = Patient value within reference range; L = Patient value below the lower limit of normal Laboratory type Analyte Patient value Reference value T Amphetamines Positive Negative T Blood alcohol concentration 70.0 H 0.0-10.0 mg/dL CBC Leukocytes 15.8 x 10-3 H 4.5-10.0x10-3/uL CMP Aspartate transaminase (AST) 50 H 13-39 IU/L CMP Alanine aminotransferase (ALT) 22 N 7-52 IU/L CMP Lactate 8.04 H 0.90-1.70 mmol/L CMP Phosphorus 6.4 H 2.5-5.0 mg/dL CMP Creatinine 2.1 H 0.60-1.30 mg/dL ABG pH 7.452 H 7.350-7.450 ABG pCO2 25.0 L 35.0-45.0 mm Hg The patient was admitted to the internal medicine service with the working diagnosis of acute metabolic encephalopathy secondary to alcohol intoxication or amphetamine overdose with concomitant rhabdomyolysis. The patient was carefully monitored on an inpatient basis. By day two of admission, the patient's creatine kinase (CK) dramatically increased from 4,281 IU/L to 213,800 IU/L (reference range 30-223 IU/L). A longitudinal scatter plot of the patient’s CK over the course of admission is provided in Figure 1. Creatinine also increased despite fluid hydration. His mentation failed to improve, and he became aggressive, requiring physical restraints. The patient remained afebrile throughout his admission. He was persistently tachycardic with stable oxygen saturation (95%-100% on room air). Although the patient presented afebrile, all other signs and symptoms suggested NMS. The patient was transferred to the intensive care unit. Psychotropic medications were withheld, with the exception of lorazepam as needed for agitation. The patient’s normal basal temperature, mild muscle rigidity, and elevated liver enzymes precluded the use of dantrolene at that time. Figure 1 Longitudinal Creatine Kinase Levels During Admission Blue = Patient creatine kinase levels; Orange = Reference values Despite aggressive fluid resuscitation, the patient experienced acute renal failure with a creatinine increasing steadily from 2.10 mg/dL on admission to 7.2 mg/dL on day two (Figure 2). Other metabolic derangements were evident, including worsening metabolic acidosis and hyperkalemia. The patient underwent hemodialysis on post-admission day two and his clinical course improved without incident over the next 18 days. The patient was discharged requiring routine dialysis for the foreseeable future. Figure 2 Longitudinal Creatinine Levels During Admission Blue = Patient creatinine levels; Orange = Reference values Discussion Neuroleptic malignant syndrome (NMS) is a rare and life-threatening emergency leading to mortality in 30%-50% of unmanaged patients [3-4]. Prompt identification and continuous monitoring are necessary to reduce the risk of morbidity and mortality. Recognition can be challenging and complex, requiring careful consideration of symptoms that may overlap with a myriad of concomitant disease states. In this case, we report a middle-aged man presenting to the emergency department in an obtunded state. The patient had a prior history of suicide attempts and his past medical history was significant for depression with psychotic features controlled with more than one psychotropic medication. Although the totality of the circumstances suggested overdose toxicity, the patient’s symptoms were not fully characteristic of an overdose with any one of his prescription medications alone. Reports of quetiapine-induced NMS are limited, however, a case report analysis of 19 cases was conducted by Murri and colleagues, which revealed pooled clinical features with respect to quetiapine-induced NMS to include: 1) tachycardia, tachypnea, diaphoresis, and tremor in 100% of patients; 2) hyperpyrexia and rigidity in 92.3% of patients; 3) dysautonomia in 90% of patients; 4) mental status change in 85.7% of patients; and 5) fever in 78.9% patients [6]. Commensurate with this study, a set of diagnostic criteria proposed by Levenson in 1985 suggested similar features were characteristic of NMS and categorized them into major criteria (fever, rigidity, elevated creatine phosphokinase (CPK)) and minor criteria (tachycardia, abnormal arterial pressure, altered consciousness, diaphoresis, and leukocytosis) [2]. The presence of three major or two major and four minor signs suggests a high probability of NMS. In this case, the patient displayed moderate rigidity, elevated CPK, tachycardia, altered consciousness, leukocytosis, and abnormal arterial pressure, thereby satisfying two major and four minor criteria. However, these symptoms overlap with other more common conditions, such as malignant hyperthermia, in which full rigidity and mental status change are characteristic. Serotonin syndrome is also accompanied by similar symptoms, such as high fever, tachycardia, and confusion, while other well-reported entities, such as central nervous system (CNS) infections and toxins, can also be present in a similar manner and may complicate diagnosis and treatment [1,5]. Symptom onset and inciting medications can help identify or rule out NMS. For instance, NMS presents with an idiosyncratic onset, commonly developing between 24 hours and one month of newly introduced neuroleptic medication. Sixty-five percent of patients experience symptoms within one week, with a modicum of cases documenting symptoms within 24 hours [3]. First-generation antipsychotics (i.e., haloperidol, chlorpromazine, fluphenazine) are more commonly associated with NMS than second-generation antipsychotics [7]. Although, almost any medication that produces fulminant reductions in dopaminergic activity (either by blocking D2 receptors or abrupt withdrawal of D2 receptor stimulation) may cause suggestive symptoms [4-5]. Symptoms can arise from the initial introduction of antipsychotic therapy but have also been reported in patients with longstanding histories of neuroleptic use without incident [8]. Therefore, the duration of quetiapine therapy prior to the presentation should not be a deciding factor when considering NMS in a differential diagnosis. Quetiapine is commonly used off-label for sleep so even patients without known psychiatric histories may have the potential to develop the condition [9]. Coadministration of neuroleptics and selective serotonin reuptake inhibitors, such as in this patient suffering from depression with psychotic features, may increase the risk of developing NMS [10]. This calls particular attention to patients suffering from mixed depressive and psychotic disorders who may receive these medications concomitantly. At the same time, these patients are inherently predisposed to impulsivity and risk-taking behavior, such as suicide, by the virtue of their disease state [11-13]. Thus, patients with mixed depressive and psychotic disorders in the setting of overdose should prompt thorough medication reconciliation for NMS-inducing agents. The exact mechanism of NMS is not fully understood, but contemporary theories revolve around dopamine’s inhibitory effect on centrally and peripherally acting neuronal networks that may help explain presentations of NMS in the absence of fever and rigidity. The prevailing theory of NMS pathophysiology suggests a disruption of dopamine receptor antagonism, specifically within the hypothalamus, leading to hyperthermia and dysautonomia [14]. Similar involvement in the nigrostriatal pathways may explain rigidity and tremor associated with NMS considering this pathway is highly implicated with similar Parkinsonian manifestations [2,15]. Direct and indirect toxicity of offending agents to peripheral tissues, such as skeletal muscles, may influence mitochondrial function leading to hyperthermia secondary to muscle rigidity [16]. Lastly, dopamine’s regulatory influence on autonomic control may lead to heightened sympathetic activity impacting temperature control and muscle tone [16]. In each scenario, rigidity and hyperthermia seem to be directly correlated. This patient experienced moderate rigidity in the absence of fever, an atypical presentation, with a mild disease progression. Taken together, this information suggests that patients with NMS who are afebrile may also have the potential to lack significant muscle rigidity, further reducing a major symptom indicator for the presence of NMS. The timely diagnosis of NMS should be followed by the prompt discontinuation of inciting medication to prevent further symptom progression. The stage of NMS (mild, moderate, and severe) are used to inform the extent of supportive care and pharmacotherapy [17]. For instance, in this case, the patient’s symptoms were relatively mild, with acute renal failure that required close monitoring and muscle relaxers as needed, ultimately resolving over time. Progression to moderate or severe NMS in the presence of hyperpyrexia may warrant more intentional methods of cooling, with blankets or cooled saline. Severe cases may require direct muscle relaxers, such as dantrolene, or dopamine agonists such as bromocriptine. Monotherapy with dantrolene may actually increase mortality and should be avoided in patients with abnormal liver function due to increased risk of acute liver injury [18]. Once symptoms have resolved, approximately 30% of patients will experience a reoccurrence of symptoms [19]. Thus, it is important to slowly reintroduce an alternative antipsychotic medication in patients requiring therapy while remaining alert for signs and symptoms associated with this rare but serious condition. Conclusions Neuroleptic malignant syndrome (NMS) is a life-threatening condition requiring prompt identification and diagnosis with an array of potential presenting symptoms. Certain symptoms, such as fever and muscle rigidity, are highly characteristic of the condition, however, atypical presentations have occurred. This case serves to illustrate an attenuated and atypical presentation of NMS in the setting of overdose with the second-generation antipsychotic quetiapine. Future studies should examine whether a significant relationship exists between fever status and outcome in patients with NMS. The authors have declared that no competing interests exist. Human Ethics Consent was obtained by all participants in this study	AMPHETAMINE ASPARTATE\AMPHETAMINE SULFATE\DEXTROAMPHETAMINE SACCHARATE\DEXTROAMPHETAMINE SULFATE, FLUOXETINE HYDROCHLORIDE, QUETIAPINE	DrugsGivenReaction	CC BY	33585092	18,961,784	2021-01-10
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neuroleptic malignant syndrome'.	Atypical Neuroleptic Malignant Syndrome in the Setting of Quetiapine Overdose: A Case Report and Review of the Literature. Neuroleptic malignant syndrome (NMS) is a rare and life-threatening emergency. The condition is largely iatrogenic and is often precipitated by medications such as antipsychotics. First-generation antipsychotics are more likely to cause NMS than second-generation antipsychotics. The literature lacks an objective measure for NMS diagnosis. Instead, the diagnosis relies largely on the recognition of characteristic symptoms in the presence of an inciting medication. Additional challenges exist with concomitant disease processes and toxicities that may distort the clinical picture. Here, we report a case of a 44-year-old Caucasian man who presented with atypical NMS in the setting of quetiapine overdose. The patient remained uncharacteristically afebrile throughout his admission. Although the patient recovered, extended delays in identification and management can contribute to an increased risk of morbidity and mortality. Introduction Neuroleptic malignant syndrome (NMS) is a rare and potentially lethal constellation of symptoms [1-2]. Neuroleptic medications, particularly first-generation antipsychotics and certain antiemetics, have been shown to induce symptoms [3-5]. However, induction by second-generation antipsychotics, such as quetiapine, is less likely. Definitive diagnostic criteria do not exist for NMS, although hyperthermia, altered mental status, muscle rigidity, elevated creatine kinase (CK), and autonomic instability in the setting of newly introduced or increased doses of neuroleptic medications should prompt a high index of suspicion [3]. Unfortunately, not all cases of NMS present with hallmark signs and symptoms. NMS in the setting of alcohol or drug overdose can obfuscate the clinical picture. The risk of heightened morbidity and mortality requires prompt identification and persistent monitoring [3,5]. Here, we present a 44-year-old male with an atypical presentation of NMS in the setting of quetiapine overdose. Case presentation A 44-year-old Caucasian male with a past medical history pertinent for attention-deficit hyperactivity disorder and major depressive disorder with psychotic symptoms controlled with quetiapine (30 mg daily), fluoxetine (40 mg daily), and dextroamphetamine salts (30 mg daily) presented to the emergency department via ambulance after being found on the floor of his home. The patient has a known history of suicide attempts. Upon examination, the patient was obtunded, disheveled, speaking unintelligibly, and only responsive to tactile stimuli. The patient’s vital signs included a blood pressure of 119/83, pulse of 108, temperature of 96.6 F, respirations of 15, and oxygen saturation of 96% on room air. The patient was found in the presence of an empty bottle of quetiapine. His mother was unsure as to how long he had been on the floor. However, she advised that he might have consumed excessive amounts of alcohol the night before. Further workup revealed a urine toxicology screen positive for amphetamines and an elevated blood alcohol concentration (70 mg/dL; reference range 0-10 mg/dL). Acetaminophen and salicylate levels were within normal limits. Serology was remarkable for leukocytosis (15.8x10-3/uL; reference range 4.5-10.0x10-3/uL), a liver profile with slight elevation of aspartate transaminase (50 IU/uL; reference range 13-39 IU/L), and elevated lactate (8.04 mmol/L; reference range 0.90-1.70 mmol/L). Urinalysis was positive for a few bacteria and 2+ blood. A basic metabolic panel was impressive for hyperkalemia (l6.4 mEq/L; reference range 3.5-5.1 mEq/L) and elevated creatinine (2.6 mg/dL; reference range 0.60-1.30 mg/dL) in an otherwise healthy kidney. Phosphorus and phosphokinase were also elevated. Arterial blood gas revealed a high anion gap metabolic acidosis. A summary of the patient’s acute workup, with notable findings, can be found in Table 1. Table 1 Summary of Pertinent Laboratory Values at Time of Admission ABG = Arterial blood gas; CBC = Complete blood count; CMP = Comprehensive metabolic panel; UA = Urinalysis; S = Serology; T = Toxicology; H = Patient value above the upper limit of normal; N = Patient value within reference range; L = Patient value below the lower limit of normal Laboratory type Analyte Patient value Reference value T Amphetamines Positive Negative T Blood alcohol concentration 70.0 H 0.0-10.0 mg/dL CBC Leukocytes 15.8 x 10-3 H 4.5-10.0x10-3/uL CMP Aspartate transaminase (AST) 50 H 13-39 IU/L CMP Alanine aminotransferase (ALT) 22 N 7-52 IU/L CMP Lactate 8.04 H 0.90-1.70 mmol/L CMP Phosphorus 6.4 H 2.5-5.0 mg/dL CMP Creatinine 2.1 H 0.60-1.30 mg/dL ABG pH 7.452 H 7.350-7.450 ABG pCO2 25.0 L 35.0-45.0 mm Hg The patient was admitted to the internal medicine service with the working diagnosis of acute metabolic encephalopathy secondary to alcohol intoxication or amphetamine overdose with concomitant rhabdomyolysis. The patient was carefully monitored on an inpatient basis. By day two of admission, the patient's creatine kinase (CK) dramatically increased from 4,281 IU/L to 213,800 IU/L (reference range 30-223 IU/L). A longitudinal scatter plot of the patient’s CK over the course of admission is provided in Figure 1. Creatinine also increased despite fluid hydration. His mentation failed to improve, and he became aggressive, requiring physical restraints. The patient remained afebrile throughout his admission. He was persistently tachycardic with stable oxygen saturation (95%-100% on room air). Although the patient presented afebrile, all other signs and symptoms suggested NMS. The patient was transferred to the intensive care unit. Psychotropic medications were withheld, with the exception of lorazepam as needed for agitation. The patient’s normal basal temperature, mild muscle rigidity, and elevated liver enzymes precluded the use of dantrolene at that time. Figure 1 Longitudinal Creatine Kinase Levels During Admission Blue = Patient creatine kinase levels; Orange = Reference values Despite aggressive fluid resuscitation, the patient experienced acute renal failure with a creatinine increasing steadily from 2.10 mg/dL on admission to 7.2 mg/dL on day two (Figure 2). Other metabolic derangements were evident, including worsening metabolic acidosis and hyperkalemia. The patient underwent hemodialysis on post-admission day two and his clinical course improved without incident over the next 18 days. The patient was discharged requiring routine dialysis for the foreseeable future. Figure 2 Longitudinal Creatinine Levels During Admission Blue = Patient creatinine levels; Orange = Reference values Discussion Neuroleptic malignant syndrome (NMS) is a rare and life-threatening emergency leading to mortality in 30%-50% of unmanaged patients [3-4]. Prompt identification and continuous monitoring are necessary to reduce the risk of morbidity and mortality. Recognition can be challenging and complex, requiring careful consideration of symptoms that may overlap with a myriad of concomitant disease states. In this case, we report a middle-aged man presenting to the emergency department in an obtunded state. The patient had a prior history of suicide attempts and his past medical history was significant for depression with psychotic features controlled with more than one psychotropic medication. Although the totality of the circumstances suggested overdose toxicity, the patient’s symptoms were not fully characteristic of an overdose with any one of his prescription medications alone. Reports of quetiapine-induced NMS are limited, however, a case report analysis of 19 cases was conducted by Murri and colleagues, which revealed pooled clinical features with respect to quetiapine-induced NMS to include: 1) tachycardia, tachypnea, diaphoresis, and tremor in 100% of patients; 2) hyperpyrexia and rigidity in 92.3% of patients; 3) dysautonomia in 90% of patients; 4) mental status change in 85.7% of patients; and 5) fever in 78.9% patients [6]. Commensurate with this study, a set of diagnostic criteria proposed by Levenson in 1985 suggested similar features were characteristic of NMS and categorized them into major criteria (fever, rigidity, elevated creatine phosphokinase (CPK)) and minor criteria (tachycardia, abnormal arterial pressure, altered consciousness, diaphoresis, and leukocytosis) [2]. The presence of three major or two major and four minor signs suggests a high probability of NMS. In this case, the patient displayed moderate rigidity, elevated CPK, tachycardia, altered consciousness, leukocytosis, and abnormal arterial pressure, thereby satisfying two major and four minor criteria. However, these symptoms overlap with other more common conditions, such as malignant hyperthermia, in which full rigidity and mental status change are characteristic. Serotonin syndrome is also accompanied by similar symptoms, such as high fever, tachycardia, and confusion, while other well-reported entities, such as central nervous system (CNS) infections and toxins, can also be present in a similar manner and may complicate diagnosis and treatment [1,5]. Symptom onset and inciting medications can help identify or rule out NMS. For instance, NMS presents with an idiosyncratic onset, commonly developing between 24 hours and one month of newly introduced neuroleptic medication. Sixty-five percent of patients experience symptoms within one week, with a modicum of cases documenting symptoms within 24 hours [3]. First-generation antipsychotics (i.e., haloperidol, chlorpromazine, fluphenazine) are more commonly associated with NMS than second-generation antipsychotics [7]. Although, almost any medication that produces fulminant reductions in dopaminergic activity (either by blocking D2 receptors or abrupt withdrawal of D2 receptor stimulation) may cause suggestive symptoms [4-5]. Symptoms can arise from the initial introduction of antipsychotic therapy but have also been reported in patients with longstanding histories of neuroleptic use without incident [8]. Therefore, the duration of quetiapine therapy prior to the presentation should not be a deciding factor when considering NMS in a differential diagnosis. Quetiapine is commonly used off-label for sleep so even patients without known psychiatric histories may have the potential to develop the condition [9]. Coadministration of neuroleptics and selective serotonin reuptake inhibitors, such as in this patient suffering from depression with psychotic features, may increase the risk of developing NMS [10]. This calls particular attention to patients suffering from mixed depressive and psychotic disorders who may receive these medications concomitantly. At the same time, these patients are inherently predisposed to impulsivity and risk-taking behavior, such as suicide, by the virtue of their disease state [11-13]. Thus, patients with mixed depressive and psychotic disorders in the setting of overdose should prompt thorough medication reconciliation for NMS-inducing agents. The exact mechanism of NMS is not fully understood, but contemporary theories revolve around dopamine’s inhibitory effect on centrally and peripherally acting neuronal networks that may help explain presentations of NMS in the absence of fever and rigidity. The prevailing theory of NMS pathophysiology suggests a disruption of dopamine receptor antagonism, specifically within the hypothalamus, leading to hyperthermia and dysautonomia [14]. Similar involvement in the nigrostriatal pathways may explain rigidity and tremor associated with NMS considering this pathway is highly implicated with similar Parkinsonian manifestations [2,15]. Direct and indirect toxicity of offending agents to peripheral tissues, such as skeletal muscles, may influence mitochondrial function leading to hyperthermia secondary to muscle rigidity [16]. Lastly, dopamine’s regulatory influence on autonomic control may lead to heightened sympathetic activity impacting temperature control and muscle tone [16]. In each scenario, rigidity and hyperthermia seem to be directly correlated. This patient experienced moderate rigidity in the absence of fever, an atypical presentation, with a mild disease progression. Taken together, this information suggests that patients with NMS who are afebrile may also have the potential to lack significant muscle rigidity, further reducing a major symptom indicator for the presence of NMS. The timely diagnosis of NMS should be followed by the prompt discontinuation of inciting medication to prevent further symptom progression. The stage of NMS (mild, moderate, and severe) are used to inform the extent of supportive care and pharmacotherapy [17]. For instance, in this case, the patient’s symptoms were relatively mild, with acute renal failure that required close monitoring and muscle relaxers as needed, ultimately resolving over time. Progression to moderate or severe NMS in the presence of hyperpyrexia may warrant more intentional methods of cooling, with blankets or cooled saline. Severe cases may require direct muscle relaxers, such as dantrolene, or dopamine agonists such as bromocriptine. Monotherapy with dantrolene may actually increase mortality and should be avoided in patients with abnormal liver function due to increased risk of acute liver injury [18]. Once symptoms have resolved, approximately 30% of patients will experience a reoccurrence of symptoms [19]. Thus, it is important to slowly reintroduce an alternative antipsychotic medication in patients requiring therapy while remaining alert for signs and symptoms associated with this rare but serious condition. Conclusions Neuroleptic malignant syndrome (NMS) is a life-threatening condition requiring prompt identification and diagnosis with an array of potential presenting symptoms. Certain symptoms, such as fever and muscle rigidity, are highly characteristic of the condition, however, atypical presentations have occurred. This case serves to illustrate an attenuated and atypical presentation of NMS in the setting of overdose with the second-generation antipsychotic quetiapine. Future studies should examine whether a significant relationship exists between fever status and outcome in patients with NMS. The authors have declared that no competing interests exist. Human Ethics Consent was obtained by all participants in this study	AMPHETAMINE ASPARTATE\AMPHETAMINE SULFATE\DEXTROAMPHETAMINE SACCHARATE\DEXTROAMPHETAMINE SULFATE, FLUOXETINE HYDROCHLORIDE, QUETIAPINE	DrugsGivenReaction	CC BY	33585092	18,961,784	2021-01-10
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxicity to various agents'.	Atypical Neuroleptic Malignant Syndrome in the Setting of Quetiapine Overdose: A Case Report and Review of the Literature. Neuroleptic malignant syndrome (NMS) is a rare and life-threatening emergency. The condition is largely iatrogenic and is often precipitated by medications such as antipsychotics. First-generation antipsychotics are more likely to cause NMS than second-generation antipsychotics. The literature lacks an objective measure for NMS diagnosis. Instead, the diagnosis relies largely on the recognition of characteristic symptoms in the presence of an inciting medication. Additional challenges exist with concomitant disease processes and toxicities that may distort the clinical picture. Here, we report a case of a 44-year-old Caucasian man who presented with atypical NMS in the setting of quetiapine overdose. The patient remained uncharacteristically afebrile throughout his admission. Although the patient recovered, extended delays in identification and management can contribute to an increased risk of morbidity and mortality. Introduction Neuroleptic malignant syndrome (NMS) is a rare and potentially lethal constellation of symptoms [1-2]. Neuroleptic medications, particularly first-generation antipsychotics and certain antiemetics, have been shown to induce symptoms [3-5]. However, induction by second-generation antipsychotics, such as quetiapine, is less likely. Definitive diagnostic criteria do not exist for NMS, although hyperthermia, altered mental status, muscle rigidity, elevated creatine kinase (CK), and autonomic instability in the setting of newly introduced or increased doses of neuroleptic medications should prompt a high index of suspicion [3]. Unfortunately, not all cases of NMS present with hallmark signs and symptoms. NMS in the setting of alcohol or drug overdose can obfuscate the clinical picture. The risk of heightened morbidity and mortality requires prompt identification and persistent monitoring [3,5]. Here, we present a 44-year-old male with an atypical presentation of NMS in the setting of quetiapine overdose. Case presentation A 44-year-old Caucasian male with a past medical history pertinent for attention-deficit hyperactivity disorder and major depressive disorder with psychotic symptoms controlled with quetiapine (30 mg daily), fluoxetine (40 mg daily), and dextroamphetamine salts (30 mg daily) presented to the emergency department via ambulance after being found on the floor of his home. The patient has a known history of suicide attempts. Upon examination, the patient was obtunded, disheveled, speaking unintelligibly, and only responsive to tactile stimuli. The patient’s vital signs included a blood pressure of 119/83, pulse of 108, temperature of 96.6 F, respirations of 15, and oxygen saturation of 96% on room air. The patient was found in the presence of an empty bottle of quetiapine. His mother was unsure as to how long he had been on the floor. However, she advised that he might have consumed excessive amounts of alcohol the night before. Further workup revealed a urine toxicology screen positive for amphetamines and an elevated blood alcohol concentration (70 mg/dL; reference range 0-10 mg/dL). Acetaminophen and salicylate levels were within normal limits. Serology was remarkable for leukocytosis (15.8x10-3/uL; reference range 4.5-10.0x10-3/uL), a liver profile with slight elevation of aspartate transaminase (50 IU/uL; reference range 13-39 IU/L), and elevated lactate (8.04 mmol/L; reference range 0.90-1.70 mmol/L). Urinalysis was positive for a few bacteria and 2+ blood. A basic metabolic panel was impressive for hyperkalemia (l6.4 mEq/L; reference range 3.5-5.1 mEq/L) and elevated creatinine (2.6 mg/dL; reference range 0.60-1.30 mg/dL) in an otherwise healthy kidney. Phosphorus and phosphokinase were also elevated. Arterial blood gas revealed a high anion gap metabolic acidosis. A summary of the patient’s acute workup, with notable findings, can be found in Table 1. Table 1 Summary of Pertinent Laboratory Values at Time of Admission ABG = Arterial blood gas; CBC = Complete blood count; CMP = Comprehensive metabolic panel; UA = Urinalysis; S = Serology; T = Toxicology; H = Patient value above the upper limit of normal; N = Patient value within reference range; L = Patient value below the lower limit of normal Laboratory type Analyte Patient value Reference value T Amphetamines Positive Negative T Blood alcohol concentration 70.0 H 0.0-10.0 mg/dL CBC Leukocytes 15.8 x 10-3 H 4.5-10.0x10-3/uL CMP Aspartate transaminase (AST) 50 H 13-39 IU/L CMP Alanine aminotransferase (ALT) 22 N 7-52 IU/L CMP Lactate 8.04 H 0.90-1.70 mmol/L CMP Phosphorus 6.4 H 2.5-5.0 mg/dL CMP Creatinine 2.1 H 0.60-1.30 mg/dL ABG pH 7.452 H 7.350-7.450 ABG pCO2 25.0 L 35.0-45.0 mm Hg The patient was admitted to the internal medicine service with the working diagnosis of acute metabolic encephalopathy secondary to alcohol intoxication or amphetamine overdose with concomitant rhabdomyolysis. The patient was carefully monitored on an inpatient basis. By day two of admission, the patient's creatine kinase (CK) dramatically increased from 4,281 IU/L to 213,800 IU/L (reference range 30-223 IU/L). A longitudinal scatter plot of the patient’s CK over the course of admission is provided in Figure 1. Creatinine also increased despite fluid hydration. His mentation failed to improve, and he became aggressive, requiring physical restraints. The patient remained afebrile throughout his admission. He was persistently tachycardic with stable oxygen saturation (95%-100% on room air). Although the patient presented afebrile, all other signs and symptoms suggested NMS. The patient was transferred to the intensive care unit. Psychotropic medications were withheld, with the exception of lorazepam as needed for agitation. The patient’s normal basal temperature, mild muscle rigidity, and elevated liver enzymes precluded the use of dantrolene at that time. Figure 1 Longitudinal Creatine Kinase Levels During Admission Blue = Patient creatine kinase levels; Orange = Reference values Despite aggressive fluid resuscitation, the patient experienced acute renal failure with a creatinine increasing steadily from 2.10 mg/dL on admission to 7.2 mg/dL on day two (Figure 2). Other metabolic derangements were evident, including worsening metabolic acidosis and hyperkalemia. The patient underwent hemodialysis on post-admission day two and his clinical course improved without incident over the next 18 days. The patient was discharged requiring routine dialysis for the foreseeable future. Figure 2 Longitudinal Creatinine Levels During Admission Blue = Patient creatinine levels; Orange = Reference values Discussion Neuroleptic malignant syndrome (NMS) is a rare and life-threatening emergency leading to mortality in 30%-50% of unmanaged patients [3-4]. Prompt identification and continuous monitoring are necessary to reduce the risk of morbidity and mortality. Recognition can be challenging and complex, requiring careful consideration of symptoms that may overlap with a myriad of concomitant disease states. In this case, we report a middle-aged man presenting to the emergency department in an obtunded state. The patient had a prior history of suicide attempts and his past medical history was significant for depression with psychotic features controlled with more than one psychotropic medication. Although the totality of the circumstances suggested overdose toxicity, the patient’s symptoms were not fully characteristic of an overdose with any one of his prescription medications alone. Reports of quetiapine-induced NMS are limited, however, a case report analysis of 19 cases was conducted by Murri and colleagues, which revealed pooled clinical features with respect to quetiapine-induced NMS to include: 1) tachycardia, tachypnea, diaphoresis, and tremor in 100% of patients; 2) hyperpyrexia and rigidity in 92.3% of patients; 3) dysautonomia in 90% of patients; 4) mental status change in 85.7% of patients; and 5) fever in 78.9% patients [6]. Commensurate with this study, a set of diagnostic criteria proposed by Levenson in 1985 suggested similar features were characteristic of NMS and categorized them into major criteria (fever, rigidity, elevated creatine phosphokinase (CPK)) and minor criteria (tachycardia, abnormal arterial pressure, altered consciousness, diaphoresis, and leukocytosis) [2]. The presence of three major or two major and four minor signs suggests a high probability of NMS. In this case, the patient displayed moderate rigidity, elevated CPK, tachycardia, altered consciousness, leukocytosis, and abnormal arterial pressure, thereby satisfying two major and four minor criteria. However, these symptoms overlap with other more common conditions, such as malignant hyperthermia, in which full rigidity and mental status change are characteristic. Serotonin syndrome is also accompanied by similar symptoms, such as high fever, tachycardia, and confusion, while other well-reported entities, such as central nervous system (CNS) infections and toxins, can also be present in a similar manner and may complicate diagnosis and treatment [1,5]. Symptom onset and inciting medications can help identify or rule out NMS. For instance, NMS presents with an idiosyncratic onset, commonly developing between 24 hours and one month of newly introduced neuroleptic medication. Sixty-five percent of patients experience symptoms within one week, with a modicum of cases documenting symptoms within 24 hours [3]. First-generation antipsychotics (i.e., haloperidol, chlorpromazine, fluphenazine) are more commonly associated with NMS than second-generation antipsychotics [7]. Although, almost any medication that produces fulminant reductions in dopaminergic activity (either by blocking D2 receptors or abrupt withdrawal of D2 receptor stimulation) may cause suggestive symptoms [4-5]. Symptoms can arise from the initial introduction of antipsychotic therapy but have also been reported in patients with longstanding histories of neuroleptic use without incident [8]. Therefore, the duration of quetiapine therapy prior to the presentation should not be a deciding factor when considering NMS in a differential diagnosis. Quetiapine is commonly used off-label for sleep so even patients without known psychiatric histories may have the potential to develop the condition [9]. Coadministration of neuroleptics and selective serotonin reuptake inhibitors, such as in this patient suffering from depression with psychotic features, may increase the risk of developing NMS [10]. This calls particular attention to patients suffering from mixed depressive and psychotic disorders who may receive these medications concomitantly. At the same time, these patients are inherently predisposed to impulsivity and risk-taking behavior, such as suicide, by the virtue of their disease state [11-13]. Thus, patients with mixed depressive and psychotic disorders in the setting of overdose should prompt thorough medication reconciliation for NMS-inducing agents. The exact mechanism of NMS is not fully understood, but contemporary theories revolve around dopamine’s inhibitory effect on centrally and peripherally acting neuronal networks that may help explain presentations of NMS in the absence of fever and rigidity. The prevailing theory of NMS pathophysiology suggests a disruption of dopamine receptor antagonism, specifically within the hypothalamus, leading to hyperthermia and dysautonomia [14]. Similar involvement in the nigrostriatal pathways may explain rigidity and tremor associated with NMS considering this pathway is highly implicated with similar Parkinsonian manifestations [2,15]. Direct and indirect toxicity of offending agents to peripheral tissues, such as skeletal muscles, may influence mitochondrial function leading to hyperthermia secondary to muscle rigidity [16]. Lastly, dopamine’s regulatory influence on autonomic control may lead to heightened sympathetic activity impacting temperature control and muscle tone [16]. In each scenario, rigidity and hyperthermia seem to be directly correlated. This patient experienced moderate rigidity in the absence of fever, an atypical presentation, with a mild disease progression. Taken together, this information suggests that patients with NMS who are afebrile may also have the potential to lack significant muscle rigidity, further reducing a major symptom indicator for the presence of NMS. The timely diagnosis of NMS should be followed by the prompt discontinuation of inciting medication to prevent further symptom progression. The stage of NMS (mild, moderate, and severe) are used to inform the extent of supportive care and pharmacotherapy [17]. For instance, in this case, the patient’s symptoms were relatively mild, with acute renal failure that required close monitoring and muscle relaxers as needed, ultimately resolving over time. Progression to moderate or severe NMS in the presence of hyperpyrexia may warrant more intentional methods of cooling, with blankets or cooled saline. Severe cases may require direct muscle relaxers, such as dantrolene, or dopamine agonists such as bromocriptine. Monotherapy with dantrolene may actually increase mortality and should be avoided in patients with abnormal liver function due to increased risk of acute liver injury [18]. Once symptoms have resolved, approximately 30% of patients will experience a reoccurrence of symptoms [19]. Thus, it is important to slowly reintroduce an alternative antipsychotic medication in patients requiring therapy while remaining alert for signs and symptoms associated with this rare but serious condition. Conclusions Neuroleptic malignant syndrome (NMS) is a life-threatening condition requiring prompt identification and diagnosis with an array of potential presenting symptoms. Certain symptoms, such as fever and muscle rigidity, are highly characteristic of the condition, however, atypical presentations have occurred. This case serves to illustrate an attenuated and atypical presentation of NMS in the setting of overdose with the second-generation antipsychotic quetiapine. Future studies should examine whether a significant relationship exists between fever status and outcome in patients with NMS. The authors have declared that no competing interests exist. Human Ethics Consent was obtained by all participants in this study	AMPHETAMINE ASPARTATE\AMPHETAMINE SULFATE\DEXTROAMPHETAMINE SACCHARATE\DEXTROAMPHETAMINE SULFATE, FLUOXETINE HYDROCHLORIDE, QUETIAPINE	DrugsGivenReaction	CC BY	33585092	18,961,784	2021-01-10
What was the dosage of drug 'AMPHETAMINE ASPARTATE\AMPHETAMINE SULFATE\DEXTROAMPHETAMINE SACCHARATE\DEXTROAMPHETAMINE SULFATE'?	Atypical Neuroleptic Malignant Syndrome in the Setting of Quetiapine Overdose: A Case Report and Review of the Literature. Neuroleptic malignant syndrome (NMS) is a rare and life-threatening emergency. The condition is largely iatrogenic and is often precipitated by medications such as antipsychotics. First-generation antipsychotics are more likely to cause NMS than second-generation antipsychotics. The literature lacks an objective measure for NMS diagnosis. Instead, the diagnosis relies largely on the recognition of characteristic symptoms in the presence of an inciting medication. Additional challenges exist with concomitant disease processes and toxicities that may distort the clinical picture. Here, we report a case of a 44-year-old Caucasian man who presented with atypical NMS in the setting of quetiapine overdose. The patient remained uncharacteristically afebrile throughout his admission. Although the patient recovered, extended delays in identification and management can contribute to an increased risk of morbidity and mortality. Introduction Neuroleptic malignant syndrome (NMS) is a rare and potentially lethal constellation of symptoms [1-2]. Neuroleptic medications, particularly first-generation antipsychotics and certain antiemetics, have been shown to induce symptoms [3-5]. However, induction by second-generation antipsychotics, such as quetiapine, is less likely. Definitive diagnostic criteria do not exist for NMS, although hyperthermia, altered mental status, muscle rigidity, elevated creatine kinase (CK), and autonomic instability in the setting of newly introduced or increased doses of neuroleptic medications should prompt a high index of suspicion [3]. Unfortunately, not all cases of NMS present with hallmark signs and symptoms. NMS in the setting of alcohol or drug overdose can obfuscate the clinical picture. The risk of heightened morbidity and mortality requires prompt identification and persistent monitoring [3,5]. Here, we present a 44-year-old male with an atypical presentation of NMS in the setting of quetiapine overdose. Case presentation A 44-year-old Caucasian male with a past medical history pertinent for attention-deficit hyperactivity disorder and major depressive disorder with psychotic symptoms controlled with quetiapine (30 mg daily), fluoxetine (40 mg daily), and dextroamphetamine salts (30 mg daily) presented to the emergency department via ambulance after being found on the floor of his home. The patient has a known history of suicide attempts. Upon examination, the patient was obtunded, disheveled, speaking unintelligibly, and only responsive to tactile stimuli. The patient’s vital signs included a blood pressure of 119/83, pulse of 108, temperature of 96.6 F, respirations of 15, and oxygen saturation of 96% on room air. The patient was found in the presence of an empty bottle of quetiapine. His mother was unsure as to how long he had been on the floor. However, she advised that he might have consumed excessive amounts of alcohol the night before. Further workup revealed a urine toxicology screen positive for amphetamines and an elevated blood alcohol concentration (70 mg/dL; reference range 0-10 mg/dL). Acetaminophen and salicylate levels were within normal limits. Serology was remarkable for leukocytosis (15.8x10-3/uL; reference range 4.5-10.0x10-3/uL), a liver profile with slight elevation of aspartate transaminase (50 IU/uL; reference range 13-39 IU/L), and elevated lactate (8.04 mmol/L; reference range 0.90-1.70 mmol/L). Urinalysis was positive for a few bacteria and 2+ blood. A basic metabolic panel was impressive for hyperkalemia (l6.4 mEq/L; reference range 3.5-5.1 mEq/L) and elevated creatinine (2.6 mg/dL; reference range 0.60-1.30 mg/dL) in an otherwise healthy kidney. Phosphorus and phosphokinase were also elevated. Arterial blood gas revealed a high anion gap metabolic acidosis. A summary of the patient’s acute workup, with notable findings, can be found in Table 1. Table 1 Summary of Pertinent Laboratory Values at Time of Admission ABG = Arterial blood gas; CBC = Complete blood count; CMP = Comprehensive metabolic panel; UA = Urinalysis; S = Serology; T = Toxicology; H = Patient value above the upper limit of normal; N = Patient value within reference range; L = Patient value below the lower limit of normal Laboratory type Analyte Patient value Reference value T Amphetamines Positive Negative T Blood alcohol concentration 70.0 H 0.0-10.0 mg/dL CBC Leukocytes 15.8 x 10-3 H 4.5-10.0x10-3/uL CMP Aspartate transaminase (AST) 50 H 13-39 IU/L CMP Alanine aminotransferase (ALT) 22 N 7-52 IU/L CMP Lactate 8.04 H 0.90-1.70 mmol/L CMP Phosphorus 6.4 H 2.5-5.0 mg/dL CMP Creatinine 2.1 H 0.60-1.30 mg/dL ABG pH 7.452 H 7.350-7.450 ABG pCO2 25.0 L 35.0-45.0 mm Hg The patient was admitted to the internal medicine service with the working diagnosis of acute metabolic encephalopathy secondary to alcohol intoxication or amphetamine overdose with concomitant rhabdomyolysis. The patient was carefully monitored on an inpatient basis. By day two of admission, the patient's creatine kinase (CK) dramatically increased from 4,281 IU/L to 213,800 IU/L (reference range 30-223 IU/L). A longitudinal scatter plot of the patient’s CK over the course of admission is provided in Figure 1. Creatinine also increased despite fluid hydration. His mentation failed to improve, and he became aggressive, requiring physical restraints. The patient remained afebrile throughout his admission. He was persistently tachycardic with stable oxygen saturation (95%-100% on room air). Although the patient presented afebrile, all other signs and symptoms suggested NMS. The patient was transferred to the intensive care unit. Psychotropic medications were withheld, with the exception of lorazepam as needed for agitation. The patient’s normal basal temperature, mild muscle rigidity, and elevated liver enzymes precluded the use of dantrolene at that time. Figure 1 Longitudinal Creatine Kinase Levels During Admission Blue = Patient creatine kinase levels; Orange = Reference values Despite aggressive fluid resuscitation, the patient experienced acute renal failure with a creatinine increasing steadily from 2.10 mg/dL on admission to 7.2 mg/dL on day two (Figure 2). Other metabolic derangements were evident, including worsening metabolic acidosis and hyperkalemia. The patient underwent hemodialysis on post-admission day two and his clinical course improved without incident over the next 18 days. The patient was discharged requiring routine dialysis for the foreseeable future. Figure 2 Longitudinal Creatinine Levels During Admission Blue = Patient creatinine levels; Orange = Reference values Discussion Neuroleptic malignant syndrome (NMS) is a rare and life-threatening emergency leading to mortality in 30%-50% of unmanaged patients [3-4]. Prompt identification and continuous monitoring are necessary to reduce the risk of morbidity and mortality. Recognition can be challenging and complex, requiring careful consideration of symptoms that may overlap with a myriad of concomitant disease states. In this case, we report a middle-aged man presenting to the emergency department in an obtunded state. The patient had a prior history of suicide attempts and his past medical history was significant for depression with psychotic features controlled with more than one psychotropic medication. Although the totality of the circumstances suggested overdose toxicity, the patient’s symptoms were not fully characteristic of an overdose with any one of his prescription medications alone. Reports of quetiapine-induced NMS are limited, however, a case report analysis of 19 cases was conducted by Murri and colleagues, which revealed pooled clinical features with respect to quetiapine-induced NMS to include: 1) tachycardia, tachypnea, diaphoresis, and tremor in 100% of patients; 2) hyperpyrexia and rigidity in 92.3% of patients; 3) dysautonomia in 90% of patients; 4) mental status change in 85.7% of patients; and 5) fever in 78.9% patients [6]. Commensurate with this study, a set of diagnostic criteria proposed by Levenson in 1985 suggested similar features were characteristic of NMS and categorized them into major criteria (fever, rigidity, elevated creatine phosphokinase (CPK)) and minor criteria (tachycardia, abnormal arterial pressure, altered consciousness, diaphoresis, and leukocytosis) [2]. The presence of three major or two major and four minor signs suggests a high probability of NMS. In this case, the patient displayed moderate rigidity, elevated CPK, tachycardia, altered consciousness, leukocytosis, and abnormal arterial pressure, thereby satisfying two major and four minor criteria. However, these symptoms overlap with other more common conditions, such as malignant hyperthermia, in which full rigidity and mental status change are characteristic. Serotonin syndrome is also accompanied by similar symptoms, such as high fever, tachycardia, and confusion, while other well-reported entities, such as central nervous system (CNS) infections and toxins, can also be present in a similar manner and may complicate diagnosis and treatment [1,5]. Symptom onset and inciting medications can help identify or rule out NMS. For instance, NMS presents with an idiosyncratic onset, commonly developing between 24 hours and one month of newly introduced neuroleptic medication. Sixty-five percent of patients experience symptoms within one week, with a modicum of cases documenting symptoms within 24 hours [3]. First-generation antipsychotics (i.e., haloperidol, chlorpromazine, fluphenazine) are more commonly associated with NMS than second-generation antipsychotics [7]. Although, almost any medication that produces fulminant reductions in dopaminergic activity (either by blocking D2 receptors or abrupt withdrawal of D2 receptor stimulation) may cause suggestive symptoms [4-5]. Symptoms can arise from the initial introduction of antipsychotic therapy but have also been reported in patients with longstanding histories of neuroleptic use without incident [8]. Therefore, the duration of quetiapine therapy prior to the presentation should not be a deciding factor when considering NMS in a differential diagnosis. Quetiapine is commonly used off-label for sleep so even patients without known psychiatric histories may have the potential to develop the condition [9]. Coadministration of neuroleptics and selective serotonin reuptake inhibitors, such as in this patient suffering from depression with psychotic features, may increase the risk of developing NMS [10]. This calls particular attention to patients suffering from mixed depressive and psychotic disorders who may receive these medications concomitantly. At the same time, these patients are inherently predisposed to impulsivity and risk-taking behavior, such as suicide, by the virtue of their disease state [11-13]. Thus, patients with mixed depressive and psychotic disorders in the setting of overdose should prompt thorough medication reconciliation for NMS-inducing agents. The exact mechanism of NMS is not fully understood, but contemporary theories revolve around dopamine’s inhibitory effect on centrally and peripherally acting neuronal networks that may help explain presentations of NMS in the absence of fever and rigidity. The prevailing theory of NMS pathophysiology suggests a disruption of dopamine receptor antagonism, specifically within the hypothalamus, leading to hyperthermia and dysautonomia [14]. Similar involvement in the nigrostriatal pathways may explain rigidity and tremor associated with NMS considering this pathway is highly implicated with similar Parkinsonian manifestations [2,15]. Direct and indirect toxicity of offending agents to peripheral tissues, such as skeletal muscles, may influence mitochondrial function leading to hyperthermia secondary to muscle rigidity [16]. Lastly, dopamine’s regulatory influence on autonomic control may lead to heightened sympathetic activity impacting temperature control and muscle tone [16]. In each scenario, rigidity and hyperthermia seem to be directly correlated. This patient experienced moderate rigidity in the absence of fever, an atypical presentation, with a mild disease progression. Taken together, this information suggests that patients with NMS who are afebrile may also have the potential to lack significant muscle rigidity, further reducing a major symptom indicator for the presence of NMS. The timely diagnosis of NMS should be followed by the prompt discontinuation of inciting medication to prevent further symptom progression. The stage of NMS (mild, moderate, and severe) are used to inform the extent of supportive care and pharmacotherapy [17]. For instance, in this case, the patient’s symptoms were relatively mild, with acute renal failure that required close monitoring and muscle relaxers as needed, ultimately resolving over time. Progression to moderate or severe NMS in the presence of hyperpyrexia may warrant more intentional methods of cooling, with blankets or cooled saline. Severe cases may require direct muscle relaxers, such as dantrolene, or dopamine agonists such as bromocriptine. Monotherapy with dantrolene may actually increase mortality and should be avoided in patients with abnormal liver function due to increased risk of acute liver injury [18]. Once symptoms have resolved, approximately 30% of patients will experience a reoccurrence of symptoms [19]. Thus, it is important to slowly reintroduce an alternative antipsychotic medication in patients requiring therapy while remaining alert for signs and symptoms associated with this rare but serious condition. Conclusions Neuroleptic malignant syndrome (NMS) is a life-threatening condition requiring prompt identification and diagnosis with an array of potential presenting symptoms. Certain symptoms, such as fever and muscle rigidity, are highly characteristic of the condition, however, atypical presentations have occurred. This case serves to illustrate an attenuated and atypical presentation of NMS in the setting of overdose with the second-generation antipsychotic quetiapine. Future studies should examine whether a significant relationship exists between fever status and outcome in patients with NMS. The authors have declared that no competing interests exist. Human Ethics Consent was obtained by all participants in this study	30 mg (milligrams).	DrugDosage	CC BY	33585092	18,961,784	2021-01-10
What was the dosage of drug 'FLUOXETINE HYDROCHLORIDE'?	Atypical Neuroleptic Malignant Syndrome in the Setting of Quetiapine Overdose: A Case Report and Review of the Literature. Neuroleptic malignant syndrome (NMS) is a rare and life-threatening emergency. The condition is largely iatrogenic and is often precipitated by medications such as antipsychotics. First-generation antipsychotics are more likely to cause NMS than second-generation antipsychotics. The literature lacks an objective measure for NMS diagnosis. Instead, the diagnosis relies largely on the recognition of characteristic symptoms in the presence of an inciting medication. Additional challenges exist with concomitant disease processes and toxicities that may distort the clinical picture. Here, we report a case of a 44-year-old Caucasian man who presented with atypical NMS in the setting of quetiapine overdose. The patient remained uncharacteristically afebrile throughout his admission. Although the patient recovered, extended delays in identification and management can contribute to an increased risk of morbidity and mortality. Introduction Neuroleptic malignant syndrome (NMS) is a rare and potentially lethal constellation of symptoms [1-2]. Neuroleptic medications, particularly first-generation antipsychotics and certain antiemetics, have been shown to induce symptoms [3-5]. However, induction by second-generation antipsychotics, such as quetiapine, is less likely. Definitive diagnostic criteria do not exist for NMS, although hyperthermia, altered mental status, muscle rigidity, elevated creatine kinase (CK), and autonomic instability in the setting of newly introduced or increased doses of neuroleptic medications should prompt a high index of suspicion [3]. Unfortunately, not all cases of NMS present with hallmark signs and symptoms. NMS in the setting of alcohol or drug overdose can obfuscate the clinical picture. The risk of heightened morbidity and mortality requires prompt identification and persistent monitoring [3,5]. Here, we present a 44-year-old male with an atypical presentation of NMS in the setting of quetiapine overdose. Case presentation A 44-year-old Caucasian male with a past medical history pertinent for attention-deficit hyperactivity disorder and major depressive disorder with psychotic symptoms controlled with quetiapine (30 mg daily), fluoxetine (40 mg daily), and dextroamphetamine salts (30 mg daily) presented to the emergency department via ambulance after being found on the floor of his home. The patient has a known history of suicide attempts. Upon examination, the patient was obtunded, disheveled, speaking unintelligibly, and only responsive to tactile stimuli. The patient’s vital signs included a blood pressure of 119/83, pulse of 108, temperature of 96.6 F, respirations of 15, and oxygen saturation of 96% on room air. The patient was found in the presence of an empty bottle of quetiapine. His mother was unsure as to how long he had been on the floor. However, she advised that he might have consumed excessive amounts of alcohol the night before. Further workup revealed a urine toxicology screen positive for amphetamines and an elevated blood alcohol concentration (70 mg/dL; reference range 0-10 mg/dL). Acetaminophen and salicylate levels were within normal limits. Serology was remarkable for leukocytosis (15.8x10-3/uL; reference range 4.5-10.0x10-3/uL), a liver profile with slight elevation of aspartate transaminase (50 IU/uL; reference range 13-39 IU/L), and elevated lactate (8.04 mmol/L; reference range 0.90-1.70 mmol/L). Urinalysis was positive for a few bacteria and 2+ blood. A basic metabolic panel was impressive for hyperkalemia (l6.4 mEq/L; reference range 3.5-5.1 mEq/L) and elevated creatinine (2.6 mg/dL; reference range 0.60-1.30 mg/dL) in an otherwise healthy kidney. Phosphorus and phosphokinase were also elevated. Arterial blood gas revealed a high anion gap metabolic acidosis. A summary of the patient’s acute workup, with notable findings, can be found in Table 1. Table 1 Summary of Pertinent Laboratory Values at Time of Admission ABG = Arterial blood gas; CBC = Complete blood count; CMP = Comprehensive metabolic panel; UA = Urinalysis; S = Serology; T = Toxicology; H = Patient value above the upper limit of normal; N = Patient value within reference range; L = Patient value below the lower limit of normal Laboratory type Analyte Patient value Reference value T Amphetamines Positive Negative T Blood alcohol concentration 70.0 H 0.0-10.0 mg/dL CBC Leukocytes 15.8 x 10-3 H 4.5-10.0x10-3/uL CMP Aspartate transaminase (AST) 50 H 13-39 IU/L CMP Alanine aminotransferase (ALT) 22 N 7-52 IU/L CMP Lactate 8.04 H 0.90-1.70 mmol/L CMP Phosphorus 6.4 H 2.5-5.0 mg/dL CMP Creatinine 2.1 H 0.60-1.30 mg/dL ABG pH 7.452 H 7.350-7.450 ABG pCO2 25.0 L 35.0-45.0 mm Hg The patient was admitted to the internal medicine service with the working diagnosis of acute metabolic encephalopathy secondary to alcohol intoxication or amphetamine overdose with concomitant rhabdomyolysis. The patient was carefully monitored on an inpatient basis. By day two of admission, the patient's creatine kinase (CK) dramatically increased from 4,281 IU/L to 213,800 IU/L (reference range 30-223 IU/L). A longitudinal scatter plot of the patient’s CK over the course of admission is provided in Figure 1. Creatinine also increased despite fluid hydration. His mentation failed to improve, and he became aggressive, requiring physical restraints. The patient remained afebrile throughout his admission. He was persistently tachycardic with stable oxygen saturation (95%-100% on room air). Although the patient presented afebrile, all other signs and symptoms suggested NMS. The patient was transferred to the intensive care unit. Psychotropic medications were withheld, with the exception of lorazepam as needed for agitation. The patient’s normal basal temperature, mild muscle rigidity, and elevated liver enzymes precluded the use of dantrolene at that time. Figure 1 Longitudinal Creatine Kinase Levels During Admission Blue = Patient creatine kinase levels; Orange = Reference values Despite aggressive fluid resuscitation, the patient experienced acute renal failure with a creatinine increasing steadily from 2.10 mg/dL on admission to 7.2 mg/dL on day two (Figure 2). Other metabolic derangements were evident, including worsening metabolic acidosis and hyperkalemia. The patient underwent hemodialysis on post-admission day two and his clinical course improved without incident over the next 18 days. The patient was discharged requiring routine dialysis for the foreseeable future. Figure 2 Longitudinal Creatinine Levels During Admission Blue = Patient creatinine levels; Orange = Reference values Discussion Neuroleptic malignant syndrome (NMS) is a rare and life-threatening emergency leading to mortality in 30%-50% of unmanaged patients [3-4]. Prompt identification and continuous monitoring are necessary to reduce the risk of morbidity and mortality. Recognition can be challenging and complex, requiring careful consideration of symptoms that may overlap with a myriad of concomitant disease states. In this case, we report a middle-aged man presenting to the emergency department in an obtunded state. The patient had a prior history of suicide attempts and his past medical history was significant for depression with psychotic features controlled with more than one psychotropic medication. Although the totality of the circumstances suggested overdose toxicity, the patient’s symptoms were not fully characteristic of an overdose with any one of his prescription medications alone. Reports of quetiapine-induced NMS are limited, however, a case report analysis of 19 cases was conducted by Murri and colleagues, which revealed pooled clinical features with respect to quetiapine-induced NMS to include: 1) tachycardia, tachypnea, diaphoresis, and tremor in 100% of patients; 2) hyperpyrexia and rigidity in 92.3% of patients; 3) dysautonomia in 90% of patients; 4) mental status change in 85.7% of patients; and 5) fever in 78.9% patients [6]. Commensurate with this study, a set of diagnostic criteria proposed by Levenson in 1985 suggested similar features were characteristic of NMS and categorized them into major criteria (fever, rigidity, elevated creatine phosphokinase (CPK)) and minor criteria (tachycardia, abnormal arterial pressure, altered consciousness, diaphoresis, and leukocytosis) [2]. The presence of three major or two major and four minor signs suggests a high probability of NMS. In this case, the patient displayed moderate rigidity, elevated CPK, tachycardia, altered consciousness, leukocytosis, and abnormal arterial pressure, thereby satisfying two major and four minor criteria. However, these symptoms overlap with other more common conditions, such as malignant hyperthermia, in which full rigidity and mental status change are characteristic. Serotonin syndrome is also accompanied by similar symptoms, such as high fever, tachycardia, and confusion, while other well-reported entities, such as central nervous system (CNS) infections and toxins, can also be present in a similar manner and may complicate diagnosis and treatment [1,5]. Symptom onset and inciting medications can help identify or rule out NMS. For instance, NMS presents with an idiosyncratic onset, commonly developing between 24 hours and one month of newly introduced neuroleptic medication. Sixty-five percent of patients experience symptoms within one week, with a modicum of cases documenting symptoms within 24 hours [3]. First-generation antipsychotics (i.e., haloperidol, chlorpromazine, fluphenazine) are more commonly associated with NMS than second-generation antipsychotics [7]. Although, almost any medication that produces fulminant reductions in dopaminergic activity (either by blocking D2 receptors or abrupt withdrawal of D2 receptor stimulation) may cause suggestive symptoms [4-5]. Symptoms can arise from the initial introduction of antipsychotic therapy but have also been reported in patients with longstanding histories of neuroleptic use without incident [8]. Therefore, the duration of quetiapine therapy prior to the presentation should not be a deciding factor when considering NMS in a differential diagnosis. Quetiapine is commonly used off-label for sleep so even patients without known psychiatric histories may have the potential to develop the condition [9]. Coadministration of neuroleptics and selective serotonin reuptake inhibitors, such as in this patient suffering from depression with psychotic features, may increase the risk of developing NMS [10]. This calls particular attention to patients suffering from mixed depressive and psychotic disorders who may receive these medications concomitantly. At the same time, these patients are inherently predisposed to impulsivity and risk-taking behavior, such as suicide, by the virtue of their disease state [11-13]. Thus, patients with mixed depressive and psychotic disorders in the setting of overdose should prompt thorough medication reconciliation for NMS-inducing agents. The exact mechanism of NMS is not fully understood, but contemporary theories revolve around dopamine’s inhibitory effect on centrally and peripherally acting neuronal networks that may help explain presentations of NMS in the absence of fever and rigidity. The prevailing theory of NMS pathophysiology suggests a disruption of dopamine receptor antagonism, specifically within the hypothalamus, leading to hyperthermia and dysautonomia [14]. Similar involvement in the nigrostriatal pathways may explain rigidity and tremor associated with NMS considering this pathway is highly implicated with similar Parkinsonian manifestations [2,15]. Direct and indirect toxicity of offending agents to peripheral tissues, such as skeletal muscles, may influence mitochondrial function leading to hyperthermia secondary to muscle rigidity [16]. Lastly, dopamine’s regulatory influence on autonomic control may lead to heightened sympathetic activity impacting temperature control and muscle tone [16]. In each scenario, rigidity and hyperthermia seem to be directly correlated. This patient experienced moderate rigidity in the absence of fever, an atypical presentation, with a mild disease progression. Taken together, this information suggests that patients with NMS who are afebrile may also have the potential to lack significant muscle rigidity, further reducing a major symptom indicator for the presence of NMS. The timely diagnosis of NMS should be followed by the prompt discontinuation of inciting medication to prevent further symptom progression. The stage of NMS (mild, moderate, and severe) are used to inform the extent of supportive care and pharmacotherapy [17]. For instance, in this case, the patient’s symptoms were relatively mild, with acute renal failure that required close monitoring and muscle relaxers as needed, ultimately resolving over time. Progression to moderate or severe NMS in the presence of hyperpyrexia may warrant more intentional methods of cooling, with blankets or cooled saline. Severe cases may require direct muscle relaxers, such as dantrolene, or dopamine agonists such as bromocriptine. Monotherapy with dantrolene may actually increase mortality and should be avoided in patients with abnormal liver function due to increased risk of acute liver injury [18]. Once symptoms have resolved, approximately 30% of patients will experience a reoccurrence of symptoms [19]. Thus, it is important to slowly reintroduce an alternative antipsychotic medication in patients requiring therapy while remaining alert for signs and symptoms associated with this rare but serious condition. Conclusions Neuroleptic malignant syndrome (NMS) is a life-threatening condition requiring prompt identification and diagnosis with an array of potential presenting symptoms. Certain symptoms, such as fever and muscle rigidity, are highly characteristic of the condition, however, atypical presentations have occurred. This case serves to illustrate an attenuated and atypical presentation of NMS in the setting of overdose with the second-generation antipsychotic quetiapine. Future studies should examine whether a significant relationship exists between fever status and outcome in patients with NMS. The authors have declared that no competing interests exist. Human Ethics Consent was obtained by all participants in this study	40 mg (milligrams).	DrugDosage	CC BY	33585092	18,961,784	2021-01-10
What was the dosage of drug 'QUETIAPINE'?	Atypical Neuroleptic Malignant Syndrome in the Setting of Quetiapine Overdose: A Case Report and Review of the Literature. Neuroleptic malignant syndrome (NMS) is a rare and life-threatening emergency. The condition is largely iatrogenic and is often precipitated by medications such as antipsychotics. First-generation antipsychotics are more likely to cause NMS than second-generation antipsychotics. The literature lacks an objective measure for NMS diagnosis. Instead, the diagnosis relies largely on the recognition of characteristic symptoms in the presence of an inciting medication. Additional challenges exist with concomitant disease processes and toxicities that may distort the clinical picture. Here, we report a case of a 44-year-old Caucasian man who presented with atypical NMS in the setting of quetiapine overdose. The patient remained uncharacteristically afebrile throughout his admission. Although the patient recovered, extended delays in identification and management can contribute to an increased risk of morbidity and mortality. Introduction Neuroleptic malignant syndrome (NMS) is a rare and potentially lethal constellation of symptoms [1-2]. Neuroleptic medications, particularly first-generation antipsychotics and certain antiemetics, have been shown to induce symptoms [3-5]. However, induction by second-generation antipsychotics, such as quetiapine, is less likely. Definitive diagnostic criteria do not exist for NMS, although hyperthermia, altered mental status, muscle rigidity, elevated creatine kinase (CK), and autonomic instability in the setting of newly introduced or increased doses of neuroleptic medications should prompt a high index of suspicion [3]. Unfortunately, not all cases of NMS present with hallmark signs and symptoms. NMS in the setting of alcohol or drug overdose can obfuscate the clinical picture. The risk of heightened morbidity and mortality requires prompt identification and persistent monitoring [3,5]. Here, we present a 44-year-old male with an atypical presentation of NMS in the setting of quetiapine overdose. Case presentation A 44-year-old Caucasian male with a past medical history pertinent for attention-deficit hyperactivity disorder and major depressive disorder with psychotic symptoms controlled with quetiapine (30 mg daily), fluoxetine (40 mg daily), and dextroamphetamine salts (30 mg daily) presented to the emergency department via ambulance after being found on the floor of his home. The patient has a known history of suicide attempts. Upon examination, the patient was obtunded, disheveled, speaking unintelligibly, and only responsive to tactile stimuli. The patient’s vital signs included a blood pressure of 119/83, pulse of 108, temperature of 96.6 F, respirations of 15, and oxygen saturation of 96% on room air. The patient was found in the presence of an empty bottle of quetiapine. His mother was unsure as to how long he had been on the floor. However, she advised that he might have consumed excessive amounts of alcohol the night before. Further workup revealed a urine toxicology screen positive for amphetamines and an elevated blood alcohol concentration (70 mg/dL; reference range 0-10 mg/dL). Acetaminophen and salicylate levels were within normal limits. Serology was remarkable for leukocytosis (15.8x10-3/uL; reference range 4.5-10.0x10-3/uL), a liver profile with slight elevation of aspartate transaminase (50 IU/uL; reference range 13-39 IU/L), and elevated lactate (8.04 mmol/L; reference range 0.90-1.70 mmol/L). Urinalysis was positive for a few bacteria and 2+ blood. A basic metabolic panel was impressive for hyperkalemia (l6.4 mEq/L; reference range 3.5-5.1 mEq/L) and elevated creatinine (2.6 mg/dL; reference range 0.60-1.30 mg/dL) in an otherwise healthy kidney. Phosphorus and phosphokinase were also elevated. Arterial blood gas revealed a high anion gap metabolic acidosis. A summary of the patient’s acute workup, with notable findings, can be found in Table 1. Table 1 Summary of Pertinent Laboratory Values at Time of Admission ABG = Arterial blood gas; CBC = Complete blood count; CMP = Comprehensive metabolic panel; UA = Urinalysis; S = Serology; T = Toxicology; H = Patient value above the upper limit of normal; N = Patient value within reference range; L = Patient value below the lower limit of normal Laboratory type Analyte Patient value Reference value T Amphetamines Positive Negative T Blood alcohol concentration 70.0 H 0.0-10.0 mg/dL CBC Leukocytes 15.8 x 10-3 H 4.5-10.0x10-3/uL CMP Aspartate transaminase (AST) 50 H 13-39 IU/L CMP Alanine aminotransferase (ALT) 22 N 7-52 IU/L CMP Lactate 8.04 H 0.90-1.70 mmol/L CMP Phosphorus 6.4 H 2.5-5.0 mg/dL CMP Creatinine 2.1 H 0.60-1.30 mg/dL ABG pH 7.452 H 7.350-7.450 ABG pCO2 25.0 L 35.0-45.0 mm Hg The patient was admitted to the internal medicine service with the working diagnosis of acute metabolic encephalopathy secondary to alcohol intoxication or amphetamine overdose with concomitant rhabdomyolysis. The patient was carefully monitored on an inpatient basis. By day two of admission, the patient's creatine kinase (CK) dramatically increased from 4,281 IU/L to 213,800 IU/L (reference range 30-223 IU/L). A longitudinal scatter plot of the patient’s CK over the course of admission is provided in Figure 1. Creatinine also increased despite fluid hydration. His mentation failed to improve, and he became aggressive, requiring physical restraints. The patient remained afebrile throughout his admission. He was persistently tachycardic with stable oxygen saturation (95%-100% on room air). Although the patient presented afebrile, all other signs and symptoms suggested NMS. The patient was transferred to the intensive care unit. Psychotropic medications were withheld, with the exception of lorazepam as needed for agitation. The patient’s normal basal temperature, mild muscle rigidity, and elevated liver enzymes precluded the use of dantrolene at that time. Figure 1 Longitudinal Creatine Kinase Levels During Admission Blue = Patient creatine kinase levels; Orange = Reference values Despite aggressive fluid resuscitation, the patient experienced acute renal failure with a creatinine increasing steadily from 2.10 mg/dL on admission to 7.2 mg/dL on day two (Figure 2). Other metabolic derangements were evident, including worsening metabolic acidosis and hyperkalemia. The patient underwent hemodialysis on post-admission day two and his clinical course improved without incident over the next 18 days. The patient was discharged requiring routine dialysis for the foreseeable future. Figure 2 Longitudinal Creatinine Levels During Admission Blue = Patient creatinine levels; Orange = Reference values Discussion Neuroleptic malignant syndrome (NMS) is a rare and life-threatening emergency leading to mortality in 30%-50% of unmanaged patients [3-4]. Prompt identification and continuous monitoring are necessary to reduce the risk of morbidity and mortality. Recognition can be challenging and complex, requiring careful consideration of symptoms that may overlap with a myriad of concomitant disease states. In this case, we report a middle-aged man presenting to the emergency department in an obtunded state. The patient had a prior history of suicide attempts and his past medical history was significant for depression with psychotic features controlled with more than one psychotropic medication. Although the totality of the circumstances suggested overdose toxicity, the patient’s symptoms were not fully characteristic of an overdose with any one of his prescription medications alone. Reports of quetiapine-induced NMS are limited, however, a case report analysis of 19 cases was conducted by Murri and colleagues, which revealed pooled clinical features with respect to quetiapine-induced NMS to include: 1) tachycardia, tachypnea, diaphoresis, and tremor in 100% of patients; 2) hyperpyrexia and rigidity in 92.3% of patients; 3) dysautonomia in 90% of patients; 4) mental status change in 85.7% of patients; and 5) fever in 78.9% patients [6]. Commensurate with this study, a set of diagnostic criteria proposed by Levenson in 1985 suggested similar features were characteristic of NMS and categorized them into major criteria (fever, rigidity, elevated creatine phosphokinase (CPK)) and minor criteria (tachycardia, abnormal arterial pressure, altered consciousness, diaphoresis, and leukocytosis) [2]. The presence of three major or two major and four minor signs suggests a high probability of NMS. In this case, the patient displayed moderate rigidity, elevated CPK, tachycardia, altered consciousness, leukocytosis, and abnormal arterial pressure, thereby satisfying two major and four minor criteria. However, these symptoms overlap with other more common conditions, such as malignant hyperthermia, in which full rigidity and mental status change are characteristic. Serotonin syndrome is also accompanied by similar symptoms, such as high fever, tachycardia, and confusion, while other well-reported entities, such as central nervous system (CNS) infections and toxins, can also be present in a similar manner and may complicate diagnosis and treatment [1,5]. Symptom onset and inciting medications can help identify or rule out NMS. For instance, NMS presents with an idiosyncratic onset, commonly developing between 24 hours and one month of newly introduced neuroleptic medication. Sixty-five percent of patients experience symptoms within one week, with a modicum of cases documenting symptoms within 24 hours [3]. First-generation antipsychotics (i.e., haloperidol, chlorpromazine, fluphenazine) are more commonly associated with NMS than second-generation antipsychotics [7]. Although, almost any medication that produces fulminant reductions in dopaminergic activity (either by blocking D2 receptors or abrupt withdrawal of D2 receptor stimulation) may cause suggestive symptoms [4-5]. Symptoms can arise from the initial introduction of antipsychotic therapy but have also been reported in patients with longstanding histories of neuroleptic use without incident [8]. Therefore, the duration of quetiapine therapy prior to the presentation should not be a deciding factor when considering NMS in a differential diagnosis. Quetiapine is commonly used off-label for sleep so even patients without known psychiatric histories may have the potential to develop the condition [9]. Coadministration of neuroleptics and selective serotonin reuptake inhibitors, such as in this patient suffering from depression with psychotic features, may increase the risk of developing NMS [10]. This calls particular attention to patients suffering from mixed depressive and psychotic disorders who may receive these medications concomitantly. At the same time, these patients are inherently predisposed to impulsivity and risk-taking behavior, such as suicide, by the virtue of their disease state [11-13]. Thus, patients with mixed depressive and psychotic disorders in the setting of overdose should prompt thorough medication reconciliation for NMS-inducing agents. The exact mechanism of NMS is not fully understood, but contemporary theories revolve around dopamine’s inhibitory effect on centrally and peripherally acting neuronal networks that may help explain presentations of NMS in the absence of fever and rigidity. The prevailing theory of NMS pathophysiology suggests a disruption of dopamine receptor antagonism, specifically within the hypothalamus, leading to hyperthermia and dysautonomia [14]. Similar involvement in the nigrostriatal pathways may explain rigidity and tremor associated with NMS considering this pathway is highly implicated with similar Parkinsonian manifestations [2,15]. Direct and indirect toxicity of offending agents to peripheral tissues, such as skeletal muscles, may influence mitochondrial function leading to hyperthermia secondary to muscle rigidity [16]. Lastly, dopamine’s regulatory influence on autonomic control may lead to heightened sympathetic activity impacting temperature control and muscle tone [16]. In each scenario, rigidity and hyperthermia seem to be directly correlated. This patient experienced moderate rigidity in the absence of fever, an atypical presentation, with a mild disease progression. Taken together, this information suggests that patients with NMS who are afebrile may also have the potential to lack significant muscle rigidity, further reducing a major symptom indicator for the presence of NMS. The timely diagnosis of NMS should be followed by the prompt discontinuation of inciting medication to prevent further symptom progression. The stage of NMS (mild, moderate, and severe) are used to inform the extent of supportive care and pharmacotherapy [17]. For instance, in this case, the patient’s symptoms were relatively mild, with acute renal failure that required close monitoring and muscle relaxers as needed, ultimately resolving over time. Progression to moderate or severe NMS in the presence of hyperpyrexia may warrant more intentional methods of cooling, with blankets or cooled saline. Severe cases may require direct muscle relaxers, such as dantrolene, or dopamine agonists such as bromocriptine. Monotherapy with dantrolene may actually increase mortality and should be avoided in patients with abnormal liver function due to increased risk of acute liver injury [18]. Once symptoms have resolved, approximately 30% of patients will experience a reoccurrence of symptoms [19]. Thus, it is important to slowly reintroduce an alternative antipsychotic medication in patients requiring therapy while remaining alert for signs and symptoms associated with this rare but serious condition. Conclusions Neuroleptic malignant syndrome (NMS) is a life-threatening condition requiring prompt identification and diagnosis with an array of potential presenting symptoms. Certain symptoms, such as fever and muscle rigidity, are highly characteristic of the condition, however, atypical presentations have occurred. This case serves to illustrate an attenuated and atypical presentation of NMS in the setting of overdose with the second-generation antipsychotic quetiapine. Future studies should examine whether a significant relationship exists between fever status and outcome in patients with NMS. The authors have declared that no competing interests exist. Human Ethics Consent was obtained by all participants in this study	30 mg (milligrams).	DrugDosage	CC BY	33585092	18,961,784	2021-01-10
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Device related infection'.	Clinical utilization of long-acting granulocyte colony-stimulating factor (pegfilgrastim) prophylaxis in breast cancer patients with adjuvant docetaxel-cyclophosphamide chemotherapy. Treatment with 4 cycles of docetaxel and cyclophosphamide (TC) in the adjuvant setting is associated with better outcomes than treatment with doxorubicin and cyclophosphamide (AC). However, Western guidelines have indicated that TC confers a high risk (>20%) of febrile neutropenia (FN), while AC confers an intermediate risk (10%-20%) of FN. Threrefore, we evaluated the incidence of FN and the clinical utilization of pegfilgrastim prophylaxis after adjuvant TC chemotherapy. We categorized 201 patients who received adjuvant TC chemotherapy into 3 groups according to the method of prophylaxis and compared neutropenic events, other adverse events, and hospital care costs in the 3 groups. The incidence of grade 4 neutropenia decreased from 93.0% in patients without prophylaxis to 82.4% in those who received secondary prophylaxis and 16.7% in those who received primary prophylaxis. Although the incidence of FN was not different between patients without prophylaxis and patients who received secondary prophylaxis (15.7% and 14.9%), none of the patients who received primary prophylaxis developed FN. Moreover, a decrease in neutropenic events resulted in a significant decrease in the mean duration of neutropenia (2.50 days to 0.08 days, P < 0.001), the risk of hospitalization (29.8% to 2.2%, P < 0.001), and the mean total hospital care cost for all chemotherapy cycles (790.80 to 486.00 US dollars, P < 0.001). The use of pegfilgrastim prophylaxis during adjuvant TC chemotherapy is associated with significant decreases in the incidence of neutropenic events, hospitalization, and hospital care cost compared to those seen in patients without prophylaxis. INTRODUCTION Adjuvant chemotherapy for early-stage breast cancer (EBC) reduces recurrence rates and improves survival rates [1]. Among various adjuvant chemotherapy regimens, anthracycline-based chemotherapy remains the core of most adjuvant chemotherapy regimens for EBC. However, because cardiotoxicity and secondary leukemia have been associated with anthracycline-based regimens, the development of the adjuvant chemotherapy landscape for EBC is ongoing [234]. Since 2005, when studies suggested that taxane-based regimens without anthracycline might provide equivalent or superior results to anthracycline-based regimens [5], the use of anthracycline-based regimens has declined while the use of taxane-based regimens has increased among patients with breast cancer in the United States [6]. Previous studies indicate that taxane-based regimens have become the standard for adjuvant chemotherapy. Treatment with 4 cycles of docetaxel and cyclophosphamide (TC) in the adjuvant setting was shown to be associated with significant improvements in 5-year disease-free survival (DFS) and overall survival (OS) over doxorubicin and cyclophosphamide (AC) in a phase III randomized clinical trial [7]. After that, second-generation phase III trials demonstrated that survival outcomes for 6 cycles of TC and 4 cycles of epirubicin + cyclophosphamide followed by 4 cycles of docetaxel were equally excellent in human epidermal growth factor receptor (HER) 2-negative EBC with lower risk [89]. Thus, the TC regimen is attracting attention for adjuvant chemotherapy of EBC. Febrile neutropenia (FN) is a serious adverse effect encountered in patients undergoing myelosuppressive chemotherapy for EBC [10]. Because chemotherapy-induced FN is associated with life-threatening infections, prolonged hospitalization, increased health care costs, and modification of the dose or schedule of chemotherapy, it is critical to assess the risk of FN and prevent it with recombinant granulocyte colony-stimulating factor (G-CSF) in a myelosuppressive chemotherapy regimen [11]. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Hematopoietic Growth Factors indicate that TC confers a high risk (>20%) of FN and recommends the use of primary prophylactic G-CSF [12]. In a meta-analysis with 902 patients from 13 studies, the estimated rate of FN without primary G-CSF was 29.1%, while that with primary G-CSF prophylaxis was 6.8% for TC [13]. However, in an early phase III randomized clinical trial, treatment with 4 cycles of adjuvant TC was associated with a 5% risk of FN [5]. Moreover, in a randomized study conducted in Japan, treatment with 6 cycles of neoadjuvant TC was associated with a 13.8% risk of FN [14]. Considering the ethnic differences in hematologic toxicity and the absence of any Korean reports on FN risk after adjuvant TC chemotherapy, we evaluated the incidence of chemotherapy-related neutropenic events and other adverse events during adjuvant TC chemotherapy in Korean patients with EBC. Furthermore, we assessed the clinical utilization of primary or secondary prophylactic support with long-acting G-CSF (pegfilgrastim) in these patients. METHODS Study population This study was approved by the Institutional Review Board of The Catholic University of Korea, St. Vincent's Hospital (No. VC18RESI0162). Written informed consent was obtained from all patients. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The electronic medical records were reviewed for patients with EBC who received adjuvant TC chemotherapy from July 2015 to December 2019. In total, 209 consecutive patients who received adjuvant TC chemotherapy were included in this study. Eight patients, including 2 patients who did not complete adjuvant TC chemotherapy and 6 patients treated with neoadjuvant chemotherapy, were excluded to minimize other confounding factors. A total of 201 patients were included in the current study. We reviewed the patients' demographics and tumor characteristics, including age, body mass index (BMI [kg/m2]), body surface area (BSA [m2]), menopausal status, type of surgery, pathological T and N staging, histologic grade and type, hormone receptor (HR) and HER2 expression, and comorbidities. HR status was determined using an enzyme immunoassay and reported in the patients' medical records. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or silver in situ hybridization (SISH) was used to evaluate HER2 status, and an IHC score of 0 or +1 or an IHC score of +2 and negative FISH/SISH were defined as negative HER2 overexpression. Chemotherapy and use of granulocyte colony-stimulating factor All patients received a total of 4 cycles of TC chemotherapy, 3 weeks apart. In each cycle, docetaxel (75 mg/m2, intravenous [IV] for 1 hour) was initially administered, immediately followed by cyclophosphamide (600 mg/m2, IV for 1 hour). Secondary prophylaxis using pegfilgrastim (Neulasta, Amgen, Thousand Oaks, CA, USA) has been used in Korea since 2015, when it became covered by the National Health Insurance. Secondary prophylaxis with pegfilgrastim was defined as the use of G-CSF if a patient experienced a neutropenic event in the previous chemotherapy cycle. Primary prophylaxis using pegfilgrastim has been used in Korea since April 2018 with the approval of the National Health Insurance program. Pegfilgrastim was administered subcutaneously between 24 and 48 hours after the administration of chemotherapy. When not using pegfilgrastim, short-acting recombinant G-CSF (filgrastim) was administered daily after each cycle for grade 3 or 4 neutropenia until the absolute neutrophil count (ANC) was restored to 1,000/mm3. Laboratory tests, including complete blood cell (CBC) counts with differential and chemistry assays, were checked before each chemotherapy cycle and on day 6. After chemotherapy, baseline CBC counts were measured from day 6 until the ANC was restored to 1,000/mm3. All patients with FN received prophylactic antibiotic therapy comprising 1-g IV cefoperazone twice daily and 200-mg tobramycin sulfate once daily, unless contraindicated. Adverse events assessment The incidence of FN and FN-related complications according to the Common Terminology Criteria for Adverse Events (CTCAE, version 4.02) were investigated. FN was defined as neutropenia (grade 4 or grade 3 for over 48 hours) with a febrile event (oral temperature of ≥38.3℃, or ≥38.0℃ for over 1 hour) observed by medical staff. Dose reduction was defined as a reduction in the delivered dosage(s) of agent(s) administered relative to the standard values, and dose delay was defined as a chemotherapy interval of more than 21 days. The chemotherapy relative dose intensity (RDI) was estimated based on the ratio of delivered dose intensity and the reference standard dose intensity [15]. Total hospital care cost was calculated as the costs associated with all medical claims during the entire cycle or within each cycle. Outpatient hospital visit costs, hospitalization costs, chemotherapy costs, and G-CSF costs were all included in the total hospital care cost measure. The costs represented the reimbursed amount paid by the patient, as documented in the electronic medical record. Statistical analysis The chi-square test and Fisher exact test were used to determine differences in categorical variables between groups. The unpaired t-test and analysis of variance were used for comparison between continuous and independent variables that follow a normal distribution (age, BMI, BSA, RDI, recovery from neutropenia [days]). Continuous and independent variables that do not follow a normal distribution were analyzed using Mann-Whitney tests (weight gain [kg]). A P-value of <0.05 was considered to be statistically significant. The analyses were performed using PASW Statistics, ver. 18.0 for Windows (IBM Corp., Armonk, NY, USA). RESULTS Between July 2015 and December 2019, 201 Korean patients (804 cycles) with EBC who received adjuvant TC chemotherapy were included in the analysis. A total of 115 patients (57.2%) did not receive prophylaxis with pegfilgrastim, 74 (36.8%) received secondary prophylaxis, and 12 (6.0%) received primary prophylaxis with pegfilgrastim during adjuvant TC chemotherapy. The demographics and clinical characteristics of the study population by the method of prophylaxis with pegfilgrastim are shown in Table 1. Overall, the median age was 55 years (range, 21–79 years). A total of 37 patients (18.4%) were older than 65 years. The mean BMI and BSA were 24.71 ± 3.48 kg/m2 and 1.60 ± 0.13 m2, respectively. Patients who received primary prophylaxis had a significantly older median age at diagnosis than patients who did not receive prophylaxis or received secondary prophylaxis (P = 0.009). There were no significant differences in menopausal status, type of surgery, tumor stage, histologic grade, histologic type, comorbidity, or HR or HER2 status among the 3 groups (Table 1). Chemotherapy-related neutropenic events The combined incidence of grade 3 and 4 neutropenia was 3.5%, and 93.0% of patients did not receive prophylaxis with pegfilgrastim (Table 2). However, the incidence of grade 4 neutropenia decreased to 82.4% with secondary prophylaxis (P = 0.035) and 16.7% with primary prophylaxis (P < 0.001). In the analysis of 804 chemotherapy cycles, the incidence of grade 4 neutropenia was 74.6% in all cycles without prophylaxis and 5.3% in all cycles with prophylaxis with pegfilgrastim (P < 0.001) (Table 3). Moreover, the mean period of recovery from neutropenia was significantly shorter in chemotherapy cycles with prophylaxis with pegfilgrastim than in chemotherapy cycles without prophylaxis (2.50 ± 1.09 days vs . 0.08 ± 0.26 days, P < 0.001) (Table 3). The ANC changes after the chemotherapy cycle according to pegfilgrastim prophylaxis status are shown in Fig. 1. The incidence of FN was not significantly different between patients who did not receive prophylaxis and patients who received secondary prophylaxis (15.7% and 14.9%, P = 0.528) (Table 2). However, no patients who received primary prophylaxis with pegfilgrastim developed FN. Overall, FN occurred in 6.9% of all chemotherapy cycles without prophylaxis and 0.9% of all cycles with prophylaxis with pegfilgrastim (P < 0.001) (Table 3). Other chemotherapy-related adverse events Regarding hematologic toxicities other than neutropenia, there were no differences in the incidence of anemia, thrombocytopenia, and transfusion between patients who did not receive prophylaxis and patients with secondary prophylaxis (Table 2). These findings were the same when the results were analyzed by chemotherapy cycle (Table 3). There was no anemia or thrombocytopenia in patients who received primary prophylaxis. Moreover, the weight gained due to chemotherapy was less in patients who received primary prophylaxis than in the other 2 groups (Table 2). Among all patients who received TC chemotherapy, no patient experienced severe hepatotoxicity or nephrotoxicity. Among the 115 patients who did not receive prophylaxis with pegfilgrastim, 6 (5.2%) developed neutropenic infections, which included 2 patients with chemoport infection and 4 patients with wound infections. Among the 74 patients who received secondary prophylaxis, 5 (6.8%) developed neutropenic infections, which included 1 patient with a chemoport infection and 4 patients with wound infections. Among patients who received primary prophylaxis, there were no neutropenia-associated infections (Table 2). Although there were no significant differences in dose reduction (2.6% vs. 2.7%, P = 0.651) or treatment delay (3.5% vs. 1.4%, P = 0.078) between patients who did not receive prophylaxis and patients who received secondary prophylaxis, the RDI was lower in patients who did not receive prophylaxis than in those who received secondary prophylaxis (99.33% vs. 99.69%, respectively; P = 0.025). In patients who received primary prophylaxis, there was no association between treatment and dose reduction and treatment delay, and the RDI was 100% (Table 2). Compared with treatment without prophylaxis, patients who received secondary prophylaxis were not associated with a reduction in the risk of hospitalization (37.4% vs. 31.1%, P = 0.233), whereas primary prophylaxis was significantly associated with a reduction in the risk of hospitalization compared with the other 2 groups (37.4% vs . 8.3%, P = 0.038; 31.1% vs. 8.3%, P = 0.045) (Table 2). The incidence of hospitalization in each chemotherapy cycle was 29.8% in patients who did not receive prophylaxis and 2.2% in patients who received pegfilgrastim prophylaxis (P < 0.001) (Table 3). Hospital care cost The mean total hospital care cost for all chemotherapy cycles was greater for patients who did not receive prophylaxis than for patients who received secondary prophylaxis (790.80 US dollars [USD] vs. 728.40 USD, P = 0.008). In patients who received primary prophylaxis, the mean total hospital care cost for all chemotherapy cycles was 486.00 USD, and this cost was significantly lower than that for the other 2 groups (P < 0.001). In the analysis of each chemotherapy cycle, the mean hospital care cost for each chemotherapy cycle was significantly greater for patients who did not receive prophylaxis than for patients who received prophylactic pegfilgrastim (199.20 USD vs. 157.20 USD, P < 0.001). DISCUSSION In this study, we assessed the clinical effectiveness of pegfilgrastim prophylaxis in adjuvant TC chemotherapy by directly comparing the incidences of chemotherapy-related neutropenic events and other adverse events according to the method of prophylaxis in Korean EBC patients who received adjuvant TC chemotherapy. Primary prophylaxis with pegfilgrastim after adjuvant TC chemotherapy was significantly associated with a decrease in the incidence of chemotherapy-related neutropenic events, including FN, and the mean period of recovery from neutropenia, the risk of hospitalization, and the cost of hospital care for chemotherapy compared to those in patients who did not receive prophylaxis or who received secondary prophylaxis. With longer follow-up, 4 cycles of adjuvant TC chemotherapy showed a significant benefit over 4 cycles of AC chemotherapy in regard to DFS and OS and had a lower risk of anthracycline-related cardiac toxicity than the AC regimen [7]. Although the TC regimen has these clinical benefits over the AC regimen, the TC regimen results in a significantly higher incidence of chemotherapy-induced hematologic toxicities, such as neutropenia and FN, than the AC regimen [71316]. In a previous meta-analysis with 902 patients from 13 studies and with 2,532 patients from 14 studies, the estimated FN rates without primary G-CSF were 29.1% and 31.3% [1316]. Furthermore, the NCCN guidelines have indicated that TC confers a high risk (>20% chance of occurrence) of FN, while AC confers an intermediate risk (10%–20% chance) of FN [12]. However, the incidence of FN after adjuvant TC chemotherapy was not reported in more than 20% of all studies. The clinical trial conducted by the US Oncology Group reported a 5% FN incidence [5], and the West German Study PlanB trial reported a 6% FN incidence without primary prophylaxis [9]. In this study, the overall incidence rates of grade 4 neutropenia and FN were 93.0% and 15.7%, respectively, in patients who did not receive prophylaxis with pegfilgrastim after adjuvant TC chemotherapy. The incidence of grade 4 neutropenia in the present study was a significantly higher than that observed in previous studies conducted in Western countries (10.7%–50.8%) [5917]. However, the incidence of FN in the present study was rather low compared to that observed in 2 previous meta-analyses [1316]. Although it is difficult to explain the exact reason why the incidence rates of FN were low compared to those of the previous 2 meta-analyses and previous studies conducted in Western countries, ethnic differences in hematologic toxicity from docetaxel-based chemotherapy may be an important factor. The pharmacokinetics of docetaxel exhibit wide interindividual variability, which might lead to poor predictability of treatment-related side effects and outcomes [181920]. This variability of docetaxel pharmacokinetics or pharmacodynamics was also seen in a study conducted exclusively in Asian patients, including 103 Chinese, 111 Malay, and 73 Indian patients [19]. In a randomized study conducted in Japan, treatment with 6 cycles of neoadjuvant TC was associated with a 13.8% risk of FN [14]. Moreover, the incidence of FN was 25.2% for 4 cycles of the AC regimen and 4.7% for 4 cycles of the docetaxel regimen (75 or 100 mg/m2) in a Korean study on sequential AC and docetaxel chemotherapy [21]. The use of long-acting G-CSF results in better supportive care and improved quality of life in breast cancer patients by significantly reducing grade 4 neutropenia and FN [10111316]. In our study, the incidence of grade 4 neutropenia decreased from 93.0% to 16.7%, and the incidence of FN decreased from 15.7% to 0%, among all patients who received primary prophylactic pegfilgrastim. Moreover, a decrease in the incidence of grade 4 neutropenia and FN resulted in a significant decrease in the mean duration of neutropenia (from 2.50 days to 0.08 days), the risk of hospitalization (from 29.8% to 2.2%), and the mean total hospital care cost for all chemotherapy cycles (from 790.80 to 486.00 USD). The rate of hospitalization after the use of primary prophylactic pegfilgrastim in our current study was much lower than the rate of hospitalization adjusted for G-CSF primary prophylaxis observed in a previous study (6.7%–13.1%) [22]. Furthermore, the use of long-acting G-CSF results in the preservation of RDI, which is an important factor in achieving optimal survival outcomes after adjuvant chemotherapy. In this study, the RDI was significantly higher in patients who received primary prophylaxis than in patients who did not receive prophylactic pegfilgrastim (99.33% vs . 100%, P = 0.049). Although our current study did not analyze survival outcomes due to the short follow-up period, further studies with long-term follow-up will provide conclusions about improving survival outcomes with the use of long-acting G-CSF. Our study has some limitations, such as its retrospective nature. The number of patients was small because only patients who received adjuvant TC chemotherapy at a single institution were included. Moreover, decisions regarding hospitalization, dose reduction, and treatment delays were made based on our institutional treatment protocol. Additionally, only FN observed by medical staff was counted in the current study. Therefore, the incidence of FN may have been underestimated, as febrile events confirmed by the patient prior to the hospital visit were not included. However, we believe that this study has clinical value because it is the first study assessing the incidence of chemotherapy-related neutropenic events and other adverse events, and the clinical utilization of primary or secondary prophylactic support with long-acting G-CSF (pegfilgrastim) during adjuvant TC chemotherapy, in Korean patients with EBC. In summary, our study demonstrated that the overall incidence of grade 4 neutropenia, at 93.0%, was significantly higher than that observed in previous studies conducted in Western countries. Although the incidence of FN was 15.7%, rather low compared to that observed in the previous 2 meta-analyses, the use of pegfilgrastim prophylaxis during adjuvant TC chemotherapy was associated with significant decreases in the incidence of grade 4 neutropenia, FN, the risk of hospitalization, and the cost of hospital care for chemotherapy compared to no prophylaxis. Further large-scale prospective studies will help fill the gap in the evidence regarding FN risk and will thus inform the use of pegfilgrastim prophylaxis for this regimen in real-world practices. Fund/Grant Support: This research was sponsored by Kyowa Kirin Korea Co., Ltd. Conflicts of Interest: The authors declare that they have no conflict of interest. Author Contribution: Conceptualization: YWJ, YJS. Formal Analysis: YWJ, STL. Investigation: YWJ, SYP, JS, HSH. Methodology: YWJ, HG. Project Administration: YWJ. Writing — Original Draft: YWJ, STL, HG, SYP, JS, HSH. Writing — Review & Editing: YWJ, YJS. Fig. 1 The absolute neutrophil count (ANC) changes after chemotherapy according to the use of prophylaxis with pegfilgrastim. Table 1 Patient and tumor characteristics Values are presented as mean ± standard deviation (range) or number (%). ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2. Table 2 Comparison of chemotherapy-related neutropenia and other adverse events in all patients according to the method of prophylaxis Values are presented as number (%) or mean ± standard deviation unless otherwise specified. RDI, relative dose intensity. Table 3 Comparison of chemotherapy-related neutropenia and other adverse events in all chemotherapy cycles according to prophylaxis with pegfilgrastim Values are presented as number (%) or mean ± standard deviation.	CYCLOPHOSPHAMIDE, DOCETAXEL, PEGFILGRASTIM	DrugsGivenReaction	CC BY-NC	33585350	18,963,860	2021-02
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenic infection'.	Clinical utilization of long-acting granulocyte colony-stimulating factor (pegfilgrastim) prophylaxis in breast cancer patients with adjuvant docetaxel-cyclophosphamide chemotherapy. Treatment with 4 cycles of docetaxel and cyclophosphamide (TC) in the adjuvant setting is associated with better outcomes than treatment with doxorubicin and cyclophosphamide (AC). However, Western guidelines have indicated that TC confers a high risk (>20%) of febrile neutropenia (FN), while AC confers an intermediate risk (10%-20%) of FN. Threrefore, we evaluated the incidence of FN and the clinical utilization of pegfilgrastim prophylaxis after adjuvant TC chemotherapy. We categorized 201 patients who received adjuvant TC chemotherapy into 3 groups according to the method of prophylaxis and compared neutropenic events, other adverse events, and hospital care costs in the 3 groups. The incidence of grade 4 neutropenia decreased from 93.0% in patients without prophylaxis to 82.4% in those who received secondary prophylaxis and 16.7% in those who received primary prophylaxis. Although the incidence of FN was not different between patients without prophylaxis and patients who received secondary prophylaxis (15.7% and 14.9%), none of the patients who received primary prophylaxis developed FN. Moreover, a decrease in neutropenic events resulted in a significant decrease in the mean duration of neutropenia (2.50 days to 0.08 days, P < 0.001), the risk of hospitalization (29.8% to 2.2%, P < 0.001), and the mean total hospital care cost for all chemotherapy cycles (790.80 to 486.00 US dollars, P < 0.001). The use of pegfilgrastim prophylaxis during adjuvant TC chemotherapy is associated with significant decreases in the incidence of neutropenic events, hospitalization, and hospital care cost compared to those seen in patients without prophylaxis. INTRODUCTION Adjuvant chemotherapy for early-stage breast cancer (EBC) reduces recurrence rates and improves survival rates [1]. Among various adjuvant chemotherapy regimens, anthracycline-based chemotherapy remains the core of most adjuvant chemotherapy regimens for EBC. However, because cardiotoxicity and secondary leukemia have been associated with anthracycline-based regimens, the development of the adjuvant chemotherapy landscape for EBC is ongoing [234]. Since 2005, when studies suggested that taxane-based regimens without anthracycline might provide equivalent or superior results to anthracycline-based regimens [5], the use of anthracycline-based regimens has declined while the use of taxane-based regimens has increased among patients with breast cancer in the United States [6]. Previous studies indicate that taxane-based regimens have become the standard for adjuvant chemotherapy. Treatment with 4 cycles of docetaxel and cyclophosphamide (TC) in the adjuvant setting was shown to be associated with significant improvements in 5-year disease-free survival (DFS) and overall survival (OS) over doxorubicin and cyclophosphamide (AC) in a phase III randomized clinical trial [7]. After that, second-generation phase III trials demonstrated that survival outcomes for 6 cycles of TC and 4 cycles of epirubicin + cyclophosphamide followed by 4 cycles of docetaxel were equally excellent in human epidermal growth factor receptor (HER) 2-negative EBC with lower risk [89]. Thus, the TC regimen is attracting attention for adjuvant chemotherapy of EBC. Febrile neutropenia (FN) is a serious adverse effect encountered in patients undergoing myelosuppressive chemotherapy for EBC [10]. Because chemotherapy-induced FN is associated with life-threatening infections, prolonged hospitalization, increased health care costs, and modification of the dose or schedule of chemotherapy, it is critical to assess the risk of FN and prevent it with recombinant granulocyte colony-stimulating factor (G-CSF) in a myelosuppressive chemotherapy regimen [11]. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Hematopoietic Growth Factors indicate that TC confers a high risk (>20%) of FN and recommends the use of primary prophylactic G-CSF [12]. In a meta-analysis with 902 patients from 13 studies, the estimated rate of FN without primary G-CSF was 29.1%, while that with primary G-CSF prophylaxis was 6.8% for TC [13]. However, in an early phase III randomized clinical trial, treatment with 4 cycles of adjuvant TC was associated with a 5% risk of FN [5]. Moreover, in a randomized study conducted in Japan, treatment with 6 cycles of neoadjuvant TC was associated with a 13.8% risk of FN [14]. Considering the ethnic differences in hematologic toxicity and the absence of any Korean reports on FN risk after adjuvant TC chemotherapy, we evaluated the incidence of chemotherapy-related neutropenic events and other adverse events during adjuvant TC chemotherapy in Korean patients with EBC. Furthermore, we assessed the clinical utilization of primary or secondary prophylactic support with long-acting G-CSF (pegfilgrastim) in these patients. METHODS Study population This study was approved by the Institutional Review Board of The Catholic University of Korea, St. Vincent's Hospital (No. VC18RESI0162). Written informed consent was obtained from all patients. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The electronic medical records were reviewed for patients with EBC who received adjuvant TC chemotherapy from July 2015 to December 2019. In total, 209 consecutive patients who received adjuvant TC chemotherapy were included in this study. Eight patients, including 2 patients who did not complete adjuvant TC chemotherapy and 6 patients treated with neoadjuvant chemotherapy, were excluded to minimize other confounding factors. A total of 201 patients were included in the current study. We reviewed the patients' demographics and tumor characteristics, including age, body mass index (BMI [kg/m2]), body surface area (BSA [m2]), menopausal status, type of surgery, pathological T and N staging, histologic grade and type, hormone receptor (HR) and HER2 expression, and comorbidities. HR status was determined using an enzyme immunoassay and reported in the patients' medical records. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or silver in situ hybridization (SISH) was used to evaluate HER2 status, and an IHC score of 0 or +1 or an IHC score of +2 and negative FISH/SISH were defined as negative HER2 overexpression. Chemotherapy and use of granulocyte colony-stimulating factor All patients received a total of 4 cycles of TC chemotherapy, 3 weeks apart. In each cycle, docetaxel (75 mg/m2, intravenous [IV] for 1 hour) was initially administered, immediately followed by cyclophosphamide (600 mg/m2, IV for 1 hour). Secondary prophylaxis using pegfilgrastim (Neulasta, Amgen, Thousand Oaks, CA, USA) has been used in Korea since 2015, when it became covered by the National Health Insurance. Secondary prophylaxis with pegfilgrastim was defined as the use of G-CSF if a patient experienced a neutropenic event in the previous chemotherapy cycle. Primary prophylaxis using pegfilgrastim has been used in Korea since April 2018 with the approval of the National Health Insurance program. Pegfilgrastim was administered subcutaneously between 24 and 48 hours after the administration of chemotherapy. When not using pegfilgrastim, short-acting recombinant G-CSF (filgrastim) was administered daily after each cycle for grade 3 or 4 neutropenia until the absolute neutrophil count (ANC) was restored to 1,000/mm3. Laboratory tests, including complete blood cell (CBC) counts with differential and chemistry assays, were checked before each chemotherapy cycle and on day 6. After chemotherapy, baseline CBC counts were measured from day 6 until the ANC was restored to 1,000/mm3. All patients with FN received prophylactic antibiotic therapy comprising 1-g IV cefoperazone twice daily and 200-mg tobramycin sulfate once daily, unless contraindicated. Adverse events assessment The incidence of FN and FN-related complications according to the Common Terminology Criteria for Adverse Events (CTCAE, version 4.02) were investigated. FN was defined as neutropenia (grade 4 or grade 3 for over 48 hours) with a febrile event (oral temperature of ≥38.3℃, or ≥38.0℃ for over 1 hour) observed by medical staff. Dose reduction was defined as a reduction in the delivered dosage(s) of agent(s) administered relative to the standard values, and dose delay was defined as a chemotherapy interval of more than 21 days. The chemotherapy relative dose intensity (RDI) was estimated based on the ratio of delivered dose intensity and the reference standard dose intensity [15]. Total hospital care cost was calculated as the costs associated with all medical claims during the entire cycle or within each cycle. Outpatient hospital visit costs, hospitalization costs, chemotherapy costs, and G-CSF costs were all included in the total hospital care cost measure. The costs represented the reimbursed amount paid by the patient, as documented in the electronic medical record. Statistical analysis The chi-square test and Fisher exact test were used to determine differences in categorical variables between groups. The unpaired t-test and analysis of variance were used for comparison between continuous and independent variables that follow a normal distribution (age, BMI, BSA, RDI, recovery from neutropenia [days]). Continuous and independent variables that do not follow a normal distribution were analyzed using Mann-Whitney tests (weight gain [kg]). A P-value of <0.05 was considered to be statistically significant. The analyses were performed using PASW Statistics, ver. 18.0 for Windows (IBM Corp., Armonk, NY, USA). RESULTS Between July 2015 and December 2019, 201 Korean patients (804 cycles) with EBC who received adjuvant TC chemotherapy were included in the analysis. A total of 115 patients (57.2%) did not receive prophylaxis with pegfilgrastim, 74 (36.8%) received secondary prophylaxis, and 12 (6.0%) received primary prophylaxis with pegfilgrastim during adjuvant TC chemotherapy. The demographics and clinical characteristics of the study population by the method of prophylaxis with pegfilgrastim are shown in Table 1. Overall, the median age was 55 years (range, 21–79 years). A total of 37 patients (18.4%) were older than 65 years. The mean BMI and BSA were 24.71 ± 3.48 kg/m2 and 1.60 ± 0.13 m2, respectively. Patients who received primary prophylaxis had a significantly older median age at diagnosis than patients who did not receive prophylaxis or received secondary prophylaxis (P = 0.009). There were no significant differences in menopausal status, type of surgery, tumor stage, histologic grade, histologic type, comorbidity, or HR or HER2 status among the 3 groups (Table 1). Chemotherapy-related neutropenic events The combined incidence of grade 3 and 4 neutropenia was 3.5%, and 93.0% of patients did not receive prophylaxis with pegfilgrastim (Table 2). However, the incidence of grade 4 neutropenia decreased to 82.4% with secondary prophylaxis (P = 0.035) and 16.7% with primary prophylaxis (P < 0.001). In the analysis of 804 chemotherapy cycles, the incidence of grade 4 neutropenia was 74.6% in all cycles without prophylaxis and 5.3% in all cycles with prophylaxis with pegfilgrastim (P < 0.001) (Table 3). Moreover, the mean period of recovery from neutropenia was significantly shorter in chemotherapy cycles with prophylaxis with pegfilgrastim than in chemotherapy cycles without prophylaxis (2.50 ± 1.09 days vs . 0.08 ± 0.26 days, P < 0.001) (Table 3). The ANC changes after the chemotherapy cycle according to pegfilgrastim prophylaxis status are shown in Fig. 1. The incidence of FN was not significantly different between patients who did not receive prophylaxis and patients who received secondary prophylaxis (15.7% and 14.9%, P = 0.528) (Table 2). However, no patients who received primary prophylaxis with pegfilgrastim developed FN. Overall, FN occurred in 6.9% of all chemotherapy cycles without prophylaxis and 0.9% of all cycles with prophylaxis with pegfilgrastim (P < 0.001) (Table 3). Other chemotherapy-related adverse events Regarding hematologic toxicities other than neutropenia, there were no differences in the incidence of anemia, thrombocytopenia, and transfusion between patients who did not receive prophylaxis and patients with secondary prophylaxis (Table 2). These findings were the same when the results were analyzed by chemotherapy cycle (Table 3). There was no anemia or thrombocytopenia in patients who received primary prophylaxis. Moreover, the weight gained due to chemotherapy was less in patients who received primary prophylaxis than in the other 2 groups (Table 2). Among all patients who received TC chemotherapy, no patient experienced severe hepatotoxicity or nephrotoxicity. Among the 115 patients who did not receive prophylaxis with pegfilgrastim, 6 (5.2%) developed neutropenic infections, which included 2 patients with chemoport infection and 4 patients with wound infections. Among the 74 patients who received secondary prophylaxis, 5 (6.8%) developed neutropenic infections, which included 1 patient with a chemoport infection and 4 patients with wound infections. Among patients who received primary prophylaxis, there were no neutropenia-associated infections (Table 2). Although there were no significant differences in dose reduction (2.6% vs. 2.7%, P = 0.651) or treatment delay (3.5% vs. 1.4%, P = 0.078) between patients who did not receive prophylaxis and patients who received secondary prophylaxis, the RDI was lower in patients who did not receive prophylaxis than in those who received secondary prophylaxis (99.33% vs. 99.69%, respectively; P = 0.025). In patients who received primary prophylaxis, there was no association between treatment and dose reduction and treatment delay, and the RDI was 100% (Table 2). Compared with treatment without prophylaxis, patients who received secondary prophylaxis were not associated with a reduction in the risk of hospitalization (37.4% vs. 31.1%, P = 0.233), whereas primary prophylaxis was significantly associated with a reduction in the risk of hospitalization compared with the other 2 groups (37.4% vs . 8.3%, P = 0.038; 31.1% vs. 8.3%, P = 0.045) (Table 2). The incidence of hospitalization in each chemotherapy cycle was 29.8% in patients who did not receive prophylaxis and 2.2% in patients who received pegfilgrastim prophylaxis (P < 0.001) (Table 3). Hospital care cost The mean total hospital care cost for all chemotherapy cycles was greater for patients who did not receive prophylaxis than for patients who received secondary prophylaxis (790.80 US dollars [USD] vs. 728.40 USD, P = 0.008). In patients who received primary prophylaxis, the mean total hospital care cost for all chemotherapy cycles was 486.00 USD, and this cost was significantly lower than that for the other 2 groups (P < 0.001). In the analysis of each chemotherapy cycle, the mean hospital care cost for each chemotherapy cycle was significantly greater for patients who did not receive prophylaxis than for patients who received prophylactic pegfilgrastim (199.20 USD vs. 157.20 USD, P < 0.001). DISCUSSION In this study, we assessed the clinical effectiveness of pegfilgrastim prophylaxis in adjuvant TC chemotherapy by directly comparing the incidences of chemotherapy-related neutropenic events and other adverse events according to the method of prophylaxis in Korean EBC patients who received adjuvant TC chemotherapy. Primary prophylaxis with pegfilgrastim after adjuvant TC chemotherapy was significantly associated with a decrease in the incidence of chemotherapy-related neutropenic events, including FN, and the mean period of recovery from neutropenia, the risk of hospitalization, and the cost of hospital care for chemotherapy compared to those in patients who did not receive prophylaxis or who received secondary prophylaxis. With longer follow-up, 4 cycles of adjuvant TC chemotherapy showed a significant benefit over 4 cycles of AC chemotherapy in regard to DFS and OS and had a lower risk of anthracycline-related cardiac toxicity than the AC regimen [7]. Although the TC regimen has these clinical benefits over the AC regimen, the TC regimen results in a significantly higher incidence of chemotherapy-induced hematologic toxicities, such as neutropenia and FN, than the AC regimen [71316]. In a previous meta-analysis with 902 patients from 13 studies and with 2,532 patients from 14 studies, the estimated FN rates without primary G-CSF were 29.1% and 31.3% [1316]. Furthermore, the NCCN guidelines have indicated that TC confers a high risk (>20% chance of occurrence) of FN, while AC confers an intermediate risk (10%–20% chance) of FN [12]. However, the incidence of FN after adjuvant TC chemotherapy was not reported in more than 20% of all studies. The clinical trial conducted by the US Oncology Group reported a 5% FN incidence [5], and the West German Study PlanB trial reported a 6% FN incidence without primary prophylaxis [9]. In this study, the overall incidence rates of grade 4 neutropenia and FN were 93.0% and 15.7%, respectively, in patients who did not receive prophylaxis with pegfilgrastim after adjuvant TC chemotherapy. The incidence of grade 4 neutropenia in the present study was a significantly higher than that observed in previous studies conducted in Western countries (10.7%–50.8%) [5917]. However, the incidence of FN in the present study was rather low compared to that observed in 2 previous meta-analyses [1316]. Although it is difficult to explain the exact reason why the incidence rates of FN were low compared to those of the previous 2 meta-analyses and previous studies conducted in Western countries, ethnic differences in hematologic toxicity from docetaxel-based chemotherapy may be an important factor. The pharmacokinetics of docetaxel exhibit wide interindividual variability, which might lead to poor predictability of treatment-related side effects and outcomes [181920]. This variability of docetaxel pharmacokinetics or pharmacodynamics was also seen in a study conducted exclusively in Asian patients, including 103 Chinese, 111 Malay, and 73 Indian patients [19]. In a randomized study conducted in Japan, treatment with 6 cycles of neoadjuvant TC was associated with a 13.8% risk of FN [14]. Moreover, the incidence of FN was 25.2% for 4 cycles of the AC regimen and 4.7% for 4 cycles of the docetaxel regimen (75 or 100 mg/m2) in a Korean study on sequential AC and docetaxel chemotherapy [21]. The use of long-acting G-CSF results in better supportive care and improved quality of life in breast cancer patients by significantly reducing grade 4 neutropenia and FN [10111316]. In our study, the incidence of grade 4 neutropenia decreased from 93.0% to 16.7%, and the incidence of FN decreased from 15.7% to 0%, among all patients who received primary prophylactic pegfilgrastim. Moreover, a decrease in the incidence of grade 4 neutropenia and FN resulted in a significant decrease in the mean duration of neutropenia (from 2.50 days to 0.08 days), the risk of hospitalization (from 29.8% to 2.2%), and the mean total hospital care cost for all chemotherapy cycles (from 790.80 to 486.00 USD). The rate of hospitalization after the use of primary prophylactic pegfilgrastim in our current study was much lower than the rate of hospitalization adjusted for G-CSF primary prophylaxis observed in a previous study (6.7%–13.1%) [22]. Furthermore, the use of long-acting G-CSF results in the preservation of RDI, which is an important factor in achieving optimal survival outcomes after adjuvant chemotherapy. In this study, the RDI was significantly higher in patients who received primary prophylaxis than in patients who did not receive prophylactic pegfilgrastim (99.33% vs . 100%, P = 0.049). Although our current study did not analyze survival outcomes due to the short follow-up period, further studies with long-term follow-up will provide conclusions about improving survival outcomes with the use of long-acting G-CSF. Our study has some limitations, such as its retrospective nature. The number of patients was small because only patients who received adjuvant TC chemotherapy at a single institution were included. Moreover, decisions regarding hospitalization, dose reduction, and treatment delays were made based on our institutional treatment protocol. Additionally, only FN observed by medical staff was counted in the current study. Therefore, the incidence of FN may have been underestimated, as febrile events confirmed by the patient prior to the hospital visit were not included. However, we believe that this study has clinical value because it is the first study assessing the incidence of chemotherapy-related neutropenic events and other adverse events, and the clinical utilization of primary or secondary prophylactic support with long-acting G-CSF (pegfilgrastim) during adjuvant TC chemotherapy, in Korean patients with EBC. In summary, our study demonstrated that the overall incidence of grade 4 neutropenia, at 93.0%, was significantly higher than that observed in previous studies conducted in Western countries. Although the incidence of FN was 15.7%, rather low compared to that observed in the previous 2 meta-analyses, the use of pegfilgrastim prophylaxis during adjuvant TC chemotherapy was associated with significant decreases in the incidence of grade 4 neutropenia, FN, the risk of hospitalization, and the cost of hospital care for chemotherapy compared to no prophylaxis. Further large-scale prospective studies will help fill the gap in the evidence regarding FN risk and will thus inform the use of pegfilgrastim prophylaxis for this regimen in real-world practices. Fund/Grant Support: This research was sponsored by Kyowa Kirin Korea Co., Ltd. Conflicts of Interest: The authors declare that they have no conflict of interest. Author Contribution: Conceptualization: YWJ, YJS. Formal Analysis: YWJ, STL. Investigation: YWJ, SYP, JS, HSH. Methodology: YWJ, HG. Project Administration: YWJ. Writing — Original Draft: YWJ, STL, HG, SYP, JS, HSH. Writing — Review & Editing: YWJ, YJS. Fig. 1 The absolute neutrophil count (ANC) changes after chemotherapy according to the use of prophylaxis with pegfilgrastim. Table 1 Patient and tumor characteristics Values are presented as mean ± standard deviation (range) or number (%). ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2. Table 2 Comparison of chemotherapy-related neutropenia and other adverse events in all patients according to the method of prophylaxis Values are presented as number (%) or mean ± standard deviation unless otherwise specified. RDI, relative dose intensity. Table 3 Comparison of chemotherapy-related neutropenia and other adverse events in all chemotherapy cycles according to prophylaxis with pegfilgrastim Values are presented as number (%) or mean ± standard deviation.	CYCLOPHOSPHAMIDE, DOCETAXEL, PEGFILGRASTIM	DrugsGivenReaction	CC BY-NC	33585350	18,963,860	2021-02
What was the administration route of drug 'CYCLOPHOSPHAMIDE'?	Clinical utilization of long-acting granulocyte colony-stimulating factor (pegfilgrastim) prophylaxis in breast cancer patients with adjuvant docetaxel-cyclophosphamide chemotherapy. Treatment with 4 cycles of docetaxel and cyclophosphamide (TC) in the adjuvant setting is associated with better outcomes than treatment with doxorubicin and cyclophosphamide (AC). However, Western guidelines have indicated that TC confers a high risk (>20%) of febrile neutropenia (FN), while AC confers an intermediate risk (10%-20%) of FN. Threrefore, we evaluated the incidence of FN and the clinical utilization of pegfilgrastim prophylaxis after adjuvant TC chemotherapy. We categorized 201 patients who received adjuvant TC chemotherapy into 3 groups according to the method of prophylaxis and compared neutropenic events, other adverse events, and hospital care costs in the 3 groups. The incidence of grade 4 neutropenia decreased from 93.0% in patients without prophylaxis to 82.4% in those who received secondary prophylaxis and 16.7% in those who received primary prophylaxis. Although the incidence of FN was not different between patients without prophylaxis and patients who received secondary prophylaxis (15.7% and 14.9%), none of the patients who received primary prophylaxis developed FN. Moreover, a decrease in neutropenic events resulted in a significant decrease in the mean duration of neutropenia (2.50 days to 0.08 days, P < 0.001), the risk of hospitalization (29.8% to 2.2%, P < 0.001), and the mean total hospital care cost for all chemotherapy cycles (790.80 to 486.00 US dollars, P < 0.001). The use of pegfilgrastim prophylaxis during adjuvant TC chemotherapy is associated with significant decreases in the incidence of neutropenic events, hospitalization, and hospital care cost compared to those seen in patients without prophylaxis. INTRODUCTION Adjuvant chemotherapy for early-stage breast cancer (EBC) reduces recurrence rates and improves survival rates [1]. Among various adjuvant chemotherapy regimens, anthracycline-based chemotherapy remains the core of most adjuvant chemotherapy regimens for EBC. However, because cardiotoxicity and secondary leukemia have been associated with anthracycline-based regimens, the development of the adjuvant chemotherapy landscape for EBC is ongoing [234]. Since 2005, when studies suggested that taxane-based regimens without anthracycline might provide equivalent or superior results to anthracycline-based regimens [5], the use of anthracycline-based regimens has declined while the use of taxane-based regimens has increased among patients with breast cancer in the United States [6]. Previous studies indicate that taxane-based regimens have become the standard for adjuvant chemotherapy. Treatment with 4 cycles of docetaxel and cyclophosphamide (TC) in the adjuvant setting was shown to be associated with significant improvements in 5-year disease-free survival (DFS) and overall survival (OS) over doxorubicin and cyclophosphamide (AC) in a phase III randomized clinical trial [7]. After that, second-generation phase III trials demonstrated that survival outcomes for 6 cycles of TC and 4 cycles of epirubicin + cyclophosphamide followed by 4 cycles of docetaxel were equally excellent in human epidermal growth factor receptor (HER) 2-negative EBC with lower risk [89]. Thus, the TC regimen is attracting attention for adjuvant chemotherapy of EBC. Febrile neutropenia (FN) is a serious adverse effect encountered in patients undergoing myelosuppressive chemotherapy for EBC [10]. Because chemotherapy-induced FN is associated with life-threatening infections, prolonged hospitalization, increased health care costs, and modification of the dose or schedule of chemotherapy, it is critical to assess the risk of FN and prevent it with recombinant granulocyte colony-stimulating factor (G-CSF) in a myelosuppressive chemotherapy regimen [11]. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Hematopoietic Growth Factors indicate that TC confers a high risk (>20%) of FN and recommends the use of primary prophylactic G-CSF [12]. In a meta-analysis with 902 patients from 13 studies, the estimated rate of FN without primary G-CSF was 29.1%, while that with primary G-CSF prophylaxis was 6.8% for TC [13]. However, in an early phase III randomized clinical trial, treatment with 4 cycles of adjuvant TC was associated with a 5% risk of FN [5]. Moreover, in a randomized study conducted in Japan, treatment with 6 cycles of neoadjuvant TC was associated with a 13.8% risk of FN [14]. Considering the ethnic differences in hematologic toxicity and the absence of any Korean reports on FN risk after adjuvant TC chemotherapy, we evaluated the incidence of chemotherapy-related neutropenic events and other adverse events during adjuvant TC chemotherapy in Korean patients with EBC. Furthermore, we assessed the clinical utilization of primary or secondary prophylactic support with long-acting G-CSF (pegfilgrastim) in these patients. METHODS Study population This study was approved by the Institutional Review Board of The Catholic University of Korea, St. Vincent's Hospital (No. VC18RESI0162). Written informed consent was obtained from all patients. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The electronic medical records were reviewed for patients with EBC who received adjuvant TC chemotherapy from July 2015 to December 2019. In total, 209 consecutive patients who received adjuvant TC chemotherapy were included in this study. Eight patients, including 2 patients who did not complete adjuvant TC chemotherapy and 6 patients treated with neoadjuvant chemotherapy, were excluded to minimize other confounding factors. A total of 201 patients were included in the current study. We reviewed the patients' demographics and tumor characteristics, including age, body mass index (BMI [kg/m2]), body surface area (BSA [m2]), menopausal status, type of surgery, pathological T and N staging, histologic grade and type, hormone receptor (HR) and HER2 expression, and comorbidities. HR status was determined using an enzyme immunoassay and reported in the patients' medical records. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or silver in situ hybridization (SISH) was used to evaluate HER2 status, and an IHC score of 0 or +1 or an IHC score of +2 and negative FISH/SISH were defined as negative HER2 overexpression. Chemotherapy and use of granulocyte colony-stimulating factor All patients received a total of 4 cycles of TC chemotherapy, 3 weeks apart. In each cycle, docetaxel (75 mg/m2, intravenous [IV] for 1 hour) was initially administered, immediately followed by cyclophosphamide (600 mg/m2, IV for 1 hour). Secondary prophylaxis using pegfilgrastim (Neulasta, Amgen, Thousand Oaks, CA, USA) has been used in Korea since 2015, when it became covered by the National Health Insurance. Secondary prophylaxis with pegfilgrastim was defined as the use of G-CSF if a patient experienced a neutropenic event in the previous chemotherapy cycle. Primary prophylaxis using pegfilgrastim has been used in Korea since April 2018 with the approval of the National Health Insurance program. Pegfilgrastim was administered subcutaneously between 24 and 48 hours after the administration of chemotherapy. When not using pegfilgrastim, short-acting recombinant G-CSF (filgrastim) was administered daily after each cycle for grade 3 or 4 neutropenia until the absolute neutrophil count (ANC) was restored to 1,000/mm3. Laboratory tests, including complete blood cell (CBC) counts with differential and chemistry assays, were checked before each chemotherapy cycle and on day 6. After chemotherapy, baseline CBC counts were measured from day 6 until the ANC was restored to 1,000/mm3. All patients with FN received prophylactic antibiotic therapy comprising 1-g IV cefoperazone twice daily and 200-mg tobramycin sulfate once daily, unless contraindicated. Adverse events assessment The incidence of FN and FN-related complications according to the Common Terminology Criteria for Adverse Events (CTCAE, version 4.02) were investigated. FN was defined as neutropenia (grade 4 or grade 3 for over 48 hours) with a febrile event (oral temperature of ≥38.3℃, or ≥38.0℃ for over 1 hour) observed by medical staff. Dose reduction was defined as a reduction in the delivered dosage(s) of agent(s) administered relative to the standard values, and dose delay was defined as a chemotherapy interval of more than 21 days. The chemotherapy relative dose intensity (RDI) was estimated based on the ratio of delivered dose intensity and the reference standard dose intensity [15]. Total hospital care cost was calculated as the costs associated with all medical claims during the entire cycle or within each cycle. Outpatient hospital visit costs, hospitalization costs, chemotherapy costs, and G-CSF costs were all included in the total hospital care cost measure. The costs represented the reimbursed amount paid by the patient, as documented in the electronic medical record. Statistical analysis The chi-square test and Fisher exact test were used to determine differences in categorical variables between groups. The unpaired t-test and analysis of variance were used for comparison between continuous and independent variables that follow a normal distribution (age, BMI, BSA, RDI, recovery from neutropenia [days]). Continuous and independent variables that do not follow a normal distribution were analyzed using Mann-Whitney tests (weight gain [kg]). A P-value of <0.05 was considered to be statistically significant. The analyses were performed using PASW Statistics, ver. 18.0 for Windows (IBM Corp., Armonk, NY, USA). RESULTS Between July 2015 and December 2019, 201 Korean patients (804 cycles) with EBC who received adjuvant TC chemotherapy were included in the analysis. A total of 115 patients (57.2%) did not receive prophylaxis with pegfilgrastim, 74 (36.8%) received secondary prophylaxis, and 12 (6.0%) received primary prophylaxis with pegfilgrastim during adjuvant TC chemotherapy. The demographics and clinical characteristics of the study population by the method of prophylaxis with pegfilgrastim are shown in Table 1. Overall, the median age was 55 years (range, 21–79 years). A total of 37 patients (18.4%) were older than 65 years. The mean BMI and BSA were 24.71 ± 3.48 kg/m2 and 1.60 ± 0.13 m2, respectively. Patients who received primary prophylaxis had a significantly older median age at diagnosis than patients who did not receive prophylaxis or received secondary prophylaxis (P = 0.009). There were no significant differences in menopausal status, type of surgery, tumor stage, histologic grade, histologic type, comorbidity, or HR or HER2 status among the 3 groups (Table 1). Chemotherapy-related neutropenic events The combined incidence of grade 3 and 4 neutropenia was 3.5%, and 93.0% of patients did not receive prophylaxis with pegfilgrastim (Table 2). However, the incidence of grade 4 neutropenia decreased to 82.4% with secondary prophylaxis (P = 0.035) and 16.7% with primary prophylaxis (P < 0.001). In the analysis of 804 chemotherapy cycles, the incidence of grade 4 neutropenia was 74.6% in all cycles without prophylaxis and 5.3% in all cycles with prophylaxis with pegfilgrastim (P < 0.001) (Table 3). Moreover, the mean period of recovery from neutropenia was significantly shorter in chemotherapy cycles with prophylaxis with pegfilgrastim than in chemotherapy cycles without prophylaxis (2.50 ± 1.09 days vs . 0.08 ± 0.26 days, P < 0.001) (Table 3). The ANC changes after the chemotherapy cycle according to pegfilgrastim prophylaxis status are shown in Fig. 1. The incidence of FN was not significantly different between patients who did not receive prophylaxis and patients who received secondary prophylaxis (15.7% and 14.9%, P = 0.528) (Table 2). However, no patients who received primary prophylaxis with pegfilgrastim developed FN. Overall, FN occurred in 6.9% of all chemotherapy cycles without prophylaxis and 0.9% of all cycles with prophylaxis with pegfilgrastim (P < 0.001) (Table 3). Other chemotherapy-related adverse events Regarding hematologic toxicities other than neutropenia, there were no differences in the incidence of anemia, thrombocytopenia, and transfusion between patients who did not receive prophylaxis and patients with secondary prophylaxis (Table 2). These findings were the same when the results were analyzed by chemotherapy cycle (Table 3). There was no anemia or thrombocytopenia in patients who received primary prophylaxis. Moreover, the weight gained due to chemotherapy was less in patients who received primary prophylaxis than in the other 2 groups (Table 2). Among all patients who received TC chemotherapy, no patient experienced severe hepatotoxicity or nephrotoxicity. Among the 115 patients who did not receive prophylaxis with pegfilgrastim, 6 (5.2%) developed neutropenic infections, which included 2 patients with chemoport infection and 4 patients with wound infections. Among the 74 patients who received secondary prophylaxis, 5 (6.8%) developed neutropenic infections, which included 1 patient with a chemoport infection and 4 patients with wound infections. Among patients who received primary prophylaxis, there were no neutropenia-associated infections (Table 2). Although there were no significant differences in dose reduction (2.6% vs. 2.7%, P = 0.651) or treatment delay (3.5% vs. 1.4%, P = 0.078) between patients who did not receive prophylaxis and patients who received secondary prophylaxis, the RDI was lower in patients who did not receive prophylaxis than in those who received secondary prophylaxis (99.33% vs. 99.69%, respectively; P = 0.025). In patients who received primary prophylaxis, there was no association between treatment and dose reduction and treatment delay, and the RDI was 100% (Table 2). Compared with treatment without prophylaxis, patients who received secondary prophylaxis were not associated with a reduction in the risk of hospitalization (37.4% vs. 31.1%, P = 0.233), whereas primary prophylaxis was significantly associated with a reduction in the risk of hospitalization compared with the other 2 groups (37.4% vs . 8.3%, P = 0.038; 31.1% vs. 8.3%, P = 0.045) (Table 2). The incidence of hospitalization in each chemotherapy cycle was 29.8% in patients who did not receive prophylaxis and 2.2% in patients who received pegfilgrastim prophylaxis (P < 0.001) (Table 3). Hospital care cost The mean total hospital care cost for all chemotherapy cycles was greater for patients who did not receive prophylaxis than for patients who received secondary prophylaxis (790.80 US dollars [USD] vs. 728.40 USD, P = 0.008). In patients who received primary prophylaxis, the mean total hospital care cost for all chemotherapy cycles was 486.00 USD, and this cost was significantly lower than that for the other 2 groups (P < 0.001). In the analysis of each chemotherapy cycle, the mean hospital care cost for each chemotherapy cycle was significantly greater for patients who did not receive prophylaxis than for patients who received prophylactic pegfilgrastim (199.20 USD vs. 157.20 USD, P < 0.001). DISCUSSION In this study, we assessed the clinical effectiveness of pegfilgrastim prophylaxis in adjuvant TC chemotherapy by directly comparing the incidences of chemotherapy-related neutropenic events and other adverse events according to the method of prophylaxis in Korean EBC patients who received adjuvant TC chemotherapy. Primary prophylaxis with pegfilgrastim after adjuvant TC chemotherapy was significantly associated with a decrease in the incidence of chemotherapy-related neutropenic events, including FN, and the mean period of recovery from neutropenia, the risk of hospitalization, and the cost of hospital care for chemotherapy compared to those in patients who did not receive prophylaxis or who received secondary prophylaxis. With longer follow-up, 4 cycles of adjuvant TC chemotherapy showed a significant benefit over 4 cycles of AC chemotherapy in regard to DFS and OS and had a lower risk of anthracycline-related cardiac toxicity than the AC regimen [7]. Although the TC regimen has these clinical benefits over the AC regimen, the TC regimen results in a significantly higher incidence of chemotherapy-induced hematologic toxicities, such as neutropenia and FN, than the AC regimen [71316]. In a previous meta-analysis with 902 patients from 13 studies and with 2,532 patients from 14 studies, the estimated FN rates without primary G-CSF were 29.1% and 31.3% [1316]. Furthermore, the NCCN guidelines have indicated that TC confers a high risk (>20% chance of occurrence) of FN, while AC confers an intermediate risk (10%–20% chance) of FN [12]. However, the incidence of FN after adjuvant TC chemotherapy was not reported in more than 20% of all studies. The clinical trial conducted by the US Oncology Group reported a 5% FN incidence [5], and the West German Study PlanB trial reported a 6% FN incidence without primary prophylaxis [9]. In this study, the overall incidence rates of grade 4 neutropenia and FN were 93.0% and 15.7%, respectively, in patients who did not receive prophylaxis with pegfilgrastim after adjuvant TC chemotherapy. The incidence of grade 4 neutropenia in the present study was a significantly higher than that observed in previous studies conducted in Western countries (10.7%–50.8%) [5917]. However, the incidence of FN in the present study was rather low compared to that observed in 2 previous meta-analyses [1316]. Although it is difficult to explain the exact reason why the incidence rates of FN were low compared to those of the previous 2 meta-analyses and previous studies conducted in Western countries, ethnic differences in hematologic toxicity from docetaxel-based chemotherapy may be an important factor. The pharmacokinetics of docetaxel exhibit wide interindividual variability, which might lead to poor predictability of treatment-related side effects and outcomes [181920]. This variability of docetaxel pharmacokinetics or pharmacodynamics was also seen in a study conducted exclusively in Asian patients, including 103 Chinese, 111 Malay, and 73 Indian patients [19]. In a randomized study conducted in Japan, treatment with 6 cycles of neoadjuvant TC was associated with a 13.8% risk of FN [14]. Moreover, the incidence of FN was 25.2% for 4 cycles of the AC regimen and 4.7% for 4 cycles of the docetaxel regimen (75 or 100 mg/m2) in a Korean study on sequential AC and docetaxel chemotherapy [21]. The use of long-acting G-CSF results in better supportive care and improved quality of life in breast cancer patients by significantly reducing grade 4 neutropenia and FN [10111316]. In our study, the incidence of grade 4 neutropenia decreased from 93.0% to 16.7%, and the incidence of FN decreased from 15.7% to 0%, among all patients who received primary prophylactic pegfilgrastim. Moreover, a decrease in the incidence of grade 4 neutropenia and FN resulted in a significant decrease in the mean duration of neutropenia (from 2.50 days to 0.08 days), the risk of hospitalization (from 29.8% to 2.2%), and the mean total hospital care cost for all chemotherapy cycles (from 790.80 to 486.00 USD). The rate of hospitalization after the use of primary prophylactic pegfilgrastim in our current study was much lower than the rate of hospitalization adjusted for G-CSF primary prophylaxis observed in a previous study (6.7%–13.1%) [22]. Furthermore, the use of long-acting G-CSF results in the preservation of RDI, which is an important factor in achieving optimal survival outcomes after adjuvant chemotherapy. In this study, the RDI was significantly higher in patients who received primary prophylaxis than in patients who did not receive prophylactic pegfilgrastim (99.33% vs . 100%, P = 0.049). Although our current study did not analyze survival outcomes due to the short follow-up period, further studies with long-term follow-up will provide conclusions about improving survival outcomes with the use of long-acting G-CSF. Our study has some limitations, such as its retrospective nature. The number of patients was small because only patients who received adjuvant TC chemotherapy at a single institution were included. Moreover, decisions regarding hospitalization, dose reduction, and treatment delays were made based on our institutional treatment protocol. Additionally, only FN observed by medical staff was counted in the current study. Therefore, the incidence of FN may have been underestimated, as febrile events confirmed by the patient prior to the hospital visit were not included. However, we believe that this study has clinical value because it is the first study assessing the incidence of chemotherapy-related neutropenic events and other adverse events, and the clinical utilization of primary or secondary prophylactic support with long-acting G-CSF (pegfilgrastim) during adjuvant TC chemotherapy, in Korean patients with EBC. In summary, our study demonstrated that the overall incidence of grade 4 neutropenia, at 93.0%, was significantly higher than that observed in previous studies conducted in Western countries. Although the incidence of FN was 15.7%, rather low compared to that observed in the previous 2 meta-analyses, the use of pegfilgrastim prophylaxis during adjuvant TC chemotherapy was associated with significant decreases in the incidence of grade 4 neutropenia, FN, the risk of hospitalization, and the cost of hospital care for chemotherapy compared to no prophylaxis. Further large-scale prospective studies will help fill the gap in the evidence regarding FN risk and will thus inform the use of pegfilgrastim prophylaxis for this regimen in real-world practices. Fund/Grant Support: This research was sponsored by Kyowa Kirin Korea Co., Ltd. Conflicts of Interest: The authors declare that they have no conflict of interest. Author Contribution: Conceptualization: YWJ, YJS. Formal Analysis: YWJ, STL. Investigation: YWJ, SYP, JS, HSH. Methodology: YWJ, HG. Project Administration: YWJ. Writing — Original Draft: YWJ, STL, HG, SYP, JS, HSH. Writing — Review & Editing: YWJ, YJS. Fig. 1 The absolute neutrophil count (ANC) changes after chemotherapy according to the use of prophylaxis with pegfilgrastim. Table 1 Patient and tumor characteristics Values are presented as mean ± standard deviation (range) or number (%). ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2. Table 2 Comparison of chemotherapy-related neutropenia and other adverse events in all patients according to the method of prophylaxis Values are presented as number (%) or mean ± standard deviation unless otherwise specified. RDI, relative dose intensity. Table 3 Comparison of chemotherapy-related neutropenia and other adverse events in all chemotherapy cycles according to prophylaxis with pegfilgrastim Values are presented as number (%) or mean ± standard deviation.	Intravenous (not otherwise specified)	DrugAdministrationRoute	CC BY-NC	33585350	18,963,860	2021-02
What was the administration route of drug 'DOCETAXEL'?	Clinical utilization of long-acting granulocyte colony-stimulating factor (pegfilgrastim) prophylaxis in breast cancer patients with adjuvant docetaxel-cyclophosphamide chemotherapy. Treatment with 4 cycles of docetaxel and cyclophosphamide (TC) in the adjuvant setting is associated with better outcomes than treatment with doxorubicin and cyclophosphamide (AC). However, Western guidelines have indicated that TC confers a high risk (>20%) of febrile neutropenia (FN), while AC confers an intermediate risk (10%-20%) of FN. Threrefore, we evaluated the incidence of FN and the clinical utilization of pegfilgrastim prophylaxis after adjuvant TC chemotherapy. We categorized 201 patients who received adjuvant TC chemotherapy into 3 groups according to the method of prophylaxis and compared neutropenic events, other adverse events, and hospital care costs in the 3 groups. The incidence of grade 4 neutropenia decreased from 93.0% in patients without prophylaxis to 82.4% in those who received secondary prophylaxis and 16.7% in those who received primary prophylaxis. Although the incidence of FN was not different between patients without prophylaxis and patients who received secondary prophylaxis (15.7% and 14.9%), none of the patients who received primary prophylaxis developed FN. Moreover, a decrease in neutropenic events resulted in a significant decrease in the mean duration of neutropenia (2.50 days to 0.08 days, P < 0.001), the risk of hospitalization (29.8% to 2.2%, P < 0.001), and the mean total hospital care cost for all chemotherapy cycles (790.80 to 486.00 US dollars, P < 0.001). The use of pegfilgrastim prophylaxis during adjuvant TC chemotherapy is associated with significant decreases in the incidence of neutropenic events, hospitalization, and hospital care cost compared to those seen in patients without prophylaxis. INTRODUCTION Adjuvant chemotherapy for early-stage breast cancer (EBC) reduces recurrence rates and improves survival rates [1]. Among various adjuvant chemotherapy regimens, anthracycline-based chemotherapy remains the core of most adjuvant chemotherapy regimens for EBC. However, because cardiotoxicity and secondary leukemia have been associated with anthracycline-based regimens, the development of the adjuvant chemotherapy landscape for EBC is ongoing [234]. Since 2005, when studies suggested that taxane-based regimens without anthracycline might provide equivalent or superior results to anthracycline-based regimens [5], the use of anthracycline-based regimens has declined while the use of taxane-based regimens has increased among patients with breast cancer in the United States [6]. Previous studies indicate that taxane-based regimens have become the standard for adjuvant chemotherapy. Treatment with 4 cycles of docetaxel and cyclophosphamide (TC) in the adjuvant setting was shown to be associated with significant improvements in 5-year disease-free survival (DFS) and overall survival (OS) over doxorubicin and cyclophosphamide (AC) in a phase III randomized clinical trial [7]. After that, second-generation phase III trials demonstrated that survival outcomes for 6 cycles of TC and 4 cycles of epirubicin + cyclophosphamide followed by 4 cycles of docetaxel were equally excellent in human epidermal growth factor receptor (HER) 2-negative EBC with lower risk [89]. Thus, the TC regimen is attracting attention for adjuvant chemotherapy of EBC. Febrile neutropenia (FN) is a serious adverse effect encountered in patients undergoing myelosuppressive chemotherapy for EBC [10]. Because chemotherapy-induced FN is associated with life-threatening infections, prolonged hospitalization, increased health care costs, and modification of the dose or schedule of chemotherapy, it is critical to assess the risk of FN and prevent it with recombinant granulocyte colony-stimulating factor (G-CSF) in a myelosuppressive chemotherapy regimen [11]. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Hematopoietic Growth Factors indicate that TC confers a high risk (>20%) of FN and recommends the use of primary prophylactic G-CSF [12]. In a meta-analysis with 902 patients from 13 studies, the estimated rate of FN without primary G-CSF was 29.1%, while that with primary G-CSF prophylaxis was 6.8% for TC [13]. However, in an early phase III randomized clinical trial, treatment with 4 cycles of adjuvant TC was associated with a 5% risk of FN [5]. Moreover, in a randomized study conducted in Japan, treatment with 6 cycles of neoadjuvant TC was associated with a 13.8% risk of FN [14]. Considering the ethnic differences in hematologic toxicity and the absence of any Korean reports on FN risk after adjuvant TC chemotherapy, we evaluated the incidence of chemotherapy-related neutropenic events and other adverse events during adjuvant TC chemotherapy in Korean patients with EBC. Furthermore, we assessed the clinical utilization of primary or secondary prophylactic support with long-acting G-CSF (pegfilgrastim) in these patients. METHODS Study population This study was approved by the Institutional Review Board of The Catholic University of Korea, St. Vincent's Hospital (No. VC18RESI0162). Written informed consent was obtained from all patients. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The electronic medical records were reviewed for patients with EBC who received adjuvant TC chemotherapy from July 2015 to December 2019. In total, 209 consecutive patients who received adjuvant TC chemotherapy were included in this study. Eight patients, including 2 patients who did not complete adjuvant TC chemotherapy and 6 patients treated with neoadjuvant chemotherapy, were excluded to minimize other confounding factors. A total of 201 patients were included in the current study. We reviewed the patients' demographics and tumor characteristics, including age, body mass index (BMI [kg/m2]), body surface area (BSA [m2]), menopausal status, type of surgery, pathological T and N staging, histologic grade and type, hormone receptor (HR) and HER2 expression, and comorbidities. HR status was determined using an enzyme immunoassay and reported in the patients' medical records. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or silver in situ hybridization (SISH) was used to evaluate HER2 status, and an IHC score of 0 or +1 or an IHC score of +2 and negative FISH/SISH were defined as negative HER2 overexpression. Chemotherapy and use of granulocyte colony-stimulating factor All patients received a total of 4 cycles of TC chemotherapy, 3 weeks apart. In each cycle, docetaxel (75 mg/m2, intravenous [IV] for 1 hour) was initially administered, immediately followed by cyclophosphamide (600 mg/m2, IV for 1 hour). Secondary prophylaxis using pegfilgrastim (Neulasta, Amgen, Thousand Oaks, CA, USA) has been used in Korea since 2015, when it became covered by the National Health Insurance. Secondary prophylaxis with pegfilgrastim was defined as the use of G-CSF if a patient experienced a neutropenic event in the previous chemotherapy cycle. Primary prophylaxis using pegfilgrastim has been used in Korea since April 2018 with the approval of the National Health Insurance program. Pegfilgrastim was administered subcutaneously between 24 and 48 hours after the administration of chemotherapy. When not using pegfilgrastim, short-acting recombinant G-CSF (filgrastim) was administered daily after each cycle for grade 3 or 4 neutropenia until the absolute neutrophil count (ANC) was restored to 1,000/mm3. Laboratory tests, including complete blood cell (CBC) counts with differential and chemistry assays, were checked before each chemotherapy cycle and on day 6. After chemotherapy, baseline CBC counts were measured from day 6 until the ANC was restored to 1,000/mm3. All patients with FN received prophylactic antibiotic therapy comprising 1-g IV cefoperazone twice daily and 200-mg tobramycin sulfate once daily, unless contraindicated. Adverse events assessment The incidence of FN and FN-related complications according to the Common Terminology Criteria for Adverse Events (CTCAE, version 4.02) were investigated. FN was defined as neutropenia (grade 4 or grade 3 for over 48 hours) with a febrile event (oral temperature of ≥38.3℃, or ≥38.0℃ for over 1 hour) observed by medical staff. Dose reduction was defined as a reduction in the delivered dosage(s) of agent(s) administered relative to the standard values, and dose delay was defined as a chemotherapy interval of more than 21 days. The chemotherapy relative dose intensity (RDI) was estimated based on the ratio of delivered dose intensity and the reference standard dose intensity [15]. Total hospital care cost was calculated as the costs associated with all medical claims during the entire cycle or within each cycle. Outpatient hospital visit costs, hospitalization costs, chemotherapy costs, and G-CSF costs were all included in the total hospital care cost measure. The costs represented the reimbursed amount paid by the patient, as documented in the electronic medical record. Statistical analysis The chi-square test and Fisher exact test were used to determine differences in categorical variables between groups. The unpaired t-test and analysis of variance were used for comparison between continuous and independent variables that follow a normal distribution (age, BMI, BSA, RDI, recovery from neutropenia [days]). Continuous and independent variables that do not follow a normal distribution were analyzed using Mann-Whitney tests (weight gain [kg]). A P-value of <0.05 was considered to be statistically significant. The analyses were performed using PASW Statistics, ver. 18.0 for Windows (IBM Corp., Armonk, NY, USA). RESULTS Between July 2015 and December 2019, 201 Korean patients (804 cycles) with EBC who received adjuvant TC chemotherapy were included in the analysis. A total of 115 patients (57.2%) did not receive prophylaxis with pegfilgrastim, 74 (36.8%) received secondary prophylaxis, and 12 (6.0%) received primary prophylaxis with pegfilgrastim during adjuvant TC chemotherapy. The demographics and clinical characteristics of the study population by the method of prophylaxis with pegfilgrastim are shown in Table 1. Overall, the median age was 55 years (range, 21–79 years). A total of 37 patients (18.4%) were older than 65 years. The mean BMI and BSA were 24.71 ± 3.48 kg/m2 and 1.60 ± 0.13 m2, respectively. Patients who received primary prophylaxis had a significantly older median age at diagnosis than patients who did not receive prophylaxis or received secondary prophylaxis (P = 0.009). There were no significant differences in menopausal status, type of surgery, tumor stage, histologic grade, histologic type, comorbidity, or HR or HER2 status among the 3 groups (Table 1). Chemotherapy-related neutropenic events The combined incidence of grade 3 and 4 neutropenia was 3.5%, and 93.0% of patients did not receive prophylaxis with pegfilgrastim (Table 2). However, the incidence of grade 4 neutropenia decreased to 82.4% with secondary prophylaxis (P = 0.035) and 16.7% with primary prophylaxis (P < 0.001). In the analysis of 804 chemotherapy cycles, the incidence of grade 4 neutropenia was 74.6% in all cycles without prophylaxis and 5.3% in all cycles with prophylaxis with pegfilgrastim (P < 0.001) (Table 3). Moreover, the mean period of recovery from neutropenia was significantly shorter in chemotherapy cycles with prophylaxis with pegfilgrastim than in chemotherapy cycles without prophylaxis (2.50 ± 1.09 days vs . 0.08 ± 0.26 days, P < 0.001) (Table 3). The ANC changes after the chemotherapy cycle according to pegfilgrastim prophylaxis status are shown in Fig. 1. The incidence of FN was not significantly different between patients who did not receive prophylaxis and patients who received secondary prophylaxis (15.7% and 14.9%, P = 0.528) (Table 2). However, no patients who received primary prophylaxis with pegfilgrastim developed FN. Overall, FN occurred in 6.9% of all chemotherapy cycles without prophylaxis and 0.9% of all cycles with prophylaxis with pegfilgrastim (P < 0.001) (Table 3). Other chemotherapy-related adverse events Regarding hematologic toxicities other than neutropenia, there were no differences in the incidence of anemia, thrombocytopenia, and transfusion between patients who did not receive prophylaxis and patients with secondary prophylaxis (Table 2). These findings were the same when the results were analyzed by chemotherapy cycle (Table 3). There was no anemia or thrombocytopenia in patients who received primary prophylaxis. Moreover, the weight gained due to chemotherapy was less in patients who received primary prophylaxis than in the other 2 groups (Table 2). Among all patients who received TC chemotherapy, no patient experienced severe hepatotoxicity or nephrotoxicity. Among the 115 patients who did not receive prophylaxis with pegfilgrastim, 6 (5.2%) developed neutropenic infections, which included 2 patients with chemoport infection and 4 patients with wound infections. Among the 74 patients who received secondary prophylaxis, 5 (6.8%) developed neutropenic infections, which included 1 patient with a chemoport infection and 4 patients with wound infections. Among patients who received primary prophylaxis, there were no neutropenia-associated infections (Table 2). Although there were no significant differences in dose reduction (2.6% vs. 2.7%, P = 0.651) or treatment delay (3.5% vs. 1.4%, P = 0.078) between patients who did not receive prophylaxis and patients who received secondary prophylaxis, the RDI was lower in patients who did not receive prophylaxis than in those who received secondary prophylaxis (99.33% vs. 99.69%, respectively; P = 0.025). In patients who received primary prophylaxis, there was no association between treatment and dose reduction and treatment delay, and the RDI was 100% (Table 2). Compared with treatment without prophylaxis, patients who received secondary prophylaxis were not associated with a reduction in the risk of hospitalization (37.4% vs. 31.1%, P = 0.233), whereas primary prophylaxis was significantly associated with a reduction in the risk of hospitalization compared with the other 2 groups (37.4% vs . 8.3%, P = 0.038; 31.1% vs. 8.3%, P = 0.045) (Table 2). The incidence of hospitalization in each chemotherapy cycle was 29.8% in patients who did not receive prophylaxis and 2.2% in patients who received pegfilgrastim prophylaxis (P < 0.001) (Table 3). Hospital care cost The mean total hospital care cost for all chemotherapy cycles was greater for patients who did not receive prophylaxis than for patients who received secondary prophylaxis (790.80 US dollars [USD] vs. 728.40 USD, P = 0.008). In patients who received primary prophylaxis, the mean total hospital care cost for all chemotherapy cycles was 486.00 USD, and this cost was significantly lower than that for the other 2 groups (P < 0.001). In the analysis of each chemotherapy cycle, the mean hospital care cost for each chemotherapy cycle was significantly greater for patients who did not receive prophylaxis than for patients who received prophylactic pegfilgrastim (199.20 USD vs. 157.20 USD, P < 0.001). DISCUSSION In this study, we assessed the clinical effectiveness of pegfilgrastim prophylaxis in adjuvant TC chemotherapy by directly comparing the incidences of chemotherapy-related neutropenic events and other adverse events according to the method of prophylaxis in Korean EBC patients who received adjuvant TC chemotherapy. Primary prophylaxis with pegfilgrastim after adjuvant TC chemotherapy was significantly associated with a decrease in the incidence of chemotherapy-related neutropenic events, including FN, and the mean period of recovery from neutropenia, the risk of hospitalization, and the cost of hospital care for chemotherapy compared to those in patients who did not receive prophylaxis or who received secondary prophylaxis. With longer follow-up, 4 cycles of adjuvant TC chemotherapy showed a significant benefit over 4 cycles of AC chemotherapy in regard to DFS and OS and had a lower risk of anthracycline-related cardiac toxicity than the AC regimen [7]. Although the TC regimen has these clinical benefits over the AC regimen, the TC regimen results in a significantly higher incidence of chemotherapy-induced hematologic toxicities, such as neutropenia and FN, than the AC regimen [71316]. In a previous meta-analysis with 902 patients from 13 studies and with 2,532 patients from 14 studies, the estimated FN rates without primary G-CSF were 29.1% and 31.3% [1316]. Furthermore, the NCCN guidelines have indicated that TC confers a high risk (>20% chance of occurrence) of FN, while AC confers an intermediate risk (10%–20% chance) of FN [12]. However, the incidence of FN after adjuvant TC chemotherapy was not reported in more than 20% of all studies. The clinical trial conducted by the US Oncology Group reported a 5% FN incidence [5], and the West German Study PlanB trial reported a 6% FN incidence without primary prophylaxis [9]. In this study, the overall incidence rates of grade 4 neutropenia and FN were 93.0% and 15.7%, respectively, in patients who did not receive prophylaxis with pegfilgrastim after adjuvant TC chemotherapy. The incidence of grade 4 neutropenia in the present study was a significantly higher than that observed in previous studies conducted in Western countries (10.7%–50.8%) [5917]. However, the incidence of FN in the present study was rather low compared to that observed in 2 previous meta-analyses [1316]. Although it is difficult to explain the exact reason why the incidence rates of FN were low compared to those of the previous 2 meta-analyses and previous studies conducted in Western countries, ethnic differences in hematologic toxicity from docetaxel-based chemotherapy may be an important factor. The pharmacokinetics of docetaxel exhibit wide interindividual variability, which might lead to poor predictability of treatment-related side effects and outcomes [181920]. This variability of docetaxel pharmacokinetics or pharmacodynamics was also seen in a study conducted exclusively in Asian patients, including 103 Chinese, 111 Malay, and 73 Indian patients [19]. In a randomized study conducted in Japan, treatment with 6 cycles of neoadjuvant TC was associated with a 13.8% risk of FN [14]. Moreover, the incidence of FN was 25.2% for 4 cycles of the AC regimen and 4.7% for 4 cycles of the docetaxel regimen (75 or 100 mg/m2) in a Korean study on sequential AC and docetaxel chemotherapy [21]. The use of long-acting G-CSF results in better supportive care and improved quality of life in breast cancer patients by significantly reducing grade 4 neutropenia and FN [10111316]. In our study, the incidence of grade 4 neutropenia decreased from 93.0% to 16.7%, and the incidence of FN decreased from 15.7% to 0%, among all patients who received primary prophylactic pegfilgrastim. Moreover, a decrease in the incidence of grade 4 neutropenia and FN resulted in a significant decrease in the mean duration of neutropenia (from 2.50 days to 0.08 days), the risk of hospitalization (from 29.8% to 2.2%), and the mean total hospital care cost for all chemotherapy cycles (from 790.80 to 486.00 USD). The rate of hospitalization after the use of primary prophylactic pegfilgrastim in our current study was much lower than the rate of hospitalization adjusted for G-CSF primary prophylaxis observed in a previous study (6.7%–13.1%) [22]. Furthermore, the use of long-acting G-CSF results in the preservation of RDI, which is an important factor in achieving optimal survival outcomes after adjuvant chemotherapy. In this study, the RDI was significantly higher in patients who received primary prophylaxis than in patients who did not receive prophylactic pegfilgrastim (99.33% vs . 100%, P = 0.049). Although our current study did not analyze survival outcomes due to the short follow-up period, further studies with long-term follow-up will provide conclusions about improving survival outcomes with the use of long-acting G-CSF. Our study has some limitations, such as its retrospective nature. The number of patients was small because only patients who received adjuvant TC chemotherapy at a single institution were included. Moreover, decisions regarding hospitalization, dose reduction, and treatment delays were made based on our institutional treatment protocol. Additionally, only FN observed by medical staff was counted in the current study. Therefore, the incidence of FN may have been underestimated, as febrile events confirmed by the patient prior to the hospital visit were not included. However, we believe that this study has clinical value because it is the first study assessing the incidence of chemotherapy-related neutropenic events and other adverse events, and the clinical utilization of primary or secondary prophylactic support with long-acting G-CSF (pegfilgrastim) during adjuvant TC chemotherapy, in Korean patients with EBC. In summary, our study demonstrated that the overall incidence of grade 4 neutropenia, at 93.0%, was significantly higher than that observed in previous studies conducted in Western countries. Although the incidence of FN was 15.7%, rather low compared to that observed in the previous 2 meta-analyses, the use of pegfilgrastim prophylaxis during adjuvant TC chemotherapy was associated with significant decreases in the incidence of grade 4 neutropenia, FN, the risk of hospitalization, and the cost of hospital care for chemotherapy compared to no prophylaxis. Further large-scale prospective studies will help fill the gap in the evidence regarding FN risk and will thus inform the use of pegfilgrastim prophylaxis for this regimen in real-world practices. Fund/Grant Support: This research was sponsored by Kyowa Kirin Korea Co., Ltd. Conflicts of Interest: The authors declare that they have no conflict of interest. Author Contribution: Conceptualization: YWJ, YJS. Formal Analysis: YWJ, STL. Investigation: YWJ, SYP, JS, HSH. Methodology: YWJ, HG. Project Administration: YWJ. Writing — Original Draft: YWJ, STL, HG, SYP, JS, HSH. Writing — Review & Editing: YWJ, YJS. Fig. 1 The absolute neutrophil count (ANC) changes after chemotherapy according to the use of prophylaxis with pegfilgrastim. Table 1 Patient and tumor characteristics Values are presented as mean ± standard deviation (range) or number (%). ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2. Table 2 Comparison of chemotherapy-related neutropenia and other adverse events in all patients according to the method of prophylaxis Values are presented as number (%) or mean ± standard deviation unless otherwise specified. RDI, relative dose intensity. Table 3 Comparison of chemotherapy-related neutropenia and other adverse events in all chemotherapy cycles according to prophylaxis with pegfilgrastim Values are presented as number (%) or mean ± standard deviation.	Intravenous (not otherwise specified)	DrugAdministrationRoute	CC BY-NC	33585350	18,963,860	2021-02
What was the administration route of drug 'PEGFILGRASTIM'?	Clinical utilization of long-acting granulocyte colony-stimulating factor (pegfilgrastim) prophylaxis in breast cancer patients with adjuvant docetaxel-cyclophosphamide chemotherapy. Treatment with 4 cycles of docetaxel and cyclophosphamide (TC) in the adjuvant setting is associated with better outcomes than treatment with doxorubicin and cyclophosphamide (AC). However, Western guidelines have indicated that TC confers a high risk (>20%) of febrile neutropenia (FN), while AC confers an intermediate risk (10%-20%) of FN. Threrefore, we evaluated the incidence of FN and the clinical utilization of pegfilgrastim prophylaxis after adjuvant TC chemotherapy. We categorized 201 patients who received adjuvant TC chemotherapy into 3 groups according to the method of prophylaxis and compared neutropenic events, other adverse events, and hospital care costs in the 3 groups. The incidence of grade 4 neutropenia decreased from 93.0% in patients without prophylaxis to 82.4% in those who received secondary prophylaxis and 16.7% in those who received primary prophylaxis. Although the incidence of FN was not different between patients without prophylaxis and patients who received secondary prophylaxis (15.7% and 14.9%), none of the patients who received primary prophylaxis developed FN. Moreover, a decrease in neutropenic events resulted in a significant decrease in the mean duration of neutropenia (2.50 days to 0.08 days, P < 0.001), the risk of hospitalization (29.8% to 2.2%, P < 0.001), and the mean total hospital care cost for all chemotherapy cycles (790.80 to 486.00 US dollars, P < 0.001). The use of pegfilgrastim prophylaxis during adjuvant TC chemotherapy is associated with significant decreases in the incidence of neutropenic events, hospitalization, and hospital care cost compared to those seen in patients without prophylaxis. INTRODUCTION Adjuvant chemotherapy for early-stage breast cancer (EBC) reduces recurrence rates and improves survival rates [1]. Among various adjuvant chemotherapy regimens, anthracycline-based chemotherapy remains the core of most adjuvant chemotherapy regimens for EBC. However, because cardiotoxicity and secondary leukemia have been associated with anthracycline-based regimens, the development of the adjuvant chemotherapy landscape for EBC is ongoing [234]. Since 2005, when studies suggested that taxane-based regimens without anthracycline might provide equivalent or superior results to anthracycline-based regimens [5], the use of anthracycline-based regimens has declined while the use of taxane-based regimens has increased among patients with breast cancer in the United States [6]. Previous studies indicate that taxane-based regimens have become the standard for adjuvant chemotherapy. Treatment with 4 cycles of docetaxel and cyclophosphamide (TC) in the adjuvant setting was shown to be associated with significant improvements in 5-year disease-free survival (DFS) and overall survival (OS) over doxorubicin and cyclophosphamide (AC) in a phase III randomized clinical trial [7]. After that, second-generation phase III trials demonstrated that survival outcomes for 6 cycles of TC and 4 cycles of epirubicin + cyclophosphamide followed by 4 cycles of docetaxel were equally excellent in human epidermal growth factor receptor (HER) 2-negative EBC with lower risk [89]. Thus, the TC regimen is attracting attention for adjuvant chemotherapy of EBC. Febrile neutropenia (FN) is a serious adverse effect encountered in patients undergoing myelosuppressive chemotherapy for EBC [10]. Because chemotherapy-induced FN is associated with life-threatening infections, prolonged hospitalization, increased health care costs, and modification of the dose or schedule of chemotherapy, it is critical to assess the risk of FN and prevent it with recombinant granulocyte colony-stimulating factor (G-CSF) in a myelosuppressive chemotherapy regimen [11]. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Hematopoietic Growth Factors indicate that TC confers a high risk (>20%) of FN and recommends the use of primary prophylactic G-CSF [12]. In a meta-analysis with 902 patients from 13 studies, the estimated rate of FN without primary G-CSF was 29.1%, while that with primary G-CSF prophylaxis was 6.8% for TC [13]. However, in an early phase III randomized clinical trial, treatment with 4 cycles of adjuvant TC was associated with a 5% risk of FN [5]. Moreover, in a randomized study conducted in Japan, treatment with 6 cycles of neoadjuvant TC was associated with a 13.8% risk of FN [14]. Considering the ethnic differences in hematologic toxicity and the absence of any Korean reports on FN risk after adjuvant TC chemotherapy, we evaluated the incidence of chemotherapy-related neutropenic events and other adverse events during adjuvant TC chemotherapy in Korean patients with EBC. Furthermore, we assessed the clinical utilization of primary or secondary prophylactic support with long-acting G-CSF (pegfilgrastim) in these patients. METHODS Study population This study was approved by the Institutional Review Board of The Catholic University of Korea, St. Vincent's Hospital (No. VC18RESI0162). Written informed consent was obtained from all patients. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The electronic medical records were reviewed for patients with EBC who received adjuvant TC chemotherapy from July 2015 to December 2019. In total, 209 consecutive patients who received adjuvant TC chemotherapy were included in this study. Eight patients, including 2 patients who did not complete adjuvant TC chemotherapy and 6 patients treated with neoadjuvant chemotherapy, were excluded to minimize other confounding factors. A total of 201 patients were included in the current study. We reviewed the patients' demographics and tumor characteristics, including age, body mass index (BMI [kg/m2]), body surface area (BSA [m2]), menopausal status, type of surgery, pathological T and N staging, histologic grade and type, hormone receptor (HR) and HER2 expression, and comorbidities. HR status was determined using an enzyme immunoassay and reported in the patients' medical records. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or silver in situ hybridization (SISH) was used to evaluate HER2 status, and an IHC score of 0 or +1 or an IHC score of +2 and negative FISH/SISH were defined as negative HER2 overexpression. Chemotherapy and use of granulocyte colony-stimulating factor All patients received a total of 4 cycles of TC chemotherapy, 3 weeks apart. In each cycle, docetaxel (75 mg/m2, intravenous [IV] for 1 hour) was initially administered, immediately followed by cyclophosphamide (600 mg/m2, IV for 1 hour). Secondary prophylaxis using pegfilgrastim (Neulasta, Amgen, Thousand Oaks, CA, USA) has been used in Korea since 2015, when it became covered by the National Health Insurance. Secondary prophylaxis with pegfilgrastim was defined as the use of G-CSF if a patient experienced a neutropenic event in the previous chemotherapy cycle. Primary prophylaxis using pegfilgrastim has been used in Korea since April 2018 with the approval of the National Health Insurance program. Pegfilgrastim was administered subcutaneously between 24 and 48 hours after the administration of chemotherapy. When not using pegfilgrastim, short-acting recombinant G-CSF (filgrastim) was administered daily after each cycle for grade 3 or 4 neutropenia until the absolute neutrophil count (ANC) was restored to 1,000/mm3. Laboratory tests, including complete blood cell (CBC) counts with differential and chemistry assays, were checked before each chemotherapy cycle and on day 6. After chemotherapy, baseline CBC counts were measured from day 6 until the ANC was restored to 1,000/mm3. All patients with FN received prophylactic antibiotic therapy comprising 1-g IV cefoperazone twice daily and 200-mg tobramycin sulfate once daily, unless contraindicated. Adverse events assessment The incidence of FN and FN-related complications according to the Common Terminology Criteria for Adverse Events (CTCAE, version 4.02) were investigated. FN was defined as neutropenia (grade 4 or grade 3 for over 48 hours) with a febrile event (oral temperature of ≥38.3℃, or ≥38.0℃ for over 1 hour) observed by medical staff. Dose reduction was defined as a reduction in the delivered dosage(s) of agent(s) administered relative to the standard values, and dose delay was defined as a chemotherapy interval of more than 21 days. The chemotherapy relative dose intensity (RDI) was estimated based on the ratio of delivered dose intensity and the reference standard dose intensity [15]. Total hospital care cost was calculated as the costs associated with all medical claims during the entire cycle or within each cycle. Outpatient hospital visit costs, hospitalization costs, chemotherapy costs, and G-CSF costs were all included in the total hospital care cost measure. The costs represented the reimbursed amount paid by the patient, as documented in the electronic medical record. Statistical analysis The chi-square test and Fisher exact test were used to determine differences in categorical variables between groups. The unpaired t-test and analysis of variance were used for comparison between continuous and independent variables that follow a normal distribution (age, BMI, BSA, RDI, recovery from neutropenia [days]). Continuous and independent variables that do not follow a normal distribution were analyzed using Mann-Whitney tests (weight gain [kg]). A P-value of <0.05 was considered to be statistically significant. The analyses were performed using PASW Statistics, ver. 18.0 for Windows (IBM Corp., Armonk, NY, USA). RESULTS Between July 2015 and December 2019, 201 Korean patients (804 cycles) with EBC who received adjuvant TC chemotherapy were included in the analysis. A total of 115 patients (57.2%) did not receive prophylaxis with pegfilgrastim, 74 (36.8%) received secondary prophylaxis, and 12 (6.0%) received primary prophylaxis with pegfilgrastim during adjuvant TC chemotherapy. The demographics and clinical characteristics of the study population by the method of prophylaxis with pegfilgrastim are shown in Table 1. Overall, the median age was 55 years (range, 21–79 years). A total of 37 patients (18.4%) were older than 65 years. The mean BMI and BSA were 24.71 ± 3.48 kg/m2 and 1.60 ± 0.13 m2, respectively. Patients who received primary prophylaxis had a significantly older median age at diagnosis than patients who did not receive prophylaxis or received secondary prophylaxis (P = 0.009). There were no significant differences in menopausal status, type of surgery, tumor stage, histologic grade, histologic type, comorbidity, or HR or HER2 status among the 3 groups (Table 1). Chemotherapy-related neutropenic events The combined incidence of grade 3 and 4 neutropenia was 3.5%, and 93.0% of patients did not receive prophylaxis with pegfilgrastim (Table 2). However, the incidence of grade 4 neutropenia decreased to 82.4% with secondary prophylaxis (P = 0.035) and 16.7% with primary prophylaxis (P < 0.001). In the analysis of 804 chemotherapy cycles, the incidence of grade 4 neutropenia was 74.6% in all cycles without prophylaxis and 5.3% in all cycles with prophylaxis with pegfilgrastim (P < 0.001) (Table 3). Moreover, the mean period of recovery from neutropenia was significantly shorter in chemotherapy cycles with prophylaxis with pegfilgrastim than in chemotherapy cycles without prophylaxis (2.50 ± 1.09 days vs . 0.08 ± 0.26 days, P < 0.001) (Table 3). The ANC changes after the chemotherapy cycle according to pegfilgrastim prophylaxis status are shown in Fig. 1. The incidence of FN was not significantly different between patients who did not receive prophylaxis and patients who received secondary prophylaxis (15.7% and 14.9%, P = 0.528) (Table 2). However, no patients who received primary prophylaxis with pegfilgrastim developed FN. Overall, FN occurred in 6.9% of all chemotherapy cycles without prophylaxis and 0.9% of all cycles with prophylaxis with pegfilgrastim (P < 0.001) (Table 3). Other chemotherapy-related adverse events Regarding hematologic toxicities other than neutropenia, there were no differences in the incidence of anemia, thrombocytopenia, and transfusion between patients who did not receive prophylaxis and patients with secondary prophylaxis (Table 2). These findings were the same when the results were analyzed by chemotherapy cycle (Table 3). There was no anemia or thrombocytopenia in patients who received primary prophylaxis. Moreover, the weight gained due to chemotherapy was less in patients who received primary prophylaxis than in the other 2 groups (Table 2). Among all patients who received TC chemotherapy, no patient experienced severe hepatotoxicity or nephrotoxicity. Among the 115 patients who did not receive prophylaxis with pegfilgrastim, 6 (5.2%) developed neutropenic infections, which included 2 patients with chemoport infection and 4 patients with wound infections. Among the 74 patients who received secondary prophylaxis, 5 (6.8%) developed neutropenic infections, which included 1 patient with a chemoport infection and 4 patients with wound infections. Among patients who received primary prophylaxis, there were no neutropenia-associated infections (Table 2). Although there were no significant differences in dose reduction (2.6% vs. 2.7%, P = 0.651) or treatment delay (3.5% vs. 1.4%, P = 0.078) between patients who did not receive prophylaxis and patients who received secondary prophylaxis, the RDI was lower in patients who did not receive prophylaxis than in those who received secondary prophylaxis (99.33% vs. 99.69%, respectively; P = 0.025). In patients who received primary prophylaxis, there was no association between treatment and dose reduction and treatment delay, and the RDI was 100% (Table 2). Compared with treatment without prophylaxis, patients who received secondary prophylaxis were not associated with a reduction in the risk of hospitalization (37.4% vs. 31.1%, P = 0.233), whereas primary prophylaxis was significantly associated with a reduction in the risk of hospitalization compared with the other 2 groups (37.4% vs . 8.3%, P = 0.038; 31.1% vs. 8.3%, P = 0.045) (Table 2). The incidence of hospitalization in each chemotherapy cycle was 29.8% in patients who did not receive prophylaxis and 2.2% in patients who received pegfilgrastim prophylaxis (P < 0.001) (Table 3). Hospital care cost The mean total hospital care cost for all chemotherapy cycles was greater for patients who did not receive prophylaxis than for patients who received secondary prophylaxis (790.80 US dollars [USD] vs. 728.40 USD, P = 0.008). In patients who received primary prophylaxis, the mean total hospital care cost for all chemotherapy cycles was 486.00 USD, and this cost was significantly lower than that for the other 2 groups (P < 0.001). In the analysis of each chemotherapy cycle, the mean hospital care cost for each chemotherapy cycle was significantly greater for patients who did not receive prophylaxis than for patients who received prophylactic pegfilgrastim (199.20 USD vs. 157.20 USD, P < 0.001). DISCUSSION In this study, we assessed the clinical effectiveness of pegfilgrastim prophylaxis in adjuvant TC chemotherapy by directly comparing the incidences of chemotherapy-related neutropenic events and other adverse events according to the method of prophylaxis in Korean EBC patients who received adjuvant TC chemotherapy. Primary prophylaxis with pegfilgrastim after adjuvant TC chemotherapy was significantly associated with a decrease in the incidence of chemotherapy-related neutropenic events, including FN, and the mean period of recovery from neutropenia, the risk of hospitalization, and the cost of hospital care for chemotherapy compared to those in patients who did not receive prophylaxis or who received secondary prophylaxis. With longer follow-up, 4 cycles of adjuvant TC chemotherapy showed a significant benefit over 4 cycles of AC chemotherapy in regard to DFS and OS and had a lower risk of anthracycline-related cardiac toxicity than the AC regimen [7]. Although the TC regimen has these clinical benefits over the AC regimen, the TC regimen results in a significantly higher incidence of chemotherapy-induced hematologic toxicities, such as neutropenia and FN, than the AC regimen [71316]. In a previous meta-analysis with 902 patients from 13 studies and with 2,532 patients from 14 studies, the estimated FN rates without primary G-CSF were 29.1% and 31.3% [1316]. Furthermore, the NCCN guidelines have indicated that TC confers a high risk (>20% chance of occurrence) of FN, while AC confers an intermediate risk (10%–20% chance) of FN [12]. However, the incidence of FN after adjuvant TC chemotherapy was not reported in more than 20% of all studies. The clinical trial conducted by the US Oncology Group reported a 5% FN incidence [5], and the West German Study PlanB trial reported a 6% FN incidence without primary prophylaxis [9]. In this study, the overall incidence rates of grade 4 neutropenia and FN were 93.0% and 15.7%, respectively, in patients who did not receive prophylaxis with pegfilgrastim after adjuvant TC chemotherapy. The incidence of grade 4 neutropenia in the present study was a significantly higher than that observed in previous studies conducted in Western countries (10.7%–50.8%) [5917]. However, the incidence of FN in the present study was rather low compared to that observed in 2 previous meta-analyses [1316]. Although it is difficult to explain the exact reason why the incidence rates of FN were low compared to those of the previous 2 meta-analyses and previous studies conducted in Western countries, ethnic differences in hematologic toxicity from docetaxel-based chemotherapy may be an important factor. The pharmacokinetics of docetaxel exhibit wide interindividual variability, which might lead to poor predictability of treatment-related side effects and outcomes [181920]. This variability of docetaxel pharmacokinetics or pharmacodynamics was also seen in a study conducted exclusively in Asian patients, including 103 Chinese, 111 Malay, and 73 Indian patients [19]. In a randomized study conducted in Japan, treatment with 6 cycles of neoadjuvant TC was associated with a 13.8% risk of FN [14]. Moreover, the incidence of FN was 25.2% for 4 cycles of the AC regimen and 4.7% for 4 cycles of the docetaxel regimen (75 or 100 mg/m2) in a Korean study on sequential AC and docetaxel chemotherapy [21]. The use of long-acting G-CSF results in better supportive care and improved quality of life in breast cancer patients by significantly reducing grade 4 neutropenia and FN [10111316]. In our study, the incidence of grade 4 neutropenia decreased from 93.0% to 16.7%, and the incidence of FN decreased from 15.7% to 0%, among all patients who received primary prophylactic pegfilgrastim. Moreover, a decrease in the incidence of grade 4 neutropenia and FN resulted in a significant decrease in the mean duration of neutropenia (from 2.50 days to 0.08 days), the risk of hospitalization (from 29.8% to 2.2%), and the mean total hospital care cost for all chemotherapy cycles (from 790.80 to 486.00 USD). The rate of hospitalization after the use of primary prophylactic pegfilgrastim in our current study was much lower than the rate of hospitalization adjusted for G-CSF primary prophylaxis observed in a previous study (6.7%–13.1%) [22]. Furthermore, the use of long-acting G-CSF results in the preservation of RDI, which is an important factor in achieving optimal survival outcomes after adjuvant chemotherapy. In this study, the RDI was significantly higher in patients who received primary prophylaxis than in patients who did not receive prophylactic pegfilgrastim (99.33% vs . 100%, P = 0.049). Although our current study did not analyze survival outcomes due to the short follow-up period, further studies with long-term follow-up will provide conclusions about improving survival outcomes with the use of long-acting G-CSF. Our study has some limitations, such as its retrospective nature. The number of patients was small because only patients who received adjuvant TC chemotherapy at a single institution were included. Moreover, decisions regarding hospitalization, dose reduction, and treatment delays were made based on our institutional treatment protocol. Additionally, only FN observed by medical staff was counted in the current study. Therefore, the incidence of FN may have been underestimated, as febrile events confirmed by the patient prior to the hospital visit were not included. However, we believe that this study has clinical value because it is the first study assessing the incidence of chemotherapy-related neutropenic events and other adverse events, and the clinical utilization of primary or secondary prophylactic support with long-acting G-CSF (pegfilgrastim) during adjuvant TC chemotherapy, in Korean patients with EBC. In summary, our study demonstrated that the overall incidence of grade 4 neutropenia, at 93.0%, was significantly higher than that observed in previous studies conducted in Western countries. Although the incidence of FN was 15.7%, rather low compared to that observed in the previous 2 meta-analyses, the use of pegfilgrastim prophylaxis during adjuvant TC chemotherapy was associated with significant decreases in the incidence of grade 4 neutropenia, FN, the risk of hospitalization, and the cost of hospital care for chemotherapy compared to no prophylaxis. Further large-scale prospective studies will help fill the gap in the evidence regarding FN risk and will thus inform the use of pegfilgrastim prophylaxis for this regimen in real-world practices. Fund/Grant Support: This research was sponsored by Kyowa Kirin Korea Co., Ltd. Conflicts of Interest: The authors declare that they have no conflict of interest. Author Contribution: Conceptualization: YWJ, YJS. Formal Analysis: YWJ, STL. Investigation: YWJ, SYP, JS, HSH. Methodology: YWJ, HG. Project Administration: YWJ. Writing — Original Draft: YWJ, STL, HG, SYP, JS, HSH. Writing — Review & Editing: YWJ, YJS. Fig. 1 The absolute neutrophil count (ANC) changes after chemotherapy according to the use of prophylaxis with pegfilgrastim. Table 1 Patient and tumor characteristics Values are presented as mean ± standard deviation (range) or number (%). ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2. Table 2 Comparison of chemotherapy-related neutropenia and other adverse events in all patients according to the method of prophylaxis Values are presented as number (%) or mean ± standard deviation unless otherwise specified. RDI, relative dose intensity. Table 3 Comparison of chemotherapy-related neutropenia and other adverse events in all chemotherapy cycles according to prophylaxis with pegfilgrastim Values are presented as number (%) or mean ± standard deviation.	Subcutaneous	DrugAdministrationRoute	CC BY-NC	33585350	18,963,860	2021-02
What was the dosage of drug 'CYCLOPHOSPHAMIDE'?	Clinical utilization of long-acting granulocyte colony-stimulating factor (pegfilgrastim) prophylaxis in breast cancer patients with adjuvant docetaxel-cyclophosphamide chemotherapy. Treatment with 4 cycles of docetaxel and cyclophosphamide (TC) in the adjuvant setting is associated with better outcomes than treatment with doxorubicin and cyclophosphamide (AC). However, Western guidelines have indicated that TC confers a high risk (>20%) of febrile neutropenia (FN), while AC confers an intermediate risk (10%-20%) of FN. Threrefore, we evaluated the incidence of FN and the clinical utilization of pegfilgrastim prophylaxis after adjuvant TC chemotherapy. We categorized 201 patients who received adjuvant TC chemotherapy into 3 groups according to the method of prophylaxis and compared neutropenic events, other adverse events, and hospital care costs in the 3 groups. The incidence of grade 4 neutropenia decreased from 93.0% in patients without prophylaxis to 82.4% in those who received secondary prophylaxis and 16.7% in those who received primary prophylaxis. Although the incidence of FN was not different between patients without prophylaxis and patients who received secondary prophylaxis (15.7% and 14.9%), none of the patients who received primary prophylaxis developed FN. Moreover, a decrease in neutropenic events resulted in a significant decrease in the mean duration of neutropenia (2.50 days to 0.08 days, P < 0.001), the risk of hospitalization (29.8% to 2.2%, P < 0.001), and the mean total hospital care cost for all chemotherapy cycles (790.80 to 486.00 US dollars, P < 0.001). The use of pegfilgrastim prophylaxis during adjuvant TC chemotherapy is associated with significant decreases in the incidence of neutropenic events, hospitalization, and hospital care cost compared to those seen in patients without prophylaxis. INTRODUCTION Adjuvant chemotherapy for early-stage breast cancer (EBC) reduces recurrence rates and improves survival rates [1]. Among various adjuvant chemotherapy regimens, anthracycline-based chemotherapy remains the core of most adjuvant chemotherapy regimens for EBC. However, because cardiotoxicity and secondary leukemia have been associated with anthracycline-based regimens, the development of the adjuvant chemotherapy landscape for EBC is ongoing [234]. Since 2005, when studies suggested that taxane-based regimens without anthracycline might provide equivalent or superior results to anthracycline-based regimens [5], the use of anthracycline-based regimens has declined while the use of taxane-based regimens has increased among patients with breast cancer in the United States [6]. Previous studies indicate that taxane-based regimens have become the standard for adjuvant chemotherapy. Treatment with 4 cycles of docetaxel and cyclophosphamide (TC) in the adjuvant setting was shown to be associated with significant improvements in 5-year disease-free survival (DFS) and overall survival (OS) over doxorubicin and cyclophosphamide (AC) in a phase III randomized clinical trial [7]. After that, second-generation phase III trials demonstrated that survival outcomes for 6 cycles of TC and 4 cycles of epirubicin + cyclophosphamide followed by 4 cycles of docetaxel were equally excellent in human epidermal growth factor receptor (HER) 2-negative EBC with lower risk [89]. Thus, the TC regimen is attracting attention for adjuvant chemotherapy of EBC. Febrile neutropenia (FN) is a serious adverse effect encountered in patients undergoing myelosuppressive chemotherapy for EBC [10]. Because chemotherapy-induced FN is associated with life-threatening infections, prolonged hospitalization, increased health care costs, and modification of the dose or schedule of chemotherapy, it is critical to assess the risk of FN and prevent it with recombinant granulocyte colony-stimulating factor (G-CSF) in a myelosuppressive chemotherapy regimen [11]. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Hematopoietic Growth Factors indicate that TC confers a high risk (>20%) of FN and recommends the use of primary prophylactic G-CSF [12]. In a meta-analysis with 902 patients from 13 studies, the estimated rate of FN without primary G-CSF was 29.1%, while that with primary G-CSF prophylaxis was 6.8% for TC [13]. However, in an early phase III randomized clinical trial, treatment with 4 cycles of adjuvant TC was associated with a 5% risk of FN [5]. Moreover, in a randomized study conducted in Japan, treatment with 6 cycles of neoadjuvant TC was associated with a 13.8% risk of FN [14]. Considering the ethnic differences in hematologic toxicity and the absence of any Korean reports on FN risk after adjuvant TC chemotherapy, we evaluated the incidence of chemotherapy-related neutropenic events and other adverse events during adjuvant TC chemotherapy in Korean patients with EBC. Furthermore, we assessed the clinical utilization of primary or secondary prophylactic support with long-acting G-CSF (pegfilgrastim) in these patients. METHODS Study population This study was approved by the Institutional Review Board of The Catholic University of Korea, St. Vincent's Hospital (No. VC18RESI0162). Written informed consent was obtained from all patients. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The electronic medical records were reviewed for patients with EBC who received adjuvant TC chemotherapy from July 2015 to December 2019. In total, 209 consecutive patients who received adjuvant TC chemotherapy were included in this study. Eight patients, including 2 patients who did not complete adjuvant TC chemotherapy and 6 patients treated with neoadjuvant chemotherapy, were excluded to minimize other confounding factors. A total of 201 patients were included in the current study. We reviewed the patients' demographics and tumor characteristics, including age, body mass index (BMI [kg/m2]), body surface area (BSA [m2]), menopausal status, type of surgery, pathological T and N staging, histologic grade and type, hormone receptor (HR) and HER2 expression, and comorbidities. HR status was determined using an enzyme immunoassay and reported in the patients' medical records. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or silver in situ hybridization (SISH) was used to evaluate HER2 status, and an IHC score of 0 or +1 or an IHC score of +2 and negative FISH/SISH were defined as negative HER2 overexpression. Chemotherapy and use of granulocyte colony-stimulating factor All patients received a total of 4 cycles of TC chemotherapy, 3 weeks apart. In each cycle, docetaxel (75 mg/m2, intravenous [IV] for 1 hour) was initially administered, immediately followed by cyclophosphamide (600 mg/m2, IV for 1 hour). Secondary prophylaxis using pegfilgrastim (Neulasta, Amgen, Thousand Oaks, CA, USA) has been used in Korea since 2015, when it became covered by the National Health Insurance. Secondary prophylaxis with pegfilgrastim was defined as the use of G-CSF if a patient experienced a neutropenic event in the previous chemotherapy cycle. Primary prophylaxis using pegfilgrastim has been used in Korea since April 2018 with the approval of the National Health Insurance program. Pegfilgrastim was administered subcutaneously between 24 and 48 hours after the administration of chemotherapy. When not using pegfilgrastim, short-acting recombinant G-CSF (filgrastim) was administered daily after each cycle for grade 3 or 4 neutropenia until the absolute neutrophil count (ANC) was restored to 1,000/mm3. Laboratory tests, including complete blood cell (CBC) counts with differential and chemistry assays, were checked before each chemotherapy cycle and on day 6. After chemotherapy, baseline CBC counts were measured from day 6 until the ANC was restored to 1,000/mm3. All patients with FN received prophylactic antibiotic therapy comprising 1-g IV cefoperazone twice daily and 200-mg tobramycin sulfate once daily, unless contraindicated. Adverse events assessment The incidence of FN and FN-related complications according to the Common Terminology Criteria for Adverse Events (CTCAE, version 4.02) were investigated. FN was defined as neutropenia (grade 4 or grade 3 for over 48 hours) with a febrile event (oral temperature of ≥38.3℃, or ≥38.0℃ for over 1 hour) observed by medical staff. Dose reduction was defined as a reduction in the delivered dosage(s) of agent(s) administered relative to the standard values, and dose delay was defined as a chemotherapy interval of more than 21 days. The chemotherapy relative dose intensity (RDI) was estimated based on the ratio of delivered dose intensity and the reference standard dose intensity [15]. Total hospital care cost was calculated as the costs associated with all medical claims during the entire cycle or within each cycle. Outpatient hospital visit costs, hospitalization costs, chemotherapy costs, and G-CSF costs were all included in the total hospital care cost measure. The costs represented the reimbursed amount paid by the patient, as documented in the electronic medical record. Statistical analysis The chi-square test and Fisher exact test were used to determine differences in categorical variables between groups. The unpaired t-test and analysis of variance were used for comparison between continuous and independent variables that follow a normal distribution (age, BMI, BSA, RDI, recovery from neutropenia [days]). Continuous and independent variables that do not follow a normal distribution were analyzed using Mann-Whitney tests (weight gain [kg]). A P-value of <0.05 was considered to be statistically significant. The analyses were performed using PASW Statistics, ver. 18.0 for Windows (IBM Corp., Armonk, NY, USA). RESULTS Between July 2015 and December 2019, 201 Korean patients (804 cycles) with EBC who received adjuvant TC chemotherapy were included in the analysis. A total of 115 patients (57.2%) did not receive prophylaxis with pegfilgrastim, 74 (36.8%) received secondary prophylaxis, and 12 (6.0%) received primary prophylaxis with pegfilgrastim during adjuvant TC chemotherapy. The demographics and clinical characteristics of the study population by the method of prophylaxis with pegfilgrastim are shown in Table 1. Overall, the median age was 55 years (range, 21–79 years). A total of 37 patients (18.4%) were older than 65 years. The mean BMI and BSA were 24.71 ± 3.48 kg/m2 and 1.60 ± 0.13 m2, respectively. Patients who received primary prophylaxis had a significantly older median age at diagnosis than patients who did not receive prophylaxis or received secondary prophylaxis (P = 0.009). There were no significant differences in menopausal status, type of surgery, tumor stage, histologic grade, histologic type, comorbidity, or HR or HER2 status among the 3 groups (Table 1). Chemotherapy-related neutropenic events The combined incidence of grade 3 and 4 neutropenia was 3.5%, and 93.0% of patients did not receive prophylaxis with pegfilgrastim (Table 2). However, the incidence of grade 4 neutropenia decreased to 82.4% with secondary prophylaxis (P = 0.035) and 16.7% with primary prophylaxis (P < 0.001). In the analysis of 804 chemotherapy cycles, the incidence of grade 4 neutropenia was 74.6% in all cycles without prophylaxis and 5.3% in all cycles with prophylaxis with pegfilgrastim (P < 0.001) (Table 3). Moreover, the mean period of recovery from neutropenia was significantly shorter in chemotherapy cycles with prophylaxis with pegfilgrastim than in chemotherapy cycles without prophylaxis (2.50 ± 1.09 days vs . 0.08 ± 0.26 days, P < 0.001) (Table 3). The ANC changes after the chemotherapy cycle according to pegfilgrastim prophylaxis status are shown in Fig. 1. The incidence of FN was not significantly different between patients who did not receive prophylaxis and patients who received secondary prophylaxis (15.7% and 14.9%, P = 0.528) (Table 2). However, no patients who received primary prophylaxis with pegfilgrastim developed FN. Overall, FN occurred in 6.9% of all chemotherapy cycles without prophylaxis and 0.9% of all cycles with prophylaxis with pegfilgrastim (P < 0.001) (Table 3). Other chemotherapy-related adverse events Regarding hematologic toxicities other than neutropenia, there were no differences in the incidence of anemia, thrombocytopenia, and transfusion between patients who did not receive prophylaxis and patients with secondary prophylaxis (Table 2). These findings were the same when the results were analyzed by chemotherapy cycle (Table 3). There was no anemia or thrombocytopenia in patients who received primary prophylaxis. Moreover, the weight gained due to chemotherapy was less in patients who received primary prophylaxis than in the other 2 groups (Table 2). Among all patients who received TC chemotherapy, no patient experienced severe hepatotoxicity or nephrotoxicity. Among the 115 patients who did not receive prophylaxis with pegfilgrastim, 6 (5.2%) developed neutropenic infections, which included 2 patients with chemoport infection and 4 patients with wound infections. Among the 74 patients who received secondary prophylaxis, 5 (6.8%) developed neutropenic infections, which included 1 patient with a chemoport infection and 4 patients with wound infections. Among patients who received primary prophylaxis, there were no neutropenia-associated infections (Table 2). Although there were no significant differences in dose reduction (2.6% vs. 2.7%, P = 0.651) or treatment delay (3.5% vs. 1.4%, P = 0.078) between patients who did not receive prophylaxis and patients who received secondary prophylaxis, the RDI was lower in patients who did not receive prophylaxis than in those who received secondary prophylaxis (99.33% vs. 99.69%, respectively; P = 0.025). In patients who received primary prophylaxis, there was no association between treatment and dose reduction and treatment delay, and the RDI was 100% (Table 2). Compared with treatment without prophylaxis, patients who received secondary prophylaxis were not associated with a reduction in the risk of hospitalization (37.4% vs. 31.1%, P = 0.233), whereas primary prophylaxis was significantly associated with a reduction in the risk of hospitalization compared with the other 2 groups (37.4% vs . 8.3%, P = 0.038; 31.1% vs. 8.3%, P = 0.045) (Table 2). The incidence of hospitalization in each chemotherapy cycle was 29.8% in patients who did not receive prophylaxis and 2.2% in patients who received pegfilgrastim prophylaxis (P < 0.001) (Table 3). Hospital care cost The mean total hospital care cost for all chemotherapy cycles was greater for patients who did not receive prophylaxis than for patients who received secondary prophylaxis (790.80 US dollars [USD] vs. 728.40 USD, P = 0.008). In patients who received primary prophylaxis, the mean total hospital care cost for all chemotherapy cycles was 486.00 USD, and this cost was significantly lower than that for the other 2 groups (P < 0.001). In the analysis of each chemotherapy cycle, the mean hospital care cost for each chemotherapy cycle was significantly greater for patients who did not receive prophylaxis than for patients who received prophylactic pegfilgrastim (199.20 USD vs. 157.20 USD, P < 0.001). DISCUSSION In this study, we assessed the clinical effectiveness of pegfilgrastim prophylaxis in adjuvant TC chemotherapy by directly comparing the incidences of chemotherapy-related neutropenic events and other adverse events according to the method of prophylaxis in Korean EBC patients who received adjuvant TC chemotherapy. Primary prophylaxis with pegfilgrastim after adjuvant TC chemotherapy was significantly associated with a decrease in the incidence of chemotherapy-related neutropenic events, including FN, and the mean period of recovery from neutropenia, the risk of hospitalization, and the cost of hospital care for chemotherapy compared to those in patients who did not receive prophylaxis or who received secondary prophylaxis. With longer follow-up, 4 cycles of adjuvant TC chemotherapy showed a significant benefit over 4 cycles of AC chemotherapy in regard to DFS and OS and had a lower risk of anthracycline-related cardiac toxicity than the AC regimen [7]. Although the TC regimen has these clinical benefits over the AC regimen, the TC regimen results in a significantly higher incidence of chemotherapy-induced hematologic toxicities, such as neutropenia and FN, than the AC regimen [71316]. In a previous meta-analysis with 902 patients from 13 studies and with 2,532 patients from 14 studies, the estimated FN rates without primary G-CSF were 29.1% and 31.3% [1316]. Furthermore, the NCCN guidelines have indicated that TC confers a high risk (>20% chance of occurrence) of FN, while AC confers an intermediate risk (10%–20% chance) of FN [12]. However, the incidence of FN after adjuvant TC chemotherapy was not reported in more than 20% of all studies. The clinical trial conducted by the US Oncology Group reported a 5% FN incidence [5], and the West German Study PlanB trial reported a 6% FN incidence without primary prophylaxis [9]. In this study, the overall incidence rates of grade 4 neutropenia and FN were 93.0% and 15.7%, respectively, in patients who did not receive prophylaxis with pegfilgrastim after adjuvant TC chemotherapy. The incidence of grade 4 neutropenia in the present study was a significantly higher than that observed in previous studies conducted in Western countries (10.7%–50.8%) [5917]. However, the incidence of FN in the present study was rather low compared to that observed in 2 previous meta-analyses [1316]. Although it is difficult to explain the exact reason why the incidence rates of FN were low compared to those of the previous 2 meta-analyses and previous studies conducted in Western countries, ethnic differences in hematologic toxicity from docetaxel-based chemotherapy may be an important factor. The pharmacokinetics of docetaxel exhibit wide interindividual variability, which might lead to poor predictability of treatment-related side effects and outcomes [181920]. This variability of docetaxel pharmacokinetics or pharmacodynamics was also seen in a study conducted exclusively in Asian patients, including 103 Chinese, 111 Malay, and 73 Indian patients [19]. In a randomized study conducted in Japan, treatment with 6 cycles of neoadjuvant TC was associated with a 13.8% risk of FN [14]. Moreover, the incidence of FN was 25.2% for 4 cycles of the AC regimen and 4.7% for 4 cycles of the docetaxel regimen (75 or 100 mg/m2) in a Korean study on sequential AC and docetaxel chemotherapy [21]. The use of long-acting G-CSF results in better supportive care and improved quality of life in breast cancer patients by significantly reducing grade 4 neutropenia and FN [10111316]. In our study, the incidence of grade 4 neutropenia decreased from 93.0% to 16.7%, and the incidence of FN decreased from 15.7% to 0%, among all patients who received primary prophylactic pegfilgrastim. Moreover, a decrease in the incidence of grade 4 neutropenia and FN resulted in a significant decrease in the mean duration of neutropenia (from 2.50 days to 0.08 days), the risk of hospitalization (from 29.8% to 2.2%), and the mean total hospital care cost for all chemotherapy cycles (from 790.80 to 486.00 USD). The rate of hospitalization after the use of primary prophylactic pegfilgrastim in our current study was much lower than the rate of hospitalization adjusted for G-CSF primary prophylaxis observed in a previous study (6.7%–13.1%) [22]. Furthermore, the use of long-acting G-CSF results in the preservation of RDI, which is an important factor in achieving optimal survival outcomes after adjuvant chemotherapy. In this study, the RDI was significantly higher in patients who received primary prophylaxis than in patients who did not receive prophylactic pegfilgrastim (99.33% vs . 100%, P = 0.049). Although our current study did not analyze survival outcomes due to the short follow-up period, further studies with long-term follow-up will provide conclusions about improving survival outcomes with the use of long-acting G-CSF. Our study has some limitations, such as its retrospective nature. The number of patients was small because only patients who received adjuvant TC chemotherapy at a single institution were included. Moreover, decisions regarding hospitalization, dose reduction, and treatment delays were made based on our institutional treatment protocol. Additionally, only FN observed by medical staff was counted in the current study. Therefore, the incidence of FN may have been underestimated, as febrile events confirmed by the patient prior to the hospital visit were not included. However, we believe that this study has clinical value because it is the first study assessing the incidence of chemotherapy-related neutropenic events and other adverse events, and the clinical utilization of primary or secondary prophylactic support with long-acting G-CSF (pegfilgrastim) during adjuvant TC chemotherapy, in Korean patients with EBC. In summary, our study demonstrated that the overall incidence of grade 4 neutropenia, at 93.0%, was significantly higher than that observed in previous studies conducted in Western countries. Although the incidence of FN was 15.7%, rather low compared to that observed in the previous 2 meta-analyses, the use of pegfilgrastim prophylaxis during adjuvant TC chemotherapy was associated with significant decreases in the incidence of grade 4 neutropenia, FN, the risk of hospitalization, and the cost of hospital care for chemotherapy compared to no prophylaxis. Further large-scale prospective studies will help fill the gap in the evidence regarding FN risk and will thus inform the use of pegfilgrastim prophylaxis for this regimen in real-world practices. Fund/Grant Support: This research was sponsored by Kyowa Kirin Korea Co., Ltd. Conflicts of Interest: The authors declare that they have no conflict of interest. Author Contribution: Conceptualization: YWJ, YJS. Formal Analysis: YWJ, STL. Investigation: YWJ, SYP, JS, HSH. Methodology: YWJ, HG. Project Administration: YWJ. Writing — Original Draft: YWJ, STL, HG, SYP, JS, HSH. Writing — Review & Editing: YWJ, YJS. Fig. 1 The absolute neutrophil count (ANC) changes after chemotherapy according to the use of prophylaxis with pegfilgrastim. Table 1 Patient and tumor characteristics Values are presented as mean ± standard deviation (range) or number (%). ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2. Table 2 Comparison of chemotherapy-related neutropenia and other adverse events in all patients according to the method of prophylaxis Values are presented as number (%) or mean ± standard deviation unless otherwise specified. RDI, relative dose intensity. Table 3 Comparison of chemotherapy-related neutropenia and other adverse events in all chemotherapy cycles according to prophylaxis with pegfilgrastim Values are presented as number (%) or mean ± standard deviation.	FOR 1 HOUR	DrugDosageText	CC BY-NC	33585350	18,963,860	2021-02
What was the dosage of drug 'DOCETAXEL'?	Clinical utilization of long-acting granulocyte colony-stimulating factor (pegfilgrastim) prophylaxis in breast cancer patients with adjuvant docetaxel-cyclophosphamide chemotherapy. Treatment with 4 cycles of docetaxel and cyclophosphamide (TC) in the adjuvant setting is associated with better outcomes than treatment with doxorubicin and cyclophosphamide (AC). However, Western guidelines have indicated that TC confers a high risk (>20%) of febrile neutropenia (FN), while AC confers an intermediate risk (10%-20%) of FN. Threrefore, we evaluated the incidence of FN and the clinical utilization of pegfilgrastim prophylaxis after adjuvant TC chemotherapy. We categorized 201 patients who received adjuvant TC chemotherapy into 3 groups according to the method of prophylaxis and compared neutropenic events, other adverse events, and hospital care costs in the 3 groups. The incidence of grade 4 neutropenia decreased from 93.0% in patients without prophylaxis to 82.4% in those who received secondary prophylaxis and 16.7% in those who received primary prophylaxis. Although the incidence of FN was not different between patients without prophylaxis and patients who received secondary prophylaxis (15.7% and 14.9%), none of the patients who received primary prophylaxis developed FN. Moreover, a decrease in neutropenic events resulted in a significant decrease in the mean duration of neutropenia (2.50 days to 0.08 days, P < 0.001), the risk of hospitalization (29.8% to 2.2%, P < 0.001), and the mean total hospital care cost for all chemotherapy cycles (790.80 to 486.00 US dollars, P < 0.001). The use of pegfilgrastim prophylaxis during adjuvant TC chemotherapy is associated with significant decreases in the incidence of neutropenic events, hospitalization, and hospital care cost compared to those seen in patients without prophylaxis. INTRODUCTION Adjuvant chemotherapy for early-stage breast cancer (EBC) reduces recurrence rates and improves survival rates [1]. Among various adjuvant chemotherapy regimens, anthracycline-based chemotherapy remains the core of most adjuvant chemotherapy regimens for EBC. However, because cardiotoxicity and secondary leukemia have been associated with anthracycline-based regimens, the development of the adjuvant chemotherapy landscape for EBC is ongoing [234]. Since 2005, when studies suggested that taxane-based regimens without anthracycline might provide equivalent or superior results to anthracycline-based regimens [5], the use of anthracycline-based regimens has declined while the use of taxane-based regimens has increased among patients with breast cancer in the United States [6]. Previous studies indicate that taxane-based regimens have become the standard for adjuvant chemotherapy. Treatment with 4 cycles of docetaxel and cyclophosphamide (TC) in the adjuvant setting was shown to be associated with significant improvements in 5-year disease-free survival (DFS) and overall survival (OS) over doxorubicin and cyclophosphamide (AC) in a phase III randomized clinical trial [7]. After that, second-generation phase III trials demonstrated that survival outcomes for 6 cycles of TC and 4 cycles of epirubicin + cyclophosphamide followed by 4 cycles of docetaxel were equally excellent in human epidermal growth factor receptor (HER) 2-negative EBC with lower risk [89]. Thus, the TC regimen is attracting attention for adjuvant chemotherapy of EBC. Febrile neutropenia (FN) is a serious adverse effect encountered in patients undergoing myelosuppressive chemotherapy for EBC [10]. Because chemotherapy-induced FN is associated with life-threatening infections, prolonged hospitalization, increased health care costs, and modification of the dose or schedule of chemotherapy, it is critical to assess the risk of FN and prevent it with recombinant granulocyte colony-stimulating factor (G-CSF) in a myelosuppressive chemotherapy regimen [11]. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Hematopoietic Growth Factors indicate that TC confers a high risk (>20%) of FN and recommends the use of primary prophylactic G-CSF [12]. In a meta-analysis with 902 patients from 13 studies, the estimated rate of FN without primary G-CSF was 29.1%, while that with primary G-CSF prophylaxis was 6.8% for TC [13]. However, in an early phase III randomized clinical trial, treatment with 4 cycles of adjuvant TC was associated with a 5% risk of FN [5]. Moreover, in a randomized study conducted in Japan, treatment with 6 cycles of neoadjuvant TC was associated with a 13.8% risk of FN [14]. Considering the ethnic differences in hematologic toxicity and the absence of any Korean reports on FN risk after adjuvant TC chemotherapy, we evaluated the incidence of chemotherapy-related neutropenic events and other adverse events during adjuvant TC chemotherapy in Korean patients with EBC. Furthermore, we assessed the clinical utilization of primary or secondary prophylactic support with long-acting G-CSF (pegfilgrastim) in these patients. METHODS Study population This study was approved by the Institutional Review Board of The Catholic University of Korea, St. Vincent's Hospital (No. VC18RESI0162). Written informed consent was obtained from all patients. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The electronic medical records were reviewed for patients with EBC who received adjuvant TC chemotherapy from July 2015 to December 2019. In total, 209 consecutive patients who received adjuvant TC chemotherapy were included in this study. Eight patients, including 2 patients who did not complete adjuvant TC chemotherapy and 6 patients treated with neoadjuvant chemotherapy, were excluded to minimize other confounding factors. A total of 201 patients were included in the current study. We reviewed the patients' demographics and tumor characteristics, including age, body mass index (BMI [kg/m2]), body surface area (BSA [m2]), menopausal status, type of surgery, pathological T and N staging, histologic grade and type, hormone receptor (HR) and HER2 expression, and comorbidities. HR status was determined using an enzyme immunoassay and reported in the patients' medical records. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or silver in situ hybridization (SISH) was used to evaluate HER2 status, and an IHC score of 0 or +1 or an IHC score of +2 and negative FISH/SISH were defined as negative HER2 overexpression. Chemotherapy and use of granulocyte colony-stimulating factor All patients received a total of 4 cycles of TC chemotherapy, 3 weeks apart. In each cycle, docetaxel (75 mg/m2, intravenous [IV] for 1 hour) was initially administered, immediately followed by cyclophosphamide (600 mg/m2, IV for 1 hour). Secondary prophylaxis using pegfilgrastim (Neulasta, Amgen, Thousand Oaks, CA, USA) has been used in Korea since 2015, when it became covered by the National Health Insurance. Secondary prophylaxis with pegfilgrastim was defined as the use of G-CSF if a patient experienced a neutropenic event in the previous chemotherapy cycle. Primary prophylaxis using pegfilgrastim has been used in Korea since April 2018 with the approval of the National Health Insurance program. Pegfilgrastim was administered subcutaneously between 24 and 48 hours after the administration of chemotherapy. When not using pegfilgrastim, short-acting recombinant G-CSF (filgrastim) was administered daily after each cycle for grade 3 or 4 neutropenia until the absolute neutrophil count (ANC) was restored to 1,000/mm3. Laboratory tests, including complete blood cell (CBC) counts with differential and chemistry assays, were checked before each chemotherapy cycle and on day 6. After chemotherapy, baseline CBC counts were measured from day 6 until the ANC was restored to 1,000/mm3. All patients with FN received prophylactic antibiotic therapy comprising 1-g IV cefoperazone twice daily and 200-mg tobramycin sulfate once daily, unless contraindicated. Adverse events assessment The incidence of FN and FN-related complications according to the Common Terminology Criteria for Adverse Events (CTCAE, version 4.02) were investigated. FN was defined as neutropenia (grade 4 or grade 3 for over 48 hours) with a febrile event (oral temperature of ≥38.3℃, or ≥38.0℃ for over 1 hour) observed by medical staff. Dose reduction was defined as a reduction in the delivered dosage(s) of agent(s) administered relative to the standard values, and dose delay was defined as a chemotherapy interval of more than 21 days. The chemotherapy relative dose intensity (RDI) was estimated based on the ratio of delivered dose intensity and the reference standard dose intensity [15]. Total hospital care cost was calculated as the costs associated with all medical claims during the entire cycle or within each cycle. Outpatient hospital visit costs, hospitalization costs, chemotherapy costs, and G-CSF costs were all included in the total hospital care cost measure. The costs represented the reimbursed amount paid by the patient, as documented in the electronic medical record. Statistical analysis The chi-square test and Fisher exact test were used to determine differences in categorical variables between groups. The unpaired t-test and analysis of variance were used for comparison between continuous and independent variables that follow a normal distribution (age, BMI, BSA, RDI, recovery from neutropenia [days]). Continuous and independent variables that do not follow a normal distribution were analyzed using Mann-Whitney tests (weight gain [kg]). A P-value of <0.05 was considered to be statistically significant. The analyses were performed using PASW Statistics, ver. 18.0 for Windows (IBM Corp., Armonk, NY, USA). RESULTS Between July 2015 and December 2019, 201 Korean patients (804 cycles) with EBC who received adjuvant TC chemotherapy were included in the analysis. A total of 115 patients (57.2%) did not receive prophylaxis with pegfilgrastim, 74 (36.8%) received secondary prophylaxis, and 12 (6.0%) received primary prophylaxis with pegfilgrastim during adjuvant TC chemotherapy. The demographics and clinical characteristics of the study population by the method of prophylaxis with pegfilgrastim are shown in Table 1. Overall, the median age was 55 years (range, 21–79 years). A total of 37 patients (18.4%) were older than 65 years. The mean BMI and BSA were 24.71 ± 3.48 kg/m2 and 1.60 ± 0.13 m2, respectively. Patients who received primary prophylaxis had a significantly older median age at diagnosis than patients who did not receive prophylaxis or received secondary prophylaxis (P = 0.009). There were no significant differences in menopausal status, type of surgery, tumor stage, histologic grade, histologic type, comorbidity, or HR or HER2 status among the 3 groups (Table 1). Chemotherapy-related neutropenic events The combined incidence of grade 3 and 4 neutropenia was 3.5%, and 93.0% of patients did not receive prophylaxis with pegfilgrastim (Table 2). However, the incidence of grade 4 neutropenia decreased to 82.4% with secondary prophylaxis (P = 0.035) and 16.7% with primary prophylaxis (P < 0.001). In the analysis of 804 chemotherapy cycles, the incidence of grade 4 neutropenia was 74.6% in all cycles without prophylaxis and 5.3% in all cycles with prophylaxis with pegfilgrastim (P < 0.001) (Table 3). Moreover, the mean period of recovery from neutropenia was significantly shorter in chemotherapy cycles with prophylaxis with pegfilgrastim than in chemotherapy cycles without prophylaxis (2.50 ± 1.09 days vs . 0.08 ± 0.26 days, P < 0.001) (Table 3). The ANC changes after the chemotherapy cycle according to pegfilgrastim prophylaxis status are shown in Fig. 1. The incidence of FN was not significantly different between patients who did not receive prophylaxis and patients who received secondary prophylaxis (15.7% and 14.9%, P = 0.528) (Table 2). However, no patients who received primary prophylaxis with pegfilgrastim developed FN. Overall, FN occurred in 6.9% of all chemotherapy cycles without prophylaxis and 0.9% of all cycles with prophylaxis with pegfilgrastim (P < 0.001) (Table 3). Other chemotherapy-related adverse events Regarding hematologic toxicities other than neutropenia, there were no differences in the incidence of anemia, thrombocytopenia, and transfusion between patients who did not receive prophylaxis and patients with secondary prophylaxis (Table 2). These findings were the same when the results were analyzed by chemotherapy cycle (Table 3). There was no anemia or thrombocytopenia in patients who received primary prophylaxis. Moreover, the weight gained due to chemotherapy was less in patients who received primary prophylaxis than in the other 2 groups (Table 2). Among all patients who received TC chemotherapy, no patient experienced severe hepatotoxicity or nephrotoxicity. Among the 115 patients who did not receive prophylaxis with pegfilgrastim, 6 (5.2%) developed neutropenic infections, which included 2 patients with chemoport infection and 4 patients with wound infections. Among the 74 patients who received secondary prophylaxis, 5 (6.8%) developed neutropenic infections, which included 1 patient with a chemoport infection and 4 patients with wound infections. Among patients who received primary prophylaxis, there were no neutropenia-associated infections (Table 2). Although there were no significant differences in dose reduction (2.6% vs. 2.7%, P = 0.651) or treatment delay (3.5% vs. 1.4%, P = 0.078) between patients who did not receive prophylaxis and patients who received secondary prophylaxis, the RDI was lower in patients who did not receive prophylaxis than in those who received secondary prophylaxis (99.33% vs. 99.69%, respectively; P = 0.025). In patients who received primary prophylaxis, there was no association between treatment and dose reduction and treatment delay, and the RDI was 100% (Table 2). Compared with treatment without prophylaxis, patients who received secondary prophylaxis were not associated with a reduction in the risk of hospitalization (37.4% vs. 31.1%, P = 0.233), whereas primary prophylaxis was significantly associated with a reduction in the risk of hospitalization compared with the other 2 groups (37.4% vs . 8.3%, P = 0.038; 31.1% vs. 8.3%, P = 0.045) (Table 2). The incidence of hospitalization in each chemotherapy cycle was 29.8% in patients who did not receive prophylaxis and 2.2% in patients who received pegfilgrastim prophylaxis (P < 0.001) (Table 3). Hospital care cost The mean total hospital care cost for all chemotherapy cycles was greater for patients who did not receive prophylaxis than for patients who received secondary prophylaxis (790.80 US dollars [USD] vs. 728.40 USD, P = 0.008). In patients who received primary prophylaxis, the mean total hospital care cost for all chemotherapy cycles was 486.00 USD, and this cost was significantly lower than that for the other 2 groups (P < 0.001). In the analysis of each chemotherapy cycle, the mean hospital care cost for each chemotherapy cycle was significantly greater for patients who did not receive prophylaxis than for patients who received prophylactic pegfilgrastim (199.20 USD vs. 157.20 USD, P < 0.001). DISCUSSION In this study, we assessed the clinical effectiveness of pegfilgrastim prophylaxis in adjuvant TC chemotherapy by directly comparing the incidences of chemotherapy-related neutropenic events and other adverse events according to the method of prophylaxis in Korean EBC patients who received adjuvant TC chemotherapy. Primary prophylaxis with pegfilgrastim after adjuvant TC chemotherapy was significantly associated with a decrease in the incidence of chemotherapy-related neutropenic events, including FN, and the mean period of recovery from neutropenia, the risk of hospitalization, and the cost of hospital care for chemotherapy compared to those in patients who did not receive prophylaxis or who received secondary prophylaxis. With longer follow-up, 4 cycles of adjuvant TC chemotherapy showed a significant benefit over 4 cycles of AC chemotherapy in regard to DFS and OS and had a lower risk of anthracycline-related cardiac toxicity than the AC regimen [7]. Although the TC regimen has these clinical benefits over the AC regimen, the TC regimen results in a significantly higher incidence of chemotherapy-induced hematologic toxicities, such as neutropenia and FN, than the AC regimen [71316]. In a previous meta-analysis with 902 patients from 13 studies and with 2,532 patients from 14 studies, the estimated FN rates without primary G-CSF were 29.1% and 31.3% [1316]. Furthermore, the NCCN guidelines have indicated that TC confers a high risk (>20% chance of occurrence) of FN, while AC confers an intermediate risk (10%–20% chance) of FN [12]. However, the incidence of FN after adjuvant TC chemotherapy was not reported in more than 20% of all studies. The clinical trial conducted by the US Oncology Group reported a 5% FN incidence [5], and the West German Study PlanB trial reported a 6% FN incidence without primary prophylaxis [9]. In this study, the overall incidence rates of grade 4 neutropenia and FN were 93.0% and 15.7%, respectively, in patients who did not receive prophylaxis with pegfilgrastim after adjuvant TC chemotherapy. The incidence of grade 4 neutropenia in the present study was a significantly higher than that observed in previous studies conducted in Western countries (10.7%–50.8%) [5917]. However, the incidence of FN in the present study was rather low compared to that observed in 2 previous meta-analyses [1316]. Although it is difficult to explain the exact reason why the incidence rates of FN were low compared to those of the previous 2 meta-analyses and previous studies conducted in Western countries, ethnic differences in hematologic toxicity from docetaxel-based chemotherapy may be an important factor. The pharmacokinetics of docetaxel exhibit wide interindividual variability, which might lead to poor predictability of treatment-related side effects and outcomes [181920]. This variability of docetaxel pharmacokinetics or pharmacodynamics was also seen in a study conducted exclusively in Asian patients, including 103 Chinese, 111 Malay, and 73 Indian patients [19]. In a randomized study conducted in Japan, treatment with 6 cycles of neoadjuvant TC was associated with a 13.8% risk of FN [14]. Moreover, the incidence of FN was 25.2% for 4 cycles of the AC regimen and 4.7% for 4 cycles of the docetaxel regimen (75 or 100 mg/m2) in a Korean study on sequential AC and docetaxel chemotherapy [21]. The use of long-acting G-CSF results in better supportive care and improved quality of life in breast cancer patients by significantly reducing grade 4 neutropenia and FN [10111316]. In our study, the incidence of grade 4 neutropenia decreased from 93.0% to 16.7%, and the incidence of FN decreased from 15.7% to 0%, among all patients who received primary prophylactic pegfilgrastim. Moreover, a decrease in the incidence of grade 4 neutropenia and FN resulted in a significant decrease in the mean duration of neutropenia (from 2.50 days to 0.08 days), the risk of hospitalization (from 29.8% to 2.2%), and the mean total hospital care cost for all chemotherapy cycles (from 790.80 to 486.00 USD). The rate of hospitalization after the use of primary prophylactic pegfilgrastim in our current study was much lower than the rate of hospitalization adjusted for G-CSF primary prophylaxis observed in a previous study (6.7%–13.1%) [22]. Furthermore, the use of long-acting G-CSF results in the preservation of RDI, which is an important factor in achieving optimal survival outcomes after adjuvant chemotherapy. In this study, the RDI was significantly higher in patients who received primary prophylaxis than in patients who did not receive prophylactic pegfilgrastim (99.33% vs . 100%, P = 0.049). Although our current study did not analyze survival outcomes due to the short follow-up period, further studies with long-term follow-up will provide conclusions about improving survival outcomes with the use of long-acting G-CSF. Our study has some limitations, such as its retrospective nature. The number of patients was small because only patients who received adjuvant TC chemotherapy at a single institution were included. Moreover, decisions regarding hospitalization, dose reduction, and treatment delays were made based on our institutional treatment protocol. Additionally, only FN observed by medical staff was counted in the current study. Therefore, the incidence of FN may have been underestimated, as febrile events confirmed by the patient prior to the hospital visit were not included. However, we believe that this study has clinical value because it is the first study assessing the incidence of chemotherapy-related neutropenic events and other adverse events, and the clinical utilization of primary or secondary prophylactic support with long-acting G-CSF (pegfilgrastim) during adjuvant TC chemotherapy, in Korean patients with EBC. In summary, our study demonstrated that the overall incidence of grade 4 neutropenia, at 93.0%, was significantly higher than that observed in previous studies conducted in Western countries. Although the incidence of FN was 15.7%, rather low compared to that observed in the previous 2 meta-analyses, the use of pegfilgrastim prophylaxis during adjuvant TC chemotherapy was associated with significant decreases in the incidence of grade 4 neutropenia, FN, the risk of hospitalization, and the cost of hospital care for chemotherapy compared to no prophylaxis. Further large-scale prospective studies will help fill the gap in the evidence regarding FN risk and will thus inform the use of pegfilgrastim prophylaxis for this regimen in real-world practices. Fund/Grant Support: This research was sponsored by Kyowa Kirin Korea Co., Ltd. Conflicts of Interest: The authors declare that they have no conflict of interest. Author Contribution: Conceptualization: YWJ, YJS. Formal Analysis: YWJ, STL. Investigation: YWJ, SYP, JS, HSH. Methodology: YWJ, HG. Project Administration: YWJ. Writing — Original Draft: YWJ, STL, HG, SYP, JS, HSH. Writing — Review & Editing: YWJ, YJS. Fig. 1 The absolute neutrophil count (ANC) changes after chemotherapy according to the use of prophylaxis with pegfilgrastim. Table 1 Patient and tumor characteristics Values are presented as mean ± standard deviation (range) or number (%). ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2. Table 2 Comparison of chemotherapy-related neutropenia and other adverse events in all patients according to the method of prophylaxis Values are presented as number (%) or mean ± standard deviation unless otherwise specified. RDI, relative dose intensity. Table 3 Comparison of chemotherapy-related neutropenia and other adverse events in all chemotherapy cycles according to prophylaxis with pegfilgrastim Values are presented as number (%) or mean ± standard deviation.	FOR 1 HOUR	DrugDosageText	CC BY-NC	33585350	18,963,860	2021-02
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute hepatic failure'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute respiratory failure'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anaemia'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac arrest'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac failure acute'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Decreased appetite'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dehydration'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disseminated intravascular coagulation'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dyspnoea'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Electrolyte imbalance'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Enterobacter infection'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemophagocytic lymphohistiocytosis'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypoproteinaemia'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Multiple organ dysfunction syndrome'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Oliguria'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Shock'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Splenomegaly'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Still^s disease'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment noncompliance'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vomiting'.	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	LEFLUNOMIDE, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Acute hepatic failure'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Not recovered	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Acute respiratory failure'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Not recovered	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Anaemia'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Fatal	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Cardiac arrest'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Fatal	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Cardiac failure acute'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Not recovered	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Decreased appetite'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Not recovered	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Dehydration'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Not recovered	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Diarrhoea'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Not recovered	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Disseminated intravascular coagulation'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Not recovered	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Dyspnoea'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Not recovered	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Electrolyte imbalance'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Not recovered	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Enterobacter infection'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Not recovered	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Haemophagocytic lymphohistiocytosis'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Not recovered	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Hypoproteinaemia'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Fatal	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Multiple organ dysfunction syndrome'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Not recovered	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Nausea'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Not recovered	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Oliguria'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Not recovered	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Pyrexia'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Not recovered	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Shock'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Not recovered	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Splenomegaly'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Fatal	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Still^s disease'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Fatal	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Treatment noncompliance'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Fatal	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
What was the outcome of reaction 'Vomiting'?	Adult-onset Still's disease evolving with multiple organ failure and death: A case report and review of the literature. BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. METHODS We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSIONS AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications. Core Tip: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, and the lack of disease-specific symptoms and laboratory markers hinders the diagnosis and assessment of its progression. More importantly, the treatment of AOSD remains largely empirical, with a lack of controlled clinical trials. Few cases of the disease with multiple complications have been reported. The present case highlights the characteristics of AOSD and severe complications and shares our experience in its diagnosis and treatment to provide experience for the effective recognition and treatment of this disease. The authors also note the link between the biopsychosocial model and autoimmune diseases. INTRODUCTION Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease, which is characterized by fever, arthritis, an evanescent rash, and neutrophilic leukocytosis. Other nonspecific symptoms may be observed in AOSD, such as sore throat, cardiopulmonary features, kidney disease, and neurological manifestations[1,2]. AOSD was definitively described in 1971 by Eric Bywaters, who named the disease on account of its close resemblance to the pediatric syndrome systemic-onset juvenile idiopathic arthritis (SoJIA), which was formerly called “Still's disease” for the reason that it was described by Dr George Still in 1897[3,4]. The etiology is unknown, and both infectious triggers and genetic factors have been suggested, but there is no clear evidence of an infectious etiology[5]. Available epidemiologic results show that the incidence of AOSD ranges between 0.16 and 0.4/100000 people, with an estimated prevalence rate between 1 and 34 cases/1 million people[2,6,7]. Based on some reports, females seem to be more affected than males; however, AOSD is considered to be evenly distributed between the sexes. AOSD usually afflicts young people, with a bimodal peak at ages 15-25 and 36-46 years[2,8]. Diagnosis is based on clinical grounds, following the exclusion of mimickers of autoimmune, infectious, and neoplastic disorders, with the additional consideration of nonspecific laboratory abnormalities such as elevation of serum ferritin (SF), peripheral leukocytosis, and other acute-phase reactants[9]. In general, the absence of disease-specific symptoms and laboratory markers hinders its diagnosis, and the lack of established disease activity markers makes the determination of treatment efficacy problematic. More importantly, AOSD-related complications are significantly associated with mortality. These patients may also experience different complications that affect their clinical symptoms, management, and prognosis. Moreover, clinical progression is also unpredictable, with 60%-70% of those patients developing a chronic form of the disease[2]. CASE PRESENTATION Chief complaints A 36-year-old woman presented to the Outpatient Department of our hospital complaining of poor wound healing of an incision in her right hip and AOSD. History of present illness She had developed steroid-induced femoral head osteonecrosis caused by long-term prednisone therapy for AOSD, and the incision had not healed by 2 mo after bilateral prosthetic replacement. She was hospitalized for treatment in a stable condition. During hospitalization, the patient suddenly developed high fever and diarrhea, with the highest temperature reaching 38.2 °C, accompanied by nausea, vomiting, poor appetite, and mild dehydration. The patient was transferred to the intensive care unit (ICU) after refusing fluid rehydration therapy with deep-vein puncture. After further inquiry about the patient's history, her husband said that her AOSD was greatly affected by her mood, and the patient had a high fever of 41 °C lasting for 1 mo due to depression". The next day, her condition suddenly deteriorated, blood pressure decreased, and her dyspnea, oliguria, and disease rapidly worsened. History of past illness Twenty-two years prior (at 14 years old, 1998), fever occurred due to overfright, with the highest body temperature reaching 40 °C; her body temperature often increased in the morning. This was accompanied by a red rash on her back, sore throat, migratory swelling, and pain of multiple joints and muscle in the whole body, mainly affecting the proximal interphalangeal joint of both hands, metacarpophalangeal joint, double wrist joint, double elbow joint, and bilateral temporomandibular joint. Her symptoms associated with morning stiffness eased slightly after 1 h of activity. Test results showed that SF was increased and white blood cells (WBCs) obviously increased. The first diagnosis was "juvenile rheumatoid arthritis of systemic type", and the patient was treated with prednisone up to 30 mg/d, sulfasalazine, methotrexate, and leflunomide. After her symptoms improved, the patient stopped taking the medicines. The disease then recurred, and she was diagnosed with "AOSD" and was treated with prednisone at a dose up to 60 mg (1 mg/kg), methotrexate, and traditional Chinese medicine, resulting in short-term improvement of symptoms. In 2002, bilateral alternating hip pain began to appear. After that, movement of both hip joints and knee joints was limited, with overflexion of the proximal interphalangeal joints of fingers and feet. In 2015, X-ray of her hands was performed, showing a narrow joint space of the hands and wrists. X-ray of the hip joint revealed a flattened femoral head on both sides, with multiple transparent shadows and hyperosteogeny and sclerosis, and the acetabular bone on both sides was obviously thinner; some bones were discontinuous, with hyperosteogeny and cystic shadow, and the joint space of both hips became obviously narrow. During this period, the disease recurred many times, and the patient took oral prednisone, lothorofan, and leflumide intermittently. Methotrexate, iguratimod, and Tripterygium wilfordii were discontinued due to adverse effects. In April 2016, the patient began treatment with etanercept. After that, due to frequent recurrence of the disease, the patient began to receive regular monthly intravenous administration of an interleukin (IL)-6 antagonist (Actemra) at 320 mg, and the dose of prednisone was reduced to 10 mg/d. In April 2020, she was hospitalized with the aggravation of pain in both hip joints and a limp. The test results showed that WBC count, C-reactive protein (CRP), and SF were normal. Bilateral femoral head necrosis was definitively diagnosed, and bilateral prosthetic replacement was performed. Two months after the surgery, the patient did withdrawal of Actemra and immuno-suppressive agents on her own. Physical examination After her second day in the ICU, the patient’s temperature was 36.5 °C, her heart rate was 96 bpm, her respiratory rate was 26 breaths per minute, her blood pressure was 80/41 mmHg, and her oxygen saturation in room air was 88%-96%. The patient was under some type of sedation but responded to painful stimuli. A 1 cm unhealed incision was seen on the right hip, with seepage of a reddish fluid. Other physical examinations showed no abnormal signs. Laboratory examinations On the first day in the ICU, laboratory parameters showed abnormalities of routine blood examination, coagulation function, hepatic function, and serum electrolytes (Table 1, Day 1). Table 1 Main laboratory findings (Day 1 to Day 4) Main laboratory finding Value Normal range Day 1 Day 2 Day 3 Day 4 White blood cell count 5.0 5.6 20.5 28.3 (3.5-9.5) × 109/L Lymphocyte percentage 6.6 10.1 8.9 15.6 20%-50% Neutrophil percentage 90 86.7 90.1 81 40%-75% Hemoglobin 80 99 112 98 (115-150) g/L Platelets 30 32 52 35 (125-350) × 109/L Prothrombin time 18.1 18.8 18.2 16.4 (9-14) s International normalized ratio 1.6 1.68 1.62 1.42 Prothrombin activity 54.9 51.8 54.2 63 % Activated partial thromboplastin time standardization 61 55.3 54.1 56.8 (20-40) s Thrombin time 39.7 37.1 50.6 Chyle blood, no test (14-21) s Fibrinogen 1.37 1.0 0.77 Chyle blood, no test (2-4) g/L D-Dimer 4.88 5.96 (0-0.5) μg/L Fibrinogen degradation products 272.9 90.6 (0-5) μg/L Erythrocyte sedimentation rate 10 (0-20) mm/L C-reactive protein 121.01 111.7 104.2 (0-10) mg/L Hemolytic index 15 15 60 55 0-15 Blood lipid index 2 2 2 225 0-2 Total protein 57.1 53.5 46.8 55.7 (65-85) g/L Albumin 28.8 26.3 26.3 23.2 (40-55) g/L Globin 28.3 27.3 26.2 24.4 (20-40) g/L Total bilirubin 35.9 42.9 49.6 62.1 (0-21) μmol/L Conjugated bilirubin 14.6 19.5 27.3 35.2 (0-5) μmol/L Unconjugated hyperbilirubinemia 3.5 3.5 2.6 4.2 (0-19) μmol/L Glutamic-pyruvic transaminase 84.9 90.9 139.8 153.8 (0-40) U/L Aspartate aminotransferase 295 329 593 589 (0-40) U/L Alkaline phosphatase 366 510 508 453 (38-126) U/L γ-Glutamyl transpeptidase 118 161 185 183 (6-35) U/L Cholinesterase 3584.3 3395.1 3476.1 4351.8 (4650-12220) U/L Lactate dehydrogenase 5292 5616 9299 8746 (313-618) U/L K+ 4.9 4.57 4.42 5.3 (3.6-5) mm/L Na+ 127.8 128.9 142.6 146.2 (137-145) mm/L Cl- 102 103.9 111.8 106.7 (98-107) mm/L Creatinine 288.1 299.2 298.8 311.5 (41-73) μmol/L Carbamide 16.19 17.79 22.38 28.01 (2.6-7.5) mm/L Uric acid 683 706.4 487.4 510.4 (155-357) μmol/L Hypersensitive troponin 0.012 0.138 13 52 (0-0.034) ng/L NT-ProBNP 4120 9910 35000 35000 (0-125) pg/L Myoglobin 145.7 936.4 (0-110) ng/moL Procalcitonin 10.479 24.025 (0-0.05) ng/mL This table shows the main laboratory findings of the patient during the intensive care unit. Imaging examinations Abdominal B-ultrasonography revealed splenomegaly. X-ray of the hip joints showed that the shape and position of bilateral prosthesis were normal, and there were no signs of infection. Further diagnostic work-up Over the next 3 d in the ICU, the laboratory parameters of routine blood examination, coagulation function, hepatic function, and serum electrolyte deteriorated further (Table 1, Day 2, 3 and 4). The level of SF was more than 10000 ng/mL (normal range: 13-150 ng/mL). The level of general cortisol was more than 1649.9 mmol/L (101.2-535.7 mmol/L), and that of adrenocorticotrophic hormone was less than 1.54 mL/L (7.2-63.6 mL/L). Serum κ and λ light chain levels were 60.9 mg/L (6.7-22.4 mg/L) and 1.62 (0.31-1.56 mg/L), respectively, and the ratio of κ/λ was 1.62 (0.31-1.56). Other immunological tests were almost within the normal range, including anti-phospholipid antibodies, immunoglobulin, complement, rheumatoid factor (RF), antistreptolysin O test, anti-CCP antibody, autoimmune antibody tests, and Coombs test (MGCT). No bacteria or fungi were found in blood culture, sputum culture, or secretions of surgical wound. Routine urine tests indicated urine protein 2+, occult blood 2+, and WBCs 188.5 mL/L, with no other abnormality found. Fecal flora analysis indicated 100% Enterobacter spp. The examination of lymphocyte subpopulations and cytokines was ongoing. MULTIDISCIPLINARY EXPERT CONSULTATION Given the multiple organ involvement and high SF and WBC levels, and the patient's history of stopping Actemra and immunosuppressive agents on her own for 2 mo, the diagnosis of active AOSD was confirmed by multidisciplinary expert consultation. It was discussed whether the diarrhea was a second hit. Diarrhea may trigger a pathologic process in genetically susceptible patients, finally leading to an uncontrollable increase in proinflammatory cytokines, with a severe systemic inflammatory reaction, which is responsible for AOSD development. It was agreed that the large dose of cortisol impulse therapy up to 200 mg per day was a reasonable treatment and that immunomodulatory and inflammatory suppression should be continued. Hemodialysis should also be performed to remove metabolic wastes and inflammatory factors from the blood. Furthermore, the examination of lymphocyte subpopulations and cytokines should be carried out to detect disease activity. If necessary, the patient should undergo bone marrow biopsy, flow cytometry, and chromosome testing. Treatment with cortisol at a dose of 200 mg/d was re-commended, and hemodialysis was performed. In the case of nonresponse, it was decided to consider treatment with Actemra and cyclosporine. FINAL DIAGNOSIS The final diagnoses of the presented case were shock, multiple organ dysfunction syndrome (acute heart failure, acute liver failure, acute respiratory dysfunction, and abnormal coagulation function), AOSD, acute gastroenteritis, postoperative nonunion of the right hip, electrolyte disorder, anemia, and hypoproteinemia. TREATMENT After comprehensive treatment, such as anti-shock, blood transfusion, auxiliary ventilation, plasma exchange, and cortisol impulse treatment, the patient’s body temperature returned to normal, but her diarrhea was not relieved. OUTCOME AND FOLLOW-UP On the third day in the ICU, the patient’s condition worsened; her blood pressure suddenly dropped to 50/30 mmHg, and she did not respond to increased epinephrine and dopamine doses or intravenous epinephrine. In the end, the patient had sudden cardiac arrest, and she died despite emergency rescue efforts. DISCUSSION AOSD is classified as a multigenic autoinflammatory disease because of its complex pathogenesis, involving both the innate and adaptive immune systems. It is generally considered that some unknown factors, playing as second hits, may startup a pathologic procedure in genetically susceptible patients, eventually leading to the activation of an aberrant inflammatory response, which leads to the development of AOSD. Although the pathogenesis is mostly unknown, the pivotal role of proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-17, IL-18, interferon-γ, tumor necrosis factor, and ferritin in developing the inflammatory vicious circle has been reported[10-13]. There are six sets of criteria for the diagnosis of AOSD currently, and Yamaguchi's criteria are the most sensitive as well as the most widely used. The criteria include fever evanescent rash, arthralgia, and leukocytosis as major items and other nonspecific symptoms, such as sore throat, lymphadenopathy, splenomegaly, deterioration of liver function, negative rheumatoid factor, and antinuclear antibody as minor items; more than five items including at least two major criteria are necessary for the diagnosis and to exclude malignancy or infectious disease[14]. AOSD typically manifests with a symptomatic triad characterized by fever (60%-100%), red rash (60%-80%), and arthralgia and arthritis (70%-100%) which may develop to destructive symmetric polyarthritis[1]. In AOSD, fever always precedes other manifestations' onset, and the fever shows an abrupt onset usually, commonly once or twice the quotidian pattern, with the highest temperature detected in the early evening or late afternoon. The temperature may sometimes return to a normal value without any antipyretic treatment. The rash is usually observed on the proximal trunk and limbs, appearing during the febrile attacks, and its typically histopathology shows a mixed inflammatory infiltrate, surrounding the perivascular areas without epidermal changes. Joint disease is also a common sign. Arthritis and arthralgia mostly affect knees, wrists, and ankles. Some patients may gradually develop chronic destructive symmetrical polyarthritis and ankylosis in subsequent years. Laboratory test of joint fluid may show an inflammatory fluid with neutrophil predominance. Other nonspecific symptoms may be found in AOSD, such as sore throat, cardiopulmonary features, kidney disease, neurological manifestations, enlargement of cervical lymph nodes (LNs), splenomegaly, hepatomegaly, liver dysfunction, and increased hepatic enzymes[15]. Laboratory tests commonly show increased SF, CRP, and erythrocyte sedimentation rate (ESR), neutrophilic leukocytosis, anemia, and thrombocytopenia. The levels of SF are higher than those observed in other autoimmune, infectious, inflammatory, or neoplastic diseases. It has been reported that SF is an acute-phase protein released from impaired hepatocytes; the levels may be elevated in inflammatory disorders, alcohol abuse, liver disease, infectious diseases such as HIV infection, or malignancy[16]. Eighty percent of AOSD patients were reported to have increased ferritin levels, 70% of which were more than five times the normal upper limit[17]. The median level of SF in AOSD patients is reportedly 4752 ng/mL. A SF level higher than 10000 ng/mL can be a specific marker for AOSD if there is no severe liver dysfunction or history of multiple blood transfusions, but the SF level itself is only a nonspecific marker for inflammation[18-20]. Due to its low specificity, elevated SF is not included in this disease's diagnostic criteria, but we consider that this association is worth highlighting, given that younger age and the nonspecific nature of most presentations often lead to delayed diagnosis[21-23]. It has been reported that proinflammatory cytokine levels are significantly increased in both the pathological tissues and sera of patients with active or untreated AOSD, and that ferritin synthesis is regulated by proinflammatory cytokines at various levels during cellular differentiation, proliferation, and inflammation. Cytokines may also have an effect on ferritin translation indirectly by their ability to increase inducible nitric oxide synthase (iNOS) and hence increase the levels of NO. NO in turn induces ferritin expression. These reports suggest that the level of ferritin might be a good biomarker to monitor the disease activity of AOSD[10,24]. Furthermore, thrombocytopenia and leukocytosis are reportedly promoted along with rises in SF levels, which is associated with AOSD's disease activity strongly and may also be a biomarker of AOSD[25,26]. Some studies have confirmed that SF and heme oxygenase 1 can serve as highly sensitive and specific biomarkers for AOSD[27]. AOSD patients may experience different complications affecting their clinical manifestations, management, and prognosis. The major cause of death is infection, followed by severe complications. Important systemic complications of AOSD reported until now include macrophage activation syndrome (MAS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulopathy (DIC), thrombotic microangiopathy, diffuse alveolar hemorrhage, respiratory distress syndrome, pulmonary arterial hypertension, shock, multiple organ failure, myocarditis, tamponade, constrictive endocarditis, pericarditis, fulminant hepatitis, and amyloidosis[9,15,28]. MAS or reactive hemophagocytic syndrome (HPS) is a potentially life-threatening complication characterized by excessive macrophage activity and cytokine production leading to multiple organ failure[29,30]. Primary MAS commonly occurs in children with MAS-associated genetic defects or a family history of MAS, while secondary MAS occurs after exposure to immunological trigger factors of underlying autoimmune diseases, infections, malignancies, or flares of AOSD[31]. It is reported that the incidence of MAS is up to 15% among those AOSD patients and it is considered the most severe complication, with a high mortality rate ranging from 10% to 41%[9,32]. The criteria for diagnosing MAS according to the 2004 guidelines are as follows: (1) Fever > 38.5 °C or lasting more than 7 d; (2) Cytopenia affecting at least two of three lineages in the peripheral blood (Hb < 90 g/L, absolute neutrophil count < 1.0 × 109/L, platelet < 100 × 109/L); (3) Splenomegaly; (4) Hypofibrinogenemia or hypertriglyceridemia; (5) Hyperferritinemia (SF ≥ 500 µg/L); (6) Hemophagocytosis in bone marrow, lymph nodes, or the spleen; (7) High levels of sIL-2r (s-CD25 ≥ 500 µg/L); and (8) Low or absent NK-cell activity. MAS can be diagnosed if five of the eight criteria are fulfilled[33]. However, the diagnosis of MAS is often delayed due to possible differential diagnoses. These include conditions that can present with similar clinical manifes-tations and laboratory abnormalities, such as systemic inflammatory response syndromes or sepsis. However, the level of SF is usually obviously higher in MAS patients and considered a highly characteristic feature of MAS by most scholars[34]. Bone marrow aspiration is considered the gold standard and is usually required in some untypical cases where there may be a diagnostic dilemma. In the present case, the patient presented a high fever with a body temperature of 38.3 °C, splenomegaly, hemopenia, hypertriglyceride, hypofibrinemia, and SF greater than 10000 µg/L. Inflammatory factors and bone marrow puncture were not examined, and the patient died. Although her body temperature did not meet the diagnostic criteria, the continued increase in SF and hypofibrinogenemia reflected worsening of the disease. DIC is also a lethal complication characterized by uninhibited activation of the coagulation system. Some reports suggest that its diagnosis can be challenging, even for some experienced clinicians[35]. A precipitous decrease in ESR in the context of persistent hyperferritinemia and worsening clinical condition may be a danger sign and raise the index of suspicion for the presence of DIC. Some specialists have suggested that anakinra may be recommended for patients with severe flares of AOSD and DIC[36,37]. The treatment of AOSD remains largely empirical, and therapeutic agents for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, and biological disease-modifying anti-rheumatic drugs (bDMARDs). Some studies have shown that NSAIDs may fail to control the symptoms of AOSD, and a large percentage of patients may afflict drug adverse reactions. According to some reports, only 15%-20% of AOSD patients respond to NSAIDs treatment, and a corticosteroid is required to control disease manifestations in most cases. Corticosteroids have been suggested as the first-line treatment for AOSD, producing a clinical response in approximately 60% of cases. Corticosteroids should be started at a dosage of 0.51 mg/kg per day, but intravenous high-dose corticosteroids may be considered if MAS and/or severe visceral involvement occur. Some cases may relapse over chronic treatment or tapering of the corticosteroid dosage[38]. High-dose corticosteroids seem to be more efficient in controlling those disease, but the maintenance of long-term corticosteroids can induce many potential adverse reactions[15,39]. In the present case, the patient developed femoral head necrosis due to long-term glucocorticoid use, and she experienced relapse due to repeated spontaneous reduction or withdrawal of the drug. Cyclosporine and methotrexate (MTX) are the most frequently administered sDMARDs in AOSD, mainly owning to their steroid-sparing effects. Other agents, such as azathioprine, leflunomide, cyclophosphamide, tacrolimus, hydroxychorquine sulfate, and intravenous immunoglobulin, have also been widely applied, producing various response rates. In a study, after adding MTX, 70% of patients achieved complete remission, and 39% of patients discontinued corticosteroids. Thus, csDMARDs have been used to prevent AOSD relapse and allow for reduction of the corticosteroid dosage simultaneously[39-41]. Some researchers also have found that cyclosporine can be used in patients with severe MAS as well as AOSD[42,43]. Biologic agents or biologic DMARDs (bDMARDs) targeting specific cytokines are suggested for the treatment of those cases that are refractory to csDMARDs and corticosteroids. Some studies have revealed a key role of proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-α (TNF-α) in disease pathogenesis, promoting the development of novel targeted therapies aimed at the optimum method of disease control[44]. It has been reported that bDMARDs are an important option for relapsed patients or as a first-line regimen, which may help to reduce the dosage in terms of glucocorticoid and other cDMARD exposure[45,46]. Some researchers have shown that most patients (84.4%) are able to achieve clinical remission initially by using bDMARDs[47]. It has also been reported that a case of glucocorticoid and cyclosporine refractory AOSD complicated by DIC was successfully managed with a humanized anti-IL-6 receptor monoclonal antibody. IL-6 inhibition can lead to a rapid response, symptomatic improvement, and corticosteroid sparing[48]. Wang et al[49] have found that anti-IL-6 antibody combined with MTX have significant therapeutic effects for refractory AOSD, is conducive to the reduction and discontinuation of prednisone, and may allow stabilization of the patient’s condition after reducing the dosage of anti-IL-6 antibody, with good safety. In this case, the patient experienced relapse of the disease due to voluntary drug withdrawal or dosage reduction several times, and her WBC and SF levels were significantly increased. Because of the frequent recurrence of the disease, the patient received anti-IL-6 antibody, and the frequency of disease recurrence was significantly reduced; glucocorticoid dosage was also reduced. The recurrence of her disease was caused by the spontaneous cessation of Actemra and leflunomide at 2 mo after surgery. Diarrhea was the main factor that caused the rapid progression of the disease. The most frequently implicated triggering factors include infections, medications, and disease flares[50]. This may induce T cell activation and proliferation with cytokine secretion (interferon-gamma and granulocyte macrophage colony-stimulating factor) and macrophage hyperactivation. The final result is an uncontrollable increase in IL-1, TNFα, and IL-6 production, with a severe systemic inflammatory reaction[51]. Rituximab may suppress the triggering factor effectively, but the severe AOSD flare and subsequent cytokine release required more T-cell-specific immunosuppression (i.e., cyclosporine) for effective control[52]. Furthermore, the diarrhea resulted in a large amount of fluid loss, electrolyte disturbance, and malnutrition, which aggravated the development of the disease and eventually resulted in DIC and MODS. The mortality rate of MODS patients with two-organ failure is 50%-60%, and the mortality rate of MODS patients with failure of more than four organs is 100%. In addition, a large prospective study identified an increased risk of death in patients with continued platelet depletion and poor response to treatment[53]. Our patient simultaneously developed five-organ failure, and glucocorticoid shock therapy and blood purification failed; the disease progressed violently, and the patient died before the use of cyclosporine and Actemra. In particular, attention should be paid to the signature value of the biopsychosocial model in the process of patient management, which may have great potential value, and mental health may be related to the occurrence, progression, and prognosis of the disease. The patient experienced a high fever lasting 1 mo due to bad mood. Some scholars have found the levels of ESR, CRP, and PLT in patients with rheumatoid arthritis combined with depression to be significantly higher than those in patients with no depression. Psychological intervention for rheumatoid arthritis with depression has obvious effects in improving patients' treatment compliance, as well as improving their primary symptoms and depressive state[54]. Several cross-sectional studies have revealed that those exhibiting depressive manifestations have increased levels of IL-1, IL-6, IL-2, TNF-α, and CRP, which are associated with depression in patients being treated for clinical depression[55,56]. Figueiredo-Braga et al reported that anxiety and depression in lupus are influenced by a complicated mix of biological, social, and psychological factors. Their study also found that IL-6 and IL-10 correlated with increased Hospital Anxiety and Depression Scale (HADS) depression scores in depressed patients. IL-10 is responsible for helping drive the Th2-mediated response that results in increased B cell activation, immunoglobulin G class switching, and increased antibody production. It is also strongly associated with disease activity in patients with systemic lupus erythematosus (SLE)[57]. Overall, the relationship between AOSD and psychology remains to be further studied. CONCLUSION AOSD is an exclusionary diagnosis that can be very challenging. It requires an extensive workup and multidisciplinary evaluation. Despite access to many imaging technologies and medical tests, a detailed history and good physical examination are still two powerful tools that can guide an accurate diagnosis. Importantly, more clinical studies will be useful to increase our knowledge about AOSD and complications and offer tailoring for more effective therapies. The biopsychosocial model has great potential value and should also be taken seriously. ACKNOWLEDGEMENTS We thank Li HM for her technical assistance. Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images. Conflict-of-interest statement: The authors declare that they have no conflict of interest to report. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Manuscript source: Unsolicited manuscript Peer-review started: September 5, 2020 First decision: November 20, 2020 Article in press: December 10, 2020 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): 0 Grade C (Good): C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Losurdo G, Velázquez-Soto H S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Yuan YY	Not recovered	ReactionOutcome	CC BY-NC	33585636	18,932,320	2021-02-06
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemorrhage'.	Impact of reirradiation, chemotherapy, and immunotherapy on survival of patients with recurrent lung cancer: A single-center retrospective analysis. Given the limited curative treatment options for recurrent lung cancer patients, the aim of our retrospective study was to investigate whether these patients would benefit in terms of overall survival (OS) by adding immunotherapy to high-dose reirradiation. Between 2013 and 2019, 47 consecutive patients with in-field tumor recurrence underwent high-dose thoracic reirradiation at our institute. Twenty patients (43%) received high-dose reirradiation only, while 27/47 (57%) additionally had systemic therapy (immunotherapy and/or chemotherapy). With the exception of one patent, the interval between first and second radiation was at least 9 months. All patients had an Eastern cooperative oncology group ≤2. The diagnostic work-up included a mandatory fluorodeoxyglucose-positron emission tomography-computed tomography scan and histological verification. The primary endpoint was OS after completion of the second course of irradiation. In the whole cohort of 47 patients, the median overall survival (mOS) after reirradiation was 18.9 months (95% confidence interval [CI] 16.5-21.3 months), while in the subgroup of 27 patients who received additional systemic treatment after reirradiation, mOS amounted to 21.8 months (95% CI 17.8-25.8 months). Within this group the comparison between reirradiation combined with either immunotherapy (n = 21) or chemotherapy (n = 6) revealed a difference in OS, which was in favor of the first (log-rank p value = 0.063). Three patients (11%) experienced acute side effects and one (4%) showed a late hemorrhage grade 3. Patients who received immunotherapy and reirradiation lived longer than those who did not receive immunotherapy. Abbreviations CCI Charlson co‐morbidity index CTCAE common toxicity criteria for adverse events DART dose‐differentiated accelerated radiotherapy ECOG Eastern cooperative oncology group EQD2 biologically equivalent dose in 2 Gy fractions FDG‐PET‐CT fluorodeoxyglucose‐positron emission tomography IMRT intensity modulated radiotherapy mOS median overall survival NSCLC nonsmall cell lung cancer OS overall survival RT radiotherapy SABR stereotactic ablative body therapy SCLC small‐cell lung cancer TNM tumor, node, metastasis VMAT volumetric intensity modulated arc therapy INTRODUCTION Immunotherapy has led to revolutionary advancements in cancer treatment 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 and has given new hope to the large number of patients who die from lung cancer each year. 9 Immunotherapy is now a standard first‐ and second‐line therapy for patients with advanced lung cancer. 1 , 2 , 3 , 4 , 6 , 8 With the aim of improving the options available for the treatment of lung cancer patients and based on the potential synergistic effect of radiation therapy and immunotherapy in terms of both local and systemic antitumor response as already described in preclinical models, 10 , 11 , 12 the interest of the oncological community in combining these therapeutic modalities in a clinical setting has increased. 1 , 2 , 13 , 14 As a result, clinical studies have shown remarkable benefits in terms of both progression‐free and overall survival (OS) in lung cancer patients with acceptable toxicity, 1 , 2 , 13 which may be attributed to the synergistic antitumor effect mentioned above. In contrast, numerous publications have suggested that the very complex interaction between the irradiated cells, tissue, and the immune system could enhance the effect of immunotherapy. 1 , 2 , 5 , 7 , 12 , 15 , 16 , 17 In light of this, the potential for antitumor immune activation by irradiation could play an important role for radiotherapy in systemic disease, especially since the presence of immunosuppressive mediators in the tumor microenvironment could limit the number of patients who experience the therapeutic benefits of immunotherapy. 12 , 18 Despite progress in all related clinical disciplines, there is a need to improve clinical outcomes in patients at all tumor, node, metastasis (TNM) stages, including those with recurrent lung cancer for whom curative treatment is already limited. 5 , 19 , 20 Hence, combining therapeutic modalities such as radiotherapy, chemotherapy, and immunotherapy in the hope of overcoming their therapeutic limitations and achieving a synergistic effect seems plausible. 1 , 2 With respect to the combination of reirradiation for loco‐regional relapse and immunotherapy, there is currently one review extant. 5 Additionally, the results of an ongoing study are pending (ClinicalTrials.gov identifier NCT03087760), which—as opposed to our study—uses proton reirradiation rather than photons. The aim of our retrospective analysis was to investigate whether patients with recurrent lung cancer would benefit from adding immunotherapy to ablative reirradiation in terms of OS, taking into account toxicity. Local control after reirradiation and dose to organs at risk are the subject of another paper that is currently under review. METHODS Patients Between 2013 and 2019, 47 consecutive patients who underwent high‐dose thoracic reirradiation were included in a prospective observational database. While 20 patients were reirradiated only, 27 received systemic therapy in addition to high‐dose reirradiation. In this subgroup, immunotherapy was administered alone or with chemotherapy in 21/27 patients (78%). Six out of 27 patients (22%) received chemotherapy alone. The inclusion criteria were as follows: (1) all patients had to be classified as inoperable and in all patients both the primary and the secondary tumor had to be located in the lungs; (2) if possible, patients should have received two courses of curatively intended radiation therapy with a time interval of 9 months or more between them (an exception was made in only one patient who was reirradiated 5 months after the first radiation therapy treatment); (3) the tumor was histologically verified and categorized according to the 8th edition of the TNM classification; (4) fluorodeoxyglucose‐positron emission tomography‐computed tomography (18F‐FDG‐PET‐CT) was required in the diagnostic work‐up; (5) the performance status had to be ≤2 according to the Eastern Cooperative Oncology Group (ECOG). Patients who received palliative radiation treatment, postoperative radiotherapy (RT), or those with chest wall tumors and/or out‐of‐field tumor recurrences were excluded. All patients were discussed in a multidisciplinary tumor board with pneumologists, medical oncologists, radiologists, thoracic surgeons, pathologists, and radiation oncologists. This study was reviewed and approved by the ethics committee of the Federal Province of Salzburg (No. 1070/2020). Radiation and systemic therapy Patients were reirradiated using intensity modulated radiotherapy (IMRT/VMAT) or stereotactic body radiotherapy (SABR). A planning computed tomography (CT) scan with an acquisition time of 3 s was performed prior to IMRT/VMAT. Additionally, four‐dimensional computed tomography (4D‐CT) was performed in SABR patients. Patients were immobilized using a vacuum cradle and WingSTEP. Subsequently, the planning CT was registered with 18F‐FDG‐PET‐CT. For SABR patients, the internal target volume (ITV) was created by contouring the gross tumor volume (GTV) on three breathing phases (expiration, inspiration, and average) and their subsequent union (ITV = CTV‐clinical target volume). The planning target volume (PTV) was created by adding a symmetric margin of 5 mm to the ITV and an additional 4 mm margin in the cranio‐caudal direction. In IMRT/VMAT patients, the GTV was contoured on a so called “slow CT” with an acquisition time of 4 s. This GTV actually constitutes an ITV/CTV as it includes the respiration‐dependent movement of the tumor. The PTV was defined by adding a symmetric margin of 7 mm to GTV. IMRT/VMAT was delivered in three fractionation regimens: dose‐differentiated accelerated RT in twice daily fractions of 1,8 Gy (dose‐differentiated accelerated radiotherapy [DART]‐bid) as described in two previous publications, 21 , 22 conventionally with 2 Gy per fraction, and hypofractionated RT (one fraction of 3 Gy per day). SABR included two different schemes: eight fractions of 8 Gy (65% isodose) delivered daily for central tumors (i.e. within 2 cm of the proximal bronchial tree) and three fractions of 15.4 Gy in (65% isodose) every other day for peripheral tumors. Since various fractionation regimens were used, total radiation doses were compared by biologically equivalent dose in 2 Gy fractions (EQD2). Organs at risk (OAR), such as esophagus, central vessels and airways, spinal cord, lungs, and heart were routinely contoured and dose volume histograms of both initial and reirradiation plans were used to determine the cumulative radiation dose of each critical organ. Prior to reirradiation, patients with nonsmall cell lung cancer (NSCLC) received two cycles of either cisplatin (75 mg/m2/d) combined with pemetrexed (500 mg/m2/d) or gemcitabine (1000 mg/m2/d), while small‐cell lung cancer (SCLC) patients received four cycles of cisplatin (75 mg/m2/d) together with etoposide (120 mg/m2 days 1 to 3). In the case of renal dysfunction carboplatin at an area under the curve (AUC) of 5 on day 1 (absolute maximum dose 1100 mg) was applied instead of cisplatin. Depending on the tumor histology, patients received one of the following immunotherapeutic agents after the second ablative radiation therapy: atezolizumab, durvalumab, nivolumab, or pembrolizumab. Toxicity The Common Terminology Criteria for Adverse Events version (CTCAE) 5.0 were used to report toxicity. Grade 1 toxicities were not considered as clinically relevant and have therefore not been assessed in this study. A cutoff of 90 days after completion of reirradiation was used to distinguish between acute and late toxicities, with the exception of pneumonitis, which was still considered acute if it occurred within 180 days of the end of RT. Follow up Patients were seen 6 weeks after completion of radiotherapy, then every 3 months for the first 2 years and twice a year thereafter. Clinical examinations, contrast‐enhanced CTs, and pulmonary function tests were performed at every follow‐up. If local recurrences or new lung lesions were suspected on the chest CT, 18F‐FDG‐PET‐CT was performed. Local relapse was defined as tumor growth within the reirradiated volume covered by the 95% or 65% isodose after IMRT/VMAT or SABR, respectively. Statistics The primary endpoint was OS, which was calculated using the Kaplan–Meier method. We defined OS as the time between the end of reirradiation and death or latest follow‐up. Although the subgroup of 27 patients was of interest for our analysis, a total of 47 patients—20 of whom were only reirradiated—were also analyzed. With the aim of retaining as much potential information regarding the effects of the three therapy modalities on OS as possible, the threshold for first‐order errors (α) was set at 0.2, which is a more permissible limit usually used in exploratory studies. 23 , 24 For intergroup comparisons the log‐rank test was used. RESULTS Patients Of the 47 patients in the whole cohort, 29 (62%) were men and 18 (38%) were women. The median age at the start of the reirradiation was 66 years (range 52–83 years) in both the entire cohort and the subgroup. Based on histological findings at initial diagnosis, 35/47 (75%) patients had NSCLC and 10/47 (21%) patients had SCLC across the cohort. No pathological confirmation could be obtained in two patients (4%). For details, see Table 1. TABLE 1 Patient‐ and treatment‐related parameters in the cohort (N = 47) Patients N = 47 Patient parameters Age (years) Median 66,3 Range 52–83 Sex Male 29 Female 18 Weight loss (%) >5% 22 <5% 25 ECOG 0–1 40 2 7 Histology SCLC 10 NSCLC 35 Unknown 2 T stage x 3 1 9 2 21 3 9 4 5 N stage 0 11 1 7 2 22 3 7 M stage 0 40 1 7 UICC stage I 7 II 8 III 25 IV 7 FEV1 (%) Median 71 Range 35–100 COPD grade 0 17 1 3 2 9 3 10 4 6 Unknown 2 Charison Comorbidity Index Median 5 Range 2‐10 Treatment‐related parameters Reirradiation volume (ml) Median 47 Range 4–541 Tumor location (n) Peripheral 22 Central 25 Cumulative EQD2 (Gy) Median 131 Range 77‐339 Systemic therapy (n) Yes 27 No 20 Interval between radiation courses (months) Median 20 Range 5–145 Radiation technique Accelerated 23 STX 13 Conventional (= 2 Gy/d) 6 Hypofractionated 5 Note: Tx‐means that the tumor was not able to be evaluated Abbreviations: COPD, chronic obstructive pulmonary disease; ECOG, Eastern cooperative oncology group; EQD2, biologically equivalent dose in 2 Gy fractions; FEV1, forced expiratory volume during the first second; N stage, lymph nodes; NSCLC, nonsmall cell lung cancer; M stage, metastasis; SCLC, small cell lung cancer; STX, stereotactic body irradiation; T stage, tumor; UICC, Union for International Cancer Control. The subgroup included 27 patients, of whom 17 (63%) were men and 10 (37%) were women. All tumors were histologically verified at initial diagnosis, according to which 21/27 patients (78%) had NSCLC and 6/27 patients (22%) had SCLC. The vast majority of patients (25/27, 92.5%) had an ECOG performance score ≤1 with a mean Charlson co‐morbidity index (CCI) of 6 (range 3–10). More than half of the patients (16/27, 60%) had stage III disease. Four patients (15%) were classified as oligometastic at reirradiation. Further details are shown in Table 2. TABLE 2 Patient‐ and treatment‐related parameters in the systemic therapy subgroup (N = 27) Patients N = 27 Patient parameters Age (years) Median 66,3 Range 52–83 Sex Male 17 Female 10 Weightless (%) >5% 13 <5% 14 ECOG 0–1 25 2 2 Histology SCLC 6 NSCLC 21 T stage x 2 1 6 2 11 3 4 4 4 N stage 0 5 1 4 2 13 3 5 M stage 0 23 1 4 UICC stage I 2 II 5 III 16 IV 4 FEV1 (%) Median 71,1 Range 36–100 COPD grade 0 13 1 1 2 4 3 6 4 2 Unknown 1 Charison comorbidity index Median 6 Range 3–10 Treatment‐related parameters N = 27 Reirradiation volume (ml) Median 48.8 Range 4.5–217 Tumor location (n) Peripheral 14 Central 13 Cumulative EQD2 (Gy) Median 132,8 Range 79–211 Systemic therapy Chemotherapy 6 Immunotherapy with/without Chemotherapy 21 Interval between radiation courses (months) Median 14 Range 5–80 Radiation technique Accelerated 13 STX 6 Conventional (= 2 Gy/d) 5 Hypofractionated 3 Abbreviations: COPD,chronic obstructive pulmonary disease; ECOG, Eastern cooperative oncology group; EQD2, biologically equivalent dose in 2 Gy fractions; FEV1, forced expiratory volume during the first second; N stage, lymph nodes; NSCLC, nonsmall cell lung cancer; M stage, metastasis; SCLC, small cell lung cancer; STX, stereotactic body irradiation; T stage, tumor; UICC, Union for International Cancer Control. Reirradiation and systemic therapy While 20 of the 47 patients were only reirradiated (43%), 27/47 (57%) received systemic therapy in addition to reirradiation. In this subgroup of interest, the tumor was located peripherally in 14/27 (52%) patients and centrally in 13/27 (48%) patients. Almost half of the patients (13/27, 48%, median EQD2 128 Gy, range 89–150.5 Gy) were reirradiated with DART‐bid, while 6/27 (22%, median EQD2 191 Gy, range 148–211 Gy) received SABR; in 5/27 patients (19%, median EQD2 122 Gy, range 79–134 Gy) conventional radiation therapy was applied and in 3/27 (11%, median EQD2 99 Gy, range 94–135.5 Gy) a hypofractionated schedule was used. The median reirradiation PTV was 48.8 ml (range 4.5–217 ml) and the median cumulative radiation dose EQD2 delivered in both treatments was 132.8 Gy (range 79–211 Gy). The median interval between the first and second treatment courses was 14 months (range 5–80 months). Twenty‐one patients (78%) received immunotherapy with or without chemotherapy (Table 2). The immunotherapeutic agents were administered after reirradiation over a median treatment time of 6 months (range 0.5–24 months). Six patients (22%) received chemotherapy alone prior to reirradiation. Overall survival The median follow‐up across the cohort was 11.7 months (range 0.3–64.4 months). Of the 47 patients, 21 are still alive (45%). The median OS (mOS) after reirradiation was 18.9 months (95% CI 16.5–21.3 months; Figure 1(a)). The difference in OS between the three treatment modalities in the whole cohort, i.e. reirradiation only vs. reirradiation plus chemotherapy vs. reirradiation plus immunotherapy with/without chemotherapy was in favor of the third group (log‐rank p value = 0.132; Figure 1(b)). FIGURE 1 (a) The median overall survival (mOS) in the whole cohort of 47 patients was 18.9 months (95% confidence interval [CI] 16.5–21.3 months). (b) The 47 patients in the whole cohort were stratified according to the type of systemic therapy received together with reirradiation: immunotherapy or immunochemotherapy (orange), reirradiation alone without systemic treatment (blue), chemotherapy (green). Of these, the first group had the longest survival (mOS 23.7 months, 95% CI 20.3–27.1 months, overall log‐rank p value = 0.132) In the immunotherapy subgroup, the mOS after the second radiation course was 21.8 months (95% CI 17.8–25.8 months; Figure 2(a)). Patients were followed up for a median of 18.4 months (range 1.4–60.9 months), and of these 12 (44%) are still alive, while 14 (52%) patients died from cancer‐related conditions. One patient (4%) died from peritonitis caused by bacterial infection. The median local progression‐free survival was 7.9 months (95% CI 6.7–9 months). The difference in OS was in favor of the immunotherapy subgroup (log‐rank p value = 0.063; Figure 2(b)). FIGURE 2 (a) The median OS (mOS) in the systemic therapy subgroup was 21.8 months (95% confidence interval [CI] 17.8–25.8 months). (b) Patients who received immunotherapy or chemo‐immunotherapy together with reirradiation lived longer than patients who underwent reirradiation with chemotherapy alone (mOS 23.7 months, 95% CI 20.3–27.1 months, log‐rank p value = 0.063) Toxicity Of the 47 patients, eight (17%) experienced acute side effects greater than or equal to grade 2 and 1/47 (2%) patients had late ≥grade 2 toxicity. A grade 5 acute heart failure 1 week after the end of reirradiation was reported in 1/47 (2%) patients with no history of cardiac disease. In this patient, the cumulative maximum EQD2 delivered in both radiation courses was 110 Gy, which was below the 115 Gy classified as tolerable in the literature. 25 The 43% total V20 lung (volume receiving ≥20 Gy) met the above limitation while the 45% V25 (volume receiving ≥25 Gy) heart did not because the tumor was in the central upper lobe including the left hilum and upper segments of the lower lobe. Since a therapeutic cause of death, although unlikely, could not be entirely excluded this patient was scored as having grade 5 toxicity (Table 3). TABLE 3 Treatment‐related toxicity in the whole cohort Toxicity (N = 47) Type of toxicity Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Acute Esophagitis na 4 2 0 0 Pneumonitis na 1 0 0 0 Heart na 0 0 0 1 Late Esophagitis na 0 0 0 0 Pneumonitis na 0 0 0 0 Hemorrhage na 0 1 0 0 Chest wall pain na 0 0 0 0 Abbreviation: na, not assessed. In contrast, there were no grade 4 or 5 toxicities in the immunotherapy subgroup. Acute toxicities occurred as grade 2 in three patients (11%). Two of these patients had acute esophagitis and one reported acute pneumonitis. A late grade 3 hemorrhage occurred in one patient (4%, Table 4). TABLE 4 Treatment‐related toxicity in the subgroup Toxicity (N = 27) Type of toxicity Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Acute Esophagitis na 2 0 0 0 Pneumonitis na 1 0 0 0 Heart na 0 0 0 0 Late Esophagitis na 0 0 0 0 Pneumonitis na 0 0 0 0 Hemorrhage na 0 1 0 0 Chest wall pain na 0 0 0 0 Abbreviation: na, not assessed. DISCUSSION In this analysis we could show that in patients with locoregional relapse of lung cancer a second course of irradiation together with immunotherapy leads to better OS than a combination with chemotherapy (log‐rank p value = 0.063; Figure 2(b)). Our finding is consistent with a concept published in a review by Evans 5 intended for recurrent lung cancer patients who already have limited chances of successful curative treatment. 5 , 19 , 26 , 27 According to Evans, 5 the combination of the two therapy modalities would have a synergistic effect in terms of both local and systemic disease control, given the high potential for local and systemic failure, possibly due to radiation resistance and the aggressiveness of the disease in recurrent lung cancer patients. 5 Immunotherapy could potentially play an important role in enhancing the effectiveness of reirradiation and vice versa, which could hypothetically explain the prolonged survival of the subgroup who received reirradiation followed by immunotherapy in our study. In the absence of published studies on reirradiation with immunotherapy, this consideration relies on data from patients receiving first‐time irradiation, assuming that outcome and toxicity would be similar in the reirradiation setting. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 15 , 16 , 20 , 28 , 29 , 30 In this context, there is data already available on the combination of RT and immunotherapy with primarily curative intent, indicating the potential clinical benefit in lung cancer patients. 1 , 2 This could be attributed to the potential synergistic effect of radioimmunotherapy, resulting in a local and systemic anti‐tumor response, which is currently attracting great academic interest and generating many hypotheses about the exact trigger and interaction mechanism behind it. 5 , 7 , 12 , 17 , 18 , 29 In this regard, a recently published review 17 highlighted the possible synergistic benefits of combining chemotherapy, radiation therapy, and immunotherapy such as the increase of cytotoxicity, the enhancement of immunogenic cell death and tumor necrosis as well as increased tumor‐derived and neoantigen generation, all of which could lead to a potentially enhanced antitumor effect. The details of the complex mechanism of immunotherapy and radiation, as well as the interaction between the two, are described elsewhere. 5 , 7 , 16 , 17 , 29 , 30 Briefly summarized, tumor cells evade the immune response by up‐regulating specific proteins such as programmed cell death 1 ligand 1 (PDL‐1) on their surface. These immune checkpoint ligands interact with the programmed cell death protein 1 (PD‐1) surface receptors of activated cytotoxic T cells, thereby inhibiting them. By inhibiting the PD‐1/PDL‐1 signaling pathway with inhibitors such as nivolumab, pembrolizumab, durvalumab, and atezolizumab, which were administered in our immunotherapy subgroup, the T cells can recognize the tumor cells as pathogens and eliminate them. 1 , 2 , 5 , 7 , 20 Relatedly, radiation‐induced antitumor activity is immune‐mediated by the T cells. 11 Radiation stimulates tumor antigen presentation on the surface of dendritic cells to T cells, which is to prime the T cells in the lymph nodes to respond effectively against tumor cells. 15 , 18 , 31 The sequence in which RT and immunotherapy would be applied is still under investigation, 13 , 32 however available data showed clinical benefit with acceptable toxicity when immunotherapy was administered after radiation treatment, 12 , 14 which corresponds to the toxicity results obtained in our study. Accordingly, in our study, considering the side effects of immunotherapy, particularly with regard to pneumonitis 33 and the severe systemic 7 and local side effects that could be caused by the reirradiation treatment, immunotherapy was given after reirradiation. This treatment sequence was well tolerated. Eleven percent of the patients experienced grade 2 toxicity, with esophagitis and pneumonitis being the only radiogenic side effects, and 4% reported grade 3 toxicity. No grade 4 or 5 toxicity events were reported. An obvious weakness of our analysis is the rather permissive threshold for first‐order errors (α). However, this is not unusual in exploratory studies with the aim of extracting as much potentially important information as possible. 23 , 34 Despite the small cohort and the retrospective nature, our data may gain additional significance given the fact that prospective studies on the combination of reirradiation combined with immunotherapy are lacking. CONCLUSION The combination of reirradiation with immunotherapy could potentially prolong survival with acceptable toxicity. Although prospective studies are warranted, we believe that this combined treatment approach can transform the way patients with recurrent lung cancer are treated. CONFLICT OF INTEREST All authors declare that they have no conflict of interest.	ATEZOLIZUMAB, CARBOPLATIN, CISPLATIN, DURVALUMAB, ETOPOSIDE, GEMCITABINE, NIVOLUMAB, PEMBROLIZUMAB, PEMETREXED	DrugsGivenReaction	CC BY	33586228	18,979,200	2021-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Oesophagitis'.	Impact of reirradiation, chemotherapy, and immunotherapy on survival of patients with recurrent lung cancer: A single-center retrospective analysis. Given the limited curative treatment options for recurrent lung cancer patients, the aim of our retrospective study was to investigate whether these patients would benefit in terms of overall survival (OS) by adding immunotherapy to high-dose reirradiation. Between 2013 and 2019, 47 consecutive patients with in-field tumor recurrence underwent high-dose thoracic reirradiation at our institute. Twenty patients (43%) received high-dose reirradiation only, while 27/47 (57%) additionally had systemic therapy (immunotherapy and/or chemotherapy). With the exception of one patent, the interval between first and second radiation was at least 9 months. All patients had an Eastern cooperative oncology group ≤2. The diagnostic work-up included a mandatory fluorodeoxyglucose-positron emission tomography-computed tomography scan and histological verification. The primary endpoint was OS after completion of the second course of irradiation. In the whole cohort of 47 patients, the median overall survival (mOS) after reirradiation was 18.9 months (95% confidence interval [CI] 16.5-21.3 months), while in the subgroup of 27 patients who received additional systemic treatment after reirradiation, mOS amounted to 21.8 months (95% CI 17.8-25.8 months). Within this group the comparison between reirradiation combined with either immunotherapy (n = 21) or chemotherapy (n = 6) revealed a difference in OS, which was in favor of the first (log-rank p value = 0.063). Three patients (11%) experienced acute side effects and one (4%) showed a late hemorrhage grade 3. Patients who received immunotherapy and reirradiation lived longer than those who did not receive immunotherapy. Abbreviations CCI Charlson co‐morbidity index CTCAE common toxicity criteria for adverse events DART dose‐differentiated accelerated radiotherapy ECOG Eastern cooperative oncology group EQD2 biologically equivalent dose in 2 Gy fractions FDG‐PET‐CT fluorodeoxyglucose‐positron emission tomography IMRT intensity modulated radiotherapy mOS median overall survival NSCLC nonsmall cell lung cancer OS overall survival RT radiotherapy SABR stereotactic ablative body therapy SCLC small‐cell lung cancer TNM tumor, node, metastasis VMAT volumetric intensity modulated arc therapy INTRODUCTION Immunotherapy has led to revolutionary advancements in cancer treatment 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 and has given new hope to the large number of patients who die from lung cancer each year. 9 Immunotherapy is now a standard first‐ and second‐line therapy for patients with advanced lung cancer. 1 , 2 , 3 , 4 , 6 , 8 With the aim of improving the options available for the treatment of lung cancer patients and based on the potential synergistic effect of radiation therapy and immunotherapy in terms of both local and systemic antitumor response as already described in preclinical models, 10 , 11 , 12 the interest of the oncological community in combining these therapeutic modalities in a clinical setting has increased. 1 , 2 , 13 , 14 As a result, clinical studies have shown remarkable benefits in terms of both progression‐free and overall survival (OS) in lung cancer patients with acceptable toxicity, 1 , 2 , 13 which may be attributed to the synergistic antitumor effect mentioned above. In contrast, numerous publications have suggested that the very complex interaction between the irradiated cells, tissue, and the immune system could enhance the effect of immunotherapy. 1 , 2 , 5 , 7 , 12 , 15 , 16 , 17 In light of this, the potential for antitumor immune activation by irradiation could play an important role for radiotherapy in systemic disease, especially since the presence of immunosuppressive mediators in the tumor microenvironment could limit the number of patients who experience the therapeutic benefits of immunotherapy. 12 , 18 Despite progress in all related clinical disciplines, there is a need to improve clinical outcomes in patients at all tumor, node, metastasis (TNM) stages, including those with recurrent lung cancer for whom curative treatment is already limited. 5 , 19 , 20 Hence, combining therapeutic modalities such as radiotherapy, chemotherapy, and immunotherapy in the hope of overcoming their therapeutic limitations and achieving a synergistic effect seems plausible. 1 , 2 With respect to the combination of reirradiation for loco‐regional relapse and immunotherapy, there is currently one review extant. 5 Additionally, the results of an ongoing study are pending (ClinicalTrials.gov identifier NCT03087760), which—as opposed to our study—uses proton reirradiation rather than photons. The aim of our retrospective analysis was to investigate whether patients with recurrent lung cancer would benefit from adding immunotherapy to ablative reirradiation in terms of OS, taking into account toxicity. Local control after reirradiation and dose to organs at risk are the subject of another paper that is currently under review. METHODS Patients Between 2013 and 2019, 47 consecutive patients who underwent high‐dose thoracic reirradiation were included in a prospective observational database. While 20 patients were reirradiated only, 27 received systemic therapy in addition to high‐dose reirradiation. In this subgroup, immunotherapy was administered alone or with chemotherapy in 21/27 patients (78%). Six out of 27 patients (22%) received chemotherapy alone. The inclusion criteria were as follows: (1) all patients had to be classified as inoperable and in all patients both the primary and the secondary tumor had to be located in the lungs; (2) if possible, patients should have received two courses of curatively intended radiation therapy with a time interval of 9 months or more between them (an exception was made in only one patient who was reirradiated 5 months after the first radiation therapy treatment); (3) the tumor was histologically verified and categorized according to the 8th edition of the TNM classification; (4) fluorodeoxyglucose‐positron emission tomography‐computed tomography (18F‐FDG‐PET‐CT) was required in the diagnostic work‐up; (5) the performance status had to be ≤2 according to the Eastern Cooperative Oncology Group (ECOG). Patients who received palliative radiation treatment, postoperative radiotherapy (RT), or those with chest wall tumors and/or out‐of‐field tumor recurrences were excluded. All patients were discussed in a multidisciplinary tumor board with pneumologists, medical oncologists, radiologists, thoracic surgeons, pathologists, and radiation oncologists. This study was reviewed and approved by the ethics committee of the Federal Province of Salzburg (No. 1070/2020). Radiation and systemic therapy Patients were reirradiated using intensity modulated radiotherapy (IMRT/VMAT) or stereotactic body radiotherapy (SABR). A planning computed tomography (CT) scan with an acquisition time of 3 s was performed prior to IMRT/VMAT. Additionally, four‐dimensional computed tomography (4D‐CT) was performed in SABR patients. Patients were immobilized using a vacuum cradle and WingSTEP. Subsequently, the planning CT was registered with 18F‐FDG‐PET‐CT. For SABR patients, the internal target volume (ITV) was created by contouring the gross tumor volume (GTV) on three breathing phases (expiration, inspiration, and average) and their subsequent union (ITV = CTV‐clinical target volume). The planning target volume (PTV) was created by adding a symmetric margin of 5 mm to the ITV and an additional 4 mm margin in the cranio‐caudal direction. In IMRT/VMAT patients, the GTV was contoured on a so called “slow CT” with an acquisition time of 4 s. This GTV actually constitutes an ITV/CTV as it includes the respiration‐dependent movement of the tumor. The PTV was defined by adding a symmetric margin of 7 mm to GTV. IMRT/VMAT was delivered in three fractionation regimens: dose‐differentiated accelerated RT in twice daily fractions of 1,8 Gy (dose‐differentiated accelerated radiotherapy [DART]‐bid) as described in two previous publications, 21 , 22 conventionally with 2 Gy per fraction, and hypofractionated RT (one fraction of 3 Gy per day). SABR included two different schemes: eight fractions of 8 Gy (65% isodose) delivered daily for central tumors (i.e. within 2 cm of the proximal bronchial tree) and three fractions of 15.4 Gy in (65% isodose) every other day for peripheral tumors. Since various fractionation regimens were used, total radiation doses were compared by biologically equivalent dose in 2 Gy fractions (EQD2). Organs at risk (OAR), such as esophagus, central vessels and airways, spinal cord, lungs, and heart were routinely contoured and dose volume histograms of both initial and reirradiation plans were used to determine the cumulative radiation dose of each critical organ. Prior to reirradiation, patients with nonsmall cell lung cancer (NSCLC) received two cycles of either cisplatin (75 mg/m2/d) combined with pemetrexed (500 mg/m2/d) or gemcitabine (1000 mg/m2/d), while small‐cell lung cancer (SCLC) patients received four cycles of cisplatin (75 mg/m2/d) together with etoposide (120 mg/m2 days 1 to 3). In the case of renal dysfunction carboplatin at an area under the curve (AUC) of 5 on day 1 (absolute maximum dose 1100 mg) was applied instead of cisplatin. Depending on the tumor histology, patients received one of the following immunotherapeutic agents after the second ablative radiation therapy: atezolizumab, durvalumab, nivolumab, or pembrolizumab. Toxicity The Common Terminology Criteria for Adverse Events version (CTCAE) 5.0 were used to report toxicity. Grade 1 toxicities were not considered as clinically relevant and have therefore not been assessed in this study. A cutoff of 90 days after completion of reirradiation was used to distinguish between acute and late toxicities, with the exception of pneumonitis, which was still considered acute if it occurred within 180 days of the end of RT. Follow up Patients were seen 6 weeks after completion of radiotherapy, then every 3 months for the first 2 years and twice a year thereafter. Clinical examinations, contrast‐enhanced CTs, and pulmonary function tests were performed at every follow‐up. If local recurrences or new lung lesions were suspected on the chest CT, 18F‐FDG‐PET‐CT was performed. Local relapse was defined as tumor growth within the reirradiated volume covered by the 95% or 65% isodose after IMRT/VMAT or SABR, respectively. Statistics The primary endpoint was OS, which was calculated using the Kaplan–Meier method. We defined OS as the time between the end of reirradiation and death or latest follow‐up. Although the subgroup of 27 patients was of interest for our analysis, a total of 47 patients—20 of whom were only reirradiated—were also analyzed. With the aim of retaining as much potential information regarding the effects of the three therapy modalities on OS as possible, the threshold for first‐order errors (α) was set at 0.2, which is a more permissible limit usually used in exploratory studies. 23 , 24 For intergroup comparisons the log‐rank test was used. RESULTS Patients Of the 47 patients in the whole cohort, 29 (62%) were men and 18 (38%) were women. The median age at the start of the reirradiation was 66 years (range 52–83 years) in both the entire cohort and the subgroup. Based on histological findings at initial diagnosis, 35/47 (75%) patients had NSCLC and 10/47 (21%) patients had SCLC across the cohort. No pathological confirmation could be obtained in two patients (4%). For details, see Table 1. TABLE 1 Patient‐ and treatment‐related parameters in the cohort (N = 47) Patients N = 47 Patient parameters Age (years) Median 66,3 Range 52–83 Sex Male 29 Female 18 Weight loss (%) >5% 22 <5% 25 ECOG 0–1 40 2 7 Histology SCLC 10 NSCLC 35 Unknown 2 T stage x 3 1 9 2 21 3 9 4 5 N stage 0 11 1 7 2 22 3 7 M stage 0 40 1 7 UICC stage I 7 II 8 III 25 IV 7 FEV1 (%) Median 71 Range 35–100 COPD grade 0 17 1 3 2 9 3 10 4 6 Unknown 2 Charison Comorbidity Index Median 5 Range 2‐10 Treatment‐related parameters Reirradiation volume (ml) Median 47 Range 4–541 Tumor location (n) Peripheral 22 Central 25 Cumulative EQD2 (Gy) Median 131 Range 77‐339 Systemic therapy (n) Yes 27 No 20 Interval between radiation courses (months) Median 20 Range 5–145 Radiation technique Accelerated 23 STX 13 Conventional (= 2 Gy/d) 6 Hypofractionated 5 Note: Tx‐means that the tumor was not able to be evaluated Abbreviations: COPD, chronic obstructive pulmonary disease; ECOG, Eastern cooperative oncology group; EQD2, biologically equivalent dose in 2 Gy fractions; FEV1, forced expiratory volume during the first second; N stage, lymph nodes; NSCLC, nonsmall cell lung cancer; M stage, metastasis; SCLC, small cell lung cancer; STX, stereotactic body irradiation; T stage, tumor; UICC, Union for International Cancer Control. The subgroup included 27 patients, of whom 17 (63%) were men and 10 (37%) were women. All tumors were histologically verified at initial diagnosis, according to which 21/27 patients (78%) had NSCLC and 6/27 patients (22%) had SCLC. The vast majority of patients (25/27, 92.5%) had an ECOG performance score ≤1 with a mean Charlson co‐morbidity index (CCI) of 6 (range 3–10). More than half of the patients (16/27, 60%) had stage III disease. Four patients (15%) were classified as oligometastic at reirradiation. Further details are shown in Table 2. TABLE 2 Patient‐ and treatment‐related parameters in the systemic therapy subgroup (N = 27) Patients N = 27 Patient parameters Age (years) Median 66,3 Range 52–83 Sex Male 17 Female 10 Weightless (%) >5% 13 <5% 14 ECOG 0–1 25 2 2 Histology SCLC 6 NSCLC 21 T stage x 2 1 6 2 11 3 4 4 4 N stage 0 5 1 4 2 13 3 5 M stage 0 23 1 4 UICC stage I 2 II 5 III 16 IV 4 FEV1 (%) Median 71,1 Range 36–100 COPD grade 0 13 1 1 2 4 3 6 4 2 Unknown 1 Charison comorbidity index Median 6 Range 3–10 Treatment‐related parameters N = 27 Reirradiation volume (ml) Median 48.8 Range 4.5–217 Tumor location (n) Peripheral 14 Central 13 Cumulative EQD2 (Gy) Median 132,8 Range 79–211 Systemic therapy Chemotherapy 6 Immunotherapy with/without Chemotherapy 21 Interval between radiation courses (months) Median 14 Range 5–80 Radiation technique Accelerated 13 STX 6 Conventional (= 2 Gy/d) 5 Hypofractionated 3 Abbreviations: COPD,chronic obstructive pulmonary disease; ECOG, Eastern cooperative oncology group; EQD2, biologically equivalent dose in 2 Gy fractions; FEV1, forced expiratory volume during the first second; N stage, lymph nodes; NSCLC, nonsmall cell lung cancer; M stage, metastasis; SCLC, small cell lung cancer; STX, stereotactic body irradiation; T stage, tumor; UICC, Union for International Cancer Control. Reirradiation and systemic therapy While 20 of the 47 patients were only reirradiated (43%), 27/47 (57%) received systemic therapy in addition to reirradiation. In this subgroup of interest, the tumor was located peripherally in 14/27 (52%) patients and centrally in 13/27 (48%) patients. Almost half of the patients (13/27, 48%, median EQD2 128 Gy, range 89–150.5 Gy) were reirradiated with DART‐bid, while 6/27 (22%, median EQD2 191 Gy, range 148–211 Gy) received SABR; in 5/27 patients (19%, median EQD2 122 Gy, range 79–134 Gy) conventional radiation therapy was applied and in 3/27 (11%, median EQD2 99 Gy, range 94–135.5 Gy) a hypofractionated schedule was used. The median reirradiation PTV was 48.8 ml (range 4.5–217 ml) and the median cumulative radiation dose EQD2 delivered in both treatments was 132.8 Gy (range 79–211 Gy). The median interval between the first and second treatment courses was 14 months (range 5–80 months). Twenty‐one patients (78%) received immunotherapy with or without chemotherapy (Table 2). The immunotherapeutic agents were administered after reirradiation over a median treatment time of 6 months (range 0.5–24 months). Six patients (22%) received chemotherapy alone prior to reirradiation. Overall survival The median follow‐up across the cohort was 11.7 months (range 0.3–64.4 months). Of the 47 patients, 21 are still alive (45%). The median OS (mOS) after reirradiation was 18.9 months (95% CI 16.5–21.3 months; Figure 1(a)). The difference in OS between the three treatment modalities in the whole cohort, i.e. reirradiation only vs. reirradiation plus chemotherapy vs. reirradiation plus immunotherapy with/without chemotherapy was in favor of the third group (log‐rank p value = 0.132; Figure 1(b)). FIGURE 1 (a) The median overall survival (mOS) in the whole cohort of 47 patients was 18.9 months (95% confidence interval [CI] 16.5–21.3 months). (b) The 47 patients in the whole cohort were stratified according to the type of systemic therapy received together with reirradiation: immunotherapy or immunochemotherapy (orange), reirradiation alone without systemic treatment (blue), chemotherapy (green). Of these, the first group had the longest survival (mOS 23.7 months, 95% CI 20.3–27.1 months, overall log‐rank p value = 0.132) In the immunotherapy subgroup, the mOS after the second radiation course was 21.8 months (95% CI 17.8–25.8 months; Figure 2(a)). Patients were followed up for a median of 18.4 months (range 1.4–60.9 months), and of these 12 (44%) are still alive, while 14 (52%) patients died from cancer‐related conditions. One patient (4%) died from peritonitis caused by bacterial infection. The median local progression‐free survival was 7.9 months (95% CI 6.7–9 months). The difference in OS was in favor of the immunotherapy subgroup (log‐rank p value = 0.063; Figure 2(b)). FIGURE 2 (a) The median OS (mOS) in the systemic therapy subgroup was 21.8 months (95% confidence interval [CI] 17.8–25.8 months). (b) Patients who received immunotherapy or chemo‐immunotherapy together with reirradiation lived longer than patients who underwent reirradiation with chemotherapy alone (mOS 23.7 months, 95% CI 20.3–27.1 months, log‐rank p value = 0.063) Toxicity Of the 47 patients, eight (17%) experienced acute side effects greater than or equal to grade 2 and 1/47 (2%) patients had late ≥grade 2 toxicity. A grade 5 acute heart failure 1 week after the end of reirradiation was reported in 1/47 (2%) patients with no history of cardiac disease. In this patient, the cumulative maximum EQD2 delivered in both radiation courses was 110 Gy, which was below the 115 Gy classified as tolerable in the literature. 25 The 43% total V20 lung (volume receiving ≥20 Gy) met the above limitation while the 45% V25 (volume receiving ≥25 Gy) heart did not because the tumor was in the central upper lobe including the left hilum and upper segments of the lower lobe. Since a therapeutic cause of death, although unlikely, could not be entirely excluded this patient was scored as having grade 5 toxicity (Table 3). TABLE 3 Treatment‐related toxicity in the whole cohort Toxicity (N = 47) Type of toxicity Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Acute Esophagitis na 4 2 0 0 Pneumonitis na 1 0 0 0 Heart na 0 0 0 1 Late Esophagitis na 0 0 0 0 Pneumonitis na 0 0 0 0 Hemorrhage na 0 1 0 0 Chest wall pain na 0 0 0 0 Abbreviation: na, not assessed. In contrast, there were no grade 4 or 5 toxicities in the immunotherapy subgroup. Acute toxicities occurred as grade 2 in three patients (11%). Two of these patients had acute esophagitis and one reported acute pneumonitis. A late grade 3 hemorrhage occurred in one patient (4%, Table 4). TABLE 4 Treatment‐related toxicity in the subgroup Toxicity (N = 27) Type of toxicity Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Acute Esophagitis na 2 0 0 0 Pneumonitis na 1 0 0 0 Heart na 0 0 0 0 Late Esophagitis na 0 0 0 0 Pneumonitis na 0 0 0 0 Hemorrhage na 0 1 0 0 Chest wall pain na 0 0 0 0 Abbreviation: na, not assessed. DISCUSSION In this analysis we could show that in patients with locoregional relapse of lung cancer a second course of irradiation together with immunotherapy leads to better OS than a combination with chemotherapy (log‐rank p value = 0.063; Figure 2(b)). Our finding is consistent with a concept published in a review by Evans 5 intended for recurrent lung cancer patients who already have limited chances of successful curative treatment. 5 , 19 , 26 , 27 According to Evans, 5 the combination of the two therapy modalities would have a synergistic effect in terms of both local and systemic disease control, given the high potential for local and systemic failure, possibly due to radiation resistance and the aggressiveness of the disease in recurrent lung cancer patients. 5 Immunotherapy could potentially play an important role in enhancing the effectiveness of reirradiation and vice versa, which could hypothetically explain the prolonged survival of the subgroup who received reirradiation followed by immunotherapy in our study. In the absence of published studies on reirradiation with immunotherapy, this consideration relies on data from patients receiving first‐time irradiation, assuming that outcome and toxicity would be similar in the reirradiation setting. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 15 , 16 , 20 , 28 , 29 , 30 In this context, there is data already available on the combination of RT and immunotherapy with primarily curative intent, indicating the potential clinical benefit in lung cancer patients. 1 , 2 This could be attributed to the potential synergistic effect of radioimmunotherapy, resulting in a local and systemic anti‐tumor response, which is currently attracting great academic interest and generating many hypotheses about the exact trigger and interaction mechanism behind it. 5 , 7 , 12 , 17 , 18 , 29 In this regard, a recently published review 17 highlighted the possible synergistic benefits of combining chemotherapy, radiation therapy, and immunotherapy such as the increase of cytotoxicity, the enhancement of immunogenic cell death and tumor necrosis as well as increased tumor‐derived and neoantigen generation, all of which could lead to a potentially enhanced antitumor effect. The details of the complex mechanism of immunotherapy and radiation, as well as the interaction between the two, are described elsewhere. 5 , 7 , 16 , 17 , 29 , 30 Briefly summarized, tumor cells evade the immune response by up‐regulating specific proteins such as programmed cell death 1 ligand 1 (PDL‐1) on their surface. These immune checkpoint ligands interact with the programmed cell death protein 1 (PD‐1) surface receptors of activated cytotoxic T cells, thereby inhibiting them. By inhibiting the PD‐1/PDL‐1 signaling pathway with inhibitors such as nivolumab, pembrolizumab, durvalumab, and atezolizumab, which were administered in our immunotherapy subgroup, the T cells can recognize the tumor cells as pathogens and eliminate them. 1 , 2 , 5 , 7 , 20 Relatedly, radiation‐induced antitumor activity is immune‐mediated by the T cells. 11 Radiation stimulates tumor antigen presentation on the surface of dendritic cells to T cells, which is to prime the T cells in the lymph nodes to respond effectively against tumor cells. 15 , 18 , 31 The sequence in which RT and immunotherapy would be applied is still under investigation, 13 , 32 however available data showed clinical benefit with acceptable toxicity when immunotherapy was administered after radiation treatment, 12 , 14 which corresponds to the toxicity results obtained in our study. Accordingly, in our study, considering the side effects of immunotherapy, particularly with regard to pneumonitis 33 and the severe systemic 7 and local side effects that could be caused by the reirradiation treatment, immunotherapy was given after reirradiation. This treatment sequence was well tolerated. Eleven percent of the patients experienced grade 2 toxicity, with esophagitis and pneumonitis being the only radiogenic side effects, and 4% reported grade 3 toxicity. No grade 4 or 5 toxicity events were reported. An obvious weakness of our analysis is the rather permissive threshold for first‐order errors (α). However, this is not unusual in exploratory studies with the aim of extracting as much potentially important information as possible. 23 , 34 Despite the small cohort and the retrospective nature, our data may gain additional significance given the fact that prospective studies on the combination of reirradiation combined with immunotherapy are lacking. CONCLUSION The combination of reirradiation with immunotherapy could potentially prolong survival with acceptable toxicity. Although prospective studies are warranted, we believe that this combined treatment approach can transform the way patients with recurrent lung cancer are treated. CONFLICT OF INTEREST All authors declare that they have no conflict of interest.	ATEZOLIZUMAB, CARBOPLATIN, CISPLATIN, DURVALUMAB, ETOPOSIDE, GEMCITABINE, NIVOLUMAB, PEMBROLIZUMAB, PEMETREXED	DrugsGivenReaction	CC BY	33586228	18,979,200	2021-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonitis'.	Impact of reirradiation, chemotherapy, and immunotherapy on survival of patients with recurrent lung cancer: A single-center retrospective analysis. Given the limited curative treatment options for recurrent lung cancer patients, the aim of our retrospective study was to investigate whether these patients would benefit in terms of overall survival (OS) by adding immunotherapy to high-dose reirradiation. Between 2013 and 2019, 47 consecutive patients with in-field tumor recurrence underwent high-dose thoracic reirradiation at our institute. Twenty patients (43%) received high-dose reirradiation only, while 27/47 (57%) additionally had systemic therapy (immunotherapy and/or chemotherapy). With the exception of one patent, the interval between first and second radiation was at least 9 months. All patients had an Eastern cooperative oncology group ≤2. The diagnostic work-up included a mandatory fluorodeoxyglucose-positron emission tomography-computed tomography scan and histological verification. The primary endpoint was OS after completion of the second course of irradiation. In the whole cohort of 47 patients, the median overall survival (mOS) after reirradiation was 18.9 months (95% confidence interval [CI] 16.5-21.3 months), while in the subgroup of 27 patients who received additional systemic treatment after reirradiation, mOS amounted to 21.8 months (95% CI 17.8-25.8 months). Within this group the comparison between reirradiation combined with either immunotherapy (n = 21) or chemotherapy (n = 6) revealed a difference in OS, which was in favor of the first (log-rank p value = 0.063). Three patients (11%) experienced acute side effects and one (4%) showed a late hemorrhage grade 3. Patients who received immunotherapy and reirradiation lived longer than those who did not receive immunotherapy. Abbreviations CCI Charlson co‐morbidity index CTCAE common toxicity criteria for adverse events DART dose‐differentiated accelerated radiotherapy ECOG Eastern cooperative oncology group EQD2 biologically equivalent dose in 2 Gy fractions FDG‐PET‐CT fluorodeoxyglucose‐positron emission tomography IMRT intensity modulated radiotherapy mOS median overall survival NSCLC nonsmall cell lung cancer OS overall survival RT radiotherapy SABR stereotactic ablative body therapy SCLC small‐cell lung cancer TNM tumor, node, metastasis VMAT volumetric intensity modulated arc therapy INTRODUCTION Immunotherapy has led to revolutionary advancements in cancer treatment 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 and has given new hope to the large number of patients who die from lung cancer each year. 9 Immunotherapy is now a standard first‐ and second‐line therapy for patients with advanced lung cancer. 1 , 2 , 3 , 4 , 6 , 8 With the aim of improving the options available for the treatment of lung cancer patients and based on the potential synergistic effect of radiation therapy and immunotherapy in terms of both local and systemic antitumor response as already described in preclinical models, 10 , 11 , 12 the interest of the oncological community in combining these therapeutic modalities in a clinical setting has increased. 1 , 2 , 13 , 14 As a result, clinical studies have shown remarkable benefits in terms of both progression‐free and overall survival (OS) in lung cancer patients with acceptable toxicity, 1 , 2 , 13 which may be attributed to the synergistic antitumor effect mentioned above. In contrast, numerous publications have suggested that the very complex interaction between the irradiated cells, tissue, and the immune system could enhance the effect of immunotherapy. 1 , 2 , 5 , 7 , 12 , 15 , 16 , 17 In light of this, the potential for antitumor immune activation by irradiation could play an important role for radiotherapy in systemic disease, especially since the presence of immunosuppressive mediators in the tumor microenvironment could limit the number of patients who experience the therapeutic benefits of immunotherapy. 12 , 18 Despite progress in all related clinical disciplines, there is a need to improve clinical outcomes in patients at all tumor, node, metastasis (TNM) stages, including those with recurrent lung cancer for whom curative treatment is already limited. 5 , 19 , 20 Hence, combining therapeutic modalities such as radiotherapy, chemotherapy, and immunotherapy in the hope of overcoming their therapeutic limitations and achieving a synergistic effect seems plausible. 1 , 2 With respect to the combination of reirradiation for loco‐regional relapse and immunotherapy, there is currently one review extant. 5 Additionally, the results of an ongoing study are pending (ClinicalTrials.gov identifier NCT03087760), which—as opposed to our study—uses proton reirradiation rather than photons. The aim of our retrospective analysis was to investigate whether patients with recurrent lung cancer would benefit from adding immunotherapy to ablative reirradiation in terms of OS, taking into account toxicity. Local control after reirradiation and dose to organs at risk are the subject of another paper that is currently under review. METHODS Patients Between 2013 and 2019, 47 consecutive patients who underwent high‐dose thoracic reirradiation were included in a prospective observational database. While 20 patients were reirradiated only, 27 received systemic therapy in addition to high‐dose reirradiation. In this subgroup, immunotherapy was administered alone or with chemotherapy in 21/27 patients (78%). Six out of 27 patients (22%) received chemotherapy alone. The inclusion criteria were as follows: (1) all patients had to be classified as inoperable and in all patients both the primary and the secondary tumor had to be located in the lungs; (2) if possible, patients should have received two courses of curatively intended radiation therapy with a time interval of 9 months or more between them (an exception was made in only one patient who was reirradiated 5 months after the first radiation therapy treatment); (3) the tumor was histologically verified and categorized according to the 8th edition of the TNM classification; (4) fluorodeoxyglucose‐positron emission tomography‐computed tomography (18F‐FDG‐PET‐CT) was required in the diagnostic work‐up; (5) the performance status had to be ≤2 according to the Eastern Cooperative Oncology Group (ECOG). Patients who received palliative radiation treatment, postoperative radiotherapy (RT), or those with chest wall tumors and/or out‐of‐field tumor recurrences were excluded. All patients were discussed in a multidisciplinary tumor board with pneumologists, medical oncologists, radiologists, thoracic surgeons, pathologists, and radiation oncologists. This study was reviewed and approved by the ethics committee of the Federal Province of Salzburg (No. 1070/2020). Radiation and systemic therapy Patients were reirradiated using intensity modulated radiotherapy (IMRT/VMAT) or stereotactic body radiotherapy (SABR). A planning computed tomography (CT) scan with an acquisition time of 3 s was performed prior to IMRT/VMAT. Additionally, four‐dimensional computed tomography (4D‐CT) was performed in SABR patients. Patients were immobilized using a vacuum cradle and WingSTEP. Subsequently, the planning CT was registered with 18F‐FDG‐PET‐CT. For SABR patients, the internal target volume (ITV) was created by contouring the gross tumor volume (GTV) on three breathing phases (expiration, inspiration, and average) and their subsequent union (ITV = CTV‐clinical target volume). The planning target volume (PTV) was created by adding a symmetric margin of 5 mm to the ITV and an additional 4 mm margin in the cranio‐caudal direction. In IMRT/VMAT patients, the GTV was contoured on a so called “slow CT” with an acquisition time of 4 s. This GTV actually constitutes an ITV/CTV as it includes the respiration‐dependent movement of the tumor. The PTV was defined by adding a symmetric margin of 7 mm to GTV. IMRT/VMAT was delivered in three fractionation regimens: dose‐differentiated accelerated RT in twice daily fractions of 1,8 Gy (dose‐differentiated accelerated radiotherapy [DART]‐bid) as described in two previous publications, 21 , 22 conventionally with 2 Gy per fraction, and hypofractionated RT (one fraction of 3 Gy per day). SABR included two different schemes: eight fractions of 8 Gy (65% isodose) delivered daily for central tumors (i.e. within 2 cm of the proximal bronchial tree) and three fractions of 15.4 Gy in (65% isodose) every other day for peripheral tumors. Since various fractionation regimens were used, total radiation doses were compared by biologically equivalent dose in 2 Gy fractions (EQD2). Organs at risk (OAR), such as esophagus, central vessels and airways, spinal cord, lungs, and heart were routinely contoured and dose volume histograms of both initial and reirradiation plans were used to determine the cumulative radiation dose of each critical organ. Prior to reirradiation, patients with nonsmall cell lung cancer (NSCLC) received two cycles of either cisplatin (75 mg/m2/d) combined with pemetrexed (500 mg/m2/d) or gemcitabine (1000 mg/m2/d), while small‐cell lung cancer (SCLC) patients received four cycles of cisplatin (75 mg/m2/d) together with etoposide (120 mg/m2 days 1 to 3). In the case of renal dysfunction carboplatin at an area under the curve (AUC) of 5 on day 1 (absolute maximum dose 1100 mg) was applied instead of cisplatin. Depending on the tumor histology, patients received one of the following immunotherapeutic agents after the second ablative radiation therapy: atezolizumab, durvalumab, nivolumab, or pembrolizumab. Toxicity The Common Terminology Criteria for Adverse Events version (CTCAE) 5.0 were used to report toxicity. Grade 1 toxicities were not considered as clinically relevant and have therefore not been assessed in this study. A cutoff of 90 days after completion of reirradiation was used to distinguish between acute and late toxicities, with the exception of pneumonitis, which was still considered acute if it occurred within 180 days of the end of RT. Follow up Patients were seen 6 weeks after completion of radiotherapy, then every 3 months for the first 2 years and twice a year thereafter. Clinical examinations, contrast‐enhanced CTs, and pulmonary function tests were performed at every follow‐up. If local recurrences or new lung lesions were suspected on the chest CT, 18F‐FDG‐PET‐CT was performed. Local relapse was defined as tumor growth within the reirradiated volume covered by the 95% or 65% isodose after IMRT/VMAT or SABR, respectively. Statistics The primary endpoint was OS, which was calculated using the Kaplan–Meier method. We defined OS as the time between the end of reirradiation and death or latest follow‐up. Although the subgroup of 27 patients was of interest for our analysis, a total of 47 patients—20 of whom were only reirradiated—were also analyzed. With the aim of retaining as much potential information regarding the effects of the three therapy modalities on OS as possible, the threshold for first‐order errors (α) was set at 0.2, which is a more permissible limit usually used in exploratory studies. 23 , 24 For intergroup comparisons the log‐rank test was used. RESULTS Patients Of the 47 patients in the whole cohort, 29 (62%) were men and 18 (38%) were women. The median age at the start of the reirradiation was 66 years (range 52–83 years) in both the entire cohort and the subgroup. Based on histological findings at initial diagnosis, 35/47 (75%) patients had NSCLC and 10/47 (21%) patients had SCLC across the cohort. No pathological confirmation could be obtained in two patients (4%). For details, see Table 1. TABLE 1 Patient‐ and treatment‐related parameters in the cohort (N = 47) Patients N = 47 Patient parameters Age (years) Median 66,3 Range 52–83 Sex Male 29 Female 18 Weight loss (%) >5% 22 <5% 25 ECOG 0–1 40 2 7 Histology SCLC 10 NSCLC 35 Unknown 2 T stage x 3 1 9 2 21 3 9 4 5 N stage 0 11 1 7 2 22 3 7 M stage 0 40 1 7 UICC stage I 7 II 8 III 25 IV 7 FEV1 (%) Median 71 Range 35–100 COPD grade 0 17 1 3 2 9 3 10 4 6 Unknown 2 Charison Comorbidity Index Median 5 Range 2‐10 Treatment‐related parameters Reirradiation volume (ml) Median 47 Range 4–541 Tumor location (n) Peripheral 22 Central 25 Cumulative EQD2 (Gy) Median 131 Range 77‐339 Systemic therapy (n) Yes 27 No 20 Interval between radiation courses (months) Median 20 Range 5–145 Radiation technique Accelerated 23 STX 13 Conventional (= 2 Gy/d) 6 Hypofractionated 5 Note: Tx‐means that the tumor was not able to be evaluated Abbreviations: COPD, chronic obstructive pulmonary disease; ECOG, Eastern cooperative oncology group; EQD2, biologically equivalent dose in 2 Gy fractions; FEV1, forced expiratory volume during the first second; N stage, lymph nodes; NSCLC, nonsmall cell lung cancer; M stage, metastasis; SCLC, small cell lung cancer; STX, stereotactic body irradiation; T stage, tumor; UICC, Union for International Cancer Control. The subgroup included 27 patients, of whom 17 (63%) were men and 10 (37%) were women. All tumors were histologically verified at initial diagnosis, according to which 21/27 patients (78%) had NSCLC and 6/27 patients (22%) had SCLC. The vast majority of patients (25/27, 92.5%) had an ECOG performance score ≤1 with a mean Charlson co‐morbidity index (CCI) of 6 (range 3–10). More than half of the patients (16/27, 60%) had stage III disease. Four patients (15%) were classified as oligometastic at reirradiation. Further details are shown in Table 2. TABLE 2 Patient‐ and treatment‐related parameters in the systemic therapy subgroup (N = 27) Patients N = 27 Patient parameters Age (years) Median 66,3 Range 52–83 Sex Male 17 Female 10 Weightless (%) >5% 13 <5% 14 ECOG 0–1 25 2 2 Histology SCLC 6 NSCLC 21 T stage x 2 1 6 2 11 3 4 4 4 N stage 0 5 1 4 2 13 3 5 M stage 0 23 1 4 UICC stage I 2 II 5 III 16 IV 4 FEV1 (%) Median 71,1 Range 36–100 COPD grade 0 13 1 1 2 4 3 6 4 2 Unknown 1 Charison comorbidity index Median 6 Range 3–10 Treatment‐related parameters N = 27 Reirradiation volume (ml) Median 48.8 Range 4.5–217 Tumor location (n) Peripheral 14 Central 13 Cumulative EQD2 (Gy) Median 132,8 Range 79–211 Systemic therapy Chemotherapy 6 Immunotherapy with/without Chemotherapy 21 Interval between radiation courses (months) Median 14 Range 5–80 Radiation technique Accelerated 13 STX 6 Conventional (= 2 Gy/d) 5 Hypofractionated 3 Abbreviations: COPD,chronic obstructive pulmonary disease; ECOG, Eastern cooperative oncology group; EQD2, biologically equivalent dose in 2 Gy fractions; FEV1, forced expiratory volume during the first second; N stage, lymph nodes; NSCLC, nonsmall cell lung cancer; M stage, metastasis; SCLC, small cell lung cancer; STX, stereotactic body irradiation; T stage, tumor; UICC, Union for International Cancer Control. Reirradiation and systemic therapy While 20 of the 47 patients were only reirradiated (43%), 27/47 (57%) received systemic therapy in addition to reirradiation. In this subgroup of interest, the tumor was located peripherally in 14/27 (52%) patients and centrally in 13/27 (48%) patients. Almost half of the patients (13/27, 48%, median EQD2 128 Gy, range 89–150.5 Gy) were reirradiated with DART‐bid, while 6/27 (22%, median EQD2 191 Gy, range 148–211 Gy) received SABR; in 5/27 patients (19%, median EQD2 122 Gy, range 79–134 Gy) conventional radiation therapy was applied and in 3/27 (11%, median EQD2 99 Gy, range 94–135.5 Gy) a hypofractionated schedule was used. The median reirradiation PTV was 48.8 ml (range 4.5–217 ml) and the median cumulative radiation dose EQD2 delivered in both treatments was 132.8 Gy (range 79–211 Gy). The median interval between the first and second treatment courses was 14 months (range 5–80 months). Twenty‐one patients (78%) received immunotherapy with or without chemotherapy (Table 2). The immunotherapeutic agents were administered after reirradiation over a median treatment time of 6 months (range 0.5–24 months). Six patients (22%) received chemotherapy alone prior to reirradiation. Overall survival The median follow‐up across the cohort was 11.7 months (range 0.3–64.4 months). Of the 47 patients, 21 are still alive (45%). The median OS (mOS) after reirradiation was 18.9 months (95% CI 16.5–21.3 months; Figure 1(a)). The difference in OS between the three treatment modalities in the whole cohort, i.e. reirradiation only vs. reirradiation plus chemotherapy vs. reirradiation plus immunotherapy with/without chemotherapy was in favor of the third group (log‐rank p value = 0.132; Figure 1(b)). FIGURE 1 (a) The median overall survival (mOS) in the whole cohort of 47 patients was 18.9 months (95% confidence interval [CI] 16.5–21.3 months). (b) The 47 patients in the whole cohort were stratified according to the type of systemic therapy received together with reirradiation: immunotherapy or immunochemotherapy (orange), reirradiation alone without systemic treatment (blue), chemotherapy (green). Of these, the first group had the longest survival (mOS 23.7 months, 95% CI 20.3–27.1 months, overall log‐rank p value = 0.132) In the immunotherapy subgroup, the mOS after the second radiation course was 21.8 months (95% CI 17.8–25.8 months; Figure 2(a)). Patients were followed up for a median of 18.4 months (range 1.4–60.9 months), and of these 12 (44%) are still alive, while 14 (52%) patients died from cancer‐related conditions. One patient (4%) died from peritonitis caused by bacterial infection. The median local progression‐free survival was 7.9 months (95% CI 6.7–9 months). The difference in OS was in favor of the immunotherapy subgroup (log‐rank p value = 0.063; Figure 2(b)). FIGURE 2 (a) The median OS (mOS) in the systemic therapy subgroup was 21.8 months (95% confidence interval [CI] 17.8–25.8 months). (b) Patients who received immunotherapy or chemo‐immunotherapy together with reirradiation lived longer than patients who underwent reirradiation with chemotherapy alone (mOS 23.7 months, 95% CI 20.3–27.1 months, log‐rank p value = 0.063) Toxicity Of the 47 patients, eight (17%) experienced acute side effects greater than or equal to grade 2 and 1/47 (2%) patients had late ≥grade 2 toxicity. A grade 5 acute heart failure 1 week after the end of reirradiation was reported in 1/47 (2%) patients with no history of cardiac disease. In this patient, the cumulative maximum EQD2 delivered in both radiation courses was 110 Gy, which was below the 115 Gy classified as tolerable in the literature. 25 The 43% total V20 lung (volume receiving ≥20 Gy) met the above limitation while the 45% V25 (volume receiving ≥25 Gy) heart did not because the tumor was in the central upper lobe including the left hilum and upper segments of the lower lobe. Since a therapeutic cause of death, although unlikely, could not be entirely excluded this patient was scored as having grade 5 toxicity (Table 3). TABLE 3 Treatment‐related toxicity in the whole cohort Toxicity (N = 47) Type of toxicity Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Acute Esophagitis na 4 2 0 0 Pneumonitis na 1 0 0 0 Heart na 0 0 0 1 Late Esophagitis na 0 0 0 0 Pneumonitis na 0 0 0 0 Hemorrhage na 0 1 0 0 Chest wall pain na 0 0 0 0 Abbreviation: na, not assessed. In contrast, there were no grade 4 or 5 toxicities in the immunotherapy subgroup. Acute toxicities occurred as grade 2 in three patients (11%). Two of these patients had acute esophagitis and one reported acute pneumonitis. A late grade 3 hemorrhage occurred in one patient (4%, Table 4). TABLE 4 Treatment‐related toxicity in the subgroup Toxicity (N = 27) Type of toxicity Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Acute Esophagitis na 2 0 0 0 Pneumonitis na 1 0 0 0 Heart na 0 0 0 0 Late Esophagitis na 0 0 0 0 Pneumonitis na 0 0 0 0 Hemorrhage na 0 1 0 0 Chest wall pain na 0 0 0 0 Abbreviation: na, not assessed. DISCUSSION In this analysis we could show that in patients with locoregional relapse of lung cancer a second course of irradiation together with immunotherapy leads to better OS than a combination with chemotherapy (log‐rank p value = 0.063; Figure 2(b)). Our finding is consistent with a concept published in a review by Evans 5 intended for recurrent lung cancer patients who already have limited chances of successful curative treatment. 5 , 19 , 26 , 27 According to Evans, 5 the combination of the two therapy modalities would have a synergistic effect in terms of both local and systemic disease control, given the high potential for local and systemic failure, possibly due to radiation resistance and the aggressiveness of the disease in recurrent lung cancer patients. 5 Immunotherapy could potentially play an important role in enhancing the effectiveness of reirradiation and vice versa, which could hypothetically explain the prolonged survival of the subgroup who received reirradiation followed by immunotherapy in our study. In the absence of published studies on reirradiation with immunotherapy, this consideration relies on data from patients receiving first‐time irradiation, assuming that outcome and toxicity would be similar in the reirradiation setting. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 15 , 16 , 20 , 28 , 29 , 30 In this context, there is data already available on the combination of RT and immunotherapy with primarily curative intent, indicating the potential clinical benefit in lung cancer patients. 1 , 2 This could be attributed to the potential synergistic effect of radioimmunotherapy, resulting in a local and systemic anti‐tumor response, which is currently attracting great academic interest and generating many hypotheses about the exact trigger and interaction mechanism behind it. 5 , 7 , 12 , 17 , 18 , 29 In this regard, a recently published review 17 highlighted the possible synergistic benefits of combining chemotherapy, radiation therapy, and immunotherapy such as the increase of cytotoxicity, the enhancement of immunogenic cell death and tumor necrosis as well as increased tumor‐derived and neoantigen generation, all of which could lead to a potentially enhanced antitumor effect. The details of the complex mechanism of immunotherapy and radiation, as well as the interaction between the two, are described elsewhere. 5 , 7 , 16 , 17 , 29 , 30 Briefly summarized, tumor cells evade the immune response by up‐regulating specific proteins such as programmed cell death 1 ligand 1 (PDL‐1) on their surface. These immune checkpoint ligands interact with the programmed cell death protein 1 (PD‐1) surface receptors of activated cytotoxic T cells, thereby inhibiting them. By inhibiting the PD‐1/PDL‐1 signaling pathway with inhibitors such as nivolumab, pembrolizumab, durvalumab, and atezolizumab, which were administered in our immunotherapy subgroup, the T cells can recognize the tumor cells as pathogens and eliminate them. 1 , 2 , 5 , 7 , 20 Relatedly, radiation‐induced antitumor activity is immune‐mediated by the T cells. 11 Radiation stimulates tumor antigen presentation on the surface of dendritic cells to T cells, which is to prime the T cells in the lymph nodes to respond effectively against tumor cells. 15 , 18 , 31 The sequence in which RT and immunotherapy would be applied is still under investigation, 13 , 32 however available data showed clinical benefit with acceptable toxicity when immunotherapy was administered after radiation treatment, 12 , 14 which corresponds to the toxicity results obtained in our study. Accordingly, in our study, considering the side effects of immunotherapy, particularly with regard to pneumonitis 33 and the severe systemic 7 and local side effects that could be caused by the reirradiation treatment, immunotherapy was given after reirradiation. This treatment sequence was well tolerated. Eleven percent of the patients experienced grade 2 toxicity, with esophagitis and pneumonitis being the only radiogenic side effects, and 4% reported grade 3 toxicity. No grade 4 or 5 toxicity events were reported. An obvious weakness of our analysis is the rather permissive threshold for first‐order errors (α). However, this is not unusual in exploratory studies with the aim of extracting as much potentially important information as possible. 23 , 34 Despite the small cohort and the retrospective nature, our data may gain additional significance given the fact that prospective studies on the combination of reirradiation combined with immunotherapy are lacking. CONCLUSION The combination of reirradiation with immunotherapy could potentially prolong survival with acceptable toxicity. Although prospective studies are warranted, we believe that this combined treatment approach can transform the way patients with recurrent lung cancer are treated. CONFLICT OF INTEREST All authors declare that they have no conflict of interest.	ATEZOLIZUMAB, CARBOPLATIN, CISPLATIN, DURVALUMAB, ETOPOSIDE, GEMCITABINE, NIVOLUMAB, PEMBROLIZUMAB, PEMETREXED	DrugsGivenReaction	CC BY	33586228	18,979,200	2021-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute kidney injury'.	Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication. BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment. Background Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication. Case Report A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis. At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1). Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs. During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage. Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis. Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required. After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved. The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment. At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2). Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3). After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention. At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l). Discussion In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14]. Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15]. Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication. To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome. Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation. Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19]. In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects. Conclusions The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient. In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias). Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis. Conflict of Interest None Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema. Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed. Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning.	CLOZAPINE	DrugsGivenReaction	CC BY-NC-ND	33591960	18,986,056	2021-02-16
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anticholinergic syndrome'.	Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication. BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment. Background Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication. Case Report A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis. At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1). Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs. During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage. Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis. Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required. After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved. The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment. At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2). Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3). After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention. At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l). Discussion In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14]. Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15]. Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication. To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome. Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation. Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19]. In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects. Conclusions The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient. In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias). Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis. Conflict of Interest None Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema. Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed. Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning.	CLOZAPINE	DrugsGivenReaction	CC BY-NC-ND	33591960	18,986,056	2021-02-16
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Atelectasis'.	Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication. BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment. Background Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication. Case Report A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis. At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1). Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs. During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage. Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis. Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required. After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved. The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment. At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2). Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3). After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention. At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l). Discussion In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14]. Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15]. Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication. To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome. Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation. Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19]. In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects. Conclusions The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient. In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias). Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis. Conflict of Interest None Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema. Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed. Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning.	CLOZAPINE	DrugsGivenReaction	CC BY-NC-ND	33591960	18,991,249	2021-02-16
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Coma scale abnormal'.	Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication. BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment. Background Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication. Case Report A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis. At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1). Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs. During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage. Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis. Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required. After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved. The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment. At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2). Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3). After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention. At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l). Discussion In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14]. Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15]. Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication. To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome. Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation. Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19]. In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects. Conclusions The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient. In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias). Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis. Conflict of Interest None Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema. Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed. Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning.	CLOZAPINE	DrugsGivenReaction	CC BY-NC-ND	33591960	18,991,249	2021-02-16
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Crush syndrome'.	Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication. BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment. Background Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication. Case Report A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis. At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1). Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs. During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage. Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis. Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required. After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved. The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment. At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2). Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3). After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention. At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l). Discussion In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14]. Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15]. Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication. To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome. Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation. Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19]. In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects. Conclusions The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient. In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias). Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis. Conflict of Interest None Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema. Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed. Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning.	CLOZAPINE	DrugsGivenReaction	CC BY-NC-ND	33591960	18,986,056	2021-02-16
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disturbance in attention'.	Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication. BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment. Background Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication. Case Report A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis. At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1). Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs. During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage. Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis. Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required. After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved. The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment. At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2). Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3). After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention. At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l). Discussion In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14]. Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15]. Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication. To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome. Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation. Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19]. In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects. Conclusions The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient. In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias). Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis. Conflict of Interest None Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema. Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed. Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning.	CLOZAPINE	DrugsGivenReaction	CC BY-NC-ND	33591960	18,986,056	2021-02-16
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Emphysema'.	Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication. BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment. Background Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication. Case Report A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis. At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1). Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs. During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage. Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis. Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required. After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved. The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment. At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2). Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3). After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention. At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l). Discussion In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14]. Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15]. Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication. To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome. Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation. Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19]. In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects. Conclusions The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient. In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias). Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis. Conflict of Interest None Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema. Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed. Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning.	CLOZAPINE	DrugsGivenReaction	CC BY-NC-ND	33591960	18,986,056	2021-02-16
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypertension'.	Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication. BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment. Background Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication. Case Report A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis. At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1). Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs. During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage. Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis. Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required. After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved. The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment. At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2). Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3). After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention. At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l). Discussion In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14]. Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15]. Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication. To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome. Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation. Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19]. In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects. Conclusions The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient. In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias). Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis. Conflict of Interest None Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema. Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed. Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning.	CLOZAPINE	DrugsGivenReaction	CC BY-NC-ND	33591960	18,986,056	2021-02-16
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intentional overdose'.	Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication. BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment. Background Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication. Case Report A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis. At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1). Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs. During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage. Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis. Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required. After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved. The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment. At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2). Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3). After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention. At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l). Discussion In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14]. Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15]. Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication. To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome. Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation. Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19]. In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects. Conclusions The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient. In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias). Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis. Conflict of Interest None Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema. Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed. Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning.	CLOZAPINE	DrugsGivenReaction	CC BY-NC-ND	33591960	18,986,056	2021-02-16

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