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"abstract": "BACKGROUND\nEnoxaparin is a low-molecular weight heparin (LMWH) commonly used for treatment of venous thromboembolism and acute coronary syndromes. The recommended dose for these conditions is weight-based (1 mg/kg) and doesn't require dose-capping. However, previous studies have shown that in those with a body mass index (BMI) > 40 kg/m2, this dose results in supratherapeutic levels.\n\n\nOBJECTIVE\nThis study investigated enoxaparin dosing in morbidly obese patients with a goal of identifying a dose with the greatest chance of producing favorable anti-factor Xa (anti-Xa) levels.\n\n\nMETHODS\nThis retrospective cohort study by electronic chart review was used to record data of patients who received enoxaparin with anti-Xa level monitoring between 2012 and 2017. The primary outcome was the enoxaparin dose that results in a therapeutic anti-Xa level (0.5-1.0 IU/mL) among three BMI groups. Secondary outcomes were bleeding and thromboembolic events.\n\n\nRESULTS\nTwo hundred forty-one patients were included in the study, and 132 achieved a therapeutic dose. For those with a BMI of 40-50 kg/m2, the median therapeutic dose was 0.97 mg/kg every 12 h. In subjects with a BMI of 50-60 kg/m2, the median therapeutic dose was 0.70 mg/kg. Finally, the median therapeutic dose for subjects with a BMI over 60 kg/m2 was 0.71 mg/kg. In all three groups, 53-65% of patients had a supratherapeutic anti-Xa level while less than 10% had a subtherapeutic level. Relatively few patients (4.1%) experienced major bleeding and only one thromboembolic event was reported.\n\n\nCONCLUSIONS\nStandard dosing of enoxaparin in morbidly obese patients will most likely lead to supratherapeutic anti-Xa levels and thus further investigation is warranted to better determine appropriate dosing.",
"affiliations": "Adult Medicine Division, Department of Pharmacy Practice, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, 1718 Pine Street, Abilene, TX, 79601, USA. young.lee@ttuhsc.edu.;Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, USA.;Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, USA.;Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, USA.",
"authors": "Lee|Young R|YR|http://orcid.org/0000-0002-7677-2125;Palmere|Peter J|PJ|;Burton|Caitlin E|CE|;Benavides|Taylor M|TM|",
"chemical_list": "D000925:Anticoagulants; D017984:Enoxaparin",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40261-019-00855-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1173-2563",
"issue": "40(1)",
"journal": "Clinical drug investigation",
"keywords": null,
"medline_ta": "Clin Drug Investig",
"mesh_terms": "D000328:Adult; D000368:Aged; D000925:Anticoagulants; D015992:Body Mass Index; D015331:Cohort Studies; D017984:Enoxaparin; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009767:Obesity, Morbid; D012189:Retrospective Studies; D054556:Venous Thromboembolism",
"nlm_unique_id": "9504817",
"other_id": null,
"pages": "33-40",
"pmc": null,
"pmid": "31625111",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article",
"references": "19458109;21108553;30630208;30574790;22315264;15850607;7039924;19476416;11157659;25601898;25087072;30210152;21465129;15842354;20067334",
"title": "Stratifying Therapeutic Enoxaparin Dose in Morbidly Obese Patients by BMI Class: A Retrospective Cohort Study.",
"title_normalized": "stratifying therapeutic enoxaparin dose in morbidly obese patients by bmi class a retrospective cohort study"
} | [
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"companynumb": "US-TEVA-2020-US-1186431",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ENOXAPARIN"
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"drugadditional": "3",
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{
"abstract": "Localized adult high-grade soft tissue sarcomas (STS) usually require multimodality treatment including surgery, radiotherapy, chemotherapy and hyperthermia. If maximal preoperative tumor-shrinkage is envisaged, neoadjuvant chemotherapy + radiation (CRT) is often applied, however at the expense of relatively high toxicities and increased postoperative complication rates. This study aims to compare preoperative CRT with neoadjuvant chemotherapy + regional hyperthermia (HCT) regarding histopathological response, toxicity and outcome.\n\n\n\nIn this retrospective analysis, 61 consecutive high-grade STS patients treated between 2009 and 2016 were included. All patients were treated within a prospective treatment protocol. 28 patients received neoadjuvant CRT 33 patients HCT. CRT consisted of four cycles doxorubicin/ifosfamide and two cycles ifosfamide concomitant to 50.4 Gray external beam radiotherapy. HCT consisted of 4-6 cycles doxorubicin/ifosfamide with deep regional hyperthermia administered bi-weekly during each cycle. Association of treatment modality with overall survival (OS), local control (LC) and freedom from distant metastases (FFDM) was evaluated by Kaplan-Meier and log-rank analyses.\n\n\n\nThe overall patient characteristics were well balanced. Histopathological tumor response did not differ significantly between both groups (p = .67), neither did higher-grade toxicities during neoadjuvant treatment. Wound dehiscence (p = .018) and surgical hospital re-admissions (p < .001) were both significantly more frequent in the CRT group. Two-year OS, LC and FFDM rates of all patients were 93, 85 and 71% with no significant differences between CRT and HCT.\n\n\n\nCompared to CRT, HCT seems equally efficient and appears to bear less surgical complications. Interpretation should be cautious due to the low number of patients and the retrospective nature of this study.",
"affiliations": "a Department of Radiation Oncology , Charité Universitätsmedizin Berlin , Berlin , Germany.;a Department of Radiation Oncology , Charité Universitätsmedizin Berlin , Berlin , Germany.;c Department of Surgery , Charité Universitätsmedizin Berlin , Berlin , Germany.;a Department of Radiation Oncology , Charité Universitätsmedizin Berlin , Berlin , Germany.;c Department of Surgery , Charité Universitätsmedizin Berlin , Berlin , Germany.;d Department of Hematology, Oncology, and Tumorimmunology , Charité Universitätsmedizin Berlin , Berlin , Germany.;e Charité Universitätsmedizin Berlin, Institute of Pathology , Berlin , Germany.;d Department of Hematology, Oncology, and Tumorimmunology , Charité Universitätsmedizin Berlin , Berlin , Germany.;d Department of Hematology, Oncology, and Tumorimmunology , Charité Universitätsmedizin Berlin , Berlin , Germany.;a Department of Radiation Oncology , Charité Universitätsmedizin Berlin , Berlin , Germany.",
"authors": "Zschaeck|Sebastian|S|;Wust|Peter|P|;Melcher|Ingo|I|;Nadobny|Jacek|J|;Rau|Daniel|D|;Striefler|Jana|J|;Pahl|Stefan|S|;Flörcken|Anne|A|;Kunitz|Annegret|A|;Ghadjar|Pirus|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/02656736.2018.1498137",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0265-6736",
"issue": "35(1)",
"journal": "International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group",
"keywords": "Soft tissue sarcoma; chemotherapy; hyperthermia; outcome; radiochemotherapy; response evaluation",
"medline_ta": "Int J Hyperthermia",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D008297:Male; D020360:Neoadjuvant Therapy; D012189:Retrospective Studies; D012983:Soft Tissue Neoplasms",
"nlm_unique_id": "8508395",
"other_id": null,
"pages": "1-9",
"pmc": null,
"pmid": "30300018",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Neoadjuvant chemotherapy plus radiation versus chemotherapy plus regional hyperthermia in high-grade soft tissue sarcomas: a retrospective comparison.",
"title_normalized": "neoadjuvant chemotherapy plus radiation versus chemotherapy plus regional hyperthermia in high grade soft tissue sarcomas a retrospective comparison"
} | [
{
"companynumb": "DE-JNJFOC-20190134638",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
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"drugadditional": n... |
{
"abstract": "BACKGROUND Antipsychotic medications are associated with multiple adverse effects, including metabolic syndrome, prolonged QT interval, and extrapyramidal symptoms. Acute laryngeal dystonia (ALD) is a rare and lethal form of extrapyramidal reaction. CASE REPORT A 27-year-old woman with schizophrenia on risperidone presented to our Emergency Department with a sensation of choking and respiratory distress, mimicking a panic attack. She developed a generalized dystonic reaction in the hospital, leading to diagnosis risperidone-associated ALD as a cause of her initial problems. She was discharged with an emphasis on being compliant with anticholinergic medication. However, her persistent respiratory symptoms prompted us to revisit the management plan. Her risperidone dose was tapered down to discontinue and an alternate drug was chosen. CONCLUSIONS ALD must be considered as a differential diagnosis when patients on antipsychotic medications present with respiratory distress. Our case highlights the association of ALD with an atypical antipsychotic agent, risperidone. Prompt recognition of this entity is necessary to prevent complications and guide definitive management.",
"affiliations": "Department of Emergency Medicine, King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.;Department of Emergency Medicine, King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.",
"authors": "Alkharboush|Ghassan A|GA|;Alsalamah|Majid A|MA|",
"chemical_list": "D014150:Antipsychotic Agents; D001590:Benztropine; D018967:Risperidone",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.922393",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n32506071\n10.12659/AJCR.922393\n922393\nArticles\nRisperidone-Induced Acute Laryngeal Dystonia: A Case Report\nAlkharboush Ghassan A. BEF Alsalamah Majid A. E Department of Emergency Medicine, King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia\nCorresponding Author: Majid A. Alsalamah, e-mail: malsalamah@gmail.comAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n07 6 2020 \n21 e922393-1 e9223935\n25 12 2019 07 4 2020 12 5 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 28-year-old\n\nFinal Diagnosis: Acute laryngeal dystonia\n\nSymptoms: Shortness of breath\n\nMedication:—\n\nClinical Procedure: Benzotropine administration\n\nSpecialty: General and Internal Medicine • Psychiatry\n\nObjective:\nUnusual clinical course\n\nBackground:\nAntipsychotic medications are associated with multiple adverse effects, including metabolic syndrome, prolonged QT interval, and extrapyramidal symptoms. Acute laryngeal dystonia (ALD) is a rare and lethal form of extrapyramidal reaction.\n\nCase Report:\nA 27-year-old woman with schizophrenia on risperidone presented to our Emergency Department with a sensation of choking and respiratory distress, mimicking a panic attack. She developed a generalized dystonic reaction in the hospital, leading to diagnosis risperidone-associated ALD as a cause of her initial problems. She was discharged with an emphasis on being compliant with anticholinergic medication. However, her persistent respiratory symptoms prompted us to revisit the management plan. Her risperidone dose was tapered down to discontinue and an alternate drug was chosen.\n\nConclusions:\nALD must be considered as a differential diagnosis when patients on antipsychotic medications present with respiratory distress. Our case highlights the association of ALD with an atypical antipsychotic agent, risperidone. Prompt recognition of this entity is necessary to prevent complications and guide definitive management.\n\nMeSH Keywords:\nDrug-Related Side Effects and Adverse ReactionsDystonic DisordersLaryngeal Diseases\n==== Body\nBackground\nAcute dystonia is estimated to occur in 3–20% [1,2] of patients who use antipsychotic medication. These dystonic reactions can involve any groups of muscles, thus accounting for its variable clinical presentation (e.g., oculogyric crisis, torticollis, trismus, and opisthotonos). Most dystonic reactions occur during the first 3 days of therapy [3]. Identifiable risk factors for acute dystonic reaction include male sex, young age, history of previous dystonic reaction, and recent increase in dosage [4,5].\n\nAcute laryngeal dystonia (ALD) was first described in 1958 by Christian et al. [6]. A correlation between ALD and sudden death was confirmed in 1981 after the first report of ALD-associated fatality [7]. Multiple case reports followed describing the relationship between ALD and use of multiple typical and atypical antipsychotics, some of which have proved to be deadly [8]. Traditionally, atypical antipsychotics are thought to have a lower incidence of extrapyramidal symptoms (EPS), but they are not all equal. In a meta-analysis, risperidone was found to have the highest association with EPS among atypical agents [9].\n\nIn this article, we report a case of risperidone-induced ALD presenting with acute onset shortness of breath, initially misdiagnosed as a panic attack, leading to a delay in management.\n\nCase Report\nA 27-year-old woman presented to our Emergency Department (ED) complaining of shortness of breath that developed acutely over the last 4 hours while in her home. She described the feeling as a sense of “choking”. She denied any triggers for her symptoms and reported no exacerbating or alleviating factors. Furthermore, she denied any associated chest pain, syncope, cough, fever, or gastrointestinal symptoms.\n\nThe shortness of breath reportedly waxed and waned over the last 4 hours.\n\nShe denied any prior history of allergies or atopy. No exposure to new drugs/chemicals or insect bites were reported prior to symptoms onset. She also denied any history of foreign body ingestion.\n\nHer previous medical history was significant only for a diagnosis of schizophrenia, for which she received 3 mg of risperidone once daily and 2 mg of benztropine once daily.\n\nUpon assessment, the patient was alert and conscious, moving restlessly on the bed. She was able to speak, although not in complete sentences. She was managing her secretions and no cough, stridor, or cyanosis was noted.\n\nOn physical examination, her vital signs were: heart rate of 120 beats/minute, blood pressure of 136/85 mmHg, respiratory rate of 24 breaths/minute, oxygen saturation of 97% on room air, oral temperature 36.7°C, and a Glucocheck of 144 mg/dl. No angioedema was noted, and her chest was clear to auscultation with equal breath sounds bilaterally. Her neurological exam revealed normal muscle tone and absence of weakness or sensory deficit in the upper and lower limbs. A brief cerebellar exam revealed a normal gait and absence of dysmetria. Her pupils were equal and reactive, with full extraocular muscles range of motion and no discernible nystagmus. Her cranial nerves exam was grossly unremarkable.\n\nA presumptive diagnosis of panic attack was made, and the patient was kept on a monitored bed due to the tachycardia and mild tachypnea. The emergency team was prepared for invasive airway management should the patient’s condition continue to decline. A diagnosis of anaphylaxis was initially considered but seemed unlikely due to absence of an initial trigger, as well as the clear chest, absence of gastrointestinal symptoms, and no skin or mucous membrane involvement. Furthermore, epiglottis was considered, but the absence of upper-respiratory tract infection symptoms and the intermittent nature of her symptoms made this diagnosis unlikely.\n\nApproximately 15 minutes after the initial assessment, she developed extension of the neck, upper and lower limbs bilaterally, arching of the back, and transient rolling up of the eyes. A diagnosis of an acute dystonic reaction was made, and 50 mg of intravenous diphenhydramine was given. Prompt improvement of her symptoms followed shortly thereafter, with complete return to her baseline status. Interestingly, a venous blood gas taken shortly after assessment showed a pH of 7.26, CO2 of 58 mmHg, and HCO3 of 26 mmol/l.\n\nReviewing the patient’s file, it was seen that she apparently visited the ED 1 week prior to this presentation, with a similar complaint but of lower intensity. Laboratory testing during that visit revealed only mild leukocytosis, presumably due to acute stress (17.00×109/L), with a slightly elevated lactic acid (2.43 mmol/l, reference 0.5–2.20 mmol/l). During that visit, she was managed with 1 mg of lorazepam intravenously and then discharged. Interestingly, her venous blood gas (VBG) consistently showed acute respiratory acidosis during each episode.\n\nUpon further enquiry, the patient admitted to being non-complaint with benztropine. Furthermore, her psychiatrist had increased the risperidone dosage from 2 mg to 3 mg 2 weeks prior to her visit to the ED. The case was discussed with the Psychiatry Service on-call, which recommended keeping the risperidone dose as usual to prevent a relapse of her schizophrenia but with strict compliance to benztropine. No CNS imaging was required to diagnose the patient’s condition due to a normal neurological exam, lack of focality in symptoms, and the temporal relation to antipsychotic usage, in addition to improvement with anticholinergic therapy. Therefore, she was discharged with a diagnosis of acute laryngeal dystonia and the importance of compliance with benztropine was emphasized with the patient.\n\nDuring the subsequent months, the patient revisited the ED multiple times with the same complaint. Her last visit required emergency airway attention, but all her symptoms ceased with intravenous anticholinergics, averting the need for invasive airway management. She was seen by Psychiatry on-call, which eventually reduced her risperidone dosage to 2 mg and increased benztropine to 2 mg twice daily regularly. Quetiapine was also added for augmentation to prevent relapse of her schizophrenia, with plans to slowly increase the dose while tapering the patient off risperidone.\n\nDiscussion\nTo the best of our knowledge, this article is the first case report of ALD in the Middle East. Other cases reported in the literature all had variable signs of upper-airway obstruction (e.g., cyanosis, stridor, gasping, and inability to manage secretions). In many cases, a diagnosis of ALD was made retrospectively after the patient’s death or after establishing a definitive airway. In fact, ALD has occasionally been initially misdiagnosed as anaphylaxis [10], acute anxiety [11], panic attack [12], and epiglottitis [13].\n\nMost case reports on ALD have been associated with use of typical antipsychotics [14]. Nonetheless, a growing body of evidence suggests a correlation with use of newer atypical agents, particularly risperidone [15]. Although the underlying mechanism responsible for ALD remains unclear, one hypothesis postulates paradoxical adduction of the vocal cords during inspiration, leading to upper-airway obstruction [15]. Unfortunately, this requires performing direct laryngoscopy without a paralyzing agent on all patients with suspected ALD to confirm the diagnosis, which is not feasible in normal clinical practice. Nonetheless, almost all patients diagnosed clinically with ALD who received anticholinergics had significant improvement in their symptoms [15]. This further corroborated acute dystonia as the underlying pathophysiological mechanism.\n\nFour other cases of risperidone related ALD have been reported [15–18]. Unlike 3 of the other cases [15, 17, 18], no stridor was noted in our patient. In 2 cases [16,17], the patients were managed with intramuscular Benztropine, which resulted in symptom resolution in 10–15 minutes. The third patient was observed for 48 hours as he developed on and off stridor while a surgical airway kit was at bedside [18]. In the aforementioned case, diagnosis was made in retrospect after spontaneous resolution of ALD. Notably, the patient reported by May et al. developed ALD after receiving haloperidol, chlorpromazine, and risperidone during a 3-day period [17]. The patient was later challenged with risperidone, with no recurrence reported. In addition, the patient reported by Chakravarty et al. received haloperidol prior to onset of ALD [18]. Thus, in both of the aforementioned cases, antipsychotic polypharmacy was the most likely cause of symptoms development. In fact, only in 2 other case reports were the symptoms solely attributed to risperidone [15,16]. A summary of risperidone-related ALD is presented in Table 1.\n\nA correlation between antipsychotics usage and sudden death has been reported. In a recent retrospective cohort study, Ray et al. demonstrated that users of both typical and atypical agents had more than double the rate of sudden cardiac death in comparison to nonusers, presumably due to cardiac toxicity [19]. These results have been further corroborated with recent reports showing 15–20 years decreased life expectancy in patients with schizophrenia or bipolar disorder [20,21]. Another possible cause for increased mortality in this group of patients is death by asphyxiation. To date, there have been 2 case reports of ALD-associated deaths [7,8]. Therefore, we strongly recommend that once the diagnosis is made, a clear plan is established to decrease the offending drug dose or change it as soon as possible to prevent recurrent episodes such in the present case.\n\nA review of current and influential emergency medicine textbooks failed to yield any results on ALD [22,23]. As a matter of fact, ALD has been described extensively in the psychiatry literature, but with only 4 previous case reports published in emergency medicine journals [13,24–26]. Laryngeal dystonia, although life-threatening, seems to be underappreciated in the emergency medicine literature.\n\nConclusions\nALD is a rare, life-threatening, reversible complication of anti-psychotics. This diagnosis should be considered in any psychiatric patient presenting with undifferentiated acute-onset shortness of breath, especially if associated with other features of extrapyramidal symptoms or recent increase in anti-psychotic dosage. If a high index of suspicion exists, anticholinergics administered parenterally may prevent invasive airway management. Prompt identification is key to management and prevention of these life-threatening episodes.\n\nConflict of interest\n\nNone.\n\nTable 1. Summary of the literature review regarding previous cases of acute laryngeal dystonia due to risperidone.\n\nAuthor\tTakhar (1996) [16]\tChakravarty (2005) [18]\tGanesh (2015) [15]\tMay (2016) [17]\t\nDrug\tPO risperidone\tPO risperidone, IM haloperidol. Symptoms started soon after haloperidol and were attributed to it\tPO risperidone\tPO haloperidol, chlorpromazine and risperidone\t\nPatient characteristics\t17-year-old male\tElderly male\t65-year old male\t27-year old male\t\nDiagnosis\tSchizophrenia\tPneumonia with acute confusional state\tSchizophrenia\tSchizophrenia\t\nPresentation\tOral secretions dyspnea\tInspiratory stridor\tStridor, dysphonia\tDysphonia, stridor, retrocollis opisthotonos, focal abduction/extension of the left arm\t\nInterventions\tBenztropine 2 mg IM\tTreated as anaphylaxis with intravenous hydrocortisone, subcutaneous adrenaline, and intramuscular antihistaminic drugs\t25 mg IV diphenhydramine\tBenztropine 2 mg IM\t\nOutcome\tStarted on benztropine 2 mg bid. No recurrence of laryngeal dystonia. Developed delirium secondary to risperidone and was shifted to thioridazine\tThe stridor continued intermittently for over 48 hours and then disappeared completely\tImproved within 60 min; recurred on the following day, but improved with diphenhydramine and clonazepam; discharged on clozapine and clonazepam\t24-hour antipsychotic-free period. Later challenged with risperidone 1 mg, with no extrapyramidal symptoms observed\n==== Refs\nReferences:\n1. Raja M Azzoni A Novel antipsychotics and acute dystonic reactions Int J Neuropsychopharmacol 2001 4 4 393 97 11806865 \n2. Khanna R Das A Damodaran SS Prospective study of neuroleptic-induced dystonia in mania and schizophrenia Am J Psychiatry 1992 149 4 511 13 1348162 \n3. Sramek JJ Simpson GM Morrison RL Heiser JF Anticholinergic agents for prophylaxis of neuroleptic-induced dystonic reactions: A prospective study J Clin Psychiatry 1986 47 6 305 9 2872206 \n4. Keepers GA Casey DE Prediction of neuroleptic-induced dystonia J Clin Psychopharmacol 1987 7 5 342 45 2890672 \n5. Keepers GA Casey DE Use of neuroleptic-induced extrapyramidal symptoms to predict future vulnerability to side effects Am J Psychiatry 1991 148 1 85 89 1670616 \n6. Christian CD Paulson G Severe motility disturbance after small doses of prochlorperazine N Engl J Med 1958 259 17 828 30 13590459 \n7. Modestin J Krapf R Böker W A fatality during haloperidol treatment: Mechanism of sudden death Am J Psychiatry 1981 138 12 1616 17 7304797 \n8. Yagmur F Ulusoy HB Buyukoglan H Kaya MG Acute respiratory distress due to antipsychotic drugs Pharmacopsychiatry 2010 43 3 118 19 20446229 \n9. Rummel-Kluge C Komossa K Schwarz S Second-generation anti-psychotic drugs and extrapyramidal side effects: A systematic review and meta-analysis of head-to-head comparisons Schizophr Bull 2012 38 1 167 77 20513652 \n10. Ilchef R Neuroleptic-induced laryngeal dystonia can mimic anaphylaxis Aust NZJ Psychiatry 1997 31 6 877 79 \n11. Newton-John H Acute upper airway obstruction due to supraglottic dystonia induced by a neuroleptic BMJ 1988 297 6654 964 65 3142568 \n12. Murray V Laryngeal dystonia Br J Psychiatry 1995 167 5 698 99 \n13. Barach E Dubin LM Tomlanovich MC Kottamasu S Dystonia presenting as upper airway obstruction J Emerg Med 1989 7 3 237 40 2568376 \n14. Christodoulou C Kalaitzi C Antipsychotic drug-induced acute laryngeal dystonia: Two case reports and a mini review J Psychopharmacol 2005 19 3 307 11 15888517 \n15. Ganesh M Jabbar U Iskander FH Acute laryngeal dystonia with novel anti-psychotics: A case report and review of literature J Clin Psychopharmacol 2015 35 5 613 15 \n16. Takhar J Manchanda R Acute dystonic reaction with risperidone Can J Psychiatry 1996 41 1 61 62 \n17. May R Al-Taie A Garg V Acute laryngeal dystonia: A persisting psychiatric emergency Australas Psychiatry 2016 24 5 497 98 27145799 \n18. Chakravarty A Neuroleptic-induced acute laryngeal dystonia causing stridor: A lesson to remember Mov Disord 2005 20 8 1082 83 16001412 \n19. Ray WA Chung CP Murray KT Atypical antipsychotic drugs and the risk of sudden cardiac death N Engl J Med 2009 360 3 225 35 19144938 \n20. Laursen TM Life expectancy among persons with schizophrenia or bipolar affective disorder Schizophr Res 2011 131 1–3 101 4 21741216 \n21. Laursen TM Wahlbeck K Hällgren J Life expectancy and death by diseases of the circulatory system in patients with bipolar disorder or schizophrenia in the Nordic countries PLoS One 2013 8 6 e67133 23826212 \n22. Walls R Hockberger R Gausche-Hill MP Rosen’s Emergency Medicine: Concepts and clinical practice Philadelphia (PA) Elsevier 2018 \n23. Tintinalli JE John-Ma O Yealy D Tintinalli’s emergency medicine: A comprehensive study guide New York McGraw-Hill Medical 2018 \n24. Fines RE Brady WJ Jr Martin ML Acute laryngeal dystonia related to neuroleptic agents Am J Emerg Med 1999 17 3 319 20 10337906 \n25. Russell SA Hennes HM Herson KJ Stremski ES Upper airway compromise in acute chlorpromazine ingestion Am J Emerg Med 1996 14 5 467 68 8765112 \n26. Kanburoglu MK Derinoz O Cizmeci MN Havali C Is acute dystonia an emergency? Sometimes, it really is! Pediatr Emerg Care 2013 29 3 380 82 23462398\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "21()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001590:Benztropine; D004421:Dystonia; D005260:Female; D006801:Humans; D007818:Laryngeal Diseases; D018967:Risperidone; D012559:Schizophrenia",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "e922393",
"pmc": null,
"pmid": "32506071",
"pubdate": "2020-06-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "2872206;8919428;3142568;2568376;1670616;23826212;20446229;7304797;21741216;23462398;26252439;13590459;1348162;10337906;8564339;15888517;20513652;8765112;16001412;9483263;19144938;27145799;11806865;2890672",
"title": "Risperidone-Induced Acute Laryngeal Dystonia: A Case Report.",
"title_normalized": "risperidone induced acute laryngeal dystonia a case report"
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"companynumb": "SA-JNJFOC-20200716248",
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"activesubstancename": "RISPERIDONE"
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... |
{
"abstract": "Current guidelines for assessing the risk of experiencing a hospitalized cardiovascular (CV) event discourage stress testing of asymptomatic individuals; however, these recommendations are based on evidence gathered primarily from those aged < 60 years, and do not address the possibility of unrecognized \"silent myocardial ischemia\" in middle aged and older adults.\n\n\n\nWe performed dobutamine cardiovascular magnetic resonance (CMR) stress testing in 327 consecutively recruited participants aged > 55 years without CV-related symptoms nor known coronary artery disease, but otherwise at increased risk for a future CV event due to pre-existing hypertension or diabetes mellitus for at least 5 years. After adjusting for the demographics and CV risk factors, log-rank test and Cox proportional hazards models determined the additional predictive value of the stress test results for forecasting hospitalized CV events/survival. Either stress-induced LV wall motion abnormalities or perfusion defects were used to indicate myocardial ischemia.\n\n\n\nParticipants averaged 68 ± 8 years in age; 39% men, 75% Caucasian. There were 38 hospitalized CV events or deaths which occurred during a mean follow-up of 58 months. Using Kaplan-Meier analyses, myocardial ischemia identified future CV events/survival (p < 0.001), but this finding was more evident in men (p < 0.001) versus women (p = 0.27). The crude hazard ratio (HR) of myocardial ischemia for CV events/survival was 3.13 (95% CI: 1.64-5.93; p < 0.001). After accounting for baseline demographics, CV risk factors, and left ventricular ejection fraction/mass, myocardial ischemia continued to be associated with CV events/survival [HR: 4.07 (95% CI: 1.95-8.73) p < 0.001].\n\n\n\nAmong asymptomatic middle-aged individuals with risk factors for a sentinel CV event, the presence of myocardial ischemia during dobutamine CMR testing forecasted a future hospitalized CV event or death. Further studies are needed in middle aged and older individuals to more accurately characterize the prevalence, significance, and management of asymptomatic myocardial ischemia.\n\n\n\n( ClinicalTrials.gov identifier): NCT00542503 and was retrospectively registered on October 11th, 2007.",
"affiliations": "Department of Internal Medicine, Cardiovascular Medicine Section, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina, 27157-1045, USA.;Department of Internal Medicine, Cardiovascular Medicine Section, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina, 27157-1045, USA.;Department of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.;Department of Internal Medicine, Cardiovascular Medicine Section, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina, 27157-1045, USA.;Department of Medicine (Cardiovascular Medicine), Stanford University School of Medicine, Palo Alto, CA, USA.;Department of Medicine (Cardiovascular Medicine), University of Mississippi Medical Center, Jackson, MS, USA.;Department of Internal Medicine, Cardiovascular Medicine Section, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina, 27157-1045, USA.;Department of Radiology (Division of Radiologic Sciences), Wake Forest School of Medicine, Winston-Salem, NC, USA.;Department of Internal Medicine, Cardiovascular Medicine Section, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina, 27157-1045, USA.;Department of Internal Medicine, Cardiovascular Medicine Section, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina, 27157-1045, USA. ghundley@wakehealth.edu.",
"authors": "Stacey|R Brandon|RB|;Vera|Trinity|T|;Morgan|Timothy M|TM|;Jordan|Jennifer H|JH|;Whitlock|Matthew C|MC|;Hall|Michael E|ME|;Vasu|Sujethra|S|;Hamilton|Craig|C|;Kitzman|Dalane W|DW|;Hundley|W Gregory|WG|",
"chemical_list": "D058665:Adrenergic beta-1 Receptor Agonists; D004280:Dobutamine",
"country": "England",
"delete": false,
"doi": "10.1186/s12968-018-0492-5",
"fulltext": "\n==== Front\nJ Cardiovasc Magn ResonJ Cardiovasc Magn ResonJournal of Cardiovascular Magnetic Resonance1097-66471532-429XBioMed Central London 49210.1186/s12968-018-0492-5ResearchAsymptomatic myocardial ischemia forecasts adverse events in cardiovascular magnetic resonance dobutamine stress testing of high-risk middle-aged and elderly individuals Stacey R. Brandon bstacey@wakehealth.edu 1Vera Trinity tvera@wakehealth.edu 1Morgan Timothy M. tomorgan@wakehealth.edu 2Jordan Jennifer H. jenjorda@wakehealth.edu 1Whitlock Matthew C. mattwhitlockmd@gmail.com 5Hall Michael E. mehall@umc.edu 4Vasu Sujethra 1Hamilton Craig crhamilt@wakehealth.edu 3Kitzman Dalane W. dkitzman@wakehealth.edu 1Hundley W. Gregory 336-716-6125ghundley@wakehealth.edu 11 0000 0001 2185 3318grid.241167.7Department of Internal Medicine, Cardiovascular Medicine Section, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157-1045 USA 2 0000 0001 2185 3318grid.241167.7Department of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC USA 3 0000 0001 2185 3318grid.241167.7Department of Radiology (Division of Radiologic Sciences), Wake Forest School of Medicine, Winston-Salem, NC USA 4 0000 0004 1937 0407grid.410721.1Department of Medicine (Cardiovascular Medicine), University of Mississippi Medical Center, Jackson, MS USA 5 0000000419368956grid.168010.eDepartment of Medicine (Cardiovascular Medicine), Stanford University School of Medicine, Palo Alto, CA USA 22 11 2018 22 11 2018 2018 20 752 3 2018 9 10 2018 © The Author(s). 2018Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nCurrent guidelines for assessing the risk of experiencing a hospitalized cardiovascular (CV) event discourage stress testing of asymptomatic individuals; however, these recommendations are based on evidence gathered primarily from those aged < 60 years, and do not address the possibility of unrecognized “silent myocardial ischemia” in middle aged and older adults.\n\nMethods\nWe performed dobutamine cardiovascular magnetic resonance (CMR) stress testing in 327 consecutively recruited participants aged > 55 years without CV-related symptoms nor known coronary artery disease, but otherwise at increased risk for a future CV event due to pre-existing hypertension or diabetes mellitus for at least 5 years. After adjusting for the demographics and CV risk factors, log-rank test and Cox proportional hazards models determined the additional predictive value of the stress test results for forecasting hospitalized CV events/survival. Either stress-induced LV wall motion abnormalities or perfusion defects were used to indicate myocardial ischemia.\n\nResults\nParticipants averaged 68 ± 8 years in age; 39% men, 75% Caucasian. There were 38 hospitalized CV events or deaths which occurred during a mean follow-up of 58 months. Using Kaplan-Meier analyses, myocardial ischemia identified future CV events/survival (p < 0.001), but this finding was more evident in men (p < 0.001) versus women (p = 0.27). The crude hazard ratio (HR) of myocardial ischemia for CV events/survival was 3.13 (95% CI: 1.64–5.93; p < 0.001). After accounting for baseline demographics, CV risk factors, and left ventricular ejection fraction/mass, myocardial ischemia continued to be associated with CV events/survival [HR: 4.07 (95% CI: 1.95–8.73) p < 0.001].\n\nConclusions\nAmong asymptomatic middle-aged individuals with risk factors for a sentinel CV event, the presence of myocardial ischemia during dobutamine CMR testing forecasted a future hospitalized CV event or death. Further studies are needed in middle aged and older individuals to more accurately characterize the prevalence, significance, and management of asymptomatic myocardial ischemia.\n\nTrial registration\n(ClinicalTrials.gov identifier): NCT00542503 and was retrospectively registered on October 11th, 2007.\n\nKeywords\nStress testingCardiovascular eventsAgingSex differenceCardiovascular magnetic resonancehttp://dx.doi.org/10.13039/100000002National Institutes of HealthR01HL076438issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nWhether to assess or how best to manage silent myocardial ischemia is not well defined. In a general asymptomatic population, the prevalence of silent myocardial ischemia is estimated to be between 2 and 5%, and in those with a prior myocardial infarction (MI), silent myocardial ischemia may be as high as 30% [1]. Identification of silent myocardial ischemia may be obtained with dobutamine stress testing [2–5]. Individuals with silent myocardial ischemia have the same level or higher risk for cardiovascular events and mortality as patients who present with typical angina [6–9].\n\nTo identify those at risk of a future cardiovascular (CV) event, current guidelines from the American College of Cardiology (ACC), the American Heart Association (AHA), and the European Society of Cardiology (ESC) recommend against stress testing in individuals who do not exhibit anginal symptoms consistent with CV disease. [10, 11] ACC Appropriateness Use Criteria regard the utility of stress testing asymptomatic individuals with multiple risk factors for a CV event as “uncertain” [12–15]. Therefore, when following current guidelines, one often does not perform stress testing to identify silent myocardial ischemia unless patients exhibit symptoms that may relate to angina.\n\nInterestingly, many of these recommendations rely on study results involving younger (aged 35 to 60 years) who were relatively active individuals with a low prevalence of “silent ischemia.” In a retrospective review of nearly 2000 exercise stress echocardiograms, inducible ischemia was not associated with death, but nearly half of the study population was younger than 50 years [16]. A different study in patients aged 50–75 years which included over 600 relatively healthy patients found a three-fold increase in the risk of CV events in those who had silent myocardial ischemia [17]. Older individuals, who may be less active than their younger counterparts, may not develop symptoms, and thus, it remains uncertain as to whether current AHA/ACC appropriateness criteria are arranged to identify silent myocardial ischemia in the elderly.\n\nAccordingly, we hypothesized that silent myocardial ischemia is present in higher-risk middle-aged and elderly individuals, and its presence would identify those at higher risk for CV events and death during follow-up after accounting for the presence of traditional CV disease risk factors. This prospective study funded by combined resources of the National Heart Lung and Blood Institute and the National Aging Institute of the National Institutes of Health within the United States was performed to address a gap in knowledge related to the utility of CV stress testing in middle-aged and older individuals with a) risk factors for a CV event (evaluated via calculation of their Framingham risk score), b) no concurrent symptoms associated with CV disease, and c) the potential presence of unrecognized silent ischemia.\n\nMethods\nStudy design\nThe study was approved by the Institutional Review Board of Wake Forest Health Sciences, and each participant provided witnessed, written informed consent. This study was registered with Clinicaltrials.gov (NCT00542503) and funded by National Institutes of Health grants R01HL076438 and P30AG21332. The purpose of this joint initiative was to the utility of pharmacologic cardiovascular magnetic resonance (CMR) stress testing results to identify those at risk of future hospitalizations for cardiac events. Upon enrollment risk factors for cardiac events, vital signs and fasting blood samples were collected; thereafter, each participant underwent a dobutamine stress CMR (DCMR) test in which hemodynamic and left ventricular [LV] volumes, mass, ejection fraction and stress induced LV wall motion abnormalities were recorded.\n\nAfter stress testing, active surveillance for hospitalized cardiac events was performed through follow-up telephone interviews conducted at 4-month intervals by a research nurse who was blinded to the DCMR results. If an event was suspected during the phone interview, it was substantiated by thorough review of the participant’s medical record. Clinical hospitalization events included a) incident heart failure (defined as the acute onset of dyspnea, chest x-ray evidence of congestion or a serum B-type natriuretic peptide level > 100 pg/ml, and receipt of intravenous diuretics), b) myocardial infarction (angina of ≥20 min duration and a rise in troponin or creatine kinase level above the 99 percentile of the upper reference limit) [18], c) unstable angina warranting coronary artery revascularization, d) sudden cardiac death (death during the hospital admission for acute coronary syndrome, significant cardiac arrhythmia, refractory heart failure, or death at home after chest pain complaint), or e) transient ischemic attack or cerebrovascular accident. Any participants who experienced an epicardial coronary artery revascularization procedure within 6 weeks of DCMR were excluded from the longitudinal event analysis.\n\nStudy population\nThe study included participants from central and western North Carolina who possessed established risk factors (hypertension, diabetes) for a future hospitalized cardiac event for more than 5 years prior to study enrollment. This 5-year pre-requisite of a risk factor was suggested by NHLBI to address concerns of increasing risk suspected for individuals with longstanding CV disease. Potential participants were excluded if a) they had known coronary artery disease (CAD) or had experienced a prior myocardial infarction, b) reported any cardiovascular related symptoms such as chest pain or shortness of breath at rest or with exertion 6 months prior to enrollment, or c) exhibited a contraindication to intravenous dobutamine or CMR exam (e.g., presence of incompatible bio-metallic implants or claustrophobia). Recruitment of study participants was achieved through newspaper and television advertisements and mailings to randomly selected individuals 55 to 90 years within the catchment area. To define certain covariates, such as hypertension and cholesterolemia, patients were categorized by JNC-7 and NCEP ATP-III, respectively, or by prior provider-based diagnosis [19, 20].\n\nDCMR stress test procedure\nThe DCMR stress test protocol was accomplished according to previously published techniques, [21–24] and images were acquired on a 1.5T (Avanto, Siemens Healthineers, Erlangen, Germany) whole-body imaging system. LV cines were obtained in multiple contiguous short axis slices (apex to base) and in 3 long axis views (2, 3, and 4 chamber) at baseline, peak dobutamine stress, and then after 10 min of recovery. To achieve peak stress, dobutamine was titrated up to 40 μg/kg/min (without or with up to 1.5 mg of atropine) to achieve 80% of the maximum predicted heart rate response for age. This target heart rate response was selected based on our prior studies demonstrating its efficacy for a) identifying inducible ischemia and b) adverse cardiac prognoses [22]. If the heart rate was more than 30 beats under the target heart rate at 20 μg/kg/min of dobutamine, atropine was administered. Brachial artery systolic (SBP) and diastolic blood pressure (DBP) were measured with an automatic CMR compatible sphygmomanometer.\n\nLV wall motion analysis\nThe LV wall motion at baseline, peak dobutamine stress and in recovery was assessed with a visual scoring system in which 17 LV segments were scored according to AHA guidelines by CMR trained cardiologists (see Fig. 1) [22]. Inducible LV wall motion abnormalities were defined as an increase in a score of ≥ 1 (e.g., normal to hypokinetic) in 2 or more contiguous myocardial segments. Segments with an LV wall motion score of 2 or 3 at rest with no worsening of wall motion were considered negative for ischemia [24]. Also, per previously published techniques, LV volumes were measured from the short-axis series of cine white blood imaging sequences using a modified Simpson’s rule method [25]. Image acquisition parameters included a 45 msec repetition time (TR), a 1 msec echo time (TE), a 78° flip angle (FA), a 400 × 324 mm field of view (FOV), a 192 × 109 matrix, and an 8 mm thick slice with a 2 mm gap and an acceleration factor of 2.Fig. 1 Dobutamine Stress-induced Wall Motion Abnormality. Stress-induced left ventricular (LV) wall motion abnormality obtained at peak DCMR. (Rest images on top; Stress images on bottom; Red arrow points toward an area of decreased myocardial thickening during stress)\n\n\n\nLV perfusion analysis\nIn those individuals with estimated glomerular filtration rates of > 60 ml/min., first pass perfusion imaging with gadobenate dimeglumine (0.1 mmol/kg; Multihance, Bracco Diagnostics Princeton, New Jersey, USA) was performed when 80% of the maximum predicted heart rate was achieved. At peak stress, 2 slices for assessing myocardial first pass perfusion were obtained. These perfusion images were collected in the short axis orientation in the middle and apical segments (2 slice positions due to the rapid heart rate). Image parameters included an 8 mm thick slice, TR 169 msec, TE 1.1 msec, FA of 12°, FOV of 360 × 270 mm and 192 × 108 matrix. Rest first-pass perfusion imaging was not performed. Any perfusion defect that persisted for more than 5 frames from onset of myocardial enhancement and encompassed > 25% of the thickness of the wall was further evaluated for classification as ischemic (see Fig. 2) [24].Fig. 2 Stress-induced Myocardial Perfusion Defect: Apical stress-induced perfusion defect obtained at peak stress during dobutamine stress cardiovascular magnetic resonance (DCMR) stress test. Red arrows highlight lack of contrast relative to other myocardial segments to indicate a stress-induced perfusion defect\n\n\n\nMyocardial ischemia\nFor the purposes of these analyses, unless otherwise specified, myocardial ischemia was defined according to previously published criteria including the presence of a stress-induced wall motion abnormality or the presence of a stress-induced perfusion defect for those who received contrast [24].\n\nStatistical analyses\nParticipants were analyzed in their entirety and also stratified by gender and the presence or absence of hospitalized CV events during the follow-up period. Fischer’s exact tests for dichotomous risk factor variables and two sample Student’s t-tests for continuous data were used to evaluate differences between those who did and did not experience hospitalized CV events. Cox proportional hazards regression models were used to determine the univariable association with each risk factor variable separately and the hazard of experiencing a hospitalized CV event. The increased or decreased risk of a future hospitalized CV event due to the presence or absence of a given variable was expressed by a hazard ratio (HR) with a corresponding 95% confidence interval (CI). A Cox multivariable model was constructed with a stepwise selection method using a p-value of 0.25 to enter or a p-value of 0.10 stay in the model to guard against over-fitting. Kaplan-Meier estimates were used to estimate event rates between those who did and did not demonstrate myocardial ischemia. These differences were also statistically evaluated using the log-rank test. Finally, multi-variate Cox proportional hazard models were used with incremental adjustment to evaluate the relationship between myocardial ischemia and clinical events. The different models used for this adjustment were as follows:\n\nModel 1: age, race, gender, height, weight\n\nModel 2: Model 1 + diabetes mellitus, hypertension, tobacco use, atrial fibrillation, hypercholesterolemia, systolic blood pressure\n\nModel 3: Model 2 + left ventricular ejection fraction, left ventricular mass\n\nAll statistical analyses were performed with SAS JMP Pro 13.0 software package (SAS Institute, Cary, North Carolina, USA).\n\nResults\nThe age of the 327 participants within the study averaged 68 ± 8 (range 55 to 86) years; 39% men, 75% Caucasian, 22% African-American. The study population’s demographic data are displayed in Table 1. The pre-test likelihood for CAD was 30%. The imaging associated results are shown in Table 2. Of those included in our study identified as having myocardial ischemia, 19 (5.8%) had stress-induced wall motion abnormalities only, 38 (11.5%) had a stress-induced perfusion defect only, and 22 (6.7%) had both a stress-induced wall motion abnormality and a perfusion defect. Contrast was administered to 222 (67.9%) of all participants because 108 participants had an estimated glomerular filtration rate < 60 ml/min (a pre-determined threshold for which gadolinium contrast would not be administered).Table 1 Baseline Characteristics of Demographics and Medical History by Events/Gender\n\n\tWomen\tMen\t\nNo CV events\tCV events\tp-value\tNo CV events\tCV events\tp-value\t\n(n = 177)\t(n = 22)\t(n = 112)\t(n = 16)\t\nAge (years)\t68.7 ± 8\t69 ± 7\t0.90\t69 ± 8\t72 ± 9\t0.29\t\nCaucasian (n, %)\t130 (73%)\t15 (68%)\t0.36\t86 (77%)\t15 (94%)\t0.34\t\nAfrican-American (n, %)\t4 (24%)\t6 (28%)\t–\t22 (20%)\t1 (6%)\t–\t\nBody Mass Index (kg/m2)\t31 ± 6\t32 ± 6\t0.26\t29 ± 5\t30 ± 7\t0.53\t\nHeight (cm)\t162 ± 7\t164 ± 8\t0.26\t175 ± 8\t175 ± 9\t0.98\t\nWeight (kg)\t81 ± 18\t89 ± 18\t0.12\t91 ± 17\t95 ± 16\t0.55\t\nTotal Cholesterol (mg/dL)\t163 ± 46\t172 ± 67\t0.59\t143 ± 36\t151 ± 40\t0.59\t\nHigh Density Lipoprotein Cholesterol (mg/dL)\t51 ± 14\t49 ± 16\t0.65\t42 ± 14\t41 ± 11\t0.80\t\nHypertension, n (%)\t168 (95%)\t21 (95%)\t0.91\t102 (92%)\t16 (100%)\t0.09\t\nTransient Ischemic Attack /Stroke, n (%)\t6 (3%)\t1 (5%)\t0.76\t9 (8%)\t3 (18%)\t0.21\t\nHypercholesterolemia, n (%)\t128 (72%)\t12 (55%)\t0.09\t68 (61%)\t9 (57%)\t0.73\t\nCurrent smoker, n (%)\t7 (4%)\t2 (9%)\t0.32\t4 (4%)\t1 (6%)\t0.62\t\nDiabetes, n (%)\t64 (36%)\t12 (54%)\t0.09\t50 (45%)\t6 (38%)\t0.59\t\nEstimated Glomerular Filtration Rate (mL/min/1.73 m2)\t58 ± 6\t57 ± 9\t0.58\t58 ± 5\t58 ± 4\t0.99\t\nAspirin\t109 (71%)\t13 (62%)\t0.6\t84 (73%)\t7 (53%)\t0.41\t\nAngiotensin Converting Enzyme Inhibitor\t72 (41%)\t6 (28%)\t0.21\t54 (48%)\t8 (50%)\t0.89\t\nBeta Blocker\t60 (35%)\t7 (64%)\t0.83\t28 (25%)\t3 (19%)\t0.57\t\nDiuretic\t109 (62%)\t13 (59%)\t0.82\t64 (57%)\t9 (56%)\t0.94\t\nAngiotensin Receptor Blocker\t65 (36%)\t10 (45%)\t0.43\t27 (24%)\t3 (18%)\t0.62\t\nStatin\t129 (73%)\t13 (59%)\t0.19\t82 (78%)\t12 (75%)\t0.78\t\nAldosterone antagonist\t5 (3%)\t1 (5%)\t0.67\t1 (1%)\t0 (0%)\t0.61\t\nCalcium Channel Blocker\t44 (25%)\t9 (41%)\t0.12\t37 (33%)\t6 (37%)\t0.74\t\nBaseline demographics and clinical characteristics stratified by gender. Mean ± Standard Deviation or number (percent). A p-value < 0.05 indicates statistical significance\n\nTable 2 Baseline Characteristics of Stress Testing and Cardiac Imaging Measures by Events/Gender\n\n\tWomen\tMen\t\nNo CV events\tCV events\tp-value\tNo CV events\tCV events\tp-value\t\n(n = 177)\t(n = 22)\t(n = 112)\t(n = 16)\t\nResting Systolic Blood Pressure (mmHg)\t141 ± 17\t150 ± 25\t0.11\t140 ± 17\t148 ± 16\t0.17\t\nResting Diastolic Blood Pressure (mmHg)\t77 ± 10\t83 ± 11\t0.16\t82 ± 11\t84 ± 10\t0.61\t\nResting Heat rate (beats/minute)\t67 ± 11\t66 ± 13\t0.80\t63 ± 11\t69 ± 11\t0.13\t\nPeak Systolic Blood Pressure (mmHg)\t126 ± 23\t126 ± 31\t0.98\t129 ± 15.8\t126 ± 19.5\t0.79\t\nPeak Diastolic Blood Pressure (mmHg)\t64.9 ± 13.2\t63.4 ± 18.3\t0.84\t75 ± 17\t76 ± 16\t0.85\t\nPeak stress Heat rate (beats/minute)\t126 ± 14\t117 ± 20\t0.04\t125 ± 17\t124 ± 11\t0.95\t\nRate pressure product (mmHg-bpm)\t15,923 ± 3437\t14,897 ± 4376\t0.38\t16,133 ± 3740\t15,813 ± 2984\t0.82\t\nLeft Ventricular Ejection Fraction (%)\t66 ± 7\t63 ± 9\t0.23\t61 ± 8\t60 ± 11\t0.55\t\nLeft Ventricular End Diastolic Volume (ml/m2)\t59 ± 15\t59 ± 17\t0.96\t64 ± 14\t69 ± 15\t0.13\t\nLeft Ventricular End Systolic Volume (ml/m2)\t20 ± 7\t23 ± 13\t0.32\t25 ± 10\t30 ± 12\t0.026\t\nLeft Ventricular Stroke Volume (ml/m^2)\t38 ± 8\t36 ± 7\t0.73\t39 ± 9\t39 ± 9\t0.97\t\nLeft Ventricular Mass (g/m2)\t61 ± 11\t66 ± 9\t0.08\t72 ± 14\t80 ± 12\t0.17\t\nLeft Ventricular Inducible Wall Motion Abnormality, n (%)\t18 (10%)\t2 (9%)\t0.87\t12 (10%)\t9 (56%)\t< 0.001\t\nLeft Ventricular Stress-induced Perfusion Defect (%; of those who received contrast)\t31 (27%)\t6 (37%)\t0.40\t15 (19%)\t8 (62%)\t0.001\t\nMyocardial ischemia (Wall Motion or Perfusion; out of all participants without known CAD)\t39 (22%)\t7 (32%)\t0.32\t22 (20%)\t11 (69%)\t< 0.001\t\nBaseline stress test and imaging characteristics stratified by gender. Mean ± Standard Deviation or number (percent). A p-value < 0.05 indicates statistical significance. CV cardiovascular\n\n\n\nRelative to men, women required less total dobutamine (30 ± 143 versus 357 ± 176 μg/kg, p = 0.004) and atropine (0.42 ± 0.30 versus 0.57 ± 0.31 mg, p < 0.001) to achieve their target heart rate. The difference in the total atropine persisted after adjusting for weight (5.3 ± 3.7 versus 6.3 ± 3.9 μg/kg, in women versus men, p = 0.05). There was no difference in the peak rate-pressure product between men and women (16,101 vs 15,816 mmHg-bpm, respectively; p = 0.57). Over 94% of those included followed up for > 3 years, but in those with < 3 years follow-up, the participants (21 participants) tended to be older (71.9 ± 6 vs 68.1 ± 8 years; p = 0.04), were Caucasian (100% vs 72%; p = 0.05), and more likely to be male (47.6% vs 39.0%; p = 0.4).\n\nApproximately 11.1% and 12.5% of the otherwise asymptomatic women and men that respectively underwent DCMR experienced a total of 38 hospitalized clinical events over the average follow-up period of 58 months (Table 3). Of those with a myocardial infarction or unstable angina, all underwent a percutaneous coronary intervention except for 2 men with unstable angina who underwent coronary artery bypass grafting.Table 3 Cardiovascular Events by Gender\n\n\tWomen\tMen\t\nDeath\t10\t6\t\nMyocardial Infarction\t3\t2\t\nIncident Heart Failure Warranting Hospitalization\t3\t1\t\nUnstable Angina\t2\t5\t\nTransient Ischemic Attack/Cerebrovascular Accident\t4\t2\t\nNone\t177\t112\t\nList of cardiovascular events and death stratified by gender\n\n\n\nIn univariable analysis (Table 4) with both genders combined, SBP and age were associated with hospitalized CV events and survival, p = 0.002 and 0.01, respectively. For both genders combined, stress-induced LV wall motion abnormality was associated with hospitalized CV events and survival (p = 0.003). In those who received gadolinium contrast, the presence of a stress-induced perfusion defect was also associated with hospitalized CV events and survival (p = 0.007). When combining either a stress-induced perfusion defect or a DCMR-induced LV wall motion abnormality as evidence of myocardial ischemia, it is significantly associated with CV events and survival (p < 0.001). These associations appeared stronger in men than women, but the interaction term was not significant (p > 0.20).Table 4 Univariate Cox Proportional Hazard Ratios for Cardiovascular Events/Survival\n\n\tAll\tWomen\tMen\t\nHR (95% CI)\tp-value\tHR (95% CI)\tp-value\tHR (95% CI)\tp-value\t\nAge\t1.05 (1.01–1.09)\t0.01\t1.05 (1.00–1.11)\t0.04\t1.04 (0.99–1.11)\t0.14\t\nBody Mass Index\t1.00 (0.95–1.05)\t0.86\t1.00 (0.94–1.07)\t0.91\t1.01 (0.91–1.10)\t0.82\t\nTotal Cholesterol\t1.00 (0.99–1.01)\t0.53\t1.00 (0.99–1.01)\t0.62\t1.01 (0.98–1.02)\t0.52\t\nHigh Density Lipoprotein\t0.99 (0.95–1.02)\t0.59\t0.98 (0.94–1.03)\t0.55\t0.99 (0.92–1.04)\t0.84\t\nSystolic Blood Pressure\t1.03 (1.01–1.06)\t0.002\t1.03 (0.99–1.06)\t0.08\t1.04 (1.01–1.07)\t0.007\t\nCurrent Smoker\t2.18 (0.53–6.09)\t0.19\t2.45 (0.39–8.46)\t0.22\t1.83 (0.10–9.13)\t0.59\t\nDiabetes Mellitus\t1.3 (0.69–2.48)\t0.40\t2.82 (0.85–10.77)\t0.11\t0.95 (0.18–4.33)\t0.52\t\nInducible Wall Motion Abnormality\t3.30 (1.56–6.49)\t0.003\t0.88 (0.14–3.02)\t0.86\t8.86 (3.28–224.90)\t< 0.001\t\nStress-Induced Perfusion Defect\t2.79 (1.33–5.82)\t0.007\t1.62 (0.55–4.38)\t0.36\t5.55 (1.85–18.41)\t0.003\t\nAny Ischemia\t3.13 (1.64–5.93)\t< 0.001\t1.63 (0.62–3.89)\t0.30\t7.41 (2.69–23.54)\t< 0.001\t\nLeft Ventricular Ejection Fraction\t0.99 (0.95–1.03)\t0.65\t1.04 (0.97–1.12)\t0.21\t0.96 (0.89–1.07)\t0.06\t\nLate Gadolinium Enhancement\t2.41 (0.95–5.34)\t0.06\t0.71 (0.04–3.48)\t0.72\t4.39 (1.41–13.28)\t0.01\t\nResults of univariate Cox proportional hazard relationships between different risk factors and cardiovascular events/survival. Overall study population results included and those stratified by gender. Of note, for perfusion defects and late gadolinium enhancement, the study population consisted only of those 222 who received contrast\n\n\n\nDCMR measures of myocardial ischemia did improve the prediction of hospitalized CV events and survival overall. The composite event rate for hospitalized CV events or death was 8.0% and 22.8% for those without and with inducible myocardial ischemia (p < 0.001). In women, the composite event rates were 9.8% and 15.2% (p = 0.32), but in men, they were 5.3% and 33.3% (p < 0.001) for those without versus with inducible myocardial ischemia, respectively. In Kaplan-Meier analyses, myocardial ischemia was associated with a reduced event-free survival (p < 0.001). This pattern was seen more significantly in men compared to women (p < 0.001 and p = 0.27, respectively; see Figs. 3, 4 and 5).Fig. 3 Event-free Survival by Asymptomatic Myocardial Ischemia. Kaplan Meier curves of cardiovascular event free as a function of length of follow-up for those with and without myocardial ischemia for the study population without known coronary artery disease (CAD). Test comparing the two groups is based on the log-rank test\n\nFig. 4 Event-free Survival by Asymptomatic Myocardial Ischemia: Men. Kaplan Meier curves of cardiovascular event free as a function of length of follow-up for men with and without myocardial ischemia on DCMR for the study population without known coronary artery disease. Test comparing the two groups is based on the log-rank test\n\nFig. 5 Cardiovascular Event-free Survival by Asymptomatic Myocardial Ischemia: Women. Kaplan Meier curves of cardiovascular event free as a function of length of follow-up for women with and without myocardial ischemia for the study population without known coronary artery disease. Test comparing the two groups is based on the log-rank test\n\n\n\nTo guard against compromising our results due to over-fitting our statistical models, we first performed multivariable stepwise Cox regression analysis in which the most significant contributors to events were compared with one another. As shown in Table 5, stress-induced myocardial ischemia predicted CV events/survival (p < 0.001) as well as tobacco use (p = 0.01). Other variables, such as SBP, diabetes mellitus, and LV mass, met model inclusion but did not reach statistical significance. Secondly, we performed additional Cox proportional hazard models for determining a participant’s HR of experiencing a hospitalized CV event/survival utilizing incremental adjustment models as detailed above. The crude HR for a hospitalized CV event/survival whether myocardial ischemia was present was 3.13 (95% CI: 1.64–5.93; p < 0.001; see Table 6). The significance persisted after adjustment for baseline demographics (p < 0.001) and after further adjustment for significant cardiovascular risk factors (p = < 0.001). Finally, after adjustment for imaging findings, such as LV ejection fraction and mass, myocardial ischemia continued to be associated with CV events and survival [HR: 4.07 (95% CI: 1.95–873); p < 0.001). To evaluate the fit of these models, the receiver operating curve was used to calculate the area under the curve, which was 0.710, 0.848, and 0.860 for models 1–3, respectively.Table 5 Stepwise Multivariate Regression for Cardiovascular Events and Survival\n\n\tp-Value\t\nLV Mass\t0.051\t\nDiabetes Mellitus\t0.202\t\nCurrent Tobacco Use\t0.011\t\nSystolic Blood Pressure\t0.128\t\nAsymptomatic Ischemia\t< 0.001\t\nResults of stepwise logistical regression evaluating multivariate association between variables and cardiovascular events/survival. In order to be included in the model, the p-value had to be less than 0.25\n\nTable 6 Crude and Multivariate Cox Proportional Hazard Models of Cardiovascular Events/Survival by Myocardial Ischemia\n\n\tHR (95% CI)\tp-Value\t\nUnadjusted\t3.13 (1.64–5.93)\t< 0.001\t\nModel 1\t3.12 (1.62–5.97)\t< 0.001\t\nModel 2\t4.42 (2.12–9.43)\t< 0.001\t\nModel 3\t4.07 (1.95–8.73)\t< 0.001\t\nResults of incremental adjustment with Cox proportional hazard model. The hazard ratio is for myocardial ischemia and its relationship to cardiovascular events and survival\n\n\n\nDiscussion\nThere are several important findings in this study. First, nearly a quarter of middle and older aged asymptomatic individuals with CV disease risk factors exhibited DCMR evidence of inducible “silent” myocardial ischemia (Table 2). Second, when asymptomatic myocardial ischemia was present, we observed men to experience more hospitalizations for a CV event or death than women. Finally, the presence of LV myocardial ischemia in this asymptomatic population was most predictive of a future hospitalized CV event if they had no prior CV event and no known history of CAD – both conditions for which current algorithms and appropriate use guidelines do not recommend stress testing.\n\nAs shown in Table 3, we observed a total of 38 hospitalized CV events or deaths (event rate of 11.6% over 5 years) which was lower than what we might have extrapolated from other studies such as the Framingham Heart Study cohort [15]. This may have been due to: a) a United States nationwide decline in the incidence of hospitalized CV events since publication of the initial Framingham Heart Study data [16], b) the majority of the participants (67%) received HMG Co-A reductase inhibitors (i.e. statin medications) which have been shown to reduce the incidence of hospitalized CV events [17], c) people who volunteer for studies tend to be healthier and less likely to develop a CV event warranting hospitalization when compared to non-responders [18], and d) the participants in the study were contacted by the research nurse every 4 months; such close follow-up could have changed their behavior leading to better compliance with medical or behavioral treatment directed toward reducing the risk of a hospitalization for a CV event [20].\n\nSilent myocardial ischemia has even been investigated in different stress testing modalities. In high-risk patients with type 2 diabetes mellitus for at least 15 years, the positive predictive value for silent myocardial ischemia by dobutamine stress echocardiography was 69%, 75% for single photon emission computed tomography (SPECT), and 60% for exercise stress testing [26]. While silent myocardial ischemia remains an elusive diagnosis, most clinicians more readily appreciate silent myocardial infarctions. The three risk factors most commonly associated with silent myocardial infarctions are diabetes mellitus, hypertension, and advanced age [27–30]. In our study, most individuals exhibited hypertension. This study demonstrated that DCMR in otherwise asymptomatic middle aged and older individuals identifies silent myocardial ischemia which forecasted CV events.\n\nAs one might expect in a multivariable analysis, current smoking and myocardial ischemia were associated with future cardiac events (Table 5). The unexpected finding in this study relates to the fact that the association between DCMR induced myocardial ischemia and hospitalized CV events/survival was driven by the strong association of stress induced LV wall motion abnormality or perfusion defects in men—a population that otherwise would not undergo pharmacologic stress testing.\n\nLV myocardial ischemia had a weaker ability to identify subsequent CV events in women. There are several potential reasons for this. First, in a prior study (24), gender-related differences in sensitivity for diagnosing CAD in women was partially attributed to women achieving target heart rates at lower dobutamine doses with less frequent use of atropine. In the current study, compared to men, women achieved their target heart rate at lower dobutamine doses (p = 0.004), and the total atropine dose was lower in women (p = 0.05, Table 2). Second, within the same age range, women experienced fewer hospitalized CV events than men. They experienced more deaths and cerebrovascular events than men (Table 3) for which the stress CMR may not have readily identified. It is possible that with a larger sample size that included older women (and thus an increased likelihood of experiencing a hospitalization for a CV event), we would be able to improve prediction of hospitalized CV events in women.\n\n>While the results of this study remain intriguing, few data are available to direct our diagnostic and therapeutic approach for at-risk but asymptomatic middle aged and older individuals at risk for a future CV event. Most of the guideline-based approaches focus on symptomatic individuals and lack clarity in how to approach patients who are asymptomatic [10, 12, 14, 15, 31, 32]. Under most circumstances, stress tests are not indicated unless a patient has symptoms suggestive of a coronary etiology. The results of this study suggest future research is necessary to develop evidence-based strategies for clinicians to determine how and when to identify and potentially treat asymptomatic middle aged and older men at risk for future CV events.\n\nThere are limitations pertaining to this study. First, this study actively recruited individuals with known long-standing hypertension or diabetes mellitus. As a result, our findings mainly relate to persons with long-term CV risk factor exposure, and in these particular analyses, since participants with known CAD were excluded, the individuals remaining with significant risk factors may be more resistant to developing clinically-significant CAD. Second, the true burden of silent myocardial ischemia remains unknown given the high-risk populations which were enrolled in this study. More inclusive studies would need to better define the risk of those who are at low- or intermediate-level risk. Third, there were fewer events than forecasted for the initial sample size estimates for this study. At the time of study inception, using published data, the hospitalized CV event rate was forecasted to be 4% to 7% per year. The lower than anticipated hospitalized cardiac event rate means that larger studies are needed to examine the impact of a multiplicity of risk factors toward promoting CV events. The power of our study is estimated to be 0.6. To capture sufficient events to perform more meaningful analyses would require a sample size of 2000–5000 individuals depending on the event rates used. Finally, since only 68% of the 327 participants received CMR gadolinium contrast to assess first pass perfusion, there is a risk that asymptomatic stress-induced perfusion defects are under-reported.\n\nConclusion\nAmong asymptomatic middle-aged individuals with risk factors for a sentinel CV event, the presence of myocardial ischemia during DCMR forecasted a future hospitalized CV event or death. Further studies are needed in middle aged and older individuals to more accurately characterize the prevalence, significance, and management of asymptomatic myocardial ischemia.\n\nAbbreviations\nACCAmerican College of Cardiology\n\nAHAAmerican Heart Association\n\nCADCoronary artery disease\n\nCIConfidence interval\n\nCMRCardiovascular magnetic resonance\n\nCVCardiovascular\n\nDBPDiastolic blood pressure\n\nDCMRDobutamine stress cardiovascular magnetic resonance\n\nESCEuropean Society of Cardiology\n\nFAFlip angle\n\nFOVField of view\n\nHRHazard ratio\n\nLVLeft ventricle/left ventricular\n\nMIMyocardial infarction\n\nSBPSystolic blood pressure\n\nSPECTSingle photon emission computed tomography\n\nTEEcho time\n\nTRRepetition time\n\nAcknowledgements\nMultihance contrast agent was provided for the study by Bracco Diagnostics (Princeton, New Jersey, USA).\n\nFunding\nThis work was supported by the National Institutes of Health (R01HL076438, P30AG21332, R01CA167821, R01HL118740 and T32HL091824). Multihance contrast agent was provided for the study by Bracco Diagnostics (Princeton, NJ). None of the authors have conflicts of interest to present.\n\nAvailability of data and materials\nPlease contact corresponding author for reasonable data requests.\n\nAuthors’ contributions\nRBS Statistical analyses, study design, manuscript writing/editing. TV Statistical analyses, study design, manuscript writing/editing. TOM Statistical analyses, study design, manuscript writing/editing. JJ Manuscript writing/editing. MW Manuscript writing/editing. MEH Manuscript writing/editing. SV Data analyses; Manuscript writing/editing. CH Data analyses; Manuscript writing/editing. DK Study design; Manuscript writing/editing. WGH Study design/implementation; Patient recruitment; Data Collection/Analyses; Manuscript Writing/Editing. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThis study was evaluated and approved by the Institutional Review Board of Wake Forest University School of Medicine. All patients enrolled in this study were required to understand and give their consent for participation.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Novo S Longo B Liquori M Abrignani MG Barbagallo M Sanguigni V Barbagallo Sangiorgi G Strano A Silent myocardial ischemia: prevalence, prognostic significance, diagnosis Cardiologia 1993 38 243 251 8020023 \n2. 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"fulltext_license": "CC BY",
"issn_linking": "1097-6647",
"issue": "20(1)",
"journal": "Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance",
"keywords": "Aging; Cardiovascular events; Cardiovascular magnetic resonance; Sex difference; Stress testing",
"medline_ta": "J Cardiovasc Magn Reson",
"mesh_terms": "D058665:Adrenergic beta-1 Receptor Agonists; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D058070:Asymptomatic Diseases; D018450:Disease Progression; D004280:Dobutamine; D005260:Female; D006760:Hospitalization; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors",
"nlm_unique_id": "9815616",
"other_id": null,
"pages": "75",
"pmc": null,
"pmid": "30463565",
"pubdate": "2018-11-22",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "12515758;22958960;6482932;4713110;11703435;12831817;24222018;11777220;19497454;21497307;17963870;17925612;25885436;22710040;23597799;11368702;25482397;20832344;15774494;11696689;8020023;25769563;19356575;15894765;22424518;24355759;12748199;12594722;12403662;17478139;12565080;18342240",
"title": "Asymptomatic myocardial ischemia forecasts adverse events in cardiovascular magnetic resonance dobutamine stress testing of high-risk middle-aged and elderly individuals.",
"title_normalized": "asymptomatic myocardial ischemia forecasts adverse events in cardiovascular magnetic resonance dobutamine stress testing of high risk middle aged and elderly individuals"
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"activesubstancename": "DEXTROSE MONOHYDRATE\\DEXTROSE MONOHYDRATE\\DOBUTAMINE HYDROCHLORID... |
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"abstract": "BACKGROUND Elizabethkingia meningoseptica (E. meningoseptica) is an aerobic Gram-negative bacillus known to thrive in moist environments, and is now recognized as a hospital-acquired infection, being found to contaminate hospital equipment, respiratory apparatus, hospital solutions, water, and drainage systems. Nosocomial infection with E. meningoseptica occurs in immunocompromised patients, requires specialized identification methods, and is resistant to conventional antibiotics. We report a case of E. meningoseptica infection arising from a percutaneous transhepatic biliary drainage (PTBD) tube. CASE REPORT A 55-year-old Saudi woman underwent liver transplantation. The post-operative period immediately following transplantation was complicated by anastomotic biliary stricture and bile leak, which was managed with percutaneous transhepatic cholangiography (PTC) with PTBD. She developed right upper quadrant abdominal pain, and her ultrasound (US) showed a subdiaphragmatic collection. Microbial culture from the PTBD tube was positive for E. meningoseptica, which was treated with intravenous ciprofloxacin and metronidazole. This case is the second identified infection with E. meningoseptica at our specialist center, fifteen years after isolating the first case in a hemodialysis patient. We believe that this is the first case of E. meningoseptica infection to be reported in a liver transplant patient. CONCLUSIONS The emerging nosocomial infectious organism, E. meningoseptica is being seen more often on hospital equipment and medical devices and in water. This case report highlights the need for awareness of this infection in hospitalized immunocompromised patients and the appropriate identification and management of infection with E. meningoseptica.",
"affiliations": "College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.;College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.;College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.;Department of Surgery, Section of Liver & Small Bowel Transplantation & Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Department of Medicine, Section of Gastroenterology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.",
"authors": "Musalem|Hebah M|HM|;Honjol|Yazan N|YN|;Tuleimat|Lin M|LM|;Al Abbad|Saleh I|SI|;Alsohaibani|Fahad I|FI|",
"chemical_list": null,
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"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 2893180110.12659/AJCR.905247905247ArticlesElizabethkingia Meningoseptica in a Case of Biliary Tract Infection Following Liver Transplantation Musalem Hebah M. ABCDEFG1Honjol Yazan N. ABCDEFG1Tuleimat Lin M. ABCDEFG1Al Abbad Saleh I. ACE2Alsohaibani Fahad I. ADE3\n1 College of Medicine, Alfaisal University, Riyadh, Saudi Arabia\n2 Department of Surgery, Section of Liver and Small Bowel Transplantation and Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia\n3 Department of Medicine, Section of Gastroenterology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi ArabiaAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Hebah M. Musalem, e-mail: hebamusallam91@gmail.com2017 21 9 2017 18 1014 1019 10 5 2017 12 6 2017 © Am J Case Rep, 20172017This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 55\n\nFinal Diagnosis: Percutaneous transhepatic cholangiography biliary drain infection with Elizabethkingia meningoseptica\n\nSymptoms: Right upper quadrant abdominal pain\n\nMedication: IV Ciprofloxacin 400 mg/12 hrs\n\nClinical Procedure: None\n\nSpecialty: Surgery and Internal Medicine\n\nObjective:\nRare disease\n\nBackground:\nElizabethkingia meningoseptica (E. meningoseptica) is an aerobic Gram-negative bacillus known to thrive in moist environments, and is now recognized as a hospital-acquired infection, being found to contaminate hospital equipment, respiratory apparatus, hospital solutions, water, and drainage systems. Nosocomial infection with E. meningoseptica occurs in immunocompromised patients, requires specialized identification methods, and is resistant to conventional antibiotics. We report a case of E. meningoseptica infection arising from a percutaneous transhepatic biliary drainage (PTBD) tube.\n\nCase Report:\nA 55-year-old Saudi woman underwent liver transplantation. The post-operative period immediately following transplantation was complicated by anastomotic biliary stricture and bile leak, which was managed with percutaneous transhepatic cholangiography (PTC) with PTBD. She developed right upper quadrant abdominal pain, and her ultrasound (US) showed a sub-diaphragmatic collection. Microbial culture from the PTBD tube was positive for E. meningoseptica, which was treated with intravenous ciprofloxacin and metronidazole. This case is the second identified infection with E. meningoseptica at our specialist center, fifteen years after isolating the first case in a hemodialysis patient. We believe that this is the first case of E. meningoseptica infection to be reported in a liver transplant patient.\n\nConclusions:\nThe emerging nosocomial infectious organism, E. meningoseptica is being seen more often on hospital equipment and medical devices and in water. This case report highlights the need for awareness of this infection in hospitalized immunocompromised patients and the appropriate identification and management of infection with E. meningoseptica.\n\nMeSH Keywords:\nBiliary Tract DiseasesCorynebacteriumCross InfectionLiver TransplantationSaudi Arabia\n==== Body\nBackground\nElizabethkingia meningoseptica (E. meningoseptica), previously known as Flavobacterium meningosepticum and Corynebacterium meningosepticum, is a Gram-negative aerobic bacillus commonly found in the environment [1,2]. E. meningoseptica is known to thrive in moist environments and is now recognized as a hospital-acquired or healthcare-associated infection (HAI), being found to contaminate hospital equipment, water, and drainage systems [1,2]. Water-borne acquisition of E. meningoseptica infection has been demonstrated by epidemiological and molecular studies, including in critical care units [3].\n\nElizabethkingia spp. has a widespread distribution, can resist antibiotics, creates biofilms, and grows in moist environments [1,3]. E. meningoseptica has been shown to contaminate hospital equipment, including sink drains, respiratory apparatus, solutions, disinfectants, and hospital tap water [1,2]. Infection with E. meningoseptica is most common in immunocompromised patients and premature infants, with a reported mortality rate as high as 50% [4,5].\n\nIn the United States, approximately 5–9 cases of Elizabethkingia spp. infection are reported annually in each state, usually in healthcare settings [6]. The Centers for Disease Control and Prevention (CDC) reports that there are ongoing outbreaks of Elizabethkingia spp. infection in Wisconsin, Illinois, and also Michigan, in an outbreak that was initially recognized in November 2015 [7–9]. The cases reported in these states also include the first reported outbreak of E. anopheles and the largest known outbreak of Elizabethkingia spp. recorded in the United States. [6–8].\n\nCurrently, in Saudi Arabia, there is a lack of accurate epidemiological data on the incidence of outbreaks of hospital infection with Elizabethkingia spp., including E. meningoseptica. Further studies are needed to clarify the epidemiology, risk factors, signs and symptoms, as well as treatment and antimicrobial susceptibility of different strains of this organism.\n\nWe report a case of E. meningoseptica arising from a PTBD tube in a patient who was immunocompromised following liver transplantation. A brief literature review of cases of E. meningoseptica is presented to emphasize awareness of the diagnosis and management of this emerging infection.\n\nCase Report\nA 55-year-old Saudi woman, who was known to have end-stage liver disease due to cryptogenic cirrhosis, presented to the emergency department of our hospital in Riyadh, on 20th August 2015, with a one-day history of fever and cough, progressive lower limb edema, and abdominal distention. She had type 2 diabetes mellitus and was taking oral metformin 500 mg twice daily, and was treated for hypertension with oral amlodipine 5 mg, once daily. She was a non-smoker, did not consume alcohol, and had no history of drug abuse. She was admitted to hospital for one week under the liver transplantation team for further management.\n\nOn admission, her temperature was 37.7°C, heart rate of 111 beats per minute and respiratory rate of 26 breaths per minute, with normal blood pressure and oxygen saturation on breathing room air. Laboratory investigations showed a mild peripheral blood leukocytosis (12.3×109/L), platelets (41×109/L), albumin (26 g/L), bilirubin (47 µmol/L), and creatinine (59 µmol/L). A screen for infection included examination of blood, sputum, urine, and ascitic fluid. Chest X-ray showed right-sided pleural effusion, most likely representing hydrothorax with possible consolidation. She was commenced empirically on antibiotics and the dosage of her diuretics was increased. Six liters of ascitic and pleural fluid were drained. Urine culture was found to be positive for Streptococcus agalactiae (Group B) that was sensitive to antimicrobials. Her clinical condition improved dramatically following treatment. Repeated chest X-ray showed reduction in the right hydrothorax. She was discharged home in good clinical condition. Her discharge medications included; a five-day course of oral ciprofloxacin 500 mg/12 hrs, oral lasix 20 mg, and a course of multivitamin tablets.\n\nA month later, the patient was admitted to our hospital for an elective liver transplant, with a live organ donation from a relative. She underwent total hepatectomy and transplantation using a full right lobe graft. She had three biliary anastomoses, and her arterial anastomosis was repeated twice due to procedural difficulty. She required transfusion of 12 units packed red blood cells and was transferred to the intensive care unit (ICU) following liver transplantation.\n\nIn ICU, the patient was extubated after 24 hours. However, two days later she was re-intubated for another 24 hours due to the development of acute respiratory distress syndrome (ARDS). When her clinical condition had stabilized, she was moved to the general ward, and she was commenced on immunosuppressive therapy that included oral tacrolimus 1mg, oral mycophenolate mofetil 500 mg, and oral prednisolone 5mg.\n\nThe post-operative period was also complicated by an anastomotic biliary stricture and bile leak, which was managed by percutaneous transhepatic cholangiography (PTC), and percutaneous transhepatic biliary drainage (PTBD) using an internal-external biliary catheter, with a pigtail catheter used for drainage of an intra-abdominal bile collection. The drains were kept in place for a few weeks until the drain output became minimal. The pigtail catheter was removed, and the internal-external PTBD catheter was left in place.\n\nThree weeks later, the patients developed right upper quadrant abdominal pain without fever or vomiting. There was no change in peripheral blood leukocyte count, bilirubin, ALT or alkaline phosphatase levels when compared with baseline values, but her C-reactive protein (CRP) increased from 65.1 mg/L to 155.3 mg/L. Ultrasound of the abdomen showed a right-sided sub-diaphragmatic collection measuring 3.4×4.4×2.0 cm (Figure 1).\n\nA septic screen included sampling and culture from blood, urine, biliary drain fluid, and the abdominal collection. The patient was commenced empirically on intravenous (IV) meropenem 20 mg/kg every 8 hrs. The culture from the PTBD catheter was positive for Elizabethkingia meningoseptica (E. meningoseptica), a multidrug-resistant organism.\n\nBased on the antimicrobial sensitivity, IV meropenem was changed to IV ciprofloxacin 400 mg/12 hrs and metronidazole with a loading dose of 15mg/kg over one hour and a maintenance dose of 7.5 mg/kg every six hours (Table 1). After 48 hours, PTBD catheter fluid was sent for repeat cultures. Two days later, the repeat culture results were positive for moderate levels of E. meningoseptica.\n\nThe patient’s clinical condition improved and her abdominal pain resolved. A decision was made to continue the antibiotics for a total of two weeks. After two weeks, the patient was asymptomatic with a normal peripheral blood leukocyte count (9×109/L), and her CRP dropped to 30 mg/L. Repeat fluid cultures from the PTBD catheter were negative. On follow-up, there were no complications from the antibiotic treatment.\n\nDiscussion\nElizabethkingia meningoseptica (E. meningoseptica) (formerly Chryseobacterium meningosepticum) is a member of the genus Chryseobacterium and is a non-motile, non-fastidious, catalase-positive and oxidase-positive, aerobic, glucose non-fermenting, Gram-negative bacillus that was first described by Elizabeth King in 1959 [3,6]. E. meningoseptica is commonly present in the soil, saltwater, freshwater, dry or moist clinical environments, medical equipment surfaces, intravenous lipid solutions, and municipal water supplies, including those that have been adequately chlorinated [3,6]. E. meningoseptica is associated with high mortality rates (up to 50%), partly because of the multidrug resistance of the organism [9]. However, unless patients have immunological or other susceptibility to infection, E. meningoseptica is an organism of low pathogenicity in humans [9]. Patients who may be vulnerable to infection with E. meningoseptica include preterm infants, the immunocom-promised, and those on antibiotics or in critical care units [9].\n\nThe Centers for Disease Control and Prevention (CDC) have reported that there are ongoing outbreaks of Elizabethkingia spp. infection in the USA [6–9]. The findings from the CDC have shown that the majority of patients acquiring these infections are over 65 years old, and all patients have a history of at least one underlying serious illness [6–9]. In the year 2016, there were 63 cases of Elizabethkingia spp. infection resulting in 19 deaths [6–9]. Cities in the USA where these deaths occurred include Columbia, Dodge, Fond du lac, Milwaukee, Ozaukee, Racine, Sheboygan, Washington and Waukesha (Table 2) [6–9].\n\nHypoalbuminemia and infection associated with a central venous line have been reported to be risk factors in patients with E. meningoseptica, associated with an increased mortality rate [9].\n\nClinical presentations of E. meningoseptica infection include bacteremia (most common), eye infections, pneumonia, pericardial abscess, skin and soft tissue infection (such as cellulitis, necrotizing fasciitis), intra-abdominal infection (for example, peritonitis in patients undergoing continuous ambulatory peritoneal dialysis), and surgical site infection (SSI) [10,11].\n\nElizabethkingia spp. are resistant to multiple antibiotics, including β-lactams, and may possess two different types of β-lactamases, class A extended spectrum β-lactamases and class B metallo-β-lactamases (MBLs) [3,6]. MBLs result in resistance to carbapenems, which are currently used to treat infections due to multidrug-resistant Gram-negative bacteria [3,6]. Two types of MBL, BlaB, and GOB have now been identified in E. meningosepticum, meaning that E. meningosepticum is resistant to multiple classes of antibiotic and may have varied resistance patterns that can only be determined by resistance testing in each case of infection [3,6]. Preventive measures that should be taken in hospitals to regulate this challenging infection include active infection control, such as hyper-chlorination of water, as well as regular surveillance and inspection of hospital water tanks [7,11].\n\nThis case report has presented a case of E. meningoseptica infection arising from a percutaneous transhepatic biliary drainage (PTBD) tube in a patient following liver transplantation. The patient was doing well until one month post-transplant when she experienced abdominal pain. Abdominal pain in a patient following liver transplantation can be attributed to multiple factors including transplant rejection, infection, biliary leak or obstruction, and graft failure. In this case, the patient was afebrile, most likely due to immunosuppressive therapy that included prednisone, which commonly masks fever. A full septic screen is therefore always recommended in this population of patients when symptoms arise, as infections in patients following transplantation can be life-threatening [12,13]. The findings of a study were reported in 2010 by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD) that showed that the causes of death after one year in patients following liver transplantation can be categorized as follows: 28% from hepatic causes, 22% due to malignancy, 11% from cardiovascular causes, and 9% due to infection [13].\n\nBacterial and fungal infections remain a common cause of death within the first year after liver transplantation [13,14]. Even patients who live for several years after a transplant are at significant risk of developing life-threatening infections [14]. Leuconostoc pseudomesenteroides is a rare bacterium that has been shown to originate from a bile leak in a liver transplant recipient following prolonged treatment with vancomycin [14]. Juntermanns et al. described a case of a 55-year old man who died eight years after a liver transplantation after suffering from skin and soft tissue infections [15]. Earlier detection as well as earlier surgical and antibiotic interventions could have prevented the death of the patient [15].\n\nFungal infections pose as a severe and potentially fatal complication in liver transplant patients. A retrospective study of 23 post-liver transplant patients admitted to the ICU and diagnosed with fungal infection, showed Candida spp. was found in 17/23 patients, Aspergillus spp. was found in 4/23 patients, but with no difference in mortality between infection from these two fungal pathogens [16].\n\nIn 2009, a study that analyzed bacterial infections in the early period after liver transplantation in adults followed 83 patients for four weeks after liver transplantation [17]. A total of 913 samples were cultured according to standard microbiological procedures [17]. Out of 913 samples, there were 469 isolated strains: 70.6% were Gram-positive bacteria, 28.4% were Gram-negative bacteria, and 1.0% were yeast-like fungal strains [17]. Multi-drug resistant (MDR) strains of bacteria were found [17]. In total, there were 138 strains of methicillin-resistant coagulase-negative Staphylococci (MRCNS), 10 of methicillin-resistant Staphylococcus aureus (MRSA), 80 of high-level aminoglycoside resistance (HLAR), and 19 extended-spectrum beta-lactamase (ESBL)-positive strains were detected [18].\n\nTo our knowledge, this is the first case of E. meningoseptica in a liver transplant patient. There were multiple risk factors in our patient for acquiring E. meningoseptica that included immunosuppression, hypoalbuminemia, the presence of a PTBD, all which facilitate the growth of this nosocomial infection. There have been no previously reported cases of PTBD-associated E. meningoseptica infection. Because this case report showed few E. meningoseptica bacteria in culture, which reflects the high virulence of this bacterium.\n\nConclusions\nElizabethkingia meningoseptica (E. meningoseptica) is an emerging nosocomial infection that has become recognized as the cause of outbreaks of infection and infection of individual cases of hospitalized patients. This case report demonstrates the importance of screening and early detection of this infection. Given its resistance to multiple antibiotics, healthcare providers should be aware of infection control measures to prevent outbreaks and recurrence of E. meningoseptica. Management of cases of E. meningoseptica should be directed by the findings of microbial culture and sensitivity findings to ensure rapid and effective treatment of this potentially serious infection.\n\nThe authors wish to thank Dr. Mohammad al Sebayel, MD, Chairman, Department of Liver and Small Bowel Transplant and Hepatobiliary and Pancreatic Surgery; Carla Alvarez Mercado, Senior Assistant, Department of Liver and Small Bowel Transplant and Hepatobiliary and Pancreatic Surgery, King Faisal Specialist Hospital and Research Center.\n\nConflict of interest\n\nNone.\n\nFigure 1. Ultrasound of the abdomen. A right-sided, sub-diaphragmatic collection measuring 3.4×4.4×2.0 cm is shown.\n\nTable 1. Elizabethkingia meningoseptica antimicrobial susceptibility.\n\n\tElizabethkingia meningoseptica\tMinimal inhibitory concentration (MIC) dilution\tMIC Interpretation\t\n1\tPiperacillin/tazobactam\t128\tResistent\t\n2\tCeftazidime\t64\tResistent\t\n3\tGentamicin\t16\tResistent\t\n4\tTobramycin\t16\tResistent\t\n5\tAmikacin\t64\tResistent\t\n6\tCefipime\t64\tResistent\t\n7\tImipenem\t16\tResistent\t\n8\tMeropenem\t16\tResistent\t\n9\tCiprofloxacin\t0.6\tSensitive\t\n10\tColistin\t16\tResistent\t\n11\tMinocycline\t1\tSensitive\t\n12\tTigecycline\t4\tSensitive\t\n13\tTrimethoprim/sulfamethoxazole\t40\tSensitive\t\nTable 2. Wisconsin 2016 Elizabethkingia anophelis outbreak: Elizabethkingia infections believed to be associated with this outbreak reported to Division of Public Health (DPH)*, Case counts between November 1, 2015 and May 30, 2016 [7].\n\nType of case\tNumber of cases\t\nConfirmed\t63\t\nUnder investigation\t0\t\nPossible cases**\t4\t\nTotal cases reported to Wisconsin DPH\t67\t\n* This investigation is ongoing [7]. Case counts may change as additional illnesses are identified and more cases are laboratory confirmed;\n\n** These are cases that tested positive for E. meningoseptica but will never be confirmed as the same strain of Elizabethkingia anophelis because the outbreak specimens are no longer available to test [6,8].\n==== Refs\nReferences:\n1. Young SM Lingam G Tambyah PA Elizabethkingia meningoseptica endogenous endophthalmitis – a case report Antimicrob Resist Infect Control 2014 3 35 25671096 \n2. Xie Z Zhou Y Wang S First isolation and identification of Elizabethkingia meningoseptica from cultured tiger frog, Rana tigerina rugulosa Vet Microbiol 2009 138 140 44 19327918 \n3. Kirby JT Sader HS Walsh TR Jones RN Antimicrobial susceptibility and epidemiology of a worldwide collection of Chryseobacterium spp .: Report from the SENTRY Antimicrobial Surveillance Program (1997–2001) J Clin Microbiol 2004 42 445 48 14715802 \n4. Issack MI Neetoo Y An outbreak of Elizabethkingia meningoseptica neonatal meningitis in Mauritius J Infect Dev Ctries 2011 5 834 39 22169781 \n5. Lee C Chen P Wang L Fatal case of community-acquired bacteremia and necrotizing fasciitis caused by Chryseobacterium meningosepticum : Case report and review of the literature J Clin Microbiol 2006 44 1181 83 16517926 \n6. Centers for Disease Control and Prevention (CDC) About Elizabethkingia . Updated March 30th 2016. Available from: https://www.cdc.gov/elizabeth-kingia/about/index.html \n7. Centers for Disease Control and Prevention (CDC) Wisconsin 2016 Elizabethkingia anophelis outbreak. Updated May 17th 2017. Available from: https://www.dhs.wisconsin.gov/disease/elizabethkingia.htm \n8. Centers for Disease Control and Prevention (CDC) Wisconsin Department of Health Services (DHS) Investigates Bacterial Bloodstream Infections. Updated March 2nd 2016. Available from: https://www.dhs.wisconsin.gov/news/releases/030216a.htm \n9. McQuiston J Deadly midwest outbreak of Elizabethkingia . Medscape Updated April 1st 2016 April. Available from: https://www.medscape.com/viewarticle/861096 \n10. Pereira GH de Oliveira Garcia D Abboud CS Nosocomial infections caused by Elizabethkingia meningoseptica : an emergent pathogen Braz J Infect Dis 2013 17 5 606 9 24055393 \n11. Ratnamani MS Rao R Elizabethkingia meningoseptica : Emerging nosocomial pathogen in bedside hemodialysis patients Indian J Crit Care Med 2013 17 5 304 7 24339643 \n12. Shinha T Ahuja R Bacteremia due to Elizabethkingia meningoseptica IDCases 2015 2 13 15 26793448 \n13. Watt KDS Pedersen RA Kremers WK Evolution of causes and risk factors for mortality post-liver transplant: Results of the NIDDK long-term follow-up study Am J Transplantation 2010 10 1420 27 \n14. Tholpady SS Sifri CD Sawyer RG Leuconostoc pseudomesenteroides blood stream infection following liver transplantation Ann Transplant 2010 15 61 66 \n15. Juntermanns B Radunz S Heuer M Fulminant septic shock due to Clostridium perfringens skin and soft tissue infection eight years after liver transplantation Ann Transplant 2011 16 143 46 21959524 \n16. Marzaban R Salah M Mukhtar AM Fungal infections in liver transplant patients admitted to the intensive care unit Ann Transplant 2014 19 667 73 25529380 \n17. Kawecki D Chmura A Pacholczyk M Bacterial infections in the early period after liver transplantation: Etiological agents and their susceptibility Med Sci Monit 2009 15 12 CR628 37 19946234\n\n",
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"mesh_terms": "D002761:Cholangitis; D003428:Cross Infection; D004322:Drainage; D005260:Female; D045826:Flavobacteriaceae Infections; D006801:Humans; D016867:Immunocompromised Host; D016031:Liver Transplantation; D008875:Middle Aged",
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"title": "Elizabethkingia Meningoseptica in a Case of Biliary Tract Infection Following Liver Transplantation.",
"title_normalized": "elizabethkingia meningoseptica in a case of biliary tract infection following liver transplantation"
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"abstract": "Lamivudine combined with hepatitis B immune globulin (HBIg) is the standard of care for preventing the recurrence hepatitis B virus after liver transplant. To determine the risk of hepatitis B virus (HBV) recurrence after early withdrawal of HBIg in patients receiving lamivudine maintenance therapy, 20 patients receiving a course of HBIg and lamivudine after transplantation and long-term maintenance therapy with lamivudine and 9 patients receiving HBIg and lamivudine indefinitely were analyzed. The survival rate was 90% after a mean follow-up of 83 months. The HBV recurrence rate was 14% with a mean period of 91 months free from HBV recurrence. Both groups had similar HBV recurrence rates, 15% for the combination and 11% for lamivudine alone. Four patients, 3 of whom were noncompliant with therapy, experienced posttransplant HBV recurrence. Patients who adhere to long-term prophylaxis with lamivudine after early withdrawal of HBIg have a low risk of HBV recurrence, similar to those who receive combination prophylaxis.",
"affiliations": "Hospital General Valle de Hebrón and CIBER EHD, Barcelona, Spain. mbuti@vhebronnet",
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"title": "Adherence to Lamivudine after an early withdrawal of hepatitis B immune globulin plays an important role in the long-term prevention of hepatitis B virus recurrence.",
"title_normalized": "adherence to lamivudine after an early withdrawal of hepatitis b immune globulin plays an important role in the long term prevention of hepatitis b virus recurrence"
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"abstract": "Pneumonitis from immune checkpoint inhibitors (ICI) is a potentially fatal immune-related adverse event (irAE) from antiprogrammed death 1/programmed death ligand 1 immunotherapy. Most cases of ICI pneumonitis improve or resolve with 4-6 weeks of corticosteroid therapy. Herein, we report the incidence, clinicopathological features and management of patients with non-small cell lung cancer (NSCLC) and melanoma who developed chronic ICI pneumonitis that warrants ≥12 weeks of immunosuppression.\n\n\n\nPatients with ICI pneumonitis were identified from institutional databases of ICI-treated patients with advanced melanoma and NSCLC between January 2011 and July 2018. ICI pneumonitis was defined as clinical/radiographic evidence of lung inflammation without alternative diagnoses, adjudicated by a multidisciplinary team. Chronic ICI pneumonitis was defined as pneumonitis that persists or worsens with steroid tapering, and necessitates ≥12 weeks of immunosuppression, after ICI discontinuation. Serial chest CT was used to assess radiological features, and tumor response by Response EvaluationCriteria for Solid Tumors V.1.1. Bronchoalveolar lavage fluid (BALF) samples were assessed by cell differential. Lung biopsy samples were evaluated by H&E staining and multiplex immunofluorescence (mIF), where available.\n\n\n\nAmong 299 patients, 44 developed ICI pneumonitis (NSCLC: 5/205; melanoma: 1/94), and of these, 6 experienced chronic ICI pneumonitis. The overall incidence of chronic ICI pneumonitis was thus 2%. Of those who developed chronic ICI pneumonitis: the majority had NSCLC (5/6), all sustained disease control from ICIs, and none had other concurrent irAEs. Timing of chronic ICI pneumonitis development was variable (range: 0-50 months), and occurred at a median of 12 months post ICI start. Recrudescence of ICI pneumonitis occurred at a median of 6 weeks after initial steroid start (range: 3-12 weeks), with all patients requiring steroid reintroduction when tapered to ≤10 mg prednisone/equivalent. The median total duration of steroids was 37 weeks (range: 16-43+weeks). Re-emergence of radiographic ICI pneumonitis occurred in the same locations on chest CT, in most cases (5/6). All patients who developed chronic ICI pneumonitis had BALF lymphocytosis on cell differential and organising pneumonia on lung biopsy at initial ICI pneumonitis presentation, with persistent BALF lymphocytosis and brisk CD8+ infiltration on mIF at pneumonitis re-emergence during steroid taper.\n\n\n\nA subset of patients who develop pneumonitis from ICIs will develop chronic ICI pneumonitis, that warrants long-term immunosuppression of ≥12 weeks, and has distinct clinicopathological features.",
"affiliations": "Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA jnaidoo1@jhmi.edu.;Pathology, Queen's University, Kingston, Ontario, Canada.;Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Pathology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Division of Pulmonary Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.;Radiation Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Division of Pulmonary Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.;Division of Pulmonary Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.;Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Pathology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Pathology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Radiology, Johns Hopkins University, Baltimore, Maryland, USA.;Division of Pulmonary Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.;Division of Pulmonary Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.;Division of Pulmonary Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.",
"authors": "Naidoo|Jarushka|J|0000-0002-3470-8686;Cottrell|Tricia R|TR|;Lipson|Evan J|EJ|0000-0003-2976-0911;Forde|Patrick M|PM|;Illei|Peter B|PB|;Yarmus|Lonny B|LB|;Voong|K Ranh|KR|;Feller-Kopman|David|D|;Lee|Hans|H|;Riemer|Joanne|J|;Wang|Daphne|D|;Taube|Janis M|JM|;Brahmer|Julie R|JR|;Lin|Cheng Ting|CT|;Danoff|Sonye K|SK|;D'Alessio|Franco R|FR|;Suresh|Karthik|K|",
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"doi": "10.1136/jitc-2020-000840",
"fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\njitc-2020-000840\n10.1136/jitc-2020-000840\nShort Report\n1506\nChronic immune checkpoint inhibitor pneumonitis\nhttp://orcid.org/0000-0002-3470-8686Naidoo Jarushka 12 Cottrell Tricia R 3 http://orcid.org/0000-0003-2976-0911Lipson Evan J 12 Forde Patrick M 12 Illei Peter B 4 Yarmus Lonny B 5 Voong K Ranh 6 Feller-Kopman David 5 Lee Hans 5 Riemer Joanne 1 Wang Daphne 4 Taube Janis M 4 Brahmer Julie R 12 Lin Cheng Ting 7 Danoff Sonye K 5 D'Alessio Franco R 5 Suresh Karthik 5 1 Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA\n2 The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA\n3 Pathology, Queen’s University, Kingston, Ontario, Canada\n4 Pathology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA\n5 Division of Pulmonary Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA\n6 Radiation Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA\n7 Radiology, Johns Hopkins University, Baltimore, Maryland, USA\nCorrespondence to Dr Jarushka Naidoo; jnaidoo1@jhmi.edu\n2020 \n17 6 2020 \n8 1 e00084007 5 2020 © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.Background\nPneumonitis from immune checkpoint inhibitors (ICI) is a potentially fatal immune-related adverse event (irAE) from antiprogrammed death 1/programmed death ligand 1 immunotherapy. Most cases of ICI pneumonitis improve or resolve with 4–6 weeks of corticosteroid therapy. Herein, we report the incidence, clinicopathological features and management of patients with non-small cell lung\ncancer (NSCLC) and melanoma who developed chronic ICI pneumonitis that warrants ≥12 weeks of immunosuppression.\n\nMethods\nPatients with ICI pneumonitis were identified from institutional databases of ICI-treated patients with advanced melanoma and NSCLC between January 2011 and July 2018. ICI pneumonitis was defined as clinical/radiographic evidence of lung inflammation without alternative diagnoses, adjudicated by a multidisciplinary team. Chronic ICI pneumonitis was defined as pneumonitis that persists or worsens with steroid tapering, and necessitates ≥12 weeks of immunosuppression, after ICI discontinuation. Serial chest CT was used to assess radiological features, and tumor response by Response EvaluationCriteria for Solid Tumors V.1.1. Bronchoalveolar lavage fluid (BALF) samples were assessed by cell differential. Lung biopsy samples were evaluated by H&E staining and multiplex immunofluorescence (mIF), where available.\n\nResults\nAmong 299 patients, 44 developed ICI pneumonitis (NSCLC: 5/205; melanoma: 1/94), and of these, 6 experienced chronic ICI pneumonitis. The overall incidence of chronic ICI pneumonitis was thus 2%. Of those who developed chronic ICI pneumonitis: the majority had NSCLC (5/6), all sustained disease control from ICIs, and none had other concurrent irAEs. Timing of chronic ICI pneumonitis development was variable (range: 0–50 months), and occurred at a median of 12 months post ICI start. Recrudescence of ICI pneumonitis occurred at a median of 6 weeks after initial steroid start (range: 3–12 weeks), with all patients requiring steroid reintroduction when tapered to ≤10 mg prednisone/equivalent. The median total duration of steroids was 37 weeks (range: 16–43+weeks). Re-emergence of radiographic ICI pneumonitis occurred in the same locations on chest CT, in most cases (5/6). All patients who developed chronic ICI pneumonitis had BALF lymphocytosis on cell differential and organising pneumonia on lung biopsy at initial ICI pneumonitis presentation, with persistent BALF lymphocytosis and brisk CD8+ infiltration on mIF at pneumonitis re-emergence during steroid taper.\n\nConclusions\nA subset of patients who develop pneumonitis from ICIs will develop chronic ICI pneumonitis, that warrants long-term immunosuppression of ≥12 weeks, and has distinct clinicopathological features.\n\ninflammationlung neoplasmsmelanomaprogrammed cell death 1 receptorBloomberg-Kimmel Institute for Cancer Immunotherapyspecial-featureunlocked\n==== Body\nIntroduction\nPneumonitis is an uncommon but potentially fatal toxicity of anti-PD(L)1 immune checkpoint inhibitors (ICI) for cancer.1–3 The incidence of this toxicity is approximately 5% in patients with solid tumors treated with anti-PD(L)1 monotherapy, and up to 10%, in patients receiving anti-PD(L)1-based combinations such as ipilimumab/nivolumab, or those with non-small cell lung cancer (NSCLC).4 Most cases of ICI pneumonitis resolve or improve with corticosteroids; however, a small proportion of patients may develop recurrent pneumonitis when rechallenged with ICIs.4 5 Distinct from this phenomenon, we recently observed a clinical phenotype of ‘chronic ICI pneumonitis’, where patients exhibit persistent pneumonitis without immunotherapy rechallenge. Specifically, we observed clinical and radiographic evidence of ICI pneumonitis with exacerbation of symptoms when steroids were downtitrated, despite prompt discontinuation of ICI therapy at symptom onset, necessitating an extended course of immunosuppression to ≥12 weeks. This duration of corticosteroids for ICI pneumonitis is well beyond the published guideline recommendations of 4–6 weeks.6–8 Since the features of this previously unreported clinical entity are unknown, we report herein the incidence, clinical presentation, radiographic, pathological features and management of patients who developed chronic ICI pneumonitis.\n\nMethods\nPatient selection\nWe retrospectively identified patients with advanced NSCLC or melanoma treated with anti-PD(L)1 ICIs at Johns Hopkins Hospital between January 2011 and July 2018, who were enrolled on institutional biospecimen collection protocols. Patients may have received any anti-PD(L)1 agent either as standard of care or part of a clinical trial. Follow-up data were available for all patients through December 2018.\n\nChronic ICI pneumonitis definitions and diagnosis\nThe diagnosis of ICI pneumonitis was determined by the treating medical oncologist and confirmed by a multidisciplinary team, comprising a radiologist, pulmonologist, pathologist, and second medical oncologist. Pneumonitis was defined as clinical and radiographic evidence of lung inflammation after anti-PD(L)1 therapy, where alternative diagnoses such as confirmed infection and progressive cancer had been ruled out and multidisciplinary consensus had been reached. Chronic ICI pneumonitis was defined as clinical and radiographic evidence of pneumonitis that either (1) persisted at the end of recommend steroid tapering guidelines (4–6 weeks)6–8 or (2) worsened during steroid tapering warranting increased steroid dosing and/or additional immunosuppression, and (3) necessitated a total duration of immunosuppression of ≥12 weeks.6 The decision to repeat bronchoscopy with evaluation of bronchoalveolar lavage fluid (BALF) samples for a symptomatic patient with ICI pneumonitis during steroid tapering was based on: worsening dyspnea, persistent exertional desaturation, ongoing supplemental oxygen requirement, and absence of heart failure or anemia. In addition to bronchoscopy with BALF acquisition to rule out infection, any new areas of mass-like consolidation were biopsied to rule out tumor progression in relevant cases. Resolution of ICI pneumonitis was defined as complete weaning off steroids followed by no evidence of new lung abnormalities on chest CT or worsening dyspnea for at least 3 months.\n\nRadiology\nSerial radiological imaging for ICI pneumonitis with chest CT was collected, and tumor radiological response by Response Evaluation Criteria for Solid Tumors (RECIST) 1.1 (v. 4.03) was reported.\n\nPathology\nBALF samples were assessed by automated cell differential. Lung biopsy samples where available were pathologically assessed by a thoracic pathologist using H&E staining. Profiling of the inflammatory microenvironment with immunofluorescence (mIF) was completed in available samples, as previously described.9 Briefly, 4 µm thick formalin-fixed, paraffin-embedded sections were stained with a 6-plex panel, including Ki67, CD8, CD20, programmed death 1 (PD-1), Pan-cytokeratin, and CD4 (online supplementary table 1).\n\n10.1136/jitc-2020-000840.supp3Supplementary data \n\n Results\nIncidence of chronic ICI pneumonitis\nWe identified 205 patients with advanced NSCLC and 94 patients with advanced melanoma treated with anti-PD-1/PD-L1 ICIs from January 2011 to July 2018. Among 299 patients, 44 developed ICI pneumonitis, and of these, 6 experienced chronic ICI pneumonitis. The overall incidence of chronic ICI pneumonitis in patients with advanced NSCLC and melanoma was 2% (6/299), and 14% in patients who developed ICI pneumonitis (6/44). In patients with NSCLC, 19% developed ICI pneumonitis (39/205, reported elsewhere).10 11 In our original dataset of 39 pneumonitis cases in NSCLC, 4 developed chronic pneumonitis. Since that publication, we adjudicated one additional case of chronic pneumonitis, for a total of five cases in those with NSCLC. In patients with melanoma, 5% developed ICI pneumonitis (5/94), and one patient developed chronic ICI pneumonitis. In total, six patients were identified as having developed chronic ICI pneumonitis, and the clinical features of this cohort are detailed below. Of note, chronic ICI pneumonitis eventually resolved with continued immunosuppression (either steroids alone or steroids in combination with a second immunosuppressive agent) in only three out of six patients.\n\nClinical presentation of chronic ICI pneumonitis\nBaseline clinical characteristics\nThe patient-level clinical details of patients who developed chronic ICI pneumonitis are depicted in table 1. The median age at time of diagnosis was 75 years (range: 56–77 years). Five of the six patients were diagnosed with NSCLC as the primary tumor; one patient had melanoma. Only two of the six patients had received antecedent chemotherapy, and one of the six patients had a distant history of prior chest radiation. All patients demonstrated either a radiographic response or stable disease from immunotherapy.\n\nTable 1 Patients with chronic immune checkpoint inhibitor (ICI) pneumonitis\n\n\tChronic ICI pneumonitis with resolution\tChronic ICI pneumonitis without resolution\t\nPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\tPatient 6\t\nPatient characteristics\t\nAge (years)\t73\t77\t77\t56\t77\t65\t\nSex\tM\tM\tF\tM\tF\tF\t\nRace\tW\tW\tB\tW\tW\tW\t\nSmoking status\tFormer\tFormer\tNever\tNever\tNever\tFormer\t\nPrimary tumor site\tNSCLC\tNSCLC\tNSCLC\tMelanoma\tNSCLC\tNSCLC\t\nTumor histology\tSquamous\tSquamous\tAdenocarcinoma\tN/A\tSquamous\tAdenocarcinoma\t\nInitial cancer stage\tI\tIV\tIB\tIV\tIV\tIV\t\nPrior systemic therapy\tCarboplatin\tNone\tNone\tNone\tNone\tCarboplatin\n/pemetrexed††\t\nInitial surgery (Y/N)\tY\tN\tY\tY\tN\tN\t\nPrior radiation (Y/N)\tY*\tN\tN\tY†\tY\tN\t\nImmunotherapy agent(s)\tNivolumab\tIpilimumab/Nivolumab\tPembrolizumab\tIpilimumab/Nivolumab\tIpilimumab/Nivolumab\tPembrolizumab\t\nEnrolled in clinical trial\tN\tY\tY\tN\tY\tN\t\nBest Objective response to ICI‡‡\tComplete\tPartial\tPartial\tStable disease\tPartial\tPartial\t\nAge (years)\t73\t77\t77\t56\t77\t65\t\nSex\tM\tM\tF\tM\tF\tF\t\nRace\tW\tW\tB\tW\tW\tW\t\nPneumonitis characteristics\t\nTime to initial Pneumonitis (days)¶\t238\t370\t498\t0 (4 hours)\t606\t359\t\nInitial Pneumonitis grade§§\t3\t2\t3\t3\t2\t2\t\nPneumonitis grade at re-emergence\t3\tFirst re-emergence: 2\nSecond re-emergence: 3\t3\tFirst re-emergence: 3\nSecond re-emergence: 3\t2\t2\t\nNumber of Pneumonitis episodes\t1\t2\t1\t2\t1\t2\t\nTiming of second episode (days after initiation of steroids)\t84\t42\t42\t21\t49\t38\t\nAdditional immunosuppression\tYes**\tNo\tNo\tYes‡\tYes§\tNo\t\n*Radiation: patient 1 received thoracic radiation for a lung metastasis 3 years prior to ICI start.\n\n†Patient 4 received whole brain radiation for brain metastases 5 months after ICI start.\n\n‡Patient 4 not given a second course of steroids, started on infliximab, followed by intravenousimmunoglobulin (approximately 3 months after initiation of steroids).\n\n§Patient 5 started a second course of steroids for ongoing symptoms (6 months after initiation of steroids) as well as starting mycophenolate.\n\n¶Day 0=start of ICI.\n\n**Patient 1 treated with mycophenolate.\n\n††Patient 6: received concurrent chemotherapy plus pembrolizumab for first four cycles.\n\n‡‡Response to ICI by Response EvaluationCriteria for Solid Tumors V.1.1 criteria.\n\n§§CTCAE grade.\n\nB, black; CTCAE, common toxicity criteria for adverse events; Ipi, ipilimumab; N/A, not applicable; Nivo, nivolumab; NSCLC, non-small cell lung cancer; W, Caucasian.\n\nComparison of chronic and acute ICI pneumonitis\nTo contrast clinical characteristics of chronic ICI pneumonitis with cases of non-chronic (ie, acute) ICI pneumonitis, we compared the six cases of chronic ICI pneumonitis described here with 41 cases of acute ICI pneumonitis cases in NSCLC and melanoma (online supplementary table 2). While no differences in age, sex, tumor stage or histology, we did observe an increased proportion of combination ICI therapy in the chronic ICI pneumonitis group (83%) compared with the acute ICI pneumonitis group (19%; p=0.02). While the distribution of tumor histology subtypes was not significantly different between the groups, interestingly, both cases of adenocarcinoma in the chronic ICI pneumonitis group harbored KRASmutations.\n\nTiming of chronic ICI pneumonitis\nThe first episode of pneumonitis in these patients occurred at a median time of 12 months after anti-PD(L)1 start (range: 0–50 months). One patient (patient 4) developed pneumonitis within a few hours of ICI infusion (0 days). In the other five patients, the median time to pneumonitis onset from ICI initiation was 12 months. Despite experiencing repeated bouts of ICI pneumonitis during steroid taper, the initial pneumonitis grade by CTCAE criteria was either 2 or 3 for all patients. No cases of grade 4 or grade 5 ICI pneumonitis were observed. All patients had been on steroids for at least 3 weeks when recrudescence of ICI pneumonitis was diagnosed, and the grade of ICI pneumonitis was also grade 3 or lower at these times. The second episode of ICI pneumonitis occurred at a median time of 6 weeks (range: 3–12 weeks) after the first episode. The grade of the subsequent bout of ICI pneumonitis was never higher than the initial event grade.\n\nAssociation with other irAEs\nWhile three of the six patients were also diagnosed with other non-pulmonary irAEs, none of the patients were diagnosed with irAEs concomitantly with ICI pneumonitis.\n\nRadiographic manifestations\nWhile the heterogeneity of radiographic findings in ICI pneumonitis has been described previously, the evolution of radiographic abnormalities on chest CT in patients with ICI pneumonitis who experience persistent and/or repeated symptoms is not known. Thus, we examined serial CT radiography in this cohort of patients with chronic ICI pneumonitis. All patients underwent serial CT imaging to characterize radiographic abnormalities on chest CT during initial and subsequent presentations (figure 1). When ICI pneumonitis re-developed, we observed recrudescence of ground-glass opacities (GGO) or consolidations in the peribronchovascular distribution seen during the initial presentation (square boxes, figure 1). The pattern (GGO vs consolidation) of ICI pneumonitis abnormalities on chest CT was similar to the initial episode in five out of six instances. In one patient (patient 2), ICI pneumonitis re-emergence involved new airspace opacities in previously uninvolved portions of the lung parenchyma.\n\nFigure 1 Serial radiological imaging in patients with chronic immune checkpoint inhibitor pneumonitis. Representative CT images at baseline—1: (pre-bronch): prior to first bronchoscopy, 1 (recovery): after treatment of first pneumonitis episode, 2: second episode of pneumonitis, 3: third episode of pneumonitis. Solid boxes show initial sites of pneumonitis and recrudescence, with radiographic pattern in keeping with acute lung injury or organizing pneumonia. Dotted line box highlights a new area of airspace opacity.\n\nBronchoalveolar lavage findings\nWhile the BALF cell characteristics of ICI pneumonitis at initial presentation have been described by us previously,12 changes in the composition of the BALF cell differential in individual patients with repeated ICI pneumonitis episodes are unknown. In this cohort, all six patients underwent BALF and cell differential assessment at the time of initial ICI pneumonitis development and at re-emergence during steroid taper. Since only two patients experienced a third episode of ICI pneumonitis, we restricted our analyses to changes in BALF cell composition between the first and second ICI pneumonitis episode. Similar to our prior findings, the BALF differential was notable for significant lymphocytosis (approximately 30%) at the initial ICI pneumonitis episode. Despite being treated with steroids, persistent (ie, >10%) lymphocytosis was present in all six cases. Further, in four of the six cases, a higher lymphocyte percent was observed in the BALF obtained during the subsequent ICI pneumonitis presentation (online supplementary figure 1). In comparison, the percentage of monocytes remained either unchanged or decreased. The neutrophil percentage was <50% in five out of six patients both on initial and repeat bronchoscopy.\n\n10.1136/jitc-2020-000840.supp2Supplementary data \n\n Pathological findings\nAll six patients underwent transbronchial biopsy (TBBx) during bronchoscopy at initial ICI pneumonitis presentation. Interestingly, as shown in figure 2, evidence of bronchiolitis obliterans with organizing pneumonia (BOOP) was found on all six pathological specimens. Tissue cultures were negative for infection in all six cases. No granulomas or lymphoid aggregates were observed in any of the pathological specimens.\n\nFigure 2 Pathological assessment by H&E staining in chronic immune checkpoint inhibitor pneumonitis. (A) Patient 1: bronchiolitis obliterans organizing pneumonia (BOOP), described in manuscript as organizing pneumonia, with an intra-alveolar fibroblast plug and organizing alveolar fibrin. (B) Patient 2: acute lung injury with acute fibrinous organizing pneumonia and organizing diffuse alveolar damage. (C) Patient 3: organizing alveolar fibrin consistent with exudative phase of BOOP. (D) Patient 4: organizing pneumonia (BOOP) with organizing alveolar fibrin. (E) Patient 5: organizing alveolar fibrin consistent with exudative phase of BOOP. (F) Patient 6: organizing pneumonia (BOOP). PD-1, programmed death 1.\n\nAs mentioned earlier, we previously showed that alveolar lymphocytosis was present in the BALF of patients with chronic ICI pneumonitis. To determine if similar lymphocytic infiltration was present in the lung parenchyma, we performed mIF to determine the cellular characteristics of BOOP observed on H&E staining in the aforementioned samples. Interestingly, as shown in figure 3, mIF analysis also revealed significant lymphocytic infiltration, specifically of proliferative (Ki67+) PD-1+ CD8 cells in lung biopsy samples at the time of pneumonitis re-emergence during steroid taper. To determine whether tissue lymphocytosis was a global phenomenon or restricted to the areas with histopathological evidence of BOOP, we examined tissue sections in another patient where areas of BOOP and adjacent normal lung were available. As shown in online supplementary figure 2, we again observed increased Ki-67+, PD-1+ lymphocytes in the areas affected by pneumonitis but such lymphocytic infiltration was not present in adjacent normal lung.\n\nFigure 3 Highly proliferative PD-1+ cell accumulation characterizes chronic immune checkpoint inhibitor pneumonitis. Low power H&E and immunofluorescence images highlight the relative abundance of Ki67+ PD-1+ lymphocytes in chronic pneumonitis (top row) relative to sparse inflammatory cells seen in histologically unremarkable lung tissue (bottom row). Original magnification 200×. PD-1, programmed death 1.\n\nSteroid therapy and additional immunosuppression\nFollowing diagnosis of ICI pneumonitis based on clinical, radiological (and pathological, when available) grounds, all patients were initiated on steroid treatment. As shown in online supplementary table 3, the initial steroid dosing was between 60 mg and 120 mg of prednisone (or equivalent). However, unlike typical cases of ICI pneumonitis, the median total duration of steroids in these six cases of chronic ICI pneumonitis was 37 weeks (rang: 16–43+ weeks). This is because radiographic and clinical evidence of ICI pneumonitis recrudesced when steroids were tapered to 10 mg or less, and necessitated reinitiation of steroids followed by prolonged tapers in all six cases. Temporal changes in steroid dosing at the patient level and overall are outlined in online supplementary figure 3. In three out of six patients, ongoing steroid requirement necessitated initiation of second-line ICI pneumonitis therapy (either mycophenolate mofetil, infliximab or intravenous\nimmunoglobulin; table 1).\n\nDiscussion\nICI-associated pneumonitis that persists or worsens with steroid tapering and necessitates ≥12 weeks of immunosuppression after ICI discontinuation (ie, chronic ICI pneumonitis) has not been previously described. In one report of patients with melanoma with ICI pneumonitis, persistent radiographic evidence of pneumonitis was seen in 20% of cases.13 Whether a subset of these patients were also clinically symptomatic is not known. Here, we present a comprehensive clinical, radiographic and pathological assessment of this phenomenon across tumor types.\n\nIn our study, we report the incidence of chronic ICI pneumonitis at 2% in patients with both NSCLC and melanoma treated with anti-PD-(L)1±CTLA4 ICIs. We describe the clinical course of six patients with chronic ICI pneumonitis, and in these patients we note: (1) that the time to onset of chronic ICI pneumonitis is highly variable, (2) no relationship between onset of chronic ICI pneumonitis and other irAEs, (3) no worsening of ICI pneumonitis grade between initial and subsequent episodes, (4) median steroid durations well in excess of the recommended 4–6 weeks, (5) persistent BALF lymphocytosis despite steroid therapy and (6) histopathological evidence of BOOP with increased infiltration of highly proliferative CD8+ T-cells.\n\nFrom a management standpoint, ICI pneumonitis eventually improved/resolved in three patients, while three patients necessitated long-term, continuing steroid use. This is in contrast with currently published literature on irAEs from anti-PD(L)1 therapy, which suggests that most toxicities, except for endocrinopathies and selected arthritides, resolve with a relatively short corticosteroid taper of 4–6 weeks. Prospective studies with longer follow-up periods are needed to determine the clinical course of pneumonitis in ICI-treated patients.\n\nFundamentally, this population of patients with chronic ICI pneumonitis likely represents a clinically distinct population different from patients with a singleton episode of acute ICI pneumonitis. For one, a significant survival bias exists; excluding the one patient who developed ICI pneumonitis at day 0, five out of six patients developed pneumonitis only after at least 7 months of ICI therapy. This suggests that these patients experienced sufficient tumor responses to survive long enough to develop chronic ICI pneumonitis. When adjusted for guaranteed time bias, we recently showed that development of ICI pneumonitis actually worsened survival in NSCLC.14 However, given the lack of any patients with grade 4 pneumonitis and the prolonged time on ICI therapy before onset of symptoms in five out of six patients, the effect of chronic ICI pneumonitis on survival may be different, and similar to other irAEs, where a survival benefit has been observed. Our comparison of patients with chronic versus acute ICI pneumonitis suggests that the type of immunotherapy (eg, combination vs monotherapy) may be a risk factor for chronic ICI pneumonitis. However, given the small numbers involved, these intriguing findings will need to be replicated in a larger dataset.\n\nOur pathology and bronchoalveolar lavage findings, taken together, suggest that the continued presence of proliferative lymphocytes, possibly T-cell subsets that are resistant to steroid-induced apoptosis, may be contributing to the pathobiology of chronic ICI pneumonitis. In this study, we observed lymphocytes in the BALF and tissue of patients with chronic ICI pneumonitis. This extends our earlier observations of increased T-cell subsets in the BALF of patients during the first episode of ICI pneumonitis, prior to initiation of steroids.12 Clinically, the presence of BALF lymphocytes, ongoing steroid requirement, and steroid dose (10–20 mg of prednisone/equivalent) at which ICI pneumonitis re-emerges is similar to the natural history of refractory cryptogenic organizing pneumonia (COP). Indeed, the overall duration and rate of steroid tapering presented in this study is similar to prior reports of rates of steroid weaning in COP.15 Despite these initial observations, whether the presence of BOOP on TBBx is sufficient to increase the pretest suspicion for a patient developing chronic ICI pneumonitis remains unknown. In one other published series, a range of pathological appearances were seen at the time of acute ICI pneumonitis, including cellular interstitial pneumonitis, organizing pneumonia, diffuse alveolar damage, or no notable pathological findings.4 The early observations in this manuscript, however, provide a rationale for prospective study of BALF cell differentials and lung tissue cytometry in patients with ICI pneumonitis, to determine whether the pathological findings observed during the index ICI pneumonitis episode could serve as biomarkers for risk of subsequent re-emergence, or could inform the length of steroid tapering.\n\nIn conclusion, this report of chronic pneumonitis from anti-PD-(L)1 therapy describes a unique subset of ICI pneumonitis with a distinct natural history. These patients require longer durations of corticosteroid therapy, and occasional lifelong immunosuppression. Lung biopsy data from this study suggest that the presence of organizing pneumonia on histological assessment may portend a chronic clinical course for ICI pneumonitis. Future areas of study include identifying whether this phenomenon may occur in other tumor types treated with ICIs, examining the relationship between BALF cell differential as a means to risk stratify outcomes for symptomatic ICI pneumonitis, and investigating associations between BALF, lung biopsy features, and both response to immunosuppression and clinical ICI pneumonitis outcome in a prospective fashion. Crucially, even in a small number of patients, these data suggest a role for bronchoscopic assessment where possible for patients with ICI pneumonitis, outside of ruling out alternative diagnoses—an area that has been hotly debated in the medical oncology field.\n\n10.1136/jitc-2020-000840.supp1Supplementary data \n\n Twitter: @DrJNaidoo, @jriemer3\n\nContributors: JN, KS, EL, PMF, TC, PBI, LBY, DF-K, HL, JR, JRB, SKD and FRD: identification, analysis, and interpretation of patient data. TC, DW and JT: multispectral immunofluorescence examination and interpretation. PBI: histological examination lung biopsy samples. CTL and KS: radiological data analysis and interpretation. JN and KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.\n\nFunding: Bloomberg-Kimmel Institute for Cancer Immunotherapy (JN). Funding was used to support multiplex immunofluorescence data collection, analysis and interpretation.\n\nCompeting interests: JN: research funding: AstraZeneca, Merck, Consulting/Advisory Board: AstraZeneca, Merck, Bristol-Myers Squibb, Honoraria: AstraZeneca, Merck, Bristol-Myers Squibb. EL: research funding: Bristol-Myers Squibb, Merck, Regeneron, Consulting/Advisory Board: Bristol-Myers Squibb, Merck, Novartis, EMD Serono, Array BioPharma, MacroGenics, Sanofi. PMF: research funding: AstraZeneca, Bristol-Myers Squibb, Corvus, Kyowa, Novartis, Consulting/Advisory Board: AstraZeneca, Bristol-Myers Squibb, Janssen, Merck, Novartis, Lilly, Boehringer. LBY: research funding: Rocket Medical, Consulting/Advisory Board: Boston Scientific. HL: Consulting/Advisory Board: Boston Scientific; DFK/Advisory Board: Consulting: Boston Scientific. JT: research funding: Bristol-Myers Squibb, Consulting/Advisory Board: Bristol-Myers Squibb, Merck, AstraZeneca. JRB: research funding: Bristol-Myers Squibb, Consulting/Advisory Board: Bristol-Myers Squibb, Merck, AstraZeneca, and Genentech, and reports receiving commercial.\n\nPatient consent for publication: Obtained.\n\nEthics approval: Ethical approval was obtained by the Johns Hopkins Hospital IRB, for collection of clinical, radiographic and pathological data and patient samples and biospecimen collection protocols J1655 (PI: PMF) and J13139 (PI: EJL) as well as institutional database Z15114 (PI: JN).\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData availability statement: Data are available upon reasonable request. The datasets used during the current study are available from the corresponding author on reasonable request.\n==== Refs\nReferences\n1 Naidoo J , Page DB , Li BT , et al \nToxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies\n. Ann Oncol \n2016 ;27 :1362 . 10.1093/annonc/mdw141 27072927 \n2 Nishino M , Sholl LM , Hatabu H , et al \nAnti-PD-1-Related pneumonitis during cancer immunotherapy\n. N Engl J Med \n2015 ;373 :288 –90\n. 10.1056/NEJMc1505197 26176400 \n3 Nishino M , Ramaiya NH , Awad MM , et al \nPD-1 Inhibitor-related pneumonitis in advanced cancer patients: radiographic patterns and clinical course\n. Clin Cancer Res \n2016 ;22 :6051 –60\n. 10.1158/1078-0432.CCR-16-1320 27535979 \n4 Naidoo J , Wang X , Woo KM , et al \nPneumonitis in patients treated with anti–programmed death-1/programmed death ligand 1 therapy\n. JCO \n2017 ;35 :709 –17\n. 10.1200/JCO.2016.68.2005 \n5 Sears CR , Peikert T , Possick JD , et al \nKnowledge gaps and research priorities in immune checkpoint Inhibitor-related pneumonitis. An official American thoracic society research statement\n. Am J Respir Crit Care Med \n2019 ;200 :e31 –43\n. 10.1164/rccm.201906-1202ST 31518182 \n6 Brahmer JR , Lacchetti C , Thompson JA \nManagement of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline summary\n. J Oncol Pract \n2018 ;14 :247 –9\n. 10.1200/JOP.18.00005 29517954 \n7 Puzanov I , Diab A , Abdallah K , et al \nManaging toxicities associated with immune checkpoint inhibitors: consensus recommendations from the society for immunotherapy of cancer (SITC) toxicity management Working group\n. J Immunother Cancer \n2017 ;5 :95 . 10.1186/s40425-017-0300-z 29162153 \n8 Thompson JA \nNew NCCN guidelines: recognition and management of immunotherapy-related toxicity\n. J Natl Compr Canc Netw \n2018 ;16 :594 –6\n. 10.6004/jnccn.2018.0047 29784734 \n9 Topalian SL , Taube JM , Pardoll DM \nNeoadjuvant checkpoint blockade for cancer immunotherapy\n. Science \n2020 ;367 :eaax0182. 10.1126/science.aax0182 32001626 \n10 Suresh K , Voong KR , Shankar B , et al \nPneumonitis in non-small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors\n. J Thorac Oncol \n2018 ;13 :1930 –9\n. 10.1016/j.jtho.2018.08.2035 30267842 \n11 Suresh K , Psoter KJ , Voong KR , et al \nImpact of checkpoint inhibitor pneumonitis on survival in NSCLC patients receiving immune checkpoint immunotherapy\n. J Thorac Oncol \n2019 ;14 :494 –502\n. 10.1016/j.jtho.2018.11.016 30503891 \n12 Suresh K , Naidoo J , Zhong Q , et al \nThe alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis\n. J Clin Invest \n2019 ;130 :4305 –15\n. 10.1172/JCI128654 \n13 Johnson DB , Taylor KB , Cohen JV , et al \nAnti-PD-1-Induced pneumonitis is associated with persistent imaging abnormalities in melanoma patients\n. Cancer Immunol Res \n2019 ;7 :1755 –9\n. 10.1158/2326-6066.CIR-18-0717 31462410 \n14 Suresh K , Naidoo J \nLower survival in patients who develop pneumonitis following immunotherapy for lung cancer\n. Clin Lung Cancer \n2020 ;21 :e169 –70\n. 10.1016/j.cllc.2019.10.009 31787546 \n15 Lazor R , Vandevenne A , Pelletier A , et al \nCryptogenic organizing pneumonia. Characteristics of relapses in a series of 48 patients. The groupe d'etudes et de recherche sur les maladles \"orphelines\" pulmonaires (GERM\"O\"P)\n. Am J Respir Crit Care Med \n2000 ;162 :571 –7\n. 10.1164/ajrccm.162.2.9909015 10934089\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2051-1426",
"issue": "8(1)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "inflammation; lung neoplasms; melanoma; programmed cell death 1 receptor",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008297:Male; D008875:Middle Aged; D011014:Pneumonia; D012189:Retrospective Studies",
"nlm_unique_id": "101620585",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32554618",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "27072927;29517954;32001626;29784734;31462410;26176400;31518182;30267842;29162153;31310589;27646942;31787546;30503891;10934089;27535979",
"title": "Chronic immune checkpoint inhibitor pneumonitis.",
"title_normalized": "chronic immune checkpoint inhibitor pneumonitis"
} | [
{
"companynumb": "US-009507513-2007USA011035",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAcetylcysteine prevents hepatic injury when administered soon after acetaminophen overdose. The most commonly used treatment protocols are a 72-hour oral and a 21-hour intravenous (IV) protocol. Between 1984 and 1994, 409 patients were enrolled in a study to describe the outcomes of patients who were treated using a 48-hour IV protocol. In 1991, an interim analysis reported the first 223 patients. The objective of this manuscript is to report the rates of hepatotoxicity and adverse events occurring during a 48-hour IV acetylcysteine protocol in the entire 409 patient cohort.\n\n\nMETHODS\nThis was a multicenter, single-arm, open-label clinical trial enrolling patients who presented with a toxic serum acetaminophen concentration within 24 h of acute acetaminophen ingestion. Patients were treated with 140 mg/kg loading dose followed by 70 mg/kg every 4 h for 12 doses. Serum aminotransferase activities were measured every 8 h during the protocol, and adverse events were recorded. The primary outcome was the percentage of subjects who developed hepatotoxicity defined as a peak serum aminotransferase greater than 1000 IU/L.\n\n\nRESULTS\nFour hundred and nine patients were enrolled, and 309 met inclusion for the outcome analysis. The overall percentage of patients developing hepatotoxicity was 18.1%, and 3.4% of patients treated within 10 h developed hepatotoxicity. One acetaminophen-related death occurred in a patient treated at 22 h. Adverse events occurred in 28.9% of enrolled subjects; the most common adverse events were nausea, vomiting, and flushing, and no events were rated as serious by the investigator.\n\n\nCONCLUSIONS\nAcetaminophen-overdosed patients treated with IV acetylcysteine administered as 140 mg/kg loading dose followed by 70 mg/kg every 4 h for 12 doses had a low rate of hepatotoxicity and few adverse events. This protocol delivers a higher dose of acetylcysteine which may be useful in selected cases involving very large overdoses.",
"affiliations": "Rocky Mountain Poison and Drug Center , Denver, CO , USA.",
"authors": "Heard|K|K|;Rumack|B H|BH|;Green|J L|JL|;Bucher-Bartelson|B|B|;Heard|S|S|;Bronstein|A C|AC|;Dart|R C|RC|",
"chemical_list": "D000931:Antidotes; D000082:Acetaminophen; D000637:Transaminases; D000111:Acetylcysteine",
"country": "England",
"delete": false,
"doi": "10.3109/15563650.2014.902955",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "52(5)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Acetaminophen; Acetylcysteine; Antidote; Liver injury; Poisoning",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000082:Acetaminophen; D000111:Acetylcysteine; D061605:Administration, Intravenous; D000293:Adolescent; D000328:Adult; D000931:Antidotes; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D062787:Drug Overdose; D005260:Female; D006801:Humans; D008297:Male; D011446:Prospective Studies; D013997:Time Factors; D000637:Transaminases; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "512-8",
"pmc": null,
"pmid": "24708414",
"pubdate": "2014-06",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A single-arm clinical trial of a 48-hour intravenous N-acetylcysteine protocol for treatment of acetaminophen poisoning.",
"title_normalized": "a single arm clinical trial of a 48 hour intravenous n acetylcysteine protocol for treatment of acetaminophen poisoning"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2015US-96346",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"dr... |
{
"abstract": "The diagnosis of autoimmune epilepsy is often challenging, and may be misdiagnosed as epileptic disorders or viral encephalitis. Autoimmune epilepsy has a strong association with other autoimmune diseases, especially systemic lupus erythematosus (SLE). In addition, autoimmune epilepsy was reported to present with complex partial seizure (CPS), simple partial seizure (SPS), and secondarily generalized tonic-clonic seizure (sGTCS). In our case, we present a different seizure type of tonic seizure in autoimmune epilepsy caused by SLE, which has not been reported, and it will provide with a new understanding of autoimmune epilepsy. A 17-year-old Chinese girl was diagnosed as having SLE for 1 month but with no epilepsy history. After this admission, she presented with different seizure types. Then EEG, magnetic resonance imaging, and lumbar puncture were performed. We have found generalized tonic seizure and excluded CNS infection and lupus encephalopathy. After antiepileptic therapy, no improvement has been found in seizure control. According to the previous history, clinical manifestation, and relevant examinations, we have made a clinical diagnosis of autoimmune epilepsy (tonic seizure) and SLE has been confirmed again by the immunological test. After the hormonotherapy, anti-inflammatory, and anti-tuberculosis therapy, the tonic seizure decreased significantly, and patient's consciousness improved. Autoimmune epilepsy should call the attentions of the clinicians, especially when the patient presented with SLE. Tonic seizure has not been described in autoimmune epilepsy before, which was different from other seizures reported, such as SPS, CPS, and sGTCS, and may bring a new insight into the autoimmune epilepsy.",
"affiliations": "Department of Neurology, Department of Neurology and Neuroscience Center, The First Hospital of JiLin University, Changchun, People's Republic of China.",
"authors": "Lv|Yudan|Y|;Zheng|Xiangyu|X|;Zhang|Xiao|X|;Zhao|Danyang|D|;Cui|Li|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/NMD.0000000000000946",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3018",
"issue": "207(3)",
"journal": "The Journal of nervous and mental disease",
"keywords": null,
"medline_ta": "J Nerv Ment Dis",
"mesh_terms": "D000293:Adolescent; D004827:Epilepsy; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D012640:Seizures",
"nlm_unique_id": "0375402",
"other_id": null,
"pages": "188-191",
"pmc": null,
"pmid": "30741775",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Tonic Seizure as a Different Seizure Type Presented in Autoimmune Epilepsy Caused by Systemic Lupus Erythematosus.",
"title_normalized": "tonic seizure as a different seizure type presented in autoimmune epilepsy caused by systemic lupus erythematosus"
} | [
{
"companynumb": "CN-UCBSA-2019018276",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MEROPENEM"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Abdominal tuberculosis (ATB) constitutes 12% of the extra pulmonary disease and is a rare but well-documented cause of perforation peritonitis, occasionally occurring in cases where the diagnosis has been delayed but may occur even after antituberculous therapy has been initiated. Most patients with tuberculosis strictures respond well to medical treatment and should be resorted to surgery only if drug therapy fails. Despite surgical intervention, tuberculosis perforation has a high complication and mortality rate. We present a case of 54-year-old male patient with a perforated jejunal stricture who had completed his treatment for pulmonary tuberculosis one month earlier. This case was unusual because of the age of patient at presentation (usually seen in young - 25 to 45 y), involvement of jejunum (commonly ileocaecal region), initial presentation with subacute obstruction followed by peritonitis (refused treatment at first instance) and patient having completed treatment for pulmonary tuberculosis recently.",
"affiliations": "Senior Resident, Department of Plastic Surgery, RajaRajeswari Medical College and Hospital , Bangalore, India .;Associate Professor, Department of General Surgery, College of Medicine and JNM Hospital, West Bengal University of Health Sciences , Kolkata, India .",
"authors": "N|Naveen|N|;Mukherjee|Avijeet|A|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2014/10802.5346",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-709X",
"issue": "8(12)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Abdominal tuberculosis; Intestinal obstruction; Intestinal stricture; Perforation peritonitis",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "ND07-8",
"pmc": null,
"pmid": "25653991",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports",
"references": "3558313;5033841;9625110;18329027;15195856;9926119;7448517;12409545",
"title": "A rare case of perforation peritonitis with jejunal stricture in a patient recently treated for pulmonary tuberculosis.",
"title_normalized": "a rare case of perforation peritonitis with jejunal stricture in a patient recently treated for pulmonary tuberculosis"
} | [
{
"companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2016-02246",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"drugadditional"... |
{
"abstract": "Moderate-to-severe psoriasis is treated using biological drugs targeting cytokines involved in the pathogenesis of the disease, such as tumor necrosis factor alpha (TNF-α) (adalimumab, infliximab, etanercept) and interleukin 12/23 (IL 12/23) (ustekinumab). There is a slight risk of developing hematological malignancies, such as monoclonal gammopathy of undetermined significance (MGUS) with anti TNF-α agents. There are no data available on anti-IL12/23 drugs. This retrospective study of data from 191 patients describes the appearance and follow-up of MGUS in three patients with psoriasis receiving long-term biological therapy. Since the appearance of MGUS occurred after about 6 years of anti-TNFα treatment in only three subjects, it was deemed unlikely to be due to the biological treatment. The decision not to suspend biological therapy after the appearance of MGUS was taken after careful assessment of the possible risks and benefits.",
"affiliations": "Dermatology Unit, Department of Head and Neck Surgery, Azienda Ospedaliero Universitaria Policlinico di Modena, Modena, Italy.",
"authors": "Conti|Andrea|A|;Esposito|Ilaria|I|;Lasagni|Claudia|C|;Miglietta|Roberta|R|;Padalino|Claudia|C|;Fabiano|Antonella|A|;Pellacani|Giovanni|G|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D053759:Interleukin-23; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D000069285:Infliximab; D000069549:Ustekinumab; D000068879:Adalimumab; D000068800:Etanercept",
"country": "United States",
"delete": false,
"doi": "10.1002/ddr.21191",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-4391",
"issue": "75 Suppl 1()",
"journal": "Drug development research",
"keywords": "anti-interleukin (IL)12/23; anti-tumor necrosis factor alpha (anti-TNFα); biologic therapy; monoclonal gammopathy of undetermined significance (MGUS); psoriasis",
"medline_ta": "Drug Dev Res",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001691:Biological Therapy; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D000069285:Infliximab; D018664:Interleukin-12; D053759:Interleukin-23; D007558:Italy; D008297:Male; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance; D011565:Psoriasis; D018124:Receptors, Tumor Necrosis Factor; D012189:Retrospective Studies; D014409:Tumor Necrosis Factor-alpha; D000069549:Ustekinumab",
"nlm_unique_id": "8204468",
"other_id": null,
"pages": "S35-7",
"pmc": null,
"pmid": "25381972",
"pubdate": "2014-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Monoclonal gammopathy of undetermined significance in patients with psoriasis: is it really a side effect of biological therapy?",
"title_normalized": "monoclonal gammopathy of undetermined significance in patients with psoriasis is it really a side effect of biological therapy"
} | [
{
"companynumb": "IT-JNJFOC-20141115437",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Primary brain tumors are a leading cause of cancer-related morbidity and mortality in children. Glioblastoma (GBM) is a high-grade astrocytoma that occurs in both children and adults and is associated with a poor prognosis. Despite extensive study in recent years, the clinical management of these tumors has remained largely unchanged, consisting of surgical resection, conventional chemotherapy, and radiotherapy. Although the etiology and genomic drivers in GBM are diverse, constitutional mismatch repair-deficiency (CMMRD) syndrome is a rare, recessively inherited disease with a predisposition to gliomagenesis. CMMRD results from biallelic mutations in one of the mismatch repair genes including mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), and post-meiotic segregation increased 2 (PMS2). In this report, we present the case of a 5-year-old female with GBM and CMMRD due to an MSH6 homozygous c.1883G>A mutation, who continues to experience an exceptional and durable response (9 months) to the immune checkpoint inhibitor (ICPI) nivolumab. Our patient presented with acute neurologic decline and increased intracranial pressure. Neuroimaging studies revealed a large left frontoparietal mass requiring neurosurgical decompression and resection. Histopathologic analyses resulted in a diagnosis of de novo GBM that was BRAF wild type and negative for programmed death-ligand 1 protein expression. She received standard-of-care treatment with surgery, radiation therapy, and temozolomide; however, the tumor recurred 3 months after the initial diagnosis. Molecular analyses of tumor and blood tissues revealed an MSH6 homozygous c.1883G>A mutation consistent with CMMRD. Given her CMMRD status, she was treated with nivolumab (3 mg/kg doses every 2 weeks for 36 weeks) and showed a 60% reduction in tumor size, improved clinical symptoms, and an ongoing durable response lasting 10 months to date. Our study highlights a durable response to the ICPI nivolumab in a pediatric patient with recurrent/refractory CMMRD-associated GBM. We show that incorporating genomic and/or molecular testing for CMMRD into routine pediatric oncology clinical care can identify a subset of patients likely to benefit from ICPI. KEY POINTS: Constitutional mismatch repair-deficiency (CMMRD) syndrome, alternatively known as biallelic mismatch repair deficiency syndrome, occurs in subset of pediatric cancer patients, including those with primary brain tumors.Patients from Arab and other developing countries are predicted to have higher incidence of CMMRD due to high prevalence of consanguinity.Integration of molecular and/or genomic testing into routine clinical care for pediatric cancer patients is important to identify patients with CMMRD syndrome.Patient with CMMRD-associated cancers may show increased responsiveness to immune checkpoint inhibitors.To the authors' knowledge, this is the first report in the Arab world of a durable response to immune checkpoint inhibitors in a pediatric glioblastoma patient.",
"affiliations": "Department of Oncology, Comprehensive Cancer Centre, King Fahad Medical City, Riyadh, Saudi Arabia.;Department of Oncology, Comprehensive Cancer Centre, King Fahad Medical City, Riyadh, Saudi Arabia.;Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.;Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.;Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.;Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.;Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.;Radiology Department, King Fahad Medical City, Riyadh, Saudi Arabia.;Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.;Department of Radiation Oncology, Comprehensive Cancer Centre, King Fahad Medical City, Riyadh, Saudi Arabia.;Division of Genetics, Department of Pediatric, King Abdulaziz Medical City, Riyadh, Saudi Arabia.;Department of Pathology, King Abdulaziz Medical City, National Guard Health Affair, Riyadh, Saudi Arabia.;Genetics Department, King Faisal Specialists Hospital and Research Center, Riyadh, Saudi Arabia.;Wake Forest Comprehensive Cancer Center and Department of Pathology, Winston-Salem, North Carolina, USA.;Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia malthagafi@kfmc.med.sa.",
"authors": "AlHarbi|Musa|M|;Ali Mobark|Nahla|N|;AlMubarak|Latifa|L|;Aljelaify|Rasha|R|;AlSaeed|Mariam|M|;Almutairi|Amal|A|;Alqubaishi|Fatmah|F|;Hussain|M Emarat|ME|;Balbaid|Ali Abdullah O|AAO|;Said Marie|Amal|A|;AlSubaie|Lamia|L|;AlShieban|Saeed|S|;alTassan|Nada|N|;Ramkissoon|Shakti H|SH|;Abedalthagafi|Malak|M|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000077594:Nivolumab; D045643:DNA Repair Enzymes",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2018-0163",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "23(12)",
"journal": "The oncologist",
"keywords": null,
"medline_ta": "Oncologist",
"mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D001932:Brain Neoplasms; D002675:Child, Preschool; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes; D005260:Female; D005909:Glioblastoma; D006801:Humans; D000077594:Nivolumab",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "1401-1406",
"pmc": null,
"pmid": "30104292",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "28321817;26545842;28885639;23891238;28472902;28096717;28881921;25642631;27001570;26293621;24440087;28596308;21339192",
"title": "Durable Response to Nivolumab in a Pediatric Patient with Refractory Glioblastoma and Constitutional Biallelic Mismatch Repair Deficiency.",
"title_normalized": "durable response to nivolumab in a pediatric patient with refractory glioblastoma and constitutional biallelic mismatch repair deficiency"
} | [
{
"companynumb": "SA-BRISTOL-MYERS SQUIBB COMPANY-BMS-2019-009057",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "Whether somatostatin analogs for acromegaly improve or worsen a patient's glycemic profile is controversial. A risk of hypoglycemia should be presumed, especially when patients receive insulin therapy, as the package inserts caution. However, a detailed clinical course of such a case has never been reported in research articles. An 80-year-old Japanese female diabetes patient treated with insulin therapy was diagnosed with acromegaly, and the somatostatin analog, lanreotide, was given. On day 4 of lanreotide treatment, repeated hypoglycemia as a result of exogenous insulin arose and the patient required inpatient care. After lanreotide treatment, the total daily insulin dose could be reduced, but her fasting C-peptide level decreased from 1.6 to 0.4 ng/mL, implying improved insulin resistance and impaired endogenous insulin secretion. In the present case, marked alteration surrounding lanreotide administration was observed; careful co-administration with insulin therapy is required, as the package insert cautions.",
"affiliations": "Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.;Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.;Department of Neurological Surgery, Nihon University School of Medicine, Tokyo, Japan.;Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.;Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.;Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.;Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.;Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.;Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.;Department of Neurological Surgery, Nihon University School of Medicine, Tokyo, Japan.;Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.",
"authors": "Tanaka|Sho|S|http://orcid.org/0000-0003-0091-7284;Haketa|Akira|A|;Yamamuro|Shun|S|;Suzuki|Toshiko|T|;Kobayashi|Hiroki|H|;Hatanaka|Yoshinari|Y|;Ueno|Takahiro|T|;Fukuda|Noboru|N|;Abe|Masanori|M|;Yoshino|Atsuo|A|;Soma|Masayoshi|M|",
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"fulltext": "\n==== Front\nJ Diabetes InvestigJ Diabetes Investig10.1111/(ISSN)2040-1124JDIJournal of Diabetes Investigation2040-11162040-1124John Wiley and Sons Inc. Hoboken 10.1111/jdi.12675JDI12675Case ReportArticlesClinical Science and CareMarked alteration of glycemic profile surrounding lanreotide administration in acromegaly: A case report Tanaka et al.Tanaka Sho http://orcid.org/0000-0003-0091-7284\n1\nHaketa Akira haketa07@gmail.com \n1\nYamamuro Shun \n2\nSuzuki Toshiko \n1\nKobayashi Hiroki \n1\nHatanaka Yoshinari \n1\nUeno Takahiro \n1\nFukuda Noboru \n1\nAbe Masanori \n1\nYoshino Atsuo \n2\nSoma Masayoshi \n1\n\n1 \nDivision of Nephrology, Hypertension and Endocrinology\nDepartment of Internal Medicine\nNihon University School of Medicine\nTokyo\nJapan\n\n2 \nDepartment of Neurological Surgery\nNihon University School of Medicine\nTokyo\nJapan\n* Correspondence\n\nAkira Haketa\n\nTel.: +81‐3‐3972‐8111\n\nFax: +81‐3‐3972‐8311\n\nE‐mail address: haketa07@gmail.com\n26 6 2017 1 2018 9 1 10.1111/jdi.2018.9.issue-1223 225 18 1 2017 23 3 2017 04 4 2017 © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, LtdThis is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abstract\nWhether somatostatin analogs for acromegaly improve or worsen a patient's glycemic profile is controversial. A risk of hypoglycemia should be presumed, especially when patients receive insulin therapy, as the package inserts caution. However, a detailed clinical course of such a case has never been reported in research articles. An 80‐year‐old Japanese female diabetes patient treated with insulin therapy was diagnosed with acromegaly, and the somatostatin analog, lanreotide, was given. On day 4 of lanreotide treatment, repeated hypoglycemia as a result of exogenous insulin arose and the patient required inpatient care. After lanreotide treatment, the total daily insulin dose could be reduced, but her fasting C‐peptide level decreased from 1.6 to 0.4 ng/mL, implying improved insulin resistance and impaired endogenous insulin secretion. In the present case, marked alteration surrounding lanreotide administration was observed; careful co‐administration with insulin therapy is required, as the package insert cautions.\n\nAcromegalyDiabetes mellitusLanreotide source-schema-version-number2.0component-idjdi12675cover-dateJanuary 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.2.8 mode:remove_FC converted:05.01.2018\n\nJ Diabetes Investig \n2018 ; 9 : 223 –225\n==== Body\nIntroduction\nAcromegaly is an endocrine disorder characterized by overgrowth with subsequent metabolic complications in response to a chronic excess of growth hormone (GH) and insulin‐like growth factor‐1 (IGF‐1)1. Impaired glucose metabolism is a frequent complication.\n\nLanreotide, a somatostatin analog (SSA), is frequently used for acromegaly. However, whether SSAs improve or worsen glycemic profiles is controversial2, 3, 4. Furthermore, although the package insert clearly cautions the risk of hypoglycemia, especially in patients receiving insulin therapy, a detailed clinical course of such a case has never been reported in research articles5.\n\nHerein, we report an acromegaly patient whose glycemic profile was markedly altered after lanreotide administration.\n\nCase Report\nAn 80‐year‐old Japanese woman with diabetes mellitus presented at the Nihon University Itabashi Hospital, Tokyo, Japan. Diabetes was diagnosed at 50 years‐of‐age, which was finally treated with multiple daily insulin injections (MDII) from 72 years‐of‐age onwards. Glycated hemoglobin was 7.1%, maintained with 56 units of a total insulin daily dose: 20 units of insulin degludec at bedtime, and 10–14 units of insulin aspart before meals. She did not take any medicine, including oral hypoglycemic agent, other than insulin.\n\nThe patient's body mass index was 22.2 kg/m2 (height 153 cm, weight 52 kg). Her vital signs were unremarkable. Acromegalic facies and enlarged extremities were observed. Cushingoid signs were not evident. Hormones under the above MDII were measured (Table 1). GH and IGF‐1 were pathologically high. Adrenocorticotropic hormone and cortisol were not consistently high, and midnight serum cortisol was atypical for Cushing's disease (Table 2). Magnetic resonance imaging showed a tumor on the pituitary, and the patient was diagnosed with acromegaly. Pituitary hormones, other than GH, were unremarkable in pituitary function tests. Acute octreotide suppression test was positive.\n\nTable 1 Hormones regulating glucose surrounding lanreotide administration\n\n\tBefore\tAfter\t\t\nGlucose\t7.9\t8.2\t(4.0–6.0 mmol/L)\t\nGH\t8.72\t3.26\t(<5.0 ng/mL)\t\nIGF‐1\t403\t128\t(49–158 ng/mL)\t\nSerum C‐peptide\t1.6\t0.4\t(1.5–3.5 ng/mL)\t\nUrine C‐peptide\tNot measured\t17.5\t(41–145 μg/day)\t\nGlucagon\tNot measured\t134\t(40–180 pg/mL)\t\nACTH\t83.3\t54.7\t(9–52 pg/mL)\t\nCortisol\t17.1\t17.3\t(3.8–18.4 μg/dL)\t\nTSH\t0.18\t0.12\t(0.4–4 μIU/mL)\t\nFree T3\t3.20\t2.80\t(2.2–4.5 pg/dL)\t\nFree T4\t1.84\t1.62\t(0.8–1.9 ng/dL)\t\nHormones were examined after overnight fasting, and before and after lanreotide administration. Diabetes was treated with multiple daily insulin injections using 52 units of total insulin daily dose (before) and vildagliptin 100 mg/day (after), respectively. ACTH, adrenocorticotropic hormone; GH, growth hormone; IGF‐1, insulin‐like growth factor‐1; T3, triiodothyronine; T4, thyroxine; TSH, thyroid‐stimulating hormone.\n\nJohn Wiley & Sons, LtdTable 2 Repeated measurement of adrenocorticotropic hormone and cortisol level\n\n\tACTH (9–52 pg/mL)\tCortisol (3.8–18.4 μg/dL)\t\nMorning\t37.0\t14.2\t\n83.3\t17.1\t\n18.8\t6.6\t\n29.6\t13.7\t\nMidnight\t12.0\t4.8\t\nAdrenocorticotropic hormone (ACTH) and cortisol were measured at four different early morning fasting times and midnight before lanreotide administration.\n\nJohn Wiley & Sons, LtdAn intramuscular injection of 90 mg lanreotide was given, and blood glucose declined (Figure 1). The patient continued MDII as aforementioned, and was admitted because of repeated hypoglycemia on the fourth day. Insulin injections were temporarily suspended, and dextrose was intravenously infused to prevent a hypoglycemic attack. Levels of immunoreactive insulin (0.2 μU/mL; measured using Roche's Cobas 8,000 modular analyzer, which does not detect exogenous insulin analogs), serum C‐peptide (0.1 ng/mL) and plasma glucose (1.4 mmol/L) implied exogenous insulin‐induced hypoglycemia. With this hypoglycemic event as a trigger, the patient hoped to avoid use of antidiabetic medicine with hypoglycemic risk, including insulin. To maintain glucose without hypoglycemia, vildagliptin (100 mg/day) and metformin (500 mg/day) were given instead of insulin. However, a response to an oral hypoglycemic agent was not achieved. Then, 4 units of insulin aspart before each meal was restarted, and the patient's preprandial blood glucose (an average of glucose levels before each meal) was maintained.\n\nFigure 1 Clinical course surrounding lanreotide administration. The black line indicates mean preprandial glucose (an average of blood glucose levels before each meal), and the vertical gray bar indicates the total daily insulin dose, respectively. Dosages of vildagliptin and metformin were 100 and 500 mg/day, respectively.\n\nWith vildagliptin (100 mg/day), hormones were measured on the seventh day, but the results of serum and urine C‐peptide were obtained on the 11th day (Table 1). GH and IGF‐1 were naturally lower; meanwhile, serum and urine C‐peptide showed low values.\n\nDiscussion\nAcromegaly is an endocrine disease characterized by inappropriate systemic overgrowth1. Impaired glucose metabolism is a frequent complication, with half of patients showing glycemic intolerance2, 4, 6. SSA is frequently used, but whether SSA improves or worsens glycemic profiles is controversial. Indeed, lanreotide multifariously modified glucose in 30–40% of patients2, 3. Its risk of causing hypoglycemia, especially in patients receiving insulin therapy, is clinically well‐recognized. However, a detailed clinical course of such a case has never been reported in research articles5.\n\nThe 44‐unit reduction in total insulin daily dose implied a marked alteration of this patient's diabetes. As insulin secretion was impaired after administration, this improvement was attributed to increasing insulin sensitivity. GH influences glucose metabolism through two contradictory pathways; while IGF‐1 mediated by GH plays a similar role to insulin, GH interferes with insulin receptor substrate 2, phosphatidylinositol 3‐kinase and Akt activation, resulting in insulin resistance, a dominant factor for glucose intolerance in acromegaly1, 7. Similar to somatostatin inhibiting hormone release through binding somatostatin receptor (SSTR) 1–5, lanreotide binds SSTR2 strongly and SSTR5 weakly, to inhibit hormone release, including GH, thus modifying glucose1, 8. Disease controllability and a lower body mass index are predictors for glycemic improvement in lanreotide therapy for acromegaly3, 4. The early normalization of IGF‐1 and non‐obesity in the present case did not conflict with an improvement. Furthermore, the patient's race was also possibly implicated in the her response to treatment: East Asians have high insulin sensitivity, suggesting improved insulin resistance can be more easily attained9.\n\nThe impaired insulin secretion after lanreotide administration was also of interest. Low levels of serum and urine C‐peptide imply lanreotide altered the patient's diabetes to an insulin‐dependent state. Serum glucagon remained unaltered; however, it was presumed that lanreotide severely impaired β‐cell function through SSTR5. While it is well recognized that pasireotide binds with high affinity to SSTR5 and causes hyperglycemia, lanreotide also has certain affinities to SSTR510, 11. From another angle, the decreased C‐peptide level to that before lanreotide treatment probably meant decreased insulin resistance. Ohkura reported that ‘20 / (fasting C‐peptide × fasting plasma glucose)’ correlates well with insulin resistance estimated by a glucose infusion rate evaluated by euglycemic clamp12. Although insulin therapy makes a fair judgment difficult, the regression equation in that article estimated the glucose infusion rate of the present case at 5.64 mg/kg/min (before) and 18.38 mg/kg/min (after).\n\nThe present case included several limitations. First, with regard to an oral glucose tolerance test, the standard diagnostic method for acromegaly, tests on insulin resistance and glucose stimulated insulin secretion were not carried out, because severe hyperglycemia was predicted based on the high‐dose insulin requirement of the patient's MDII regimen. Second, the transient withdrawal of insulin injections and environmental factors, such as physical activity and diet, that become altered on admission, might have affected the clinical course. Therefore, the reduction observed in the total insulin daily dose might not simply reflect the influence of lanreotide.\n\nImportantly, SSAs should be administered with inpatient medical care to ensure appropriate treatment for any altered glycemic profile, if they are administered to diabetes patients receiving high‐dose insulin therapy.\n\nDisclosure\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1 \n\nMelmed \nS \n. Acromegaly pathogenesis and treatment . J Clin Invest \n2009 ; 119 : 3189 –3202 .19884662 \n2 \n\nCaron \nPJ \n, \nPetersenn \nS \n, \nHouchard \nA \n, et al\nGlucose and lipids levels with lanreotide autogel 120 mg in treatment‐naive patients with acromegaly: data from the PRIMARYS study . Clin Endocrinol (Oxf) \n2016 ; 86 : 541 –551 .27874199 \n3 \n\nCouture \nE \n, \nBongard \nV \n, \nMaiza \nJC \n, et al\nGlucose status in patients with acromegaly receiving primary treatment with the somatostatin analog lanreotide . Pituitary \n2012 ; 15 : 518 –525 .22058008 \n4 \n\nColao \nA \n, \nAuriemma \nRS \n, \nSavastano \nS \n, et al\nGlucose tolerance and somatostatin analog treatment in acromegaly: a 12‐month study . J Clin Endocrinol Metab \n2009 ; 94 : 2907 –2914 .19491229 \n5 \n\nTolis \nG \n, \nAngelopoulos \nNG \n, \nKatounda \nE \n, et al\nMedical treatment of acromegaly: comorbidities and their reversibility by somatostatin analogs . Neuroendocrinology \n2006 ; 83 : 249 –257 .17047390 \n6 \n\nAlexopoulou \nO \n, \nBex \nM \n, \nKamenicky \nP \n, et al\nPrevalence and risk factors of impaired glucose tolerance and diabetes mellitus at diagnosis of acromegaly: a study in 148 patients . Pituitary \n2014 ; 17 : 81 –89 .23446424 \n7 \n\nSasaki‐Suzuki \nN \n, \nArai \nK \n, \nOgata \nT \n, et al\nGrowth hormone inhibition of glucose uptake in adipocytes occurs without affecting GLUT4 translocation through an insulin receptor substrate‐2‐phosphatidylinositol 3‐kinase‐dependent pathway . J Biol Chem \n2009 ; 284 : 6061 –6070 .19122000 \n8 \n\nRen \nSG \n, \nTaylor \nJ \n, \nDong \nJ \n, et al\nFunctional association of somatostatin receptor subtypes 2 and 5 in inhibiting human growth hormone secretion . J Clin Endocrinol Metab \n2003 ; 88 : 4239 –4245 .12970293 \n9 \n\nKodama \nK \n, \nTojjar \nD \n, \nYamada \nS \n, et al\nEthnic differences in the relationship between insulin sensitivity and insulin response: a systematic review and meta‐analysis . Diabetes Care \n2013 ; 36 : 1789 –1796 .23704681 \n10 \n\nKumar \nU \n, \nSasi \nR \n, \nSuresh \nS \n, et al\nSubtype‐selective expression of the five somatostatin receptors (hSSTR1‐5) in human pancreatic islet cells: a quantitative double‐label immunohistochemical analysis . Diabetes \n1999 ; 48 : 77 –85 .9892225 \n11 \n\nSilverstein \nJM \n. Hyperglycemia induced by pasireotide in patients with Cushing's disease or acromegaly . Pituitary \n2016 ; 19 : 536 –543 .27405306 \n12 \n\nOhkura \nT \n, \nShiochi \nH \n, \nFujioka \nY \n, et al\n20/(fasting C‐peptide x fasting plasma glucose) is a simple and effective index of insulin resistance in patients with type 2 diabetes mellitus: a preliminary report . Cardiovasc Diabetol \n2013 ; 12 : 21 .23339473\n\n",
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"journal": "Journal of diabetes investigation",
"keywords": "Acromegaly; Diabetes mellitus; Lanreotide",
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"mesh_terms": "D000172:Acromegaly; D000369:Aged, 80 and over; D001786:Blood Glucose; D048909:Diabetes Complications; D003920:Diabetes Mellitus; D005260:Female; D006801:Humans; D007003:Hypoglycemia; D007004:Hypoglycemic Agents; D007328:Insulin; D010456:Peptides, Cyclic; D013004:Somatostatin",
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"title": "Marked alteration of glycemic profile surrounding lanreotide administration in acromegaly: A case report.",
"title_normalized": "marked alteration of glycemic profile surrounding lanreotide administration in acromegaly a case report"
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"abstract": "Waldenstrom macroglobulinemia (WM) is a lymphoplasmacytic lymphoma associated with a monoclonal immunoglobulin M protein. Extranodal involvement in WM is not very common. In this article, we present a rare case of WM with kidney and central nervous system involvement. Bing-Neel syndrome is a distinct complication of WM where lymphoplasmacytic cells involve the central nervous system (CNS). Our patient was initially treated with dialysis and steroids with improvement in his kidney function. He was then started on systemic treatment with rituximab, cyclophosphamide, and dexamethasone with stable kidney function but persistent CNS symptoms. Due to rarity of cases, there is no standard treatment for Bing-Neel syndrome. His treatment was switched to ibrutinib with dramatic improvement in his CNS symptoms as well as radiological findings on magnetic resonance imaging.",
"affiliations": "Marshall University, Huntington, WV, USA.;Marshall University, Huntington, WV, USA.;Marshall University, Huntington, WV, USA.;Marshall University, Huntington, WV, USA.;Marshall University, Huntington, WV, USA.;Marshall University, Huntington, WV, USA.;Marshall University, Huntington, WV, USA.",
"authors": "Jafri|Hassaan|H|0000-0003-1733-101X;Khan|Isna|I|;Sidda|Adarsh|A|;Khan|Noman Ahmed Jang|NAJ|;Kheetan|Murad|M|;Griswold|Doreen|D|;Pacioles|Toni|T|",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096\nSAGE Publications Sage CA: Los Angeles, CA\n\n34078157\n10.1177/23247096211021228\n10.1177_23247096211021228\nCase Report\nWaldenstrom Macroglobulinemia Manifesting as Acute Kidney Injury and Bing-Neel Syndrome With Excellent Response to Ibrutinib\nhttps://orcid.org/0000-0003-1733-101X\nJafri Hassaan MD 1\nKhan Isna MD 1\nSidda Adarsh MD 1\nKhan Noman Ahmed Jang MD 1\nKheetan Murad MD 1\nGriswold Doreen MD 1\nPacioles Toni MD 1\n1 Marshall University, Huntington, WV, USA\nHassaan Jafri, MD, Marshall University Joan C. Edwards School of Medicine, 1400 Hal Greer Blvd, Huntington, WV 25701-3655, USA. Email: hassaanjafrimd@gmail.com\n2 6 2021\nJan-Dec 2021\n9 232470962110212288 3 2021\n30 4 2021\n10 5 2021\n© 2021 American Federation for Medical Research\n2021\nAmerican Federation for Medical Research\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nWaldenstrom macroglobulinemia (WM) is a lymphoplasmacytic lymphoma associated with a monoclonal immunoglobulin M protein. Extranodal involvement in WM is not very common. In this article, we present a rare case of WM with kidney and central nervous system involvement. Bing-Neel syndrome is a distinct complication of WM where lymphoplasmacytic cells involve the central nervous system (CNS). Our patient was initially treated with dialysis and steroids with improvement in his kidney function. He was then started on systemic treatment with rituximab, cyclophosphamide, and dexamethasone with stable kidney function but persistent CNS symptoms. Due to rarity of cases, there is no standard treatment for Bing-Neel syndrome. His treatment was switched to ibrutinib with dramatic improvement in his CNS symptoms as well as radiological findings on magnetic resonance imaging.\n\nBing-Neel syndrome\nibrutinib\nWaldenstrom macroglobulinemia\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nWaldenstrom macroglobulinemia (WM) is a lymphoproliferative disorder characterized by the proliferation of lymphoplasmacytic elements in the bone marrow and the presence of monoclonal immunoglobulin M (IgM) gammopathy. Extranodal involvement in WM is rare.\n\nOur case involves rare presentation of WM with kidney and central nervous system (CNS) involvement. Remarkably, our patient had a dramatic response to CNS symptoms as well as radiological findings on magnetic resonance imaging (MRI) on ibrutinib monotherapy after initially being treated with rituximab, cyclophosphamide, and dexamethasone.\n\nCase Presentation\n\nA 58-year-old male with a past medical history of prostate cancer presented to our facility with worsening confusion, weakness, and oliguria. Prostate biopsy 5 months prior to admission showed Gleason 4+3 T2aN0M0 prostate adenocarcinoma, for which he was treated with combined brachytherapy and external beam radiation. He developed left lower extremity and weakness after treatment. MRI of lumbar spine showed degenerative changes but no attributable etiology for his weakness was evident. Around the same time, he also started developing short-term memory loss.\n\nOn presentation to our facility, complete blood count was unremarkable, and creatinine was 5.97 mg/dL. Baseline creatinine was 0.85 mg/dL 6 months prior to admission. Urinalysis revealed specific gravity 1.017, large occult blood, white blood cells (WBC) 15 to 25 cells, trace ketones, and no evidence of infection. Due to oliguric acute kidney injury with altered mental status suggestive of uremia, dialysis was initiated. Workup for the confusion including noncontrast MRI brain showed extensive white matter changes. Cerebrospinal fluid (CSF) analysis showed glucose 29 mg/dL, protein 120 mg/dL, WBC 68 cells/mm3 with 77% lymphocytes, and red blood cells 119 cells/mm3. Computed tomography (CT) scan of chest, abdomen, and pelvis showed pleural effusion and mildly enlarged subcarinal lymph node. Infectious workup was also negative. Urine microalbumin to creatinine ratio was 851 (0-28) and urine protein to creatinine ratio was 1.81 (normal less than 0.20). Serum protein electrophoresis (SPEP) was positive for M spike. Immunofixation electrophoresis showed IgM kappa monoclonal protein and second IgM monoclonal protein with probable kappa light chain. IgM kappa monoclonal protein #1 concentration was 0.2 g/dL and IgM monoclonal protein #2 concentration was less than 0.1 g/dL. Urine protein electrophoresis showed M spike and urine immunofixation electrophoresis showed Bence Jones protein, kappa type. Free kappa light chain was 924 mg/dL (3.3-19.4 mg/dL), free lambda light chain was 24 mg/dL (5.7-26.3 mg/dL), with a kappa/lambda ratio of 38.2 (0.26-1.65). A kidney biopsy was ultimately performed, which showed extensive glomerular and arteriolar IgM kappa hyaline thrombi and glomerular features of thrombotic microangiopathy. A few kappa light chain restricted casts were seen suspicious for light chain nephropathy. Findings were deemed secondary to IgM kappa monoclonal protein. A subsequent bone marrow biopsy was consistent with lymphoplasmacytic lymphoma. Lymphoid aggregates were composed of CD20 positive B cells with admixed CD138 positive plasma cells with kappa predominance (Figures 1-6). Karyotype showed normal cytogenetics and molecular studies detected a MYD88 L265P mutation. CXCR4 mutation was not detected. HIV and hepatitis B tests were negative. He was treated with methylprednisolone 500 mg for 3 days followed by a prednisone taper. He also underwent 2 sessions of plasmapheresis as viscosity was not available at that time and patients had concerning symptoms of hyperviscosity. Later on, his serum viscosity turned out to be normal (1.5 centipoises). Dialysis was discontinued prior to discharge from hospital as his kidney function recovered with good urine output (creatinine 2.81 mg/dL). Subsequently, a month later, his creatinine in the follow-up hematology clinic visit was 1.35 mg/dL. He had a follow-up with nephrology and no more dialysis was needed. He was then initiated on treatment with rituximab, cyclophosphamide, and dexamethasone (RCD). IgM level at the time of treatment initiation was 1402 mg/dL. It increased to 1650 mg/dL after 1 month and 1877 mg/dL after 2 months. He was readmitted 3 months after initiation of chemotherapy with a 30-minute episode of right-sided facial weakness, slurred speech, and right upper extremity weakness. CT head showed severe white matter changes with scattered areas of enhancement with surrounding vasogenic edema. CT angiography was unremarkable. CSF studies showed opening pressure of 17, glucose 70 mg/dL, protein 72 mg/dL, WBC 4 cells/mm3, and red blood cells 4 cells/mm3. No definitive etiology was again attributable to these findings. A month later, he was readmitted with seizures. His hospital course was complicated by atrial fibrillation with rapid ventricular rate and aspiration pneumonia. He was started on eliquis. MRI brain showed persistent extensive periventricular leukomalacia. He was placed on dexamethasone. He continued to have issues with memory loss and weakness. He benefited with RCD treatment with continued stabilization of his renal function but his M protein was overall unchanged. After 5 cycles of RCD, his IgM was 1108 mg/dL. His SPEP showed an IgM monoclonal spike of 0.8 with kappa light chain specificity. Another lumbar puncture was pursued after holding his steroids for 2 weeks and the CSF analysis indicated elevated protein, decreased glucose, and elevated WBC with lymphocytic predominance. His lumbar puncture was abnormal but not definitive for diagnosis of CNS involvement by lymphoma. Brain biopsy was discussed but patient deferred the procedure. A repeat MRI was done that showed progression of white matter enhancement (Figure 7). Due to the persistent imaging findings, suspicion of CNS involvement by lymphoma was high. As he had been treated with multiple courses of steroids, the diagnostic yield of CSF for definitive diagnosis was likely low. He was started on ibrutinib 420 mg daily. Eliquis was held in consultation with cardiology. After initiation of therapy, the patient noted dramatic improvement in memory and weakness. Repeat MRI brain after 2 months of ibrutinib showed complete resolution of intracranial enhancement (Figure 8). His IgM protein as well as his M spike have largely remained stable since. The patient is currently tolerating ibrutinib well with no complications.\n\nFigure 1. Hematoxylin-eosin–stained slide of the subcortical hypocellular bone marrow showing small non-paratrabecular aggregates and scattered interstitial cells (50× oil).\n\nFigure 2. Immunohistochemistry for CD20 shows that the majority of the cells within the aggregate and many within the interstitium are B cells (20×).\n\nFigure 3. Conversely, CD3 immunohistochemistry shows only occasional scattered T cells (20×).\n\nFigure 4. CD138 demonstrates increased numbers of plasma cells within the interstitium and the aggregate.\n\nFigure 5. The plasmacytoid lymphocytes and plasma cells are kappa restricted.\n\nFigure 6. The histograms represent the gated lymphocytes. Of the gated lymphocytes, approximately 34% (red dots) are B cells that coexpress CD19 and CD20 and exhibit surface kappa light chain restriction.\n\nFigure 7. Magnetic resonance imaging of the brain showing intracranial white matter enhancements consistent with disease progression (blue arrows).\n\nFigure 8. Magnetic resonance imaging of the brain 2 months after treatment with ibrutinib showing complete resolution of previously noticed white matter enhancements.\n\nDiscussion\n\nWe present this interesting case of WM with kidney and central nervous system involvement.\n\nAccording to the World Health Organization, WM is lymphoplasmacytic lymphoma related to monoclonal IgM protein. Incidence rate for males (0.92 per 100 000) and females (0.30 per 100 000) person years has remained stable over the past 50 years. 1\n\nDiagnostic criteria for WM include bone marrow involvement by lymphoplasmacytoma and monoclonal IgM gammopathy in blood. Mayo Clinic consensus stressed 10% lymphoplasmacytic plasma cell involvement to differentiate WM form IgM monoclonal gammopathy of undetermined significance. Second International workshop does not have specific percentage of bone marrow involvement for diagnosis. 2\n\nSymptoms of WM are because of lymphoplasmcytic cells which infiltrate different organs. Paraproteins are also responsible for clinical features associated with WM. In addition, WM can have symptoms that are similar to other non-Hodgkin’s lymphoma. It can lead to enlargement of liver, spleen, and lymph nodes, and less commonly involves extranodal tissues. 2 In contrast to multiple myeloma, kidney involvement in WM is not quite common. Vos et al did a study in patients with WM where 44 out of 1391 patients had kidney involvement by lymphoma. At 15 years, the incidence was 5.1%. Only 2 patients had thrombotic microangiopathy making it a rare manifestation. 3 This makes our patient unique in his presentation, as he had evidence of thrombotic microangiopathy on kidney biopsy.\n\nBing-Neel syndrome (BNS) is a distinct complication of WM where lymphoplasmacytic cells involve CNS. In 1936, Jens Bing and Axel Valdemar first explained this entity. They described 2 patients who had CNS symptoms with elevated globulins and had no evidence of myeloma. 4 Studies about BNS have shown low prevalence of the disease. According to analysis by Kulkarni et al, 13 (0.8%) out of total 1523 WM patients had BNS. 5\n\nWhenever patients with WM present with altered mental status, a prompt neurological evaluation with an MRI of the brain and CSF studies are warranted. Simon et al studied 44 patients with BNS where 80% patients had CNS abnormalities on imaging. There was no single consistent pattern associated with BNS on the imaging studies. There can be brain or medullary parenchymal as well as leptomeningeal enhancement. 6\n\nThe gold standard to diagnose BNS include sampling of brain parenchyma and meninges that should reveal lymphoplasmacytic lymphoma. On immunohistochemistry like WM, B cells have pan B-cell antigens (CD19, CD20, CD79a, and CD79b). They also express CD27 and CD52 mostly which are memory B-cell markers. Some monotypic plasma cells may be seen that express CD38 and IgM. CSF should be analyzed which has clonal B cells with similar features as the bone marrow. 7 CSF analysis typically shows increased intracranial pressure, increased protein (>100 mg/dL), decreased or normal glucose, and elevated white blood cells (between 100 and 500 cell/mm3). Flow cytometry is compulsory to demonstrate clonality in B cells. Positive CSF study supports the diagnosis; however, negative results cannot rule out BNS due to low sensitivity of the test.4,8,9 This was evident in our patient, where we did not have histological confirmation with a biopsy or CSF flow cytometry, but we did have a confirmatory diagnosis by bone marrow as well as a rapid response to treatment. Due to above-mentioned reasons, we strongly feel our patient had BNS.\n\nManagement of WM with no symptomatology is usually with observation. Indications for treatment include WM-related constitutional symptoms like B symptoms from any other non-Hodgkin’s lymphoma, symptomatic anemia, lymphadenopathy, or hepatosplenomegaly, as well as coexisting AL amyloidosis with organ dysfunction. 10 Acute kidney injury is also an indication to start treatment. In a study by Higgins et al in patients with kidney involvement by WM, treatment was not uniform as multiple agents were used in different lines of treatment. Some patients were treated with anti-CD20 antibodies and alkylating agents while others with novel agents like bortezomib. Rituximab was used as the first-line treatment in 60% of patients in the study. Autologous stem cell transplant was also done in few patients, all with amyloid-related glomerulopathy. Some patients had also required plasmapheresis. 11 Our patient was treated with plasmapheresis initially and renal replacement therapy with hemodialysis was needed with steroids resulting in improvement of kidney function. Subsequently, his kidney function remained stable on systemic treatment with rituximab, cyclophosphamide, and dexamethasone.\n\nDue to the rarity of BNS, no standard guideline for treatment is currently well established. Treatment of BNS involves initiation of treatment at the time of symptoms with goal of therapy being to improve the symptoms. High-dose methotrexate and cytarabine have been used for BNS due to their activity in CNS lymphoma but because of toxicity they are not recommended in the front-line setting. Other recommended agents include bendamustine, fludarabine, and cladribine. These are significantly less toxic than methotrexate but still have side effects including myelosuppression, immunosuppression, refractory cytopenias, and secondary myeloid neoplasms. Rituximab monotherapy is not recommended in BNS because of limited CNS penetration but can be used in conjunction with other therapies for systemic control of disease. 12\n\nIn 2015, ibrutinib was first approved for symptomatic WM by study done by Treon et al where ibrutinib was given to patients with WM in second-line setting. Patients with BNS were not included. The overall response rate was 90.5%, and the major response rate was 73.0%. Analysis showed progression-free survival and overall survival benefit at 2 years (progression-free survival = 69.1%, overall survival = 95.2). 13 Another study published by Treon et al showed WM treated with ibrutinib showed durable responses in the first-line setting. In both studies, responses to ibrutinib were better in patients with MYD88 mutation and wild type CXCR as was the case in our patient.\n\nIn a study by Castillo et al, 28 patients with BNS were treated with ibrutinib. Thirty-nine percent patients received ibrutinib in first-line setting. Forty-six percent received 560 mg and 54% received 420 mg dose of ibritinib. Within 3 months, 85% patients reported improvement in symptoms and 60% had improvement on imaging. At best response, 85% of patients reported minimal to absent BNS symptoms, 83% had improvement or resolution of changes on imaging, and 47% had negative CSF cytology. The 2-year event-free survival rate with ibrutinib was 80%, the 2-year ibrutinib survival rate was 81%, and the 5-year BNS survival rate was 86%. 14 Only 2 patients in the study had resolution of findings in MRI. Event-free survival was similar between 2 doses of ibrutinib. 14 Patients with BNS have been successfully treated with doses of 420 mg daily. Hence it is recommended to start the lower dose as the initial first line of treatment. 9 Our patient had a good response with 420 mg dose of ibrutinib.\n\nConclusions\n\nIn conclusion, our case will be useful addition to literature of cases with rare extranodal presentation of WM with acute kidney injury and symptoms concerning for BNS. Although rare we suggest BNS should be considered in differential diagnosis of WM patients who have CNS symptoms. As BNS has no specific treatment due to rarity of cases, we suggest ibrutinib should be strongly considered for treatment of WM patients with concern for BNS.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: Verbal Informed consent was obtained from the patient for their anonymized information including facial images to be published in this article.\n\nORCID iD: Hassaan Jafri https://orcid.org/0000-0003-1733-101X\n==== Refs\nReferences\n\n1 Gertz MA. Waldenström macroglobulinemia: 2019 update on diagnosis, risk stratification, and management. Am J Hematol. 2019;94 :266-276.30328142\n2 Mazzucchelli M Frustaci AM Deodato M Cairoli R Tedeschi A. Waldenstrom’s macroglobulinemia: an update. Mediterr J Hematol Infect Dis. 2018;10 :e2018004.\n3 Vos JM Gustine J Rennke HG , et al . Renal disease related to Waldenström macroglobulinaemia: incidence, pathology and clinical outcomes. Br J Haematol. 2016;175 :623-630.27468978\n4 Varettoni M Defrancesco I Diamanti L , et al . Bing-Neel syndrome: illustrative cases and comprehensive review of the literature. Mediterr J Hematol Infect Dis. 2017;9 :e2017061.\n5 Kulkarni T Treon SP Manning RA , et al . Clinical characteristics and treatment outcome of CNS involvement (Bing-Neel syndrome) in Waldenstroms macroglobulinemia. Blood. 2013;22 :5090.\n6 Simon L Aikaterini F Lemal R , et al . Bing-Neel syndrome, a rare complication of Waldenstorm macroglobulinemia: analysis of 44 cases and review of the literature. A study on behalf of the French Innovative Leukemia Organization (FILO). Haematologica. 2015;100 :1587-1594.26385211\n7 Minnema MC Kimby E D’Sa S , et al . Guideline for the diagnosis, treatment, and response criteria for Bing-Neel syndrome. Haematologica. 2017;102 :43-51.27758817\n8 Malkani RG Tallman M Gottardi-Littell N , et al . Bing-Neel syndrome: an illustrative case and a comprehensive review of the published literature. J Neurooncol. 2010;96 :301-312.19618118\n9 Plander M Szendrei T Vadvári Á Iványi J. Standard dose of ibrutinib is effective in the treatment of Bing-Neel syndrome. Pathol Oncol Res. 2020;26 :591-592.30357751\n10 Kapoor P Ansell S Fonesca R , et al . Diagnosis and management of Waldenström macroglobulinemia Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) guidelines. JAMA Oncol. 2017;3 :1257-1265.28056114\n11 Higgins L Nasr SH Said SM , et al . Kidney involvement of patients with Waldenström macroglobulinemia and other IgM-producing B cell lymphoproliferative disorders. Clin J Am Soc Nephrol. 2018;13 :1037-1046.29848505\n12 Castillo JJ Treon SP. How we manage Bing-Neel syndrome. Br J Haematol. 2019;187 :277-285.31430829\n13 Treon SP Tripsas CK Meid K , et al . Ibrutinib in previously treated Waldenström’s macroglobulinemia. N Engl J Med. 2015;372 :1430-1440.25853747\n14 Castillo JJ Itchaki G Paludo J , et al . Ibrutinib for the treatment of Bing-Neel syndrome: a multicenter study. Blood. 2019;133 :299-305.30523119\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2324-7096",
"issue": "9()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "Bing-Neel syndrome; Waldenstrom macroglobulinemia; ibrutinib",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D000225:Adenine; D001927:Brain Diseases; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D010880:Piperidines; D008258:Waldenstrom Macroglobulinemia",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "23247096211021228",
"pmc": null,
"pmid": "34078157",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25853747;28056114;30328142;30523119;19618118;29848505;27468978;31430829;26385211;27758817;29326801;30357751;29181138",
"title": "Waldenstrom Macroglobulinemia Manifesting as Acute Kidney Injury and Bing-Neel Syndrome With Excellent Response to Ibrutinib.",
"title_normalized": "waldenstrom macroglobulinemia manifesting as acute kidney injury and bing neel syndrome with excellent response to ibrutinib"
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"abstract": "B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells.\n\n\n\nIn two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times weekly for 96 weeks. The primary end point was the annualized relapse rate.\n\n\n\nThe annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a.\n\n\n\nAmong patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required. (Funded by F. Hoffmann-La Roche; OPERA I and II ClinicalTrials.gov numbers, NCT01247324 and NCT01412333 , respectively.).",
"affiliations": "From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.;From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.;From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.;From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.;From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.;From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.;From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.;From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.;From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.;From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.;From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.;From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.;From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.;From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.;From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.;From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.;From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.;From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.;From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.;From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.;From the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., P.C., H.G.) - both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver, BC (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); Hospital Vall d'Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.); Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.",
"authors": "Hauser|Stephen L|SL|;Bar-Or|Amit|A|;Comi|Giancarlo|G|;Giovannoni|Gavin|G|;Hartung|Hans-Peter|HP|;Hemmer|Bernhard|B|;Lublin|Fred|F|;Montalban|Xavier|X|;Rammohan|Kottil W|KW|;Selmaj|Krzysztof|K|;Traboulsee|Anthony|A|;Wolinsky|Jerry S|JS|;Arnold|Douglas L|DL|;Klingelschmitt|Gaelle|G|;Masterman|Donna|D|;Fontoura|Paulo|P|;Belachew|Shibeshih|S|;Chin|Peter|P|;Mairon|Nicole|N|;Garren|Hideki|H|;Kappos|Ludwig|L|;|||",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20; D007155:Immunologic Factors; D016899:Interferon-beta; C533411:ocrelizumab",
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"doi": "10.1056/NEJMoa1601277",
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"issue": "376(3)",
"journal": "The New England journal of medicine",
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"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20; D001402:B-Lymphocytes; D001921:Brain; D018450:Disease Progression; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D007262:Infusions, Intravenous; D016899:Interferon-beta; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting; D012008:Recurrence",
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"pages": "221-234",
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"pubdate": "2017-01-19",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis.",
"title_normalized": "ocrelizumab versus interferon beta 1a in relapsing multiple sclerosis"
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"abstract": "A 40-year-old man with systemic lupus erythematosus taking consecutive oral corticosteroids developed a high-grade fever and disorder of consciousness following acute rhinitis. Haemophilus influenzae type f (Hif) was found and isolated from the blood and cerebrospinal fluid by culture, leading to a diagnosis of meningitis. The prevalence of H. influenzae type b (Hib) infections has decreased due to routine immunization. As a result, the prevalence of invasive non-Hib, including Hif infection, is increasing as a common H. influenzae infection in children and adults. Physicians should be aware of non-Hib H. influenzae infection, even though the Hib vaccine is widely used in Japan.",
"affiliations": "Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Japan.;Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Japan.;Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Japan.;Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Japan.;Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Japan.;Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Japan.;Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Japan.;Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Japan.;Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Japan.;Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Japan.;Department of Infection Control and Infectious Diseases, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Japan.;Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Japan.",
"authors": "Hasegawa|Yasuhiro|Y|;Arinuma|Yoshiyuki|Y|;Tanaka|Sumiaki|S|;Tono|Toshihiro|T|;Tanaka|Tomoki|T|;Muramatsu|Takumi|T|;Kondo|Junichi|J|;Matsueda|Yu|Y|;Hoshiyama|Takayuki|T|;Wada|Tatsuhiko|T|;Takayama|Yoko|Y|;Yamaoka|Kunihiro|K|",
"chemical_list": null,
"country": "Japan",
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"doi": "10.2169/internalmedicine.4562-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918 1349-7235 The Japanese Society of Internal Medicine \n\n32759581\n10.2169/internalmedicine.4562-20\nCase Report\n\nHaemophilus influenzae Non-type b Infection in an Adult Patient with Systemic Lupus Erythematosus\nHasegawa Yasuhiro 1 Arinuma Yoshiyuki 1 Tanaka Sumiaki 1 Tono Toshihiro 1 Tanaka Tomoki 1 Muramatsu Takumi 1 Kondo Junichi 1 Matsueda Yu 1 Hoshiyama Takayuki 1 Wada Tatsuhiko 1 Takayama Yoko 2 Yamaoka Kunihiro 1 \n1 Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Japan\n\n2 Department of Infection Control and Infectious Diseases, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Japan\nCorrespondence to Dr. Yoshiyuki Arinuma, y-arinuma@med.kitasato-u.ac.jp\n\n\n4 8 2020 \n1 12 2020 \n59 23 3097 3101\n28 1 2020 16 6 2020 Copyright © 2020 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 40-year-old man with systemic lupus erythematosus taking consecutive oral corticosteroids developed a high-grade fever and disorder of consciousness following acute rhinitis. Haemophilus influenzae type f (Hif) was found and isolated from the blood and cerebrospinal fluid by culture, leading to a diagnosis of meningitis. The prevalence of H. influenzae type b (Hib) infections has decreased due to routine immunization. As a result, the prevalence of invasive non-Hib, including Hif infection, is increasing as a common H. influenzae infection in children and adults. Physicians should be aware of non-Hib H. influenzae infection, even though the Hib vaccine is widely used in Japan. \n\nHaemophilus influenzae type fHib vaccinationbacterial meningitissystemic lupus erythematosus\n==== Body\nIntroduction\nHaemophilus influenzae is a Gram-negative bacillus classified into two types, depending on the possession of a capsule. H. influenzae with a capsule is also divided into six types (a-f) based on the capsulated strains. Of these capsular strains, type b (Hib) causes invasive infections most frequently, such as meningitis and epiglottitis, which can be fatal even in adults.\n\nThe Hib vaccine was developed to prevent critical complications due to Hib, and with its introduction, Hib infections have recently become uncommon in Western countries (1-3). However, patients infected with invasive H. influenzae due to types other than b or non-type H. influenzae (NTHi) remain relatively common (1-5). Since vaccination against Hib started in Japan in 2008, invasive H. influenzae infection by non-type b is increasing, in line with Western countries. In adults, invasive H. influenzae infection prevalently occurs in compromised hosts, such as patients receiving immunosuppressants for an autoimmune disease or those receiving chemotherapy for cancer (2,3).\n\nWe herein report an adult patient with systemic lupus erythematosus (SLE) who developed meningitis caused by H. influenzae type f (Hif), which initially infected the upper respiratory tract as acute rhinitis and then translocated to the brain as meningitis. This case can be a useful model for considering invasive non-Hib infection even in adult patients, especially those under immunosuppressive treatment.\n\nCase Report\nThe patient was a 40-year-old man who had been diagnosed with SLE at 32 years old based on pancytopenia, the presence of serum anti-nuclear antibodies, anti-DNA antibodies, and seizure disorder as a neuropsychiatric SLE (NPSLE) at the disease onset. Following the diagnosis, high-dose methylprednisolone with tacrolimus was administered as an induction therapy, after which methylprednisolone tapering was started. During the maintenance therapy with methylprednisolone (18 mg/day), the patient presented to the community clinic with symptoms he described as “runny nose”; subsequently, he was diagnosed with acute viral rhinitis. He developed a high fever and progressive disorder of consciousness 10 days following his clinic visit. He was urgently transported and admitted to the authors' university hospital.\n\nAn assessment of his social history revealed no pre-hospitalization contact with children, and he did not live or work with children. Upon admission, the patient's vital signs were as follows: temperature, 40.9℃; blood pressure, 142/98 mmHg; pulse, 130 bpm; and respiratory rate, 32 breaths/min. Oxygen saturation was 98% on room air, and his Glasgow coma scale score was E4V1M4. On a physical examination, the findings in the chest and abdomen were normal, but significant neck stiffness was noted. On a neurologic examination, the patient's eyes exhibited conjugate deviation to the right. In addition, involuntary movements on both arms were observed.\n\nThe laboratory results revealed lymphopenia and thrombocytopenia (Table 1, 2). In addition, the patient had mild renal failure based on the definition for acute renal injury (6). Because his C-reactive protein (CRP) and procalcitonin concentrations were extremely high, the development of severe systemic inflammation was initially suspected, such as sepsis or SLE complications. However, stable anti-DNA antibody concentrations indicated a low level of SLE activity.\n\nTable 1. Urine and Serum Data upon Hospital Admission.\n\nUrine\t\tBiochemistry\t\tImmunity\t\nUP (1+)\t\t\t\t\tTP\t\t6.1\tg/dL\t\tCRP\t\t19.22\tmg/dL\t\nUB (±)\t\t\t\t\tAlb\t\t3.4\tg/dL\t\tPCT\t\t3.27\tng/mL\t\nWBC\t\t<1\t/HPF\t\tAST\t\t33\tU/L\t\tIgG\t\t984\tmg/dL\t\n\t\t\t\t\tALT\t\t33\tU/L\t\tIgA\t\t129\tmg/dL\t\nCBC\t\tLDH\t\t238\tU/L\t\tIgM\t\t13\tmg/dL\t\nWBC\t\t7,100\t/µL\t\tBUN\t\t24.5\tmg/dL\t\tC3\t\t67\tmg/mL\t\nLymp\t\t490\t/µL\t\tCr\t\t1.39\tmg/dL\t\tC4\t\t16\tmg/mL\t\nHb\t\t14.3\tg/dL\t\tGlu\t\t93\tmg/dL\t\tCH50\t\t25\tU/mL\t\nPlt\t\t123,000\t/µL\t\tNa\t\t144\tmEq/L\t\tADNA\t\t6.1\tIU/mL\t\nCoagulation\t\tK\t\t4.0\tmEq/L\t\tC1q\t\t1.6\tµg/mL\t\nPT-INR\t\t1.00\t\t\tCl\t\t110\tmEq/L\t\t\t\t\t\t\nAPT\t\t25.3\ts\t\t\t\t\t\t\t\t\t\t\t\nFIB\t\t702\tmg/dL\t\t\t\t\t\t\t\t\t\t\t\nFDP\t\t4.70\tµg/mL\t\t\t\t\t\t\t\t\t\t\t\nD-dimer\t\t1.69\tµg/mL\t\t\t\t\t\t\t\t\t\t\t\nUP: urinary protein, UB: urinary blood, Lymp: lymphocytes, PLT: platelet, PT-INR: prothrombin time-international normalized ratio, APTT: activated partial thromboplastin time, FIB: fibrinogen, FDP: fibrinogen degradation products, TP: total protein, Alb: albumin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, LDH: lactate dehydrogenase, BUN: blood urea nitrogen, Cr: creatinine, Glu: glucose, CRP: C-reactive protein, PCT: procalcitonin, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM: immunoglobulin M, CH50: 50% hemolytic unit of complement, ADNA: anti-DNA antibodies, C1q: immune complex quantified by C1\n\nTable 2. Cerebrospinal Fluid CSF Data on Hospital Admission.\n\nCell\t\t385/μL\t\n\t\t(Mono 1% Poly 99%)\t\nTurbidity\t\t(+)\t\nblood\t\t(-)\t\nProtein\t\t513 mg/dL\t\nGlucose\t\t16 mg/dL\t\nIgG-IDX\t\t0.77\t\nOligoclonal band\t\t(-)\t\nMBP\t\t<31.3 pg/mL\t\nCSF: cerebrospinal fluid, IDX: index, MBP: myelin basic protein\n\nBecause meningitis was strongly suspected due to the significant neck stiffness, lumbar puncture was performed. A cerebrospinal fluid (CSF) analysis revealed polynuclear leukocyte-dominant leukocytosis and significantly low glucose CSF concentrations compared with serum. A latex agglutination test (Pastorex Meningitis; Bio-Rad Laboratories, Hercules, USA) with CSF was negative for all antigens, including Hib, Streptococcus pneumoniae, Group B Streptococcus, Neisseria meningitidis type A/C/Y/W-135, and Escherichia coli with K1 capsular polysaccharide antigen. To exclude parenchymal lesions causing disorder of consciousness due to other diseases, such as NPSLE, brain magnetic resonance imaging was performed, which revealed high intensities in the right temporal lobe on diffusion-weighted imaging and high intensities scattered over the sulcus of the cerebral hemisphere on fluid-attenuated inversion recovery, suggesting bacterial meningitis (7) (Figure).\n\nFigure. Magnetic resonance imaging findings at admission. High intensities in the right temporal lobe on DWI (circle) and high-intensity areas in the sulcus of the cerebral hemisphere on FLAIR imaging (arrow), indicating bacterial meningitis. DWI: diffusion-weighted imaging, FLAIR: fluid-attenuated inversion recovery\n\nThe patient was diagnosed with bacterial meningitis based on significant neck stiffness, high CRP level, polynuclear leukocyte-dominant leukocytosis, and low glucose concentrations in the CSF. The patient was intravenously administered meropenem 6 g/day and vancomycin 2 g/day with betamethasone 40 mg/day based on the guidelines for bacterial meningitis (8). On hospital Day 2, Gram-negative bacilli were detected in his primary smear preparation, and H. influenzae was detected from both the CSF and blood culture. The administration of betamethasone for 3 days was completed according to the guidelines, and then the administration of methylprednisolone 18 mg/day was started again as maintenance therapy for SLE. Vancomycin was discontinued on hospital Day 4, as no Gram-positive cocci were detected. On hospital Day 5, Hif was confirmed in both the CSF and blood by the latex agglutination test. The patient was diagnosed with an invasive H. influenzae infection, and accordingly, the case was reported to the Public Health Center as a Category V Infectious Disease. On hospital Day 10, elevation of serum creatinine was observed, and meropenem was changed to ceftriaxone 4 g/day, based on the susceptibility tests (Table 3).\n\nTable 3. Antimicrobial Susceptibility Testing of Haemophilus influenzae Type f.\n\nAntibiotics\t\tMIC (μg/mL)\t\tInterpretation\t\nAmpicillin\t\t>16\t\tR\t\nCefotaxime\t\t2\t\tS\t\nCeftriaxone\t\t≤1\t\tS\t\nImipenem\t\t≤0.5\t\tS\t\nMeropenem\t\t≤0.125\t\tS\t\nClarithromycin\t\t≤4\t\tS\t\nLevofloxacin\t\t≤1\t\tS\t\nMIC: minimal inhibitory concentrations, R: resistant, S: susceptible\n\nThe CSF leukocyte count decreased to 6 /μL following the 10-day administration of antibiotics. During follow-up, 25 days after hospital admission, pancytopenia was documented that was thought to have been caused by ceftriaxone. Treatment was changed to ciprofloxacin 800 mg/day, which reversed his pancytopenia. After the CSF leukocyte count dropped below the upper limit during follow-up, 32 days after admission, antibiotic therapy was halted with no subsequent disease recurrence.\n\nDiscussion\nH. influenzae type b is a significant cause of invasive bacterial infections and can occasionally cause fatal invasive infections, such as meningitis and acute epiglottitis (9). Studies have shown that Hib vaccination can reduce the rate of invasive Hib infections from about 80% to 20% in Western countries (2). Since the Hib vaccine was first introduced and has been used for more than 10 years in Western countries, non-type b H. influenzae infections are expected to be the more prevalent type of H. influenzae infections worldwide. Indeed, some evidence suggests that non-type b, NTHi, and Hif are as common as H. influenzae infections. According to recent reports, one of the most common causes of invasive infections by H. influenzae in older adults was Hif, following NTHi in Western countries (1,2,4). In Japan, routine immunization against Hib started in 2013, and the annual incidence of invasive Hib infections drastically decreased from 98.2% to 5.0% in children younger than 5 years old (10). However, the same report also demonstrated that the frequency of invasive non-type b H. influenzae infections has been increasing (10). Interestingly, the numbers of invasive infections by H. influenzae are increasing, even in older adults in Japan (11,12). This increase may be the result of decreased antibodies (13) and opsonization (14) against H. influenzae in the older adult population. In addition, the reported number of cases in Japan may have increased based on the revised Infectious Diseases Control Law in 2013, requiring the reporting of invasive H. influenzae infection. Thus, the relative increase in non-Hib infections in the pediatric population may be particularly associated with increased infections in the older adult population.\n\nThe Hib vaccine has reduced the prevalence of pediatric Hib infection (15), which may have led to a relative increase in non-Hib. In fact, invasive Hif infection is becoming the most common infection in adults among those with capsular strains (1,2,4). In the case of invasive Hif infection alone, about 75% of patients were reported to be ≥15 years old (16). The incidence of bacterial meningitis caused by Hif was also shown to be higher in adults than in children, most of whom had underlying diseases (16). In the present report, we described an adult patient with SLE who developed meningitis caused by Hif; the clinical features of our case were consistent with those in previous reports. Although the patient in this case survived, older adults and immunosuppressed patients have a higher mortality rate than healthy individuals (16,17). Other reports have also shown that older adults have a higher frequency of invasive non-Hib infections, including Hif, and higher associated mortality rates with 1.5 to 2.5 folds (1-4). These findings suggest that the physicians must consider the possibility of H. influenzae infections in all populations. Technically, the latex agglutination test of CSF can only detect Hib, not non-Hib H. influenzae. Compared with Hib infection, Hif infection is more likely to cause bacterial meningitis in adults (16), leading to a poor prognosis. In addition, not only Hif infection but also other non-Hibs infections, such as NTHi, can cause bacterial meningitis in adults (1). Therefore, if the rapid latex agglutination test is negative for H. influenzae, clinicians should still consider H. influenzae meningitis caused by non-Hib infection.\n\nPrevious reports indicated that comorbid diseases, such as chronic obstructive pulmonary disease, malignancy, and immunosuppression, are risk factors for invasive infections caused by H. influenzae (3). To compare this case with the trend in recent invasive Hif infections, the authors surveyed case reports on PubMed using the search terms “H. influenzae type f” and “adult” and used the results to build a summary table (Table 4) of case report of invasive Hif infections since 2013, when routine immunization against Hib started in Japan (18-24). In these cases, the median age was 63 years old, with some differences in sex. Many of the patients had comorbid disease. Although the patient in the present case was younger than the age distribution in Table 4, he was immunocompromised with SLE and was using immunosuppressants.\n\nTable 4. Cases of Invasive Haemophilus influenzae Type f Infections in Adults since 2013.\n\nCase\tReference\tAge\tSex\tNation\tFocus\tComorbidities\tAntibiotics\tPrognosis\t\n1\t18\t36\tF\tJPN\tmeningitis\tNone\tVCM+ABPC+CTRX\n→CTRX\tRecovered\t\n2\t19\t66\tM\tJPN\tCellulitis\tIgG4-RD\tMEPM→CTRX+ABPC\tRecovered\t\n3\t20\t73\tF\tUSA\tinfective endocarditis, \nseptic arthritis\tDM, OA\tVCM+MEPM→CTRX\tRecovered\t\n4\t21\t58\tM\tUSA\tartery aneurysm\tDM, COPD\tVCM+PIPC/TAZ→CTRX\tRecovered\t\n5\t22\t73\tF\tUSA\tseptic arthritis\tOA\tCTRX\tRecovered\t\n6\t23\t63\tF\tUSA\tNecrotizing Fasciitis\tBreast cancer\tVCM+CTRX\n→CLDM+CFPM→CTRX\tRecovered\t\n7\t24\t58\tM\tUSA\tMycotic Aortic \nAneurysm\tDM, COPD\tCTRX\tRecovered\t\nF: female, M: male, JPN: Japan, USA: The United States of America, IgG4-RD: IgG4-related disease, DM: diabetes mellitus, OA: osteoarthritis, COPD: chronic obstructive pulmonary disease, VCM: vancomycin, ABPC: ampicillin, CTRX: ceftriaxone, MEPM: meropenem, PIPC/TAZ: piperacillin/tazobactam, CFPM: cefpirome, CLDM: clindamycin\n\nAs presented in Table 4, invasive Hif can cause a variety of types of organ damage in infected patients. Because older adults can have comorbidities similar to those noted previously, the risk of non-Hib infection in adults is expected to increase in Japan. Although 60-70% of adult cases of invasive non-Hib infections presented with pneumonia (1-4,17), the absence of pneumonia cannot be used to rule out non-Hib infections. The patient in the present case had multiple risk factors for infection, including immunosuppressant use with corticosteroids and lymphopenia (25-27). In addition, patients with SLE have immunologic abnormalities in the complement system, which is associated with decreased protection against capsulated bacteria, including H. influenzae (28). The acquisition of Hif infection in the present case may have been associated with the widespread use of the Hib vaccine in Japan. In addition, the presence of multiple risk factors for immunocompromise likely led to the development of meningitis in our patient.\n\nConclusion\nAlthough Hib vaccination is currently widespread in Japan, physicians should still consider the diagnosis of non-Hib infection, especially in an immunocompromised host with multiple comorbidities. The incidence of invasive non-Hib infections is expected to increase in Japan (12), so clinicians should take care not to miss cases of non-Hib infections, given the associated high mortality rate in immunocompromised patients.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Whittaker R , Economopoulou A , Dias JG , et al \nEpidemiology of Invasive Haemophilus influenzae Disease, Europe, 2007-2014\n. Emerg Infect Dis \n23 : 396 -404\n, 2017 .28220749 \n2. Urwin G , Krohn JA , Robinson KD , et al \nInvasive disease due to Haemophilus influenzae serotype f: clinical and epidemiologic characteristics in the H. influenzae serotype b vaccine era\n. Clin infect Dis \n22 : 1069 -1076\n, 1996 .8783712 \n3. Ladhani SN , Collions S , Vickers A , et al \nInvasive Haemophilus influenzae serotype e and f disease, England and Wales\n. Emerg Infect Dis \n18 : 725 -732\n, 2012 .22515912 \n4. Desai S , Jamieson FB , Patel SN , et al \nThe Epidemiology of invasive Haemophilus influenzae non-serotype B disease in Ontario, Canada from 2004 to 2013\n. PLoS One \n10 : e0142179 , 2015 .26569613 \n5. Polkowska A , Toropainen M , Ollgren J , Lyytikäinen O , Nuorti JP \nBacterial meningitis in Finland, 1995-2014: a population-based observational study\n. BMJ Open \n7 : e015080 , 2017 .\n6. Doi K , Nishida O , Shigematsu T , et al \nThe Japanese clinical practice guideline for acute kidney injury 2016\n. Clin Exp Nephrol \n22 : 985 -1045\n, 2018 .30039479 \n7. Castillo M \nImaging of meningitis\n. Semin Roentgenol \n39 : 458 -464\n, 2004 .15526529 \n8. \nSocietas Neurologica Japonica , Japanese Society of Neurological Therapeutics , Japanese Society for Neuroinfectious Disease . Practical Guideline for Bacterial Meningitis\n. 2014 (in Japanese).\n9. Peltola H \nWorldwide Haemophilus influenzae type b disease at the beginning of the 21st century: global analysis of the disease burden 25 years after the use of the polysaccharide vaccine and a decade after the advent of conjugates\n. Clin Microbiol Rev \n13 : 302 -317\n, 2000 .10756001 \n10. Suga S , Ishiwada N , Sasaki Y , et al \nA nationwide population-based surveillance of invasive Haemophilus influenzae diseases in children after the introduction of the Haemophilus influenzae type b vaccine in Japan\n. Vaccine \n36 : 5678 -5684\n, 2018 .30122645 \n11. National Institute of Infectious Diseases, Japan Notification of Invasive Haemophilus influenzae Infections Based on the Infectious Diseases Act, 2013-2018 [Internet]. Available from: \nhttps://www.niid.go.jp/niid/ja/ihd-m/ihd-idwrs/8609-ihd-20190221.html (in Japanese).\n12. Ishioka T , Oishi K \n[The clinical characteristics of invasive Haemophilus influenzae infection in adults]\n. IASR \n35 : 232 -233\n, 2014 (in Japanese).\n13. Hawdon N , Biman B , McCready W , et al \nAntibody against Haemophilus influenzae protein D in patients with chronic conditions causing secondary immunodeficiency\n. Vaccine \n30 : 1235 -1238\n, 2012 .22230580 \n14. Garbett ND , Matharu GS , Cole PJ \nDefective opsonization of Haemophilus influenzae by sera of elderly patients\n. Clin Exp Immunol \n76 : 73 -75\n, 1989 .2786781 \n15. Mohle-Boetani JC , Ajello G , Breneman E , et al \nCarriage of Haemophilus influenzae type b in children after widespread vaccination with conjugate Haemophilus influenzae type b vaccines\n. Pediatr Infect Dis J \n12 : 589 -593\n, 1993 .8346003 \n16. Campos J , Román F , Pérez-Vázquez M , et al \nAntibiotic resistance and clinical significance of Haemophilus influenzae type f\n. J Antimicrob Chemother \n52 : 961 -966\n, 2003 .14613949 \n17. Resman F , Ristovski M , Ahl J , et al \nInvasive disease caused by Haemophilus influenzae in Sweden 1997-2009; evidence of increasing incidence and clinical burden of non-type b strains\n. Clin Microbiol Infect \n17 : 1638 -1645\n, 2011 .21054663 \n18. Sakamoto S , Sakamoto N \nBacterial meningitis caused by β-lactamase non-producing ampicillin-resistant Haemophilus influenzae type f in an immunocompetent woman\n. Intern Med \n58 : 307 -310\n, 2019 .30146561 \n19. Ussui Y , Kakuta R , Araki M , et al \nAdult-onset invasive Haemophilus influenzae type f caused by acute lower leg cellulitis\n. Intern Med \n55 : 1811 -1813\n, 2016 .27374690 \n20. Oikonomou K , Alhaddad B , Kelly K , Rajmane R , Apergis G \nHaemophilus influenzae serotype f endocarditis and septic arthritis\n. IDCases \n9 : 79 -81\n, 2017 .28725560 \n21. Suarez CJ , Glover WA , Cowan J , Smith A , Clarridge JE \nMycotic aneurysm of the abdominal aorta caused by Haemophilus influenzae type f\n. J Med Microbiol \n62 : 658 -660\n, 2013 .23355310 \n22. Ungprasert P , Prasidthrathsint K , Permpalung N , Srivali N , Kaewpoowat Q \nHaemophilus influenzae serotype f as a rare cause of septic arthritis\n. Am J Emerg Med \n31 : 1156.e5 -1156.e6\n, 2013 .\n23. Arnold CJ , Garrigues G , St Geme JW , Sexton DJ \nNecrotizing fasciitis caused by Haemophilus influenzae serotype f\n. J Clin Microbiol \n52 : 3471 -3474\n, 2014 .24989609 \n24. Wheeler HK , Quiroga E , Kohler TR , Tang GL \nMycotic aortic aneurysm caused by Haemophilus influenzae group f\n. Ann Vasc Surg \n27 : 353.e13 -353.e16\n, 2013 .\n25. Iñigo Rúa-Figueroa , Francisco J , López-Longo J , et al \nBacteremia in systemic lupus erythematosus in patients from a Spanish registry: risk factors, clinical and microbiological characteristics, and outcomes\n. J Rheumatol \n46 : 10.3899 , 2019 .\n26. Baizabal-Carvallo JF , Delgadillo-Márquez G , Estañol B , García-Ramos G \nClinical characteristics and outcomes of the meningitides in systemic lupus erythematosus\n. Eur Neurol \n61 : 143 -148\n, 2009 .19092250 \n27. Ng WL , Chu CM , Wu AK , Cheng VC , Yuen KY \nLymphopenia at presentation is associated with increased risk of infections in patients with systemic lupus erythematosus\n. QJM \n99 : 37 -47\n, 2006 .16371405 \n28. Wallace DJ , Hahn BH \nSLE and Infections\n. In: DUBOIS' Lupus Erythematosus and Related Syndrome . 8 ed. \nELSEVIER , Frisco , 2012 : 555 -562\n.\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "59(23)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Haemophilus influenzae type f; Hib vaccination; bacterial meningitis; systemic lupus erythematosus",
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D006192:Haemophilus Infections; D019741:Haemophilus influenzae type b; D006801:Humans; D007564:Japan; D008180:Lupus Erythematosus, Systemic; D008297:Male",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "3097-3101",
"pmc": null,
"pmid": "32759581",
"pubdate": "2020-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8783712;15526529;14613949;26569613;8346003;30122645;28725560;27374690;21054663;22230580;16371405;24989609;23688572;23498319;2786781;28592578;28220749;30146561;30039479;22515912;10756001;23355310;19092250",
"title": "Haemophilus influenzae Non-type b Infection in an Adult Patient with Systemic Lupus Erythematosus.",
"title_normalized": "haemophilus influenzae non type b infection in an adult patient with systemic lupus erythematosus"
} | [
{
"companynumb": "JP-PFIZER INC-2020509380",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "We report the case of a patient who died from the rare complication of Listeriosis in the immediate phase following alemtuzumab administration one month after discontinuing dimethyl fumarate (DMF). There is considerable overlap with typical post-infusion symptoms therefore high surveillance and low threshold for empirical or possible prophylactic antibiotic therapy is advocated.",
"affiliations": "Bristol Brain Centre, Department of Neurosciences, North Bristol NHS Trust, Southmead Road, Westbury-On-Trym, BS10 5NB Bristol, United Kingdom. Electronic address: luke.canham@nbt.nhs.uk.;Bristol Brain Centre, Department of Neurosciences, North Bristol NHS Trust, Southmead Road, Westbury-On-Trym, BS10 5NB Bristol, United Kingdom. Electronic address: alex.manara@nbt.nhs.uk.;Bristol Brain Centre, Department of Neurosciences, North Bristol NHS Trust, Southmead Road, Westbury-On-Trym, BS10 5NB Bristol, United Kingdom. Electronic address: joanna.fawcett@nbt.nhs.uk.;Bristol Brain Centre, Department of Neurosciences, North Bristol NHS Trust, Southmead Road, Westbury-On-Trym, BS10 5NB Bristol, United Kingdom. Electronic address: michal.rolinski@nbt.nhs.uk.;Bristol Brain Centre, Department of Neurosciences, North Bristol NHS Trust, Southmead Road, Westbury-On-Trym, BS10 5NB Bristol, United Kingdom. Electronic address: alex.mortimer@nbt.nhs.uk.;Bristol Brain Centre, Department of Neurosciences, North Bristol NHS Trust, Southmead Road, Westbury-On-Trym, BS10 5NB Bristol, United Kingdom. Electronic address: kirsty.inglis@nbt.nhs.uk.;Bristol Brain Centre, Department of Neurosciences, North Bristol NHS Trust, Southmead Road, Westbury-On-Trym, BS10 5NB Bristol, United Kingdom. Electronic address: david.cottrell@nbt.nhs.uk.",
"authors": "Canham|L J W|LJW|;Manara|A|A|;Fawcett|J|J|;Rolinski|M|M|;Mortimer|A|A|;Inglis|K E A|KEA|;Cottrell|D A|DA|",
"chemical_list": "D007155:Immunologic Factors; D000074323:Alemtuzumab",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.msard.2018.05.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-0348",
"issue": "24()",
"journal": "Multiple sclerosis and related disorders",
"keywords": null,
"medline_ta": "Mult Scler Relat Disord",
"mesh_terms": "D000328:Adult; D000074323:Alemtuzumab; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D008089:Listeria monocytogenes; D008297:Male; D008584:Meningitis, Listeria; D008590:Meningoencephalitis; D020529:Multiple Sclerosis, Relapsing-Remitting",
"nlm_unique_id": "101580247",
"other_id": null,
"pages": "38-41",
"pmc": null,
"pmid": "29885597",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mortality from Listeria monocytogenes meningoencephalitis following escalation to alemtuzumab therapy for relapsing-remitting Multiple Sclerosis.",
"title_normalized": "mortality from listeria monocytogenes meningoencephalitis following escalation to alemtuzumab therapy for relapsing remitting multiple sclerosis"
} | [
{
"companynumb": "GB-PFIZER INC-2019204134",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ALEMTUZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nSodium-glucose cotransporter 2 inhibitors (SGLT2i) (such as canagliflozin, empagliflozin, and dapagliflozin) are widely used to treat patients with type 2 diabetes mellitus (T2DM) to improve glycemic, cardiovascular and renal outcomes. However, based on post-marketing data, a warning label was added regarding possible occurrence of acute kidney injury (AKI).\n\n\nOBJECTIVE\nTo describe the clinical presentation of T2DM patients treated with SGLT2i who were evaluated for AKI at our institution and to discuss the potential pathophysiologic mechanisms.\n\n\nMETHODS\nA retrospective study of a computerized database was conducted of patients with T2DM who were hospitalized or evaluated for AKI while receiving SGLT2i, including descriptions of clinical and laboratory characteristics, at our institution.\n\n\nRESULTS\nWe identified seven patients in whom AKI occurred 7-365 days after initiation of SGLT2i. In all cases, renin-angiotensin-aldosterone system blockers had also been prescribed. In five patients, another concomitant nephrotoxic agent (injection of contrast-product, use of nonsteroidal anti-inflammatory drugs or cox-2 inhibitors) or occurrence of an acute medical event potentially associated with AKI (diarrhea, sepsis) was identified. In two patients, only the initiation of SGLT2i was evident. The mechanisms by which AKI occurs under SGLT2i are discussed with regard to the associated potential triggers: altered trans-glomerular filtration or, alternatively, kidney medullary hypoxia.\n\n\nCONCLUSIONS\nSGLT2i are usually safe and provide multiple benefits for patients with T2DM. However, during particular medical circumstances, and in association with usual co-medications, particularly if baseline glomerular filtration rate is decreased, patients treated with SGLT2i may be at risk of AKI, thus warranting caution when prescribed.",
"affiliations": "Department of Medicine, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem, Israel.;Department of Medicine, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem, Israel.;Department of Medicine, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem, Israel.;Department of Medicine, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem, Israel.;Department of Medicine, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem, Israel.;Department of Medicine, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem, Israel.",
"authors": "Perlman|Amichai|A|;Heyman|Samuel N|SN|;Stokar|Joshua|J|;Darmon|David|D|;Muszkat|Mordechai|M|;Szalat|Auryan|A|",
"chemical_list": "D007004:Hypoglycemic Agents; D000077203:Sodium-Glucose Transporter 2 Inhibitors",
"country": "Israel",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "20(8)",
"journal": "The Israel Medical Association journal : IMAJ",
"keywords": null,
"medline_ta": "Isr Med Assoc J",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D003924:Diabetes Mellitus, Type 2; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D007668:Kidney; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D000077203:Sodium-Glucose Transporter 2 Inhibitors",
"nlm_unique_id": "100930740",
"other_id": null,
"pages": "513-516",
"pmc": null,
"pmid": "30084579",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical Spectrum and Mechanism of Acute Kidney Injury in Patients with Diabetes Mellitus on SGLT-2 Inhibitors.",
"title_normalized": "clinical spectrum and mechanism of acute kidney injury in patients with diabetes mellitus on sglt 2 inhibitors"
} | [
{
"companynumb": "IL-TEVA-2018-IL-980108",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DAPAGLIFLOZIN"
},
"drugadditional": "1",
... |
{
"abstract": "Diabetic ketoacidosis (DKA) accounts for up to a third of all new presentations of Type 1 Diabetes Mellitus (T1DM) in children and adolescents. While most cases are relatively uncomplicated new onset presentations, if DKA is compounded with an additional underlying severe illness, such as appendicitis or severe infection, diagnostic delays may be experienced, and treatment response and outcomes may be compromised. We report an atypical case of new onset diabetes with severe DKA and underlying severe sepsis, which responded poorly to traditional therapy resulting in maximal intensive care management including mechanical ventilation, inotropes, extracorporeal membrane oxygenation (ECMO) for cardiorespiratory support, and kidney replacement therapy.",
"affiliations": "Department of Women's and Children's Health, Otago Medical School - Dunedin Campus, University of Otago, PO Box 56, Dunedin, 9054 New Zealand.;Department of Women's and Children's Health, Otago Medical School - Dunedin Campus, University of Otago, PO Box 56, Dunedin, 9054 New Zealand.;Department of Medicine, Otago Medical School - Dunedin Campus, University of Otago, Dunedin, New Zealand.;Department of Medicine, Southern District Health Board, Invercargill, New Zealand.;Department of Women's and Children's Health, Otago Medical School - Dunedin Campus, University of Otago, PO Box 56, Dunedin, 9054 New Zealand.",
"authors": "Asarani|Nurul Aliah Mohd|NAM|;Paddison|Justine|J|;Walker|Robert|R|;Downie|Michelle|M|;Wheeler|Benjamin J|BJ|0000-0003-3348-5238",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s40200-021-00736-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2251-6581",
"issue": "20(1)",
"journal": "Journal of diabetes and metabolic disorders",
"keywords": "Acute renal injury; Extracorporeal membrane oxygenation; Ketoacidosis diabetic; Kidney replacement therapy; Severe sepsis; Type 1 diabetes",
"medline_ta": "J Diabetes Metab Disord",
"mesh_terms": null,
"nlm_unique_id": "101590741",
"other_id": null,
"pages": "1075-1079",
"pmc": null,
"pmid": "34178873",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
"references": "24685959;30559241;20453704;25442866;19564476;28098591;31939787;19754623;5409813;31622273;6346304",
"title": "New-onset type 1 diabetes complicated by diabetic ketoacidosis and severe sepsis requiring extracorporeal membrane oxygenation and kidney replacement therapy.",
"title_normalized": "new onset type 1 diabetes complicated by diabetic ketoacidosis and severe sepsis requiring extracorporeal membrane oxygenation and kidney replacement therapy"
} | [
{
"companynumb": "NZ-B.BRAUN MEDICAL INC.-2117778",
"fulfillexpeditecriteria": "1",
"occurcountry": "NZ",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": ... |
{
"abstract": "A 48-year-old woman with Parkinson disease (PD) suffered from auditory hallucinations (AH). We had treated her with a reduction in antiparkinsonian agents and the use of atypical antipsychotic agents. However, her symptoms did not improve, and her extrapyramidal symptoms (EPS) worsened. To lessen her depressive symptoms, treatment with a new-generation antidepressant, mirtazapine (MRZ), was commenced. The patient's AH gradually decreased with no worsening of EPS, and the AH disappeared 4 weeks after the commencement of treatment with MRZ. The present case suggests the effectiveness of MRZ for the treatment of refractory AHs in patients with PD.",
"affiliations": "Department of Psychiatry, Jikei University School of Medicine, Tokyo, Japan. t.nagata@jikei.ac.jp",
"authors": "Nagata|Tomoyuki|T|;Shinagawa|Shunichiro|S|;Tagai|Kenji|K|;Nakayama|Kazuhiko|K|",
"chemical_list": "D000929:Antidepressive Agents, Tricyclic; D008803:Mianserin; D000078785:Mirtazapine",
"country": "England",
"delete": false,
"doi": "10.1017/S1041610212002037",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1041-6102",
"issue": "25(7)",
"journal": "International psychogeriatrics",
"keywords": null,
"medline_ta": "Int Psychogeriatr",
"mesh_terms": "D000929:Antidepressive Agents, Tricyclic; D001480:Basal Ganglia Diseases; D003866:Depressive Disorder; D005260:Female; D006212:Hallucinations; D006801:Humans; D008803:Mianserin; D008875:Middle Aged; D000078785:Mirtazapine; D010300:Parkinson Disease; D016896:Treatment Outcome",
"nlm_unique_id": "9007918",
"other_id": null,
"pages": "1199-201",
"pmc": null,
"pmid": "23195073",
"pubdate": "2013-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case in which mirtazapine reduced auditory hallucinations in a patient with Parkinson disease.",
"title_normalized": "a case in which mirtazapine reduced auditory hallucinations in a patient with parkinson disease"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2014-RO-01572RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "QUETIAPINE FUMARATE"
},
... |
{
"abstract": "OBJECTIVE\nRecently, many cases of vitamin K-dependent coagulopathy of unknown origin have been reported. Such patients lack any relevant family history and have no systemic disease, raising suspicion of superwarfarin intoxication. We evaluated individual risk factors causing coagulopathy and hemorrhagic symptoms in patients with suspected superwarfarin intoxication. In addition, we determined how to effectively treat vitamin K-dependent coagulopathy caused by suspected superwarfarin intoxication.\n\n\nMETHODS\nSeven patients with suspected superwarfarin intoxication who lacked any definitive history of rodenticide ingestion were included. Thirty-one patients initially diagnosed with rodenticide poisoning were also included. We performed a retrospective chart review of all subjects and examined clinical data including patient demographics and medical histories.\n\n\nRESULTS\nPatients initially diagnosed with rodenticide poisoning were divided into two groups, one of which had a laboratory abnormality (prothrombin time [PT] > 13 seconds) and another group with PTs in the normal range. There was no significant difference between the two groups in any of age, gender, the extent of chronic alcohol consumption, the causative rodenticide, psychiatric problems, ingestion of drugs interacting with warfarin, the extent of intoxication, or the type of ingestion attempt. The albumin level of the former group was significantly lower than that of the latter group (p = 0.014). Furthermore, a significant difference between the two groups was evident in terms of simultaneous ingestion of rodenticide and alcohol (p = 0.023).\n\n\nCONCLUSIONS\nMost patients with superwarfarin poisoning did not exhibit any complication. When such complications were evident, they were associated with serum albumin level and coingestion of rodenticide and alcohol.",
"affiliations": "Division of Hematology and Oncology, Department of Internal Medicine, Chosun University Hospital, Gwangju, Korea.;Division of Hematology and Oncology, Department of Internal Medicine, Chosun University Hospital, Gwangju, Korea.;Division of Hematology and Oncology, Department of Internal Medicine, Chosun University Hospital, Gwangju, Korea.;Division of Hematology and Oncology, Department of Internal Medicine, Chosun University Hospital, Gwangju, Korea.;Division of Hematology and Oncology, Department of Internal Medicine, Chosun University Hospital, Gwangju, Korea.;Division of Hematology and Oncology, Department of Internal Medicine, Chosun University Hospital, Gwangju, Korea.;Division of Hematology and Oncology, Department of Internal Medicine, Chosun University Hospital, Gwangju, Korea.",
"authors": "Lee|Hee-Jeong|HJ|;You|Mi-Ra|MR|;Moon|Woo-Ram|WR|;Sul|Hyoung|H|;Chung|Choon-Hae|CH|;Park|Chi-Young|CY|;Park|Sang-Gon|SG|",
"chemical_list": "D015110:4-Hydroxycoumarins; C422455:ALB protein, human; D000925:Anticoagulants; D012378:Rodenticides; D012709:Serum Albumin; D014812:Vitamin K; C013418:bromfenacoum; D000075462:Serum Albumin, Human",
"country": "Korea (South)",
"delete": false,
"doi": "10.3904/kjim.2014.29.4.498",
"fulltext": "\n==== Front\nKorean J Intern MedKorean J. Intern. MedKJIMThe Korean Journal of Internal Medicine1226-33032005-6648The Korean Association of Internal Medicine 10.3904/kjim.2014.29.4.498Original ArticleEvaluation of risk factors in patients with vitamin K-dependent coagulopathy presumed to be caused by exposure to brodifacoum Lee Hee-Jeong You Mi-Ra Moon Woo-Ram Sul Hyoung Chung Choon-Hae Park Chi-Young Park Sang-Gon Division of Hematology and Oncology, Department of Internal Medicine, Chosun University Hospital, Gwangju, Korea.\nCorrespondence to Sang-Gon Park, M.D. Division of Hematology and Oncology, Department of Internal Medicine, Chosun University Hospital, 365 Pilmun-daero, Dong-gu, Gwangju 501-717, Korea. Tel: +82-62-220-3984, Fax: +82-62-234-9653, psk1779@lycos.co.kr7 2014 27 6 2014 29 4 498 508 14 5 2013 22 7 2013 04 10 2013 Copyright © 2014 The Korean Association of Internal Medicine2014This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background/Aims\nRecently, many cases of vitamin K-dependent coagulopathy of unknown origin have been reported. Such patients lack any relevant family history and have no systemic disease, raising suspicion of superwarfarin intoxication. We evaluated individual risk factors causing coagulopathy and hemorrhagic symptoms in patients with suspected superwarfarin intoxication. In addition, we determined how to effectively treat vitamin K-dependent coagulopathy caused by suspected superwarfarin intoxication.\n\nMethods\nSeven patients with suspected superwarfarin intoxication who lacked any definitive history of rodenticide ingestion were included. Thirty-one patients initially diagnosed with rodenticide poisoning were also included. We performed a retrospective chart review of all subjects and examined clinical data including patient demographics and medical histories.\n\nResults\nPatients initially diagnosed with rodenticide poisoning were divided into two groups, one of which had a laboratory abnormality (prothrombin time [PT] > 13 seconds) and another group with PTs in the normal range. There was no significant difference between the two groups in any of age, gender, the extent of chronic alcohol consumption, the causative rodenticide, psychiatric problems, ingestion of drugs interacting with warfarin, the extent of intoxication, or the type of ingestion attempt. The albumin level of the former group was significantly lower than that of the latter group (p = 0.014). Furthermore, a significant difference between the two groups was evident in terms of simultaneous ingestion of rodenticide and alcohol (p = 0.023).\n\nConclusions\nMost patients with superwarfarin poisoning did not exhibit any complication. When such complications were evident, they were associated with serum albumin level and coingestion of rodenticide and alcohol.\n\nVitamin K deficiency bleedingBrodifacoumPoisoningChosun University Hospital\n==== Body\nINTRODUCTION\nRecently, many cases of vitamin K-dependent coagulopathy of unknown origin have been reported. Relevant family history is lacking and systemic disease absent [1,2]. Such cases are suggestive of superwarfarin intoxication. However, most patients have no definitive history of rodenticide poisoning. Many case reports suggest that patients manifested Munchausen syndrome, or had developed rodenticide intoxication via a nonoral route, such as inhalation or absorption through the skin [1,3,4]. However, such theories do not explain individual variations in the symptoms of, or coagulopathies among, the various cases, and no report has yet addressed individual risk factors for superwarfarin intoxication.\n\nIn the present study, we sought to evaluate individual risk factors causing coagulopathy and hemorrhagic symptoms in patients suspected of superwarfarin intoxication. In addition, in the absence of any consensus, we sought to describe an effective treatment for vitamin K-dependent coagulopathy in patients lacking evidence of definitive rodenticide poisoning who presented to a single center.\n\nMETHODS\nSubjects\nBetween October 2009 and April 2012, we treated seven patients with suspected superwarfarin intoxication who lacked definitive histories of rodenticide ingestion. All were admitted to our hospital with complaints of various hemorrhagic events and were diagnosed with vitamin K-dependent coagulopathies after measurement of coagulation factor levels. Six were evaluated in terms of serum brodifacoum levels, which confirmed superwarfarin intoxication despite the lack of any definitive history of such intoxication.\n\nIn addition, 31 patients were diagnosed with rodenticide poisoning in Chosun University Hospital from January 2006 to March 2013. All had definitive clinical histories of ingestion of superwarfarin-type rodenticides. We analyzed the incidence of coagulopathy in these patients, and evaluated associated factor(s), via statistical analysis.\n\nMethods\nWe performed a retrospective chart review of all seven subjects mentioned above, and examined clinical data, patient information, and medical histories; comparing these with those of the 31 patients with definitive rodenticide intoxication.\n\nDiagnosis of brodifacoum intoxication was confirmed by high-performance liquid chromatography (HPLC) featuring brodifacoum detection via ultraviolet light absorption. We also noted comedications (principally warfarin-interacting drugs), alcohol consumption habits, histories of psychiatric illness and consultation, and the presence of genetic factors (the cytochrome P450 2C9 [CYP2C9] and the vitamin K epoxide reductase complex subunit 1 [VKORC1] alleles), to detect risk factors.\n\nStatistical analysis\nA probability p value < 0.05 was considered to indicate a significant difference. All statistical analyses were performed using SPSS version 21.0 (IBM Co., Armonk, NY, USA). Differences between continuous variables were analyzed using Student t test and those between categorical variables employing the chi-square test.\n\nRESULTS\nBaseline characteristics of patients with definitive rodenticide intoxication\nWe studied a total of 31 patients (19 males and 12 females) of median age 48 years (range, 2 to 88). The poisoning agents were brodifacoum (n = 21), flocumafen (n = 5), bromodiolone (n = 2), coumatetralyl (n = 1), and unknown (n = 2). Thirteen patients had psychiatric conditions including depressive disorders (n = 5), intellectual disabilities (n = 5), a cognitive impairment (n = 1), an adjustment disorder (n = 1), or another condition (n = 1). Eleven patients (35.5%) had histories of ingestion of agents that probably interact with warfarin, including antidepressants (selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants [TCAs]; n = 6); nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 3); antiplatelet agents (n = 3); and antacids (cimetidine, ranitidine; n = 2). Two patients abused herbal treatment(s). No patient had a history of hepatitis or liver cirrhosis. Ten patients were accidentally exposed to rodenticide, whereas 21 ingested rodenticide to attempt suicide.\n\nThe mean amount of ingested rodenticide was 0.79 mg (range, 0.2 to 2), with one tablet containing 0.2 mg. However, those who ingested over 10 tablets could not accurately report how much rodenticide they had ingested, because of their psychological conditions. Notably, rodenticide and alcohol were simultaneously ingested by 11 patients (35.5%).\n\nOnly one patient (3.2%) had hemorrhagic symptoms (hematuria and hematoma). However, 11 of the 31 patients (35.5%) had a laboratory abnormality (prothrombin time [PT] > 13 seconds) attributable to rodenticide intoxication. Laboratory data (international normality ratio > 1.5) revealed that only four patients had coagulopathies (12.9%). Upon chart review, the basal PT (pre-ingestion or post-follow-up) in all cases of rodenticide intoxication was within the normal range (under 13 seconds). PT prolongation (to over 13 seconds) may be caused by such intoxication.\n\nTherefore, to evaluate individual risk factors causing coagulopathy, patients were divided into two groups: those with a laboratory abnormality (PT > 13 seconds), and the others.\n\nThe general characteristics of the 31 study subjects, all of whom had acute rodenticide poisoning symptoms at presentation, are summarized in Table 1.\n\nComparison of clinical characteristics between the two groups\nThere was no significant difference between the two groups in terms of age, gender, the extent of chronic alcohol consumption, the rodenticide agent present, psychiatric problems, the taking of warfarin-interacting drugs, the extent of intoxication, or the type of poisoning. However, in the PT > 13 seconds group, the albumin level (4.06 g/dL) was significantly lower than that of the other group (4.53 g/dL; p = 0.014). Furthermore, a significant between-group difference was evident in terms of simultaneous rodenticide ingestion and alcohol consumption (p = 0.023). This may be a significant risk factor for coagulopathy and development of hemorrhagic symptoms in patients suspected of superwarfarin intoxication.\n\nIn summary, the two groups differed significantly in serum albumin level and a history of rodenticide ingestion with alcohol (Table 2).\n\nBaseline characteristics of patients suspected of superwarfarin intoxication but lacking definitive histories of rodenticide ingestion\nAll seven patients were admitted to our hospital with various hemorrhagic symptoms and were diagnosed with vitamin K-dependent coagulopathies based on evaluation of the levels of coagulation factors. The seven patients (four males and three females) ranged from 38 to 81 years of age, with a median age of 64 years. The principal hemorrhagic events were bleeding gums (four patients), epistaxis (three patients), hematuria (one patient), hematoma formation (one patient), and hematochezia (one patient). All patients had prolonged PTs and activated partial thromboplastin times (aPTTs). The plasma-mixing test was performed for all patients and the activities of coagulation factors measured. All patients were similar; the PTs and aPTTs were abnormal and the levels of factors II, VII, IX, and X reduced. Serum brodifacoum tests were run on six of the seven patients (all except patient 1), and the results were positive. Two patients (patients 1 and 7) lived in the city and the others in nonurban areas. Three patients (patients 2, 4, and 5) were farmers; two were housekeepers (patients 3 and 7); one was a salesman (patient 1); and one was a demolition worker (patient 6). However, the two housekeepers also worked on farms on a daily basis (patients 3 and 7). No patient had a history of hepatitis or liver cirrhosis. One patient had schizophrenia, but none had Munchausen syndrome based on a review of psychiatric history and consultations (however, patient 1 was not assessed). One patient had well-controlled depression that developed after a cerebral stroke (patient 2: treated with a TCA, valproic acid, ranitidine, and aspirin); one well-controlled schizophrenia (patient 3: treated with a SSRI); one severe asthma (patient 4: treated with oral and inhaled steroid); and one Parkinson disease (patient 5: treated with an SSRI).\n\nThree patients (patients 1, 2, and 3) had taken various herbal medications of unknown origin. In particular, patient 3 experienced two episodes of coagulopathy after taking the same herbal preparation, suggesting that the medication may have contained warfarin or a warf arin-interacting component. However, we were unable to obtain a sample of the material to explore this suggestion further. Three patients (patients 1, 4, and 6) were chronic heavy drinkers, especially patient 6, who had been diagnosed with chronic alcoholic hepatitis.\n\nFour patients were subjected to CYP2C9 and VKORC1 1173C/T genotyping, but all were wild-type at the CYP2C9 locus. Interestingly, two patients had the VKORC1 1173C/T allele (which is well-known to reduce warfarin activity), but no patient had the CYP2C9*2, CYP2C9*3, or VKORC1 1639 G/A allele, which are well known to enhance warfarin activity and trigger hemorrhagic complications.\n\nFinally, environmental exposure was a possible cause of intoxication in five patients who were full-time (patients 2, 4, and 5) or part-time farmers (patients 3 and 7). The poison may have been absorbed through the skin. Patient 7, who was a demolition worker, may have been exposed to various superwarfarins via inhalation. Environmental exposure and herbal medication were other possible sources of exposure to superwarfarins. Chronic alcohol ingestion, the taking of various drugs interacting with warfarin, and the use of herbal medications, may have induced coagulopathies.\n\nAll patients were initially given fresh frozen plasma (FFP), followed by various (high) intravenous doses of vitamin K (10 to 40 mg). Two patients (patients 1 and 6) were transferred to another hospital and became lost to follow-up. Treatment of the other patients (except for patient 7) was later changed to oral vitamin K. Patient 7 was given intravenous vitamin K until discontinuation of vitamin therapy because the oral route was difficult to access. Total treatment duration varied but, for most patients, was over 6 months.\n\nInformation on patients' characteristics, symptoms, and treatments is summarized in Tables 3 and 4.\n\nDISCUSSION\nRodenticides are a heterogeneous group of compounds, the toxicities of which differ markedly in humans and rodents. Many rodenticides have been used throughout history. Before the mid-20th century, heavy metals (arsenic, thallium) were most frequently employed. Since that time, second-generation anticoagulant rodenticides including brodifacoum, diffnacoum, bromdialone, counatetralyl, and the latest (Food and Drug Administration-approved) agent flocumafen, have been the mainstays of rodenticide products. These agents are long-acting warfarin derivatives termed superwarfarins, are tasteless and colorless, are used as poisons, and are still marketed as pesticides to kill rats and mice [1,2,5,6].\n\nSuperwarfarins are popular and readily available, but may cause intoxication upon overexposure, triggering coagulopathy, or abnormal bleeding. This is an important public health problem. Most ingestions are accidental, and many patients are children. However, attempted suicide, ingestion associated with psychiatric disorders, and deliberate self-poisoning with denial (Munchausen syndrome), have been reported [7,8,9]. Superwarfarin intoxication via the oral route is well known, but it remains unclear how warfarin enters the sera of patients without any history of oral ingestion. However, some cases of poisoning caused by inhalation or direct skin contact have been reported [3,4].\n\nSuperwarfarin-type rodenticides act like warfarin, reducing γ-carboxylation of vitamin K-dependent clotting factors by inhibiting vitamin K 2, 3-epoxide reductase. Such inhibition triggers coagulopathy manifesting as increases in the PT and aPTT, and reductions in the levels of vitamin K-dependent clotting factors (factor II, VII, IX, and X; protein C; protein S; and antithrombin III). Most superwarfarin-type rodenticides have a considerably longer half-life than warfarin (at least 16 to 69 days), are 100-fold more potent, and have a more rapid onset of action, because phenyl groups replace the terminal methyl group in the warfarin structure. The increased efficacy of superwarfarins as rodenticides is attributable to high-level lipid solubility, a high affinity for hepatic tissue, and extremely slow elimination from the body [10,11,12].\n\nThe most common clinical feature of superwarfarin intoxication is bleeding from any mucosal site or organ. Epistaxis and gingival bleeding, gastrointestinal and pulmonary hemorrhage, hematoma, and/or hematuria, may be evident [13].\n\nIn a patient with a definitive history of superwarfarin ingestion, PT and aPTT are the optimal screening tests. However, in those presenting with a vitamin K-dependent coagulation factor deficiency of unknown cause, diagnosis of superwarfarin-induced coagulopathy can be difficult. A definitive diagnosis requires a blood test featuring the use of HPLC. This accurately measures superwarfarin levels, but the technology is not yet widely available. However, if superwarfarin intoxication is suspected, and the test is not readily available, high-dose vitamin K may be administered empirically [14,15].\n\nMost patients presenting with superwarfarin exposure or poisoning do not exhibit or develop major complications. The 2009 Annual Report of the American Association of Poison Control Centers' National Poison Data System stated that 11,091 instances of long-acting anticoagulant rodenticide exposure had been reported to United State Poison Control Centers in that year. However, the outcomes were generally benign. One death, and 36 and 12 instances of moderate and major clinical effects, respectively, were described (0.4%) [5]. Only 35.5% of cases were associated with coagulopathy as measured in the laboratory, and symptomatic complications were rare (3.2%).\n\nHowever, the LD50 (i.e., the dose causing 50% of a group to die) of warfarin in humans is unknown; only animal data are available. Also, the human ED50 level (the dose effective in 50% of a group) is unknown [4,11,12,13]. In fact, the toxic dose of brodifacoum varies widely among individuals, as reflected by variations in the half-life. Thus, brodifacoum metabolism may differ individually, but this remains unclear. The mechanism of action of the superwarfarins is the same as that of warfarin [10,11,16,17].\n\nUsually, warfarin therapy is associated with a significant risk of bleeding complications because the warfarin therapeutic index is narrow. It is well known that certain factors increase the risk of over-anticoagulation. Such factors are 1) impaired liver function and hypoalbuminemia; 2) alcohol consumption; 3) drug-drug interactions; and 4) genetic polymorphisms (CYP2c9 and VKORC1) affecting the levels or activities of enzymes metabolizing warfarin [18,19].\n\nFirst, anticoagulants accumulate principally in the liver. Superwarfarins exhibit high liver to serum concentration ratios (ca. 20:1 in rats) because the rodenticides are very lipid-soluble and exhibit an affinity for hepatic tissue. Thus, impaired liver function may trigger symptoms of superwarfarin poisoning [11,17,20].\n\nWarfarin is extensively protein-bound (97% to 99%, when albumin levels are > 3.2 mg/100 mL), and only the free drug exerts any biological effects. When albumin levels are low, the amount of free warfarin thus increases. Hence, such patients generally require less warfarin. As the albumin level rises, the warfarin maintenance dose also rises. Thus, hypoalbuminemia may trigger increased warfarin activity and symptoms of coagulopathy [18,21].\n\nThe anticoagulant effect of warfarin is dramatically altered by ingestion of even small amounts of alcohol. In those taking warfarin and ingesting a few alcoholic drinks in a single sitting, the anticlotting effects may become greater than medically required, placing the patient at risk of increased bleeding. Such excessive warfarin action is the result of alcohol-related inhibition of warfarin metabolism by liver cytochrome P450. Conversely, in those who chronically consume alcohol, long-term cytochrome P450 is constitutively activated and warfarin metabolism thus permanently affected. Warfarin is metabolized more rapidly than normal in such subjects, and higher warfarin doses are generally required to achieve the desired anticoagulant effects [22,23].\n\nDrug-drug interactions are of major concern, triggering adverse drug reactions in patients under warfarin treatment. Comedications may inhibit the hepatic P450 system, triggering hemorrhagic symptoms. Such medications include SSRIs, NSAIDs, metronidazole, and cimetidine [24,25,26,27,28,29,30].\n\nFinally, genetic screens have identified two genes responsible for most of the genetic effect; these are the CYP2C9 allele (encoding CYP2C9 that metabolizes S-warfarin) and VKORC1 (encoding the target of warfarin; vitamin K epoxide reductase). Certain loss-of-function CYP2C9 and VKORC1 polymorphisms are known to be associated with reductions in enzymatic activity and, thus, an increased risk of hemorrhage. These alleles are CYP2C9*2 (Cysl44/Ile359), CYP2C9*3 (Argl44/Leu359), and VKORC1 (.1639 G>A) [31,32]. Furthermore, certain patients have CYP2C9 poor metabolizer alleles and experience rates of major bleeding 3.68-fold higher than those of patients with the wild-type gene. Therefore, in known carriers of variant CYP2C9 alleles, the initial loading dose of warfarin should be reduced to as little as 10% of the standard recommendation. The VKORC 1639 G>A allele is associated with increased warfarin activity. On the other hand, the VKORC1 1173 C>T variant causes partial resistance to warfarin, and very high doses are thus required to obtain therapeutic effects [31,32,33,34,35,36,37,38,39,40].\n\nTreatment options for superwarfarin intoxication include administration of vitamin K1, FFP, and/or a prothrombin complex concentrate. If a patient has active bleeding, or is at a high risk of bleeding, FFP transfusions are given. Administration of recombinant factor VIIa also controls acute bleeding. However, the effect of either treatment is short-lived. After controlling bleeding, patients with prolonged PTs and aPTTs should be given high doses of vitamin K to normalize the coagulopathy. The optimal dose and duration of vitamin K1 therapy have yet to be established. However, early tapering or discontinuation will cause repeat prolongation of PT and aPTT even after normal values have been attained [11,41,42,43]. Our experience supports the use of multiple treatments (daily oral or intermittent intravenous vitamin K); prolonged treatment (for a minimum of 6 months if hemorrhagic symptoms are evident); and high-dose (10 to 60 mg) vitamin K1 supplementation.\n\nTo date, no report has identified risk factors for superwarfarin intoxication or discussed suspected superwarfarin intoxication in patients without definitive histories of rodenticide ingestion. This is the first report to detail individual risk factors, to investigate routes of poisoning other than the oral, and to explore treatments for superwarfarin intoxication especially in those without definitive histories of ingestion.\n\nWe found that albumin levels and simultaneous ingestion of rodenticide and alcohol may be associated with coagulopathy. Superwarfarin may be ingested with alcohol in a single sitting, or rodenticide may be chronically absorbed through the skin or via inhalation.\n\nTo our knowledge, no previous report has identified individual risk factors for development of coagulopathy or hemorrhagic symptoms, or has sought to identify the source of exposure, in patients suspected of superwarfarin intoxication.\n\nFurther studies are required to ascertain whether albumin level, acute or chronic alcohol consumption, and use of herbal medications, are important in the context of superwarfarin poisoning.\n\nKEY MESSAGE\n\nMost patients with superwarfarin poisoning do not exhibit any complications.\n\nComplications of superwarfarin poisoning may be associated with serum albumin level and simultaneous ingestion of rodenticide and alcohol.\n\nThe serum brodifacoum test should be performed to identify vitamin K-dependent coagulopathy in adult patients even in the absence of a definitive history of rodenticide poisoning.\n\nThe source of exposure in patients exhibiting superwarfarin toxicity of unknown origin may be long-term transdermal absorption or inhalation.\n\nThe CYP2C9 and VKORC1 genotypes were not noted among our 31 subjects, despite the fact that these mutations are well-known sensitizers to warfarin poisoning.\n\nChronic heavy alcohol drinkers may be at risk of hemorrhagic complications because of chronic rodenticide absorption from the skin, or via respiration.\n\nIn cases with hemorrhagic complications, the optimal route of vitamin K administration is initially intravenous, followed by a later change to the oral route. However, if oral vitamin K cannot be easily obtained (in Korea, oral vitamin K is no longer on sale), intravenous vitamin K can be given every other day. Regardless of modality, treatment should be continued for at least 6 months.\n\n\n\n\nAcknowledgments\nThis work was supported by a grant from the Clinical Medicine Research Institute of the Chosun University Hospital (2013).\n\nNo potential conflict of interest relevant to this article was reported.\n\nTable 1 General characteristics of the 31 study subjects presenting with acute rodenticide poisoning\n\nValues are presented as median (range) or number (%).\n\nSSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; NSAID, nonsteroidal anti-inflammatory drug; equiv., equivalent; PT, prothrombin time; INR, international normality ratio.\n\naEach tablet has 0.2 mg at 0.005% (w/w).\n\nTable 2 Comparison of clinical characteristics between the group with a laboratory abnormality (prothrombin time > 13 sec) and the other group\n\nap < 0.05.\n\nTable 3 Patients with vitamin K-dependent coagulopathy presumed to be caused by exposure to brodifacoum\n\nM, male; F, female; PT, prothrombin time; INR, international normality ratio; CYP2C9, cytochrome P450 2C9; VKORC1, vitamin K epoxide reductase complex subunit 1; TCA, tricyclic antidepressant; SSRI, selective serotonin reuptake inhibitor; NSAID, nonsteroidal anti-inflammatory drug.\n\nTable 4 Patients with vitamin K-dependent coagulopathy presumed to be associated with exposure to brodifacoum\n\nFFP, fresh frozen plasma; IV, intravenous; q.d., queque die (every day); PO, per os (by mouth); SSRI, selective serotonin reuptake inhibitor; NSAID, nonsteroidal anti-inflammatory drug.\n==== Refs\n1 Hong J Yhim HY Bang SM Korean patients with superwarfarin intoxication and their outcome J Korean Med Sci 2010 25 1754 1758 21165290 \n2 Rauch AE Weininger R Pasquale D Superwarfarin poisoning: a significant public health problem J Community Health 1994 19 55 65 8169251 \n3 Abell TL Merigian KS Lee JM Holbert JM McCall JW 3rd Cutaneous exposure to warfarin-like anticoagulant causing an intracerebral hemorrhage: a case report J Toxicol Clin Toxicol 1994 32 69 73 8308951 \n4 Kim HY Jeon HJ Ko BS Lee KH Kim ST Two cases of brodifacoum poisoning from inhalation route Korean J Hematol 1996 31 473 479 \n5 Hadler MR Shadbolt RS Novel 4-hydroxycoumarin anticoagulants active against resistant rats Nature 1975 253 275 277 1113846 \n6 Chua JD Friedenberg WR Superwarfarin poisoning Arch Intern Med 1998 158 1929 1932 9759690 \n7 Pavlu J Harrington DJ Voong K Savidge GF Jan-Mohamed R Kaczmarski R Superwarfarin poisoning Lancet 2005 365 628 15708110 \n8 Lipton RA Klass EM Human ingestion of a 'superwarfarin' rodenticide resulting in a prolonged anticoagulant effect JAMA 1984 252 3004 3005 6502864 \n9 Bronstein AC Spyker DA Cantilena LR Jr Green JL Rumack BH Giffin SL 2009 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 27th Annual Report Clin Toxicol (Phila) 2010 48 979 1178 21192756 \n10 Park BK Leck JB A comparison of vitamin K antagonism by warfarin, difenacoum and brodifacoum in the rabbit Biochem Pharmacol 1982 31 3635 3639 7181945 \n11 Bachmann KA Sullivan TJ Dispositional and pharmacodynamic characteristics of brodifacoum in warfarin-sensitive rats Pharmacology 1983 27 281 288 6657737 \n12 Bruno GR Howland MA McMeeking A Hoffman RS Long-acting anticoagulant overdose: brodifacoum kinetics and optimal vitamin K dosing Ann Emerg Med 2000 36 262 267 10969235 \n13 Hui CH Lie A Lam CK Bourke C 'Superwarfarin' poisoning leading to prolonged coagulopathy Forensic Sci Int 1996 78 13 18 8855043 \n14 Wu YF Chang CS Chung CY Lin HY Wang CC Shen MC Superwarfarin intoxication: hematuria is a major clinical manifestation Int J Hematol 2009 90 170 173 19588218 \n15 Jin MC OuYang XK Chen XH High-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry for the determination of flocoumafen and brodifacoum in whole blood J Appl Toxicol 2007 27 18 24 17177169 \n16 Olmos V Lenzken SC del Carmen Paz M Quantification of brodifacoum, bromadiolone and difenacoum in human serum by HPLC with ultraviolet and fluorometric detection Acta Toxicol Argent 2004 12 9 14 \n17 Watt BE Proudfoot AT Bradberry SM Vale JA Anticoagulant rodenticides Toxicol Rev 2005 24 259 269 16499407 \n18 Eason CT Murphy EC Wright GR Spurr EB Assessment of risks of brodifacoum to non-target birds and mammals in New Zealand Ecotoxicology 2002 11 35 48 11898799 \n19 Wadelius M Pirmohamed M Pharmacogenetics of warfarin: current status and future challenges Pharmacogenomics J 2007 7 99 111 16983400 \n20 Makris M Watson HG The management of coumarin-induced over-anticoagulation Annotation Br J Haematol 2001 114 271 280 11529844 \n21 O'Bryan SM Constable DJ Quantification of brodifacoum in plasma and liver tissue by HPLC J Anal Toxicol 1991 15 144 147 1943058 \n22 Kaminsky LS Zhang ZY Human P450 metabolism of warfarin Pharmacol Ther 1997 73 67 74 9014207 \n23 Lieber CS Alcohol and the liver: 1994 update Gastroenterology 1994 106 1085 1105 8143977 \n24 Weathermon R Crabb DW Alcohol and medication interactions Alcohol Res Health 1999 23 40 54 10890797 \n25 Schalekamp T Klungel OH Souverein PC de Boer A Increased bleeding risk with concurrent use of selective serotonin reuptake inhibitors and coumarins Arch Intern Med 2008 168 180 185 18227365 \n26 Dalton SO Sorensen HT Johansen C SSRIs and upper gastrointestinal bleeding: what is known and how should it influence prescribing? CNS Drugs 2006 20 143 151 16478289 \n27 Greenblatt DJ von Moltke LL Harmatz JS Shader RI Drug interactions with newer antidepressants: role of human cytochromes P450 J Clin Psychiatry 1998 59 Suppl 15 19 27 9786307 \n28 Choi KH Kim AJ Son IJ Risk factors of drug interaction between warfarin and nonsteroidal anti-inflammatory drugs in practical setting J Korean Med Sci 2010 25 337 341 20191029 \n29 O'Reilly RA Comparative interaction of cimetidine and ranitidine with racemic warfarin in man Arch Intern Med 1984 144 989 991 6324710 \n30 Hungin AP Rubin GP O'Flanagan H Co-prescription of H2 receptor blockers and proton pump inhibitors with warfarin in general practice Postgrad Med J 1999 75 721 722 10567597 \n31 Rost S Fregin A Ivaskevicius V Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2 Nature 2004 427 537 541 14765194 \n32 D'Andrea G D'Ambrosio RL Di Perna P A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin Blood 2005 105 645 649 15358623 \n33 Rettie AE Korzekwa KR Kunze KL Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions Chem Res Toxicol 1992 5 54 59 1581537 \n34 Higashi MK Veenstra DL Kondo LM Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy JAMA 2002 287 1690 1698 11926893 \n35 Li T Chang CY Jin DY Lin PJ Khvorova A Stafford DW Identification of the gene for vitamin K epoxide reductase Nature 2004 427 541 544 14765195 \n36 Gage BF Eby C Johnson JA Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin Clin Pharmacol Ther 2008 84 326 331 18305455 \n37 Gage BF Lesko LJ Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues J Thromb Thrombolysis 2008 25 45 51 17906972 \n38 Visser LE van Vliet M van Schaik RH The risk of overanticoagulation in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon Pharmacogenetics 2004 14 27 33 15128048 \n39 Steward DJ Haining RL Henne KR Genetic association between sensitivity to warfarin and expression of CYP2C9*3 Pharmacogenetics 1997 7 361 367 9352571 \n40 Aithal GP Day CP Kesteven PJ Daly AK Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications Lancet 1999 353 717 719 10073515 \n41 Schalekamp T Brasse BP Roijers JF VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement Clin Pharmacol Ther 2007 81 185 193 17192772 \n42 Spahr JE Maul JS Rodgers GM Superwarfarin poisoning: a report of two cases and review of the literature Am J Hematol 2007 82 656 660 17022046 \n43 Zupancic-Salek S Kovacevic-Metelko J Radman I Successful reversal of anticoagulant effect of superwarfarin poisoning with recombinant activated factor VII Blood Coagul Fibrinolysis 2005 16 239 244 15870542\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1226-3303",
"issue": "29(4)",
"journal": "The Korean journal of internal medicine",
"keywords": "Brodifacoum; Poisoning; Vitamin K deficiency bleeding",
"medline_ta": "Korean J Intern Med",
"mesh_terms": "D015110:4-Hydroxycoumarins; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000428:Alcohol Drinking; D000925:Anticoagulants; D001777:Blood Coagulation; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D056910:Republic of Korea; D012189:Retrospective Studies; D012307:Risk Factors; D012378:Rodenticides; D012709:Serum Albumin; D000075462:Serum Albumin, Human; D014812:Vitamin K; D006475:Vitamin K Deficiency Bleeding; D055815:Young Adult",
"nlm_unique_id": "8712418",
"other_id": null,
"pages": "498-508",
"pmc": null,
"pmid": "25045298",
"pubdate": "2014-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "10567597;10969235;10890797;11529844;9352571;1943058;15708110;6324710;18305455;21192756;15870542;17177169;6502864;7181945;8143977;9014207;9759690;15128048;16499407;10073515;18227365;17906972;17022046;16478289;6657737;15358623;8855043;9786307;11926893;14765195;16983400;8169251;14765194;19588218;11898799;20191029;1113846;1581537;17192772;21165290;8308951",
"title": "Evaluation of risk factors in patients with vitamin K-dependent coagulopathy presumed to be caused by exposure to brodifacoum.",
"title_normalized": "evaluation of risk factors in patients with vitamin k dependent coagulopathy presumed to be caused by exposure to brodifacoum"
} | [
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"abstract": "Rituximab is used as a steroid/calcineurin inhibitor-saving agent in patients with nephrotic syndrome. Safety is a crucial issue for justifying widespread use of the drug in this clinical setting. Rituximab-associated lung injury (RALI) is a severe and potentially life-threatening complication in oncohaematological and rheumatological patients, while it has only been anecdotally reported in association with idiopathic nephrotic syndrome (2 cases described, 1 with fatal outcome). We describe a benign form of RALI occurring in two adolescents treated with rituximab (single pulse of 375 mg/m(2)) for nephrotic syndrome. Before treatment, the patients were in good clinical condition while receiving a combination of steroids and calcineurin inhibitors (tacrolimus, case 1 and cyclosporine, case 2). The two patients developed full blown RALI (ie, ground-glass lesions on CT, negative bronchoscopy with bronchoalveolar lavage and deficit in diffusion lung CO transfer), 14 and 40 days after rituximab infusion, respectively. Recovery was rapid and complete after administering steroids in case 1 and with no therapy in case 2. We conclude that RALI may occur in stable non-immunocompromised patients with nephrotic syndrome and its frequency may be higher than expected. Clinical presentation may be mild and resolve after steroids, suggesting hypersensitivity as the main mechanism. Rapid recognition and prompt steroid therapy, if needed, are mandatory for resolution.",
"affiliations": "Division of Pneumology, Dipartimento Biomedico di Medicina Interna e Specialistica, Università di Palermo, Palermo, Italy.;Division of Nephrology, Dialysis and Transplantation, Giannina Gaslini Children's Hospital, Genoa, Italy.;Division of Pneumology, Dipartimento Biomedico di Medicina Interna e Specialistica, Università di Palermo, Palermo, Italy.;Division of Nephrology, Dialysis and Transplantation, Giannina Gaslini Children's Hospital, Genoa, Italy.",
"authors": "Spatafora|Mario|M|;Bellini|Tommaso|T|;Giordano|Carmela|C|;Ghiggeri|Gian Marco|GM|",
"chemical_list": "D007155:Immunologic Factors; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D002648:Child; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D055370:Lung Injury; D008297:Male; D009404:Nephrotic Syndrome; D000069283:Rituximab",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26661285",
"pubdate": "2015-12-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23052653;19608586;22157468;12383196;9818234;25929598;19681063;22581994;20140460;9310469;21566104;25592855;17597477;19396468;25584803;25752834;24965823",
"title": "A mild form of rituximab-associated lung injury in two adolescents treated for nephrotic syndrome.",
"title_normalized": "a mild form of rituximab associated lung injury in two adolescents treated for nephrotic syndrome"
} | [
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"companynumb": "IT-ROCHE-1699795",
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"activesubstancename": "TACROLIMUS"
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"abstract": "Calciphylaxis is uncommon and typically seen in patients with end-stage renal disease. It has been defined as a vasculopathic disorder characterised by cutaneous ischaemia and necrosis due to calcification, intimal fibroplasia and thrombosis of pannicular arterioles. We present the case of a 74-year-old woman with chronic kidney disease stage III who developed calciphylaxis leading to mitral valve calcification, chordae tendineae rupture and acute mitral regurgitation. Although an alternative explanation can typically be found for non-uraemic calciphylaxis, her evaluation did not reveal any usual non-uraemic causes including elevated calcium-phosphorus product, hyperparathyroidism, or evidence of connective tissue disease. Her wounds improved with sodium thiosulfate, pamidronate, penicillin and hyperbaric oxygen therapies but she ultimately decompensated with the onset of acute mitral regurgitation attributed to rupture of a previously calcified chordae tendineae. This case highlights an unusual case of calciphylaxis without clear precipitant as well as a novel manifestation of the disease.",
"affiliations": "Department of Internal Medicine, Keesler Medical Center, Biloxi, Mississippi, USA.",
"authors": "Gallimore|Grant Gardner|GG|;Curtis|Blair|B|;Smith|Andria|A|;Benca|Michael|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
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"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D001707:Biopsy, Needle; D002115:Calciphylaxis; D002405:Catheterization, Central Venous; D002815:Chordae Tendineae; D018450:Disease Progression; D004359:Drug Therapy, Combination; D015150:Echocardiography, Doppler; D017809:Fatal Outcome; D005260:Female; D006341:Heart Rupture; D006801:Humans; D007150:Immunohistochemistry; D007676:Kidney Failure, Chronic; D008944:Mitral Valve Insufficiency; D012720:Severity of Illness Index; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24789150",
"pubdate": "2014-04-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16797398;21872378;14982274;16191185;12028462;12834180;15252173;18417747;10739777;6697794;21652561;15168392;14668726;11422768;9740153;18627391;9052783;12642050;23254751;16968979;11682664;9426423;17141359",
"title": "Curious case of calciphylaxis leading to acute mitral regurgitation.",
"title_normalized": "curious case of calciphylaxis leading to acute mitral regurgitation"
} | [
{
"companynumb": "US-TEVA-526770USA",
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{
"abstract": "Optical coherence tomography (OCT) can guide percutaneous coronary interventions to optimize results, thus minimizing the risk of stent thrombosis. We present the case of a cancer patient, paroxysmal atrial fibrillation, and unstable angina who underwent OCT-guided complex percutaneous coronary intervention and who required early discontinuation of antiplatelet therapy because of major bleeding. (Level of Difficulty: Beginner.).",
"affiliations": "First Cardiology Department, Ioannina University Hospital, Ioannina, Greece.;First Cardiology Department, Ioannina University Hospital, Ioannina, Greece.;First Cardiology Department, Ioannina University Hospital, Ioannina, Greece.;First Cardiology Department, Ioannina University Hospital, Ioannina, Greece.",
"authors": "Gkirdis|Ioannis|I|;Nikas|Dimitrios N|DN|;Bampali|Theodora|T|;Kolettis|Theofilos M|TM|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jaccas.2020.04.049",
"fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(20)30487-3\n10.1016/j.jaccas.2020.04.049\nCase Report\nClinical Case\nOptical Coherence Tomography Facilitating Early Withdrawal of Antiplatelet Agents in a High–Bleeding Risk Patient\nGkirdis Ioannis MD john_girdis@yahoo.gr\n∗∗\nNikas Dimitrios N. MD, MS, PhD ∗\nBampali Theodora MD\nKolettis Theofilos M. MD, PhD\nFirst Cardiology Department, Ioannina University Hospital, Ioannina, Greece\n∗ Address for correspondence: Dr. Ioannis P. Gkirdis, First Cardiology Department, Ioannina University Hospital, St. Niarchos Avenue, 455 00 Ioannina, Greece. john_girdis@yahoo.gr\n∗ Drs. Gkirdis and Nikas contributed equally to this work and are co-first authors.\n\n15 7 2020\n7 2020\n15 7 2020\n2 8 11861191\n14 4 2020\n17 4 2020\n© 2020 The Authors\n2020\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nOptical coherence tomography (OCT) can guide percutaneous coronary interventions to optimize results, thus minimizing the risk of stent thrombosis. We present the case of a cancer patient, paroxysmal atrial fibrillation, and unstable angina who underwent OCT–guided complex percutaneous coronary intervention and who required early discontinuation of antiplatelet therapy because of major bleeding. (Level of Difficulty: Beginner.)\n\nGraphical abstract\n\nOptical coherence tomography can guide percutaneous coronary interventions to optimize results, thus minimizing the risk of stent thrombosis. We…\n\nKey Words\n\nDOAC\nhigh bleeding risk\noptical coherence tomography\nunprotected left main angioplasty\nAbbreviations and Acronyms\n\nDK, double-kissing\nDOAC, direct oral anticoagulant\nLAD, left anterior descending coronary artery\nLCx, left circumflex coronary artery\nLM, left main coronary artery\nOAC, oral anticoagulant agent\nOCT, optical coherence tomography\nPCI, percutaneous coronary intervention\n==== Body\nHistory of Presentation\n\nAn 82-year-old man was referred to our hospital (Ioannina University Hospital, Ioannina, Greece) for investigation of dyspnea on low effort and chest discomfort for the past 5 days (angina equivalent). On physical examination, he was normotensive, in sinus rhythm (55 beats/min), and with normal lung and heart sounds and no peripheral edema.Learning Objectives\n\n• Patients with multiple comorbidities, including cancer and atrial fibrillation, who undergo complex multivessel PCI, create a challenging clinical setting for optimal combined antiplatelet and antithrombotic therapy.\n\n• Given the high bleeding risk in these patients, optimizing short-term PCI results by using advanced imaging techniques, such as OCT, may reduce the risk of future coronary thrombotic events and allow early discontinuation of antiplatelet drugs, thus limiting bleeding complications.\n\nPast Medical History\n\nThe patient had an active lifestyle until recently, when he received a diagnosis of colon cancer (moderately differentiated adenocarcinoma). He underwent right hemicolectomy 3 months ago, and chemotherapy (5-fluorouracil, oxaliplatin, and leucovorin) was initiated. Two months later, hepatic metastases were detected. He also had a history of paroxysmal atrial fibrillation treated with apixaban, 5 mg twice daily, and a beta-blocker.\n\nDifferential Diagnosis\n\nThe differential diagnosis comprised pulmonary embolism, chemotherapy-induced cardiomyopathy, and unstable angina.\n\nInvestigations\n\nThe electrocardiogram demonstrated poor R-wave progress in leads V2 to V4. Blood tests revealed anemia (hemoglobin, 9.9 g/dl; normal range 13.5 to 17.5 g/dl) and mild elevation of D-dimers (0.7 mg/dl; normal range 0 to 0.5 g/dl). The troponin value was normal. The echocardiogram was negative for wall motion abnormalities or other remarkable findings; ejection fraction was slightly decreased (50% to 55%). Although the Wells score (= 1) was low, pulmonary embolism was excluded with computed tomography pulmonary angiography. Finally, a coronary angiogram was performed, revealing 3-vessel coronary artery disease with severe stenoses in the proximal and distal left anterior descending coronary artery (LAD) and the proximal left circumflex coronary artery (LCx), and moderate stenosis (>50%) in the proximal right coronary artery (Figures 1A to 1D).Figure 1 Initial Coronary Angiography\n\n(A to C) Coronary angiogram shows atheromatic plaque in the left main coronary artery (black arrowhead), a complicated severe lesion in the proximal left circumflex coronary artery (LCx) (white arrow), and severe stenoses in the proximal (black arrows) and distal (white arrowhead) left anterior descending coronary artery. (D) Moderate lesion >50% proximal in the right coronary artery.\n\nManagement\n\nTherapy for unstable angina with aspirin, clopidogrel, a statin, an angiotensin-converting enzyme inhibitor, and transcutaneous nitrates was initiated. Apixaban had already been substituted for enoxaparin. An oncological consultation suggested that we proceed with the necessary revascularization, even though the patient could possibly require multiple hepatic operations in the future. Despite the low surgical risk (European System for Cardiac Operative Risk Evaluation [EuroSCORE] II, 1.72%; Society of Thoracic Surgeons [STS] score, 1.59% vs. SYNTAX score, 28), the heart team decided to forgo surgical revascularization in the light of the patient’s active cancer. Therefore, we proceeded to perform a double-kissing (DK) crush percutaneous coronary intervention (PCI) technique in the left main coronary artery (LM) bifurcation. We used 2 drug-eluting stents placed under complete optical coherence tomography (OCT) guidance at every step of the procedure (sizing, distal and middle rewiring, proximal optimization technique) to achieve the best result possible. A DK-crush procedure was selected instead of provisional stenting to ensure complete LCx ostium coverage and patency, in case of plaque-shifting toward the LCx during LAD-LM stenting. A third drug-eluting stent was implanted at the distal lesion of the LAD (Figures 2A to 2G). After OCT imaging, significant numbers of stent struts were found to be malapposed, particularly in the LM (Figures 3A to 3C). The proximal optimization technique with a larger noncompliant balloon achieved complete strut apposition, which was confirmed with OCT (Figures 4A to 4C). The patient was discharged a few days later, completely relieved of symptoms. The following antithrombotic therapy was prescribed: dabigatran, 110 mg twice daily (CHA2DS2-VASc [congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65 to 74 years, and sex category female] score = 3); clopidogrel, 75 mg; and aspirin, 100 mg daily. Taking into consideration the patient’s high bleeding risk (HAS-BLED [hypertension, abnormal renal/hepatic function, stroke, bleeding history, labile international normalized ratio, elderly >65 years of age, drugs/alcohol concomitantly] score = 3), along with the OCT-optimized PCI, aspirin was discontinued after 1 week.Figure 2 Double-Kissing Crush PCI in LM Bifurcation\n\n(A) After initial pre-dilatations, a 3.5 × 2 6 mm drug-eluting stent was placed in the left circumflex coronary artery and (B) was crushed into the left main coronary artery (LM). (C) First kissing balloon and (D) implantation of a 3.5 × 34 mm drug-eluting stent from the left anterior descending coronary artery toward the left main coronary artery shaft. (E) Both stents were post-dilated with 3.5 × 8 mm noncompliant balloons, and a second kissing balloon was performed with 3.0 × 20 mm noncompliant balloons. (F) Final proximal optimization technique with a 4.5 × 8 mm noncompliant balloon. (G) A third drug-eluting stent, 2.5 × 12 mm, was implanted in the distal left anterior descending coronary artery. PCI = percutaneous coronary intervention.\n\nFigure 3 Detection of Malapposed Stent Struts\n\n(A and B) Despite good angiographic results, (C) optical coherence tomography imaging, using stent apposition software, detected a significant number of stent struts malapposed to the vessel wall (red), especially in the left main coronary artery (arrows); well-apposed struts are white (arrowheads).\n\nFigure 4 Appropriate Stent Strut Apposition\n\n(A) After proximal optimization technique with a 5. 0 × 12 mm noncompliant balloon, (B) optical coherence tomography imaging confirmed good apposition of the previously malapposed struts in the left main coronary artery (arrowheads). (C) A 3-dimensional reconstruction of the stented carina.\n\nFollow-Up\n\nThe patient continued his chemotherapy schedule, with subsequent regression of the hepatic metastatic lesions. Nevertheless, he had 2 episodes of major gastrointestinal bleeding that were attributed to a cecum ulcer at the level of the previous surgical anastomosis. The first episode was on day 40 post-PCI (while he was receiving dabigatran and clopidogrel; hematocrit, 18%; 5 U of red blood cells transfused). The second episode was 3.5 months after PCI (while taking dabigatran and clopidogrel; hematocrit, 20%; 4 U of red blood cells transfused), and, at that point, clopidogrel was permanently stopped. The decision for the early withdrawal of clopidogrel was once more supported by the satisfying angioplasty result, as confirmed by OCT, and the dose of dabigatran was titrated to 150 mg twice daily. On the latest scheduled follow-up (10 months after PCI), the patient was free of angina, without any further bleeding events. One month ago, the patient underwent partial hepatectomy without any hemorrhagic complications and with an uneventful recovery.\n\nDiscussion\n\nAccording to current guidelines, triple antithrombotic therapy with an oral anticoagulant agent (DOAC or OAC), aspirin, and clopidogrel is necessary for most patients with atrial fibrillation (provided the CHA2DS2-VASc score is ≥2, without discrimination between paroxysmal and other types of atrial fibrillation) and recent PCI. The duration of this triple regimen depends on several clinical and procedural factors reflecting the individual patient’s ischemic and bleeding risk and usually ranges between 1 and 6 months (dual antiplatelet therapy should be confined to the periprocedural phase in patients at high bleeding risk and low ischemic risk). After this period, guidelines recommend discontinuation of aspirin or clopidogrel until 12 months after PCI. Beyond 12 months after PCI, DOAC or OAC monotherapy is indicated, with possible extension of single antiplatelet therapy when high–ischemic risk features prevail (1, 2, 3).\n\nIn the aforementioned group of patients, cancer patients constitute a special subgroup with additional thromboembolic, ischemic, and hemorrhagic risk. Cancer therapies themselves may promote or worsen myocardial ischemia, thrombosis, and atrial fibrillation. Current position papers do not shed much light on the optimal revascularization strategy or on the optimal antithrombotic regimen after PCI in such patients. Furthermore, with the exception of the STS score, widely used risk scores (EuroSCORE II, SYNTAX II, CHA2DS2-VASc, HAS-BLED) are not validated in cancer patients (4). The use of direct oral anticoagulant agents (DOACs) is considered relatively safe in cancer patients (5). Considering the high bleeding risk of our patient and the possible need for operations in the near future, immediate anticoagulant reversal with a DOAC antidote may be needed. Therefore, dabigatran was chosen as the best option because it is the only DOAC with a proven specific antidote—idarucizumab, a monoclonal antibody fragment that specifically binds to dabigatran and completely reverses its anticoagulant action (6).\n\nAmong several other characteristics (including acute coronary syndrome presentation and bifurcation lesions), stent underexpansion and malapposition are well recognized factors related to an increased risk of stent thrombosis (7). Intravascular imaging, either with intravascular ultrasound or OCT, is useful for detecting these conditions, hence guiding PCI procedures to better results. OCT, in particular, uses an optical fiber core and near-infrared light to produce a 10- to 20-μm level of resolution, thus enabling superior imaging of the intimal layer and stent struts (7,8). Finally, compared with other 2-stent techniques, the DK-crush technique seems to have the most favorable outcomes when treating unprotected LM bifurcation lesions (9). In the setting of this complex bifurcation lesion, we used the DK-crush technique with OCT optimization, to achieve the best short- and long-term outcome for this patient with a complex case.\n\nConclusions\n\nOCT imaging has an important role in optimizing stent apposition, especially after complex PCI procedures. Optimized PCI results could possibly facilitate the clinical decision of early withdrawal of antithrombotic agents in patients with subsequent major bleeding.\n\nThe authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n\nThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Case Reportsauthor instructions page.\n==== Refs\nReferences\n\n1 Neumann F.J. Sousa-Uva M. Ahlsson A. 2018 ESC/EACTS guidelines on myocardial revascularization Eur Heart J 40 2019 87 165 30165437\n2 Kirchhof P. Benussi S. Kotecha D. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS Eur Heart J 37 2016 2893 2962 27567408\n3 January C.T. Wann L.S. Calkins H. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society J Am Coll Cardiol 74 2019 104 132 30703431\n4 Zamorano J.L. Lancellotti P. Muñoz D.R. 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the Task Force for Cancer Treatments and Cardiovascular Toxicity of the European Society of Cardiology Eur Heart J 37 2016 2768 2801 27567406\n5 Larsen T.B. Nielsen P.B. Skjoth F. Non-vitamin K antagonist oral anticoagulants and the treatment of venous thromboembolism in cancer patients: a semi systematic review and meta-analysis of safety and efficacy outcomes PLoS One 9 2014 e114445 25479007\n6 Pollack C. Reilly P. van Ryan J. Idarucizumab for dabigatran reversal — full cohort analysis N Engl J Med 377 2017 431 441 28693366\n7 Kirtane A.J. Stone G.W. How to minimize stent thrombosis Circulation 124 2011 1283 1287 21911796\n8 Lofti A. Jeremias A. Fearon W.F. Expert consensus statement on the use of fractional flow reserve, intravascular ultrasound, and optical coherence tomography: a consensus statement of the society of cardiovascular angiography and interventions Catheter Cardiovasc Interv 83 2014 509 518 24227282\n9 Chen S.L. Zhang J.J. Han Y. Double kissing crush versus provisional stenting for left main distal bifurcation lesions: DKCRUSH-V randomized trial J Am Coll Cardiol 70 2017 2605 2617 29096915\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2666-0849",
"issue": "2(8)",
"journal": "JACC. Case reports",
"keywords": "DK, double-kissing; DOAC; DOAC, direct oral anticoagulant; LAD, left anterior descending coronary artery; LCx, left circumflex coronary artery; LM, left main coronary artery; OAC, oral anticoagulant agent; OCT, optical coherence tomography; PCI, percutaneous coronary intervention; high bleeding risk; optical coherence tomography; unprotected left main angioplasty",
"medline_ta": "JACC Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101757292",
"other_id": null,
"pages": "1186-1191",
"pmc": null,
"pmid": "34317445",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports",
"references": "30703431;27567408;21911796;25479007;28693366;29096915;30165437;27567406;24227282",
"title": "Optical Coherence Tomography Facilitating Early Withdrawal of Antiplatelet Agents in a High-Bleeding Risk Patient.",
"title_normalized": "optical coherence tomography facilitating early withdrawal of antiplatelet agents in a high bleeding risk patient"
} | [
{
"companynumb": "GR-PFIZER INC-2020285159",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
... |
{
"abstract": "In July of 2016, carfentanil (CF) emerged in Northeast Ohio resulting in over 25 deaths within a 30-day period. A total of 125 deaths have occurred in Summit County and Cuyahoga County has reported 40 deaths, relating to the presence of CF either alone, or in combinations with heroin and fentanyl. Prior to this surge in CF cases, positive fentanyl enzyme-linked immunosorbent assay (ELISA) screening results were increasing in number. Many were negative for fentanyl confirmation by gas chromatography-mass spectrometry. Fentanyl analogs such as CF, acetyl fentanyl (AF), 2-furanyl fentanyl (2-Fu-F) and 3-methylfentanyl (3-MF) may be present in these cases. Some fentanyl analogs like CF and 3-MF do not cross-react with the Immunalysis ELISA fentanyl assay. With the emergence of potent synthetic fentanyl analogs, questions arose as to how to interpret their very low concentrations or absence in the blood in relation to cause of death. Driving under the influence of drugs (DUID) blood specimens had also tested positive for CF by reference laboratories. A liquid chromatography-tandem mass spectrometry method was developed to identify and quantify fentanyl, norfentanyl (NF) and four analogs: AF, 2-Fu-F, 3-MF and CF. The method has been utilized to quantify these fentanyl analogs in blood and vitreous humor in authentic antemortem and postmortem cases. Calibration curves were established between 0.10-4.0 ng/mL (NF, AF, 3-MF, 2-Fu-F and CF) and 1.0-40 ng/mL for fentanyl. In total, 98 postmortem cases analyzed produced the following blood concentration ranges: CF (0.11-0.88 ng/mL), 3-MF (0.15-1.7 ng/mL), 2-Fu-F (0.15-0.30 ng/mL), AF (0.14-0.16 ng/mL), fentanyl (1.1-15 ng/mL) and NF (0.10-3.7 ng/mL). Only CF, fentanyl and NF were detected in a statistically significant subset DUID population of 26 cases producing concentration ranges between 0.11 and 0.47 ng/mL, 1.0 and 9.8 ng/mL, and 0.11 and 3.5 ng/mL, respectively.",
"affiliations": "Cuyahoga County Medical Examiner's Office, Toxicology Department, 11001 Cedar Avenue, Cleveland, OH 44106, USA.;Cuyahoga County Medical Examiner's Office, Toxicology Department, 11001 Cedar Avenue, Cleveland, OH 44106, USA.;Cuyahoga County Medical Examiner's Office, Toxicology Department, 11001 Cedar Avenue, Cleveland, OH 44106, USA.;Cuyahoga County Medical Examiner's Office, Toxicology Department, 11001 Cedar Avenue, Cleveland, OH 44106, USA.;Cuyahoga County Medical Examiner's Office, Toxicology Department, 11001 Cedar Avenue, Cleveland, OH 44106, USA.;Cuyahoga County Medical Examiner's Office, Toxicology Department, 11001 Cedar Avenue, Cleveland, OH 44106, USA.;Cuyahoga County Medical Examiner's Office, Toxicology Department, 11001 Cedar Avenue, Cleveland, OH 44106, USA.;Cuyahoga County Medical Examiner's Office, Toxicology Department, 11001 Cedar Avenue, Cleveland, OH 44106, USA.;Summit County Medical Examiner's Office, Toxicology Department, 85 North Summit Street, Akron, OH 44308, USA.",
"authors": "Sofalvi|Szabolcs|S|;Schueler|Harold E|HE|;Lavins|Eric S|ES|;Kaspar|Claire K|CK|;Brooker|Ian T|IT|;Mazzola|Carrie D|CD|;Dolinak|David|D|;Gilson|Thomas P|TP|;Perch|Steve|S|",
"chemical_list": "D000701:Analgesics, Opioid; D005663:Furans; C080127:norfentanyl; C000620436:furanyl fentanyl; C017114:carfentanil; C030592:3-methylfentanyl; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkx052",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "41(6)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000701:Analgesics, Opioid; D001344:Autopsy; D002853:Chromatography, Liquid; D000066448:Driving Under the Influence; D004797:Enzyme-Linked Immunosorbent Assay; D005283:Fentanyl; D005663:Furans; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D015813:Substance Abuse Detection; D053719:Tandem Mass Spectrometry",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "473-483",
"pmc": null,
"pmid": "28830122",
"pubdate": "2017-07-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "An LC-MS-MS Method for the Analysis of Carfentanil, 3-Methylfentanyl, 2-Furanyl Fentanyl, Acetyl Fentanyl, Fentanyl and Norfentanyl in Postmortem and Impaired-Driving Cases.",
"title_normalized": "an lc ms ms method for the analysis of carfentanil 3 methylfentanyl 2 furanyl fentanyl acetyl fentanyl fentanyl and norfentanyl in postmortem and impaired driving cases"
} | [
{
"companynumb": "US-SA-2017SA269280",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIAMORPHINE"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Teduglutide, a glucagon-like peptide 2 analog, has demonstrated efficacy in treating adult patients with short bowel syndrome (SBS) and dependence on parenteral nutrition (PN), but its role in chronic malabsorptive states that do not necessitate PN remains uncertain.\n\n\n\nTo evaluate teduglutide use beyond its approved indications and to discuss the results of this adjunctive treatment in patients resistant to established therapy.\n\n\n\nThis series reports four patients treated with teduglutide off-label. The first case had Crohn's disease (CD) with persistent colocutaneous fistulae that demonstrated complete closure after 8 months of teduglutide therapy. The second case involved a PN-dependent CD patient with persistent fistulae and intra-abdominal abscesses who weaned off PN and had a significant improvement in her nutritional status after 3 months of teduglutide therapy. The third case had CD complicated by severe malnutrition and previous PN-associated line infections, but by 9 months of teduglutide therapy, she gained 5 kg and no longer required re-initiation of PN. The fourth case had a high-output diverting ileostomy with resultant impaired healing of a stage IV decubitus ulcer, and after 2 months of therapy, the patient's pre-albumin increased by 250% and the ulcer had decreased by 40% in size.\n\n\n\nThe use of teduglutide might be broadened to include patients with functional SBS not meeting strict criteria for intestinal failure. Further studies should evaluate the efficacy of teduglutide in patients who may require short-term small intestine rehabilitation or who have chronically impaired absorptive capacity not yet requiring PN.",
"affiliations": "Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, 840 S Wood St (M/C 716), Chicago, IL, 60612, USA.;Department of Internal Medicine, University of Chicago Medicine, Chicago, IL, USA.;Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, 840 S Wood St (M/C 716), Chicago, IL, 60612, USA. rcarroll@uic.edu.",
"authors": "George|Alvin T|AT|;Li|Betty H|BH|;Carroll|Robert E|RE|",
"chemical_list": "D005765:Gastrointestinal Agents; D010455:Peptides; C494910:teduglutide",
"country": "United States",
"delete": false,
"doi": "10.1007/s10620-019-5473-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-2116",
"issue": "64(6)",
"journal": "Digestive diseases and sciences",
"keywords": "Crohn’s disease; Intestinal failure; Malabsorption; Parenteral nutrition; Short bowel syndrome; Teduglutide",
"medline_ta": "Dig Dis Sci",
"mesh_terms": "D000328:Adult; D000368:Aged; D002908:Chronic Disease; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D007408:Intestinal Absorption; D008286:Malabsorption Syndromes; D008297:Male; D008875:Middle Aged; D009752:Nutritional Status; D056687:Off-Label Use; D010455:Peptides; D012307:Risk Factors; D016896:Treatment Outcome; D015430:Weight Gain",
"nlm_unique_id": "7902782",
"other_id": null,
"pages": "1599-1603",
"pmc": null,
"pmid": "30730014",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29761915;23333663;19005872;8755576;11231933;17395898;27324885;26844839;15772387;22982184;21317170;19821509;19523469;16890611;9227451",
"title": "Off-Label Teduglutide Therapy in Non-intestinal Failure Patients with Chronic Malabsorption.",
"title_normalized": "off label teduglutide therapy in non intestinal failure patients with chronic malabsorption"
} | [
{
"companynumb": "US-PFIZER INC-2019240924",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CALCIUM CHLORIDE\\MAGNESIUM CHLORIDE\\POTASSIUM CHLORIDE\\SODIUM A... |
{
"abstract": "The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mostly affects adults with limited information on possible vertical transmission from pregnant mothers. We present here two very preterm infants born to mothers with COVID-19, whose respiratory course was significant for initial mild respiratory distress syndrome who developed acute onset severe air leak syndrome at approximately 24 to 36 hours of age requiring thoracentesis. Their respiratory status improved gradually with resolution of air leak and respiratory failure by 2 weeks of age. Both infants tested negative for SARS-CoV-2 by reverse transcriptase-polymerase chain reaction of multiple respiratory specimens collected beyond 24 hours after birth. As the incidence of severe air leak syndrome is relatively low in preterm infants without risk factors, this presentation in two very preterm infants born to mothers with COVID-19 is intriguing and needs to be further evaluated in larger cohorts. If confirmed, this data could potentially be the first step toward generating hypotheses for mechanisms of lung injury, intrauterine transmission, or how to detect COVID-19 in preterm infants. In addition, these data will be critical for developing evidence-based guidelines for perinatal management of these infants as we continue to battle against the COVID-19 pandemic for the foreseeable future.",
"affiliations": "Division of Neonatology, Department of Pediatrics, Rutgers University, Robert Wood Johnson Medical School, New Brunswick, New Jersey.;Division of Neonatology, Department of Pediatrics, Rutgers University, Robert Wood Johnson Medical School, New Brunswick, New Jersey.;Division of Neonatology, Department of Pediatrics, Rutgers University, Robert Wood Johnson Medical School, New Brunswick, New Jersey.",
"authors": "Reddy|Ajay|A|;Engelhardt|Krystin|K|;Jain|Deepak|D|0000-0002-6226-2204",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1055/s-0040-1715180",
"fulltext": "\n==== Front\nAJP Rep\nAJP Rep\n10.1055/s-00000169\nAJP Reports\n2157-6998 2157-7005 Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA. \n\n10.1055/s-0040-1715180\n200072\nCase Report\nAir Leak Syndrome in Two Very Preterm Infants Born to Mothers with Coronavirus Disease 2019: An Association or a Coincidence?\nReddy Ajay MD1 Engelhardt Krystin DO1 http://orcid.org/0000-0002-6226-2204Jain Deepak MD1 1 Division of Neonatology, Department of Pediatrics, Rutgers University, Robert Wood Johnson Medical School, New Brunswick, New Jersey\nAddress for correspondence Deepak Jain, MD Department of Pediatrics, Rutgers, The State University of New JerseyMEB – room no: 396, 1, Robert Wood Johnson Palace, New Brunswick, NJ 08901dj392@rwjms.rutgers.edu\n7 2020 \n02 9 2020 \n10 3 e266 e269\n31 5 2020 23 6 2020 \nThe Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/\n).\n2020The Author(s).This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mostly affects adults with limited information on possible vertical transmission from pregnant mothers. We present here two very preterm infants born to mothers with COVID-19, whose respiratory course was significant for initial mild respiratory distress syndrome who developed acute onset severe air leak syndrome at approximately 24 to 36 hours of age requiring thoracentesis. Their respiratory status improved gradually with resolution of air leak and respiratory failure by 2 weeks of age. Both infants tested negative for SARS-CoV-2 by reverse transcriptase–polymerase chain reaction of multiple respiratory specimens collected beyond 24 hours after birth. As the incidence of severe air leak syndrome is relatively low in preterm infants without risk factors, this presentation in two very preterm infants born to mothers with COVID-19 is intriguing and needs to be further evaluated in larger cohorts. If confirmed, this data could potentially be the first step toward generating hypotheses for mechanisms of lung injury, intrauterine transmission, or how to detect COVID-19 in preterm infants. In addition, these data will be critical for developing evidence-based guidelines for perinatal management of these infants as we continue to battle against the COVID-19 pandemic for the foreseeable future.\n\nKeywords\nCOVID-19coronavirusSARS-CoV-2pneumothoraxpreterm\n==== Body\nThe novel coronavirus disease 2019 (COVID-19) is a potentially life-threatening condition caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has rapidly spread across the globe and presented itself as a significant public health problem. There is limited data on whether the clinical course of COVID-19 in pregnant women is different from nonpregnant adults, with some evidence that it may not be associated with poor maternal or perinatal outcomes. The majority of the women in these studies presented in third trimester with delivery at late preterm or term, and neonates had unremarkable hospital course with no clear evidence of vertical transmission.\n1\n2\n3\n\n\n\nThere is very limited data on the clinical course of preterm infants of less than 32 weeks of gestation (very preterm) born to mothers with SARS-CoV-2 infection, thereby presenting a significant challenge to the management of these infants.\n4\n5\nWe report here two very preterm infants born to mothers with COVID-19 with an atypical respiratory course complicated by air leak syndrome.\n\n\nCase 1\n\nPatient was a female infant born at 29\n3/7\nweeks of gestation with a birthweight of 1,490 g. She was born to a 37-year-old gravida 6, para 4 mother with history of gestational diabetes on metformin and Class II obesity.\n\n\nMaternal history was significant for cough, sore throat, body ache, chills, frontal headache, and abdominal pain 10 days prior to delivery, and she tested positive for SARS-CoV-2 on reverse transcriptase–polymerase chain reaction (RT-PCR) by nasopharyngeal (NP) swab. Her other prenatal laboratories were unremarkable. She was observed for 1 day and was discharged home. She presented 2 days later in the emergency department (ED) with increasing complaints of headache, body aches, and contractions, and was admitted for observation for 24 hours. During this period, her examination remained unchanged, with intact membranes, stable respiratory status, and a reactive nonstress test. She was discharged home with follow-up in high-risk clinic. She presented 2 days later in preterm labor and noted to be fully dilated with crowning of head on exam. She went on to have precipitous delivery of a female infant. Mother did not receive antenatal steroids.\n\n\nThe neonatal resuscitation team followed airborne isolation precautions, and cord was clamped immediately after birth due to maternal COVID-19 status. Patient was vigorous at birth and required continuous positive airway pressure (CPAP) of 5 cm of H\n2\nO and FiO\n2\nof 0.3. Apgar's scores were 8 and 8 at 1 and 5 minutes, respectively. She was admitted to the neonatal intensive care unit (NICU) in a negative pressure isolation room with airborne precautions and started on CPAP of 6 cm of H\n2\nO and FiO\n2\nof 0.3. Initial chest radiograph (CXR) was suggestive of respiratory distress syndrome (RDS) (\nFig. 1A\n), and her initial capillary blood gas showed pH of 7.3, PCO\n2\n51, PO\n2\n44, and base excess 1.1. Infant was started on caffeine prophylaxis for apnea of prematurity, and empiric ampicillin and gentamicin due to preterm labor. She continued to be on CPAP of 6 cm of H\n2\nO and FiO\n2\nof 0.25 to 0.3 until approximately 20 hours of age when she had acute respiratory decompensation with recurrent episodes of apnea, bradycardia, and desaturations requiring increase in oxygen supplementation. She was intubated and given surfactant with some improvement in oxygen requirement. However, the CXR performed for tube position showed left-sided tension pneumothorax (\nFig. 1B\n) which required needle thoracentesis followed by chest tube placement. Over the next few days, the infant developed diffuse pulmonary interstitial emphysema, subcutaneous emphysema, and a right-sided pneumothorax requiring right chest tube placement (\nFig. 1C\n). Her respiratory status gradually improved, and she was extubated on day 5 to CPAP, and the chest tubes were removed by day 10. Follow-up CXRs denoted complete resolution of air leaks. The infant was weaned to nasal cannula on day 11 and weaned to room air on day 17.\n\n\nFig. 1 \nSeries of chest radiographs from the first case with initial image showing diffuse ground glass pattern (\nA\n), a large left pneumothorax on second image (\nB\n), and the third image showing right pneumothorax, pulmonary interstitial emphysema, and subcutaneous emphysema (\nC\n).\n\n\nRT-PCR performed on NP swab at 24 hours and repeat NP swab and tracheal aspirate at 60 hours of age were negative for SARS-CoV-2. A respiratory viral panel was negative. Infant received antibiotics for 10 days for presumed pneumonia. Her clinical course was remarkable for development of a left grade 4 and right grade 2 intraventricular hemorrhage.\n\nAfter delivery, mother developed COVID-19 pneumonia and required nasal cannula oxygen. Hydroxychloroquine was added to the medication regimen on postpartum day 3. Her respiratory status improved, and mother was discharged on postpartum day 5.\n\nCase 2\n\nPatient was a male infant born at 29\n3/7\nweeks of gestation with a birthweight of 1,220 g. Infant was born to a 28-year-old gravida 4, para 3 mother with antenatal history significant for chronic hypertension, chronic kidney disease, and obesity.\n\n\n\nThe mother presented to the ED 12 days prior to delivery with fever, cough, sore throat, and shortness of breath. She tested positive for SARS-CoV-2 on RT-PCR of NP swab, and was admitted for monitoring due to COVID-19 superimposed on worsening preeclampsia. Her other prenatal laboratories were unremarkable. During her hospital course, she received labetalol, magnesium, and a course of betamethasone 11 days prior to delivery. Due to worsening preeclampsia and COVID-19 pneumonia, caesarian section was performed at 29 weeks\n3/7\nof gestation. At the time of delivery, she was on high-flow nasal cannula oxygen and prophylactic anticoagulation with heparin due to the risk for thrombosis in pregnancy and COVID-19.\n\n\n\nUpon delivery, the neonatal team followed airborne precautions during resuscitation, and cord was clamped immediately after delivery. The infant was vigorous at birth and did not require any respiratory support with Apgar's scores of 9 and 9 at 1 and 5 minutes, respectively. The infant was transferred to the NICU in room air and admitted to a negative pressure isolation room due to maternal COVID-19. Within few hours of birth, infant was noted to have increased work of breathing and was placed on nasal CPAP of 6 cm of H\n2\nO with and FiO\n2\nof 0.25 to 0.3. CXR at this time was suggestive of RDS (\nFig. 2A\n), and a capillary blood gas showed pH of 7.38, PCO\n2\n43, PO\n2\n44, and a base excess of 0.5. At approximately 36 hours of age, infant had sudden deterioration with increased work of breathing and oxygen requirement, and CXR showed a right sided tension pneumothorax (\nFig. 2B\n). Needle thoracentesis followed by right-sided chest tube placement was performed immediately with improvement in pneumothorax. The infant had to be intubated 16 hours after chest tube placement for recurrent apnea episodes and increase in oxygen requirement. Over next few days, ventilator settings were gradually weaned, and he was extubated to CPAP on day 6. Chest tube was removed on day 9 and he was weaned off respiratory support by day 14.\n\n\nFig. 2 \nSeries of chest radiographs from the second case with initial image showing diffuse ground glass pattern (\nA\n), and a large right pneumothorax on the second image (\nB\n).\n\n\nRepeated testing for SARS-CoV-2 on RT-PCR by NP swab at 36 and 72 hours and tracheal aspirate at day 6 were negative. The infant reached full enteral feeds by day 9. Serial head ultrasounds obtained on day 3 and 7 have been unremarkable.\n\nDiscussion\nWe report the perinatal and early neonatal course of two very preterm infants born to mothers with COVID-19. Both of these infants followed similar respiratory courses with initial mild RDS complicated by development of severe air leak syndrome around 24 to 36 hours after birth requiring chest tube placement. Both infants tested negative for SARS-CoV-2 by RT-PCR of multiple respiratory specimens collected beyond 24 hours after birth.\n\n\nAlthough pneumothorax is not a rare diagnosis in the NICU, its incidence is relatively low in very preterm infants without any risk factors.\n6\nSome of the factors associated with the development of pneumothorax in premature infants include pulmonary hypoplasia, severe RDS, or use of high level of CPAP during resuscitation at birth.\n7\nBoth infants in the current case report had mild RDS on initial CXR, low oxygen requirement, and adequate ventilation on CPAP of 5 to 6 cm of H\n2\nO before acute deterioration. The respiratory status of both cases improved rapidly after chest tube placement, and the infants were weaned from respiratory support within 2 weeks. Whether this atypical respiratory course in the setting of maternal COVID-19 reflects an insult to the developing lung needs to be further explored in larger studies.\n\n\n\nThe inconsistency in the use of ANS between the two cases in the current case series reflects the lack of evidence and ongoing debate on their use in mothers with SARS-CoV-2 infection. It is plausible that the lack of exposure to ANS in the first case contributed to the air leak syndrome; however, it is important to note that though ANS have been shown to reduce the risk of RDS, the studies have failed to show any reduction in the incidence of air leak syndrome.\n8\nWhile the Centers for Disease Control and Prevention recommends against the use of corticosteroids in general population with COVID-19 due to possible risk of prolonged viral replication, it has not provided any guidelines specific for ANS. On the other hand, American College of Obstetricians and Gynecologists have continued to recommend ANS for mother with SARS-CoV-2 infection at less than 34 weeks of gestation while recommending against their use beyond 34 weeks of gestation.\n9\nThese inconsistencies reflect an urgent need for studies to evaluate the effects of ANS not only on the maternal SARS-CoV-2 infection, but also on the fetal organ development to develop guidelines with a stronger evidence base.\n10\n\n\n\nThere is very limited information on the clinical presentation of SARS-CoV-2 in the neonatal period for multiple reasons. These include the low incidence of positive NP RT-PCR and the overlap between common clinical manifestations of COVID-19 in adults and respiratory conditions affecting neonates at birth, such as transient tachypnea of newborn or RDS.\n3\n11\nOf note, in one of the few described cases of neonates with positive SARS-CoV-2, Coronado et al described a 3-week-old infant with late-onset sepsis complicated by the development of pneumothorax.\n12\n\n\n\nNone of the infants in this case report were positive for SARS-CoV-2 by RT-PCR of respiratory specimen. One of the shortcomings of the current case series is that we did not evaluate respiratory specimen for any bacteria. In addition, we could not evaluate any other specimen such as amniotic fluid, placenta, stool, or cord blood for presence of virus or serum antibody testing, thereby limiting the ability to comment on possibility of vertical transmission. The sensitivity and specificity of respiratory specimen to detect transplacental transmission has not been fully evaluated. In one recent case series, infants born to mothers with COVID-19 pneumonia had positive serum IgG and IgM with negative RT-PCR tests.\n13\nIn another study of adults evaluating SARS-CoV-2 in different clinical specimens, broncheoalveolar lavage fluid had the highest positive rate; in addition to virus being positive in sputum, nasal swab, stool, blood, and urine.\n14\nThese reports do raise the question as to whether a negative RT-PCR from a respiratory specimen in at-risk infants should be considered as an absence of infection, and whether there is a need for more comprehensive testing in these infants.\n15\n16\n\n\n\nThe evidence for vertical transmission of SARS-CoV-2 has been sparse, with most of the case series reporting no neonates with positive RT-PCR in the respiratory specimen. Most of this data are from late-term or full-term neonates born to asymptomatic mothers or those with mild symptoms.\n2\n17\nThere is increasing evidence that this may not hold true in neonates born at earlier gestations or to mothers with severe COVID-19, with recent case reports suggesting possible vertical transmission in infants born to mothers with severe COVID-19 illness.\n18\n19\n\n\n\nAs evidence accumulates for the effect of maternal COVID-19 in preterm infants, majority of the focus has been on transmissibility of the virus from mother to the neonate around the time of birth. Some of the questions remaining center on the transplacental transfer of virus during early part of gestation and the potential effect of maternal COVID-19 on the development of the fetal lungs and other organ systems. The observational data from case reports like the one presented here, if replicated in larger cohorts, could potentially be the first step toward generating hypotheses to be tested in the preclinical or clinical models. The resultant data will be key to develop evidence-based perinatal care strategies like use of ANS, delayed cord clamping, or choice of respiratory support after birth.\n20\n21\n\n\nConclusion\nWe describe two very preterm infants born to mothers with COVID-19 with early respiratory course complicated by severe air leak syndrome. These observations need to be further investigated in larger cohorts and if confirmed may have significant implications on perinatal management of these infants as we continue to battle against the COVID-19 pandemic for the foreseeable future.\n\nConflict of Interest None declared.\n==== Refs\nReferences\n1 Breslin N COVID-19 infection among asymptomatic and symptomatic pregnant women: two weeks of confirmed presentations to an affiliated pair of New York City hospitals\nAm J Obstet Gynecol MFM 2020 100118 32292903 \n2 Elshafeey F Magdi R Hindi N A systematic scoping review of COVID-19 during pregnancy and childbirth\nInt J Gynaecol Obstet 2020 150 01 47 52\n32330287 \n3 Zeng L Neonatal Early-Onset Infection With SARS-CoV-2 in 33 Neonates Born to Mothers With COVID-19 in Wuhan, China\nJAMA Pediatr 2020 174 07 722 725\n32215598 \n4 Juan J Gil M M Rong Z Zhang Y Yang H Poon L C Effect of coronavirus disease 2019 (COVID-19) on maternal, perinatal and neonatal outcome: systematic review\nUltrasound Obstet Gynecol 2020 56 01 15 27\n32430957 \n5 Piersigilli F Carkeek K Hocq C COVID-19 in a 26-week preterm neonate\nLancet Child Adolesc Health 2020 4 06 476 478\n32386562 \n6 Vibede L Vibede E Bendtsen M Pedersen L Ebbesen F Neonatal pneumothorax: a descriptive regional danish study\nNeonatology 2017 111 04 303 308\n28013308 \n7 COIN Trial Investigators Morley C J Davis P G Doyle L W Brion L P Hascoet J M Carlin J B Nasal CPAP or intubation at birth for very preterm infants\nN Engl J Med 2008 358 07 700 708\n18272893 \n8 Roberts D Brown J Medley N Dalziel S R Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth\nCochrane Database Syst Rev 2017 3 CD004454 28321847 \n9 American College of Obstetricians and Gynecologists COVID-19 FAQs for obstetricians-gynecologists, obstetrics\nWashington, DC ACOG 2020 American College of Obstetricians and Gynecologists: American Journal of Obstetrics and Gynecology. Accessed May 29, 2020 at:https://www.acog.org/clinical-information/physician-faqs/covid-19-faqs-for-ob-gyns-obstetrics\n10 McIntosh J J Corticosteroid guidance for pregnancy during COVID-19 pandemic\nAm J Perinatol 2020 37 08 809 812\n32274772 \n11 Chen H Guo J Wang C Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records\nLancet 2020 395 (10226):809 815\n32151335 \n12 Coronado Munoz A Nawaratne U McMann D Ellsworth M Meliones J Boukas K Late-onset neonatal sepsis in a patient with covid-19\nN Engl J Med 2020 382 19 e49 32320556 \n13 Zeng H Xu C Fan J Antibodies in infants born to mothers with COVID-19 pneumonia\nJAMA 2020 323 18 1848 1849\n32215589 \n14 Wang W Xu Y Gao R Detection of SARS-CoV-2 in different types of clinical specimens\nJAMA 2020 323 18 1843 1844\n32159775 \n15 Shah P S Diambomba Y Acharya G Morris S K Bitnun A Classification system and case definition for SARS-CoV-2 infection in pregnant women, fetuses, and neonates\nActa Obstet Gynecol Scand 2020 99 05 565 568\n32277845 \n16 Baud D Greub G Favre G Second-trimester miscarriage in a pregnant woman with SARS-CoV-2 infection\nJAMA 2020 323 21 2198 2200\n32352491 \n17 Yang Z Wang M Zhu Z Liu Y Coronavirus disease 2019 (COVID-19) and pregnancy: a systematic review\nJ Matern Fetal Neonatal Med 2020 1 4\n\n18 Alzamora M C Paredes T Caceres D Webb C M Valdez L M La Rosa M Severe COVID-19 during pregnancy and possible vertical transmission\nAm J Perinatol 2020 37 08 861 865\n32305046 \n19 Zamaniyan M Preterm delivery in pregnant woman with critical COVID-19 pneumonia and vertical transmission\nPrenat Diagn2020 \n20 Mimouni F Lakshminrusimha S Pearlman S A Raju T Gallagher P G Mendlovic J Perinatal aspects on the covid-19 pandemic: a practical resource for perinatal-neonatal specialists\nJ Perinatol 2020 40 05 820 826\n32277162 \n21 Sichitiu J Fakhouri F Desseauve D Antenatal corticosteroid therapy and COVID-19: Pathophysiological considerations\nActa Obstet Gynecol Scand 2020 99 07 952 32356302\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2157-7005",
"issue": "10(3)",
"journal": "AJP reports",
"keywords": "COVID-19; SARS-CoV-2; coronavirus; pneumothorax; preterm",
"medline_ta": "AJP Rep",
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"nlm_unique_id": "101569862",
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"pages": "e266-e269",
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"pubdate": "2020-07",
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"references": "32386562;32356302;32274772;32330287;32292903;32354293;32277162;32352491;32215598;32159775;18272893;32430957;32277845;28321847;32151335;32320556;28013308;32305046;32215589",
"title": "Air Leak Syndrome in Two Very Preterm Infants Born to Mothers with Coronavirus Disease 2019: An Association or a Coincidence?",
"title_normalized": "air leak syndrome in two very preterm infants born to mothers with coronavirus disease 2019 an association or a coincidence"
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"abstract": "Pembrolizumab, one of many novel immune checkpoint inhibitors (ICPi), is a monoclonal antibody that enhances immunity against cancer cells. Extensive escalation in immune activity predisposes to unsought immune-related adverse events. Due to progressive mesothelioma, a 67-year-old man was referred to the research unit and enrolled in a clinical trial with a cluster of differentiation (CD) 27 chemotherapeutic agent. He began crossover treatment and received just two doses of pembrolizumab, 33 and 16 days prior to admission. He subsequently presented to the emergency department with three days of acute onset severe diplopia and a drooping left eye. Acetylcholine receptor (AChR) antibodies returned positive at 13.9 nmol/L, and a diagnosis of ocular myasthenia gravis (OMG) was made. During his hospitalization, the patient was managed with methylprednisolone 80 mg intravenously daily, with conversion to prednisone 60 mg by mouth daily at time of discharge. Neuro-ophthalmology consultation was sought in the outpatient setting, and the patient was started on pyridostigmine. He was readmitted two weeks later with symptoms of progressive diffuse weakness, unsteady gait, and dysphagia, all in the setting of persistent diplopia. Intravenous immunoglobulin (IVIG) was promptly initiated, in addition to the pyridostigmine previously initiated in the outpatient setting. Unfortunately, after three IVIG treatments, the patient had experienced little improvement in his symptoms, and therefore elected hospice care. Although ICPis have revolutionized the management of a multitude of malignancies, recognition of immune-related adverse events is of critical importance.",
"affiliations": "Internal Medicine, Sarasota Memorial Hospital, Florida State University College of Medicine, Sarasota, USA.;Pharmacy, Sarasota Memorial Hospital, Sarasota, USA.;Internal Medicine, Sarasota Memorial Hospital, Florida State University College of Medicine, Sarasota, USA.;Internal Medicine, Sarasota Memorial Hospital, Florida State University College of Medicine, Sarasota, USA.;Internal Medicine, Sarasota Memorial Hospital, Florida State University College of Medicine, Sarasota, USA.",
"authors": "Lorenzo|Christian J|CJ|;Fitzpatrick|Haley|H|;Campdesuner|Victoria|V|;George|Justin|J|;Lattanzio|Natalia|N|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.9192\nNeurology\nOphthalmology\nOncology\nPembrolizumab-Induced Ocular Myasthenic Crisis\nMuacevic Alexander Adler John R Lorenzo Christian J 1 Fitzpatrick Haley 2 Campdesuner Victoria 1 George Justin 1 Lattanzio Natalia 1 \n1 \nInternal Medicine, Sarasota Memorial Hospital, Florida State University College of Medicine, Sarasota, USA \n\n2 \nPharmacy, Sarasota Memorial Hospital, Sarasota, USA \n\nChristian J. Lorenzo christian.lorenzo16@gmail.com\n14 7 2020 \n7 2020 \n12 7 e919223 5 2020 14 7 2020 Copyright © 2020, Lorenzo et al.2020Lorenzo et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/31371-pembrolizumab-induced-ocular-myasthenic-crisisPembrolizumab, one of many novel immune checkpoint inhibitors (ICPi), is a monoclonal antibody that enhances immunity against cancer cells. Extensive escalation in immune activity predisposes to unsought immune-related adverse events. Due to progressive mesothelioma, a 67-year-old man was referred to the research unit and enrolled in a clinical trial with a cluster of differentiation (CD) 27 chemotherapeutic agent. He began crossover treatment and received just two doses of pembrolizumab, 33 and 16 days prior to admission. He subsequently presented to the emergency department with three days of acute onset severe diplopia and a drooping left eye. Acetylcholine receptor (AChR) antibodies returned positive at 13.9 nmol/L, and a diagnosis of ocular myasthenia gravis (OMG) was made. During his hospitalization, the patient was managed with methylprednisolone 80 mg intravenously daily, with conversion to prednisone 60 mg by mouth daily at time of discharge. Neuro-ophthalmology consultation was sought in the outpatient setting, and the patient was started on pyridostigmine. He was readmitted two weeks later with symptoms of progressive diffuse weakness, unsteady gait, and dysphagia, all in the setting of persistent diplopia. Intravenous immunoglobulin (IVIG) was promptly initiated, in addition to the pyridostigmine previously initiated in the outpatient setting. Unfortunately, after three IVIG treatments, the patient had experienced little improvement in his symptoms, and therefore elected hospice care. Although ICPis have revolutionized the management of a multitude of malignancies, recognition of immune-related adverse events is of critical importance. \n\npembrolizumabkeytrudamyasthenia gravisocularmyasthenic crisisanti-pd-1diplopiaptosisimmune checkpoint inhibitorThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nPembrolizumab, one of many novel immune checkpoint inhibitors (ICPi), is a highly selective humanized immunoglobulin 4 (IgG4) monoclonal antibody that enhances immunity against cancer cells. This is achieved by inhibition of the programmed death (PD) pathway. During cell-mediated immune encounters, tumor cell PD-1 ligands (PDL) are appreciated by PD receptors on the surface of T-cells. This interaction will halt T-cell defenses, allowing the cancer cells to continue to proliferate. Pembrolizumab and nivolumab (a similar monoclonal antibody) act by inhibiting PD-1 ligation, permitting restoration in T-cell-driven anti-tumor response [1]. Unfortunately, extensive escalation in immune activity predisposes to unsought immune-related adverse events. Myasthenia gravis (MG) is a neurological disorder that affects the neuromuscular junction causing muscle weakness and fatigability in a plethora of clinical presentations [2]. MG is a relatively rare adverse event associated with both pembrolizumab and nivolumab. Among 23 reported cases of ICPi-associated MG summarized in 2017, 72.7% were de novo presentations, 18.2% were exacerbations of pre-existing MG, and 9.1% were considered to be exacerbations of subclinical MG [3]. Additionally, MG very rarely may manifest with symptomatology exclusive to the ocular muscles, known as ocular myasthenia gravis (OMG). Although there have been multiple post-surveillance case reports of patients receiving anti-PD-1 therapy presenting with new or exacerbated MG, to date, there have only been eight reported cases of anti-PD-1 associated OMG; five of which were a direct result of pembrolizumab [4-9]. A case of pembrolizumab-induced OMG is described.\n\nCase presentation\nA 67-year-old male with a medical history of malignant mesothelioma presented to the emergency department with three days of acute onset severe diplopia. He had associated frontal headache, blurred vision, and horizontal binocular diplopia. Symptoms were alleviated when he closed either eye. He also noticed drooping of the left eye. He notably denied any focal deficits or dysarthria. The patient previously had been receiving chemotherapy for the past 10 years including cisplatin, pemetrexed, and gemcitabine. Prior to admission, due to progression of his mesothelioma, he was referred to the research unit and was enrolled in a clinical trial with a novel cluster of differentiation (CD) 27 chemotherapeutic agent. He began crossover treatment and received a total of just two pembrolizumab doses, 33 and 16 days prior to admission. Physical examination was pertinent for a visual acuity of 20/20 in the right eye and 20/25 in the left eye. Pupils were equal, round, and reactive to light. Examination of extraocular movements revealed a right eye abduction deficit of approximately 25% and a 100% abduction deficit in the left eye. He denied diplopia on primary gaze. On rightward gaze, there was a horizontal diplopia with an oblique component appreciated. There was ptosis of the left eye present. Fundoscopic examination revealed no papilledema. The patient had normal muscle bulk and tone with 5/5 strength in all four extremities. \n\nSedimentation rate was found elevated at 37 mm/hr. Lumbar puncture was performed, which yielded 15 cc of cerebral spinal fluid (CSF) with an opening pressure measured at 17 cmH2O. Cytology of the fluid was grossly unremarkable, as were cultures. Of the CSF studies, glucose was 64 mg/dL, protein was 41 mg/dL, and Venereal Disease Research Laboratory test (VDRL) was negative. CT angiogram of the head and neck revealed no occlusion or flow-limiting stenosis. Acetylcholine receptor (AChR) antibodies returned positive at 13.9 nmol/L. While hospitalized, the patient, with an admission weight of 86.1 kg, was treated with methylprednisolone 80 mg intravenously daily, with conversion to prednisone 60 mg by mouth daily at the time of discharge. However, several days later, the patient experienced progressive diffuse weakness and unsteady gait, in addition to persistent diplopia. Neuro-ophthalmologic consultation was sought in the outpatient setting, and he was started on pyridostigmine. He was readmitted two weeks later with worsening neurological symptoms of paresis and dysphagia. Intravenous immunoglobulin (IVIG) was initiated for a planned five days of treatment, in addition to his pyridostigmine. After three days of therapy with little improvement in his symptoms, the patient elected hospice care, which was coordinated.\n\nDiscussion\nThe neuromuscular junction is a synaptic communication between nerve endings and a muscle. When an action potential propagates down a motor nerve to the nerve terminal, acetylcholine (ACh) is released from 150-200 vesicles, also known as quama, from the presynaptic nerve fiber. The subsequent ligation of ACh to AChR can depolarize the postsynaptic membrane, allowing for the muscle to contract. The pathophysiology of MG most commonly includes the creation of antibodies against the AChR, which decreases the number of available AChRs at the postsynaptic muscle membrane. Therefore, despite adequate ACh release, end-plate action potentials fail to trigger muscle action potentials resulting in muscular paresis [2]. A large population of patients with systemic MG also have ocular involvement that can occur either initially or later during the clinical course of the disease [10].\n\nOMG is a subtype of MG where muscular fatigue is clinically isolated to the extraocular muscles (EOMs), levator, and orbicularis oculi. Signs and symptoms of OMG include ptosis and diplopia, which are present in over 50% of systemic MG. The majority of OMG patients (50%-80%) go on to develop generalized MG. OMG can mimic cranial nerve pathology, gaze palsies, internuclear ophthalmoplegia, blepharospasm, and stroke. All of these etiologies were in the differential diagnosis of this patient. Serum antibodies are present in 99% of patients with generalized MG but only 40%-70% of patients with OMG. EOMs develop tension quicker and have a higher frequency of synaptic firing than muscle groups of the upper and lower extremities. As a result, they are more vulnerable to fatigue and exhaustion. Additionally, tonic muscle fibers are critical to sustainment of ocular gaze [10].\n\nLower temperatures have been hypothesized to decrease the activity of acetylcholinesterase (AChE), which is an enzyme present within the synaptic folds responsible for hydrolyzing ACh. If a patient has ptosis, application of an ice pack over the ptotic eye often will result in clinical improvement of ptosis. This is hypothesized to be secondary to decreased AChE activity, in addition to less depletion of quanta occurring secondary to decreased temperature. The ice test is not necessarily diagnostic but can raise the suspicion of MG [1,2]. The sleep test evaluates for resolution of ptosis or ophthalmoparesis immediately after a 30-minute period of sleep [10].\n\nIn a patient with typical symptomatology and physical exam findings of OMG, the diagnosis can be solidified with a positive AChR antibody titer. If titers are negative, as they are in about 30%-77% of cases, electromyography with repetitive nerve stimulation or single-fiber electromyography is necessary in order to establish a diagnosis. If the above studies are negative, MRI of the brain and lumbar puncture with CSF analysis may be warranted to exclude further inflammatory or structural pathology of the central nervous system [10]. \n\nAdverse events are unfavorable signs, symptoms, or diseases which are temporally associated with the use of a medical treatment or procedure that may or may not be considered related to said treatment or procedure. A grading system, developed by the Cancer Therapy Evaluation Program, spanning from grade 1-5 evaluates the severity of these adverse events. Grade 1 indicates a mild event in which intervention is not indicated. Grade 2 is deemed as moderate, grade 3 as severe, grade 4 as life-threatening, and grade 5 as resulting in death; all warranting implementation of intervention.\n\nIn regard to the management of anti-PD-1 associated MG, there is no grade 1 toxicity. All grades warrant a thorough diagnostic workup and intervention given the potential risk of progression of MG-induced respiratory insufficiency. In grade 2 MG (adverse event), it is recommended to hold the anti-PD1 ICPi which may be resumed if symptoms resolve. Neurology consultation should be sought, and the patient should be offered pyridostigmine with an initial dose of 30 mg by mouth three times daily. The dose can gradually be increased to a maximum daily dose of 480 mg divided in four doses. In all grades of MG, systemic steroids remain the mainstay treatment (e.g., prednisone 1-1.5 mg/kg by mouth daily). Notably, if the patient presents with grade 3 or 4 MG, the anti-PD1 ICPi must be permanently discontinued. The patient should be admitted potentially to the intensive care unit and again, neurology consultation is warranted. IVIG 2 g/kg administered over five days versus plasmapheresis for five days is currently recommended in addition to corticosteroid therapy. Frequent pulmonary function assessment should be offered due to the risk of respiratory compromise seen in systemic MG [11].\n\nConclusions\nThis case demonstrates an infrequent and uniquely characteristic complication of pembrolizumab presenting in the form of ptosis, oculomotor paresis, and diplopia. A diagnosis of OMG was confirmed with AChR antibody positivity. A comprehensive diagnostic workup for all grades of ICPi-induced MG is warranted, including laboratory, imaging, and potential pulmonary function testing. As the majority of OMG patients do, this patient eventually progressed to systemic MG requiring not only corticosteroid therapy but also IVIG. Although ICPis have revolutionized the management of a multitude of oncologic malignancies, recognition of immune-related adverse events is of critical importance.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Cancer treatment and chemotherapy Pharmacotherapy: A Pathophysiologic Approach, 10e Cordes LM Shord SS 2029 2077 New York McGraw-Hill 1 2017 https://accesspharmacy.mhmedical.com/book.aspx?bookID=1861 \n2 Myasthenia gravis and other diseases of the neuromuscular junction Harrison's Principles of Internal Medicine, 20e Amato AA 3232 3238 New York McGraw-Hill 1 2018 https://accessmedicine.mhmedical.com/book.aspx?bookID=2129 \n3 Myasthenia gravis: an emerging toxicity of immune checkpoint inhibitors Eur J Cancer Makarious D Horwood K Coward JIG 128 136 82 2017 28666240 \n4 Pembrolizumab-induced ocular myasthenia gravis with anti-titin antibody and necrotizing myopathy Intern Med Onda A Miyagawa S Takahashi N 1635 1638 58 2019 30713313 \n5 Pembrolizumab‐associated ocular myasthenia gravis Clin Exp Ophthalmol Liu Q Ayyappan S Broad A Narita A 796 798 47 2019 30859689 \n6 Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan Neurology Suzuki S Ishikawa N Konoeda F 1127 1134 89 2017 28821685 \n7 Two cases of clinical myasthenia gravis associated with pembrolizumab use in responding melanoma patients Melanoma Res Nguyen BH Kuo J Budiman A Christie H Ali S 152 154 27 2017 27776019 \n8 Neurologic complications of immune checkpoint inhibitors J Neurooncol Fellner A Makranz C Lotem M 601 609 137 2018 29332184 \n9 Myasthenia gravis induced by nivolumab therapy in a patient with non-small-cell lung cancer Muscle Nerve Polat P Donofrio PD 507 54 2016 \n10 Ocular myasthenia gravis: a review Indian J Ophthalmol Nair AG Patil-Chhablani P Venkatramani DV Ghandi RA 985 991 62 2014 25449931 \n11 Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline summary J Oncol Pract Brahmer J Lacchetti C Thompson JA 247 249 14 2018 29517954\n\n",
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"keywords": "anti-pd-1; diplopia; immune checkpoint inhibitor; keytruda; myasthenia gravis; myasthenic crisis; ocular; pembrolizumab; ptosis",
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"title": "Pembrolizumab-Induced Ocular Myasthenic Crisis.",
"title_normalized": "pembrolizumab induced ocular myasthenic crisis"
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"abstract": "Donor-derived Strongyloides stercoralis infections in transplant recipients are a rare but recognized complication. In this case series, we report donor-derived allograft transmission of Strongyloides in three solid organ transplant recipients. Following detection of infection in heart and kidney-pancreas recipients at two different transplant centers, a third recipient from the same donor was identified and diagnosed. S. stercoralis larvae were detected in duodenal aspirates, bronchial washings, cerebrospinal fluid, urine and stool specimens. Treatment with ivermectin and albendazole was successful in two of the three patients identified. The Centers for Disease Control and Prevention was contacted and performed an epidemiologic investigation. Donor serology was strongly positive for S. stercoralis antibodies on retrospective testing while all pretransplant recipient serum was negative. There should be a high index of suspicion for parasitic infection in transplant recipients and donors from endemic regions of the world. This case series underscores the need for expanded transplant screening protocols for Strongyloides. Positive serologic or stool tests should prompt early treatment or prophylaxis in donors and recipients as well as timely notification of organ procurement organizations and transplant centers.",
"affiliations": "Department of Transplantation and Liver Surgery, Geisinger Medical Center, Danville, PA.",
"authors": "Le|M|M|;Ravin|K|K|;Hasan|A|A|;Clauss|H|H|;Muchant|D G|DG|;Pasko|J K|JK|;Cipollina|G|G|;Abanyie|F|F|;Montgomery|S P|SP|;Loy|M|M|;Ahmed|M|M|;Mathur|M|M|;Chokkalingam Mani|B|B|;Mehr|J|J|;Kotru|A|A|;Varma|C|C|;Maksimak|M|M|;Schultz|M|M|;Obradovic|G|G|;Alvarez|R|R|;Toyoda|Y|Y|;Birkenbach|M|M|;Brunner|E|E|;Nelson|J|J|",
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"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "Donor screening; Strongyloides; donor-to-host transmission; heart transplantation; renal and pancreas transplantation; renal transplant; strongyloidiasis; survivors; transplant infectious diseases",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000293:Adolescent; D000818:Animals; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D011379:Prognosis; D017171:Strongyloides stercoralis; D013322:Strongyloidiasis; D014019:Tissue Donors; D066027:Transplant Recipients; D014184:Transplantation, Homologous",
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"title": "Single donor-derived strongyloidiasis in three solid organ transplant recipients: case series and review of the literature.",
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"abstract": "We are reporting a rare case of oesophageal candidiasis in an immunocompetent child secondary to prolonged use of inhaled steroids.",
"affiliations": null,
"authors": "Hassan|T I Y|TI|;Mahony|M|M|",
"chemical_list": null,
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0332-3102",
"issue": "107(8)",
"journal": "Irish medical journal",
"keywords": null,
"medline_ta": "Ir Med J",
"mesh_terms": "D002177:Candidiasis; D002648:Child; D004935:Esophageal Diseases; D005260:Female; D006801:Humans; D007121:Immunocompetence",
"nlm_unique_id": "0430275",
"other_id": null,
"pages": "243-4",
"pmc": null,
"pmid": "25282966",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Oesophageal candidiasis in an immunocompetent child.",
"title_normalized": "oesophageal candidiasis in an immunocompetent child"
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"abstract": "A 67-year-old male, with a known diagnosis of myelodysplastic syndromes with multilineage dysplasia (MDS-MLD) was admitted to our hospital with a primary complaint of subcutaneous bleeding in his left thigh. Laboratory data showed anaemia and prolongation of activated partial thromboplastin time (85.8 s, normal range 24-39 s) without thrombocytopenia. Coagulation factor VIII (FVIII) activity was less than 1% (normal range 60-150%), and a FVIII inhibitor was identified and quantified at 166 BU/mL to indicate a diagnosis of acquired haemophilia A (AHA). A recent, but sustained circulating monocytosis (>1 × 109/L) was observed, which combined with elevated numbers of neutrophil and monocytic cells in the marrow, suggested evolution of MDS-MLD to chronic myelomonocytic leukaemia (CMML), coinciding with AHA. Further analysis revealed a karyotype of 46, XY, i(14) (q10), which was the same abnormality previously identified in the patient. To treat bleeding caused by AHA, steroid and activated prothrombin complex concentrate were administered. Azacitidine (AZA) was used to treat CMML. During the clinical course, bleeding partially improved; however, subsequent acute myocardial infarction occurred on day 87. Worsening bone marrow failure was observed 4 months after the original admission, despite administration of AZA therapy, and the patient died due to bleeding from AHA. This case suggests that the evolution of MDS to CMML status can be associated with AHA conferring a bleeding tendency.",
"affiliations": "Department of Hematology and Oncology, Kita-Harima Medical Center, Hyogo, Japan.;Department of Hematology and Oncology, Kita-Harima Medical Center, Hyogo, Japan.;Department of Nephrology, Kobe University Hospital, Hyogo, Japan.;Division of Laboratory Medicine, Kita-Harima Medical Center, Hyogo, Japan.;Department of Cardiology, Kita-Harima Medical Centre, Hyogo, Japan.;Department of Cardiology, Kita-Harima Medical Centre, Hyogo, Japan.;Department of Hematology, Hyogo Cancer Center, Akashi, Japan.;Department of Hematology and Oncology, Kita-Harima Medical Center, Hyogo, Japan.",
"authors": "Araki|Takeshi|T|;Ohata|Shinya|S|;Okamoto|Kohei|K|;Morimoto|Kazuhide|K|;Hiraishi|Mana|M|;Yamada|Shinichiro|S|;Mizuno|Ishikazu|I|;Sugimoto|Takeshi|T|0000-0002-8121-5323",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2019/8612031",
"fulltext": "\n==== Front\nCase Rep HematolCase Rep HematolCRIHEMCase Reports in Hematology2090-65602090-6579Hindawi 10.1155/2019/8612031Case ReportA Case of Acquired Haemophilia A in a Patient with Chronic Myelomonocytic Leukaemia Araki Takeshi \n1\nOhata Shinya \n1\nOkamoto Kohei \n2\nMorimoto Kazuhide \n3\nHiraishi Mana \n4\nYamada Shinichiro \n4\nMizuno Ishikazu \n5\nhttp://orcid.org/0000-0002-8121-5323Sugimoto Takeshi takeshi_sugimoto@kitahari-mc.jp\n1\n\n1Department of Hematology and Oncology, Kita-Harima Medical Center, Hyogo, Japan\n2Department of Nephrology, Kobe University Hospital, Hyogo, Japan\n3Division of Laboratory Medicine, Kita-Harima Medical Center, Hyogo, Japan\n4Department of Cardiology, Kita-Harima Medical Centre, Hyogo, Japan\n5Department of Hematology, Hyogo Cancer Center, Akashi, JapanAcademic Editor: Sudhir Tauro\n\n2019 27 2 2019 2019 86120312 10 2018 8 12 2018 10 2 2019 Copyright © 2019 Takeshi Araki et al.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.A 67-year-old male, with a known diagnosis of myelodysplastic syndromes with multilineage dysplasia (MDS-MLD) was admitted to our hospital with a primary complaint of subcutaneous bleeding in his left thigh. Laboratory data showed anaemia and prolongation of activated partial thromboplastin time (85.8 s, normal range 24–39 s) without thrombocytopenia. Coagulation factor VIII (FVIII) activity was less than 1% (normal range 60–150%), and a FVIII inhibitor was identified and quantified at 166 BU/mL to indicate a diagnosis of acquired haemophilia A (AHA). A recent, but sustained circulating monocytosis (>1 × 109/L) was observed, which combined with elevated numbers of neutrophil and monocytic cells in the marrow, suggested evolution of MDS-MLD to chronic myelomonocytic leukaemia (CMML), coinciding with AHA. Further analysis revealed a karyotype of 46, XY, i(14) (q10), which was the same abnormality previously identified in the patient. To treat bleeding caused by AHA, steroid and activated prothrombin complex concentrate were administered. Azacitidine (AZA) was used to treat CMML. During the clinical course, bleeding partially improved; however, subsequent acute myocardial infarction occurred on day 87. Worsening bone marrow failure was observed 4 months after the original admission, despite administration of AZA therapy, and the patient died due to bleeding from AHA. This case suggests that the evolution of MDS to CMML status can be associated with AHA conferring a bleeding tendency.\n==== Body\n1. Introduction\nAcquired haemophilia A (AHA) is a bleeding disorder caused by antibodies against coagulation factor VIII (FVIII). The reported incidence of AHA is between 1.0 and 1.5 cases per million population per year [1, 2]. The resulting coagulopathy can be life threatening, and if left untreated, has an overall mortality rate of 7.9%–22% [3]. Almost half of the AHA cases presented are idiopathic; the other half are associated with autoimmune disease, malignancy, dermatological disease, or pregnancy [4, 5]. The case presented herein had AHA with chronic myelomonocytic leukaemia (CMML).\n\n2. Case Presentation\nA 67-year-old man presented to our hospital with a primary complaint of subcutaneous bleeding in his left thigh and development of purpura, over the last 3 months. It had been pointed out to him that there was a mild anaemia with haemoglobin level of 10.4 g/dL. He had been diagnosed two years previously with myelodysplastic syndromes with multilineage dysplasia (MDS-MLD) considered in the context of the 2016 World Health Organization (WHO) classification criteria. The 46, XY, i(14) (q10) abnormality was detected in 100% of marrow metaphases (Figure 1(a)). The bone marrow blast was 3.3%. He was categorized as low risk in Revised International Prognostic Scoring System (IPSS-R), and he had not received cytokine therapy or blood transfusion. He had a medical history of hypertension, type 2 diabetes mellitus, spinal canal stenosis, and idiopathic osteonecrosis of the femoral head and underwent right total hip arthroplasty (r-THA).\n\nPhysical examination showed conjunctival pallor and a swelling on the left thigh with overlying bruising (Figure 2(a)). Computed tomography revealed a large bleed in the left quadriceps femoris muscle (Figure 2(b)). Laboratory data showed the following: white blood cell count, 13.6 × 109/L (normal range 3.5–9.7 × 109/L); monocyte count, 4.6 × 109/L (monocyte percentage, 33.6%); haemoglobin level, 8.8 g/dL (13.2–17.2 g/dL); haematocrit, 28.1% (40–52%); and platelet count, 258 × 109/L (140–370 × 109/L) (Table 1). On review, the monocyte count on three months previously too had been elevated (3.0 × 109/L). Activated partial thromboplastin time (APTT) was significantly prolonged (85.8 s, normal range 24–39 s). Prothrombin time was within the normal range (10.5–14 s). Mixing studies demonstrated that the prolongation of APTT was not corrected by the addition of an equal volume of pooled normal plasma either instantaneously or over two hours of incubation, indicating the presence of an inhibitor. When coagulation factors of the intrinsic pathway were measured, FVIII activity was less than 1% (normal range 60–150%), and coagulation factors IX, XI, and XII were also found to be reduced. Further tests did not detect lupus anticoagulant antibody. The inhibitor for FVIII was quantified using the Bethesda method and showed a high level of 166 BU/mL, but there was no inhibitory activity against factor IX inhibitor (Table 1). Since the patient's coagulation profile had previously been normal, the current results indicated that he had developed acquired haemophilia A (AHA).\n\n3. Clinical Course\nIn order to treat bleeding caused by AHA, we administered activated prothrombin complex concentrate (aPCC; FEIBA, Baxalta©) at a loading dose of 50 U/kg. Immunosuppression with oral prednisolone (PSL) at a dose of 1 mg/kg/day was started on day 3 of hospitalization. Once the patient was less hemorrhagic, further investigations were performed: to assess a possible change in the underlying haematological malignancy, bone marrow examination was undertaken 3 weeks after starting PSL therapy. The bone marrow aspirate revealed normocellular marrow (nucleated cell counts (NCC), 29.7 × 104/µL) and normal myeloid/erythroid (M/E) ratio (1.7). Blast cells accounted for two percentage of NCC. Bone marrow aspirate also shown an elevated number of neutrophils and monocytes with cytoplasmic vacuoles (Table 2) with micromegakaryocyte and erythroblast dysplasia, and the karyotype was determined to be 46, XY, i(14) (q10), which was the same abnormality as previously identified (Figures 2(c)–2(e)). Polymerase chain reaction was negative for both bcr/abl1 fusion gene and JAK2 mutation. Based on the blood monocytosis and marrow appearances, a diagnosis of chronic myelomonocytic leukaemia (CMML-0) was made. He was not eligible for allogeneic stem cell transplantation because of his age and general status. At the time of bone marrow examination, AHA had not remitted on PSL therapy. FVIII activity was still less than 1%, and inhibitor titer was 109 BU/mL (Figure 3). Platelet count was 142 × 109/L, APTT was 90.9 s, and fibrinogen titer was 131 mg/dL. Assuming a causal relationship between CMML and AHA, we decided to initiate treatment of CMML with the hypomethylating agent, azacitidine (AZA; 75 mg/m2 × 7 days, repeated an intervals of 4 weeks), starting 4 weeks after commencing the patient on PSL therapy. After two months of therapy with PSL, the titer of FVIII inhibitor had reduced to 22 BU/mL, but subcutaneous bleeding in his thigh and hemorrhage at the site where blood was drawn had not settled. The laboratory parameter for coagulation did not improve (platelet count, 36 × 109/L; APTT, 94 s; fibrinogen titer, 185 mg/dL; and FVIII activity level, below 3%). We speculated that hypofibrinogenemia was caused by the consumption of fibrinogen on the bleeding with AHA. Cyclosporine A (100 mg/day) was added in to PSL therapy, which improved bleeding events in the extremities and trunk, and FVIII activity level increased to 6% by day 75. However, the patient now began to complain of chest pain and was diagnosed as angina pectoris and was listed for elective percutaneous coronary artery intervention (PCI). On day 87, prior to PCI, the patient received prophylactic platelet transfusion for his low platelet count (25 × 109/L) and aPCC administration as preoperative treatment to prevent bleeding by PCI, but he suffered an acute myocardial infarction. PCI was urgently performed with successful revascularization and resolution of chest pain. He did not receive antiplatelet agent because of his thrombocytopenia. Bleeding symptoms were not evident until 1 month after PCI in which FVIII inhibitor could reach to undetectable level on day 84 and 98 but worsened thereafter coinciding with the appearance of FVIII inhibitor. CyA was switched to 100 mg/day of cyclophosphamide (CPA) with continuous use of PSL on day 117. Prior to the fourth course of AZA therapy, bleeding symptoms emerged and the titer of APTT increased to 100.8 s on day 122, suggesting activation of AHA. Bone marrow reexamination performed on day 138 showed hypocellular marrow, with reduced M/E ratio (1.7 to 0.1). There was no increase in blasts to suggest transformation to acute leukaemic transformation (Table 2). Karyotype analysis, using both G-banding and spectral karyotyping (SKY) methods, revealed an abnormal karyotype, i.e., [idic (14), +1, and der (1; 7)(q10; p10)] (G-banding method [18/20] clone, SKY method [5/5] clone), suggesting clonal evolution (Figure 1(b)) and therefore failure of AZA treatment [6]. AZA was stopped and CPA was replaced with azathioprine 50 mg/day on day 143. He continued on 7.5 mg/day of PSL. He developed recurrent episodes of bruising with APTT index of 100–110 s. Seven months after presenting with AHA, the patient developed gastrointestinal bleeding and died (Figure 3). The response of AHA to treatment was non-CR based on the UK Haemophilia Centre Doctors' Organization criteria [7], despite normalization of FVIII activity and transient disappearance of FVIII inhibitor from hospital day 84 to 98.\n\n4. Discussion\nThe case presented herein had AHA with evolution of MDS-MLD to CMML, which is classified as a rare cause among haematological malignancies. The relationship between MDS or CMML and autoimmune disease has been previously discussed. Approximately 10%–30% MDS or CMML cases are associated with autoimmune diseases [8–10], of which CMML is the most predominant condition [8]. In terms of haematological autoimmune diseases, idiopathic thrombocytopenic purpura, autoimmune hemolytic anaemia, and pure red cell aplasia are commonly seen. Acquired haemophilia complication as a haematological autoimmune disease is rare in MDS or CMML cases. The reason for this may be due to the rare incidental rate of acquired haemophilia. Several cases of AHA complicated with CMML or MDS have been reported [11–16]. Including our case, four out of eight AHA cases went into remission after treatment; three of these cases were administered a hypomethylating agent (AZA or decitabine) for CMML (Table 3). The No. 1 case [11] treated with AZA and panobinostat (histone deacetylase inhibitor) achieved CR. In the three CMML cases (No. 1, 3, and 4) reached to CR of AHA, bone marrow status was examined in only one case (No. 1), which showed CR of CMML status. Bone marrow assessment for the evaluation of CMML status after treatment will be required. In our case, coagulation bypass therapy involving aPCC was performed to stop the bleeding caused by AHA; immunosuppressive therapy by PSL, involving CyA and CPA, was also initiated to prevent the production of AHA antibody. In addition, AZA was administered to treat CMML, which appeared to be the primary disease underlying AHA. During the clinical course of our case, the bleeding symptoms transiently improved after combination therapy with AZA, PSL, and immunosuppressive drugs (CyA, CPA, and azathioprine); however, bleeding tendency recurred in accordance with a reduction of bone marrow cells. We speculated that this bleeding was caused by both AHA-related coagulopathy and thrombocytopenia. Bone marrow examination on day 138 showed the prevalence of abnormal karyotype, i.e., [idic (14), +1, and der (1; 7)(q10; p10)], even if the effect of cell reduction by AZA might remain. The result of additional cytogenetic abnormality implied that the progression of CMML is related to the AHA condition. In non-CR cases, progressive bleeding such as severe subcutaneous and muscle bleeding in case No. 6 [15], intracranial hemorrhage in case No. 2 [11], or gastrointestinal bleeding in case No. 8 (our case) caused the patient's death. These cases had the ineffective condition for haemostatic treatment in the last part of the clinical course.\n\nThe mechanism of secondary AHA due to the presence of CMML or MDS remains unclear. In haematological malignancy complicated by AHA, lymphoid malignancy, including lymphoma, chronic lymphoid leukaemia, or macroglobulinaemia, is more common than myeloid malignancy [17]. However, myeloid malignancy is possible to complicate with AIHA infrequently. CMML is predominant in the eight cases shown in Table 3, indicating that CMML may possess a factor responsible for the development of AHA in myeloid malignancy. It is possible that the reason for this is increased inflammatory cytokines levels such as interleukin-6 (IL-6) or tumor necrosis factor alpha that activates the autoimmune function. However, the precise mechanism responsible is unclear. One possibility is that monocytic cells affect autoimmune diseases via the activation of B-cell activating factor (BAFF). In this scenario, BAFF would suppress the production of monocytic cells via a negative feedback mechanism; under normal conditions, BAFF activation would be strictly controlled [18]. Under the CMML conditions, it is possible that increased proportions of monocytic cells, caused by tumorigenesis, do not decrease if BAFF exerts an influence upon the monocytic cell regulation system; the continuation of BAFF activation facilitates the development of autoimmune diseases, such as AHA.\n\nRecombinant factor VIIa or aPCC is generally used for the management of bleeding during surgical treatment of AHA. We chose the use of aPCC because these two agents were used as the similar position for haemostasis, and either choice of these agents would be enough for the management of bleeding. In the present case, elective PCI was scheduled for angina pectoris; the use of aPCC as a pretreatment for the prevention of PCI may have triggered the onset of acute myocardial infarction. With regards to the side effects of aPCC, thrombotic diseases such as disseminated intravascular coagulation, acute myocardial infarction, and pulmonary embolism have been reported [19]. The European Acquired Haemophilia Registry reported that the rate of thrombotic adverse events is 4.8% during aPCC treatment for AHA [20]. Our case had additional risk factors for arteriosclerotic coronary artery disease, such as a smoking habit, hypertension, diabetes mellitus, and obesity. We speculate that the existence of AHA prevented the occurrence of coronary artery disease naturally by inhibiting the intrinsic coagulation pathway and that both normalization of FVIII activity and bypass therapy with aPCC may have stimulated thrombosis of the coronary artery in this patient. A similar case complicated by acute myocardial infarction in partial remission of AHA has been already reported [21]. Consequently, the relationship between the use of haemostatic agents and thrombotic event should be studied further.\n\nConcerning abnormal karyotype, isochromosome 14 (q10) is not common but is recognized in myelocytic malignancy, especially in MDS subtypes RA and CMML [22]. This abnormality can exist as a sole abnormality. Another abnormality, der (1; 7) (q10; p10), is observed in about 1–3% of MDS and less commonly in acute myeloid leukaemia (AML) and myeloproliferative disorders [23]. As chromosome 14 abnormality was observed on three sequential bone marrow tests, chromosome 14 abnormality seems to be the potential cause in this case.\n\nIn conclusion, we have presented a case of AHA with CMML. The bleeding symptoms improved transiently on a combination therapy with AZA, PSL, and immunosuppressive drugs. The relative contribution of each therapy cannot accurately be established. Because bleeding tendency becomes steadily worse as CMML status advances, it follows that the control of CMML appears to be essential for the management of AHA.\n\nAcknowledgments\nThe authors would like to thank Enago (http://www.enago.jp) for their English language review.\n\nConflicts of Interest\nThe authors have no conflicts of interest to declare.\n\nFigure 1 (a) G-banding karyotype showing the i(14q) (q10) with a bone marrow aspiration test at two years before admission. (b) Karyotype analysis using spectral karyotyping (SKY) method with a bone marrow aspiration test on day 138. SKY analysis identified an anomaly [idic (14), +1, and der (1; 7) (q10; p10)], which was the same abnormality as the result by G-banding analysis (data not shown).\n\nFigure 2 (a) Swelling of the left thigh with subcutaneous hemorrhage. (b) Computed tomography showing a large muscle bleed in the left quadriceps femoris muscle (arrow). (c–e) Bone marrow aspiration test on hospital day 24 (HE staining). (c) Normocellular marrow with an adequate proportion of erythrocytes (×400). (d) Granular cells possess a vacuole; 12% of nucleated cell count (NCC) were classified as monocytic cells (×1000, arrow). (e) Abnormal cells stained positive for peroxidase staining (×1000, arrow).\n\nFigure 3 The clinical course of our patient. PSL: prednisolone; CyA: cyclosporine A; CPA: cyclophosphamide; AZP: azathioprine; AZA: azacitidine; aPCC: activated prothrombin complex concentrate; RBC: red blood cells; PC: platelet concentrates; PCI: percutaneous coronary artery intervention.\n\nTable 1 Clinical data on admission.\n\n \tNormal range\t\nWhite blood cell\t13.6 × 109/L\t(3.5–9.7)\t\nNeutrophil\t7.6 (56.1%) × 109/L\t(38–74%)\t\nEosinophil\t0.16 (1.2%) × 109/L\t(0–8.5%)\t\nBasophil\t0.03 (0.2%) × 109/L\t(0–2.5%)\t\nMonocyte\t4.6 (33.6%) × 109/L\t(2–10%)\t\nLymphocyte\t1.2 (8.9%) × 109/L\t(16–50%)\t\nRed blood cell 312\t× 104/μL\t(400–550)\t\nHaemoglobin\t8.8 g/dL\t(13.2–17.2)\t\nHaematocrit\t28.1%\t(40–52)\t\nMCV\t90.1%\t(85–103)\t\nPlatelet\t258 × 109/L\t(140–370)\t\nAST\t18 IU/L\t(13–33)\t\nALT\t12 IU/L\t(8–42)\t\nCK\t38 IU/L\t(62–287)\t\nLD\t270 IU/L\t(119–229)\t\nTotal bilirubin\t0.93 mg/dL\t(0.2–1.3)\t\nBUN\t15.0 mg/dL\t(8–20)\t\nCreatinine\t0.77 mg/dL\t(0.6–1.1)\t\nTotal protein\t6.4 g/dL\t(6.7–8.3)\t\nAlbumin\t3.7 g/dL\t(3.9–4.9)\t\nCRP\t2.37 mg/dL\t(<0.3)\t\nPT\t13.7 s\t(10.5–14)\t\nAPTT\t85.8 s\t(24–39)\t\nFibrinogen\t458 mg/dL\t(200–400)\t\nFDP\t5.6 μg/mL\t(<5)\t\nAnticardiolipin β2GPI\t<1.2 U/mL\t(<3.5)\t\nAnticardiolipin antibody\t<8 U/mL\t(<10)\t\nLupus anticoagulant\t1.06 ratio\t(<1.3)\t\nFactor VIII activity\t<1%\t(60–150)\t\nFactor IX activity\t34%\t(70–130)\t\nFactor XI activity\t20%\t(75–145)\t\nFactor XII activity\t19%\t(50–150)\t\nFactor VIII inhibitor\t166 BU/mL\t(<1)\t\nFactor IX inhibitor\t1 BU/mL\t(<1)\t\nvWF activity\t>200%\t(60–170)\t\nTable 2 The results of bone marrow aspiration.\n\n \tTwo years before admission\tHospital day 24\tHospital day 138\t\nNCC (×104/µL)\t6.1\t29.7\t1.2\t\nMegakaryocyte (/µL)\t60\t156\t18\t\nM/E ratio\t1.3\t1.7\t0.1\t\nErythroid cell (%)\t36.8\t31.0\t71.4\t\nMyeloblast (%)\t3.3\t2.0\t0.8\t\nPromyelocyte (%)\t2.9\t4.2\t0.4\t\nMyelocyte (%)\t5.6\t8.0\t1.0\t\nMetamyelocyte (%)\t5.3\t4.6\t0.2\t\nStabform cell (%)\t8.1\t4.8\t0.2\t\nSegmented cell (%)\t19.8\t28.8\t6.8\t\nEosinophilic cell (%)\t1.4\t0.4\t0.8\t\nBasophilic cell (%)\t0.2\t0.0\t0.0\t\nLymphocyte (%)\t9.4\t3.0\t17.6\t\nMonocyte (%)\t6.4\t12.0\t0.4\t\nPlasma cell (%)\t0.2\t0.8\t0.2\t\nTable 3 Cases of acquired haemophilia A with chronic myelomonocytic leukaemia or myelodysplastic syndromes.\n\nNo\tAge/gender\tDisease\tClinical manifestation\tAPTT (second)\tFVIII activity (%)\tFVIII inhibitor titer (BU/ml)\tTreatment for bleeding and antibody eradication\tAnti-tumor agent\tOutcome of AHA\tReference\t\n1\t54/M\tCMML-1\tLarge ecchymosis at trunk and extremities\t73.4\tNo data\t21\tPSL\tAzacitidine, panobinostat\tCR\t[11]\t\n2\t41/M\tCMML-2\tExcessive bleeding\t91\tNo data\t107.5\tCPA, PSL\t \tNon-CR\t[11]\t\n3\t58/M\tCMML-1\tDiffuse ecchymosis and spontaneous iliopsoas hematoma\t96.3\t<1\t>200\tAPCC, PSL, CPA, rituximab, IVIG\tDecitabine\tCR\t[12]\t\n4\t71/M\tCMML-1\tGross hematuria\t118.6\t6.7\t7.4\tHU, rFVIII\tDecitabine, CAG regimen\tCR\t[13]\t\n5\t75/F\tMDS\tExtensive bruising on body and limbs\t71\t2\t420\tPSL, pyridoxine\t \tCR\t[14]\t\n6\t84/M\tMDS (RAEB-1)\tSubcutaneous and muscle bleeding\t71.8\t3\t3\trFVIIa, PSL\t \tNon-CR\t[15]\t\n7\t71/M\tMDS/MPN\tSpontaneous hematoma and muscle hemorrhage\t64\t24\t9\trFVIII, rFVIIa, APCC, PSL, CPA, IVIG\t \tNon-CR\t[16]\t\n8\t67/M\tCMML-0∗\tSubcutaneous and muscle bleeding\t85.8\t<1\t166\tAPCC, PSL, CyA, CPA, AZP\tAzacitidine\tNon-CR\tOur case\t\nM: male; F: female; CMML: chronic myelomonocytic leukaemia; MDS: myelodysplastic syndromes; PSL: prednisolone; CyA: cyclosporine A; CPA: cyclophosphamide; AZP: azathioprine; HU: hydroxyurea; IVIG: intravenous immunoglobulin; rFVIIa: recombinant factor VIIa; rFVIII: recombinant factor VIII; APCC: activated prothrombin complex concentrate; CR: complete remission; Ref: reference. ∗Diagnosed by WHO 2016 classification.\n==== Refs\n1 Collins P. Macartney N. Davies R. Lees S. Giddings J. Majer R. A population based, unselected, consecutive cohort of patients with acquired haemophilia A British Journal of Haematology 2004 124 1 86 90 10.1046/j.1365-2141.2003.04731.x 2-s2.0-0345802754 14675412 \n2 Franchini M. Mannucci P. Acquired haemophilia A: a 2013 update Thrombosis and Haemostasis 2013 110 12 1114 1120 10.1160/th13-05-0363 2-s2.0-84888426309 24008306 \n3 Franchini M. Targher G. Montagnana M. Lippi G. Laboratory, clinical and therapeutic aspects of acquired hemophilia A Clinica Chimica Acta 2008 395 1-2 14 18 10.1016/j.cca.2008.05.003 2-s2.0-47649105365 \n4 Kessler C. M. Knöbl P. Acquired haemophilia: an overview for clinical practice European Journal of Haematology 2015 95 36 44 10.1111/ejh.12689 2-s2.0-84952772845 26679396 \n5 Knoebl P. Marco P. Baudo F. Demographic and clinical data in acquired hemophilia A: results from the European acquired haemophilia registry (EACH2) Journal of Thrombosis and Haemostasis 2012 10 4 622 631 10.1111/j.1538-7836.2012.04654.x 2-s2.0-84859181554 22321904 \n6 Onida F. Barosi G. Leone G. Management recommendations for chronic myelomonocytic leukemia: consensus statements from the SIE, SIES, GITMO groups Haematologica 2013 98 9 1344 1352 10.3324/haematol.2013.084020 2-s2.0-84883619210 24006407 \n7 Collins P. W. Hirsch S. Baglin T. P. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom haemophilia centre doctors’ organisation Blood 2007 109 5 1870 1877 10.1182/blood-2006-06-029850 2-s2.0-33847411624 17047148 \n8 Braun T. Fenaux P. Myelodysplastic syndromes (MDS) and autoimmune disorders (AD): cause or consequence? Best Practice & Research Clinical Haematology 2013 26 4 327 336 10.1016/j.beha.2013.09.003 2-s2.0-84893811075 24507810 \n9 Peker D. Padron E. Bennett J. M. A close association of autoimmune-mediated processes and autoimmune disorders with chronic myelomonocytic leukemia: observation from a single institution Acta Haematologica 2015 133 2 249 256 10.1159/000365877 2-s2.0-84923211148 25413011 \n10 Zahid M. F. Barraco D. Lasho T. L. Spectrum of autoimmune diseases and systemic inflammatory syndromes in patients with chronic myelomonocytic leukemia Leukemia & Lymphoma 2017 58 6 1488 1493 10.1080/10428194.2016.1243681 2-s2.0-84991031836 27739921 \n11 Uaprasert N. Wongrakpanich S. Rojnuckarin P. Two cases of acquired haemophilia A associated with chronic myelomonocytic leukaemia Blood Coagulation & Fibrinolysis 2013 24 6 655 657 10.1097/mbc.0b013e328360d038 2-s2.0-84882454119 23571686 \n12 Shah D. Kumar R. Gaikazian S. A rare case of acquired haemophilia in a patient with chronic myelomonocytic leukaemia successfully treated with decitabine Haemophilia 2014 20 1 e92 e94 10.1111/hae.12301 2-s2.0-84890857582 24261579 \n13 Liang Y. Lu R.-N. Wang R. Chronic myelomonocytic leukaemia associated with acquired haemophilia A: case report and literature review Haemophilia 2015 21 4 e341 e343 10.1111/hae.12714 2-s2.0-84931956132 25982484 \n14 Lin C. K. Liang R. Liu H. W. Tse P. W. T. Chan G. T. C. Myelodysplastic syndrome and acquired factor VIII inhibitor with severe subcutaneous haemorrhage Acta Haematologica 1991 85 4 206 208 10.1159/000204894 2-s2.0-0025892793 1906670 \n15 Raval M. Kallamadi R. Bande D. A rare case of acquired hemophilia A associated with myelodysplastic syndrome International Journal of Clinical and Experimental Medicine 2012 5 3 262 266 22837802 \n16 Biss T. Crossman L. Neilly I. Hanley J. An acquired factor VIII inhibitor in association with a myeloproliferative/myelodysplastic disorder presenting with severe subcutaneous haemorrhage Haemophilia 2003 9 5 638 641 10.1046/j.1365-2516.2003.00806.x 2-s2.0-0141921405 14511307 \n17 Franchini M. Targher G. Manzato F. Lippi G. Acquired factor VIII inhibitors in oncohematology: a systematic review Critical Reviews in Oncology/Hematology 2008 66 3 194 199 10.1016/j.critrevonc.2007.12.004 2-s2.0-42749089017 18243727 \n18 Steri M. Orrù V. Idda M. L. Overexpression of the cytokine BAFF and autoimmunity risk New England Journal of Medicine 2017 376 17 1615 1626 10.1056/nejmoa1610528 2-s2.0-85018305337 28445677 \n19 Ehrlich H. J. Henzl M. J. Gomperts E. D. Safety of factor VIII inhibitor bypass activity (FEIBAR): 10-year compilation of thrombotic adverse events Haemophilia 2002 8 2 83 90 10.1046/j.1365-2516.2002.00532.x 2-s2.0-0036489638 11952842 \n20 Baudo F. Collins P. Huth-Kuhne A. Management of bleeding in acquired hemophilia A: results from the European acquired haemophilia (EACH2) registry Blood 2012 120 1 39 46 10.1182/blood-2012-02-408930 2-s2.0-84863538387 22618709 \n21 Routledge D. J. M. Fraser D. Thachil J. Nash M. J. Management of a myocardial infarction in a patient with classical acquired haemophilia patient in partial remission Haemophilia 2015 21 6 e494 e496 10.1111/hae.12757 2-s2.0-84946499253 26189485 \n22 Welborn J. Acquired robertsonian translocations are not rare events in acute leukemia and lymphoma Cancer Genetics and Cytogenetics 2004 151 1 14 35 10.1016/j.cancergencyto.2003.09.019 2-s2.0-2342590058 15120908 \n23 Bacher U. Schanz J. Braulke F. Haase D. Rare cytogenetic abnormalities in myelodysplastic syndromes Mediterranean Journal of Hematology and Infectious Diseases 2015 7 1 e2015034 10.4084/mjhid.2015.034 2-s2.0-84942645816\n\n",
"fulltext_license": "CC BY",
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"journal": "Case reports in hematology",
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"title": "A Case of Acquired Haemophilia A in a Patient with Chronic Myelomonocytic Leukaemia.",
"title_normalized": "a case of acquired haemophilia a in a patient with chronic myelomonocytic leukaemia"
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"abstract": "A 23-year-old low-risk primiparous patient, who was 35 weeks pregnant, presented in the emergency department after collapsing at home. Her observations showed severe hypertension with proteinuria. On examination, she had left hemiparesis and was aphasic. Fetal monitoring was reassuring. Initial CT did not reveal any evidence of intracranial pathology. She was stabilised and delivered via emergency caesarean section. Subsequent MRI and CT showed an acute right-sided infarct involving the right middle cerebral artery territory, frontal and parietal regions, and increased mass effect. She was transferred to the nearest neurosurgical centre where she was conservatively managed and discharged home 3 weeks later for continuing rehabilitation. She achieved a good recovery.",
"affiliations": "Obstetrics and Gynaecology, Buckinghamshire Healthcare NHS Trust, Ayelsbury, UK alexgrammatis@gmail.com.;Anesthetics, Buckinghamshire Healthcare NHS Trust, Ayelsbury, UK.;Neurology, Wexham Park Hospital, Wexham, UK.",
"authors": "Grammatis|Alexandros Loukas|AL|;Catton|Hannah Louise|HL|;Hilton|Derek|D|",
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"fulltext": "\n==== Front\nBMJ Case RepBMJ Case RepbmjcrbmjcasereportsBMJ Case Reports1757-790XBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bcr-2019-22963510.1136/bcr-2019-229635Reminder of Important Clinical Lesson1506152413322002322761302251301Case reportIschaemic stroke and pre-eclampsia in the third trimester of pregnancy: a diagnostic and therapeutic challenge Grammatis Alexandros Loukas 1Catton Hannah Louise 2Hilton Derek 3\n1 \nObstetrics and Gynaecology, Buckinghamshire Healthcare NHS Trust, Ayelsbury, UK\n\n2 \nAnesthetics, Buckinghamshire Healthcare NHS Trust, Ayelsbury, UK\n\n3 \nNeurology, Wexham Park Hospital, Wexham, UK\nCorrespondence to Alexandros Loukas Grammatis; alexgrammatis@gmail.com2019 5 12 2019 5 12 2019 12 12 e22963523 11 2019 © BMJ Publishing Group Limited 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.A 23-year-old low-risk primiparous patient, who was 35 weeks pregnant, presented in the emergency department after collapsing at home. Her observations showed severe hypertension with proteinuria. On examination, she had left hemiparesis and was aphasic. Fetal monitoring was reassuring. Initial CT did not reveal any evidence of intracranial pathology. She was stabilised and delivered via emergency caesarean section. Subsequent MRI and CT showed an acute right-sided infarct involving the right middle cerebral artery territory, frontal and parietal regions, and increased mass effect. She was transferred to the nearest neurosurgical centre where she was conservatively managed and discharged home 3 weeks later for continuing rehabilitation. She achieved a good recovery.\n\nobstetrics and gynaecologystrokepregnancyhypertensionanaesthesiaspecial-featureunlocked\n==== Body\nBackground\nRecognising and managing hypertension in pregnancy is the bread and butter of obstetricians worldwide. However, managing the rare and sometimes catastrophic neurological consequences of pregnancy-induced hypertension or pre-eclampsia can prove a diagnostic and multidisciplinary challenge. This case demonstrates how recognising the need for prompt transfer to an appropriate critical care environment, organising the necessary imaging, having appropriate discussions and then acting on the results is critical for providing optimal care and ultimately achieving good outcomes for these patients.\n\nCase presentation\nA 23-year-old woman who was 35 weeks pregnant presented to the emergency department after her husband had found her collapsed at home. There was no witnessed seizure activity and no suggestion of previous episodes. This, her first pregnancy, had thus far been low risk but she had missed a community antenatal appointment at 32/40 weeks. Her booking blood pressure was 100/60 mm Hg.\n\nThe patient was previously fit and well with no significant medical history, and she took no regular medications. She lived at home with her husband and parents-in-law, was a non-smoker and did not drink alcohol. There was no family history of VTE or stroke.\n\nOn examination, she had dense left hemiparesis, power was 1/5 in the left upper and lower limbs, and was aphasic, leading to a GCS score of 14/15, demonstrating a clear neurological component to her presentation. She could communicate by writing with her right hand and was able to indicate a severe right-sided headache. She denied visual disturbances or abdominal pain. Her blood pressure was 190/120 mm Hg which was relevant due to concerns about pre-eclampsia.\n\nInvestigations\nInitial biochemical and haematological investigations, including full blood count and a clotting profile, were unremarkable. On admission, an ECG to exclude arrhythmia demonstrated normal sinus rhythm. Urinalysis showed proteinuria and subsequent PCR was elevated at 170, supporting an initial diagnosis of pre-eclampsia. An initial CT scan (figure 1) was performed to exclude intracranial bleeding and did not show any acute pathology; however, subsequent MRI imaging (figure 2) showed an acute infarct involving the right middle cerebral artery (MCA) and frontal and parietal regions. Further CT imaging 12 hours later also demonstrated increased mass effect.\n\nFigure 1 First CT head image after initial stabilisation of the patient.\n\nFigure 2 MRI head image showing ischaemic changes consistent with an ischaemic stroke in the right middle cerebral artery territory.\n\nAfter the initial acute phase, the patient was repatriated to her local stroke unit. Here, she underwent further investigation for the cause of the stroke. CT angiogram aortic arch and carotids demonstrated grossly normal anatomy other than mild attenuation of the branches of the right MCA. A transthoracic echocardiogram with agitated saline did not show any abnormalities. The thrombophilia and antiphospholipid syndrome screen were also negative.\n\nDifferential diagnosis\nIn pregnant patients, the clinical features of ischaemic stroke are similar as in the non-pregnant patients. The proposed mechanisms that render pregnant women at increased risk of ischaemic/thrombotic stroke are endothelial dysfunction, abnormal cerebral autoregulation resulting in higher perfusion pressures, haemoconcentration due to third spacing of intravascular fluids and activation of coagulation cascade with microthrombi formation.1 The most common obstetric aetiologies of both ischaemic and haemorrhagic stroke are pre-eclampsia, eclampsia and HELLP syndrome; the proportion of patients with a pregnancy-related stroke who have pre-eclampsia is 25%–45%.2 Less common causes include cardiac causes of arterial emboli or arrhythmias, mitral valve disease, peripartum cardiomyopathy, infective endocarditis, paradoxical embolus through an atrial septal defect or patent foramen ovale, aortic/carotid artery dissection, antiphospholipid syndrome, vasculitis, sickle cell disease and thrombotic thrombocytopaenic purpura.3\n\n\nCareful consideration and a multidisciplinary approach should be used to differentiate between an acute hypertensive response secondary to a stroke and severe hypertension as a result of pre-eclampsia. Stroke can result in direct injury of autonomic inhibitory regions of the brain and reduction of parasympathetic activity. These changes lead to an abrupt increase in systemic vascular resistance and impaired carotid baroreceptor activity leading to dysregulated elevated blood pressure.4 However, severe hypertension (>160/100 mm Hg) combined with significant proteinuria (urine protein:creatinine ratio of more than 30 mg/mmol) in pregnancy is associated with severe pre-eclampsia and the aim should be a gradual reduction of the blood pressure.\n\nRisk factors for stroke in non-pregnant patients, such as hypertension, diabetes and smoking, are found less commonly in pregnancy-related stroke. Clinicians should, however, be aware of an association with a history of migraines, gestational diabetes and aforementioned pre-eclampsia.5\n\n\nMain differential diagnoses include intracerebral haemorrhage, subarachnoid haemorrhage, cerebral venous thrombosis, posterior reversible encephalopathy syndrome and reversible cerebral vasoconstriction syndrome. The first imaging modality is usually a head CT scan, as it is both readily available and can differentiate haemorrhage from infarction. However, brain MRI is more sensitive for the detection of small infarcts and the visualisation of very early infarction when diffusion-weighted imaging is used.6 MR venography (MRV) can also be considered to diagnose cerebral venous sinus thrombosis. However, sinus thrombosis usually presents as an evolving severe focal headache, only very late in its course might a stroke (and hence focal neurological deficits) occur. Given that the patient’s presentation was a sudden focal neurological deficit, it was appropriate to be suspicious of stroke and not sinus thrombosis. Hence, an MRV was not indicated in this case. Echocardiography and carotid Doppler studies may be useful if clinical findings suggest cardiac or carotid pathology. Blood investigations, including full blood count, biochemical studies, peripheral blood smear, clotting profile and thrombophilia screen, can help in pointing towards the right diagnosis.\n\nTreatment\nBlood pressure was controlled with intravenous labetalol, aiming for a gradual reduction of 15%–25%. A total of 4 g of intravenous magnesium sulfate was also administered as a bolus, followed by an infusion of 1 g/hour for 24 hours, for eclamptic seizure prophylaxis.\n\nAfter the patient was stabilised and the CT head excluded a haemorrhagic stroke, the decision was taken to deliver the fetus by caesarean section, given the diagnosis of severe pre-eclampsia. This was after extensive discussion between obstetric teams in both secondary and tertiary centres, anaesthetic teams, stroke physicians and neurology physicians. We administered one dose of intramuscular betamethasone (12 mg) for fetal lung maturation.\n\nAnaesthetic technique was considered from two approaches; the logistics of performing neuraxial versus general anaesthetic, and the physiological implications of these in turn. In light of unclear intracranial pathology with labile blood pressure, this woman was deemed not to be a candidate for neuraxial anaesthetic. She could also not be positioned safely. Hence, the procedure was performed under general anaesthetic. The patient’s blood pressure was monitored non-invasively and intravenous labetalol was titrated with good effect. It was decided that invasive blood pressure monitoring would not be necessary at this point. A modified rapid sequence approach was taken; propofol and 1.2 mg/kg of rocuronium were used to induce general anaesthesia and to obtain good intubating conditions. Fentanyl was used as a co-induction agent; 200 μg at induction was adequate to attenuate the response to laryngoscopy. Anaesthesia was maintained with the volatile agent sevoflurane. Standard caesarean-section drugs were also administered throughout the procedure, including antibiotics (cefuroxime and metronidazole). The operation was uneventful with an estimated blood loss of 500 mL. The blood pressure intraoperatively was between 120–130 mm Hg over 80–90 mm Hg. The baby was born in good condition and did not need admission to the special care baby unit. This woman was very slow to wake and was extubated successfully around 90 min postprocedure. Arterial blood gas analysis was unremarkable.\n\nThe patient was later transferred to ITU and was reintubated for a head MRI, which confirmed a right-sided MCA ischaemic stroke. Her blood pressure in ITU continued to be stable, while on intravenous labetalol, with average values between 130–140 mm Hg over 80–90 mm Hg. The next day, the repeat CT head showed increased mass effect with low attenuation in the right frontal–parietal cortex, now extending to the basal ganglia. The decision was taken then to transfer the patient to the nearest tertiary centre for a possible hemicraniectomy. Surgery was halted in favour of conservative management; however, the patient had ongoing oxygen desaturations. A CTPA excluded a pulmonary embolus; however, it showed pneumonia and she was started on intravenous co-amoxiclav. She was transferred back to the local unit 3 days later for stroke rehabilitation. She was treated with aspirin and low-molecular weight heparin. Aspirin was switched to clopidogrel after 14 days. She was also started on ramipril to control her blood pressure. She received intense rehabilitation with physiotherapy, occupational therapy, and speech and language therapy.\n\nOutcome and follow-up\nThis patient has made excellent progress. Her speech returned fully, and she has regained full power and movement of her left lower limb. Six weeks poststroke, there is only minimal weakness of her left upper limb, mainly her forearm. Ramipril was also stopped 6 weeks postoperatively as the blood pressure was well-controlled.\n\nShe was counselled that the risk of recurrent ischaemic stroke was low in future pregnancies, with one study showing a risk of 2%, which is not statistically different from outside pregnancy.7\n\n\nShe will be managed with low-dose aspirin and low-molecular weight heparin in future pregnancies to prevent the risk of recurrent pre-eclampsia and thrombosis.\n\nDiscussion\nAntenatal stroke is a rare entity with an estimated incidence of 1.5 per 100 000 women delivering in the UK. Poor outcomes have been reported with a case fatality rate of 20% of all strokes.5 To this day, there is a wide discrepancy in the treatment of stroke in pregnancy.\n\nMBRRACE guidelines support that pregnancy should not alter the standard of care for women with a stroke and that all women should be initially admitted to a hyperacute stroke unit.8 The diagnosis in this patient was unclear and it was felt safer for her to be taken to an area of obstetric care. However, a learning point from this case would be to seek advice from and possible admission to a tertiary centre with both obstetric and acute stroke services available, if a stroke was suspected in an obstetric patient.\n\nStudies have shown that the use of thrombolysis in pregnancy is safe, without any significant increase in maternal deaths or major bleeding events.9–11 However, haemorrhage during parturition or caesarean delivery is a particular risk with fibrinolytic therapy if the patient goes into labour or operative delivery is required, so the benefits of such treatment must be carefully weighed against the risks, particularly in cases of severe pre-eclampsia, when delivery must be expedited.\n\nHigh-quality evidence has shown that mechanical thrombectomy is superior to standard treatment with intravenous thrombolysis alone for ischaemic stroke caused by a documented large artery occlusion in the proximal anterior circulation, which is the most common type of ischaemic stroke in pregnancy.12 The evidence for its use in pregnancy is limited, but case reports have been reassuring.13 It may be preferred over intravenous thrombolytic therapy for women considered to have a high risk of haemorrhage. New guidelines from the American Heart Association also advise that it can be performed up to 24 hours after the diagnosis of stroke.14 Unfortunately, adoption of thrombectomy has been slow in the UK, compared with the USA, Germany and France. However, over 400 patients received thrombectomy in England, Wales and Northern Ireland in 2015–2016.15\n\n\nFor women with severe pre-eclampsia leading to a stroke, such as in our case, the usual management would be to stabilise them and deliver the baby first, to prevent further deterioration of the mother. Evidence for what the optimal management of ischaemic strokes caused by pre-eclampsia should be is scarce. Careful consideration should be given in these cases to the possibility that proteinuria can be the result of severe hypertension exceeding a critical limit and leading to malignant nephrosclerosis, rather than pre-eclampsia causing proteinuria, although the evidence is not very clear.16 What is certain is that close liaison between the obstetric, anaesthetic and neurology teams is needed for these patients to decide the safest approach initially for the mother and subsequently for the fetus. In our case, the outcome was good despite thrombolysis not being administered or mechanical thrombectomy being performed, but the patient was considered for and almost required neurosurgical intervention. Early recognition and timely transfer to a tertiary centre ensured that the best available care was offered to the patient and contributed to the good outcome.\n\nLearning points\nA multidisciplinary approach, with a discussion between obstetricians, neurologists and anaesthetists, is imperative to manage a suspected stroke in pregnancy.\n\nAntihypertensive treatment in obstetric patients with acute stroke is only recommended if the diagnosis of pre-eclampsia is confirmed.\n\nThe initial place of assessment should be the hyperacute stroke unit when possible. Ideally, this should be in a tertiary centre where both obstetric and stroke services are available.\n\nWe would like to thank Shaku Kalla (Obstetric Consultant) and Dr Dinesh Selvan (Anaesthetic Consultant) who were both involved in this case and offered fundamental advice about the management of this patient. We would also like to extend thanks to Dr Hilton (Consultant Neurologist) for his valuable contribution in writing up this case.\n\nContributors: The report was written solely by ALG and HLC. Edited and supervised by DH.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 \nTreadwell SD , Thanvi B , Robinson TG \nStroke in pregnancy and the puerperium . Postgrad Med J \n2008 ;84 :238 –45 . 10.1136/pgmj.2007.066167 \n18508980 \n2 \nSharshar T , Lamy C , Mas JL \nIncidence and causes of strokes associated with pregnancy and puerperium. A study in public hospitals of Ile de France. stroke in pregnancy Study Group . Stroke \n1995 ;26 :930 –6 . 10.1161/01.str.26.6.930 \n7762040 \n3 \nNelson-Piercy C \nIschaemic (non-haemorrhagic) stroke : Handbook of obstetric medicine . 5th edn \nCRC Press , 2015 : 181 –2 .\n4 \nQureshi AI \nAcute hypertensive response in patients with stroke: pathophysiology and management . Circulation \n2008 ;118 :176 –87 . 10.1161/CIRCULATIONAHA.107.723874 \n18606927 \n5 \nScott CA , Bewley S , Rudd A , et al \nIncidence, risk factors, management, and outcomes of stroke in pregnancy . Obstet Gynecol \n2012 ;120 :318 –24 . 10.1097/AOG.0b013e31825f287c \n22825091 \n6 \nLee MJ MD , Hickenbottom S MD \nCerebrovascular disorders complicating pregnancy , 2018 Available: https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy?source=mostViewed_widget#H14 [Accessed 13 Jan 2019 ].\n7 \nLamy C , Hamon JB , Coste J , et al \nIschemic stroke in young women: risk of recurrence during subsequent pregnancies. French Study Group on stroke in pregnancy . Neurology \n2000 ;55 :269 –74 . 10.1212/wnl.55.2.269 \n10908903 \n8 \nKnight M , Tuffnell D , Kenyon S , et al , Saving Lives, Improving Mothers’ Care - Surveillance of maternal deaths in the UK 2011-13 and lessons learned to inform maternity care from the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2009-13 . National Perinatal Epidemiology Unit, University of Oxford : Oxford , 2015 .\n9 \nGartman EJ \nThe use of thrombolytic therapy in pregnancy . Obstet Med \n2013 ;6 :105 –11 . 10.1177/1753495X13488771 \n27708701 \n10 \nLeffert LR , Clancy CR , Bateman BT , et al \nTreatment patterns and short-term outcomes in ischemic stroke in pregnancy or postpartum period . Am J Obstet Gynecol \n2016 ;214 :723.e1 –723.e11 . 10.1016/j.ajog.2015.12.016 \n26709084 \n11 \nSousa Gomes M , Guimarães M , Montenegro N \nThrombolysis in pregnancy: a literature review . J Matern Fetal Neonatal Med \n2019 ;32 :2418 –28 . 10.1080/14767058.2018.1434141 \n29378443 \n12 \nCampbell BCV , Donnan GA , Lees KR , et al \nEndovascular stent thrombectomy: the new standard of care for large vessel ischaemic stroke . The Lancet Neurology \n2015 ;14 :846 –54 . 10.1016/S1474-4422(15)00140-4 \n26119323 \n13 \nBhogal P , Aguilar M , AlMatter M , et al \nMechanical thrombectomy in pregnancy: report of 2 cases and review of the literature . Interv Neurol \n2017 ;6 :49 –56 . 10.1159/000453461 \n28611834 \n14 \nPowers WJ , Rabinstein AA , Ackerson T , et al \n2018 guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American heart Association/American stroke association . Stroke \n2018 ;49 :e46 –99 . 10.1161/STR.0000000000000158 \n29367334 \n15 \nStroke Association \nState of the nation, stroke statistics , 2018 Available: https://www.stroke.org.uk/system/files/sotn_2018.pdf [Accessed 13 Jan 2019 ].\n16 \nGriffin KA , Polichnowski A , Litbarg N , et al \nCritical blood pressure threshold dependence of hypertensive injury and repair in a malignant nephrosclerosis model . Hypertension \n2014 ;64 :801 –7 . 10.1161/HYPERTENSIONAHA.114.03609 \n24958497\n\n",
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"mesh_terms": "D002545:Brain Ischemia; D002585:Cesarean Section; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D010291:Paresis; D011225:Pre-Eclampsia; D011247:Pregnancy; D011263:Pregnancy Trimester, Third; D011296:Prenatal Diagnosis; D014057:Tomography, X-Ray Computed; D055815:Young Adult",
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"title": "Ischaemic stroke and pre-eclampsia in the third trimester of pregnancy: a diagnostic and therapeutic challenge.",
"title_normalized": "ischaemic stroke and pre eclampsia in the third trimester of pregnancy a diagnostic and therapeutic challenge"
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"abstract": "We herein report a 76-year-old Japanese man with myelofibrosis who developed cryptococcal meningitis. After treatment for 5 months with ruxolitinib, the patient presented with fever and disturbance of consciousness. Marked nuchal stiffness was noted. The magnetic resonance imaging results of the brain were normal. Lumbar puncture showed an opening cerebrospinal fluid (CSF) pressure of 110 mm H2O, pleocytosis (85 mononuclear cells and 222 polymorphonuclear cells/μL), decreased CSF/serum glucose ratio (43%), and elevated protein (194 mg/dL). Blood and CSF cultures grew no bacteria or fungi. However, cryptococcal antigen was detected in the blood and CSF samples. We discontinued ruxolitinib and started administration of amphotericin B. His condition improved gradually 1 week after initiation of treatment. There have been only a few reports on cryptococcal meningitis associated with ruxolitinib. Physicians should consider the possibility of cryptococcal meningitis in patients receiving ruxolitinib.",
"affiliations": "Department of Neurology, Dokkyo Medical University, Mibu, Tochigi, Japan.",
"authors": "Tsukui|Daisuke|D|;Fujita|Hiroaki|H|;Suzuki|Keisuke|K|;Hirata|Koichi|K|",
"chemical_list": "D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D000666:Amphotericin B; C540383:ruxolitinib",
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"doi": "10.1097/MD.0000000000019587",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Wolters Kluwer Health \n\n32221077\nMD-D-19-10012\n10.1097/MD.0000000000019587\n19587\n5300\nResearch Article\nObservational Study\nA case report of cryptococcal meningitis associated with ruxolitinib\nTsukui Daisuke MD Fujita Hiroaki MD, PhD∗ Suzuki Keisuke MD, PhD Hirata Koichi MD, PhD Abdinia. Babak Department of Neurology, Dokkyo Medical University, Mibu, Tochigi, Japan.\n∗ Correspondence: Hiroaki Fujita, Department of Neurology, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, Japan (e-mail: fujita-h@dokkyomed.ac.jp).\n27 3 2020 \n3 2020 \n99 13 e1958717 12 2019 4 2 2020 18 2 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nWe herein report a 76-year-old Japanese man with myelofibrosis who developed cryptococcal meningitis. After treatment for 5 months with ruxolitinib, the patient presented with fever and disturbance of consciousness. Marked nuchal stiffness was noted. The magnetic resonance imaging results of the brain were normal. Lumbar puncture showed an opening cerebrospinal fluid (CSF) pressure of 110 mm H2O, pleocytosis (85 mononuclear cells and 222 polymorphonuclear cells/μL), decreased CSF/serum glucose ratio (43%), and elevated protein (194 mg/dL). Blood and CSF cultures grew no bacteria or fungi. However, cryptococcal antigen was detected in the blood and CSF samples. We discontinued ruxolitinib and started administration of amphotericin B. His condition improved gradually 1 week after initiation of treatment. There have been only a few reports on cryptococcal meningitis associated with ruxolitinib. Physicians should consider the possibility of cryptococcal meningitis in patients receiving ruxolitinib.\n\nKeywords\ncryptococcusimmunosuppressionJanus kinase inhibitormeningitisruxolitinibOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nRuxolitinib, an inhibitor of Janus kinase (JAK) 1 and 2, has been approved for the treatment of myelofibrosis (MF) and polycythemia vera (PV) by reducing spleen size, ameliorating debilitating symptoms, and improving overall survival.[1,2] The JAK/signal transducer and activator of transcription (STAT) pathway is the principal signaling mechanism for numerous cytokines and growth factors. JAK inhibitors exert immunosuppressive activities through the downregulation of several cytokines, such as interleukins, interferon-γ, and tumor necrosis factor-α,[3] and result in dysfunction of dendritic cells (DCs),[4] T-regulatory cells,[5] and natural killer (NK) cells.[6] Cryptococcal meningitis is known to occur particularly frequently in immunocompromised hosts.[7] However, there have been only 2 reports of cryptococcal meningitis in patients treated with JAK inhibitors. Here, we report a case of cryptococcal meningitis in a ruxolitinib-treated patient with primary MF.\n\n2 Case report\nAt the age of 64 years, the present patient was diagnosed with essential thrombocythemia, and hydroxycarbamide was initiated. His condition had been stable for several years. At the age of 72 years, anagrelide hydrochloride hydrate was started instead of hydroxycarbamide because of worsening thrombocytosis. In February 2019, the patient was diagnosed with MF according to the results of bone-marrow puncture. Although the JAK2 mutation was negative, the myeloproliferative leukemia virus oncogene (MPL) W515L mutation was detected. Since then, he had been treated with ruxolitinib (10 mg/d). At the age of 76 years (5 months after initiation of ruxolitinib), the patient was admitted to our hospital because of high-grade fever and disturbance of consciousness from a day before admission. On examination, his body temperature was 38.8°C; his other vital signs were normal. Marked nuchal stiffness was noted. The patient was disoriented to time and place. Cranial nerves were intact. There was no motor weakness or cerebellar ataxia. Tendon reflexes were normal and symmetrical without any pathological reflexes. No sensory impairment was noted. Laboratory data showed mildly elevated C-reactive protein levels (0.31 mg/dL) and procalcitonin levels (0.10 ng/mL). Markedly elevated ferritin levels (2203.5 ng/mL) were observed. The white blood cell count (7000/μL) and platelet count (25.9 × 104/μL) were preserved, but the red blood cell count was decreased (227/μL). Normal levels of β-d-glucan were observed (6.0 pg/mL). Lumbar puncture yielded an opening cerebrospinal fluid (CSF) pressure of 110 mm H2O and pleocytosis (85 mononuclear cells and 222 polymorphonuclear cells/μL). The CSF glucose level was 69 mg/dL with a low CSF/serum glucose ratio of 43%, and the protein level (194 mg/dL) was elevated. Herpes simplex virus DNA and varicella-zoster virus DNA were negative. CSF cultures grew no bacteria or fungi. A human immunodeficiency virus test was negative. The magnetic resonance imaging results of the brain were normal. Figure 1 shows the clinical course and treatment of the patient. He was suspected of having meningitis and was empirically treated with micafungin (150 mg/d) and cefozopran (4 g/d), followed by meropenem (3 g/d), acyclovir (2250 mg/d), and amphotericin B (350 mg/d). However, cryptococcal antigen was detected in CSF (titers, 1:16) and serum on day 6 (Table 1). We discontinued the treatment with ruxolitinib and continued the administration of amphotericin B (350 mg/d), and the patient's condition improved until day 10. Amphotericin B was used until day 37, followed by administration of fluconazole (400 mg/d). The patient was on continuous therapy at the time of this report.\n\nFigure 1 Clinical course of the present case. ACV = acyclovir, CSF = cerebrospinal fluid, CZOP = cefozopran, FLCZ = fluconazole, L-AMB = amphotericin, MCFG = micafungin, MEPM = meropenem.\n\nTable 1 Laboratory data.\n\n3 Discussion\nRuxolitinib is a selective JAK 1/2 inhibitor that has been approved for the treatment of MF and PV. The JAK/STAT pathway plays an important role in hematopoiesis and the immune response in vivo.[1] After engagement of the receptor by the corresponding ligand, JAK becomes activated via phosphorylation, followed by JAK/STAT pathway activation.[8] Activated STATs dimerize and translocate to the nucleus, where they regulate transcription and release proinflammatory cytokines and growth factors, including erythropoietin, granulocyte macrophage colony-stimulating factor, and thrombopoietin.[9] In patients with MF, gene mutations, such as those in JAK2 and MPL, are in a constant phosphorylated state, independent of the binding of ligand to its receptor.[10,11] Excess release of proinflammatory cytokines and growth factors triggers the systemic symptoms of MF and ineffective hematopoiesis.[12] Blockage of JAK1 mainly improves systemic symptoms via a reduction in proinflammatory cytokines, and blockage of JAK2 mainly improves splenomegaly and anemia via a reduction in growth factors and prevents ineffective hematopoiesis.[9,13–15] However, some opportunistic infections related to ruxolitinib have been reported previously.[16–25]\n\nThe present case involved cryptococcal meningitis in a patient treated with ruxolitinib. To the best of our knowledge, only 2 cases of cryptococcal meningitis in ruxolitinib-treated patients have been previously reported.[16,17]Table 2 summarizes cryptococcal meningitis associated with ruxolitinib, including our case, and 2 clinical features were found. First, the opening pressure of lumbar puncture in the present case was not high, although raised CSF pressure is one of the typical clinical features of cryptococcal meningitis. Half of patients with cryptococcal meningitis show a CSF opening pressure over 250 mm H2O; additionally, a quarter of patients show an extremely high pressure over 350 mm H2O.[7] The mechanism of high CSF pressure is presumed to block CSF reabsorption by live or dead organisms, with shed cryptococcal polysaccharide at the level of the arachnoid granulations and other CSF reabsorption sites. Loyse et al[26] reported that arachnoid granulation tissue contains many fungal cells in comparison with other sites of the brain, and high numbers of organisms are associated with increased antemortem CSF pressure. Bicanic et al[27] reported that high CSF pressure in cryptococcal meningitis is associated with the phenotype of an infectious Cryptococcus neoformans strain and host factors other than the numbers of fungal cells. Among 3 patients with cryptococcal meningitis associated with ruxolitinib, 2 had normal opening CSF pressure (opening CSF pressure was not describe in 1 patient) (Table 2). Among the 3 cases, no trend was observed in CSF findings, such as the degree of pleocytosis and protein elevation. To the best of our knowledge, there has been no report of cryptococcal meningitis associated with ruxolitinib showing the numbers of fungal bodies in a postmortem study. Because only 2 cases have previously been reported, more studies are needed to confirm whether a normal CSF pressure is one of the features of cryptococcal meningitis associated with ruxolitinib or just the finding in our case.\n\nTable 2 Cryptococcal meningitis associated with ruxolitinib.\n\nSecond, the outcome of the present case was relatively good compared to typical cryptococcal meningitis.[7] The 2 previous cases of cryptococcal meningitis associated with ruxolitinib also showed good clinical outcomes (Table 2).[16,17] In the present case, ruxolitinib was discontinued on day 6, and in 1 previous report, ruxolitinib was discontinued when fungal infection was found (in the other case, whether ruxolitinib was discontinued was not described). Hirano et al[18] suggested that ruxolitinib administration should be discontinued if possible; otherwise, the treatment with ruxolitinib may be ineffective against a pulmonary cryptococcus infection. Additionally, in our case, discontinuing ruxolitinib may lead to a good outcome; therefore, as ruxolitinib may impact the immune response against cryptococcosis, ruxolitinib should be discontinued immediately when cryptococcal meningitis is suspected.\n\nA phase III study of ruxolitinib reported that reactivation of tuberculosis and herpes zoster virus were the predominant opportunistic infections observed with ruxolitinib.[28] Since that time, some cases of opportunistic infection associated with ruxolitinib have been reported.[16–25] Dioverti et al[29] published a review of 32 cases identified as opportunistic infections associated with ruxolitinib. Although the majority of cases reported were reactivations of tuberculosis (34%), several fungal infections were also reported (22%), and cryptococcus was the most frequently reported fungus. In a phase II, phase III, and long-term extension clinical trial with 5671 patients treated with tofacitinib, another JAK inhibitor approved for the treatment of adult patients with rheumatoid arthritis, cryptococcal infections were also reported (2 pulmonary infections and 1 case of meningitis).[30]\n\nMany studies have tried to elucidate the mechanism by which ruxolitinib impacts the immune system. A review of the literature conducted by Manduzio indicated that the immunological derangement of ruxolitinib is mainly based on T cells, DCs, and NK cell defects.[31] Heine et al[4] reported that ruxolitinib affects the function and phenotype of DCs, leading to impaired T-cell activation. Ostoji et al reported that ruxolitinib suppresses cell-mediated immunity by inhibiting the T-helper lymphocyte 1 response and reducing the production of interferon-γ.[32] The host defense against C neoformans infection is associated with cell-mediated immunity, especially accomplished by the combined action of activated macrophages, NK cells, and T cells.[33] In addition, Hardison et al[34] reported that STAT1 and signaling through the JAK/STAT pathway play an important role in the protective response against cryptococcosis via STAT1-mediated classical macrophage activation. In the present case, suppression of anticryptococcal responses was likely to induce the development of cryptococcal meningitis, as in the previously reported cases of cryptococcal infection.[16–19,22] Ruxolitinib-associated opportunistic infections are not time-dependent and may occur any time after initiation of the drug.[28] However, whether this effect is dose dependent is still controversial.[16]\n\nIn conclusion, we report a case of cryptococcal meningitis associated with ruxolitinib. Ruxolitinib administration is known to lead to opportunistic infections,[28] and thus, it can cause cryptococcal meningitis, as the incidence of cryptococcal meningitis increases in patients with immunosuppressant conditions.[7] Physicians should consider the possibility of cryptococcal meningitis in patients receiving ruxolitinib and discontinue the drug if possible when high-grade fever persists even in the absence of headache. Because ruxolitinib is a relatively new drug, further accumulation of clinical experience to monitor possible side effects is needed.\n\nAcknowledgment\nThe authors thank Dr Honoka Arai and Dr Yuko Nakamura, Department of Hematology and Oncology, Dokkyo Medical University Hospital, for their assistance with this study.\n\nAuthor contributions\nConceptualization: Daisuke Tsukui, Hiroaki Fujita.\n\nWriting – original draft: Hiroaki Fujita, Keisuke Suzuki.\n\nWriting – review and editing: Hiroaki Fujita, Koichi Hirata.\n\nHiroaki Fujita orcid: 0000-0003-2184-7916.\n\nAbbreviations: CSF = cerebrospinal fluid, DCs = dendritic cells, JAK = Janus kinase, MF = myelofibrosis, MPL = myeloproliferative leukemia virus oncogene, NK = natural killer, PV = polycythemia vera, STAT = signal transducer and activator of transcription.\n\nHow to cite this article: Tsukui D, Fujita H, Suzuki K, Hirata K. A case report of cryptococcal meningitis associated with ruxolitinib. Medicine. 2020;99:13(e19587).\n\nAll data generated or analyzed during this study are included in this published article [and its supplementary information files].\n\nThe approval of an ethics committee is not required as this is a single case report.\n\nWritten informed consent was obtained from the patient for publication.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Harrison C Kiladjian JJ Al-Ali HK \nJAK inhibition with ruxolitinib versus best available therapy for myelofibrosis\n. N Engl J Med \n2012 ;366 :787 –98\n.22375970 \n[2] Verstovsek S Mesa RA Gotlib J \nA double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis\n. N Engl J Med \n2012 ;366 :799 –807\n.22375971 \n[3] Quintas-Cardama A Verstovsek S \nMolecular pathways: Jak/STAT pathway: mutations, inhibitors, and resistance\n. Clin Cancer Res \n2013 ;19 :1933 –40\n.23406773 \n[4] Heine A Held SA Daecke SN \nThe JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo\n. Blood \n2013 ;122 :1192 –202\n.23770777 \n[5] Parampalli Yajnanarayana S Stubig T Cornez I \nJAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms\n. Br J Haematol \n2015 ;169 :824 –33\n.25824483 \n[6] Schonberg K Rudolph J Vonnahme M \nJAK inhibition impairs NK cell function in myeloproliferative neoplasms\n. Cancer Res \n2015 ;75 :2187 –99\n.25832652 \n[7] Williamson PR Jarvis JN Panackal AA \nCryptococcal meningitis: epidemiology, immunology, diagnosis and therapy\n. Nat Rev Neurol \n2017 ;13 :13 –24\n.27886201 \n[8] Rawlings JS Rosler KM Harrison DA \nThe JAK/STAT signaling pathway\n. J Cell Sci \n2004 ;117 (Pt 8) :1281 –3\n.15020666 \n[9] Murray PJ \nThe JAK-STAT signaling pathway: input and output integration\n. J Immunol \n2007 ;178 :2623 –9\n.17312100 \n[10] Pikman Y Lee BH Mercher T \nMPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia\n. PLoS Med \n2006 ;3 :e270 .16834459 \n[11] Verstovsek S \nTherapeutic potential of Janus-activated kinase-2 inhibitors for the management of myelofibrosis\n. Clin Cancer Res \n2010 ;16 :1988 –96\n.20215535 \n[12] Vannucchi AM Guglielmelli P Tefferi A \nAdvances in understanding and management of myeloproliferative neoplasms\n. CA Cancer J Clin \n2009 ;59 :171 –91\n.19369682 \n[13] Quintas-Cardama A Vaddi K Liu P \nPreclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms\n. Blood \n2010 ;115 :3109 –17\n.20130243 \n[14] Cazzola M \nSomatic mutations of JAK2 exon 12 as a molecular basis of erythrocytosis\n. Haematologica \n2007 ;92 :1585 –9\n.18055979 \n[15] Tefferi A Vaidya R Caramazza D \nCirculating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study\n. J Clin Oncol \n2011 ;29 :1356 –63\n.21300928 \n[16] Prakash K Richman D \nA case report of disseminated histoplasmosis and concurrent cryptococcal meningitis in a patient treated with ruxolitinib\n. BMC Infect Dis \n2019 ;19 :287 .30917797 \n[17] Chen CC Chen YY Huang CE \nCryptococcal meningoencephalitis associated with the long-term use of ruxolitinib\n. Ann Hematol \n2016 ;95 :361 –2\n.26486358 \n[18] Hirano A Yamasaki M Saito N \nPulmonary cryptococcosis in a ruxolitinib-treated patient with primary myelofibrosis\n. Respir Med Case Rep \n2017 ;22 :87 –90\n.28721333 \n[19] Liu J Mouhayar E Tarrand JJ \nFulminant Cryptococcus neoformans infection with fatal pericardial tamponade in a patient with chronic myelomonocytic leukaemia who was treated with ruxolitinib: case report and review of fungal pericarditis\n. Mycoses \n2018 ;61 :245 –55\n.29280197 \n[20] Goldberg RA Reichel E Oshry LJ \nBilateral toxoplasmosis retinitis associated with ruxolitinib\n. N Engl J Med \n2013 ;369 :681 –3\n.23944322 \n[21] Lee SC Feenstra J Georghiou PR \nPneumocystis jiroveci pneumonitis complicating ruxolitinib therapy\n. BMJ Case Rep \n2014 ;2014 :\n[22] Wysham NG Sullivan DR Allada G \nAn opportunistic infection associated with ruxolitinib, a novel janus kinase 1,2 inhibitor\n. Chest \n2013 ;143 :1478 –9\n.23648912 \n[23] Wathes R Moule S Milojkovic D \nProgressive multifocal leukoencephalopathy associated with ruxolitinib\n. N Engl J Med \n2013 ;369 :197 –8\n.\n[24] Colomba C Rubino R Siracusa L \nDisseminated tuberculosis in a patient treated with a JAK2 selective inhibitor: a case report\n. BMC Res Notes \n2012 ;5 :552 .23039051 \n[25] Shen CH Hwang CE Chen YY \nHepatitis B virus reactivation associated with ruxolitinib\n. Ann Hematol \n2014 ;93 :1075 –6\n.24173089 \n[26] Loyse A Wainwright H Jarvis JN \nHistopathology of the arachnoid granulations and brain in HIV-associated cryptococcal meningitis: correlation with cerebrospinal fluid pressure\n. AIDS \n2010 ;24 :405 –10\n.19952714 \n[27] Bicanic T Brouwer AE Meintjes G \nRelationship of cerebrospinal fluid pressure, fungal burden and outcome in patients with cryptococcal meningitis undergoing serial lumbar punctures\n. AIDS \n2009 ;23 :701 –6\n.19279443 \n[28] Harrison CN Vannucchi AM Kiladjian JJ \nLong-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis\n. Leukemia \n2016 ;30 :1701 –7\n.27211272 \n[29] Dioverti MV Abu Saleh OM Tande AJ \nInfectious complications in patients on treatment with ruxolitinib: case report and review of the literature\n. Infect Dis (Lond) \n2018 ;50 :381 –7\n.29251529 \n[30] Harigai M \nGrowing evidence of the safety of JAK inhibitors in patients with rheumatoid arthritis\n. Rheumatology (Oxford) \n2019 ;58 : Suppl 1 : i34 –42\n.30806708 \n[31] Manduzio P \nRuxolitinib in myelofibrosis: to be or not to be an immune disruptor\n. Ther Clin Risk Manag \n2017 ;13 :169 –77\n.28243106 \n[32] Ostojic A Vrhovac R Verstovsek S \nRuxolitinib for the treatment of myelofibrosis: its clinical potential\n. Ther Clin Risk Manag \n2012 ;8 :95 –103\n.22399854 \n[33] Kronstad J Saikia S Nielson ED \nAdaptation of Cryptococcus neoformans to mammalian hosts: integrated regulation of metabolism and virulence\n. Eukaryot Cell \n2012 ;11 :109 –18\n.22140231 \n[34] Hardison SE Herrera G Young ML \nProtective immunity against pulmonary cryptococcosis is associated with STAT1-mediated classical macrophage activation\n. J Immunol \n2012 ;189 :4060 –8\n.22984078\n\n",
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"mesh_terms": "D000368:Aged; D000666:Amphotericin B; D006801:Humans; D008297:Male; D016919:Meningitis, Cryptococcal; D009570:Nitriles; D055728:Primary Myelofibrosis; D011720:Pyrazoles; D011743:Pyrimidines",
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"title": "A case report of cryptococcal meningitis associated with ruxolitinib.",
"title_normalized": "a case report of cryptococcal meningitis associated with ruxolitinib"
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"abstract": "OBJECTIVE\nThe first published report of the use of triple therapy in a patient with hepatitis C virus (HCV) genotype 6 infection-a treatment that was prescribed due to incorrect HCV genotyping and which ultimately failed-is presented.\n\n\nCONCLUSIONS\nA 70-year-old male U.S. resident of Vietnamese descent requested treatment for chronic HCV infection acquired decades earlier. He reported experiencing hepatitis C treatment failures twice before-13 years prior (interferon alfa monotherapy for six months) and 7 years prior (standard dual therapy with pegylated interferon alfa-2b and ribavirin for nine months). Initial viral genotyping indicated infection with HCV genotypes 1a and 6c (a form of mixed HCV disease amenable to triple therapy), and treatment with pegylated interferon alfa-2a, ribavirin, and boceprevir was initiated. By week 8 of triple therapy, the patient's viral load had decreased from 15,700,000 (7.20 log) to 462,882 (5.67 log) IU/mL, but the viral load subsequently rebounded to baseline levels, and treatment was discontinued at week 16. When repeat HCV genotyping was performed, it was discovered that initial genotyping was incorrect and that the man's infection involved not mixed genotypes but only genotype 6; he was not an appropriate candidate for triple therapy. The case emphasizes the need for clinicians to be cognizant of potential HCV genotyping errors, particularly with regard to patients of Southeast Asian descent.\n\n\nCONCLUSIONS\nThree courses of interferon-based treatment, including triple therapy with boceprevir, failed to produce a sustained therapeutic response in a 70-year-old ethnic Vietnamese man with genotype 6 HCV infection.",
"affiliations": "Roseann S. Gammal, Pharm.D., is Postgraduate Year 1 Pharmacy Practice Resident, Department of Pharmacy, University of North Carolina Hospitals and Clinics, Chapel Hill. Linda M. Spooner, Pharm.D., BCPS, is Associate Professor of Pharmacy Practice, School of Pharmacy, MCPHS University, Worcester, MA. George M. Abraham, M.D., M.P.H., is Professor of Medicine, University of Massachusetts Medical School, Worcester, and Associate Chief of Medicine, Division of Infectious Disease and Geographic Medicine, Saint Vincent Hospital, Worcester.",
"authors": "Gammal|Roseann S|RS|;Spooner|Linda M|LM|;Abraham|George M|GM|",
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"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D003951:Diagnostic Errors; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D016898:Interferon-alpha; D008297:Male; D011092:Polyethylene Glycols; D011392:Proline; D011994:Recombinant Proteins; D012254:Ribavirin; D017211:Treatment Failure; D014481:United States; D014744:Vietnam; D019562:Viral Load",
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"title": "Failed triple therapy in a treatment-experienced patient with genotype 6 hepatitis C infection.",
"title_normalized": "failed triple therapy in a treatment experienced patient with genotype 6 hepatitis c infection"
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"abstract": "OBJECTIVE\nTreatment of recalcitrant moderate-to-severe psoriasis can be challenging. Combination therapy of biologics and immunosuppressive agents can be a new strategy for treating therapy-resistant cases with comorbidities, where many systemic medications are contraindicated.\n\n\nMETHODS\nWe report a case of a 62-year-old diabetic man with a 30-year history of severe plaque psoriasis and psoriatic arthritis with cirrhosis and diabetic nephropathy that was treated successfully in combination with apremilast and etanercept after multiple previous unsuccessful treatment attempts.\n\n\nCONCLUSIONS\nThere are no data supporting the combination of apremilast and etanercept in the management of recalcitrant cases of moderate-to-severe psoriasis and multiple comorbidities including psoriatic arthritis, diabetic nephropathy, and cirrhosis. In patients who do not respond to multiple approaches for the treatment of psoriasis, combination therapy with biologic agents and new systemic medications may lead to dramatic disease control.",
"affiliations": "Department of Dermatology, University Medical Center Mainz, Mainz, Germany.;Department of Dermatology, University Medical Center Mainz, Mainz, Germany.;Department of Dermatology, R.D. Gardi Medical College, Ujjain, India.;Department of Dermatology, University Medical Center Mainz, Mainz, Germany.;Department of Dermatology, University Medical Center Mainz, Mainz, Germany.;Department of Dermatology, University Medical Center Mainz, Mainz, Germany.",
"authors": "Zimmer|Sebastian|S|;Goldust|Mohamad|M|https://orcid.org/0000-0002-8646-1179;Bhargava|Shashank|S|https://orcid.org/0000-0003-4141-5520;Wegner|Joanna|J|;Grabbe|Stephan|S|;Staubach-Renz|Petra|P|",
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"keywords": "apremilast; cirrhosis; etanercept; guselkumab; moderate-to-severe psoriasis",
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"pubdate": "2021-08-20",
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"title": "Combination therapy of recalcitrant severe psoriasis with psoriatic arthritis, diabetes nephropathy, and liver cirrhosis.",
"title_normalized": "combination therapy of recalcitrant severe psoriasis with psoriatic arthritis diabetes nephropathy and liver cirrhosis"
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{
"abstract": "A 32-year-old G2P1 woman presented for induction of labor at term. Her past medical history included polysubstance use disorder and methadone maintenance, scant prenatal care, morbid obesity, and intimate partner violence. Her induction was progressing smoothly until the acute onset of altered mental status near to the time of delivery, several minutes after a clinician-administered epidural local anesthetic bolus for significant pain. Given concern about local anesthetic systemic toxicity, lipid emulsion was administered and resulted in an immediate and drastic clinical response. The epidural infusion bag and pump system were evaluated and found to be correct and there was no clinical suspicion of an intravascular epidural catheter. The woman remained stable and was transferred to the postpartum unit, where she experienced a similar episode of altered mental status approximately 12 h postpartum. This episode self-resolved and she was managed conservatively. Shortly after this event, it was discovered that the patient had been self-administering benzodiazepines throughout the course of her labor, in addition to her hospital staff-administered medications. Presumably, her intrapartum altered mental status was a result of self-administered benzodiazepine that was then \"rescued\" with lipid emulsion. This case illustrates the potential for lipid emulsion as a reversal agent for medications other than local anesthetics.",
"affiliations": "Division of Obstetric, Gynecologic, and Fetal Anesthesia, Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Hospital, Baltimore, USA. Electronic address: DaveBerman@jhmi.edu.",
"authors": "Berman|D J|DJ|",
"chemical_list": "D000779:Anesthetics, Local; D005217:Fat Emulsions, Intravenous; D001569:Benzodiazepines",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijoa.2019.12.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-289X",
"issue": "42()",
"journal": "International journal of obstetric anesthesia",
"keywords": "Alprazolam; Benzodiazepine; Bupivacaine; Lipid rescue; Local anesthetic systemic toxicity",
"medline_ta": "Int J Obstet Anesth",
"mesh_terms": "D000328:Adult; D000779:Anesthetics, Local; D001569:Benzodiazepines; D062787:Drug Overdose; D005217:Fat Emulsions, Intravenous; D005260:Female; D006801:Humans; D007743:Labor, Obstetric; D011247:Pregnancy",
"nlm_unique_id": "9200430",
"other_id": null,
"pages": "109-111",
"pmc": null,
"pmid": "32044218",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A case of local anesthetic toxicity that wasn't: lipid rescue from self-administered benzodiazepine overdose in labor.",
"title_normalized": "a case of local anesthetic toxicity that wasn t lipid rescue from self administered benzodiazepine overdose in labor"
} | [
{
"companynumb": "US-APOTEX-2020AP013883",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "6",
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"activesubstancename": "BUPIVACAINE"
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{
"abstract": "There is little information on survival rates of patients with primary biliary cholangtis (PBC) in developing countries. This is particularly true in Latin America, where the number of liver transplants performed remains extremely low for patients with advanced liver disease who fulfill criteria for liver transplantation. The goal of this study was to compare survival rate of patients with PBC in developing countries who were treated with ursodeoxycholic acid (UDCA) versus survival of patients who received other treatments (OT) without UDCA, prescribed before the UDCA era.\n\n\n\nA retrospective study was performed, including records of 78 patients with PBC in the liver unit in a third level referral hospital in Mexico City. Patients were followed for five years from initial diagnosis until death related to liver disease or to the end of the study. Patients received UDCA (15 mg/kg/per day) (n = 41) or OT (n = 37) before introduction of UDCA in Mexico.\n\n\n\nResponse to treatment was higher in the group that received UDCA. In the five years of follow-up, survival rates were significantly higher in the UDCA group than in the OT group. The hazard ratio of death was higher in the OT group vs. UDCA group, HR 8.78 (95% CI, 2.52-30.61); Mayo Risk Score and gender were independently associated with the risk of death.\n\n\n\nThe study confirms that the use of UDCA in countries with a limited liver transplant program increases survival in comparison to other treatments used before the introduction of UDCA.",
"affiliations": "Social Service and Department of Pathology, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Mexico City.;Social Service and Department of Pathology, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Mexico City.;Laboratory of Gastro-Hepatology Research, Hospital of Pediatrics, National Medical Center XXI Century, Mexican Institute of Social Security, Mexico.;Laboratory of Gastro-Hepatology Research, Hospital of Pediatrics, National Medical Center XXI Century, Mexican Institute of Social Security, Mexico.;Laboratory of Gastro-Hepatology Research, Hospital of Pediatrics, National Medical Center XXI Century, Mexican Institute of Social Security, Mexico.;Medica Sur Clinic Foundation, Mexico.",
"authors": "Melchor-Mendoza|Yazmín Karel|YK|;Martínez-Benítez|Braulio|B|;Mina-Hawat|Aline|A|;Rodríguez-Leal|Gustavo|G|;Duque|Ximena|X|;Moran-Villota|Segundo|S|",
"chemical_list": "D002756:Cholagogues and Choleretics; D014580:Ursodeoxycholic Acid",
"country": "Mexico",
"delete": false,
"doi": "10.5604/16652681.1235486",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1665-2681",
"issue": "16(3)",
"journal": "Annals of hepatology",
"keywords": null,
"medline_ta": "Ann Hepatol",
"mesh_terms": "D000328:Adult; D002756:Cholagogues and Choleretics; D002761:Cholangitis; D005260:Female; D006297:Health Services Accessibility; D006801:Humans; D053208:Kaplan-Meier Estimate; D008105:Liver Cirrhosis, Biliary; D016031:Liver Transplantation; D008297:Male; D008800:Mexico; D008875:Middle Aged; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate; D013997:Time Factors; D014019:Tissue Donors; D016896:Treatment Outcome; D014580:Ursodeoxycholic Acid",
"nlm_unique_id": "101155885",
"other_id": null,
"pages": "430-435",
"pmc": null,
"pmid": "28425413",
"pubdate": "2017",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Ursodeoxycholic Acid Therapy in Patients with Primary Biliary Cholangitis with Limited Liver Transplantation Availability.",
"title_normalized": "ursodeoxycholic acid therapy in patients with primary biliary cholangitis with limited liver transplantation availability"
} | [
{
"companynumb": "MX-ALLERGAN-1763667US",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "URSODIOL"
},
"drugadditional": null,
"d... |
{
"abstract": "BACKGROUND\nPatients with inadequately controlled or uncontrolled asthma are at a greater risk of attacks for asthma requiring emergency room visits or hospital admissions. There is a significant correlation between the severity of the disease and the severity of exacerbations. Patients with poorly controlled asthma are at a higher risk for complications.\n\n\nMETHODS\nWe present a 24-year-old aspirin-intolerant, uncontrolled asthma patient with the complication of pneumomediastinum.\n\n\nRESULTS\nSevere symptoms persisted after the resolution of the pneumomediastinum despite intense anti-inflammatory and anti-obstructive therapy. A bronchoscopy revealed an endobronchial lesion and she was diagnosed with a carcinoid tumor.\n\n\nCONCLUSIONS\nThis case is an example of the importance of re-evaluating asthma patients who do not respond to standard medical treatment. Clinicians should be aware of the complications associated with asthma attacks such as pneumomediastinum and the possibility of a differential diagnosis that worsen asthma symptoms such as a carcinoid tumor.",
"affiliations": "a School of Medicine, Koç University , Istanbul , Turkey .;b Department of Allergy and Immunology , Koç University Hospital , Istanbul , Turkey .;c Department of Allergy and Immunology , School of Medicine, Koç University , Istanbul , Turkey .;d Department of Thoracic Surgery , Koç University Hospital , Istanbul , Turkey .;e Department of Thoracic Surgery , and.;e Department of Thoracic Surgery , and.;f Department of Pulmonary Medicine , School of Medicine, Koç University , Istanbul , Turkey.",
"authors": "Biçer|Elif Nur|EN|;Öztürk|Ayse Bilge|AB|;Ozyigit|Leyla Pur|LP|;Erus|Suat|S|;Tanju|Serhan|S|;Dilege|Şükrü|Ş|;Tabak|Levent|L|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3109/02770903.2015.1054402",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0903",
"issue": "52(10)",
"journal": "The Journal of asthma : official journal of the Association for the Care of Asthma",
"keywords": "Carcinoid tumor; pneumomediastinum; severe asthma",
"medline_ta": "J Asthma",
"mesh_terms": "D000328:Adult; D001249:Asthma; D002276:Carcinoid Tumor; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008478:Mediastinal Emphysema; D008479:Mediastinal Neoplasms; D012720:Severity of Illness Index",
"nlm_unique_id": "8106454",
"other_id": null,
"pages": "1095-8",
"pmc": null,
"pmid": "26291136",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of uncontrolled severe asthma patient with coexisting carcinoid tumor presenting as pneumomediastinum.",
"title_normalized": "a case of uncontrolled severe asthma patient with coexisting carcinoid tumor presenting as pneumomediastinum"
} | [
{
"companynumb": "TR-BAYER-2015-417467",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "We describe two clinical prenatal cases with rare de novo RIT1 variants, which showed more severe clinical manifestations than other Noonan Syndrome genotypes, resulting in fetal death. Extra attention is recommended when these variants are detected.",
"affiliations": "Department of Clinical Genetics Odense University Hospital Odense Denmark.;Fetal Medicine Unit Department of Obstetrics and Gynecology Odense University Hospital Odense Denmark.;Department of Clinical Genetics Odense University Hospital Odense Denmark.;Department of Clinical Genetics Odense University Hospital Odense Denmark.;Department of Clinical Genetics Odense University Hospital Odense Denmark.",
"authors": "Miceikaite|Ieva|I|https://orcid.org/0000-0002-5188-7647;Bak|Geske Sidsel|GS|;Larsen|Martin Jakob|MJ|;Kristiansen|Britta Schlott|BS|;Torring|Pernille Mathiesen|PM|https://orcid.org/0000-0002-7303-7619",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.4507",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4507\nCCR34507\nCase Report\nCase Reports\nPrenatal cases with rare RIT1 variants causing severe fetal hydrops and death\nMICEIKAITE et al.\nMiceikaite Ieva https://orcid.org/0000-0002-5188-7647\n1 2\nBak Geske Sidsel 3 geske.bak@rsyd.dk\n\nLarsen Martin Jakob 1 2\nKristiansen Britta Schlott 1\nTorring Pernille Mathiesen https://orcid.org/0000-0002-7303-7619\n1\n1 Department of Clinical Genetics Odense University Hospital Odense Denmark\n2 Human Genetics Unit Department of Clinical Research Faculty of Health Sciences University of Southern Denmark Odense Denmark\n3 Fetal Medicine Unit Department of Obstetrics and Gynecology Odense University Hospital Odense Denmark\n* Correspondence\nGeske Sidsel Bak, Fetal Medicine Unit, Department of Obstetrics and Gynecology, Odense University Hospital, Odense, Denmark.\nEmail: geske.bak@rsyd.dk\n\n21 7 2021\n7 2021\n9 7 10.1002/ccr3.v9.7 e0450715 5 2021\n13 4 2021\n24 5 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.\n\nAbstract\n\nWe describe two clinical prenatal cases with rare de novo RIT1 variants, which showed more severe clinical manifestations than other Noonan Syndrome genotypes, resulting in fetal death. Extra attention is recommended when these variants are detected.\n\nWe describe two clinical prenatal cases with rare de novo RIT1 variants, which showed more severe clinical manifestations than other Noonan Syndrome genotypes, resulting in fetal death. Extra attention is recommended when these variants are detected.\n\ncystic hygroma\nhydrops fetalis\nNoonan syndrome\nprenatal screening\nRIT1\nFonden til Lægevidenskabens Fremme 10.13039/501100006197 19‐L‐0281 Aase og Ejnar Danielsens Fond 10.13039/501100003035 19‐10‐0259 Aase og Ejnar Danielsens Fond 10.13039/501100003035 19‐10‐0259 A.P. Møller—Fonden til Lægevidenskabens Fremme 10.13039/501100006197 19‐L‐0281 source-schema-version-number2.0\ncover-dateJuly 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:21.07.2021\nMiceikaite I , Bak GS , Larsen MJ , Kristiansen BS , Torring PM . Prenatal cases with rare RIT1 variants causing severe fetal hydrops and death. Clin Case Rep. 2021;9 :e04507. 10.1002/ccr3.4507\n==== Body\n1 INTRODUCTION\n\nHere, we describe two clinical prenatal cases with rare de novo RIT1 variants, which showed more severe clinical manifestations than other Noonan Syndrome genotypes, resulting in fetal death. It is recommended that extra attention would be exercised when these variants are detected, and an appropriate patient counselling would be provided.\n\nNoonan Syndrome (NS) is a multisystemic developmental disorder with an incidence of 1:1000–2500 in the general population. 1 It follows an autosomal dominant inheritance. 30–75% of patients with NS have an affected parent; nonetheless, NS can also be caused by a de novo variant. The disease has a wide spectrum of phenotypical features, which are associated with different genotypes. At present, 11 genes have been reported to cause NS when carrying a pathogenic variant. 2 Based on the chromosomal locations and genes involved, NS is divided into different types. 3\n\nThe RIT1 (Ras‐like without CAAX 1) gene is associated with Noonan Syndrome type 8 (NS8, OMIM #615355). The RIT1 gene is located on chromosome 1q22. The protein coded by RIT1 is involved in MAPK‐dependent signaling pathways (involved in stress‐mediated activation of p38‐MK2‐HSP27‐AKT complex in cell‐survival mechanism) and NGF (nerve growth factor) dependent nerve growth and differentiation. 4 Proteins coded by a mutated RIT1 gene cause hyperactivation of MAPK‐ERK or transactivation of ELK pathways, participating in NS pathogenesis. 4 The gain‐of‐function mutations of RIT1 are responsible for around 5% of all NS cases, making RIT1 one of the most common genetic causes of NS. 5\n\nThe common distinctive characteristic in individuals with NS8 is hypertrophic cardiomyopathy, which is seen in at least 50% of the cases with a mutated RIT1 gene. 5 , 6 , 7 Congenital heart disease in NS gives one of the worst prognoses, as almost 25% of all NS patients die within a year due to heart failure. 1 Other more frequently observed characteristics among these patients are pulmonary stenosis and atrial or ventricular septal defects. 6 , 7\n\nWebbed and short neck is more common in RIT1 patients; however, short stature, pectus deformity, and intellectual disability are less common, compared with patients carrying mutations in other NS‐associated genes. 4 , 8 , 9\n\nPrenatally, NS is suspected in cases with increased nuchal translucency (NT), a cystic hygroma, or hydrops fetalis. 10 Prenatal lymphatic malfunctions are more often observed in RIT1 NS cases, 6 which result in high birth weight and possible complications.\n\nHere, we describe two prenatally detected NS cases with pathogenic RIT1 variants, which resulted in severe fetal hydrops and death.\n\n2 PRESENTATION OF CASE 1\n\nA healthy nulliparous woman was referred to our tertiary fetal medicine clinic at the gestational age of (GA) 15 weeks +3 days. The family history revealed no congenital abnormalities and no consanguinity. The combined first‐trimester screening (cFTR) was done in the primary care center at GA 12 weeks +5 days. An ultrasound scan showed a cystic hygroma with NT of 14.2 mm. The risk of trisomy 21 was 1:8. Chorionic villus sampling (CVS) was done on the following day. A normal male karyotype was reported in the chromosomal microarray. An early ultrasound of the fetal anatomy was performed at 15 weeks +3 days that showed a persistent cystic hygroma with NT of 14 mm and large jugular lymphatic sacs at each side of the neck measuring 24 × 16 mm for the left side and 20 × 10 mm for the right side. The fetus was not hydropic.\n\nAt GA 19 weeks +5 days, ultrasound scan showed smaller NT (12.4 mm) and jugular lymphatic sacs at both sides of neck, in the axial view of 7 × 10 mm on the left side and 5 × 8 mm on the right side. No other malformations were observed. The couple was offered a trio exome analysis and screened for variants in known Noonan‐associated genes. The result showed a de novo heterozygous pathogenic RIT1 variant (c.268A>G (p. Met90Val), NM_006912.6). The couple was counseled about NS and their options. They decided to continue the pregnancy. At GA 28 weeks +6 days, an ultrasound showed normal growth with an estimated fetal weight of 1265 g. The enlarged NT and jugular lymphatic sacs had disappeared. A new ultrasound was planned for GA 34 weeks, but the patient came in at GA 31 week +2 days due to reduced fetal movements. Bilateral severe hydrothorax (chylothorax) was revealed by the ultrasound. The fetal echocardiography was normal. Betamethasone was given for lung maturation. The intrauterine drainage of the hydrothorax was only possible to insert at one side. It confirmed chylothorax. However, the fetus died in utero the day after the drainage was performed. It had hypertelorism and a broad webbed neck, but otherwise no characteristic Noonan features. The couple did not opt for autopsy. A postnatal picture and ultrasound scan findings can be seen in Figure 1 as Case 1.\n\nFIGURE 1 Postnatal pictures and ultrasound scans during pregnancy for Cases 1 and 2. Case 1: A, Postnatal picture of the baby, who died in utero at the gestational age of (GA) 31 week +5 days. It shows hypertelorism and a webbed neck. B, Jugular lymphatic sacs at GA 18 weeks, decreasing in size compared to an earlier scan. C, Large nuchal translucency (NT) / hygroma at GA 19 weeks +3 days, decreased from earlier scan. D, Bilateral pleural exudate at GA 31 week +2 days before insertion of drains. Case 2: E, Postnatal picture of the baby at GA 28 weeks +6 days showing universal hydrops with a large hygroma. F, Large NT / hygroma at GA 12 weeks +3 days. G, Kidneys with bilateral pyelectasis at GA 18 weeks +2 days. H, Enlarged abdominal circumference with ascites at GA 28 weeks +2 days\n\n3 PRESENTATION OF CASE 2\n\nThe patient was a nulliparous woman with a history of 2 years of infertility, but otherwise healthy, who became spontaneously pregnant. There were no congenital abnormalities and no consanguinity registered in the family history. The combined first‐trimester screening was performed at GA 12 weeks +3 days, which showed a cystic hygroma with a large NT of 10.2 mm and mild cutaneous edema at the thorax and abdomen. The risk of trisomy 21 was 1:3. She was informed about the risks of genetic diseases, fetal malformations, and intrauterine fetal demise. She was offered a CVS analysis. A normal chromosomal microarray result was received. Due to the residual risk of genetic disease, she was offered trio exome analysis. An ultrasound of the fetal anatomy at GA 15 weeks +6 days still showed a cystic hygroma with NT of 15 mm. Furthermore, the fetus had pyelectasis of a slightly hyperechogenic left kidney.\n\nAt GA 18 weeks +2 days, a likely pathogenic, heterozygous de novo variant in the RIT1 gene (c.245T>G (p. Phe82Cys), NM_006912.6) was detected by trio exome analysis. The couple was counseled about NS. Ultrasound showed an NT of 18 mm, bilateral pyelectasis, and mild ascites. The patient decided to continue the pregnancy and was evaluated with ultrasound every 1–2 weeks due to increasing fetal hydrops. At GA 19 weeks +6 days, there was bilateral pyelectasis (hydronephrosis). Fetal echocardiography was normal.\n\nAt GA 23 weeks +6 days, she developed mild polyhydramnios with an amnion fluid index (AFI) of 25 cm. At GA 26 weeks +6 days, she still had mild polyhydramnios, but at GA 28 weeks +2 days, the polyhydramnios became severe, AFI 48 cm, and it started to bother the patient. At the same time, fetal hydrops kept increasing with moderate‐to‐severe hydrothorax, and ascites that enlarged the abdominal circumference to +12 in Z‐score, giving an estimated fetal weight of 3000 g (equivalent to +130% of normal for the GA). The NT was 23 mm, and the fetus had large jugular lymphatic sacs on each side of the neck. The flow in the umbilical cord had an absent‐end diastolic flow. The patient was offered therapeutic amniocentesis after 48 hours of fetal lung maturation with betamethasone.\n\nThe patient came back at GA 28 weeks +6 days for the amniocentesis and pediatric counseling. She reported that her condition had worsened during the previous 24 h with sleep problems and dyspnea. Further testing showed mirror syndrome resembling HELLP syndrome/preeclampsia. The amniocentesis was cancelled, and she had a subacute cesarean section. She was offered ex utero intrapartum treatment (EXIT) with intubation of the baby during cesarean before clamping of the umbilical cord. She declined that option, but otherwise, full treatment was planned. The newborn was severely hydropic at birth. It was intubated, ventilated, and given Curosurf® (poractant alfa). Bilateral pleural drainage was inserted. The treatment had no effect, and resuscitation was terminated after 27 min; the newborn died shortly after. It was severely hydropic with flattened facies. The birth weight of 2935 g was equivalent to +109% of normal for the GA and calculated to be >10 SD, based on Hadlock. 11 The couple did not opt for autopsy of the newborn. A postnatal picture and ultrasound scan findings can be seen in Figure 1 as Case 2.\n\n4 DISCUSSION\n\nThe two clinical prenatal cases described in this paper present rare RIT1 variants with similar, and different‐than‐usual NS manifestations. Both variants are situated at the beginning of exon 5 of the RIT1 gene. The majority of known NS‐associated pathogenic variants cluster in exons 4 and 5 (ClinVar). 6 These variants (in switch II region of RIT1), described by Milosavljevic et al. 6 lead to a change in amino acid which is in a conserved sequence of the gene.\n\nThe RIT1 variant c.268A>G (p. Met90Val) identified in Case 1, was previously detected in 4 prenatal cases, which all presented with hydrops fetalis (Table 1). In Case 2, a RIT1 variant c.245T>G (p. Phe82Cys) was detected that was previously described once in a fetus with hydrops fetalis, CNS malformations, and congenital heart defect associated with NS. 10\n\nTABLE 1 Prenatal and postnatal fetal as well as maternal phenotypic characteristics and clinical outcome for two cases described here, and other published cases with corresponding identical variants in RIT1 gene\n\nCharacteristic/Case\tCase 1\tStevens et al. 2017\tMilosavljevic et al. 2016\tMatyášová et al. 2019\tQuinlan‐Jones et al. 2019\tCase 2\tYates et al. 2017\t\nGenomic RIT1 variant (NM_006912.5)\tc.268A>G\tc.245T>G\t\nProtein variant (NP_008843.1)\tp. Met90Val\tp. Phe82Cys\t\nDe novo\t+\t+\t+\t+\t+\t+\t+\t\nFetal (prenatal)\t\nIncreased nuchal translucency\t+\td\t+\t+\t\t+\t\t\nCystic hygroma\t+\t+\t+\t\t+\t+\t+\t\nLarge jugular lymphatic sacs\t+\t+\t+\t\t\t+\t\t\nHydrops fetalis\t+\t+\t+ e\t+\t+\t+\t+\t\nBilateral hydrothorax/\n\npleural effusion\n\n\t+\t+\t+\t\t\t+\t\t\nAscites\tNo\t\t+\t+\t+\t+\t\t\nSkin edema\tNo\t\t\t\t+\t+\t\t\nSevere generalized edema/ anasarca\tNo\t+\t+\t\t\t+\t\t\nHydronephrosis/pyelectasis\tNo\t+\ta\t\t\t+ b\t\t\nFlattened facies\tNo\t+\t\t\t\t+\t\t\nCardiac defect\tNo\tNo\tNo\t\t\tNo\t+\t\nCNS malformations\tNo\tNo\tNo\t\t\tNo\t+ c\t\nMaternal\t\nPolyhydramnios\tNo\t+\t+\t\t\t+\t\t\nAmnioreduction\n\nProcedure\n\n\tNo\tSeveral\tOnce\t\t\tPlanned\t\t\nHELLP syndrome/preeclampsia/ Mirror syndrome\tNo\tNo\t+\t\t\t+\t\t\nFetal death (GA)\t31+5 IUFD\t30\n\nIUFD\n\n\t26+4\n\nduring labor\n\n\tIUFD\n\n\tIUFD\n\n\t28+6\n\nafter CS\n\n\t18\t\nFetal/child (postnatal)\t\nHigh (birth) weight\tNo\t\t>2.5 SD\t\t\t>10 SD\t\t\nHypertelorism\t+\t\t+\t\t\t\t\t\nLow set ears\tNo\t\t+\t\t\tNo\t\t\nBroad short webbed neck\t+\t\t+\t\t\t+\t\t\nOther\t\t\t\t\tp\ta\t\t\nPathological examination\tNP\t\tNP\t\t+\tNP\t\t\n+—the characteristic was present, no—the characteristic was not present, an empty square—no information, GA—gestational age in weeks and days (eg, 31+5 means 31 week +5 days), CS—caesarian section, NP—not permitted/not performed.\n\nIf GA or other information about the fetal demise is not written, it is unknown or not provided by the authors.\n\na —Duplication of renal collection system.\n\nb —Hyperechogenic left kidney.\n\nc —Dandy‐Walker malformation.\n\nd —cFTR not performed, 1st scan at GA 21.\n\ne —Severe at GA 25, p—superior vena cava, atrial septal defect, bilateral talipes.\n\nJohn Wiley & Sons, Ltd\n\nA number of publications describe postnatally identified variants in the same codons as the two RIT1 variants in Cases 1 and 2; however, these involved different nucleotides and resulted in a different amino acid after substitution, which presented milder Noonan characteristic symptoms. 8 , 9 , 12 , 13 , 14 To the best of our knowledge, there are no exact postnatally identified variants described in the literature matching the two cases we present. For all the cases with prenatally identified variants in RIT1, matching the variants described in Cases 1 and 2, intrauterine fetal demise or death during labor was reported at GA 18–32 weeks (Table 1). This suggests more severe clinical manifestations than other Noonan genotypes and a worse prognosis in cases with the RIT1 variants we have described in this case report.\n\nA recently published study, learning the genetic causes of non‐immune hydrops fetalis, showed that 29% of the cases were solely due to gene variants in MAPK‐dependent signaling pathways. 15 All of them were de novo variants, including a RIT1 variant. It indicates that Noonan‐associated gene variants are a rather frequent finding in cases with hydrops fetalis. Furthermore, that study supports the use of exome sequencing for prenatal diagnosis in cases with hydrops fetalis as the ones described here.\n\nBased on our described clinical cases and the outcomes of other recent studies, it is advised to remain attentive about the prognosis in cases where a cystic hygroma or hydrops fetalis and a rare de novo RIT1 variant are identified prenatally, as it might result in a more‐severe‐than‐usual Noonan outcome resulting in fetal death. Thus, it is recommended that the patients be counselled about these potential risks.\n\n5 ETHIC STATEMENT\n\nVerbal and written informed consent was obtained from the patients for publications of their cases.\n\nCONFLICT OF INTERESTS\n\nThe authors declare no conflict of interests.\n\nAUTHOR CONTRIBUTIONS\n\nIeva Miceikaite: contributed to conception and design for this manuscript, collection of the data, wrote and edited the paper, prepared the table and the figure, and approved the final version to be published. Geske Sidsel Bak: contributed to conception and design, acquisition of data, including ultrasound pictures, and drafting the case descriptions. Revised the paper and approved the final version to be published. Martin Jakob Larsen: contributed to conception and design, performed the analysis and interpretation of the data, critically revised the draft, and approved the final version to be published. Britta Schlott Kristiansen: contributed to acquisition of the data, critically revised the draft, and approved the final version to be published. Pernille Mathiesen Torring: contributed to conception and design, and acquisition of data. Revised the paper and approved the final version to be published.\n\nACKNOWLEDGEMENTS\n\nAuthors want to express their special thanks to the patients who allowed the publication of these clinical cases. This paper includes data from the PhD research project, which was supported by the grants from the following funds: Aase og Ejnar Danielsens Fond (grant no. 19‐10‐0259) and A.P. Møller—Fonden til Lægevidenskabens Fremme (grant no. 19‐L‐0281). Published with written consent of the patient.\n\nDATA AVAILABILITY STATEMENT\n\nThe authors confirm that the main data supporting the findings of this study are available within the article. The other data are not publicly available to protect the privacy of the patients.\n==== Refs\nREFERENCES\n\n1 Roberts AE , Allanson JE , Tartaglia M , Gelb BD . Noonan syndrome. Lancet. 2013;381 (9863 ):333‐342.23312968\n2 Cai J , Li H . A novel RIT1 mutation causes deterioration of Noonan syndrome‐associated cardiac hypertrophy. EBioMedicine. 2019;42 :6‐7.30904604\n3 Allanson JE , Roberts AE , Syndrome N . 2001 Nov 15 [Updated 2019 Aug 8]. In: GeneReviews® [Internet]; 1993‐2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1124/\n4 Cavé H , Caye A , Ghedira N , et al. Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia. Eur J Hum Genet. 2016;24 (8 ):1124‐1131.26757980\n5 Aoki Y , Niihori T , Inoue S‐I , Matsubara Y . Recent advances in RASopathies. J Hum Genet. 2016;61 (1 ):33‐39.26446362\n6 Milosavljevic D , Overwater E , Tamminga S , et al. Two cases of RIT1 associated Noonan syndrome: further delineation of the clinical phenotype and review of the literature. Am J Med Genet A. 2016;170 (7 ):1874‐1880.27109146\n7 Calcagni G , Baban A , Lepri FR , Marino B , Tartaglia M , Digilio MC . Congenital heart defects in Noonan syndrome and RIT1 mutation. Genet Med. 2016;18 (12 ):1320.27684039\n8 Yaoita M , Niihori T , Mizuno S , et al. Spectrum of mutations and genotype‐phenotype analysis in Noonan syndrome patients with RIT1 mutations. Hum Genet. 2016;135 (2 ):209‐222.26714497\n9 Bertola DR , Yamamoto GL , Almeida TF , et al. Further evidence of the importance of RIT1 in Noonan syndrome. Am J Med Genet A. 2014;164A (11 ):2952‐2957.25124994\n10 Yates CL , Monaghan KG , Copenheaver D , et al. Whole‐exome sequencing on deceased fetuses with ultrasound anomalies: expanding our knowledge of genetic disease during fetal development. Genet Med. 2017;19 (10 ):1171‐1178.28425981\n11 Hadlock FP , Harrist RB , Sharman RS , Deter RL , Park SK . Estimation of fetal weight with the use of head, body, and femur measurements–a prospective study. Am J Obstet Gynecol. 1985;151 (3 ):333‐337.3881966\n12 Aoki Y , Niihori T , Banjo T , et al. Gain‐of‐function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am J Hum Genet. 2013;93 (1 ):173‐180.23791108\n13 Gos M , Fahiminiya S , Poznański J , et al. Contribution of RIT1 mutations to the pathogenesis of Noonan syndrome: four new cases and further evidence of heterogeneity. Am J Med Genet A. 2014;164A (9 ):2310‐2316.24939608\n14 Kouz K , Lissewski C , Spranger S , et al. Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation. Genet Med. 2016;18 (12 ):1226‐1234.27101134\n15 Sparks TN , Lianoglou BR , Adami RR , et al. Exome sequencing for prenatal diagnosis in nonimmune hydrops fetalis. N Engl J Med. 2020;383 (18 ):1746‐1756.33027564\n\n",
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"keywords": "Noonan syndrome; RIT1; cystic hygroma; hydrops fetalis; prenatal screening",
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"title": "Prenatal cases with rare RIT1 variants causing severe fetal hydrops and death.",
"title_normalized": "prenatal cases with rare rit1 variants causing severe fetal hydrops and death"
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"abstract": "Solar urticaria is an uncommon condition characterized by erythema and whealing shortly after exposure to ultraviolet (UV) and/or visible light. We report a 25-year-old woman with an erythematous, edematous, pruritic reaction minutes after sun exposure while she was taking terbinafine for onychomycosis. Phototesting revealed a UVB-sensitive urticarial reaction, confirming the diagnosis of solar urticaria. This report describes the first patient with possible terbinafine-associated solar urticaria.",
"affiliations": "University of California, Davis. rksivamani@ucdavis.edu.",
"authors": "Kuo|Sandy|S|;Sivamani|Raja K|RK|",
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"title": "UVB-sensitive solar urticaria possibly associated with terbinafine.",
"title_normalized": "uvb sensitive solar urticaria possibly associated with terbinafine"
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"abstract": "BACKGROUND\nColchicine is a medication described by a complex constellation of side effects.\n\n\nMETHODS\nWe report the case of an 80s- 80-year-old subject, treated with colchicine, who developed a left monolateral ptosis with horizontal diplopia after treatment with oral colchicine. Two months later, he underwent a clinical follow-up and complete recovery of the previous third cranial nerve deficit was reported at neurological examination. A few months later, colchicine therapy was reported with a reappearance of the same ocular deficit.\n\n\nCONCLUSIONS\nOur report suggests that patients receiving colchicine should be followed prudently and, a possible iatrogenic origin of an isolated ocular cranial neuropathy must be taken into account, especially when other potential etiological entities are excluded by the instrumental and laboratory clinical investigations.",
"affiliations": "Department of Neuroscience, \"S. Giovanni di Dio\" Hospital, 88900 - Crotone, Italy.;Department of Neuroscience, \"S. Giovanni di Dio\" Hospital, 88900 - Crotone, Italy.;Department of Neuroscience, \"S. Giovanni di Dio\" Hospital, 88900 - Crotone, Italy.;Department of Neuroscience, \"Pugliese Ciaccio\" Hospital, 88100 - Catanzaro, Italy.;Department of Neuroscience, \"Pugliese Ciaccio\" Hospital, 88100 - Catanzaro, Italy.",
"authors": "Gorgone|Gaetano|G|;Plastino|Massimiliano|M|;Vaccaro|Antonio|A|;Fava|Antonietta|A|;Bosco|Domenico|D|",
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"title": "Colchicine may Induce Isolated and Reversible Oculomotor Neuropathy.",
"title_normalized": "colchicine may induce isolated and reversible oculomotor neuropathy"
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"abstract": "To assess the safety and efficacy of allogeneic stem cell transplantation from haploidentical related donors (haplo-SCT) as 2nd transplantation for patients with early relapsed disease, we retrospectively evaluated 7 consecutive patients (median age, 42 years; range, 29-63 years) who experienced relapse within 1 year of the 1st transplantation and received haplo-SCT as a 2nd transplantation. Among the 7 patients who received haplo-SCT, 2 who were in morphologically complete remission (CR) at transplantation were conditioned with a reduced-intensity regimen, and the 5 non-CR patients were conditioned with a myeloablative regimen. Both conditioning regimens included antithymocyte globulin. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methylprednisolone. Sustained neutrophil engraftment was achieved in all 7 patients. One patient developed severe acute GVHD. Notably, only 1 patient experienced relapse, and each patient achieved longer CR duration than after the 1st transplantation. Three of the 7 patients died from treatment-related causes: acute GVHD, post-transplantation lymphoproliferative disorder, and bacterial pneumonia. At the time of analysis, the 2-year overall survival rate of these 7 patients was 42.9%. This suggests that use of haploidentical related donors is a viable alternative for 2nd transplantation and should be confirmed in larger cohorts.",
"affiliations": "Department of Medicine and Clinical Science, Gunma University, Gunma, Japan; Leukemia Research Center, Saiseikai Maebashi Hospital, Gunma, Japan. Electronic address: hiroakis@ked.biglobe.ne.jp.;Leukemia Research Center, Saiseikai Maebashi Hospital, Gunma, Japan.;Leukemia Research Center, Saiseikai Maebashi Hospital, Gunma, Japan.;Leukemia Research Center, Saiseikai Maebashi Hospital, Gunma, Japan.",
"authors": "Shimizu|H|H|;Hatsumi|N|N|;Takada|S|S|;Sakura|T|T|",
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"title": "Haploidentical stem cell transplantation for acute leukemia patients who experienced early relapse within one year after the first transplantation.",
"title_normalized": "haploidentical stem cell transplantation for acute leukemia patients who experienced early relapse within one year after the first transplantation"
} | [
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"abstract": "Mandibular cortical bone measurement with x-ray imaging is known to be a potentially useful tool in the detection of dimensional changes caused by bisphosphonate. The primary purpose of this study was to assess the meaning and limitation of cortical bone measurement with computed tomography (CT) in patients with medication-related osteonecrosis of the jaw (MRONJ). The investigators obtained DentaScan images of the mandible from 15 patients with MRONJ, 15 patients with a history of antiresorptive agent administration without symptoms of MRONJ (non-MRONJ), and 15 control subjects. The cortical bone width measured on DentaScan images was compared between the three groups (ANOVA and Tukey's test). Interobserver reliability between two observers was also assessed. The values of interclass correlation coefficient were 0.48 in the MRONJ group, 0.29 in the Non-MRONJ group, and 0.34 in control group. The cortical bone widths calculated both by observer 1 and observer 2 were thicker in patients with MRONJ than in the non-MRONJ group and controls. There were significant differences in cortical bone width among the MRONJ, non-MRONJ, and control groups in observer 1 (P < 0.001) and observer 2 (P < 0.001), specifically comparing the MRONJ group with the non-MRONJ group and the control group. Cortical bone width measurement is useful for the distinction between medication-related osteonecrosis of the jaw and normal bone, in spite of the low interobserver reliability.",
"affiliations": "Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.",
"authors": "Iwata|Eiji|E|;Akashi|Masaya|M|;Kishimoto|Megumi|M|;Kusumoto|Junya|J|;Hasegawa|Takumi|T|;Furudoi|Shungo|S|;Komori|Takahide|T|",
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"keywords": " Bisphosphonates; Computed tomography; Denosumab; Mandible; Osteonecrosis",
"medline_ta": "Kobe J Med Sci",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D016022:Case-Control Studies; D000071538:Cortical Bone; D005260:Female; D006801:Humans; D008297:Male; D008334:Mandible; D008875:Middle Aged; D061330:Multidetector Computed Tomography; D015588:Observer Variation; D012189:Retrospective Studies",
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"title": "Meaning and Limitation of Cortical Bone Width Measurement with DentaScan in Medication-Related Osteonecrosis of the Jaws.",
"title_normalized": "meaning and limitation of cortical bone width measurement with dentascan in medication related osteonecrosis of the jaws"
} | [
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"abstract": "Hydroxychloroquine is considered a relatively benign drug and is regularly used by rheumatologists and dermatologists. We highlight the severe adverse drug reaction potential of this commonly prescribed medication. We report the case of a 63-year-old male, who presented with widespread skin eruption following initiation of hydroxychloroquine two weeks earlier for an inflammatory arthritis. He had typical clinical, biochemical and histological features of the now recognised formal 'diagnosis' of severe cutaneous adverse drug reaction. The culprit drug was stopped and he responded to oral and topical steroids as well as supportive measures. Severe reactions to hydroxychloroquine are uncommon; however, as in this case, drug hypersensitivity reactions often manifest in skin. In a drug normally considered to be safe, these potential cutaneous side effects should be highlighted in information given to patients prior to commencement.",
"affiliations": "1 Clinical Fellow in Dermatology, Department of Dermatology, Queen Elizabeth University Hospital, UK.;2 Consultant Dermatologist, Department of Dermatology, Queen Elizabeth University Hospital, UK.",
"authors": "Randhawa|Amritakaur|A|;Wylie|Grant|G|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D018501:Antirheumatic Agents; D000068656:Mometasone Furoate; D006886:Hydroxychloroquine; D011239:Prednisolone",
"country": "Scotland",
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"keywords": "Hydroxychloroquine; drug rash with eosinophilia and systemic symptoms; severe cutaneous adverse drug reactions",
"medline_ta": "Scott Med J",
"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D000893:Anti-Inflammatory Agents; D018501:Antirheumatic Agents; D003875:Drug Eruptions; D006801:Humans; D006886:Hydroxychloroquine; D008297:Male; D008875:Middle Aged; D000068656:Mometasone Furoate; D011239:Prednisolone; D016896:Treatment Outcome",
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"references": null,
"title": "A case of an acute cutaneous drug reaction with hydroxychloroquine.",
"title_normalized": "a case of an acute cutaneous drug reaction with hydroxychloroquine"
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"activesubstancename": "ACETAMINOPHEN\\CODEINE PHOSPHATE"
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"abstract": "In the optional extension of clinical trial 1100.1518 39/40, human immunodeficiency virus-infected patients (aged 3 to <18 years) received ≥48 weeks of treatment with extended-release nevirapine. By last visit, all patients had undetectable viral loads and no new safety signals, demonstrating the safety and efficacy of a once-daily antiretroviral regimen.",
"affiliations": "Botswana-Baylor Children's Clinical Centre of Excellence, Gaborone.;Department of Pediatrics, University Hospital Frankfurt, Goethe University, Germany.;Department of Women's and Children's Health, University of Padua, Italy.;Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut.;Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut.;Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut.;Department of Pediatric Pneumology and Immunology, Charité University Medicine, Berlin, Germany.",
"authors": "Anabwani|Gabriel|G|;Königs|Christoph|C|;Giaquinto|Carlos|C|;Aslanyan|Stella|S|;Sabo|John P|JP|;Morrow|J-Scott|JS|;Feiterna-Sperling|Cornelia|C|",
"chemical_list": "D019380:Anti-HIV Agents; D003692:Delayed-Action Preparations; D019829:Nevirapine",
"country": "United States",
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"keywords": "HIV-1; extended-release formulation; long-term follow-up; nevirapine; pediatric patients",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000293:Adolescent; D019380:Anti-HIV Agents; D002648:Child; D002675:Child, Preschool; D003692:Delayed-Action Preparations; D064420:Drug-Related Side Effects and Adverse Reactions; D005500:Follow-Up Studies; D015658:HIV Infections; D006801:Humans; D055118:Medication Adherence; D019829:Nevirapine",
"nlm_unique_id": "9203213",
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"pages": "476-9",
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"references": null,
"title": "Nevirapine extended-release formulation tablets in HIV-1-infected children--long-term follow-up.",
"title_normalized": "nevirapine extended release formulation tablets in hiv 1 infected children long term follow up"
} | [
{
"companynumb": "BW-CIPLA LTD.-2016BW02793",
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"activesubstancename": "NEVIRAPINE"
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... |
{
"abstract": "BACKGROUND\nPerioperative dynamic left ventricular outflow obstruction associated with systolic anterior motion of the mitral valve is well recognized as a cause for unexplained sudden hypotension in perioperative settings, even without underlying heart diseases such as hypertrophic obstructive cardiomyopathy. We treated a patient who experienced sudden hypoxemia without severe hypotension during emergence from anesthesia after an uneventful laparoscopic cholecystectomy.\n\n\nMETHODS\nA 65-year-old female patient with a history of hypertension presented a sudden decrease in oxygen saturation to 80% after an uneventful cholecystectomy. Although a portable chest radiograph showed bilateral hilar pulmonary infiltrates consistent with pulmonary edema, we explored the underlying cause, i.e., systolic anterior motion of the mitral valve and left ventricular outflow tract obstruction with bedside transthoracic echocardiography. We speculate that dynamic mitral regurgitation resulted in pulmonary edema and, thereby, hypoxemia in this case without severe hypotension.\n\n\nCONCLUSIONS\nCareful bedside examination with transthoracic echocardiography was useful in making diagnosis and in guiding appropriate therapy for this patient. Clinicians should be aware that systolic anterior motion of the mitral valve may present as unexplained sudden hypoxemia in the perioperative setting.",
"affiliations": "Department of Anesthesiology & ICM, Kawasaki Medical School, Okayama, Japan. fujitay@med.kawasaki-ma.ac.jp.;Division of Cardiology, Internal Medicine, Kawasaki Medical School, Department of Cardiology, Present affiliation: The Sakakibara Heart Institute of Okayama, Okayama, Japan. kgnb_27_hot@yahoo.co.jp.;Department of Anesthesiology & ICM, Kawasaki Medical School, Okayama, Japan. yoshiday@med.kawasaki-m.ac.jp.;Department of Anesthesiology & ICM, Kawasaki Medical School, Okayama, Japan. mywingsnevergiveuptoflytodream@hotmail.co.jp.",
"authors": "Fujita|Yoshihisa|Y|;Kagiyama|Nobuyuki|N|;Sakuta|Yuka|Y|;Tsuge|Masatsugu|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12871-015-0031-y",
"fulltext": "\n==== Front\nBMC AnesthesiolBMC AnesthesiolBMC Anesthesiology1471-2253BioMed Central London 259274073110.1186/s12871-015-0031-yCase ReportSudden hypoxemia after uneventful laparoscopic cholecystectomy: another form of SAM presentation Fujita Yoshihisa fujitay@med.kawasaki-ma.ac.jp 1Kagiyama Nobuyuki kgnb_27_hot@yahoo.co.jp 2Sakuta Yuka yoshiday@med.kawasaki-m.ac.jp 1Tsuge Masatsugu mywingsnevergiveuptoflytodream@hotmail.co.jp 11 Department of Anesthesiology & ICM, Kawasaki Medical School, Okayama, Japan 2 Division of Cardiology, Internal Medicine, Kawasaki Medical School, Department of Cardiology, Present affiliation: The Sakakibara Heart Institute of Okayama, Okayama, Japan 16 4 2015 16 4 2015 2015 15 518 9 2014 1 4 2015 © Fujita et al.; licensee BioMed Central. 2015This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPerioperative dynamic left ventricular outflow obstruction associated with systolic anterior motion of the mitral valve is well recognized as a cause for unexplained sudden hypotension in perioperative settings, even without underlying heart diseases such as hypertrophic obstructive cardiomyopathy. We treated a patient who experienced sudden hypoxemia without severe hypotension during emergence from anesthesia after an uneventful laparoscopic cholecystectomy.\n\nCase presentation\nA 65-year-old female patient with a history of hypertension presented a sudden decrease in oxygen saturation to 80% after an uneventful cholecystectomy. Although a portable chest radiograph showed bilateral hilar pulmonary infiltrates consistent with pulmonary edema, we explored the underlying cause, i.e., systolic anterior motion of the mitral valve and left ventricular outflow tract obstruction with bedside transthoracic echocardiography. We speculate that dynamic mitral regurgitation resulted in pulmonary edema and, thereby, hypoxemia in this case without severe hypotension.\n\nConclusions\nCareful bedside examination with transthoracic echocardiography was useful in making diagnosis and in guiding appropriate therapy for this patient. Clinicians should be aware that systolic anterior motion of the mitral valve may present as unexplained sudden hypoxemia in the perioperative setting.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s12871-015-0031-y) contains supplementary material, which is available to authorized users.\n\nKeywords\nPulmonary edemaHypoxiaSystolic anterior motionEchocardiographyMRIissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nPerioperative dynamic left ventricular outflow obstruction (LVOTO) associated with systolic anterior motion (SAM) of the mitral valve is well recognized as a cause for unexplained sudden hypotension in perioperative settings, even without underlying heart disease such as hypertrophic cardiomyopathy (HOCM) or apical ballooning syndrome [1-4]. We treated a woman who experienced a sudden decrease in oxygen saturation (SpO2) to 80% without severe hypotension during emergence from anesthesia after an uneventful laparoscopic cholecystectomy. SAM-related mitral regurgitation (MR) was suspected to be responsible. Our case demonstrates that SAM may present as unexplained hypoxemia in the perioperative setting.\n\nCase presentation\nA 65-year-old woman with a 5-year history of hypertension and depression was scheduled for laparoscopic cholecystectomy under general anesthesia. Anesthesia was induced with propofol, and the airway was secured with a size #3 ProSeal laryngeal mask airway (PLMA). Anesthesia was maintained with desflurane at 4% in an oxygen–air mixture (FiO2 = 50%), and analgesia was achieved by continuous infusion of remifentanil at a rate of 0.16-0.24 μg · kg-1 · min-1 supplemented with fentanyl to a total of 0.4 mg. Muscle relaxation was attained with intermittent rocuronium. Oxygen saturation (SpO2) was kept at 99–100%, and blood pressure was relatively stable but fluctuated between 140/40 and 90/40 mmHg. The patient’s heart rate (HR) was 65–80 beats per minute during anesthesia. Surgery took 122 minutes, without measurable blood loss. A total of 1475 ml of crystalloid solution was infused intraoperatively. The anesthetic course was uneventful until the end of surgery.\n\nSeveral minutes after the end of surgery and having confirmed spontaneous respiration, 200 mg of sugammadex was administered intravenously to reverse the neuromuscular blockade. Although spontaneous respiration resumed under 100% oxygen, SpO2 decreased to 80%, with an increase in arterial pressure to 180/100 mmHg. The attending anesthesiologist, who suspected that a poorly fitted PLMA was the cause of hypoxemia, replaced the size #3 PLMA with a size #4 PLMA, and there was a temporary increase in SpO2 to 92%. The PLMA was removed, and the patient was transferred to the recovery room with oxygen at 6 L/min via face mask.\n\nUpon arrival at the post-anesthesia care unit, the patient was calm but still had a low SpO2 of 88%. Her blood pressure was 160/85 mmHg and her HR was 81 beats per minute. SpO2 increased to 92% soon with high-flow oxygen via face mask at a concentration of 60%, but it remained in the range of 90–93% with a smooth respiration at 18 breaths per minutes. Her arterial blood gases were pH 7.354, pCO2 47.8 mmHg, pO2 53.5 mmHg and base excess +0.5 mmol/liter. A portable chest radiograph showed bilateral hilar pulmonary infiltrates consistent with pulmonary edema, a normal cardiac silhouette, and air in the stomach (Figure 1). A nasogastric tube was placed to deflate the distended stomach. Bedside transthoracic echocardiography (TTE) revealed a hypercontractile left ventricle, no right ventricular dilatation, and no segmental wall motion abnormalities; however, slight mosaic flow signals in the left ventricular outflow tract (LVOT) and a posteriorly directed slight jet of mitral regurgitation (MR) were noted on color-flow Doppler mapping (CFD) (Figure 2). Suspecting the presence of SAM, isosorbide dinitrate was sprayed under the patient’s tongue at a dose of 2.5 mg to induce vasodilation. The MR jet in the posterior direction and the mosaic-pattern LVOTO then increased significantly, while blood pressure decreased to 78/42 mmHg (Figure 3) (Additional file 1: Video 1 a, b). We could not measure LVOT velocity, because parallel alignment with the continuous Doppler signal to the blood flow in the LVOT was not possible. Based on a diagnosis of dynamic MR and LVOTO secondary to SAM, we intravenously administered 0.2 mg of phenylephrine twice and initiated rapid infusion of 500 mL of hydroxylethyl starch over the course of an hour and continuous infusion of a short-acting beta blocker. The patient’s blood pressure returned to 152/68 mmHg, and SpO2 increased to 97–99% with an oxygen mask at a concentration of 40%. She was cared for overnight in the intensive care unit uneventfully without recurrence of hypoxemia, and transferred to the ward the next day. The bilateral hilar infiltrate had disappeared on the chest radiograph taken the next day. Troponin T and BNP at the post-anesthesia care unit were slightly increased to 0.012 ng/mL (normal <0.014 ng/mL) and 19.0 pg/mL (normal <18.4 pg/mL), respectively, suggesting slight myocardial injury. Cardiac magnetic resonance imaging (MRI) (Figure 4) (Additional 2: Video 2) performed 4 days after surgery, as well as transesophageal echocardiography (TEE), showed chordal SAM with mild MR and LVOTO at rest. The imaging showed some protrusion of the basal septal wall toward the LVOT. The peak pressure gradient through the LVOT was 20 mmHg on TEE. Echocardiographic measurement was performed by TEE to assess the anatomical factors that contributed to SAM (Table 1). The coaptation point of the mitral leaflets was 17 mm, shorter than the threshold value (25 mm), indicating an anteriorly displaced coaptation point, although other measurements did not reach threshold values. The patient is now regularly checked upon, and is taking 5 mg of oral bisoprolol fumarate per day.Figure 1 Portable chest radiograph. There were bilateral hilar pulmonary infiltrates, but the periphery of the lungs was relatively spared. Cardiac silhouette was not enlarged. There was air in the stomach.\n\nFigure 2 Bedside transthoracic echocardiography with color-flow Doppler mapping in the post-anesthesia care unit (left parasternal long axis view). Slight mosaic flow signals in the left ventricular outflow tract was noted on colorflow Doppler mapping. LA = left atrium; LV = left ventricle; LVOT; left ventricular outflow tract; Ao = aorta.\n\nFigure 3 Bedside transthoracic echocardiography with color-flow Doppler mapping in the post-anesthesia care unit after sublingular nitrate (left parasternal long axis view). Significant mitral regurgitation jet in the posterior direction (arrow)and mosaic pattern left ventricular outflow (arrow head) appeared.\n\nFigure 4 Cardiac MRI obtained 4 days after surgery. It revealed systolic anterior motion (arrow). There were no abnormalities in global shape, size, and systolic function of the left ventricle, except for some protrusion of the basal interventricular septum towards the left ventricular outflow tract. LA = left atrium; LV = left ventricle; Ao = aorta.\n\nTable 1 \nEchocardiographic predictors of systolic anterior motion (SAM)\n\n\nMeasurements\tThreshold values\tPatient values\t\nBasal septal thickness at end-systole\t>15 mm\t14 mm\t\nDistance from coaptation point to septum at onset of systole\t<25 mm\t17 mm\t\nMitral-aortic angle at onset of systole\t<120°\t130°\t\nEchocardiographic predictors of SAM described in reference 5. Values outside threshold limits indicate increased likelihood of SAM. Measurement was performed on transesoephageal echocardiographic images. Coaptation point of the mitral leaflets of the patient was shorter than the threshold value. Other values were within threshold limits.\n\nMidesophageal aortic valve long-axis view with color Doppler imaging showing aortic insufficiency (arrow). LA = left atrium; LV = left ventricle; Ao = aorta.\n\n\n\nDiscussion\nSAM typically occurs in association with certain underlying heart diseases, such as HOCM and apical ballooning syndrome or in the perioperative setting of cardiac surgeries, such as mitral valve repair and aortic valve replacement [5]. Recently, its occurrence was described in critical care settings without underlying heart disease [1,6]. Whether it occurs in the presence or absence of underlying heart disease, unexpected severe hypotension is the most typical manifestation and is caused by the dynamic LVOTO secondary to SAM [2,4,6,7]. Our patient suffered from unexplained severe hypoxemia upon emergence from anesthesia, without accompanying severe hypotension.\n\nThe use of LMA for laparoscopic cholecystectomy may not be common, but it is well accepted in many centers. Although we have used both Classic and ProSeal LMAs more than ten years safely, the latter is now preferred for ease of gastric tube placement and higher sealing pressure [8]. There is a theoretical possibility of silent aspiration of residual gastric fluid in this case for hypoxemia with a ProSeal LMA. However, transient nature of hypoxemia, uneventful course in the ICU on the following night and complete disappearance of infiltrate in the chest roentgenogram on the next day exclude its possibility. Other causes such as residual neuromuscular blockade, atelectasis or acute pulmonary edema, are also unlikely to have caused severe hypoxemia with hypotension, because of reliable antagonistic effects to rocuronium with sugammadex or a short duration of laparoscopic surgery in an otherwise healthy patient.\n\nBased on findings from the chest radiograph and TTE, we speculate that MR secondary to SAM caused pulmonary edema and hypoxemia in this patient. Because SAM leads to LVOTO and a systolic coaptation defect of the mitral valve, and because the severity varies in a dynamic way depending upon cardiac loading, chronotropy, and contractility [5-7], it is not surprising that severe hypoxemia, rather than hypotension, manifested in this patient.\n\nCardiac MRI and TEE showed chordal SAM with MR at rest, suggesting that the patient was predisposed to SAM, although there were no apparent structural abnormalities. It has been reported that there are several structural predisposing factors for SAM, such as narrow LVOT, anteriorly located mitral coaptation point, and small mitral–aortic angle of <120° [5]. We identified an anteriorly located mitral coaptation point in this patient’s heart. In addition to the echocardiographic predisposing factors, we speculate that anesthesia-mediated factors, such as anesthesia-mediated vasodilation, increased catecholamine levels due to surgical stimulation, and dehydration due to preoperative fasting, increased the severity of SAM and secondary MR [4].\n\nTreatment for pulmonary edema caused by SAM-induced MR differs from treatment of other forms of cardiogenic pulmonary edema, even though left atrial pressure is increased in both conditions [3]. The accepted treatments for cardiogenic pulmonary edema, such as diuretics, vasodilators, and inotropes, may worsen hypoxemia in patients with pulmonary edema caused by SAM-induced MR or even lead to cardiogenic shock or sudden death from LVOTO, if the cause remains unrecognized. Correct diagnosis of the underlying condition, i.e., SAM, is thus critically important for initiating appropriate treatment. Although the most common clinical finding in SAM or LVOTO is a new onset of systolic murmur peaking late [6], it is often difficult to obtain clear heart sounds during surgery or in the critical care setting, because of interference from noise induced by mechanical ventilation and other surrounding monitoring devices.\n\nBedside TTE may be an important first-line diagnostic tool for the diagnosis of SAM [6]. It is also very helpful for differentiating SAM-related pulmonary edema from other forms of cardiogenic pulmonary edema. Echocardiographic visualization of the mitral leaflet–ventricular septum contact during systole on 2D or M mode, or shark-tooth velocity contour in the LVOT on continuous Doppler flow are diagnostic for SAM. In addition, mosaic flow pattern in the LVOT and a posteriorly directed MR jet on CFD may suggest LOVOT and MR, respectively, secondary to SAM. In this case, the initial TTE revealed only the mosaic pattern in the LVOT with a slight MR jet. However, careful examination of TTE using sublingual nitrate clearly demonstrated a posteriorly directed MR jet and an increase in the LVOTO mosaic pattern. We could thus establish a diagnosis of SAM and secondary MR as the cause of hypoxemia in this patient.\n\nTEE for the diagnosis of SAM is limited mostly to intraoperative intubated patients, because of its invasiveness. However, TEE could have clearly revealed systolic contact of the anterior leaflet of the mitral valve to the septum [2]. It is thus advisable to use TEE in patients for whom a bedside TTE is not sufficiently informative to diagnose SAM, especially hemodynamically unstable patients.\n\nThe present case underscores the fact that to make a diagnosis of SAM, it is important to bear in mind its possibility when unexplained hypoxemia or hypotension occur, even in patients without apparent structural abnormalities of the heart. Clinicians can then listen for systolic murmur or perform bedside TTE under vasodilation with nitrate, if necessary, and eventually perform TEE for timely initiation of appropriate treatment.\n\nConclusion\nWe reported our experience with a patient who had sudden hypoxemia with pulmonary edema at the end of anesthesia following an uneventful laparoscopic surgery. With careful bedside TTE, we were able to explore the underlying cause, i.e., SAM. Clinicians should be aware that SAM may result in unexplained hypoxemia in patients without apparent structural abnormalities of the heart.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nAdditional files\nAdditional file 1: Bedside transthoracic echocardiography (color-flow Doppler mapping). Left parasternal long axis view in the post-anesthesia care unit before (a) and after (b) sublingual nitrate. (a) hypercontractile left ventricle with slight mosaic flow signals in the left ventricular outflow tract and posteriorly directed slight jet of mitral regurgitation (MR) were noted on color-flow Doppler mapping. (b) MR jet in the posterior direction and mosaic pattern left ventricular outflow obstruction increased significantly.\n\nAdditional file 2: Cardiac MRI obtained 4 days after surgery revealed chordal systolic anterior motion with mitral regurgitation. There were no abnormalities in global shape, size, and systolic function of the left ventricle, except for some protrusion of the basal interventricular septum towards the left ventricular outflow tract.\n\n\n\nAbbreviations\nAoAorta\n\nCFDColor-flow Doppler mapping\n\nHOCMHypertrophic obstructive cardiomyopathy\n\nHRHeart rate\n\nLMALaryngeal mask airway\n\nLALeft atrium\n\nLVLeft ventricle\n\nLVOTLeft ventricular outflow tract\n\nLVOTOLeft ventricular outflow tract obstruction\n\nMRMitral regurgitation\n\nMRIMagnetic resonance imaging\n\nPLMAProSeal® laryngeal mask airway\n\nSAMSystolic anterior motion\n\nSpO2oxygen saturation\n\nTEETransesophageal echocardiography\n\nTTETransthoracic echocardiography\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nYF: Involvement of the patient care at the ICU and preparation of the manuscript. YS and MT: Substantial contribution to draft the manuscript. NK: Carrying out the TEE and MRI studies and substantial contribution to the interpretation of TEE findings. All authors read and approved the final manuscript.\n\nAuthors’ information\n\nY.F.: Professor and Chair, Department of Anesthesiology & ICM, Kawasaki Medical School N.K.: Division of Cardiology, Internal Medicine, Kawasaki Medical School, Present affiliation: Department of Cardiology, The Sakakibara Heart Institute of Okayama Y.S.: Clinical Lecturer, Department of Anesthesiology & ICM, Kawasaki Medical School M.T.: Postgraduate Student, Department of Anesthesiology & ICM, Kawasaki Medical School.\n\nAcknowledgement\nThis case report was presented, in part, at the IARS 2015 Annual Meeting, March 21-24, 2015, Hawaii.\n==== Refs\nReferences\n1. Chockalingam A Mehra A Dorairajan S Dellsperger KC Acute left ventricular dysfunction in the critically ill Chest 2010 138 198 207 10.1378/chest.09-1996 20605820 \n2. Reddy S Ueda K Unexpected refractory intra-operative hypotension during non-cardiac surgery. Diagnosis and management guided by trans-oesophageal echocardiography Indian J Anaesth 2014 58 51 4 10.4103/0019-5049.126796 24700900 \n3. Cavallaro F Marano C Sandroni C Dell'anna A Systolic anterior motion causing hemodynamic instability and pulmonary edema during bleeding Minerva Anestesiol 2010 76 653 6 20661209 \n4. Luckner G1 Margreiter J Jochberger S Mayr V Luger T Voelckel W Systolic anterior motion of the mitral valve with left ventricular outflow tract obstruction: three cases of acute perioperative hypotension in noncardiac surgery Anesth Analg 2005 100 1594 8 10.1213/01.ANE.0000152392.26910.5E 15920179 \n5. Hymel BJ Townsley MM Echocardiographic assessment of systolic anterior motion of the mitral valve Anesth Analg 2014 118 1197 201 10.1213/ANE.0000000000000196 24842174 \n6. Chockalingam A Dorairajan S Bhalla M Dellsperger KC Unexplained hypotension: the spectrum of dynamic left ventricular outflow tract obstruction in critical care settings Crit Care Med 2009 37 729 34 10.1097/CCM.0b013e3181958710 19114882 \n7. Ibrahim M1 Rao C Ashrafian H Chaudhry U Darzi A Athanasiou T Modern management of systolic anterior motion of the mitral valve Eur J Cardiothorac Surg 2012 41 1260 70 10.1093/ejcts/ezr232 22290892 \n8. Lu PP Brimacombe J Yang C Shyr M ProSeal versus the Classic laryngeal mask airway for positive pressure ventilation during laparoscopic cholecystectomy Br J Anaesth 2002 88 824 7 10.1093/bja/88.6.824 12173201\n\n",
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"mesh_terms": "D000368:Aged; D017081:Cholecystectomy, Laparoscopic; D004452:Echocardiography; D005260:Female; D006801:Humans; D000860:Hypoxia; D018810:Magnetic Resonance Angiography; D008944:Mitral Valve Insufficiency; D064847:Multimodal Imaging; D019095:Point-of-Care Systems; D011183:Postoperative Complications; D011654:Pulmonary Edema",
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"title": "Sudden hypoxemia after uneventful laparoscopic cholecystectomy: another form of SAM presentation.",
"title_normalized": "sudden hypoxemia after uneventful laparoscopic cholecystectomy another form of sam presentation"
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"abstract": "BACKGROUND\nIdiopathic ventricular tachycardia (VT) occurs in individuals without structural abnormalities in the heart, accounts for approximately 10% of total VTs. Furthermore, approximately 70% of idiopathic VTs originate from Right ventricular outflow tract (RVOT). However, among perioperative arrhythmias, incidence of VT after surgery is extremely rare and most arrhythmias are atrial origin.\nA 69-year-old man with permanent pacemaker underwent colon surgery.\nPatient suffered from low blood pressure and dizziness, sweating at post anesthetic care unit (PACU) and heart rate (HR) increased suddenly to 200 beats/min with monomorphic VT after bolus ephedrine administration and continuous dopamine infusion.\n\n\nMETHODS\nPacemaker interrogation followed by DC cardioversion was done.\n\n\nRESULTS\nPatient's vital signs became normal and symptoms are subsided.\n\n\nCONCLUSIONS\nRVOT VT can be caused by triggering activities, such as ephedrine, dopamine, and inadequate fluid management. These triggering activities are initiated by acceleration of HR from ventricles with infusion of catecholamine which lead monomorphic VT originating from RVOT.RVOT origin PVCs can be precipitated into monomorphic VT by administrating catecholamines such as ephedrine and dopamine even in patient with pacemaker. The mechanism of these VTs includes catecholamine induced acceleration of HR. Since RVOT PVCs can be recognize by 12 EKGs, we should be pay more attentions to the pre-operation EKG and be cautious using catecholamines.",
"affiliations": "Department of Anesthesiology and Pain Medicine, Inha University College of Medicine, 27, Inhang-ro, Jung-gu.;Department of Anesthesiology and Pain Medicine, Inha University College of Medicine, 27, Inhang-ro, Jung-gu.;Department of Anesthesiology and Pain Medicine, Inha University College of Medicine, 27, Inhang-ro, Jung-gu.;Department of Anesthesiology and Pain Medicine, Inha University College of Medicine, 27, Inhang-ro, Jung-gu.;Division of Cardiology, Department of Internal Medicine, Inha University Hospital, Incheon, Republic of Korea.",
"authors": "Park|Ki Hyun|KH|;Lim|Hyun Kyoung|HK|;Kim|Na Eun|NE|;Shinn|Helen Ki|HK|;Baek|Yong Soo|YS|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\n34160410\nMD-D-21-00515\n10.1097/MD.0000000000026372\n26372\n3300\nResearch Article\nClinical Case Report\nVentricular tachycardia of right ventricular outflow tract origin during the perioperative period\nA case report\nPark Ki Hyun MD a\nLim Hyun Kyoung MD a\nKim Na Eun MD a∗\nShinn Helen Ki MD, PhD a\nBaek Yong Soo MD b\nSaranathan. Maya\na Department of Anesthesiology and Pain Medicine, Inha University College of Medicine, 27, Inhang-ro, Jung-gu\nb Division of Cardiology, Department of Internal Medicine, Inha University Hospital, Incheon, Republic of Korea.\n∗ Correspondence: Na Eun Kim, Department of Anesthesiology and Pain Medicine, Inha University College of Medicine, 27, Inhang-ro, Jung-gu, Incheon 22332, Korea (e-mail: friskygril@naver.com).\n25 6 2021\n25 6 2021\n100 25 e2637210 3 2021\n23 5 2021\n2 6 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nRationale:\n\nIdiopathic ventricular tachycardia (VT) occurs in individuals without structural abnormalities in the heart, accounts for approximately 10% of total VTs. Furthermore, approximately 70% of idiopathic VTs originate from Right ventricular outflow tract (RVOT). However, among perioperative arrhythmias, incidence of VT after surgery is extremely rare and most arrhythmias are atrial origin.\n\nPatient concerns:\n\nA 69-year-old man with permanent pacemaker underwent colon surgery.\n\nDiagnoses:\n\nPatient suffered from low blood pressure and dizziness, sweating at post anesthetic care unit (PACU) and heart rate (HR) increased suddenly to 200 beats/min with monomorphic VT after bolus ephedrine administration and continuous dopamine infusion.\n\nInterventions:\n\nPacemaker interrogation followed by DC cardioversion was done.\n\nOutcomes:\n\nPatient's vital signs became normal and symptoms are subsided.\n\nLessons:\n\nRVOT VT can be caused by triggering activities, such as ephedrine, dopamine, and inadequate fluid management. These triggering activities are initiated by acceleration of HR from ventricles with infusion of catecholamine which lead monomorphic VT originating from RVOT.\n\nRVOT origin PVCs can be precipitated into monomorphic VT by administrating catecholamines such as ephedrine and dopamine even in patient with pacemaker. The mechanism of these VTs includes catecholamine induced acceleration of HR. Since RVOT PVCs can be recognize by 12 EKGs, we should be pay more attentions to the pre-operation EKG and be cautious using catecholamines.\n\nKeywords\n\nabdominal surgery\ndopamine\nephedrine\nmonomorphic ventricular tachycardia\npacemaker\nright ventricular outflow tract\nOPEN-ACCESSTRUE\n==== Body\n1 Introduction\n\nAs the number of patients with cardiac implantable electronic devices has recently increased, there are a number of cases where anesthesiologists and surgical teams need to make preparations related to this intervention before surgery. The preoperative management is performed according to the guidelines issued by the heart rhythm society in 2011.[1]\n\nNewly developed postoperative arrhythmias in patients who underwent non-cardiac surgery occurs about 4% to 20%.[2] However, among these arrhythmias, incidence of ventricular tachycardia (VT) from right ventricular outflow tract (RVOT) is extremely rare.\n\nThis report aimed to outline the management of a patient with a pacemaker implanted because of sick sinus syndrome (SSS) where RVOT - VT occurred in post anesthesia care unit (PACU).\n\n2 Case description\n\nA 69-year-old man (body weight, 64. 4 kg; height, 156. 6 cm) was diagnosed with carcinoma of the ascending colon and scheduled to undergo laparoscopic right hemicolectomy and laparoscopic cholecystectomy. He had been diagnosed with hypertension a year ago and underwent pacemaker implantation due to SSS, complete AV block, and left bundle branch block (LBBB) in the same year. He had a dual-chamber pacemaker with atrial ventricular sensing, dual response, and rate-adaptive pacemaker (DDDR). In the preoperative evaluation, the electrocardiogram (EKG) revealed AV dual-paced rhythm with frequent premature ventricular contractions (PVCs). His heart rate (HR) was 68 beats/min, and QTc was 499 ms. PVC morphology has special characteristics of LBBB at V1, R/S transition in leads V3–4, and a tall R wave in leads II, III, and aVF, indicating PVC originating in the RVOT (Fig. 1).[2] Transthoracic echocardiography showed normal-sized cardiac chambers with preserved LV global systolic function (LVEF 64%) and normal valvular structure and function. The patient's pulmonary artery pressure was 37 mmHg, with no regional wall motion abnormalities. Moreover, there was no specific finding on performing coronary angiography. An adrenal mass was noted on performing abdominal CT and pheochromocytoma was ruled out.\n\nFigure 1 Preoperative 12-lead EKG; LBBB in V1, R/S transition in V3–4, and a tall R wave in leads II, III, and aVF which indicating PVCs from RVOT.\n\nPreoperative laboratory investigation showed no specific findings, with a hemoglobin (Hgb) level of 9.8 g/dL, sodium level of 142 mEq/L, potassium level of 3.54 mEq/L, chloride level of 103 mEq/L, and calcium level of 9.6 mg/dL.\n\nElective surgery was performed, which lasted for 4 hours and 35 minutes. Total time of anesthesia was 5 hours and 10 minutes. Preoperatively, the pacemaker mode was changed from DDDR to DOO (asynchronous mode). General anesthesia was induced totally with intravenous propofol which has anti-arrhythmic effects and remifentanil. Before intubation, 40 mg of lidocaine was injected intravenously, and 40 mg of rocuronium was used as a muscle relaxant. During the operation, the target concentration of anesthetics was maintained with propofol 2.5 to 3.0 mcg/mL, remifentanil 1 to 3 ng/mL, and rocuronium 5 mcg/kg/min. During the emergence, glycopyrrolate 0.2 mg, pyridostigmine 10 mg, and sugammadex 200 mg were administered. The vital signs of the patient were stable during surgery; frequent PVC was not observed, and his blood pressure was between 100 to 130 and 60 to 90 mmHg. His HR was maintained at 60 beats/min. The total estimated blood loss was approximately 400 mL, total urine output was 630 mL, and total administered fluid volume was 2100 mL of balanced crystalloids.\n\nAt the time of transfer from the operating room to PACU, the patient had a noninvasively measured blood pressure (NIBP) of 138/60 mmHg, HR of 60 beats/min, and temperature of 35.5°C. Immediately after entering the PACU, the patient complained of sharp throbbing pain at the surgical site (abdomen) with an numeral rating scale score (NRS) of 8 points and received 50 mcg of fentanyl. Subsequently blood pressure gradually decreased. Due to the delay in transfer to the general ward, the patient stayed in the PACU for a long time. Ninety minutes after PACU admission, NIBP dropped to 80/45 mmHg. To increase the blood pressure, 400 mL of fluid and 4 mg of ephedrine were administered, but the blood pressure did not increase, and the patient was sweating; however, he was mentally alert. The NRS score in the surgical area dropped from 8 to 3 points. Furthermore, 400 mL of fluid and 8 mg of ephedrine were administered again, but blood pressure remained low. After 20 minutes, NIBP decreased to 60/40 mmHg. There were no skin rashes or symptoms of allergy (Fig. 2).\n\nFigure 2 Vital signs at the PACU.\n\nContinuous dopamine infusion was started at a rate of 5 mcg/kg/min with fluid therapy; however, after 10 minutes, blood pressure reduced to 60/35 mmHg, and dopamine infusion rate was increased to 10 mcg/kg/min. Ten minutes after infusion, NIBP was still at 61/19 mmHg, and HR suddenly increased to 200 to 230 beats/min. EKG was performed, and monomorphic VT was observed.\n\nThe patient was alert but sweating, and his femoral pulse was palpable. Monomorphic VT with pulse persisted and the patient was in sinus rhythm for 10 second intermittently. However, within a few seconds, HR again increased to 200 beats/min, and monomorphic VT with pulse continued. Arterial cannulation was performed. After administration of 2 mg of midazolam, DC cardioversion 120 J (biphasic) was performed. HR was maintained at 60 beats/min, arterial blood pressure (ABP) was 50/41 mmHg after DC cardioversion, and continuous infusion of norepinephrine was started at a rate of 0. 5 mcg/kg/min. (Fig. 3) in approximately 7 minutes, the patient recovered with an ABP of 95/60 mmHg and HR of 80 to 90 beats/min; the patient showed improved symptoms, was nearly mentally alert, and was sweating less.\n\nFigure 3 DC cardioversion (120J biphasic); monomorphic VT converse to sinus rhythm after DC cardioversion on Defibrillator EKG. HR decreased from 200 beats/min to 60 beats/min. After DC cardioversion, patient's self heart rhythm ceased and pacemaker pace at 60 beasts/min.\n\nImmediate pacemaker interrogation was performed, but no abnormalities in the pacemaker were observed. The pacemaker had a pacing rate of 60 beats/min, which eliminated pacemaker-mediated tachycardia (Figs. 4 and 5). The pacemaker mode was changed from DOO (asynchronous mode) to DDDR, and the patient was transferred to the intensive care unit (ICU) for observation. The total fluid administered at the PACU was 1000 mL and ABGA showed pH of 7. 31, PCO2 of 42. 0 mmHg, PO2 of 97. 6 mmHg, sodium level of 143 mEq/L, potassium level of 4. 0 mEq/L, calcium level of 7. 2 mg/dL and an Hgb level of 10. 4 g/dL. The total urine output at the PACU was 100 mL.\n\nFigure 4 Immediate PM interrogation result with monomorphic ventricular tachycardia (DOO mode). PM pacing the ventricle with a rate of 60 beats/min, which we could exclude pacemaker-mediated-tachycardia, and malfunction of PM. Arrow marks show a pacemaker pacing. Also we can see the VT on pacemaker interrogation with HR of 200 beats/min. Arrow head marks show ventricle contraction at a rate of 200 beats/min. (monomorphic VT).\n\nFigure 5 Pacemaker interrogation result at the time of DC cardioversion. Ventricular pacing with HR at 60 beats/min is maintained, and monomorphic VT ceased with DC cardioversion. Arrow marks show PM pacing at a rate of 60 beats/min. DC cardioversion (biphasic 120 J) was executed and arrhythmia ceased. Arrow head mark shows at the time of DC cardioversion.\n\nA 12-lead EKG which was recorded in the ICU showed no PVCs, and portable transthoracic echocardiography revealed no specific findings.\n\nOne month later, the patient visited the emergency room (ER) with symptoms of dizziness, low blood pressure (systolic blood pressure of 80–90 mmHg), and presyncope. EKG at the ER showed AV dual-paced rhythm and frequent PVC with tall R waves in leads II, III, and aVF, which was the same as frequent PVC derived from the RVOT observed previously. QTc was 495 ms. The patient recovered after supportive care, including fluid loading, and was discharged.\n\n2.1 Ethics statement\n\nThis case report was approved and registered by the Institutional Review Board of Inha university hospital (IRB No. 2020–01–005). There was no potential conflict of interest relevant to this article. The patient has provided informed consent for publication of the case.\n\n3 Discussion\n\nNewly developed postoperative arrhythmias are reported in 10% to 40% of patients undergoing cardiothoracic surgery and 4% to 20% of those undergoing non-cardiac surgery.[3] Most cases of arrhythmia during or after non-cardiac surgery occur in patients who undergo major abdominal or vascular surgery. Nonvascular abdominal surgery itself is an independent risk factor for arrhythmia. Most arrhythmias are supraventricular and include atrial fibrillation (4. 41%), atrial flutter (0. 94%), paroxysmal atrial tachycardia (0.3%), multifocal atrial tachycardia (0.4%), and paroxysmal supraventricular tachycardia (3%), and Ventricular arrhythmias are rare. [3,4] The etiology of these arrhythmias comprises stress responses due to surgery and anesthetic procedures, which increase sympathetic and hormonal activity and enhance systemic inflammatory pathways. The prognosis for newly developed postoperative arrhythmias is favorable, as most of the cases are self-limiting and return to the original heart rhythm occurs in approximately 80% of cases.[5]\n\nIdiopathic VT, which occurs in individuals without structural abnormalities in the heart, accounts for approximately 10% of all cases of VT, and the most common site of origin of VT is the RVOT.[6] Approximately 70% of idiopathic VTs originate from the RVOT.[6] This area is not only the site of origin of VT but also of PVCs. It has unique morphological characteristics in the EKG, consisting of LBBB with inferior axis, right axis deviation on standard limb leads, and early precordial transition, which can be recognized in the 12-lead EKG. (Fig. 1) The RVOT has a complex structure and it is structurally adjacent to the aortic valve, mitral valve, and left ventricular outflow tract. As a developmental feature, the distribution of connexin is low, resulting in weak intercellular connections, slow conduction rate, and no contractile force.[7] These developmental characteristics affect the conduction velocity and refractory period in myocardial cells, triggering delayed depolarization that leads to sustained Ca2+ outflow from the sarcoplasmic reticulum at phase 4 of repolarization in myocardial cells, and activation of the 3Na+/Ca2+ exchanger. These actions eventually increase intracellular Ca2+ concentration. In this process, “cAMP-mediated triggered activity” by adenylyl cyclase (AC) is important for the initiation and termination of tachycardia.[8]\n\nAcceleration of HR can be developed by programmed ventricular stimulation, burst pacing, infusion of a catecholamine or exercise. This is why termination is possible by the administration of adenosine, a beta-blocker, a calcium channel blocker and by vagal maneuvers.[9,10] (Table 1).\n\nTable 1 Ventricular tachycardia triggering factors and its treatments.\n\nVT triggering factor\tTreatment\t\nIsoproterenol\tAdenosine\t\nExercise\tVerapamil\t\nRapid burst pacing, atropine\tVagal maneuvers (acetylcholine)\t\nAminophylline\tBeta adrenergic receptor blockade\t\n\nThe patient also had a typical EKG pattern of PVC from the RVOT. Patient's vital sign and hemodynamic status was stable during surgery. However patient's blood pressure gradually decreased after pain control and EKG monitoring is not routinely performed at PACU. Although it was before EKG monitoring, it is highly likely that patient had low blood pressure, which was most likely due to decreased preload and PVCs. Patient's history of repeat visit to ER also strongly support this basis. Ephedrine, dopamine which had led on β1 adrenergic receptors agonist effects and increased activity of AC resulting in “cAMP-mediated triggered activity,” which could culminate in VT.[8,9,11] Unfortunately, in this case, since the patient initially had stable hemodynamic indices, only NIBP and pulse oximetry monitoring were performed, and EKG monitoring was performed after the vital signs became unstable at the PACU.\n\nConsidering the relatively prolonged QTc (499 ms) in the patient's initial EKG, postoperative PVCs might have occurred during the vulnerable period of the central 1/3 of the T-wave on EKG leading polymorphic VT rather than monomorphic VT.[12] Moreover, in this patient, pacemaker interrogation reveals that there was no triggering activity by DOO mode, but if the DDD mode of the dual-chamber pacemaker with ventriculoatrial (retrograde) conduction exists, PVCs could induce retrograde conduction that leads to “endless loop tachycardia,” resulting in “pacemaker-mediated tachycardia.” In such a scenario, monomorphic VT is possible.[13] These 2 scenarios that could cause VT did not occurred and could be ruled out.\n\nIdiopathic ventricular outflow tachycardia has 3 clinical forms: paroxysmal sustained monomorphic VT, repetitive non-sustained VT, or PVCs. Its symptoms are chest pain (13%), palpitations (39.8%), dizziness (3.7%), dyspnea (3.1%) and syncope (2.5%), and sometimes, it is asymptomatic (37.9%).[14,15] Even in this patient, there is a possibility of arrhythmia may cause Postoperation hypotension at the PACU. Another possibility is that the blood loss (400 mL) and the urine output (630 mL), together with the modest total volume of fluid replacement of 2100 mL, resulted in a relative hypovolemic state. Additionally, the patient repeatedly visited the ER with presyncope symptoms of dizziness and low blood pressure, and EKG at the ER also revealed frequent PVCs from the RVOT. This likely reflects that decrease in intravascular volume may led to frequent PVCs originating from RVOT and led to hypotension with patient. Interrogation with patient's pacemaker also showed that 7% of all heartbeats were PVCs which strongly support this idea.\n\nIn conclusion, we report a case of frequent PVCs from the RVOT after colon cancer surgery in a SSS patient with a permanent pacemaker, which led to VT by triggering activity. In this situation, patient's blood pressure was decreased first. At this time, not only we empirically administrate fluids but also need immediate EKG monitoring. In order to increase blood pressure, fluid resuscitation and direct acting vasoconstrictors like norepinephrine might be a better drug of choice. It is recommended to avoid ephedrine or dopamine, which may cause ventricular tachycardia due to “cAMP-mediated triggering activity” with patient who has frequent PVCs from RVOT. Furthermore, monomorphic VT is possible in patients with frequent PVC originating from the RVOT, and active pain control and fluid resuscitation should be considered with simple hemodynamic monitoring like EKG, PVI, and Pi during the perioperative period and at the PACU. Moreover, in a case of drug-resistant VT and recurrent VT, active treatment such as radiofrequency ablation could be an option.\n\nAuthor contributions\n\nConceptualization: Na Eun Kim, Yong Soo Baek, Helen Ki Shinn.\n\nData curation: Yong Soo Baek.\n\nFormal analysis: Hyun Kyoung Lim.\n\nInvestigation: Na Eun Kim.\n\nResources: Yong Soo Baek, Helen Ki Shinn.\n\nSupervision: Hyun Kyoung Lim.\n\nWriting – original draft: Kihyun Park, Na Eun Kim, Yong Soo Baek.\n\nWriting – review & editing: Kihyun Park, Hyun Kyoung Lim, Helen Ki Shinn.\n\nAbbreviations: HR = heart rate, PACU = post anesthetic care unit, RVOT = right ventricular outflow tract, VT = ventricular tachycardia.\n\nHow to cite this article: Park KH, Lim HK, Kim NE, Shinn HK, Baek YS. Ventricular tachycardia of right ventricular outflow tract origin during the perioperative period: a case report. Medicine. 2021;100:25(e26372).\n\nThe authors have no conflicts of interests to disclose.\n\nThe datasets generated during and/or analyzed during the current study are publicly available.\n==== Refs\nReferences\n\n[1] Stone ME Salter B . Perioperative management of patients with cardiac implantable electronic devices. Br J Anesth 2011;107 :16–26.\n[2] Nam GB . Right ventricular outflow tract tachycardias. Int J Arrhythmia 2015;16.4 :200–6.\n[3] Walsh Stewart R Tjun Tang . Postoperative arrhythmias in general surgical patients. Ann R Coll Surg Engl 2007;89.2 :91–5.17346395\n[4] Walsh Stewart R Tjun Tang Michael E Gaunt Hank@@ Schneider . New arrhythmias after non-cardiothoracic surgery. BMJ 2006;333 :715.17023439\n[5] Batra GS Molyneux J Scott NA . Colorectal patients and cardiac arrhythmias detected on the surgical high dependency unit. Ann R Coll Surg Engl 2001;83 :174–6.11432135\n[6] Brugada Josep Diez PD . How to recognize and manage idiopathic ventricular tachycardia. E-journal ESC Council Cardiol Pract 2010;08.\n[7] Kim RJ Iwai S Markowitz SM Shah BK Stein KM Lerman BB . Clinical and electrophysiological spectrum of idiopathic ventricular outflow tract arrhythmias. J Am Coll Cardiol 2007;49 :2035–43.17512360\n[8] Lermann BB . Mechanism, diagnosis; 1; and treatment of outflow tract tachycardia. Nature Rev Cardiol 2015;12 :597.26283265\n[9] Lermann BB . Mechanism of outflow tract tachycardia. Heart Rhythm 2007;4.7 :973–6.17599688\n[10] Lermann BB Belardinelli L West GA . Adenosine-sensitive ventricular tachycardia: evidence suggesting cyclic AMP-mediated triggered activity. Circulation 1986;74 :270–80.3015453\n[11] Johnson DM Antoons G . Arrhythmogenic mechanisms in heart failure Linking beta-adrenergic stimulation, stretch and calcium: front physiol 2018;9 :1453.30374311\n[12] Xiushui Ren Richard H Hongo . Polymorphic ventricular tachycardia from R-on-T pacing. J Am Coll Cardiol 2009;53 :218.19130992\n[13] Castellanos A Fernandez PR . Pacemaker-induced arrhythmias. William JM editor: Cardiac Arrhythmias. 3rd ed: Philadelphia Lippincott company 1995; 1075–1093.\n[14] Oh HL Chung WC Jin MC Heung SK Kwon S Kim JS . Clinical characteristics of ventricular premature beats originating from right ventricular outflow tract. Korean Circ J 2003;33.12 :1118–25.\n[15] Kim RJ Iwai S Markowitz SM Shah BK Stein KM Lerman BB . Clinical and electrophysiological spectrum of idiopathic ventricular outflow tract arrhythmias. J Am Coll Cardiol 2007;49.20 :2035–43.17512360\n\n",
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"mesh_terms": "D000368:Aged; D003082:Colectomy; D003110:Colonic Neoplasms; D004452:Echocardiography; D004554:Electric Countershock; D004562:Electrocardiography; D006327:Heart Block; D006352:Heart Ventricles; D006801:Humans; D010138:Pacemaker, Artificial; D011183:Postoperative Complications; D017180:Tachycardia, Ventricular; D016896:Treatment Outcome",
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"title": "Ventricular tachycardia of right ventricular outflow tract origin during the perioperative period: A case report.",
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"abstract": "Urticarial vasculitis is an eruption characterized by inflamed itchy or painful red papules or plaques that resemble urticaria but last longer than 24 hours and heal with residual pigmentation or purpura. Histopathologically, urticarial vasculitis presents as leukocytoclastic vasculitis with perivascular infiltrate and fibrin deposits. The treatment options are oral antihistamines, oral corticosteroids, dapsone, colchicine and hydroxychloroquine. We report four cases with normocomplementemic urticarial vasculitis who were treated with omalizumab and a brief review of the literature on the use of omalizumab in normocomplementemic urticarial vasculitis.",
"affiliations": "Department of Dermatology and Venereology, Okmeydanı Training and Research Hospital, Istanbul, Turkey.;Department of Dermatology and Venereology, Okmeydanı Training and Research Hospital, Istanbul, Turkey.;Department of Dermatology and Venereology, Okmeydanı Training and Research Hospital, Istanbul, Turkey.;Department of Dermatology and Venereology, Okmeydanı Training and Research Hospital, Istanbul, Turkey.;Department of Dermatology and Venereology, Okmeydanı Training and Research Hospital, Istanbul, Turkey.;Department of Dermatology and Venereology, Okmeydanı Training and Research Hospital, Istanbul, Turkey.",
"authors": "Degirmentepe|Ece Nur|EN|https://orcid.org/0000-0001-9596-2955;Kızıltac|Kubra|K|https://orcid.org/0000-0003-0741-1067;Etikan|Pırıl|P|https://orcid.org/0000-0002-0513-8020;Singer|Ralfi|R|https://orcid.org/0000-0002-1395-5960;Memet|Bachar|B|https://orcid.org/0000-0001-7731-943X;Kocaturk|Emek|E|https://orcid.org/0000-0003-2801-0959",
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"doi": "10.5021/ad.2019.31.3.335",
"fulltext": "\n==== Front\nAnn Dermatol\nAnn Dermatol\nAD\nAnnals of Dermatology\n1013-9087\n2005-3894\nThe Korean Dermatological Association; The Korean Society for Investigative Dermatology\n\n10.5021/ad.2019.31.3.335\nCase Report\nOmalizumab as a Succesfull Therapy in Normocomplementemic Urticarial Vasculitis: A Series of Four Patients and Review of the Literature\nhttps://orcid.org/0000-0001-9596-2955\nDegirmentepe Ece Nur\nhttps://orcid.org/0000-0003-0741-1067\nKızıltac Kubra\nhttps://orcid.org/0000-0002-0513-8020\nEtikan Pırıl\nhttps://orcid.org/0000-0002-1395-5960\nSinger Ralfi\nhttps://orcid.org/0000-0001-7731-943X\nMemet Bachar\nhttps://orcid.org/0000-0003-2801-0959\nKocaturk Emek\nDepartment of Dermatology and Venereology, Okmeydanı Training and Research Hospital, Istanbul, Turkey.\nCorresponding author: Ece Nur Degirmentepe, Department of Dermatology and Venereology, Okmeydanı Training and Research Hospital, Kaptanpasa Mah. Darülaceze Cad. No: 27, 34384 Okmeydanı-Şişli, Istanbul, Turkey. Tel: 90-212-315-55-55, Fax: 90-212-221-78-00, ecenuryksel@gmail.com\n6 2019\n01 5 2019\n31 3 335338\n23 3 2018\n05 6 2018\n10 6 2018\nCopyright © 2019 The Korean Dermatological Association and The Korean Society for Investigative Dermatology\n2019\nThe Korean Dermatological Association and The Korean Society for Investigative Dermatology\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nUrticarial vasculitis is an eruption characterized by inflamed itchy or painful red papules or plaques that resemble urticaria but last longer than 24 hours and heal with residual pigmentation or purpura. Histopathologically, urticarial vasculitis presents as leukocytoclastic vasculitis with perivascular infiltrate and fibrin deposits. The treatment options are oral antihistamines, oral corticosteroids, dapsone, colchicine and hydroxychloroquine. We report four cases with normocomplementemic urticarial vasculitis who were treated with omalizumab and a brief review of the literature on the use of omalizumab in normocomplementemic urticarial vasculitis.\n\nOmalizumab\nUrticarial vasculitis\n==== Body\nINTRODUCTION\n\nUrticarial vasculitis (UV) is a clinicopathological entity that is characterized by the coexistence of urticaria with leukocytoclastic vasculitis, perivascular infiltrate of lymphocytes, neutrophils and eosinophils, as well as fibrin deposits that are histopathologically typical features of leukocytoclastic vasculitis1. Symptoms of UV are frequently pain and burning rather than itching and resolve with persistent hyperpigmentation. UV can be classified into normocomplementemic UV (NUV) and hypocomplementemic UV (HUV) depending on the levels of complement protein in blood. Recommended treatments for UV are oral antihistamines (OAH) and systemic immunosuppressant drugs such as oral corticosteroids, colchicine, dapsone and hydroxychloroquine23. Omalizumab is a recombinant humanized monoclonal anti-immunoglobulin (Ig)E antibody that has been approved for the treatment of chronic urticaria. There have been recent reports on the use of omalizumab for the treatment of UV24567.\n\nHere we describe four cases of UV treated with omalizumab with persuasive results. We also review previous reports of patients with UV treated with omalizumab.\n\nCASE REPORT\n\nCase 1\n\nA 41-year-old female patient presented with pruritic and painful skin rash typical of urticaria on her upper and lower extremities for the last year. The lesions were erythematous infiltrated wheals lasting for longer than 24 hours that resolved with postinflammatory hyperpigmentation (Fig. 1). Histopathologic examination of the skin revealed leukocytoclastic vasculitis (Fig. 2). The patient was treated with OAH for a month without improvement which was then followed by colchicine 0.5 mg three times a day. After three months, the patient experienced relapse of skin rashes and was then treated with hydroxychloroquine 200 mg twice daily for three months without significant improvement and switched to dapsone 50 mg twice a day. After unsuccessfull treatment with dapsone for 8 months, omalizumab 300 mg subcutaneously (s.c.) once every four weeks was initiated. After the first application, complete remission of the UV was achieved with a urticaria control test (UCT) score of 16. The patient is still under treatment with omalizumab 300 mg s.c. every four weeks with sustained remission and no apparent adverse effect after 8 injections. We received the patient's consent form about publishing all photographic materials.\n\nCase 2\n\nA 34-year-old female patient with a 2-year history of UV was previously treated with OAH for at least 6 months without improvement. Oral prednisone 16 mg/day had achieved remission but with early relapse after drug cessation. After colchicine 1.5 mg/day started, the condition had worsened. Omalizumab 300 mg s.c. once every four weeks was initiated which provided complete remission of the UV after the first injection and UCT scored as 15. She remained stable after 12 injections of omalizumab 300 mg monthly and the treatment switched to omalizumab 300 mg per 6 weeks. The patient is still under treatment with sustained remission.\n\nCase 3\n\nA 26-year-old male patient with a 3-year history UV was previously treated with OAH at least 6 months without improvement which was then followed by cyclosporine 100 mg twice a day. After one month of cyclosporine treatment, the patient experienced exacerbation of skin lesions. Omalizumab 300 mg s.c. once every four weeks was initiated which provided complete remission of the UV after the first application and UCT scored as 16. The patient is still under treatment with omalizumab 300 mg s.c. every four weeks with sustained remission after 14 injections.\n\nCase 4\n\nA 58-year-old female patient with one-year history of UV, was previously treated with OAH at least 6 months without improvement. According to our previous experiences with UV, the patient was started on omalizumab 300 mg s.c. every four weeks. After the first application, complete remission of the UV was achieved and UCT score increased from 3 to 12. The patient is still treated with omalizumab 300 mg s.c. every four weeks with sustained remission after 5 injections.\n\nThe diagnosis of UV in all of the above cases was made based on the clinical, histopathological and direct immunofluorescence examination findings (Table 1).\n\nDISCUSSION\n\nUV is a leukocytoclastic vasculitis with wheals that resemble urticaria but last more than 24 hours. It represents a continuum of disease, ranging from urticaria with minimal vasculitis, to life- or organ-threatening systemic vasculitis with minimal urticaria8.\n\nUV can be divided into NUV and HUV depending on the levels of complement protein in blood. HUV has systemic manifestations such as angioedema, arthralgia, fever, abdominal or thoracic pain, renal or pulomonary disease, episcleritis and uveitis1. NUV usually presents with less systemic symptoms and without underlying diseases therefore are considered as idiopathic9. NUV might also be considered as urticaria showing signs of vasculitis in histopathology because in a series of 83 patients with chronic urticaria 10 exhibited histologic features of UV10.\n\nOmalizumab has been designed to recognise and attach to a specific structure (C3 domain) on circulating human IgE. This prevents IgE binding to high affinity receptors (FcεRI) on the surface of mast cells and basophils, thus reducing inflammatory cell activation including B- cells. It also causes eosinophil apoptosis, increases interleukin (IL)-2, IL-3, interferon-gamma and tumor necrosis factor-alpha and reduces IL-4. The mechanism of action of omalizumab in UV is not fully understood, it may be associated with downregulation of FcεRI receptors and supression of proinflammatory cytokines and therefore interfering the generation of urticarial wheals. Blocking anti-IgG IgEs which are responsible for the development of immune complexes on the vessel walls may also be considered as a possible mechanism of action. In summary, omalizumab may be effective in UV through its reduction of IgE and chemotaxis and immune complex formation11121314. The complement levels in our patients were normal, therefore they are considered as NUV. The efficacy of omalizumab in these patients is not unexpected when we consider NUV as “urticaria with minimal vasculitis.”\n\nHUV syndrome (HUVS) is a rare immune complex mediated disease which has distinct pathophysiology and outcomes. Aurich et al.15 reported that omalizumab is not effective in HUVS. This suggests the pathophysiology of HUVS is significantly different from chronic spontaneous urticaria (CSU) and NUV.\n\nOmalizumab has been shown to be effective on the symptoms of UV in case reports but there are no prospective clinical studies of omalizumab for UV (grade D recommendation)2456716. A case report by Ghazanfar and Thomsen2 described a male patient with UV who failed to respond to oral prednisolone and dapsone therapy. He was then treated with omalizumab 300 mg once every four weeks and after one month a complete remission of the disease and symptoms were observed. Ramírez Del Pozo et al.4 reported a female patient with UV and systemic lupus erythematosus. The patient was unresponsive to OAH, oral corticosteroids and azathioprine and was started on omalizumab which provided a rapid relief of symptoms. Another case report by Varricchi et al.5 described a female patient with Churg-Strauss syndrome, asthma and UV. She was treated with OAH, oral corticosteroids and immunosuppressants such as azathioprine and cyclosporine without improvement. She was then administrated omalizumab 300 mg s.c. every two weeks as an addition to her pre-treatments. The patient reported a significant improvement after 6 months of treatment with omalizumab. A case report from Spain describing three female patients with CSU difficult to control with associated vasculitis noted that omalizumab was a successful treatment option for the patients in the study6. Lately, Fueyo-Casado et al.7 reported a female patient with ten year history of chronic recurrent UV. She was treated with OAH at least 6 months, oral prednisolone and oral cyclosporine without improvement. Dapsone and antileucotrienes had only been minimally effective. She was then started omalizumab 300 mg s.c. every 4 weeks which showed clinical improvement within the firsth month and complete remission within the fifth month.\n\nOmalizumab 300 mg per a month provided symptom control in our cases within one month with a notable increase in UCT scores. Some authors use 300 mg per a month and others 300 mg per 6 weeks but there is no consensus on the dose and intervals; but applying the same dose and interval scheme as CSU seems rationale.\n\nOur report is important because we noted complete remission of the UV lesions within one month. It shows that mechanism of action of omalizumab in NUV may be similar to its mechanism of action in CSU.\n\nAs many patients with UV experience major side effects of the standard treatment and cannot be treated successfully, omalizumab gives us promising results with its safety profile in the treatment of NUV.\n\nIn conclusion, omalizumab may be useful in the treatment of vasculitic urticaria, especially with normal complement levels. This observation needs to be validated with prospective, randomized, placebo-controlled trials.\n\nFig. 1 Urticarial plaques and residual hyperpigmentation on the legs.\n\nFig. 2 Thickening in the vein walls and perivascular inflammatory cell infiltration, leukocytoclasia and fibrin accumulation (H&E, ×400).\n\nTable 1 Patients characteristics, histopathological and laboratory examination and treatment\n\nCase no.\tAge (yr)\tSex\tDD (mo)\tAngioedema\tBiopsy\tDIF\tC3\tANA\tPrevious drugs (mg/d)\tNOI\tTCR (wk)\t\n1\t41\tF\t12\tNo\tLV\tN/A\tN\t(−)\tRupatadin 10\t8\t4\t\nColchicine 1.5\t\nHydroxychloroquine 400\t\nDapsone 100\t\n2\t34\tF\t24\tYes\tLV\tPositive C1q+\tN\t(−)\tCetirizin 10\t12\t4\t\nPrednisone 16\t\nColchicine 1.5\t\n3\t26\tM\t36\tYes\tLV\tN/A\tN\t(−)\tLevocetirizin 5\t14\t4\t\nCyclosporine 200\t\n4\t58\tF\t12\tYes\tLV\tPositive C3+C1q+\tN\t(−)\tEbastine 10\t5\t4\t\nDD: duration of disease, DIF: direct immunofluorescence examination, ANA: antinuclear antibody, NOI: number of omalizumab injections, TCR: time to complete response, F: female, M: male, LV: leukocytoclastic vasculitis, N/A: nonavailable, N: normal.\n\nCONFLICTS OF INTEREST: The authors have nothing to disclose.\n==== Refs\n1 Kocatürk E Differential diagnosis in urticaria: urticarial vasculitis, neutrophilic urticarial dermatosis and urticarial dermatitis Turk Klinikleri J Dermatol-Special Top 2015 8 26 33\n2 Ghazanfar MN Thomsen SF Omalizumab for urticarial vasculitis: case report and review of the literature Case Rep Dermatol Med 2015 2015 576893 26435858\n3 Moreno-Suárez F Pulpillo-Ruiz Á Zulueta Dorado T Conejo-Mir Sánchez J Urticarial vasculitis: a retrospective study of 15 cases Actas Dermosifiliogr 2013 104 579 585 23891451\n4 Ramírez Del Pozo ME Martínez Saenz NP Vera JG Tiro JL 274 vasculitic urticaria treated with omalizumab. Case report World Allergy Organ J 2012 5 Suppl 2 S106\n5 Varricchi G Detoraki A Liccardo B Spadaro G de Paulis A Marone G 275 efficacy of omalizumab in the treatment of urticaria-vasculitis associated to Churg-Strauss Syndrome: a case report World Allergy Organ J 2012 5 Suppl 2 S106 S107\n6 Díez LS Tamayo LM Cardona R [Omalizumab: therapeutic option in chronic spontaneous urticaria difficult to control with associated vasculitis, report of three cases] Biomedica 2013 33 503 512 Spanish 24652205\n7 Fueyo-Casado A Campos-Muñoz L González-Guerra E Pedraz-Muñoz J Cortés-Toro JA López-Bran E Effectiveness of omalizumab in a case of urticarial vasculitis Clin Exp Dermatol 2017 42 403 405 28247460\n8 Brewer JD Davis MDP Urticarial vasculitis Waltham UpToDate cited 2017 Nov 5 Available from: https://www.uptodate.com/contents/urticarial-vasculitis\n9 Wisnieski JJ Urticarial vasculitis Curr Opin Rheumatol 2000 12 24 31 10647951\n10 Zuberbier T Maurer M Urticarial vasculitis and Schnitzler syndrome Immunol Allergy Clin North Am 2014 34 141 147 24262694\n11 Maurer M Rosén K Hsieh HJ Saini S Grattan C Gimenéz-Arnau A Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria N Engl J Med 2013 368 924 935 23432142\n12 Kaplan A Ledford D Ashby M Canvin J Zazzali JL Conner E Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy J Allergy Clin Immunol 2013 132 101 109 23810097\n13 Zuberbier T Aberer W Asero R Bindslev-Jensen C Brzoza Z Canonica GW The EAACI/GA(2) LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update Allergy 2014 69 868 887 24785199\n14 Kaplan AP Giménez-Arnau AM Saini SS Mechanisms of action that contribute to efficacy of omalizumab in chronic spontaneous urticaria Allergy 2017 72 519 533 27861988\n15 Aurich S Simon JC Treudler R Omalizumab does not improve skin lesions in a patient with hypocomplementemic urticarial vasculitis syndrome J Eur Acad Dermatol Venereol 2017 31 e395 e397 28273376\n16 Chia JC Mydlarski PR Dermatologic uses of omalizumabtitle J Dermatolog Treat 2017 28 332 337 27759482\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1013-9087",
"issue": "31(3)",
"journal": "Annals of dermatology",
"keywords": "Omalizumab; Urticarial vasculitis",
"medline_ta": "Ann Dermatol",
"mesh_terms": null,
"nlm_unique_id": "8916577",
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"pages": "335-338",
"pmc": null,
"pmid": "33911601",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports",
"references": "27759482;23891451;24652205;28273376;26435858;23810097;23432142;27861988;24785199;28247460;24262694;10647951",
"title": "Omalizumab as a Succesfull Therapy in Normocomplementemic Urticarial Vasculitis: A Series of Four Patients and Review of the Literature.",
"title_normalized": "omalizumab as a succesfull therapy in normocomplementemic urticarial vasculitis a series of four patients and review of the literature"
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"abstract": "Consolidation durvalumab after chemoradiation (CRT) is the current standard of care for locally advanced NSCLC. We hypothesized that adding immunotherapy concurrently with CRT (cCRT) would increase efficacy without additive toxicity.\n\n\n\nThis phase II study was conducted in two parts. Part 1 (n = 10) involved administration of conventionally fractionated CRT followed by consolidation chemotherapy (atezolizumab [two cycles] and maintenance atezolizumab up to 1 y). Part 2 (n = 30) involved administration of cCRT with atezolizumab followed by the same consolidation and maintenance therapies as in part 1. Programmed cell death ligand-1 staining cutoffs (1% or 50%) using Dako 22C3 immunohistochemistry were correlated with clinical outcomes.\n\n\n\nThe overall toxicities for part 1/2 were overall adverse events of grade 3 and above of 80%/80%; immune-related adverse events of grade 3 and above of 30%/20%; and pneumonitis of grade 2 and above of 10%/16%, respectively. In part 1, for preliminary efficacy results, with a median follow-up of 22.5 months, the median progression-free survival was 18.6 months, and the overall survival was 22.8 months. In part 2, with a median follow-up time of 15.1 months, the median progression-free survival was 13.2 months, and the overall survival was not reached. There was no difference in cancer recurrence regardless of programmed cell death ligand-1 status.\n\n\n\nAtezolizumab with cCRT is safe and feasible and has no added toxicities compared with historical rates.",
"affiliations": "Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: shlin@mdanderson.org.;Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.",
"authors": "Lin|Steven H|SH|;Lin|Yan|Y|;Yao|Luyang|L|;Kalhor|Neda|N|;Carter|Brett W|BW|;Altan|Mehmet|M|;Blumenschein|George|G|;Byers|Lauren A|LA|;Fossella|Frank|F|;Gibbons|Don L|DL|;Kurie|Jonathan M|JM|;Lu|Charles|C|;Simon|George|G|;Skoulidis|Ferdinandos|F|;Chang|Joe Y|JY|;Jeter|Melenda D|MD|;Liao|Zhongxing|Z|;Gomez|Daniel R|DR|;O'Reilly|Michael|M|;Papadimitrakopoulou|Vali|V|;Thall|Peter|P|;Heymach|John V|JV|;Tsao|Anne S|AS|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C000594389:atezolizumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jtho.2019.10.024",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-0864",
"issue": "15(2)",
"journal": "Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer",
"keywords": "Atezolizumab; Chemoradiation; Immune-related adverse events; Immunotherapy; NSCLC",
"medline_ta": "J Thorac Oncol",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D006801:Humans; D008175:Lung Neoplasms; D009364:Neoplasm Recurrence, Local",
"nlm_unique_id": "101274235",
"other_id": null,
"pages": "248-257",
"pmc": null,
"pmid": "31778797",
"pubdate": "2020-02",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase II Trial of Concurrent Atezolizumab With Chemoradiation for Unresectable NSCLC.",
"title_normalized": "phase ii trial of concurrent atezolizumab with chemoradiation for unresectable nsclc"
} | [
{
"companynumb": "US-PFIZER INC-2020054930",
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"abstract": "Pregnancy in women with systemic lupus erythematosus (SLE)-associated pulmonary arterial hypertension (PAH) remains a high risk. We successfully managed a pregnancy in a patient with SLE-PAH. A 31-year-old pregnant woman with SLE-PAH had worsening PAH and SLE flare-up during pregnancy and a sudden increase in pulmonary arterial pressure after delivery. SLE-PAH was controlled by continuous intravenous epoprostenol and inhaled nitric oxide therapy combined with high-dose corticosteroids under close hemodynamic monitoring. Women with SLE-PAH should avoid pregnancy. However, in case of a similar event, we recommend our case as a good reference for improving the outcome of pregnancy with SLE-PAH.",
"affiliations": "The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan.;The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan.;The Department of Obstetrics and Gynecology, School of Medicine, University of Occupational and Environmental Health, Japan.;The Department of Obstetrics and Gynecology, School of Medicine, University of Occupational and Environmental Health, Japan.;The Second Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan.;The Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, Japan.;The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan.",
"authors": "Kawabe|Akio|A|;Nakano|Kazuhisa|K|;Aiko|Yukiyo|Y|;Aramaki|Satoshi|S|;Onoue|Takeshi|T|;Okura|Dan|D|;Tanaka|Yoshiya|Y|",
"chemical_list": "D000959:Antihypertensive Agents; D011464:Epoprostenol",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.0033-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2932141010.2169/internalmedicine.0033-17Case ReportSuccessful Management of Pregnancy in a Patient with Systemic Lupus Erythematosus-associated Pulmonary Arterial Hypertension Kawabe Akio 1Nakano Kazuhisa 1Aiko Yukiyo 2Aramaki Satoshi 2Onoue Takeshi 3Okura Dan 4Tanaka Yoshiya 1\n1 The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan\n2 The Department of Obstetrics and Gynecology, School of Medicine, University of Occupational and Environmental Health, Japan\n3 The Second Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan\n4 The Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, JapanCorrespondence to Dr. Yoshiya Tanaka, tanaka@med.uoeh-u.ac.jp\n\n11 1 2018 1 6 2018 57 11 1655 1659 6 8 2017 14 9 2017 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Pregnancy in women with systemic lupus erythematosus (SLE)-associated pulmonary arterial hypertension (PAH) remains a high risk. We successfully managed a pregnancy in a patient with SLE-PAH. A 31-year-old pregnant woman with SLE-PAH had worsening PAH and SLE flare-up during pregnancy and a sudden increase in pulmonary arterial pressure after delivery. SLE-PAH was controlled by continuous intravenous epoprostenol and inhaled nitric oxide therapy combined with high-dose corticosteroids under close hemodynamic monitoring. Women with SLE-PAH should avoid pregnancy. However, in case of a similar event, we recommend our case as a good reference for improving the outcome of pregnancy with SLE-PAH. \n\nsystemic lupus erythematosuspulmonary arterial hypertensionpregnancy\n==== Body\nIntroduction\nWhen women of childbearing age develop systemic lupus erythematosus (SLE), it results in many difficulties during pregnancy. A high mortality rate of 66% has been reported in SLE-associated pulmonary arterial hypertension (SLE-PAH) (1). As such, patients with SLE-PAH are recommended to avoid pregnancy. Nevertheless, some patients with SLE-PAH become pregnant and wish to continue the pregnancy.\n\nIn the management of PAH during pregnancy, only conventional therapies for PAH are recommended (2), and the therapeutic strategies are unclear. Similarly, specific evidence-based therapies for SLE-PAH during pregnancy are still unknown.\n\nWe herein report the successful management of pregnancy in a woman with SLE-PAH by continuous intravenous epoprostenol therapy, high-dose corticosteroids (CS), and inhaled nitric oxide (iNO).\n\nCase Report\nA 31-year-old pregnant woman with SLE-PAH was admitted to our university hospital for the management of pregnancy and delivery. The patient had been diagnosed with SLE 16 years earlier based on the American College of Rheumatology criteria, including malar rash, photosensitivity, leukopenia, positive anti-double-stranded (ds) DNA antibody, positive antinuclear antibody (ANA), and lupus hepatitis. The patient had become pregnant nine years earlier but selected artificial abortion because of SLE flare.\n\nApproximately two years earlier, she presented with lupus flare with serositis, PAH, and 2003 International Society of Nephrology/Renal Pathology Society classification IV-S (A) lupus nephritis [systemic lupus erythematosus disease activity index (SLEDAI) score: 21]. Transthoracic echocardiography (TTE) revealed an estimated systolic pulmonary arterial pressure (sPAP) of 98 mmHg; no left-sided heart failure was noted. Lung perfusion scintigraphy revealed no definite evidence of thromboembolism. The patient was classified as World Health Organization (WHO) functional class (FC) III.\n\nRight heart catheterization (RHC) after the initiation of therapy revealed a cardiac output (CO) of 5.56 L/min, cardiac index (CI) of 4.08 L/min/m2, pulmonary arterial pressure (PAP) of 53/22 mmHg, mean PAP (mPAP) of 35 mmHg, pulmonary capillary wedge pressure of 11 mmHg, pulmonary vascular resistance (PVR) of 345 dyne·s·cm-5, and right ventricular systolic pressure of 55 mmHg; the results confirmed the diagnosis of PAH. Based on the above findings, we initiated high-dose CS combined with biweekly intravenous cyclophosphamide pulse therapy (IVCY: 15 mg/kg), bosentan (250 mg/day), sildenafil (60 mg/day), and beraprost (360 μg/day). After six courses of IVCY (integrated quantity: 3.66 g), the patient achieved clinical remission (SLEDAI score: 0), and the estimated sPAP decreased to 54.9 mmHg. Subsequently, mizoribine (150 mg/day) was used as maintenance therapy, and the administration of CS was gradually reduced to a lower dose for approximately 2 years.\n\nSeven months before this admission, her SLEDAI score was 0, and PAH was suspected based on an estimated sPAP of 43 mmHg and WHO FC I. Five months before this admission, the patient was found to be pregnant, at 6 weeks of gestation. The patient and her family were informed of maternal, fetal, and neonatal risks due to lupus flare, exacerbated PAH, medicines, and positive anti-SS-A/Ro antibody; they decided to continue her pregnancy. Because pregnancy is a contraindication for mizoribine, bosentan, and beraprost administration, CS and sildenafil were continued. Betamethasone [BMS (0.75 mg/day)] was switched to prednisolone (PSL), and the dose was increased to 25 mg/day with lupus flare (SLEDAI score: 7). The patient had dyspnea following ordinary exertion (WHO FC II) a few weeks before admission, and TTE revealed an estimated sPAP of 61.8 mmHg. Accordingly, continuing her pregnancy was difficult, and the patient was admitted to our hospital at 26 weeks and 1 day of gestation.\n\nOn admission, the pulse, blood pressure (BP), body temperature, respiratory rate, and oxygen saturation at room air were 87 beats/min, 121/64 mmHg, 37.3°C, 20 breaths/min, and 98%, respectively. A physical examination showed malar rash, erythema of the palms and proximal nail folds, and oral ulcers; cardiac auscultation findings were normal. A laboratory examination revealed microcytic anemia [hemoglobin (Hb), 9.0 g/dL], inflammatory response (erythrocyte sedimentation rate, 73 mm/h), increased N-terminal prohormone of brain natriuretic peptide level (163 pg/mL), positive anti-SS-A/Ro and SS-B/La antibody, and positive ANA (×2,560); anti-dsDNA and anti-phospholipid antibodies were negative, and the complement level, urinalysis and renal function tests, and arterial blood gas findings were normal. Chest X-ray (CXR) showed a marked increase in the size of the heart shadow [cardiothoracic ratio (CTR), 53%]. An electrocardiogram showed a normal tracing. TTE revealed a dilated right ventricle, an ejection fraction of 55-60%, estimated sPAP of 61.8 mmHg, and mPAP of 34.1 mmHg. Taken together, these findings confirmed an SLEDAI score of 4, and the disease activity was considered low. However, these cardiologic findings showed worsening PAH. Accordingly, we decided to initiate epoprostenol to prevent further worsening PAH after childbirth and resolved to perform Caesarean delivery (Figure).\n\nFigure. Clinical course. *not available due to overdampening of pulmonary artery pressure waveforms. PSL: prednisolone, IV: intravenous, mPSL: methylprednisolone, iNO: inhaled nitric oxide, PAP: pulmonary arterial pressure, sPAP: systolic pulmonary arterial pressure, dPAP: dilated pulmonary arterial pressure, SLEDAI: systemic lupus erythematosus disease activity index, WBC: white blood cells, Hb: hemoglobin, PLT: platelets, U-RBC: urinary sediment of red blood cells, HPF: high-power field\n\nSupportive therapy (such as oxygen inhalation and iron administration) was initiated. On the first 2 hospital days, BMS (12 mg/day) was administered intramuscularly to accelerate fetal lung maturation. On the fifth hospital day, a Swan-Ganz catheter was placed, and continuous epoprostenol infusion was started. RHC before the administration revealed CO of 7.5 L/min, CI of 5.5 L/min/m2, PAP of 52/22 mmHg, and mPAP of 34 mmHg. For deep vein thrombosis prevention, continuous intravenous heparin was administered until Caesarean section. On the ninth hospital day, the epoprostenol dose was increased to 2.5 ng/kg/min, and PAP was 45-64/17-24 mmHg (mPAP, 30-41 mmHg). Thereafter, the platelet (PLT) count gradually decreased to 58,000/μL, suggesting an adverse reaction of epoprostenol. However, the patient developed leukopenia (2,800/μL), hemolytic anemia (Hb, 8.0 g/dL; reticulocyte count, 157,320/μL; lactate dehydrogenase, 288 U/L; and haptoglobin, 6 mg/dL), and hematuria (urinary sediment of red blood cells, 10-19/high-power field). Hence, SLE flare (SLEDAI score: 10) was diagnosed, and the PSL dose was increased to 60 mg on the twelfth hospital day.\n\nWe decided to perform Caesarean delivery at 28 weeks and 1 day (the fifteenth hospital day) in light of the worsening maternal condition, stable PAP (PAP, 45-66/16-35 mmHg; mPAP, 29-49 mmHg) and the fetus being appropriate for gestational age. The PAP was 60/29 mmHg before the surgery. Caesarean section was performed under general anesthesia with continuing administration of epoprostenol; the baby weighed 1,286 g. Apgar scores were 1 and 4 at 1 and 5 minutes, respectively, and the baby received intensive care. Because the sPAP suddenly spiked (75 mmHg) and the systolic BP (SBP) dropped (90 mmHg) immediately after delivery and local injection of oxytocin (10 units) to the uterus, iNO at 20 ppm was initiated. The final PAP was 62/12 mmHg. iNO under intubation and mechanical ventilation was continued after the surgery, and PAP was maintained without worsening, with a PAP value of 40-62/10-29 mmHg and an mPAP value of 28-39 mmHg. iNO was therefore discontinued simultaneously with extubation on the second postoperative day. Bosentan was resumed, and epoprostenol was discontinued on the third postoperative day. PAH, thereafter, was stabilized (PAP, 46-58/17-29 mmHg; mPAP, 31-37 mmHg). Subsequently, beraprost and mizoribine were resumed, and the CS dose was switched to 40 mg/day of methylprednisolone (mPSL). Laboratory findings revealed an elevated blood cell count (White blood cell, 4,000/μL; Hb, 11.8 g/dL; PLT, 159,000/μL) and normal urinalysis results. The SLEDAI score and WHO FC decreased to 2 and I, respectively. CXR showed a marked decrease in the CTR (from 62% before delivery to 48% after). TTE revealed an estimated sPAP of 53.6 mmHg and mPAP of 31.7 mmHg. On the twelfth postoperative day, the mPSL dose was reduced to 36 mg/day, and the patient was discharged. Her baby was discharged on day 118 of life.\n\nDiscussion\nThe present case highlighted two important clinical issues: SLE-PAH during pregnancy can be controlled by intensive combination therapy, and continuous intravenous epoprostenol therapy, high-dose corticosteroids, and iNO are useful for the management of this condition.\n\nFirst, SLE-PAH during pregnancy can be controlled by intensive combination therapy. A systemic review reported the pregnancy outcome of PAH, which included connective tissue disease (CTD)-associated PAH (3). However, the treatment of SLE-PAH during pregnancy is unclear. Case reports have described in detail five pregnant patients with PAH associated with SLE (Table). Three of the patients died after delivery, with right-sided heart failure due to PAH deemed the cause of death in two of these patients (4-6). In the two patients who survived, one had been administered long-term intravenous epoprostenol therapy, and SLE and PAH had not been exacerbated during pregnancy and delivery (7). The other had been treated with prednisone, hydroxychloroquine, azathioprine, sildenafil, and inhaled iloprost, and while SLE flared up at delivery, PAH was stable (8).\n\nTable. Review of Published Cases.\n\nReference\tAge\tGravity Parity\tSLE activity\tPAH severity\tCS, Immunosapressants\tVasodilators\tDelivery\tMaternal outcome\tFetal outcome\t\n(4)\t19\tNR\tNR\tPAP 90/30 mmHg after delivery\tsmall dose of PSL\tNone\tCaesarean\tDeath on day 6 postpartum\tNR\t\n(5)\t25\tG3P0\tAbsence of lupus features\tbefore delivery, RVSP 79 mmHg with moderate to severe TR, mRAP 10 mmHg, RV and RA dilation with RV hypokinesis, mild to moderate sized pericardial effusion\tPSL 10 mg every two days → PSL 15 mg/day\tNone\tCaesarean\tDeath on day 4 postpartum\tAlive\t\n(6)\t30\tG2P1\tNo features of active SLE\tat delivery, mPAP 70-80 mmHg\tNR\tduring operation, iNO\tCaesarean\tDeath less than 24 hours after delivery\tAlive\t\n(7)\t23\tNR\tGood condition\tNo evidence of RHF, PAP 52/26 mmHg, PVR 143 dyn.sec.cm-5\tNR\tIV Epoprostenol\tCaesarean\tAlive\tAlive\t\n(8)\t29\tNR\tSLEDAI 2 → 14 at delivery\tat delivery, NYHA III, sPAP 45 mmHg, mPAP 21 mmHg, PVR 250 dyn.sec.cm-5\tprednisone 25 → 50 mg/day at delivery+ HCQ 200 mg/day, AZ 100 mg/day\tSildenafil 150 mg/day, Inhaled Iloprost 50 → 100 μg/day at delivery\tCaesarean\tAlive\tAlive\t\nPresent case\t31\tG1P0\tbefore pregnancy, SLEDAI 0; during pregnancy SLEDAI 7 → 4 → 10\tbefore pregnancy, WHO FC I, estimated sPAP 43 mmHg; during pregnancy, WHO FC II, PAP 45-66/16-35 mmHg; right after delivery, sPAP 75 mmHg\tduring pregnancy, PSL 25 → 60 mg/day; after delivery, mPSL 40 → 36 mg/day, MZR 150 mg/day\tduring pregnancy, Sildenafil 60 mg/day, IV Epoprostenol 2.5 ng/kg/min+ after delivery, iNO 20 ppm\tCaesarean\tAlive\tAlive\t\nSLE: systemic lupus erythematosus, PAH: pulmonary arterial hypertension, CS: corticosteroids, NR: not reported, PAP: pulmonary arterial pressure, PSL: prednisolone, RVSP: right ventricular systolic pressure, TR: tricuspid regurgitation, mRAP: mean right atrial pressure, RV: right ventricular, RA: right atrial, iNO: inhaled nitric oxide, RHF: Right heart failure, PVR: pulmonary vascular resistance, IV: intravenous, SLEDAI: systemic lupus erythematosus disease activity index, NYHA: New York Heart Association, sPAP: systolic pulmonary arterial pressure, HCQ: hydroxychloroquine, AZ: azathioprine, WHO FC: World Health Organization functional class, MZR: mizoribine\n\nIn the present case, SLE flared up during pregnancy, and PAH was exacerbated during pregnancy and immediately after delivery. However, intensive combination therapy inhibited further exacerbation and led to the successful management of pregnancy. To our knowledge, no patients with worsening SLE and PAH who successfully gave birth have yet been reported, and our report is the first case. We therefore feel that our case will be a good reference for similar cases.\n\nSecond, high-dose corticosteroids, iNO, and intravenous epoprostenol therapy are useful for the management of this condition. Intravenous epoprostenol inhibited the further exacerbation of PAH due to pregnancy. Generally, the blood volume and cardiac output are increased, whereas systemic vascular resistance are decreased during pregnancy, causing worsening PAH (2). Our patient continued sildenafil after pregnancy, but she experienced a rapid progression of PAH symptoms (WHO FC I to II, estimated sPAP 43 to 61.8 mmHg). Pregnancy in women with SLE-PAH has been reported to carry a high maternal mortality rate (1). Advanced therapy has been recommended to be initiated early, before cardiopulmonary decompensation (3). Epoprostenol have been used during pregnancy to improve PAH (3). The efficacy of intravenous epoprostenol has been shown in SLE-PAH patients (9). For this reason, we selected the induction of continuous intravenous epoprostenol during pregnancy.\n\nHigh-dose corticosteroid therapy is useful for the management of active SLE-PAH. Our patient had SLE flare (SLEDAI score: 10) during pregnancy that was accompanied by worsening PAH. Accordingly, high-dose corticosteroid therapy was initiated. Corticosteroid therapy has been shown to be effective for SLE-PAH (10).\n\niNO is useful for the management of PAH right after delivery. The blood volume and cardiac output are further increased after delivery; these changes cause worsening of PAH, resulting in right-sided heart failure (2). iNO is a selective pulmonary vasodilator and decreases the PVR without affecting the systemic BP (11). In our patient, the sPAP suddenly spiked (60 to 75 mmHg) and the SBP dropped immediately after delivery. Accordingly, iNO was initiated, decreasing the sPAP (62 mmHg) without a further drop in the systemic BP. iNO is often used as a last resort when PAH is unstable (3).\n\nWe must also note that controlling the SLE activity and PAH severity before pregnancy and worsening PAH with lupus flare were important to achieving a good outcome in the present patient. SLE can cause adverse maternal and fetal outcomes. The risk factors include SLE activity/flares in the last 6-12 months or at conception, the use of CS (≥10-20 mg/day of PSL equivalent), and active nephritis (12). In addition, PAH probably results in a high rate of maternal mortality. One of the major risk factors is the severity of PAH, and the risk probably increases with an increase in the PAP (2). Furthermore, as described above, SLE-PAH is typically improved with therapy for SLE, ameliorating its symptoms.\n\nIn the present case, before pregnancy, the SLE activity was “clinical remission” (SLEDAI score: 0) under low-dose CS, and the severity of PAH was also mild (WHO FC I; estimated sPAP, 43 mmHg) with appropriate therapy. SLE flare was accompanied by worsening PAH during pregnancy. Such conditions may have had a major positive effect on the good outcome in our patient.\n\nHowever, we must bear in mind that women of childbearing age with SLE-PAH should be counseled about pregnancy risks and encouraged to avoid pregnancy (12), and the termination of a pregnancy should be considered at conception given the high maternal mortality risk (2). Our patient had no cognitive dysfunction due to neuropsychiatric SLE; she decided to become pregnant and continue the pregnancy of her own will while understanding the risks as we had explained them. We must recognize that the risks should be discussed from the first physician-patient encounter, and not only patients but also their family and partner should be fully counseled (12).\n\nIn conclusion, SLE-PAH during pregnancy can be controlled by immunosuppression and vasodilators, and continuous intravenous epoprostenol therapy, high-dose corticosteroids, and iNO are effective for treating SLE-PAH. Women with SLE-PAH should avoid pregnancy. However, some will still wish to become pregnant and continue the pregnancy despite the risks. More cases, therefore, should be documented in order to improve the outcome of pregnancy with SLE-PAH.\n\n\nAuthor's disclosure of potential Conflicts of Interest (COI).\n\nYoshiya Tanaka: Honoraria, Abbvie, Chugai, Astellas, Takeda, Santen, Mitsubishi-Tanabe, Pfizer, Janssen, Eisai, Daiichi-Sankyo, UCB, GlaxoSmithKline and Bristol-Myers; Research funding, Mitsubishi-Tanabe, Chugai, MSD, Astellas and Novartis.\n==== Refs\n1. \nMartin WL , Gordon C , Kilby MD \nSystemic lupus erythematosus . Lancet \n358 : 586 , 2001 .\n2. \nRegitz-Zagrosek V , Blomstrom Lundqvist C , Borghi C , et al \nESC Guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC). European Society of Gynecology (ESG); Association for European Paediatric Cardiology (AEPC); German Society for Gender Medicine (DGesGM) . Eur Heart J \n32 : 3147 -3197 , 2011 .21873418 \n3. \nBédard E , Dimopoulos K , Gatzoulis MA \nHas there been any progress made on pregnancy outcomes among women with pulmonary arterial hypertension? \nEur Heart J \n30 : 256 -265 , 2009 .19147605 \n4. \nGreenstone MA \nDelayed diagnosis of systemic lupus erythematosus associated pulmonary hypertension . Br J Rheumatol \n30 : 391 , 1991 .\n5. \nRay J , Sermer M \nSystemic lupus erythematosus and pulmonary hypertension during pregnancy: report of a case fatality . Can J Cardiol \n12 : 753 -756 , 1996 .8794779 \n6. \nMcMillan E , Martin WL , Waugh J , et al \nManagement of pregnancy in women with pulmonary hypertension secondary to SLE and anti-phospholipid syndrome . Lupus \n11 : 392 -398 , 2002 .12139379 \n7. \nBendayan D , Hod M , Oron G , et al \nPregnancy outcome in patients with pulmonary arterial hypertension receiving prostacyclin therapy . Obstet Gynecol \n106 : 1206 -1210 , 2005 .16260574 \n8. \nStreit M , Speich R , Fischler M , Ulrich S \nSuccessful pregnancy in pulmonary arterial hypertension associated with systemic lupus erythematosus: a case report . J Med Case Rep \n3 : 7255 , 2009 .19830150 \n9. \nShirai Y , Yasuoka H , Takeuchi T , Satoh T , Kuwana M \nIntravenous epoprostenol treatment of patients with connective tissue disease and pulmonary arterial hypertension at a single center . Mod Rheumatol \n23 : 1211 -1220 , 2013 .23359006 \n10. \nKato M , Kataoka H , Odani T , et al \nThe short-term role of corticosteroid therapy for pulmonary arterial hypertension associated with connective tissue diseases: report of five cases and a literature review . Lupus \n20 : 1047 -1056 , 2011 .21676917 \n11. \nGriffiths MJ , Evans TW \nInhaled nitric oxide therapy in adults . N Engl J Med \n353 : 2683 -2695 , 2005 .16371634 \n12. \nAndreoli L , Bertsias GK , Agmon-Levin N , et al \nEULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome . Ann Rheum Dis \n76 : 476 -485 , 2017 .27457513\n\n",
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"issue": "57(11)",
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"keywords": "pregnancy; pulmonary arterial hypertension; systemic lupus erythematosus",
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"mesh_terms": "D000328:Adult; D000959:Antihypertensive Agents; D011464:Epoprostenol; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D008180:Lupus Erythematosus, Systemic; D011247:Pregnancy; D011248:Pregnancy Complications",
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"title": "Successful Management of Pregnancy in a Patient with Systemic Lupus Erythematosus-associated Pulmonary Arterial Hypertension.",
"title_normalized": "successful management of pregnancy in a patient with systemic lupus erythematosus associated pulmonary arterial hypertension"
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"abstract": "Blastic plasmacytoid dendritic-cell neoplasm (BPDCN) is an extremely rare disease that originates from dendritic cells and is associated with a poor overall survival (OS). Diagnostic and therapeutic standards are less well-established in comparison to other leukemic conditions and standards of care are lacking. Morphologic and molecular similarities to acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are hard to distinguish. We here report a BPDCN patient with a long, challenging diagnostic period. While bone marrow biopsies initially failed to prove the correct diagnosis, a cutaneous biopsy finally identified a CD45+/CD56+/CD4+/CD123+/CD33+/MPO- population suggestive of BPDCN which was confirmed by flow cytometry. Molecular analysis revealed an ASXL-1, TET2 and SRSF2-mutation, cytogenetic analysis showed a normal karyotype. Treatment with the recently approved CD123-cytotoxin Tagraxofusp showed initially a very good response. This case reflects diagnostic and therapeutic difficulties in BPDCN as very rare, easily misdiagnosed neoplasia and the need for precise diagnostic care.",
"affiliations": "Medical Clinic III for Oncology, Hematology, Immune-Oncology and Rheumatology, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany.;Medical Clinic III for Oncology, Hematology, Immune-Oncology and Rheumatology, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany.;Medical Clinic III for Oncology, Hematology, Immune-Oncology and Rheumatology, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany.;Medical Clinic III for Oncology, Hematology, Immune-Oncology and Rheumatology, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany.;Department of Dermatology and Allergy, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany.;Department of Pathology, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany.;Medical Clinic III for Oncology, Hematology, Immune-Oncology and Rheumatology, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany.;Medical Clinic III for Oncology, Hematology, Immune-Oncology and Rheumatology, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany. Annkristin.Heine@ukbonn.de.",
"authors": "Koerber|Ruth-Miriam|RM|http://orcid.org/0000-0002-8773-8221;Held|Stefanie A E|SAE|;Vonnahme|Maria|M|;Feldmann|Georg|G|http://orcid.org/0000-0002-3748-2184;Wenzel|Joerg|J|http://orcid.org/0000-0002-4744-5993;Gütgemann|Ines|I|http://orcid.org/0000-0002-2609-3095;Brossart|Peter|P|;Heine|Annkristin|A|http://orcid.org/0000-0002-5298-9880",
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"doi": "10.1007/s00432-021-03777-2",
"fulltext": "\n==== Front\nJ Cancer Res Clin Oncol\nJ Cancer Res Clin Oncol\nJournal of Cancer Research and Clinical Oncology\n0171-5216\n1432-1335\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n34529129\n3777\n10.1007/s00432-021-03777-2\nLetter to the Editor\nBlastic plasmacytoid dendritic-cell neoplasia: a challenging case report\nhttp://orcid.org/0000-0002-8773-8221\nKoerber Ruth-Miriam 1\nHeld Stefanie A. E. 1\nVonnahme Maria 1\nhttp://orcid.org/0000-0002-3748-2184\nFeldmann Georg 1\nhttp://orcid.org/0000-0002-4744-5993\nWenzel Joerg 2\nhttp://orcid.org/0000-0002-2609-3095\nGütgemann Ines 3\nBrossart Peter 1\nhttp://orcid.org/0000-0002-5298-9880\nHeine Annkristin Annkristin.Heine@ukbonn.de\n\n1\n1 grid.15090.3d 0000 0000 8786 803X Medical Clinic III for Oncology, Hematology, Immune-Oncology and Rheumatology, University Hospital Bonn, Venusberg Campus 1, 53127 Bonn, Germany\n2 grid.15090.3d 0000 0000 8786 803X Department of Dermatology and Allergy, University Hospital Bonn, Venusberg Campus 1, 53127 Bonn, Germany\n3 grid.15090.3d 0000 0000 8786 803X Department of Pathology, University Hospital Bonn, Venusberg Campus 1, 53127 Bonn, Germany\n16 9 2021\n16 9 2021\n2022\n148 3 743748\n13 6 2021\n23 8 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nBlastic plasmacytoid dendritic-cell neoplasm (BPDCN) is an extremely rare disease that originates from dendritic cells and is associated with a poor overall survival (OS). Diagnostic and therapeutic standards are less well-established in comparison to other leukemic conditions and standards of care are lacking. Morphologic and molecular similarities to acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are hard to distinguish. We here report a BPDCN patient with a long, challenging diagnostic period. While bone marrow biopsies initially failed to prove the correct diagnosis, a cutaneous biopsy finally identified a CD45+/CD56+/CD4+/CD123+/CD33+/MPO− population suggestive of BPDCN which was confirmed by flow cytometry. Molecular analysis revealed an ASXL-1, TET2 and SRSF2-mutation, cytogenetic analysis showed a normal karyotype. Treatment with the recently approved CD123-cytotoxin Tagraxofusp showed initially a very good response. This case reflects diagnostic and therapeutic difficulties in BPDCN as very rare, easily misdiagnosed neoplasia and the need for precise diagnostic care.\n\nKeywords\n\nBlastic plasmacytoid dendritic cell-neoplasms (BPDCN)\nMyeloid neoplasia\nMDS\nAML\nTagraxofusp\nUniversitätsklinikum Bonn (8930)Open Access funding enabled and organized by Projekt DEAL.\n\nissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2022\n==== Body\npmcIntroduction\n\nBlastic plasmacytoid dendritic cell neoplasm is a rare hematologic malignancy known to be derived from the precursors of plasmacytoid dendritic cells (pDC) (Bueno et al. 2004). Normal pDCs account for less than 0.4% of peripheral blood mononuclear cells and few of these cells reside in primary and secondary lymphoid organs (Swerdlow et al. 2017). Functional and non-malignant pDCs are typically lineage (Lin)−, HLA-DR+, CD56−, CD123+, CD11c−, whereas, BPDCN characteristically express CD56 and CD4 (Jegalian et al. 2009). BPDCN have morphologic and molecular similarities to monocytic myeloid leukemias and myelodysplastic syndromes (Riaz et al. 2014). Dysplastic changes can be found in BPDCN, predominantly in the megakaryopoiesis (Laribi et al. 2016). The etiology of BPDCN is unknown, though a preceding, concurrent or subsequent MDS, CMML or AML is possible. Clinical manifestations are often cutaneous lesions, leukemic dissemination and bone marrow (BM) involvement. Patients are generally older than 60 years and have a poor prognosis ∼1 year (Pagano et al. 2013).\n\nCase description\n\nIn August 2020, a 68-year old Caucasian male presented in our clinic with leukocytosis, anemia, fever, dyspnea, dizziness and exhaustion. On examination, he was severely pale with no signs of peripheral lymph node enlargement, evidence of bleeding or jaundice. The chest was clinically clear, liver and spleen were not palpable.\n\nAutomated blood count showed high leukocyte counts (34.5 G/L), severe normochromic, normocytic anemia (4.2 g/dl) and normal platelets (209 G/L). Iron stores and Vitamin B12 were in normal ranges, whereas folic acid was slightly reduced (3.94 ng/ml). Blood smears showed 3% blasts, lymphopenia (16%) and neutrophilia (71%). Monocyte counts were normal (1%). Blood counts were spontaneously fluctuating on a monthly basis, altering to pancytopenia, recovering to normal levels and again leukocytosis.\n\nAn initial BM biopsy was suggestive for myelomonocytic, acute leukemia. We repeated the aspiration a couple of days later and found a 30% infiltration of large cells with a wide basophilic cytoplasm and a blastic nucleus partially with nucleoli. Cells did not have microvacuoles or pseudopodia. POX- and esterase-staining were negative. Cells were both found disseminated and clustering (Fig. 1B). The overall appearance was not typical for an AML, ALL or multiple myeloma. Standard immunophenotyping showed no typical blasts or suspicious lymphoid populations. Paraffin-sections could also not verify the external AML diagnosis. Classical mutations for AML or myeloproliferative neoplasms were negative. Immunohistochemistry ruled out BM carcinosis, but showed a distinct CD56+ population. A reference pathologist could also not further classify this population. The karyogram was normal. NGS-analysis showed ASXL-1, TET2 and SRSF2-mutations. Since no definite diagnosis could be made, we repeated BM biopsy one month later. Here, the previously described CD56+ population was not apparent anymore. CT-scans gave no evidence of lymphadenopathy, hepatosplenomegaly or aspects of a solid tumor. Meanwhile, our patient developed multiple cutaneous reddish plaques (Fig. 1A). Histopathologic examination showed a diffuse, monomorphic infiltrate of medium-sized blasts with irregular nuclei, plenty mitoses and a small cytoplasm. The entire dermis was infiltrated, sparing the epidermis. CD45 positivity proved leukocytic origin, suitable for cutaneous chloroma. Further immunohistologic stainings showed positivity for CD4, CD56, CD33, CD123 and partially CD38. Progenitor markers like CD117 showed only weak to no expression, CD34 was negative. MPO, CD20 and CD10 were also negative. Ki-67 staining revealed a high proliferative index (70%). Therefore, we repeated the BM biopsy and found similar cells like in the first biopsy and in the skin. Furthermore, signs of dysplasia, predominantly in the megakaryopoiesis and erythropoiesis, were present. Immunophenotyping and immunohistology also revealed the same phenotype as the cutaneous lesion (Fig. 1C–E). Semi-nested PCR ruled out monoclonal rearrangement of the B-/T-cell receptor. Therefore, the diagnosis of BPDCN with extramedullary manifestation (skin) could be made. Especially, distinction of acute myelomonocytic leukemia was difficult, since these cases can also express CD33, CD123 and aberrantly CD56, but are typically positive for MPO. Though NGS-analysis (Skin and BM) detected ASXL-1, TET2 and SRSF2-mutations, secondary AML due to MDS seemed unlikely, since dysplastic features were apparent in less than 50% of non-blasts (Fig. 2).Fig. 1 a Images of cutaneous lesions of the patient with BPDCN. Multiple cutaneous nodules and papules spread over the whole body. b Bone marrow smears\n\ntaken from the patient with BPDCN. (1) Pappenheim staining of a bone marrow smear taken at diagnosis of BPDCN showing infiltration of large cells, with a wide basophilic cytoplasm and blastic nucleus partially with nucleoli. Approximately 30% infiltration (magnification 50× and 100×). (2) Peroxidase staining of a bone marrow smear exhibiting only positivity in granulopoiesis, BPDCN blasts are negative. (3) Dysplastic features of megakaryopoiesis and erythropoiesis (magnification 50× and 100×). c Immunephenotype of BPDCN. IHC staining of cutaneous lesions: (1) HE-staining (20×), (2) CD3, (3) CD56, (4) CD123, (5) MPO, (6) Giemsa 40×, (9) CD117. (D) IHC staining of bone marrow showed diffuse infiltration of the BPDCN: (1) HE-staining 20×, (2) CD4, (3) CD56, (4) CD123, (5) CD33, (6) CD34, (7) Giemsa 40×. (E) Flow cytometric analysis of peripheral blood showed, in contrast to BM, only a small distinct CD45+, CD123+, CD4+, CD56+, CD33+ population. Figure was created using Adobe Illustrator CC 2019\n\nFig. 2 Clinical course of diagnostic interventions and treatment schedule. The timeline shows the sequence of the diagnostic period and the different treatment regimes. Fluctuating blood counts during the diagnostic period are shown for absolute leukocyte- and thrombocyte counts and hemoglobin levels\n\nIntensive examinations for differential diagnosis were conducted, but all were negative (viral/bacterial/fungal infections, hemoglobin-anomalies, paroxysmal nocturnal hemoglobinuria, pure red cell aplasia, hemolysis and alcohol abuse).\n\nWe started treatment with the recently FDA-approved CD123 cytotoxin Tagraxofusp (Elzonris®) (Pemmaraju 2020) in November 2020. Due to the poor prognosis and high-risk cytogenetic mutations, a hematopoietic allogenic stem cell transplantation was planned in first remission (Ohe et al. 2018). Unfortunately, Tagraxofusp had to be discontinued after two cycles due to inacceptable hepatic toxicity and a relevant capillary leak syndrome, though clinically primary treatment response seemed to be very good. Therapy was switched to an aggressive B-ALL/B-NHL protocol analog GMALL 2002 (Garnache-Ottou 2019) in the end of December 2020. Again, progressive disease in March 2021 forced us to switch the regimen. We next decided to treat with 5-acacitidine/venetoclax, since in vitro studies show dependency on Bcl-2 of BPDCN cells (Montero et al. 2017) and clinical trials are ongoing (NCT03485547). Unfortunately, although this change of treatment approach, our patient developed again progressive disease and died in a fulminant neutropenic, septic shock. The clinical time course is shown in Fig. 2.\n\nMethods\n\nPatient samples were withdrawn for routine diagnostic tests. Cytology stainings, immunophenotyping on a Beckmann Coulter Navios EX and NGS analysis on Illumina MiniSeq platform were performed in our department. Photographies of the patients were taken after informed consent. Histomorphology and immunohistologic stainings were performed in the local Department of Pathology.\n\nDiscussion\n\nBPDCN is associated with comprised overall survival, and clinical standards are missing (Swerdlow et al. 2017). In the past, nomenclature of BPDCN frequently changed. Initially, BPDCN was listed as AML, in 2016 the WHO reclassified its own category (ancient names include: acute-agranular-NK-cell-leukemia, blastic-NK-cell-lymphoma, CD4+CD56+-hematodermic neoplasm) (Vardiman et al. 2009). Struggles in nomenclature display clinical diagnostic difficulties.\n\nAccess of targeted therapies requires correct clinical diagnostics, to supply patients with sufficient therapies. To distinguish other hematologic malignancies with cutaneous involvement from BPDCN, T-/NK-cell neoplasms and extramedullary myeloid sarcoma (EMS) must be ruled out. Cutaneous T-cell lymphoma rather infiltrates the epidermis and lacks CD56 expression. Extranodal NK-cell malignancies share common features of BPDCN, though these are typically EBER (Epstein-Barr-encoding region) positive. Furthermore, rearrangement of the B-/T-cell receptor genes can help to distinguish BPDCN from lymphoid malignancies (Ishida and Kwong 2010). To help making a correct BPDCN diagnosis we compiled Table 1 (Alayed et al. 2013; Swerdlow et al. 2017; Ishida and Kwong 2010).Table 1 Current markers are listed to delimit BPDCN from other myeloid malignancies\n\n\tTypical for BPDCN\tCommon in BPDCN\t\tTypical for BPDCN\tCommon in BPDCN\t\nT-cell marker\t\t\tB-cell marker\t\t\t\n CD4\t + \t + \t CD19\t−\t−\t\n CD3\t−\t−\t CD20\t−\t−\t\n CD5\t−\t−\t CD79a\t−\t−\t\n CD7\t−\t + \t CD38\t−\t−/ + \t\nMyeloid marker\t\t\tpDC-markers\t\t\t\n CD33\t−\t + \t CD123\t + \t + \t\n CD13\t−\t\t BDCA2 (CD303)\t + \t + \t\n CD14\t−\t\t BDCA4 (CD304)\t + \t + \t\n CD45\t + \t + \t CD2AP\t + \t + \t\n MPO\t−\t−\t Spi-B\t + \t + \t\nNK-cell marker\t\t\t\t\t\t\n CD56\t + \t + \tOther\t\t\t\n Progenitor-/activation-marker\t−\t−\t TCL-1\t + \t + \t\n CD34\t−\t−\t CD31\t + \t + \t\n CD117\t−/ + \t−/ + \t EBER\t−\t−\t\n Tdt\t−\t−/ + \t CD43\t + \t + \t\n HLA-DR\t + \t + \t CD11c\t−\t−\t\n\t\t\t Lysozyme\t−\tdim\t\nEspecially CD56 helps to distinguish reactive from malignant pDCs, though rare cases of CD56 negative BPDCNs have been described\n\nCommon somatic mutations in AML and MDS like ASXL-1, TET-2, TP53, IDH1/2, NPM1, DNMT3A and NRAS can be observed in BPDCN as well. BPDCN usually have multiple karyotypic abnormalities, though these are not specific for diagnostics (Menezes et al. 2014). Further shared features of MDS/CMML like dysplasia can be observed in BPDCN. Whether this is expression of an underlying MDS/CMML, or a primary BPDCN feature can yet not fully be defined. Probably, only the medical history of patients (preexisting cytopenia, monocytosis etc.) is helpful.\n\nFinally, our case shows typical difficulties of BPDCN diagnosis and treatment. In contrast to published data, the diagnostic time of almost 4 months was not dominated by an aggressive disease, though this changed with flaring of the cutaneous lesions. The reason for periodic fluctuation of blood counts, observed from August until November 2020, is not well-understood. Retrospective interpretation of the first biopsy was also suggestive of BPDCN infiltration, therefore, an underlying MDS/CMML was unlikely.\n\nConclusion\n\nTaken together, this case represents the difficulties in rare malignant hematologic disease and the need for expertise of hematologists, pathologists and laboratory medicine personnel. Patients presenting with skin symptoms should be evaluated for primary hematologic disease, especially if concomitant blood count abnormalities or lymphadenopathy are present. BPDCN must be distinguished from myelomonocytic acute leukemia and T-/NK-cell neoplasms. Characteristic phenotypic surface markers like CD123 or CD303 are not established in most of the diagnostic routine laboratories and specific cytogenetic abnormalities do not exist. Since a new targeted therapy for BPDCN is now available, physicians should be aware of this rare disease.\n\nAcknowledgements\n\nWe thank all our colleagues for the intensive studies of this challenging case.\n\nAuthor contributions\n\nR-MK. and AH. were responsible for preparation of the draft; R-MK, AH, and SAEH performed patients’ diagnostic evaluations and NGS molecular analyses; JW and IG performed the histological staining and analysis. R-MK, AH, MV, GF and PB were responsible for patient follow-up and clinical treatment; all authors contributed to the critical revision of the manuscript.\n\nFunding\n\nOpen Access funding enabled and organized by Projekt DEAL. Not applicable.\n\nData availability\n\nThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nDeclarations\n\nConflicts of interest\n\nThe authors declare no competing financial interests.\n\nCode availability\n\nNot applicable.\n\nEthics approval\n\nNot applicable.\n\nConsent to participate\n\nVerbal informed consent was obtained prior to the interview of this patient. The participant has consented to the submission of the case report to the journal, unfortunately he died before making written consent.\n\nConsent for publication\n\nAll authors agree to submit this manuscript.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\nAlayed K Patel KP Konoplev S Singh RR Routbort MJ Reddy N Pemmaraju N Zhang L Shaikh AA Aladily TN Jain N Luthra R Medeiros LJ Khoury JD TET2 mutations, myelodysplastic features, and a distinct immunoprofile characterize blastic plasmacytoid dendritic cell neoplasm in the bone marrow Am J Hematol 2013 88 12 1055 1061 10.1002/ajh.23567 23940084\nBueno C Almeida J Lucio P Marco J Garcia R de Pablos JM Parreira A Ramos F Ruiz-Cabello F Suarez-Vilela D San Miguel JF Orfao A Incidence and characteristics of CD4(+)/HLA DRhi dendritic cell malignancies Haematologica 2004 89 58 69 10.3324/%x 14754607\nGarnache-Ottou F How should we diagnose and treat blastic plasmacytoid dendritic cell neoplasm patients? Blood 2019 3 24 4238 4251 10.1182/bloodadvances.2019000647\nIshida F Kwong Y-L Diagnosis and management of natural killer-cell malignancies Expert Rev Hematol 2010 3 5 593 602 10.1586/ehm.10.51 21083476\nJegalian AG Facchetti F Jaffe ES Plasmacytoid dendritic cells: phys-iologic roles and pathologic states Adv Anat Pathol 2009 16 6 392 404 10.1097/PAP.0b013e3181bb6bc2 19851130\nLaribi K, Denizon N, Besançon A, Farhi J, Lemaire P, Sandrini J, Truong C, Ghnaya H, Baugier de Materre A (2016) Blastic plasmacytoid dendritic cell neoplasm: from origin of the cell to targeted therapies. Biology of Blood and Marrow Transplantation 1357–1367. 10.1016/j.bbmt.2016.03.022\nMenezes J, ACquadro F, Wiseman M, Gómez-López G, Salgado RN, Talavera-Casnas, Bruno I, Cerver JV, Montes-Morena S, Hernández-Rivas J, Ayala R, Calasanz MJ, Larrayoz MJ, Brichs LF, Gonzalez-Vincet M, Piris MA, Álvarez A, Cigudosa JC. Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm. Leukemia 28(4):823–9. 10.1038/leu.2013.283\nMontero J Stephansky J Cai T Griffin GK Cabal-Hierro L Togami HLJ Galinsky I Morgan EA Aster JC Davids MS LeBoeuf NR Stone RM Konopleva M Pemma N Blastic plasmacytoid dendritic cell neoplasm is dependent on BCL-2 and sensitive to venetoclax Cancer Discov 2017 7 2 156 164 10.1158/2159-8290.CD-16-0999 27986708\nOhe R, Ye Aung N, Shiono Y, Utsunomiya A, Kabasawa T, Tamazawa N, Tamura Y, Kato T,Yamada A, Hasegawa S, Aizawa K, Inokura K, Ito S, Toubai T (2018) Detection of Minimal Bone Marrow involvement of Blastic Plasmacytoid Dendritic Cell Neoplastic Cells—CD303 immunostaining as a diagnostic tool.J Clin Exp Hematop 58(1): 1–9. 10.3960/jslrt.17030\nPagano L Valentini CG Pulsoni A Fisogni S Carluccio P Mannelli F Lunghi M Pica G Onida F Cattaneo C Piccaluga PP Di Bona E Todisco E Musto P Spadea A D'Arco A Pileri S Leone G Amadori S Facchetti F GIMEMA-ALWP. Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: an Italian multicenter study Haematologica 2013 98 2 239 246 10.3324/haematol.2012.072645 23065521\nPemmaraju N Konopleva M Approval of tagraxofusp-erzs for blastic plasmacytoid dendritic cell neoplasm Blood (blood Adv) 2020 4 16 4020 4027 10.1182/bloodadvances.2019000173 32841341\nRiaz W Zhang L Horna P Sokol L Blastic plasmacytoid dendritic cell neoplasm: update on molecular biology, diagnosis, and therapy Cancer Control 2014 21 4 279 289 10.1177/107327481402100404 25310209\nSwerdlow SH, Campo E, Harris NL, et al (2017) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. WHO Classification of Tumours, 4th edn, vol 2. IARC Press, France\nVardiman JW Thiele J Arber DA Brunning RD Borowitz MJ Porwit A Harris NL Le Beau MM Hellström-Lindberg E Tefferi A The BCD revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes Blood 2008 114 5 937 951 10.1182/blood-2009-03-209262\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0171-5216",
"issue": null,
"journal": "Journal of cancer research and clinical oncology",
"keywords": "AML; Blastic plasmacytoid dendritic cell-neoplasms (BPDCN); MDS; Myeloid neoplasia; Tagraxofusp",
"medline_ta": "J Cancer Res Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "7902060",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34529129",
"pubdate": "2021-09-16",
"publication_types": "D016422:Letter",
"references": "23940084;14754607;21083476;19851130;27986708;23065521;25310209",
"title": "Blastic plasmacytoid dendritic-cell neoplasia: a challenging case report.",
"title_normalized": "blastic plasmacytoid dendritic cell neoplasia a challenging case report"
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"companynumb": "DE-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-333870",
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"activesubstancename": "AZACITIDINE"
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{
"abstract": "Mycoplasma genitalium (MG) infection is a sexually transmitted infection that causes up to 25% of nongonococcal urethritis (NGU). MG strains carrying genetic markers of antimicrobial resistance that may affect treatment outcomes are increasingly recognized as a public health concern. We present two cases of persistent MG NGU with strains carrying both macrolide and quinolone resistance-associated mutations that were eradicated successfully by an extended course of minocycline.",
"affiliations": "1 Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;2 Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.;3 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.;4 Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.;3 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.;1 Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.",
"authors": "Glaser|Allison M|AM|;Geisler|William M|WM|;Ratliff|Amy E|AE|;Xiao|Li|L|;Waites|Ken B|KB|;Gaisa|Michael|M|0000-0001-7432-1382",
"chemical_list": "D000900:Anti-Bacterial Agents; D008911:Minocycline",
"country": "England",
"delete": false,
"doi": "10.1177/0956462418816757",
"fulltext": null,
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"issn_linking": "0956-4624",
"issue": "30(5)",
"journal": "International journal of STD & AIDS",
"keywords": "Mycoplasma genitalium; antibiotic resistance; minocycline; urethritis",
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D053159:Dysuria; D018451:Homosexuality, Male; D006801:Humans; D008297:Male; D008911:Minocycline; D009175:Mycoplasma Infections; D045704:Mycoplasma genitalium; D016896:Treatment Outcome; D014526:Urethritis",
"nlm_unique_id": "9007917",
"other_id": null,
"pages": "512-514",
"pmc": null,
"pmid": "30999836",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Two cases of multidrug-resistant genitourinary Mycoplasma genitalium infection successfully eradicated with minocycline.",
"title_normalized": "two cases of multidrug resistant genitourinary mycoplasma genitalium infection successfully eradicated with minocycline"
} | [
{
"companynumb": "US-BAYER-2019-095542",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MOXIFLOXACIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "A 73-year-old woman presented with acute shortness of breath and exacerbation of chronic back pain. She was diagnosed with pulmonary oedema and a non-ST-elevation myocardial infarction following chest X-ray, ECG and high sensitivity troponin levels. She subsequently underwent coronary angioplasty with deployment of drug-eluting stents to her circumflex and left anterior descending arteries and was started on aspirin and clopidogrel for her dual antiplatelet therapy. Unfortunately, following the procedure, she gradually lost power and sensation in both lower limbs. MRI of her spine confirmed an extradural haematoma causing thoracic cord compression. She was managed conservatively following discussions with neurosurgeons and developed further complications secondary to her immobility.",
"affiliations": "Cardiology Department, Ninewells Hospital, Dundee, UK.;Cardiology Department, Ninewells Hospital, Dundee, UK.;Cardiology Department, Ninewells Hospital, Dundee, UK.",
"authors": "Iskandar|Muhammad Zaid|MZ|;Chong|Victor|V|;Hutcheon|Stuart|S|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D001241:Aspirin; D000077144:Clopidogrel; D004359:Drug Therapy, Combination; D017809:Fatal Outcome; D005260:Female; D006406:Hematoma; D006801:Humans; D010975:Platelet Aggregation Inhibitors; D003668:Pressure Ulcer; D018805:Sepsis; D013117:Spinal Cord Compression; D013988:Ticlopidine",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26202314",
"pubdate": "2015-07-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25677879;9834303;21384274;12931638;19635624",
"title": "Acute spinal cord compression: a rare complication of dual antiplatelet therapy.",
"title_normalized": "acute spinal cord compression a rare complication of dual antiplatelet therapy"
} | [
{
"companynumb": "GB-ROXANE LABORATORIES, INC.-2015-RO-01993RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
... |
{
"abstract": "The objective of this study was to demonstrate efficacy, benefit, and potential use of topiramate in treating obese patients with chronic low back pain. This is a case report from an outpatient academic pain multidisciplinary clinical center. The patient was a 30-year-old morbidly obese (body mass index [BMI]: 61.4 kg/m(2)) female suffering from chronic low back pain. With a known association between obesity and chronic low back pain, and a possible role of topiramate in treating both simultaneously, the patient was started on a therapeutic trial of topiramate. Over a period of a 12-week topiramate therapy, the patient experienced clinically meaningful and significant weight loss as well as improvement in her chronic low back pain and functionality. With more substantial evidence, pain physicians may start considering using topiramate in the multimodal management of obesity-related chronic low back pain based on their thoughtful consideration of the drug's efficacy and side effects and the patient's comorbidities and preferences.",
"affiliations": null,
"authors": "Gupta|Anita|A|;Kulkarni|Archana|A|;Ramanujam|Vendhan|V|;Zheng|Lu|L|;Treacy|Erin|E|",
"chemical_list": "D019440:Anti-Obesity Agents; D000077236:Topiramate; D005632:Fructose",
"country": "England",
"delete": false,
"doi": "10.3109/15360288.2015.1035837",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1536-0288",
"issue": "29(2)",
"journal": "Journal of pain & palliative care pharmacotherapy",
"keywords": "chronic low back pain; efficacy and weight decrease; obesity; topiramate",
"medline_ta": "J Pain Palliat Care Pharmacother",
"mesh_terms": "D000328:Adult; D019440:Anti-Obesity Agents; D005260:Female; D005632:Fructose; D006801:Humans; D017116:Low Back Pain; D009767:Obesity, Morbid; D000077236:Topiramate",
"nlm_unique_id": "101125608",
"other_id": null,
"pages": "140-3",
"pmc": null,
"pmid": "26095484",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Improvement in chronic low back pain in an obese patient with topiramate use.",
"title_normalized": "improvement in chronic low back pain in an obese patient with topiramate use"
} | [
{
"companynumb": "US-JNJFOC-20150700615",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nMethadone is associated with prolongation of the electrocardiographic QTc interval. QTc prolongation may be linked to cardiac dysrhythmia and sudden cardiac death. The rate of these events is unknown in methadone-maintained patients.\n\n\nMETHODS\nThis retrospective cohort study of 749 patients with opioid use disorder receiving methadone maintenance therapy through a single safety-net hospital, queried the electronic health record for electrocardiogram results, demographics, methadone dose, and diagnostic codes consistent with cardiac conduction disorder (International Classification of Disease, Ninth Revision [ICD-9] 426) and cardiac dysrhythmia (ICD-9 427). Factors associated with QTc interval were explored; Cox proportional-hazards regression models were used to analyze time to an event that may predispose to sudden cardiac death.\n\n\nRESULTS\nOne hundred thirty-four patients had an electrocardiogram while on methadone, 404 while off methadone, and 211 both while on and off methadone. Mean QTc interval while on methadone (436 ms, SD 36) was significantly greater than while off methadone (423 ms, SD 33). Age and methadone dose were weakly associated with increased QTc interval (P < 0.01 and P < 0.0005, respectively, adjusted R = 0.05). There were 44 ICD-9 426 and 427 events over 7064 patient-years (6.3 events/1000 patient-yrs). Having a QTc greater than sex-specific cut-off values was significantly associated with time to event (hazard ratio 3.32, 95% confidence interval 1.25-8.81), but being on methadone was not.\n\n\nCONCLUSIONS\nMethadone is associated with QTc prolongation in a nonclinically significant dose-related manner. Cardiac events were rare and the sudden cardiac death rate was below that of the general population. Current recommendations for cardiac risk assessment in methadone-maintained patients should be reconsidered.",
"affiliations": "Department of Medicine, Hennepin County Medical Center, Minneapolis, MN (GB, RK, BAB); Pharmacy Department, Hennepin County Medical Center, Minneapolis, MN (ZW); Biostatistical Design and Analysis Center, University of Minnesota, Minneapolis, MN (QW, JSH); and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN (JSH).",
"authors": "Bart|Gavin|G|;Wyman|Zachary|Z|;Wang|Qi|Q|;Hodges|James S|JS|;Karim|Rehan|R|;Bart|Bradley A|BA|",
"chemical_list": "D009294:Narcotics; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1097/ADM.0000000000000353",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1932-0620",
"issue": "11(6)",
"journal": "Journal of addiction medicine",
"keywords": null,
"medline_ta": "J Addict Med",
"mesh_terms": "D000328:Adult; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008133:Long QT Syndrome; D008297:Male; D008691:Methadone; D008875:Middle Aged; D009294:Narcotics; D058850:Opiate Substitution Treatment; D012189:Retrospective Studies; D064876:Safety-net Providers",
"nlm_unique_id": "101306759",
"other_id": null,
"pages": "489-493",
"pmc": null,
"pmid": "28863009",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "21355903;15136301;24145160;12820821;18774239;18549912;28488266;24685458;22026522;19392907;21355918;22026519;22763888;18833586;1986505;26746475;9792266;15781034;21147730;11898927;23787716",
"title": "Methadone and the QTc Interval: Paucity of Clinically Significant Factors in a Retrospective Cohort.",
"title_normalized": "methadone and the qtc interval paucity of clinically significant factors in a retrospective cohort"
} | [
{
"companynumb": "PHHY2018US042343",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "Acute generalized exanthematous pustulosis most often manifests 1-2 days following exposure to a characteristic drug, such as aminopenicillins, calcium-channel blockers, or terbinafine. Recovery is usually rapid following drug withdrawal, and systemic corticosteroids represent the historic treatment of choice. Herein, acute generalized exanthematous pustulosis incited by hydroxychloroquine is briefly reviewed: a prolonged latency and recalcitrance to corticosteroids are noteworthy. In this unique context, cyclosporine tapered over several months is an effective therapeutic option.",
"affiliations": "Department of Dermatology, University of South Florida Morsani College of Medicine, Tampa, Florida.;Department of Dermatology, University of Florida College of Medicine, Gainesville, Florida.;Department of Dermatology, University of Florida College of Medicine, Gainesville, Florida.",
"authors": "Castner|Nicholas Bradford|NB|;Harris|Jessica Crabbe|JC|;Motaparthi|Kiran|K|0000-0003-0562-0826",
"chemical_list": "D003879:Dermatologic Agents; D005938:Glucocorticoids; D006886:Hydroxychloroquine; D016572:Cyclosporine; D011241:Prednisone; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1111/dth.12660",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1396-0296",
"issue": "31(5)",
"journal": "Dermatologic therapy",
"keywords": "acute generalized exanthematous pustulosis; cyclosporine; hydroxychloroquine",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D016572:Cyclosporine; D003879:Dermatologic Agents; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D006886:Hydroxychloroquine; D008775:Methylprednisolone; D008875:Middle Aged; D011241:Prednisone; D019233:Retreatment",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "e12660",
"pmc": null,
"pmid": "30152569",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Cyclosporine for corticosteroid-refractory acute generalized exanthematous pustulosis due to hydroxychloroquine.",
"title_normalized": "cyclosporine for corticosteroid refractory acute generalized exanthematous pustulosis due to hydroxychloroquine"
} | [
{
"companynumb": "US-MYLANLABS-2018M1088015",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "1",
... |
{
"abstract": "Chronic hypertension is associated with adverse perinatal outcomes, although the optimal treatment is unclear. The aim of this network metaanalysis was to simultaneously compare the efficacy and safety of antihypertensive agents in pregnant women with chronic hypertension.\n\n\n\nMedline, Scopus, CENTRAL, Web of Science, Clinicaltrials.gov, and Google Scholar databases were searched systematically from inception to December 15, 2019. Both randomized controlled trials and cohort studies were held eligible if they reported the effects of antihypertensive agents on perinatal outcomes among women with chronic hypertension.\n\n\n\nThe primary outcomes were preeclampsia and small-for-gestational-age risk. A frequentist network metaanalytic random-effects model was fitted. The main analysis was based on randomized controlled trials. The credibility of evidence was assessed by taking into account within-study bias, across-studies bias, indirectness, imprecision, heterogeneity, and incoherence.\n\n\n\nTwenty-two studies (14 randomized controlled trials and 8 cohorts) were included, comprising 4464 women. Pooling of randomized controlled trials indicated that no agent significantly affected the incidence of preeclampsia. Atenolol was associated with significantly higher risk of small-for-gestational age compared with placebo (odds ratio, 26.00; 95% confidence interval, 2.61-259.29) and is ranked as the worst treatment (P-score=.98). The incidence of severe hypertension was significantly lower when nifedipine (odds ratio, 0.27; 95% confidence interval, 0.14-0.55), methyldopa (odds ratio, 0.31; 95% confidence interval, 0.17-0.56), ketanserin (odds ratio, 0.29; 95% confidence interval, 0.09-0.90), and pindolol (odds ratio, 0.17; 95% confidence interval, 0.05-0.55) were administered compared with no drug intake. The highest probability scores were calculated for furosemide (P-score=.86), amlodipine (P-score=.82), and placebo (P-score=.82). The use of nifedipine and methyldopa were associated with significantly lower placental abruption rates (odds ratio, 0.29 [95% confidence interval, 0.15-0.58] and 0.23 [95% confidence interval, 0.11-0.46], respectively). No significant differences were estimated for cesarean delivery, perinatal death, preterm birth, and gestational age at delivery.\n\n\n\nAtenolol was associated with a significantly increased risk for small-for-gestational-age infants. The incidence of severe hypertension was significantly lower when nifedipine and methyldopa were administered, although preeclampsia risk was similar among antihypertensive agents. Future large-scale trials should provide guidance about the choice of antihypertensive treatment and the goal blood pressure during pregnancy.",
"affiliations": "Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, Athens University Medical School, National and Kapodistrian University of Athens, Athens, Greece. Electronic address: bellosg@windowslive.com.;Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, Athens University Medical School, National and Kapodistrian University of Athens, Athens, Greece.;Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece.;First Department of Obstetrics and Gynecology, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece.;First Department of Obstetrics and Gynecology, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece.",
"authors": "Bellos|Ioannis|I|;Pergialiotis|Vasilios|V|;Papapanagiotou|Angeliki|A|;Loutradis|Dimitrios|D|;Daskalakis|Georgios|G|",
"chemical_list": "D000959:Antihypertensive Agents; D017311:Amlodipine; D001262:Atenolol; D008750:Methyldopa; D005665:Furosemide; D007650:Ketanserin; D010869:Pindolol; D009543:Nifedipine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajog.2020.03.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9378",
"issue": "223(4)",
"journal": "American journal of obstetrics and gynecology",
"keywords": "antihypertensive; chronic hypertension; metaanalysis; preeclampsia; pregnancy",
"medline_ta": "Am J Obstet Gynecol",
"mesh_terms": "D000037:Abruptio Placentae; D017311:Amlodipine; D000959:Antihypertensive Agents; D001262:Atenolol; D002585:Cesarean Section; D002908:Chronic Disease; D005260:Female; D005317:Fetal Growth Retardation; D005665:Furosemide; D005865:Gestational Age; D006801:Humans; D006973:Hypertension; D015994:Incidence; D007236:Infant, Small for Gestational Age; D007650:Ketanserin; D008750:Methyldopa; D000071076:Network Meta-Analysis; D009543:Nifedipine; D066087:Perinatal Death; D010869:Pindolol; D011225:Pre-Eclampsia; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D047928:Premature Birth; D012720:Severity of Illness Index",
"nlm_unique_id": "0370476",
"other_id": null,
"pages": "525-537",
"pmc": null,
"pmid": "32199925",
"pubdate": "2020-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D017418:Meta-Analysis; D016454:Review",
"references": null,
"title": "Comparative efficacy and safety of oral antihypertensive agents in pregnant women with chronic hypertension: a network metaanalysis.",
"title_normalized": "comparative efficacy and safety of oral antihypertensive agents in pregnant women with chronic hypertension a network metaanalysis"
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"companynumb": "PA-ALKEM LABORATORIES LIMITED-PA-ALKEM-2020-07093",
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"abstract": "Patients receiving treatment for tuberculosis are at risk of developing acute liver failure due to the hepatotoxicity of antitubercular drugs. We aimed to describe our experience with liver transplantation from deceased donors in this situation.\n\n\n\nWe identified patients undergoing transplantation for acute liver failure due to antitubercular drugs in our prospectively maintained database.\n\n\n\nOf 81 patients undergoing transplantation for acute liver failure, 8 cases were attributed to antitubercular drugs during the period of 2006-2016. Regarding the time of tuberculosis treatment until the onset of jaundice, patients were on antitubercular drugs for a mean of 64.7 days (21-155 days). The model for end-stage liver disease (MELD) score of patients ranged from 32 to 47 (median 38), and seven patients underwent transplantation under vasopressors. The 1-year survival was 50%. Three patients died during the week following transplantation due to septic shock (including a patient with acute liver failure due to hepatic/disseminated tuberculosis), and the remaining patient died 2 months after transplantation due to pulmonary infection. There were 2 cases of mild rejection and 1 case of moderate rejection. Of the surviving patients, all were considered cured of tuberculosis after alternative drugs were given.\n\n\n\nPatients arrived very sick and displayed poor survival after deceased donor transplantation.",
"affiliations": "Disciplina de Transplante de Figado e Orgaos do Aparelho Digestivo, Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR.;Laboratorio de Hepatite Virais - LIM-47, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR.;Disciplina de Transplante de Figado e Orgaos do Aparelho Digestivo, Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR.;Disciplina de Transplante de Figado e Orgaos do Aparelho Digestivo, Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR.;Disciplina de Transplante de Figado e Orgaos do Aparelho Digestivo, Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR.",
"authors": "Martino|Rodrigo Bronze de|RB|;Abdala|Edson|E|;Villegas|Felipe Castro|FC|;D'Albuquerque|Luiz Augusto Carneiro|LAC|;Song|Alice Tung Wan|ATW|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "Brazil",
"delete": false,
"doi": "10.6061/clinics/2018/e344",
"fulltext": "\n==== Front\nClinics (Sao Paulo)Clinics (Sao Paulo)Clinics1807-59321980-5322Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo 3002034010.6061/clinics/2018/e344cln_73p1Original ArticleLiver transplantation for acute liver failure due to antitubercular drugs – a single-center experience de Martino Rodrigo Bronze IAbdala Edson IIIIIVillegas Felipe Castro ID’Albuquerque Luiz Augusto Carneiro IIVSong Alice Tung Wan IIV*I Disciplina de Transplante de Figado e Orgaos do Aparelho Digestivo, Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BRII Laboratorio de Hepatite Virais – LIM-47, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BRIII Departamento de Doencas Infecciosas, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BRIV Laboratorio de Transplante e Cirurgia de Figado - LIM-37, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR*Corresponding author. E-mail: alicetwsong@gmail.com23 6 2018 2018 73 e34431 8 2017 22 2 2018 Copyright © 2018 CLINICS2018This is an Open Access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is properly cited.OBJECTIVES:\nPatients receiving treatment for tuberculosis are at risk of developing acute liver failure due to the hepatotoxicity of antitubercular drugs. We aimed to describe our experience with liver transplantation from deceased donors in this situation.\n\nMETHODS:\nWe identified patients undergoing transplantation for acute liver failure due to antitubercular drugs in our prospectively maintained database.\n\nRESULTS:\nOf 81 patients undergoing transplantation for acute liver failure, 8 cases were attributed to antitubercular drugs during the period of 2006-2016. Regarding the time of tuberculosis treatment until the onset of jaundice, patients were on antitubercular drugs for a mean of 64.7 days (21-155 days). The model for end-stage liver disease (MELD) score of patients ranged from 32 to 47 (median 38), and seven patients underwent transplantation under vasopressors. The 1-year survival was 50%. Three patients died during the week following transplantation due to septic shock (including a patient with acute liver failure due to hepatic/disseminated tuberculosis), and the remaining patient died 2 months after transplantation due to pulmonary infection. There were 2 cases of mild rejection and 1 case of moderate rejection. Of the surviving patients, all were considered cured of tuberculosis after alternative drugs were given.\n\nCONCLUSION:\nPatients arrived very sick and displayed poor survival after deceased donor transplantation.\n\nTuberculosisHepatic InsufficiencyDrug ToxicitySurvivalLiver Transplantation\n==== Body\nINTRODUCTION\nTuberculosis is one of the top 10 causes of death worldwide, despite being a curable infectious disease 1. Brazil is one of the countries with a high burden of tuberculosis, with an estimated incidence of 44/100,000 pulmonary tuberculosis in 2014. Because Brazil is a large country, the incidence of tuberculosis varies according to the area, city size, population density and socioeconomic indicators 2.\n\nThe cornerstone of tuberculosis treatment consists of a regimen containing rifampicin, isoniazid, pyrazinamide and ethambutol. The first three drugs are potentially hepatotoxic 3, and the incidence of hepatoxicity has been reported to vary between 2% and 28% 4. More often, these drugs lead to an asymptomatic increase in serum aminotransferase levels, but acute liver failure (ALF) even after the discontinuation of the drugs has also been reported 5. Antitubercular drug-induced hepatotoxicity is related to an idiosyncratic reaction to the released metabolites and can occur independently of the dose 4,6.\n\nALF is a life-threatening condition with variable mortality rates, depending on etiology and age, among other factors 7. Liver transplantation (LT) is the only treatment for cases within previously established criteria 8. In Europe, 8% of LT are due to ALF, and 18% of these cases are due to drug-induced liver damage 7. LT for ALF due to antitubercular drugs presents peculiarities for management and outcome prediction that deserve to be better understood. Some published case reports and series have described varying survival rates after LT for ALF. Moreover, patients in this context may present with a confounding symptom, as the disease itself can present as diffuse hepatic infiltration, also known as granulomatous hepatitis leading to ALF 9.\n\nIn this study, we aimed to describe our experience with LT for ALF resulting from the use of antitubercular drugs to aid in the decision-making for LT in patients in this situation.\n\nMETHODS\nFor case identification, we initially identified all patients listed for ALF in our informatized national list over a 10-year period (2006-2016). Afterwards, we consulted our prospectively maintained database to identify cases in which drug toxicity was the cause of ALF and finally consulted informatized patient charts to identify all patients undergoing LT for ALF related to tuberculosis treatment.\n\nALF management protocol\nPatients referred to our unit with ALF are systematically subjected to the following protocol: laboratory workup including serologies for viral hepatitis, HIV, HTLV, toxoplasmosis, cytomegalovirus, syphilis, Chagas, HCV RNA quantification, autoimmune autoantibodies, factor V, and ABO typing, in addition to routine hematological and biochemical exams; radiological workup includes Doppler ultrasound of the upper abdomen; procedures such as central line and intracerebral monitoring are performed if indicated; and written consent is obtained from the family for listing and transplantation. Antimicrobial treatment includes cefotaxime and fluconazole. Post-transplantation prophylaxis includes ivermectin, sulfametoxazol-trimetoprim, and preemptive approach for cytomegalovirus.\n\nPatients who met the previously established criteria (King’s College or Clichy) were listed for LT 10,11.\n\nThe immunosuppression protocol consisted of 500 mg intraoperative methylprednisolone, tapering until 20 mg prednisone was reached, followed by weaning over 3 months. Tacrolimus was initiated on the first post-operative day aiming at a serum level of 8-10 ng/ml. Sodium mycophenolate was added if there was renal insufficiency, and in this context, the target serum level of tacrolimus was 5-8 ng/ml.\n\nRESULTS\nFrom 2006 to 2016, 81 patients underwent LT for ALF at our institution. Fourteen (17.2%) cases were due to drug toxicity, and of these, 8 were related to antitubercular drugs.\n\nAll eight patients were women, with a median age of 39 years (range 17-56). None of the patients had any history of liver disease; three had hypertension, and one had hypothyroidism as comorbidities.\n\nClinical and laboratory data\nSix patients presented with the acute form of liver failure, and two patients presented the hyperacute form according to previous classifications 12. The interval between jaundice and encephalopathy onset ranged from 2 to 27 days (mean 13.1 days). Regarding the grade of encephalopathy, 4 patients were transplanted with West Haven grade II encephalopathy 13, 2 had grade III, and 2 had grade IV encephalopathy. On admission, the median liver functional values were as follows: AST 459 U/L (167-1623 U/L); ALT 555 U/L (141-265 U/L); TB 22.9 mg/dL (6.21-44.2 mg/dL); INR 4.34 (1.7-10.7); creatinine 0.72 mg/dL (0.42-1.74 mg/dL); model for end-stage liver disease (MELD) score 34 (30-40); and factor V 25% (13-31%).\n\nThe median MELD score immediately before transplantation was 38 (32-47). The median laboratory values immediately before transplantation were TB 23.2 mg/dL (11.4-39.3); INR 3.33 (1.29-5.09); Creatinine 1.73 mg/dL (0.32-3.65 mg/dL); and factor V 25% (15-36%).\n\nAfter being listed as priority patients, the waiting time until transplantation ranged from a few hours to 17 days (median 4 days).\n\nAll eight patients had severe hepatic insufficiency, and five patients underwent transplantation under mechanical ventilation. Two patients required renal replacement therapy before transplantation, and all of them did so after transplantation. Six patients required vasopressors before transplantation.\n\nOf the 8 transplanted patients, 4 had an additional active infection at the time of transplantation, all of pulmonary site (2 unknown etiology, 1 carbapenem-resistant Acinetobacter baumanii and 1 ESBL-producing Klebsiella pneumoniae).\n\nPre- and post-transplantation tuberculosis data\nSix patients had pulmonary tuberculosis; the remaining two had ocular and bone tuberculosis. One patient diagnosed with pulmonary tuberculosis was later diagnosed as having disseminated disease that had infiltrated the lung, liver and bowels. The diagnosis of tuberculosis was done by positive direct bacilloscopy in four patients, positive culture in two, Mycobacterium tuberculosis PCR in one, and histological, clinical and radiological characteristics in the remaining case (Table 1). Regarding the time of tuberculosis treatment until the onset of jaundice, patients were on antitubercular drugs for a mean of 69 days (21-155 days) and a median of 34 days. Four of the 8 transplanted patients received at least 2 months of antitubercular treatment before transplantation. All patients were using rifampicin and isoniazid; seven were on pyrazinamide; and six were using ethambutol at the beginning of the symptoms.\n\nAfter transplantation, patients received an alternative treatment for tuberculosis based on ethambutol in 6 cases, levofloxacin in 6 cases, streptomycin in 2 cases, ciprofloxacin in 1 case, azithromycin in 1 case, and linezolid in 1 case. The 4 patients who were alive at one year after transplantation had received alternative tuberculosis treatment for 6 months (1 patient), 9 months (2 patients) and 1 year (1 patient). All were considered cured, with no symptoms suggestive of recurrent tuberculosis.\n\nOutcome\nThe 1-year survival rate after the transplantation was 50%; two deaths occurred at 1 and 7 days post-transplantation and were related to sepsis and multiorgan failure after severe hemodynamic instability; one patient died 2 months after the procedure due to sepsis from pulmonary infection; and the last patient presented with hepatomegaly on admission and underwent LT for ALF due to antitubercular drugs after 1 month of treatment. Liver pathology showed a 1540-g liver with granulomas with caseum. He died 2 days after the transplantation due to disseminated disease that had infiltrated the lung, liver and bowels. All 4 patients who died were on vasopressor drugs pre-transplantation; 1 patient had grade II encephalopathy, and the others had grade III or IV encephalopathy, with a MELD score ranging from 33 to 47. Of the 4 patients with 1-year survival, only 2 were on vasopressors at the time of transplantation; 3 had grade II encephalopathy, and 1 had grade IV encephalopathy, with a MELD score ranging from 32 to 42. The surviving patients were followed up for a mean of 1991 days.\n\nPathology\nOn liver pathology, organ weight varied from 463.9 g to 1540 g. Histology showed massive and sub-massive hepatic necrosis in all cases, but in one patient, the necrosis was present in a micronodular liver cirrhosis background. In this case and another one, granuloma with caseum was found.\n\nDISCUSSION\nTo the best of our knowledge, this study has the largest number of transplanted patients in a single center for ALF due to antitubercular drugs. Previously published studies include series of cases and isolated case reports 14-17, and our series may contribute to the current literature regarding patient characteristics before transplantation and management of tuberculosis and outcome after transplantation.\n\nAs ours is a national reference center, 7 out of the 8 patients were referred in critical condition from other hospitals. More than half of the patients underwent transplantation under both ventilatory and circulatory support, which could explain the low 1-year survival rate of 50% even for LT due to ALF, which is typically worse than LT for chronic liver disease 18,25. Compared to the patients who had favorable outcomes, the patients who had poor outcomes underwent surgery on vasopressor drugs (50 vs 100%) and had grade III or IV encephalopathy (1 vs 3). Two of those patients with worse outcomes, in fact, had bad indications for the procedure. One had disseminated tuberculosis, and the other probably had an acute-on-chronic liver disease triggered by antitubercular drugs. The survival rate in our report is equivalent to the one described by Ichai et al. (50%), which was, until recently, the study with the largest number of transplanted patients in the same context in a single center 14. Patients with ALF are often in critical conditions, and some of them are very young. There are no current well-established factors that can predict the outcomes after transplantation. Despite the effort of some authors, this issue remains to be better understood 19,20, and as some authors suggest, the critical decision for transplantation should be made on a case-by-case basis 21.\n\nA recent comprehensive review reported on 19 transplanted individuals without known liver disease with good long-term survival rates – however, 6 of these patients were from the Ichai cohort, and 10 were single case reports 17. Based on these data, we can conclude that in general, single case reports describe cases with favorable outcomes, and authors are usually less motivated to publish cases with negative results, and therefore the reported survival rate in the review may have been overestimated. Although another recently published paper demonstrated excellent survival rates for 6 individuals undergoing emergency living donor transplantation in the same context, little information is given regarding pre-transplantation characteristics of the patients and life support, with a mean MELD score of 30.1 (compared to the mean score of 38 in our cohort). The 6 transplanted individuals came from a pool of 19 patients with ALF, and possibly those with better clinical parameters were given the chance of living donor transplantations, considering the risks for the donor 15. Another recent paper described a good survival rate of 71.4% in 7 patients undergoing living donor transplantations in India, with a median follow-up of 22 months 16. Although the authors did not mention any patient who were unfit for transplantations, patients went to the procedure very sick, with a mean MELD score greater than 35.\n\nOnce patients are referred to our clinic under antitubercular drugs, it may be difficult to differentiate whether hepatic damage is due to therapy or related to liver infiltration of disseminated tuberculosis. Additionally, it seems that the prognosis is completely different under these two circumstances. In their series, Ichai et al. 14 also reported one patient who died after the LT due to disseminated tuberculosis, and similar cases are described in single case reports, mostly post-mortem 9,22-24. In the described cases, hepatomegaly may be a signal of a disseminated disease into the liver rather than liver damage caused by drugs.\n\nTreatment after transplantation did not include the possible causative hepatotoxic drug, and alternative regimens were capable of leading to cure in 100% of the surviving cases. Other studies have reported similar findings, despite the recommendation that any mycobacterial infection should be optimally treated with documented microbiologic and radiological resolution before transplantation is considered 26.\n\nOne major difficulty in administering antitubercular therapy to transplantation patients is drug-drug interactions involving rifampin 27. This drug and, to a lesser degree, isoniazid induces the metabolism of tacrolimus via the induction of the cytochrome P450 pathway, and thus the incidence of graft rejection may be significant in solid organ transplantation recipients.\n\nThere are some limitations to our study. It is a single-center series, with a possible bias of patients with more severe disease undergoing LT. Moreover, the number of cases described is small.\n\nIn conclusion, patients were very sick at the time of transplantation and displayed poor survival after deceased donor transplantation. Except for the case in which the patient died of disseminated tuberculosis, fatal outcome was not related to tuberculosis but to complications of the transplantation performed in patients in severe clinical conditions. Current literature is lacking more sensitive diagnostic tools to predict outcomes in ALF that can help avoid futile procedures.\n\nAUTHOR CONTRIBUTIONS\nMartino RB, Abdala E, D’Albuquerque LA and Song AT designed the study, Villegas FC collected the data. Martino RB, Villegas FC and Song AT analyzed the data. Martino RB, Song AT and Abdala E wrote the paper. All authors read and approved the final version of the manuscript.\n\nNo potential conflict of interest was reported.\n\nTable 1 Demographic and clinical characteristics of patients undergoing liver transplantation for acute liver failure due to antitubercular drugs.\n\nPatient\tAge (years)\tSite of infection\tDuration of Anti-TB treatment before ALF (days)\tAnti-TB treatment pre-LT\tType of ALF\tMELD\tHE (grade)\tPre-LT VAD\tPre-LT Dialysis\tAnti-TB treatment post-LT\tOutcome (days)\tRejection\t\n1\t17\tPulmonary\t66\tRIPE\tAcute\t42\tIV\t+\t-\tETH + LFX\tAlive (483)\tModerate AR\t\n2\t17\tDisseminated\t28\tRIPE\tHyperacute\t47\tIII\t+\t-\tSM + LFX\tDead (2)\t-\t\n3\t18\tPulmonary\t40\tRIPE\tHyperacute\t33\tIII\t+\t-\tAMC + LFX + ETH\tDead (7)\t-\t\n4\t56\tPulmonary\t40\tRIPE\tAcute\t38\tIV\t+\t-\tLFX + SM + ETH\tDead (62)\tMild AR\t\n5\t59\tOcular\t133\tRIF + INH\tAcute\t32\tII\t+\t+\tETH + LFX\tAlive (3311)\t-\t\n6\t38\tPulmonary\t58\tRIF + INH + PZA\tAcute\t42\tII\t-\t-\tCFX + ETH\tAlive (3874)\tMild AR\t\n7\t56\tBone\t174\tRIPE\tAcute\t43\tII\t+\t+\t-\tDead (1)\t-\t\n8\t41\tPulmonary\t36\tRIPE\tAcute\t32\tII\t-\t-\tLFX + LNZ + ETH\tAlive (397)\t-\t\nALF, acute liver failure; AMC, azithromycin; AR, acute rejection; CFX, ciprofloxacin; ETH, ethambutol; INH, isoniazid; LFX, levofloxacin; LNZ, linezolid; PZA, pyrazinamide; RIF, rifampicin; RIPE, rifampicin-isoniazid-pyrazinamide-ethambutol; SM, streptomycin; TB, tuberculosis; HE, hepatic encephalopathy; MELD, model for end-stage liver disease; VAD, vasoactive drugs.\n==== Refs\nREFERENCES\n1 World Health Organization Tuberculosis WHO Fact Sheet No. 104. Revised October 2016. Accessed http://www.who.int/mediacentre/factsheets/fs104/en/ in January 2017 \n2 Ranzani OT Carvalho CR Waldman EA Rodrigues LC The impact of being homeless on the unsuccessful outcome of treatment of pulmonary TB in São Paulo State, Brazil BMC Med 2016 14 41 10.1186/s12916-016-0584-8 27006009 \n3 Devarbhavi H Antituberculous drug-induced liver injury: current perspective Trop Gastroenterol 2011 32 (3) 167 74 22332331 \n4 Tostmann A Boeree MJ Aarnoutse RE de Lange WC van der Ven AJ Dekhuijzen R Antituberculosis drug-induced hepatotoxicity: Concise up-to-date review J Gastroenterol Hepatol 2008 23 (2) 192 202 10.1111/j.1440-1746.2007.05207.x 17995946 \n5 Mitchell I Wendon J Fitt S Williams R Anti-tuberculous therapy and acute liver failure Lancet 1995 345 (8949) 555 6 10.1016/S0140-6736(95)90468-9 7786350 \n6 Wondwossen Abera Waqtola Cheneke Gemeda Abebe Incidence of antituberculosis-drug-induced hepatotoxicity and associated risk factors among tuberculosis patients in Dawro Zone, South Ethiopia: A cohort study Int J Mycobacteriol 2016 5 (1) 14 20 10.1016/j.ijmyco.2015.10.002 26927985 \n7 Mendizabal M Silva MO Liver transplantation in acute liver failure: A challenging scenario World J Gastroenterol 2016 22 (4) 1523 31 10.3748/wjg.v22.i4.1523 26819519 \n8 Bernal W Auzinger G Dhawan A Wendon J Acute liver failure Lancet 2010 376 (9736) 190 201 10.1016/S0140-6736(10)60274-7 20638564 \n9 Toptas T Ilhan B Bilgin H Dincses E Ozdogan O Kaygusuz-Atagunduz I Miliary Tuberculosis Induced Acute Liver Failure Case Rep Infect Dis 2015 2015 759341 26435862 \n10 O’Grady JG Alexander GJ Hayllar KM Williams R Early indicators of prognosis in fulminant hepatic failure Gastroenterology 1989 97 (2) 439 45 10.1016/0016-5085(89)90081-4 2490426 \n11 Bismuth H Samuel D Castaing D Adam R Saliba F Johann M Orthotopic liver transplantation in fulminant and subfulminant hepatitis. The Paul Brousse experience Ann Surg 1995 222 (2) 109 19 10.1097/00000658-199508000-00002 7639578 \n12 Tandon BN Bernauau J O’Grady J Gupta SD Krisch RE Liaw YF Recommendations of the International Association for the Study of the Liver Subcommittee on nomenclature of acute and subacute liver failure J Gastroenterol Hepatol 1999 14 (5) 403 4 10.1046/j.1440-1746.1999.01905.x 10355501 \n13 Ferenci P Lockwood A Mullen K Tarter R Weissenborn K Blei AT Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998 Hepatology 2002 35 (3) 716 21 10.1053/jhep.2002.31250 11870389 \n14 Ichai P Saliba F Antoun F Azoulay D Sebagh M Antonini TM Acute liver failure due to antitubercular therapy: Strategy for antitubercular treatment before and after liver transplantation Liver Transplant 2010 16 (10) 1136 46 10.1002/lt.22125 \n15 Huh JY Lee D Ahn J Shim JH Lim YS Park GC Impact of emergency adult living donor liver transplantation on the survival of patients with antituberculosis therapy-induced acute liver failure Liver Transpl 2017 23 (6) 845 6 10.1002/lt.24697 28006868 \n16 Bavikatte AP Sudhindran S Dhar P Sudheer OV Unnikrishnan G Balakrishnan D Live donor liver transplantation for antitubercular drug-induced acute liver failure Indian J Gastroenterol 2017 36 (1) 56 61 10.1007/s12664-016-0725-1 28066854 \n17 Bartoletti M Martelli G Tedeschi S Morelli M Bertuzzo V Tadolini M Liver transplantation is associated with good clinical outcome in patients with active tuberculosis and acute liver failure due to anti-tubercular treatment Transpl Infect Dis 2017 19 (2) 10.1111/tid.12658 \n18 Germani G Theocharidou E Adam R Karam V Wendon J O’Grady J Liver transplantation for acute liver failure in Europe: outcomes over 20 years from the ELTR database J Hepatol 2012 57 (2) 288 96 10.1016/j.jhep.2012.03.017 22521347 \n19 Figorilli F Putignano A Roux O Houssel-Debry P Francoz C Paugam-Burtz C Development of an organ failure score in acute liver failure for transplant selection and identification of patients at high risk of futility PloS One 2017 12 (12) e0188151 10.1371/journal.pone.0188151 29206839 \n20 Jin YJ Lim YS Han S Lee HC Hwang S Lee SG Predicting survival after living and deceased donor liver transplantation in adult patients with acute liver failure J Gastroenterol 2012 47 (10) 1115 24 10.1007/s00535-012-0570-7 22526269 \n21 Hoyer DP Munteanu M Canbay A Hartmann M Gallinat A Paul A Liver transplantation for acute liver failure: are there thresholds not to be crossed? Transpl Int 2014 27 (6) 625 33 10.1111/tri.12302 24606197 \n22 Godwin JE Coleman AA Sahn SA Miliary tuberculosis presenting as hepatic and renal failure Chest 1991 99 (3) 752 4 10.1378/chest.99.3.752 1995237 \n23 Hussain W Mutimer D Harrison R Hubscher S Neuberger J Fulminant hepatic failure caused by tuberculosis Gut 1995 36 (5) 792 4 10.1136/gut.36.5.792 7797133 \n24 Jain D Aggarwal HK Jain P Pawar S Primary hepatic tuberculosis presenting as acute liver failure Oxf Med Case Reports 2014 2014 (9) 153 5 10.1093/omcr/omu058 25988063 \n25 Barshes NR Lee TC Balkrishnan R Karpen SJ Carter BA Goss JA Risk stratification of adult patients undergoing orthotopic liver transplantation for fulminant hepatic failure Transplantation 2006 81 (2) 195 201 10.1097/01.tp.0000188149.90975.63 16436962 \n26 Fischer SA Lu K AST Infectious Diseases Community of Practice. Screening of donor and recipient in solid organ transplantation Am J Transplant 2013 13 Suppl 4 9 21 10.1111/ajt.12094 \n27 Subramanian AK Morris MI AST Infectious Diseases Community of Practice Mycobacterium tuberculosis infections in solid organ transplantation Am J Transplant 2013 13 Suppl 4 68 76 10.1111/ajt.12100 23465000\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1807-5932",
"issue": "73()",
"journal": "Clinics (Sao Paulo, Brazil)",
"keywords": null,
"medline_ta": "Clinics (Sao Paulo)",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000995:Antitubercular Agents; D001927:Brain Diseases; D005260:Female; D006801:Humans; D007565:Jaundice; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome; D014376:Tuberculosis; D055815:Young Adult",
"nlm_unique_id": "101244734",
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"pages": "e344",
"pmc": null,
"pmid": "30020340",
"pubdate": "2018-07-16",
"publication_types": "D016428:Journal Article",
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"title": "Liver transplantation for acute liver failure due to antitubercular drugs - a single-center experience.",
"title_normalized": "liver transplantation for acute liver failure due to antitubercular drugs a single center experience"
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"abstract": "We present a case of a woman who received a left single-injection supraclavicular brachial plexus block for analgesia to facilitate upper extremity orthopaedic surgery. Before tracheal extubation she desaturated, was noted to have a low tidal volume and reduced left-sided air entry on auscultation of the chest. A chest x-ray taken 1 h following tracheal extubation revealed elevation of the left hemidiaphragm and a rightward shift of the trachea and mediastinal structures, with no evidence of pneumothorax. Findings were in-keeping with phrenic nerve palsy complicating the brachial plexus block performed. The patient was asymptomatic and discharged home the next day following repeat chest x-rays. We believe this is the first report of tracheal deviation contralateral to the side of an elevated hemidiaphragm secondary to phrenic nerve palsy from a brachial plexus block.",
"affiliations": "Department of Anesthesia and Perioperative Medicine Western University London Ontario Canada.;Department of Anesthesia and Perioperative Medicine Western University London Ontario Canada.;Department of Anesthesia and Perioperative Medicine Western University London Ontario Canada.",
"authors": "Querney|J|J|https://orcid.org/0000-0002-0366-3200;Singh|S I|SI|;Sebbag|I|I|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/anr3.12100",
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"issn_linking": "2637-3726",
"issue": "9(1)",
"journal": "Anaesthesia reports",
"keywords": "elevated hemidiaphragm; interscalene block: complications; phrenic nerve palsy; tracheal deviation",
"medline_ta": "Anaesth Rep",
"mesh_terms": null,
"nlm_unique_id": "101759073",
"other_id": null,
"pages": "41-43",
"pmc": null,
"pmid": "33738457",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "11284823;22361819;18708734;18332619;28514241;671190",
"title": "Tracheal deviation with phrenic nerve palsy after brachial plexus block.",
"title_normalized": "tracheal deviation with phrenic nerve palsy after brachial plexus block"
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"abstract": "Pharmacogenomic (PGx) information can guide drug and dose selection, optimize therapy outcomes, and/or decrease the risk of adverse drug events (ADEs). This report demonstrates the impact of a pharmacist-led medication evaluation, with PGx assisted by a clinical decision support system (CDSS), of a patient with multiple comorbidities. Following several sub-optimal pharmacotherapy attempts, PGx testing was recommended. The results were integrated into the CDSS, which supported the identification of clinically significant drug-drug, drug-gene, and drug-drug-gene interactions that led to the phenoconversion of cytochrome P450. The pharmacist evaluated PGx results, concomitant medications, and patient-specific factors to address medication-related problems. The results identified the patient as a CYP2D6 intermediate metabolizer (IM). Duloxetine-mediated competitive inhibition of CYP2D6 resulted in phenoconversion, whereby the patient's CYP2D6 phenotype was converted from IM to poor metabolizer for CYP2D6 co-medication. The medication risk score suggested a high risk of ADEs. Recommendations that accounted for PGx and drug-induced phenoconversion were accepted. After 1.5 months, therapy changes led to improved pain control, depression status, and quality of life, as well as increased heart rate, evidenced by patient-reported improved sleep patterns, movement, and cognition. This case highlights the pharmacist's role in using PGx testing and a CDSS to identify and mitigate medication-related problems to optimize medication regimen and medication safety.",
"affiliations": "Office of Translational Research and Residency Programs, Tabula Rasa HealthCare, Moorestown, NJ 08057, USA.;Office of Translational Research and Residency Programs, Tabula Rasa HealthCare, Moorestown, NJ 08057, USA.;Precision Pharmacotherapy Research & Development Institute, Tabula Rasa HealthCare, Orlando, FL 32827, USA.;Precision Pharmacotherapy Research & Development Institute, Tabula Rasa HealthCare, Orlando, FL 32827, USA.;Office of Translational Research and Residency Programs, Tabula Rasa HealthCare, Moorestown, NJ 08057, USA.;Precision Pharmacotherapy Research & Development Institute, Tabula Rasa HealthCare, Orlando, FL 32827, USA.",
"authors": "Del Toro-Pagán|Nicole Marie|NM|;Matos|Adriana|A|0000-0002-7448-9799;Thacker|David|D|;Turgeon|Jacques|J|0000-0002-7978-9280;Amin|Nishita Shah|NS|;Michaud|Veronique|V|",
"chemical_list": "D004364:Pharmaceutical Preparations; D019389:Cytochrome P-450 CYP2D6",
"country": "Switzerland",
"delete": false,
"doi": "10.3390/medicina57090955",
"fulltext": "\n==== Front\nMedicina (Kaunas)\nMedicina (Kaunas)\nmedicina\nMedicina\n1010-660X\n1648-9144\nMDPI\n\n10.3390/medicina57090955\nmedicina-57-00955\nCase Report\nPharmacist-Led Medication Evaluation Considering Pharmacogenomics and Drug-Induced Phenoconversion in the Treatment of Multiple Comorbidities: A Case Report\nDel Toro-Pagán Nicole Marie 1\nhttps://orcid.org/0000-0002-7448-9799\nMatos Adriana 1\nThacker David 2\nhttps://orcid.org/0000-0002-7978-9280\nTurgeon Jacques 23\nAmin Nishita Shah 1\nMichaud Veronique 23*\nDambrova Maija Academic Editor\n1 Office of Translational Research and Residency Programs, Tabula Rasa HealthCare, Moorestown, NJ 08057, USA; npagan@trhc.com (N.M.D.T.-P.); amatos@carekinesis.com (A.M.); namin@carekinesis.com (N.S.A.)\n2 Precision Pharmacotherapy Research & Development Institute, Tabula Rasa HealthCare, Orlando, FL 32827, USA; dthacker@trhc.com (D.T.); jturgeon@trhc.com (J.T.)\n3 Faculty of Pharmacy, Université de Montréal, Montréal, QC H3C 3J7, Canada\n* Correspondence: vmichaud@trhc.com; Tel.: +1-407-454-9964\n10 9 2021\n9 2021\n57 9 95511 8 2021\n02 9 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nPharmacogenomic (PGx) information can guide drug and dose selection, optimize therapy outcomes, and/or decrease the risk of adverse drug events (ADEs). This report demonstrates the impact of a pharmacist-led medication evaluation, with PGx assisted by a clinical decision support system (CDSS), of a patient with multiple comorbidities. Following several sub-optimal pharmacotherapy attempts, PGx testing was recommended. The results were integrated into the CDSS, which supported the identification of clinically significant drug–drug, drug–gene, and drug–drug–gene interactions that led to the phenoconversion of cytochrome P450. The pharmacist evaluated PGx results, concomitant medications, and patient-specific factors to address medication-related problems. The results identified the patient as a CYP2D6 intermediate metabolizer (IM). Duloxetine-mediated competitive inhibition of CYP2D6 resulted in phenoconversion, whereby the patient’s CYP2D6 phenotype was converted from IM to poor metabolizer for CYP2D6 co-medication. The medication risk score suggested a high risk of ADEs. Recommendations that accounted for PGx and drug-induced phenoconversion were accepted. After 1.5 months, therapy changes led to improved pain control, depression status, and quality of life, as well as increased heart rate, evidenced by patient-reported improved sleep patterns, movement, and cognition. This case highlights the pharmacist’s role in using PGx testing and a CDSS to identify and mitigate medication-related problems to optimize medication regimen and medication safety.\n\nantidepressants\nβ-blockers\ncase report\nclinical decision support system (CDSS)\nCYP2D6\ndepression\nopioids\npain\npharmacogenetics\npharmacogenomics (PGx)\n==== Body\npmc\n\n1. Introduction\n\nEnvironmental, physiological, and psychological factors, as well as comorbidities and genetic variability, have been shown to affect interpatient variability in drug disposition and response [1]. Pharmacogenomics (PGx) is the study of human genome variants that impact drug response via variations in pharmacokinetic or pharmacodynamic parameters [2]. Therefore, PGx testing can support the identification of drug–gene interactions (DGIs) and drug–drug–gene interactions (DDGIs). DGIs involve a drug and a variation in a gene that codes for a protein, such as cytochrome P450 (CYP) isoenzymes (e.g., citalopram and CYP2C19), a receptor (e.g., metoprolol and adrenoceptor beta 1 (ADRB1)) or a transporter (simvastatin and solute carrier organic anion transporter 1B1 (SLCO1B1, previously referred to OATP1B1)) [3]. The superimposition of a drug–drug interaction (DDI) on a DGI can result in a DDGI, which frequently induces phenoconversion [3]. Phenoconversion is the ability of intrinsic (e.g., inflammation) [4,5] or extrinsic factors, such as drugs, to modify a genotype-predicted phenotypic expression [6]. For instance, a mismatch between the predicted phenotype from the determined CYP2C19 genotype and the observed CYP2C19 activity has been reported in patient with type 2 diabetes due to low levels of pro-inflammatory cytokines [7]. Similarly, a drug may induce CYP phenoconversion, and an individual identified as a CYP2D6 normal metabolizer (NM) with a *1|*1 genotype will be phenoconverted into a poor metabolizer (PM) while taking quinidine, a potent CYP2D6 inhibitor. Considering the two previously mentioned conditions, the metabolism of CYP2C19 or CYP2D6 substrates would be altered under such conditions, which may result in an increased risk of inappropriate response to substrates of these enzymes. To mitigate the effect of these DGIs and DDGIs, organizations such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) have developed guidance on drug and dose selection for certain drug–gene pairs (e.g., duloxetine and CYP2D6, hydrocodone and CYP2D6, metoprolol and CYP2D6) based on current clinical evidence [8].\n\nLarge interindividual differences exist in response to analgesic therapy agents, such as prodrug opioids activated by CYP2D6 (e.g., codeine, tramadol, hydrocodone, oxycodone) [9]. The presence of variants in the CYP2D6 gene can contribute to variability in opioid response in terms of efficacy and/or risk of adverse drug events (ADEs). The opioid receptor µ1 (OPRM1) and catechol-O-methyltransferase (COMT) gene variants have also been studied for their potential to affect opioid pharmacodynamic response [10]. While CPIC provides CYP2D6 genotype/phenotype-based recommendations for codeine, tramadol, and hydrocodone, no recommendations are currently available for dosing opioids based on either the OPRM1 or COMT genotype due to the lack of consistent evidence [11]. The prevalence of CYP450 DDIs among patients with chronic low back pain on long-term opioid therapy has been estimated to be 27%, which can further impact the response variability observed due to a higher risk of DDGIs [12]. The vast majority of the reported DDIs in an older adult population cohort were associated with medications known to inhibit the CYP2D6 enzyme [12].\n\nIntegrating PGx into clinical practice could support antidepressant drug and dose selection. Currently, the antidepressant medication selection for each patient is dependent upon trial-and-error treatment strategies considering endophenotype, clinician preferences and clinical experience, and the patient’s past medication history [13]. Implementation of a PGx decision support tool for antidepressant treatment may enhance the prediction of treatment response and the capability to foresee potential adverse side effects, minimizing prolonged suffered and adverse sequelae. PGx can support narrowing down the antidepressant drug and dose options, potentially leading to decreased risk of antidepressant-related toxicity and/or to achieve remission faster [14,15]. Variations in the CYP2C19 and/or CYP2D6 genes contributes to the variability observed in antidepressant response [16]. CPIC and DPWG provide genotype/phenotype-based recommendations for multiple selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants [17,18,19]. The glutamate ionotropic receptor kainate type subunit 4 (GRIK4) and 5-hydroxytryptamine receptor 2A (HTR2A) gene variants have been studied for their potential to affect antidepressant pharmacodynamic response. However, no dosing recommendations are currently provided based on either genotype due to the dearth of consistent evidence [20].\n\nPolymorphisms in CYP2D6 are also associated with altered β-blocker metabolism [21]. CYP2D6 IMs and PMs typically experience greater reduction in heart rate, and some patients develop symptomatic bradycardia [22]. The ADRB1 and G protein-coupled receptor kinase 5 (GRK5) gene variants have been studied for their potential to affect β-blockers’ pharmacodynamic response. However, no dosing recommendations are currently provided based on either genotype due to the lack of consistent evidence [21].\n\nUnquestionably, applying PGx can be beneficial in certain cases. For example, studies of patients suffering from chronic pain and depression have revealed that pain- and depression-induced neuroplasticity changes and neurobiological mechanism changes can be closely interrelated [23]. Lack of control of these conditions can result in an enormous burden to the patient, caregivers, and healthcare system, resulting in increased costs [24,25]. Uncontrolled pain also reduces functional capacity and quality of life for patients, such as those living with obesity [26]. Patients diagnosed with chronic pain living with obesity are more likely to present with depressive symptoms than patients who are normal- or overweight [27]. It should be noted that depression in the older adult population has been associated with longer length of illness, more frequent major depressive disorder (MDD) recurrences, and a greater risk of comorbidities [28]. In this population, depression has been identified as one of the psychiatric illness most closely associated with suicide [29]. In 2012, a literature review reported that patients who have an inadequate response to their antidepressant regimen are expected to spend approximately USD 10,000 more annually on healthcare-related expenses than patients who have an adequate response [30]. Uncontrolled pain in the older adult population results in an annual cost of approximately USD 61.2 billion [31], while loss of productivity for patients and caregivers due to lack of pain control has been calculated to be USD 300 billion [32]. There is potential for cost savings in these populations.\n\nThe Program of All-inclusive Care for the Elderly (PACE) receives capitated reimbursements on behalf of Medicare and Medicaid (a joint, federal and state program in the U.S.) for participants 55 years or older. PACE participants have a team of health care professionals collaborating to ensure that nursing home level coordinated care is provided in the home setting. The PACE model enables collaboration between pharmacists and other healthcare practitioners to identify and mitigate medication-related problems. PGx testing is one part of the initiatives implemented to further improve the care of PACE participants [33]. Clinical decision support systems (CDSS) are critical tools for the implementation of PGx into routine patient care and the adoption of PGx recommendations [34]. The proprietary CDSS, MedWise®, which has been described previously, incorporates PGx results in combination with the medication regimen to support clinicians with identifying clinically significant DDIs, DGIs, and DDGIs [35]. This CDSS generates a medication risk score (MRS) based on 5 factors, including CYP DDI risk. An increased MRS has been associated with a higher incidence of ADEs, healthcare-related expenditures, emergency department visits, hospitalizations and death [36]. Thus, the objective of this case report is to demonstrate the impact of a pharmacist-led medication evaluation, which incorporated PGx assisted by a CDSS, of a PACE participant with obesity and multiple comorbidities.\n\n2. Description of the Case Report\n\nA 66-year-old non-smoker female presented with a past medical history of obesity class III (body mass index = 64 kg/m2), uncontrolled chronic pain of multifactorial nature, uncontrolled MDD, hypertension, heart failure, atrial fibrillation, gout, hypothyroidism, type 2 diabetes mellitus, gastroesophageal reflux disease (GERD), insomnia, diarrhea, nausea, and candidiasis. Her medication regimen to treat her multiple comorbidities as prescribed by her primary care physician is described in Table 1. The CDSS generates a medication risk score (MRS) based on the current patient’s drug regimen. The MRS is associated with healthcare outcomes and is the indicator used to measure the risk of adverse drug events associated with a given drug regimen. The MRS for this patient’s drug regimen was 32 with a high-risk sub-score for CYP450 competitive drug interactions and very high-risk sub-score for sedative burden.\n\nThe patient’s chief complaints when she enrolled in the PACE program in 2020 were inappropriate control of her depression and poor multifactorial pain control despite numerous trials of antidepressant and analgesic therapies (Table 2). Duloxetine was initially chosen to treat her depression status since it could also provide neuropathic pain relief. However, after being prescribed duloxetine for over 10 years, the patient experienced only minor improvement of MDD symptoms, and despite the use of a multimodal analgesic regimen, the patient continued experiencing uncontrolled pain. The addition of opioids (i.e., tramadol, hydrocodone) to her analgesic regimen was unsuccessful. Of note, while under treatment with metoprolol, the patient was borderline bradycardic per clinical assessment from her primary care physician. Upon review of the patient’s drug regimen, utilizing the proprietary evidenced-based CDSS, the clinical pharmacist recommended conducting a PGx test to guide the optimization of her antidepressant and analgesic regimen. This recommendation was accepted by the primary care physician.\n\n3. Results\n\nA DNA sample was collected via buccal swab and analyzed by a Clinical Laboratory Improvement Amendments-certified laboratory (OneOme, Minneapolis, MN, USA). The clinical pharmacist was consulted to interpret the PGx results and complete a multidrug interaction screening. Genotypic results identified the patient as a CYP2D6 IM, with a *1|*4 genotype (Table 3). PGx results were integrated into the CDSS [35]. The clinical pharmacist evaluated the PGx results, concomitant medications, the CDSS-generated MRS, and other patient-specific factors in order to formulate recommendations to the primary care physician for mitigating these medication-related problems to the primary care physician. Although the clinical pharmacist assessed the complete drug regimen, only recommendations relevant to pain, depression, and heart rate control management will be discussed in the context of this case report.\n\nConsidering the patient’s CYP2D6 IM status, DGIs were identified affecting the metabolism of hydrocodone, duloxetine, and metoprolol. A CYP2D6 IM has reduced enzyme activity, which alters the clearance of duloxetine and metoprolol and can increase the risk of toxicity associated with these medications. CYP2D6-reduced enzyme activity also decreases the conversion of hydrocodone to hydromorphone and may increase the risk of pharmacotherapy failure and possibly ADEs. Therefore, the clinical pharmacist recommended changing duloxetine to desvenlafaxine, hydrocodone to morphine, and metoprolol to carvedilol. The three recommendations were accepted by the primary care physician.\n\n4. Discussion\n\nThe CDSS displays duloxetine, metoprolol, and hydrocodone (prodrug) as CYP2D6-substrates (Table 4). As a CYP2D6 IM, we would expect decreased activation of the prodrug, hydrocodone, and increased plasma concentrations of duloxetine and metoprolol due to decreased clearance of these metabolic pathways. When co-administered, duloxetine is expected to competitively inhibit the metabolism of hydrocodone and metoprolol, resulting in drug-induced phenoconversion to PM for these two drugs.\n\nThe presence of drug-induced phenoconversion was established based on the CDSS used in this study. This CDSS, supported by clinical and scientific literature, has embedded algorithms that consider several pharmacokinetic properties related to CYP450 metabolic pathways and their respective affinity (patent: WO 2019/089725). The phenotype based on the genotype (derived from PGx results) is combined with CYP450 drug-induced phenoconversion to estimate the patient phenotype for a given drug regimen. Considering that phenoconversion to a PM status was occurring at CYP2D6 for hydrocodone and metoprolol, the clinical pharmacist referred to CPIC guidance for dosing hydrocodone (Table S1) and DPWG guidelines (Table S2) recommendations for dosing metoprolol. The clinical pharmacist chose to recommend morphine, which is not dependent on CYP2D6 metabolism, avoiding DGI and DDGI on this isoenzyme. Additionally, morphine is a hydrophilic opioid; thus, the volume of distribution should not be significantly influenced by excess adipose tissue [39]. Metoprolol exhibits large inter-individual variability in pharmacodynamic response, likely due to its extensive dependence on CYP2D6 (≈75%) for its clearance [40]. Greater area under the curve concentrations and decreased apparent oral clearance in CYP2D6 PMs and IMs translate into differences in heart rate [21]. Additionally, it is worth mentioning that highly lipophilic beta-blockers, such as metoprolol, have been associated with worsening depression symptoms [41]. Highly lipophilic drugs penetrate the blood–brain barrier more readily, which can result in more profound central nervous system effects [42]. This patient did not achieve heart rate control despite multiple attempts to adjust the metoprolol tartrate dose, and she had a diagnosis of heart failure. Therefore, bisoprolol and carvedilol, which are less lipophilic than metoprolol, were the two beta-blocker alternatives considered [43]. The metabolism of bisoprolol is not dependent on CYP2D6; however, it is metabolized by the CYP3A4 enzyme, and it is subject to competitive inhibition at this enzyme by stronger substrates, such as, amlodipine, dronedarone, and loperamide. This could potentially lead to an increased risk of ADEs. On the other hand, the clearance of carvedilol is significantly dependent on CYP2D6 [44]. Current evidence has shown that CYP2D6 PMs and IMs can have up to 2.5 times higher plasma carvedilol plasma concentrations, when comparing to NMs [45]. Despite increased concentrations of carvedilol, researchers have been unable to establish a relationship between the CYP2D6 phenotype and changes in heart rate, blood pressure, or rate of ADEs in patients with heart failure [46,47]. Thus, currently the 2018 update of the DPWG guidelines claim that the effect of the CYP2D6 DGI for carvedilol is likely clinically insignificant [48]. One plausible explanation for this is that, besides its beta-blocker effects, carvedilol also has alpha-blocking properties different from metoprolol [49]. Carvedilol is administered as a racemic mixture and both isomers have been shown to have equally potent alpha blocker properties; however, the S(-)-isomer is the major contributor to the beta-blocker effect [45]. Studies have shown that decreased CYP2D6 metabolism has a more significant impact on the clearance of the R(-)-isomer (alpha blockade) [45]. In this case, the primary care provider opted to prescribe a trial of carvedilol, though it was advised to start with a lower dose and titrate as tolerated.\n\nUpon medication review, it was noted that 10 years of treatment with the SNRI duloxetine did not produce satisfactory depression remission. Achieving depression remission among older adults is a common challenge, as more than 50% of these patients do not appropriately respond to first-line therapies of SSRIs or SNRIs [50]. For duloxetine, DPWG guidelines (Table S3) do not provide CYP2D6 phenotype-based recommendations, as antidepressant plasma concentrations seem to poorly correlate with antidepressant effectiveness. However, phenotype-based recommendations appear to provide more reliable information on the risk of ADEs [51]. Selecting an alternative antidepressant for an elderly patient is challenging due to the higher prevalence of polypharmacy, higher risk of DDIs, reduced medication adherence, and greater risk of ADEs in this population [52]. Because the patient was identified as a CYP2D6 IM, the clinical pharmacist recommended changing duloxetine to desvenlafaxine, which does not depend on CYP2D6 metabolism. As for duloxetine, desvenlafaxine can also contribute to neuropathic pain relief [53].\n\nA follow-up by the pharmacist occurred one and a half months post-implementation of the aforementioned recommendations to assess the analgesic, antidepressant, and heart rate control responses. Changes in therapy led to significantly improved pain, depression, and heart rate control, improving the quality of life of the patient as reported by the primary care physician. This was evidenced by patient reports of improved sleep patterns, movement, and cognition. As a first step in a more holistic medication action plan, the patient’s MRS decreased from 32 to 29. Bankes et al. reported that each point increase in the MRS was associated with an 8.6% higher risk of having one or more ADEs per year, over USD 1000 in additional medical spending a year, 3.2 additional emergency department visits per 100 patients annually, and 2.1 more hospitalizations per 100 patients per year [36]. Ratigan et al. recently reported that although further evidence is needed to demonstrate that lowering the MRS results in a decrease in ADEs or death, interventions among patients on multiple medications that have higher MRS can enhance medication safety [54]. In this case, the decrease in the MRS was attributed to the fact that DDI-associated risk was diminished with the implementation of the clinical interventions.\n\nLimitations must be considered while integrating PGx into routine clinical practice [55]. A lack of universal training to support health care professionals with the interpretation of PGx results and issues related to their incorporation in the electronic health record exists. Other factors, such as ethnicity, sex, smoking status, and comorbidities, can contribute to interpatient variability in medication response in addition to genetic information. This is an iterative approach, and assessing PGx results is only one of the components to complete a comprehensive medication review, because not all medications have PGx recommendations or supporting evidence available. Furthermore, even when limited evidence exists on the impact of genetic variants for some drugs, this does not necessarily indicate that there is a lack of clinical impact for specific patients based on their comprehensive environment and condition. PGx is a relatively new science that is currently experiencing significant growth and has generated much interest among the research community.\n\n5. Conclusions\n\nThis patient might have achieved pain and depression remission sooner if a comprehensive preemptive PGx testing review and multidrug interaction screening had been performed. PGx testing can help predict tolerability and response [56], thus potentially enabling a more safe, effective, and cost-effective treatment [57]. This case highlights the value of PGx testing supported by CDSS, and the role of pharmacists in identifying medication-related problems and optimizing drug therapy.\n\nAcknowledgments\n\nThe authors would like to thank Pamela Dow and Dana Filippoli for their comprehensive review and comments pertaining to the contents of this manuscript.\n\nSupplementary Materials\n\nThe following are available online at https://www.mdpi.com/article/10.3390/medicina57090955/s1, Table S1: Adapted CPIC Recommendations to Guide Hydrocodone Therapy Considering CYP2D6 Phenotype, Table S2: Adapted DPWG Recommendations to Guide Metoprolol Therapy Considering CYP2D6 Phenotype, Table S3: Adapted DPWG Recommendations to Guide Duloxetine Therapy Considering CYP2D6 Phenotype. References [58,59] are cited in the supplementary materials.\n\nClick here for additional data file.\n\nAuthor Contributions\n\nWriting—original draft preparation, N.M.D.T.-P.; writing—review and editing, N.M.D.T.-P., A.M., D.T., J.T., N.S.A. and V.M.; supervision, V.M. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nThis case study was granted a determination of “exempt” from the Biomedical Research Alliance of New York (BRANY) Internal Review Board (file #21-15-105-427) (6 June 2021).\n\nInformed Consent Statement\n\nInformed consent was obtained from all subjects involved in the study.\n\nData Availability Statement\n\nThe data presented in this study are available in the article.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nmedicina-57-00955-t001_Table 1 Table 1 Current patient’s medication list at the time of the PGx testing.\n\nCondition\tMedication\tDose\tFrequency\tRoute of Administration\t\nChronic pain\tHydrocodone/acetaminophen\t7.5/325 mg\tFour times daily as needed for pain\tPO\t\nAcetaminophen\t650 mg\tThree times daily as needed for pain\tPO\t\nGabapentin\t600 mg\tThree times daily\tPO\t\nDiclofenac 1%\t2 g\tFour times daily as needed for pain\ttopical\t\nMethyl salicylate/menthol/camphor\n4%/30%/10%\t1 application\tTwice daily as needed for muscle pain\ttopical\t\nLidocaine 4%\t1 patch\tDaily as needed for pain\ttopical\t\nMDD\tDuloxetine\t30 mg\tTwice daily\tPO\t\nHypertension with heart failure\tAmlodipine\t5 mg\tDaily\tPO\t\nMetoprolol tartrate\t100 mg\tTwice daily\tPO\t\nValsartan\t320 mg\tDaily\tPO\t\nClonidine\t0.1 mg\tDaily\tPO\t\nFurosemide\t40 mg\tDaily\tPO\t\nAtrial Fibrillation\tApixaban\t5 mg\tTwice daily\tPO\t\nDronedarone\t400 mg\tTwice daily\tPO\t\nGout\tAllopurinol\t300 mg\tDaily\tPO\t\nHypothyroidism\tLevothyroxine\t88 mcg\tDaily\tPO\t\nType 2 diabetes mellitus\tInsulin aspart\t26 units\tThree times daily before meals\tSC\t\nInsulin glargine\t20 units\tDaily\tSC\t\nGERD\tPantoprazole\t40 mg\tDaily\tPO\t\nInsomnia\tMelatonin\t5 mg\tDaily\tPO\t\nDiarrhea\tLoperamide\t2 mg\tFour times daily as needed for diarrhea\tPO\t\nNausea\tOndansetron\t4 mg\tFour times daily as needed for nausea\tPO\t\nCandidiasis\tNystatin\t10,000 unit/gram\tFour times daily as needed for skin irritation\tPO\t\nSupplements\tCalcitriol\t0.25 mcg\tDaily\tPO\t\nCholecalciferol\t2000 units\tDaily\tPO\t\nIron carbonyl/ ascorbic acid\t65/125 mg\tDaily\tPO\t\nAbbreviations: GERD: Gastroesophageal Reflux Disorder; MDD: Major Depression Disorder; PO: Oral; SC, subcutaneous.\n\nmedicina-57-00955-t002_Table 2 Table 2 Primary care provider care—reported analgesic and antidepressant trials after PACE enrollment.\n\nMedication\tPrior to Nov/2020\tNov/2020\tDec/2020\tJan/2021\tFeb/2021\n(Post-PGx)\t\nAnalgesic\t\nGabapentin\t1200 mg twice daily + 600 mg daily\t\t\t\n\t600 mg three times daily\t\t\n\t300 mg twice daily\t\nTramadol\t50 to 100 mg\nthree times daily as needed\t\t\t\nHydrocodone/\nacetaminophen\t\t5/325 mg\nfour times daily as needed\t\t\t\n\t7.5/325 mg four times daily as needed\t\t\nMorphine\t\t7.5 to 15 mg\nthree times daily as needed\t\nAcetaminophen\t\t650 mg three times daily as needed\t\nLidocaine patch 4% transdermal\t\t1 patch daily as needed\t\nDiclofenac gel 1% (topical)\t2 g four times daily as needed\t\nMethyl salicylate/menthol/camphor cream 4–30%–10% (topical)\tApply twice daily as needed for muscle pain\t\nAntidepressant\t\nDuloxetine\t60 mg daily + 30 mg at bedtime\t\t\n\t30 mg twice daily\t\t\nDesvenlafaxine\t\t50 mg daily\t\nShading in Table 2 corresponds to the time frame that medications were prescribed in the patient’s drug regimen.\n\nmedicina-57-00955-t003_Table 3 Table 3 Patient’s PGx results.\n\nGene.\tResult\tPhenotype\t\nCYP1A2\t*1F|*1F\tNormal Metabolizer (Possible Rapid Metabolizer) †\t\nCYP2C9\t*1|*1\tNormal Metabolizer (NM)\t\nCYP2C19\t*1|*17\tRapid Metabolizer (RM)\t\nCYP2D6\t*1|*4\tIntermediate Metabolizer (IM)\t\n‡ CYP3A4\t*1|*22\tUndetermined\t\nCYP3A5\t*3|*3\tPoor Expresser\t\nAbbreviations: PGx: Pharmacogenomics, CYP: Cytochrome P450. † Common variants in CYP1A2 gene reflect its inducibility. CYP1A2 genetic variations, without the presence of induction (e.g., smoking, concomitant CYP1A2 inducers), have not been demonstrated to clinically alter the activity of CYP1A2 [37]. ‡ CYP3A4 gene shows some genetic variations and most variants have not been demonstrated to clinically alter the activity of CYP3A4. Many of the variants are extremely rare, making it difficult to derive a phenotype based on genetic results [38].\n\nmedicina-57-00955-t004_Table 4 Table 4 Summary of binding affinity (strength represented by color gradient) for various CYP isoforms and the percent of drug elimination by these respective CYP metabolic pathways pre- and post-PGx intervention) †.\n\nPre-PGx Clinical Interventions\tPost-PGx Clinical Interventions\t\nSubstance\tCYP1A2\tCYP2D6\tCYP3A4\tSubstance\tCYP1A2\tCYP2D6\tCYP3A4\t\nAcetaminophen\t15%\t\t\tAcetaminophen\t15%\t\t\t\nAmlodipine\t\t\t30%\tAmlodipine\t\t\t30%\t\nApixaban\t\t\t50%\tApixaban\t\t\t50%\t\nDuloxetine\t70%\t30%\t\tDesvenlafaxine\tNON-CYP\t\nDronedarone\t\t\t84%\tDronedarone\t\t\t84%\t\nHydrocodone\t\t10% ‡\t40%\tMorphine\tNON-CYP\t\nLoperamide\t\t\t65%\tLoperamide\t\t\t65%\t\nMelatonin\t60%\t\t\tMelatonin\t60%\t\t\t\nMetoprolol\t\t75%\t\tCarvedilol\t\t60%\t\t\nOndansetron\t20%\t\t35%\tOndansetron\t20%\t\t35%\t\nAbbreviations: CYP: Cytochrome P450, PGx: Pharmacogenomics. † Only CYP-metabolized oral drugs are displayed. ‡ Prodrug. Legend: MedWise® depicts the various degrees of binding affinity of a substrate for a specific enzyme using different colors, such as: light yellow (weak affinity) and dark yellow (moderate affinity). The percentages listed correspond to the use of the metabolic pathway for the substrate.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. van Westrhenen R. Aitchison K.J. Ingelman-Sundberg M. Jukić M.M. Pharmacogenomics of antidepressant and antipsychotic treatment: How far have we got and where are we going? Front. Psychiatry 2020 11 94 10.3389/fpsyt.2020.00094 32226396\n2. Relling M.V. Evans W.E. Pharmacogenomics in the clinic Nature 2015 526 343 350 10.1038/nature15817 26469045\n3. Bain K.T. Matos A. Knowlton C.H. McGain D. Genetic variants and interactions from a pharmacist-led pharmacogenomics service for PACE Pharmacogenomics 2019 20 709 718 10.2217/pgs-2019-0047 31368837\n4. 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"fulltext_license": "CC BY",
"issn_linking": "1010-660X",
"issue": "57(9)",
"journal": "Medicina (Kaunas, Lithuania)",
"keywords": "CYP2D6; antidepressants; case report; clinical decision support system (CDSS); depression; opioids; pain; pharmacogenetics; pharmacogenomics (PGx); β-blockers",
"medline_ta": "Medicina (Kaunas)",
"mesh_terms": "D019389:Cytochrome P-450 CYP2D6; D006801:Humans; D004364:Pharmaceutical Preparations; D010595:Pharmacists; D010597:Pharmacogenetics; D011788:Quality of Life",
"nlm_unique_id": "9425208",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34577878",
"pubdate": "2021-09-10",
"publication_types": "D002363:Case Reports",
"references": "19724774;31099895;33994532;33387367;25519488;20338816;25974703;26075211;24673480;28705252;8864155;28229443;23444277;9280405;27997040;32513518;16582045;27864204;24637943;29719381;14612481;15037866;20205659;29109603;24996484;24745854;32226396;18253145;32726152;12755648;29282363;26469045;31368837;24264719;12017467;29460415;7768074;20807350;22231995;32443719;28364995;30317846;32301649;19817501;34067027;31455423;28699646;28182127;21599570;21642822;18629377;24789696;22738351;19933955",
"title": "Pharmacist-Led Medication Evaluation Considering Pharmacogenomics and Drug-Induced Phenoconversion in the Treatment of Multiple Comorbidities: A Case Report.",
"title_normalized": "pharmacist led medication evaluation considering pharmacogenomics and drug induced phenoconversion in the treatment of multiple comorbidities a case report"
} | [
{
"companynumb": "US-CADILA HEALTHCARE LIMITED-US-ZYDUS-070866",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DULOXETINE"
},
"drugadditi... |
{
"abstract": "Aims: To describe the incidence and identify prognostic factors of central nervous system (CNS) adverse events (AEs) and any AEs (CNS, skin rash, or fracture) and evaluate the healthcare resource utilization (HCRU), direct medical costs, and therapy discontinuation associated with these AEs among non-metastatic prostate cancer (nmPC) patients who received secondary hormone therapies.Methods and results: nmPC patients who had initiated secondary hormonal therapy with enzalutamide, bicalutamide, or abiraterone ≥1 year after androgen deprivation therapy (ADT) were identified in the MarketScan database. Survival analyses were used to describe the incidence of CNS or any AEs. Annual HCRU and costs were compared across patient groups (CNS AE vs no CNS AE; any AE vs no AE) using propensity score weighted generalized linear models. Multivariate Cox proportional hazards models were used to identify AE predictors and compare risks of discontinuation.Results: The analysis included 532 patients who initiated secondary hormonal therapies, among whom 201 (38%) and 244 (46%) experienced a CNS AE and any AE, respectively. Median times to CNS AE and any AE from therapy initiation were 17.90 and 11.00 months, respectively. Predictors of any AE were any AE in the baseline period (≤6 months before starting therapy), Charlson Comorbidity Index (CCI) score (1 vs 0), surgical castration, and older age. Predictors of CNS AEs were CNS AE in the baseline period and CCI score (1 vs 0). CNS and any AEs were associated with significantly higher HCRU. CNS AEs were associated with significantly higher incremental total medical costs ($18,522). CNS AEs and any AEs significantly increased therapy discontinuation risk by 48% and 38%, respectively.Conclusions: AEs increase the economic burden and therapy discontinuation among nmPC patients receiving secondary hormonal therapies subsequent to ADTs. These patients should be carefully evaluated for AEs to reduce therapy discontinuation, HCRU, and direct medical costs.",
"affiliations": "Pharmerit International, Bethesda, MD, USA.;Pharmerit International, Bethesda, MD, USA.;Pharmerit International, Bethesda, MD, USA.;Bayer Healthcare Pharmaceuticals, Whippany, NJ, USA.;Pharmerit International, Bethesda, MD, USA.;Bayer Healthcare Pharmaceuticals, Whippany, NJ, USA.;University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.",
"authors": "Shah|Anuj|A|;Shah|Ruchit|R|;Kebede|Nehemiah|N|;Mohamed|Ateesha|A|;Botteman|Marc|M|http://orcid.org/0000-0003-2808-7163;Waldeck|Reg|R|;Hussain|Arif|A|",
"chemical_list": "D000726:Androgen Antagonists",
"country": "England",
"delete": false,
"doi": "10.1080/13696998.2019.1705313",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1369-6998",
"issue": "23(4)",
"journal": "Journal of medical economics",
"keywords": "C14; Enzalutamide; I10; abiraterone acetate; advanced prostate cancer; adverse events; bicalutamide; discontinuation; healthcare costs",
"medline_ta": "J Med Econ",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists; D002490:Central Nervous System; D017281:Cost of Illness; D016208:Databases, Factual; D064420:Drug-Related Side Effects and Adverse Reactions; D017048:Health Care Costs; D020249:Hormone Replacement Therapy; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011471:Prostatic Neoplasms; D016019:Survival Analysis; D014481:United States",
"nlm_unique_id": "9892255",
"other_id": null,
"pages": "330-346",
"pmc": null,
"pmid": "31835965",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Real-world incidence and burden of adverse events among non-metastatic prostate cancer patients treated with secondary hormonal therapies following androgen deprivation therapy.",
"title_normalized": "real world incidence and burden of adverse events among non metastatic prostate cancer patients treated with secondary hormonal therapies following androgen deprivation therapy"
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"companynumb": "US-JNJFOC-20190709859",
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"occurcountry": "US",
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"actiondrug": "5",
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"activesubstancename": "ABIRATERONE ACETATE"
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"abstract": "Calcium carbonate is often used to relieve Gastroesophageal Reflux Disease (GERD) in pregnant patients. This report describes a potentially serious complication.\nA pregnant female presented at 34 weeks gestation with abdominal pain, nausea, and vomiting. Home medications included an unquantifiable amount of calcium carbonate 500 mg due to constant consumption for GERD. Laboratory findings included elevated calcium, amylase, lipase, and triglyceride level. Pancreatitis was diagnosed and abdominal ultrasound excluded gallstones. Despite hydration, lipase rose and emergency cesarean section was performed. Hypercalcemia was managed by intravenous fluid administration. After delivery, pancreatitis resolved.\nPancreatitis developed in pregnant patient with hypercalcemia due to excessive calcium carbonate ingestion and resolved after delivery of the fetus, fluid resuscitation, and return of calcium level to normal.",
"affiliations": "1 Pharmacy Department, Methodist Le Bonheur Healthcare, Germantown, TN, USA.;3 Greenville Health System - Hospitalist Division, Greenville Memorial Hospital, Greenville, SC, USA.;4 Pharmacy Department, Saint Luke's Hospital, Kansas City, MO, USA.",
"authors": "Trezevant|May S|MS|;Winton|John C|JC|;Holmes|Ashley K|AK|",
"chemical_list": "D002119:Calcium Carbonate",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190017745410",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "32(2)",
"journal": "Journal of pharmacy practice",
"keywords": "calcium carbonate; hypercalcemia; pancreatitis",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000328:Adult; D002119:Calcium Carbonate; D002585:Cesarean Section; D005260:Female; D005764:Gastroesophageal Reflux; D006801:Humans; D006934:Hypercalcemia; D010195:Pancreatitis; D011247:Pregnancy; D011248:Pregnancy Complications",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "225-227",
"pmc": null,
"pmid": "29241388",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypercalcemia-Induced Pancreatitis in Pregnancy Following Calcium Carbonate Ingestion.",
"title_normalized": "hypercalcemia induced pancreatitis in pregnancy following calcium carbonate ingestion"
} | [
{
"companynumb": "PHHY2019US121875",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "POTASSIUM PHOSPHATE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe aim was to report the aqueous humor moxifloxacin concentration and proteome profile of an individual with bilateral uveitis-like syndrome with pigment dispersion.\n\n\nMETHODS\nMultiple reactions monitoring mass spectrometry quantified the aqueous concentration of moxifloxacin in the affected individual. Shotgun proteomic analysis performed via liquid chromatography tandem mass spectrometry (LC-MS/MS) defined the protein profile in the affected individual and unaffected control samples.\n\n\nRESULTS\nMoxifloxacin was present at higher than expected levels in aqueous humor 18 days following oral administration. One-third of the proteins were identified by significantly lower spectral counts in the aqueous of the individual with moxifloxacin associated uveitis compared to the unaffected control.\n\n\nCONCLUSIONS\nMoxifloxacin was detected in aqueous humor 18 days following the completion of oral administration. These results suggest that moxifloxacin toxicity may be responsible for the uveitis-like syndrome with pigment dispersion syndrome induced by moxifloxacin therapy.",
"affiliations": "Department of Ophthalmology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.;Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.;Jamaica Hospital Medical Center, Queens, New York, USA.;Research Integrity and Compliance Review Office, Colorado State University, Colorado, USA.;Massachusetts Eye Research and Surgery Institution, Cambridge, Massachusetts, USA.;Massachusetts Eye Research and Surgery Institution, Cambridge, Massachusetts, USA.",
"authors": "Hinkle|David M|DM|;Kruh-Garcia|Nicole A|NA|;Kruh|Jonathan N|JN|;Broccardo|Carolyn|C|;Doctor|Priyanka|P|;Foster|C Stephen|CS|",
"chemical_list": null,
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1874364101711010107",
"fulltext": "\n==== Front\nOpen Ophthalmol JOpen Ophthalmol JTOOPHTJThe Open Ophthalmology Journal1874-3641Bentham Open 28694894TOOPHTJ-11-10710.2174/1874364101711010107ArticleMoxifloxacin Concentration and Proteomic Analysis of Aqueous Humor in Human Uveitis Associated with Oral Moxifloxacin Therapy Hinkle David M 1*Kruh-Garcia Nicole A 2Kruh Jonathan N 3Broccardo Carolyn 4Doctor Priyanka 5Foster C Stephen 567\n1 Department of Ophthalmology, University of Massachusetts Medical School, Worcester, Massachusetts, USA\n2 Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA,\n3 Jamaica Hospital Medical Center, Queens, New York, USA\n4 Research Integrity and Compliance Review Office, Colorado State University, Colorado, USA\n5 Massachusetts Eye Research and Surgery Institution, Cambridge, Massachusetts, USA\n6 Ocular Inflammation and Uveitis Foundation, Cambridge, Massachusetts, USA\n7 Harvard Medical School, Boston, Massachusetts, USA* Address correspondence to this author at the UMass Memorial Eye Center, 281 Lincoln Street, Worcester, MA 01605, USA; Tel: 508-334-4629, Fax 508-334-4655, E-mail: david.hinkle@umassmemorial.org12 6 2017 2017 11 107 116 30 6 2016 08 12 2016 02 4 2017 © 2017 Hinkle et al.2017Bentham Open.This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Purpose:\nThe aim was to report the aqueous humor moxifloxacin concentration and proteome profile of an individual with bilateral uveitis-like syndrome with pigment dispersion.\n\nMethods:\nMultiple reactions monitoring mass spectrometry quantified the aqueous concentration of moxifloxacin in the affected individual. Shotgun proteomic analysis performed via liquid chromatography tandem mass spectrometry (LC-MS/MS) defined the protein profile in the affected individual and unaffected control samples.\n\nResults:\nMoxifloxacin was present at higher than expected levels in aqueous humor 18 days following oral administration. One-third of the proteins were identified by significantly lower spectral counts in the aqueous of the individual with moxifloxacin associated uveitis compared to the unaffected control.\n\nConclusion:\nMoxifloxacin was detected in aqueous humor 18 days following the completion of oral administration. These results suggest that moxifloxacin toxicity may be responsible for the uveitis-like syndrome with pigment dispersion syndrome induced by moxifloxacin therapy.\n==== Body\nINTRODUCTION\nFluoroquinolones are a broad spectrum antibiotic class indicated for the treatment of bacterial infections including acute exacerbation of chronic bronchitis, complicated intra-abdominal abscess, community acquired pneumonia, acute sinusitis and uncomplicated skin infections. Fluoroquinolone antibiotics inhibit DNA gyrase activity, thereby disrupting bacterial DNA replication and transcription. Adverse drug reactions unique to quinolones include tendinitis, tendon rupture, peripheral neuropathy and diplopia. Uveitis was not reported in premarketing trials in the package inserts. Following the initial report of bilateral panuveitis associated with oral moxifloxacin therapy in 2004, there have been additional reports of a bilateral uveitis-like syndrome with anterior chamber pigment dispersion and iris transillumination [1-3].\n\nWe report the moxifloxacin concentration and proteomic analysis of aqueous humor obtained during the acute phase of bilateral pigment dispersion with elevated intraocular pressure and subsequent development of diffuse iris transillumination.\n\nThe goals of this study were to establish if moxifloxacin is sequestered in aqueous humor following systemic administration and to determine whether the aqueous proteome is altered by the condition. While this phenomenon has been described clinically, the full characterization of aqueous humor to corroborate the observation has not been published. A two-pronged approach using mass spectrometry was employed to perform both relative quantification of moxifloxacin, and protein content within aqueous of affected and control eyes.\n\nMETHODS\nA 71 year old Caucasian female developed bilateral painful red eyes with photophobia 14 days following inpatient treatment for pneumonia with moxifloxacin (Bayer HealthCare Pharmaceuticals, San Francisco, CA) 400mg daily. There was no past history of uveitis, glaucoma or pigment dispersion. Best corrected visual acuity was 20/200 bilaterally (LogMAR 1.00). Microcystic corneal edema secondary to elevation of intraocular pressure greater than 40mmHg in both eyes developed despite maximal topical glaucoma therapy and oral acetazolamide 500 mg twice daily. Moxifloxacin associated uveitis was suspected due to bilateral, extensive pigment dispersion present in the anterior chamber. Anterior chamber paracentesis for diagnostic and therapeutic purposes was performed 18 days following the last oral dose of moxifloxacin. A peripheral corneal paracentesis incision was made with a sterile 15 degree steel blade and 0.15 mL of aqueous fluid was harvested from the right eye (OD) and 0.27 mL was harvested from the left eye (OS) using a blunt 27 gauge cannula. Aqueous humor samples were stored frozen at -80 °C and transported on dry ice for quantification of moxifloxacin concentration and proteome analysis.\n\nUrgent bilateral glaucoma drainage device surgery was required due to intraocular pressure elevation greater than 40mmHg despite maximal medical therapy. Pigment dispersion persisted for more than one year with subsequent development of bilateral iris transillumination and cataracts in both eyes. Bilateral posterior synechiae were observed at the time of cataract surgery and the early post-operative course was complicated by formation of fibrin in the anterior chamber.\n\nOne unaffected patient consented to harvest of aqueous humor via corneal paracentesis immediately prior to cataract surgery (control). Written informed consent was obtained from each subject. This study was performed in accordance with the Declaration of Helsinki.\n\n\nMass Spectrometry Sample Preparation: Moxifloxacin quantification was performed for each of the three samples (OS, OD and control). Proteins were precipitated using 4 volumes of cold (-20 °C) methanol. Starting volumes isolated from patients were: 150 µL control, 150 µL OD and 270 µL OS. Samples were incubated for 30 min at -80 °C and centrifuged for 10 min at 10000 rpm at 4 °C. Supernatants were dried and re-suspended in TQ-S Buffer A (0.1% formic acid in water) for multiple reaction monitoring (MRM) mass spectrometry analysis. The protein pellets were then analyzed with LTQ shotgun proteomic analysis.\n\nProtein pellets were re-suspended in 10 mM ammonium bicarbonate (ambic) and quantified by micro bicinchoninic acid assay (mBCA). The total proteins in the samples are as follows: Control (11.3 µg), OD (32.8 µg) and OS (177.7 µg). To normalize the protein samples, only 10 µg were used in the protein analysis. Samples were digested with trypsin via in-solution protocol as previously described [4]. Briefly, samples were denatured in 6 M guanidine hydrochloride, reduced with 10 mM DTT and alkylated with 100 mM iodoacetamide. After overnight micro-dialysis in 10 mM ammonium bicarbonate, the samples were digested with trypsin (1:50, trypsin:sample) in 10% acetonitrile (ACN) overnight at 37 °C. Digests were dried and re-suspended in LTQ loading buffer (3% ACN and 0.1% formic acid, in water). All digests were performed in de-plasticized tubes to reduce plastic polymer contamination.\n\n\nRelative Quantification of Moxifloxacin by Multiple Reaction Monitoring (MRM) Mass Spectrometry: All the analyses were performed on an LC-MS/MS system consisting of Waters nanoACQUITY UPLC coupled to a Waters Xevo TQ-S mass spectrometer fitted with TRIZAIC source. The instrument was operated in positive electrospray ionization mode using MassLynx V4.1 SCN810 (Waters, Milford, MA). Chromatography was performed on 150 μm × 50 mm TRIZAIC™ nanoTile packed with BEH C18 1.7 μm. Injections were 2 µl using partial loop mode. The initial solvent composition was 90% A (0.1% formic acid in water) and 10% B (0.1% formic acid in methanol). The mobile phase gradient was: 10-55% B from 0.25-1 min, 55-95% B from 1-15.5 min, 95-10% B from 15.5-16 min, and a hold at 10% B from 16-20 minutes. The flow rate was 3.06 µL/min and the column was maintained at 46 oC. The cone voltage was static at 50 V. The capillary voltage was 3.2 kV, source temperature was 100 oC, source offset was 50 V, and the collision gas was argon. Dwell time for all compounds was 0.830 s. Moxifloxacin parent mass to charge ratio (m/z) was determined to be 401.175. The two daughter ions monitored were m/z 358 and m/z 384, corresponding to the loss of CO2 and H20 respectively [5]. Collision energy necessary to generate the daughter species was determined to be 20 V (for the loss of CO2) and 30 V (for the loss of H20). Patient samples were randomized and injected in triplicate.\n\n\nMRM Data Analysis: Quantification of patient samples was done using linear regression against a standard curve in TargetLynxTM (Waters, Milford, MA). Curves were generated from the ophthalmic solution moxifloxacin in 0.5% HCI (Vigamox, Alcon, Fort Worth TX) utilizing the control patient sample as a representative background matrix. Eight concentrations ranged from 0.1 – 1000 nmol/ µL, and each sample was injected in triplicate from which one regression equation was generated per ion Fig. (1). The concentration of each daughter ion in Control, OD and OS sample was calculated based on this data (Table 1). Peak identification was performed using MassLynx software version 4.1. Upon examination and standardization of the peaks, the transition results were exported to ExcelTM (Microsoft, Redmond WA) for calculation of calibration curves (R2 values for each curve are shown in (Table 1), as well as determination of limits of detection (LOD) and quantitation (LOQ) for each transition [6, 7]. LOD = 3.3 (SD/S) and LOQ = 10 (SD/S), where SD is the standard deviation of y values and S is the slope of the calibration curve. SD of y was calculated in ExcelTM using the LINEST function (Table 2).\n\nMass Spectrometry of tryptic peptides. LC-MS/MS methods for proteomic analysis were previously published [7]. All samples were injected at a concentration of approximately 500 ng/µL. Peptides were purified and concentrated using an on-line enrichment column (Agilent Zorbax C18, 5 µm, 5×0.3 µm column, Agilent 1100 nanoHPLC,). Subsequent chromatographic separation was performed on a reverse phase nanospray column (Zorbax C18, 5 µm, 75 µm ID × 150 mm column). Samples were eluted into an LTQ linear ion trap (Thermo Scientific, Waltham, MA) using a flow rate of 300 nL/min with a linear gradient of acetonitrile. Mass spectra were recorded over a m/z range of 200–2000 Da using a dynamic exclusion limit of 2 MS/MS spectra of a given mass for 30 s (exclusion duration of 90 s). Compound lists of resulting spectra were generated using BioworksTM 3.0 software (Thermo Scientific) with intensity threshold of 5,000 and 1 scan/group. All the samples were run in triplicate.\n\n\nDatabase searching and Criteria for Protein Identification. All tandem mass spectra (.raw files) were extracted by LCQ_DTA.exe (Thermo Scientific) for subsequent loading into the Mascot (Matrix Science, London, UK; version: 2.3.02 Mascot MS/MS search engine or into Bioworks Browser (version 3.3.1 SP1) for subsequent analysis with Sequest (Thermo Finnigan, San Jose, CA; version SRF v.27, rev. 11) and X! Tandem (version CYCLONE 2010.12.01.1) [8]. All three search engines were used to query the Universal Protein Resource (UniProt) human database (created on 11/26/12) composed of 169776 entries including reverse proteins for false discovery calculation. All searches were performed assuming trypsin digestion, with a fragment ion mass tolerance of 1.5 Da, a parent ion tolerance of 2.5 Da. Oxidation of methionines (+16) and iodoacetamide derivative of cysteine residues (+57) were specified as variable modifications.\n\n All data was compiled using Scaffold (version 3.6.1, Proteome Software Inc., Portland, OR) in order to validate MS/MS based peptide and protein identification. Peptide identifications were accepted if established using the following scores: Mascot: Ion Identity: 0, Ion score +1, +2 and +3 all at 55; Sequest: DeltaCn: 0.06, XCorr +1, +2 and +3 at 1.05, 2.1 and 3.15, respectively; X! Tandem: -Log(E-Value): 2. Protein identifications were only accepted if established at greater than 99% probability and contained at least two identified peptides. Protein probabilities were assigned by the Protein Prophet algorithm [9]. False discovery rate (FDR) for proteins was calculated to be 3% at the protein level and 0.1% at the peptide level (Table 3). Raw and searched data files are accessible via http://proteomecentral.proteomexchange.org/cgi/GetDataset.\n\nRESULTS\nMRM method development on ophthalmic moxifloxacin solution afforded monitoring of the parent compound (m/z 401.175) and upon fragmentation, two daughter species, m/z 358 and m/z 384, corresponding to loss of CO2 and H20 respectively. Relative quantification of clinical samples was based on dosage response curves generated from this solution Figs. (1 and 2).\n\n As expected, the control sample did not contain detectable levels of moxifloxacin. The transition ion m/z 358 was detected well above both the LOD and LOQ in aqueous humor samples from both affected eyes. This data was used to quantitate the amount of moxifloxacin in these samples. The transition ion m/z 384 was below the LOQ and could not be used to quantitate the amount of moxifloxacin, however, since the concentration was above that of the LOD we can use it as a confirmatory ion, enhancing the confidence of the detection. The levels determined by this technique, while not absolute, are consistent with the level of moxifloxacin calculated to be present roughly 2.5 days post administration, rather than 18 days, based on the previously reported intraocular concentration and pharmacokinetics of orally administered moxifloxacin.\n\nThe protein fraction of aqueous was analyzed by shotgun tandem mass spectrometry. Thirty-three proteins were confidently in aqueous of affected eyes and 32 proteins in an unaffected control eye. Ten proteins were significantly reduced in affected eyes compared to control (Table 4).\n\nDISCUSSION\nMore than 50 cases of bilateral simultaneous uveitis-like syndrome with pigment dispersion and iris transillumination have been reported following systemic administration of moxifloxacin or levofloxacin [1, 2, 10]. Because iris transillumination is frequently observed in the light colored irides of patients with herpetic uveitis, some patients with uveitis following oral fluoroquinolone therapy were treated with oral anti-viral therapy without favorable effect on the course of the condition [10]. Furthermore, qualitative polymerase chain reaction analysis of aqueous humor obtained from 4 of 5 patients did not demonstrate amplification of DNA for herpes simplex, herpes zoster, cytomegalovirus or Epstein-Barr virus genomes [2, 10]. One individual with prior history of uveitis had PCR evidence of HSV viral genome in aqueous [2]. To our knowledge, none of the previously reported individuals were tested for, nor exhibited findings typical of, human herpes virus 6 (HHV6) associated uveitis, i.e. panuveitis in association with optic papillitis; however, it appears unlikely that a virus in the herpes family is the causative agent for the condition based on disparity between the clinical signs and lack of therapeutic response to empiric antiviral therapy.\n\nLarge, retrospective cohort studies have yielded conflicting results regarding the risk of uveitis and the use of oral fluoroquinolones. In one cohort, oral administration of fluoroquinolones confered an adjusted relative risk of 3.53 for development of uveitis within the subsequent 30 days [11]. The relative risk of uveitis was also increased in patients receiving oral macrolide and beta lactam antibiotics. The authors postulated systemic infectious disease, rather than the antibiotic administered, might be the cause of uveitis observed in these cases [11]. A second case-control study reported similar adjusted rate ratios of 2.98, 1.96 and 1.26 for the development of uveitis in first time users of moxifloxacin, ciprofloxacin and levofloxacin, respectively, compared to age and gender matched controls [12]. A third study calculated the hazard of uveitis development was not elevated after a fluoroquinolone prescription compared with the hazard of uveitis following a beta-lactam prescription and identified the risk for uveitis-associated systemic illnesses as a potential source of bias in the previous studies [13].\n\nTugal-Tutkin termed the condition bilateral acute iris transillumination (BAIT) and postulates it may be caused by an emerging respiratory pathogen rather than an adverse drug reaction because antibiotic therapy was not known to precede the condition in 38% of 26 cases [14]. Prior moxifloxacin therapy was identified in 35% of cases and antibiotics other than flouroquinolones were identified in 27% of cases. Tugal-Tutkin also described bilateral acute depigmentation of the iris (BADI), in contrast to BAIT which preferentially affects the iris pigment epithelium, a condition with predilection for loss of iris stromal pigmentation which is reversible in some cases [15]. BAIT may be a severe, irreversible form of BADI. Unilateral depigmentation of the iris was observed by one the authors (PD) following ipsilateral topical moxifloxacin therapy in an individual from India suggesting that local moxifloxacin therapy may rarely produce similar ocular findings (Fig. 2A, B).\n\nOrally administered moxifloxacin crosses the blood ocular barrier of non-inflamed human eyes and achieves concentrations of 1.58 +/-0.80µg/mL within 4 hours of administration of a single 800mg dose [16]. Rabbit studies of intravitreal moxifloxacin clearance report a vitreous half-life of 1.72 hours [17]. Because the serum half-life of orally administered moxifloxacin is 12 hours, moxifloxacin should be undetectable in human serum 5 days following oral administration [18]. Assuming human pharmacokinetics is comparable to the rabbit model, moxifloxacin should be undetectable in vitreous humor within 12 hours of a single intravitreal injection. Although aqueous clearance of antibiotics and other pharmaceuticals is typically more rapid than vitreous clearance in animals and humans, vitreous clearance of moxifloxacin may be slower in humans than animals. If we assume elimination of moxifloxacin from human aqueous is equivalent to first order elimination of moxifloxacin from rabbit vitreous then the concentration of moxifloxacin present in aqueous on the last day of systemic administration can be calculated as 3023 grams using the formula:\n\nInitial concentration = Final concentration / 2n where n = half life\n\nThis amount vastly exceeds the total systemic dose (4 grams) the patient received. There are several possible explanations for persistent moxifloxacin detected in aqueous humor 18 days following oral administration. Antibiotic clearance is generally believed to be delayed in inflamed eyes. Supra-therapeutic levels might result despite following recommended dosing due to impaired drug metabolism and elimination with resultant toxicity and shedding of iris and ciliary body pigment epithelium. Affected individuals may have a heretofore unrecognized enzyme deficiency impairing moxifloxacin elimination. To our knowledge, only one case exhibited co-morbid systemic symptoms of moxifloxacin toxicity [10]. Alternatively, moxifloxacin clearance from the anterior chamber may be impaired by the tremendous amount of pigment dispersion blocking aqueous egress through the trabecular meshwork. Serum moxifloxacin concentration was not determined in our patient nor reported in any prior publications, thus it is not clear whether persistent elevation of moxifloxacin is a local or systemic phenomenon\n\nKnape et al. observed only phakic individuals have been reported to develop BAIT and suggest that drug may be trapped behind the iris by posterior synechiae which they confirmed via optical coherence tomography in one patient [19]. Not all patients with the condition have posterior synechiae [10]. One would expect the pupil would need to be completely secluded in order to sequester drug or aqueous in the posterior chamber. Pupil seclusion should result in iris bombe and secondary angle closure but this has not been observed. Conversely, some patients have abnormally deep anterior chambers with reverse papillary block or iris concavity configuration similar to the typical pigment dispersion patient [3, 18].\n\nIntraocular injection of moxifloxacin is advocated for the prophylaxis and treatment of post-operative endophthalmitis. There are no reports of toxicity with single dose intraocular use to date. Multiple intravitreal injections (mean number injections was 6) of moxifloxacin 165 µg/0.1mL combined with pegaptanib (Macugen, Valeant Pharmacueticals, Montreal, QC) every 6 weeks as treatment for wet macular degeneration was well tolerated in 80 eyes of 65 human patients during 13.2 months median follow-up [20].\n\nToxicity studies have not detected adverse effects during the 14 days following intravitreal injection of doses up to 160 µg /0.1mL; however, a dose of 320 µg/0.1mL led to marked decreases in ERG findings in rabbits [21]. Concentrations higher than 150 µg/mL have adverse effects on primary retinal pigment epithelial cells in culture and concentrations of 500 µg/mL led to occasional, isolated retinal necrosis in mice [22, 23].\n\nPhototoxicity is a well-known class effect of fluoroquinolones which has been postulated to play a role in the pathogenesis of iris atrophy; unlike other fluoreoquinolones, phototoxicity is not a reported adverse effect of oral moxifloxacin [2, 24]. Phototoxicity does not explain the selective involvement of iris pigment epithelium. The ciliary body is also presumed to be involved given the loss of accommodation experienced by young individuals with BAIT [10]. Retinal pigment epithelium does not demonstrate any abnormality on clinical examination. To our knowledge, retinal electrophysiologic studies have not been performed on any affected individuals. Dermal phototoxicity has not been reported as a feature of BAIT. The failure to determine serum moxifloxacin concentration at the time of aqueous harvest is a weakness of this study.\n\nBecause the few PCR studies performed in patients previously afflicted with this condition were unrevealing, we performed proteome analysis in an effort to further elucidate the pathogenesis of the condition [2, 10]. Interpretation of results of proteomic analysis of the human eye in normal and disease states is limited by our incomplete, albeit rapidly expanding, knowledge. The aqueous humor proteome of otherwise healthy patients undergoing cataract surgery was initially reported to contain at least 54 unique proteins, comprised of albumin-bound, albumin-depleted fractions and 8 proteins common to both fractions [25]. A subsequent study of eyes undergoing cataract surgery identified 676 unique aqueous proteins [26]. Depletion of albumin, the dominant protein identified in these samples, as well as fractionation of the protein content of the aqueous humor would enhance the number of proteins identified in this experiment. The authors speculate that not only would additional proteins be revealed by such processes, but additional peptides would be identified—further increasing our confidence in the proteins identified. Due to the confounding level of albumin in this data set, it is unclear whether moxifloxacin present in the aqueous resulted in the low spectral counts for one-third of proteins identified. To our knowledge, there are not reports of aqueous proteome analysis in human idiopathic uveitis and the lack of a patient with idiopathic uveitis serving as a control is a weakness of this study.\n\nA second limitation of proteome analysis methods is that interpretation of shotgun proteomic data is hampered by the so called ‘protein inference problem’; the same peptide sequence can be present in multiple different proteins or isoforms leading to ambiguities in determining protein identity [27]. Proteome analysis did not aid in determining the etiology of the condition but as methods continue to evolve, this technique may be a useful adjunct in ascertaining the etiology of idiopathic ocular inflammatory conditions including BADI and BAIT.\n\nACKNOWLEDGEMENTS\nDeclared none.\n\nETHICS APPROVAL AND CONSENT TO PARTICIPATE\nNot applicable.\n\nHUMAN AND ANIMAL RIGHTS\nNo animals were used for studies but the ocular fluid of two humans was used as the basis for this research.\n\nCONSENT FOR PUBLICATION\nConsent was obtained, IRB approval was waived.\n\nCONFLICT OF INTEREST\nThe authors confirm that this article content has no conflict of interest.\n\nFig. (1) Calibration curve for both transitions of moxifloxacin determined from response in matrix. See (Table 1) for results.\n\nFig. (2) Slit lamp photomicrograph demonstrating progressive depigmentation of the iris stroma of the right eye (Panel A photo taken in 2012 and Panel B taken in 2013) in an individual following topical administration of moxifloxacin.\n\nTable 1 Results of calibration curve calculation and determination of limits of detection and quantitation.\n\n\nIon\n\t\nR2\n\t\nSD of y\n\t\nLOD (ng)\n\t\nLOQ (ng)\n\t\n358.00\t0.98\t51.42\t25.83\t86.11\t\n384.00\t0.97\t63.29\t12.34\t41.13\t\nTable 2 Concentration of moxifloxacin in the patient samples. The transition ion m/z 358 was well above both the LOD and LOQ in both of the samples and therefore was used to quantitate the amount of moxifloxacin in the original more dilute samples. The transition ion m/z 384 was below the LOQ and could not be used to quantitate the amount of moxifloxacin, however since the concentration was above that of the LOD we can use it as a confirmatory ion, enhancing the confidence of the detection.\n\n\nSample\n\t\nIon\n\t\nRole\n\t\ncalculated concentration injected (ng/µL)\n\t\nconcentration of moxifloxacin in sample (ng/µL)\n\t\nOD\t358.00\tQuantitation\t268.32\t44.72\t\nOD\t384.00\tConfirmation\t20.73\tbelow LOQ\t\nOS\t358.00\tQuantitation\t101.33\t93.82\t\nOS\t384.00\tConfirmation\t27.38\tbelow LOQ\t\nTable 3 List of proteins identified in the control and two patient samples. Three technical replicates were performed for each biological sample and the spectral counts determined for each is listed. A single protein which matched to the reverse database (in bold) is responsible for the FDR rate of 3%.\n\n#\tIdentified Proteins (33)\t\nSamples and Technical Replicates\n\t\n\nControl\n\t\nOD\n\t\nOS\n\t\n\n1\n\t\n2\n\t\n3\n\t\n1\n\t\n2\n\t\n3\n\t\n1\n\t\n2\n\t\n3\n\t\n1\tSerum albumin\t1065\t1008\t1158\t1157\t1412\t1049\t1418\t1253\t1062\t\n2\tSerotransferrin\t197\t241\t231\t99\t125\t47\t112\t115\t41\t\n3\tAlpha-1-antitrypsin\t13\t9\t12\t24\t23\t17\t23\t16\t20\t\n4\tIg gamma-1 chain C region\t22\t31\t17\t11\t12\t8\t11\t8\t3\t\n5\tProstaglandin-H2 D-isomerase\t28\t37\t29\t12\t8\t1\t3\t11\t2\t\n6\tTransthyretin\t15\t16\t12\t24\t25\t7\t20\t13\t7\t\n7\tIg kappa chain C region\t13\t22\t24\t8\t7\t4\t16\t6\t2\t\n8\tAlpha-1-acid glycoprotein 1\t9\t9\t9\t20\t14\t8\t14\t10\t7\t\n9\tHemopexin\t7\t7\t7\t22\t18\t8\t9\t6\t1\t\n10\tIg lambda-2 chain C regions\t15\t17\t13\t12\t8\t1\t15\t16\t6\t\n11\tComplement component C4B\t8\t8\t8\t8\t7\t4\t5\t9\t3\t\n12\tPigment epithelium-derived factor\t16\t17\t14\t3\t5\t1\t5\t3\t2\t\n13\tVitamin D-binding protein\t2\t4\t4\t6\t6\t6\t8\t10\t5\t\n14\tCeruloplasmin\t7\t8\t12\t2\t3\t1\t1\t1\t1\t\n15\tAlpha-1B-glycoprotein\t1\t7\t8\t5\t4\t3\t5\t9\t6\t\n16\tIsoform 2 of Clusterin\t14\t5\t4\t8\t7\t2\t4\t6\t3\t\n17\tApolipoprotein A-I\t3\t0\t5\t8\t3\t4\t5\t7\t3\t\n18\tF-box/SPRY domain-containing protein 1\t0\t1\t0\t2\t2\t1\t0\t0\t0\t\n19\tZinc-alpha-2-glycoprotein\t6\t3\t6\t2\t3\t2\t3\t4\t1\t\n20\tHemoglobin subunit beta\t7\t9\t9\t0\t0\t0\t2\t0\t0\t\n21\tAlpha-1-antichymotrypsin His-Pro-less\t5\t2\t3\t10\t11\t1\t4\t3\t3\t\n22\tRetinol-binding protein 3\t5\t3\t8\t1\t1\t0\t2\t1\t1\t\n23\tComplement C3\t1\t0\t0\t4\t5\t1\t2\t1\t3\t\n24\tIg gamma-2 chain C region\t13\t11\t16\t0\t0\t0\t0\t0\t0\t\n25\tIg gamma-4 chain C region\t8\t10\t13\t0\t0\t0\t0\t2\t0\t\n26\tApolipoprotein A-II\t3\t2\t2\t2\t4\t2\t0\t0\t2\t\n27\tHaptoglobin\t1\t1\t2\t1\t2\t1\t3\t1\t1\t\n28\tAlpha-2-HS-glycoprotein chain A\t0\t1\t1\t3\t1\t4\t0\t0\t0\t\n29\tAntithrombin-III\t0\t0\t0\t2\t1\t3\t0\t0\t0\t\n30\tIg gamma-3 chain C region\t12\t11\t6\t0\t0\t0\t0\t0\t0\t\n31\tGelsolin\t0\t0\t3\t0\t0\t0\t0\t0\t0\t\n32\tProtein shisa-7\t0\t0\t0\t0\t2\t0\t0\t0\t0\t\n33\tDickkopf-related protein 3\t0\t3\t0\t2\t1\t0\t0\t0\t1\t\nTable 4 List of proteins found to be reduced significantly by ANOVA in the patient samples compared to the control.\n\nIdentified Proteins\n\t\nAccession Number\n\t\nANOVA Test (P-Value)\n\t\nIg gamma-1 chain C region\tIGHG1_HUMAN\t0.022\t\nRetinol-binding protein 3\tRET3_HUMAN\t0.016\t\nSerotransferrin\tTRFE_HUMAN\t0.011\t\nProstaglandin-H2 D-isomerase\tPTGDS_HUMAN\t0.0028\t\nIg gamma-3 chain C region\tIGHG3_HUMAN\t0.0027\t\nCeruloplasmin\tCERU_HUMAN\t0.0014\t\nPigment epithelium-derived factor\tPEDF_HUMAN\t0.00053\t\nHemoglobin subunit beta\tHBB_HUMAN\t0.000059\t\nIg gamma-4 chain C region\tIGHG4_HUMAN\t0.00004\t\nIg gamma-2 chain C region\tIGHG2_HUMAN\t0.0000056\n==== Refs\nREFERENCES\n1 Bringas Calvo R. Iglesias Corinas D. Acute and bilateral uveitis secondary to moxifloxacin. Arch. Soc. Esp. Oftalmol. 2004 79 357 359 10.4321/S0365-66912004000700011 15286907 \n2 Wefers Bettink-Remeijer M. Brouwers K. van Langenhove L. Uveitis-like syndrome and iris transillumination after the use of oral moxifloxacin. Eye (Lond.) 2009 23 2260 2262 10.1038/eye.2009.234 19851342 \n3 Willermain F. Deflorenne C. Bouffioux C. Uveitis-like syndrome and iris transillumination after the use of oral moxifloxacin. Eye (Lond.) 2010 24 1419 10.1038/eye.2010.19 20379213 \n4 Kruh N.A. Troudt J. Izzo A. Prenni J. Dobos KM. Portrait of a pathogen: the Mycobacterium tuberculosis proteome in vivo . PLoS One 2010 5 e13938 10.1371/journal.pone.0013938 21085642 \n5 Vishwanathan K. Bartlett M.G. Stewart J.T. Determination of moxifloxacin in human plasma by liquid chromatography electrospray ionization tandem mass spectrometry. J. Pharm. Biomed. Anal. 2002 30 961 968 10.1016/S0731-7085(02)00393-X 12408886 \n6 Whiteaker J.R. Zhao L. Anderson L. Paulovich AG. An automated and multiplexed method for high throughput peptide immunoaffinity enrichment and multiple reaction monitoring mass spectrometry-based quantification of protein biomarkers. Mol. Cell. Proteomics 2010 9 184 196 10.1074/mcp.M900254-MCP200 19843560 \n7 Keshishian H. Addona T. Burgess M. Kuhn E. Carr SA. Quantitative, multiplexed assays for low abundance proteins in plasma by targeted mass spectrometry and stable isotope dilution. Mol. Cell. Proteomics 2007 6 2212 2229 10.1074/mcp.M700354-MCP200 17939991 \n8 Perkins D.N. Pappin D.J. Creasy D.M. Cottrell J.S. Probability-based protein identification by searching sequence databases using mass spectrometry data. Electrophoresis 1999 20 3551 3567 10.1002/(SICI)1522-2683(19991201)20:18<3551::AID-ELPS3551>3.0.CO;2-2 10612281 \n9 Nesvizhskii A.I. Keller D.J. Kolker E. Aebersold R. A statistical model for identifying proteins by tandem mass spectrometry. Anal. Chem. 2003 75 4646 4658 10.1021/ac0341261 14632076 \n10 Hinkle D.M. Dacey M.S. Mandelcorn E. Bilateral uveitis associated with fluoroquinolone therapy. Cutan. Ocul. Toxicol. 2012 31 111 116 10.3109/15569527.2011.617024 21981449 \n11 Forooghian F. Maberly D. Albiani D.A. Uveitis risk following oral fluoroquinolone therapy: a nested case-control Study. Ocul. Immunol. Inflamm. 2013 21 390 393 10.3109/09273948.2013.808351 23876164 \n12 Eadie B. Etminan M. Mikelberg F. Risk for Uveitis With Oral Moxifloxacin A Comparative Safety Study. JAMA Ophthalmol. 2015 133 81 84 10.1001/jamaophthalmol.2014.3598 25275293 \n13 Sandhu H.S. Brucker A.J. Ma L. Vanderbeek B.L. Oral fluoroquinolones and the risk of uveitis. 2015 JAMA Ophthalmolol 133 \n14 Tugal-Tutkun I. Onal S. Garip A. Bilateral acute iris transillumination. Arch. Ophthalmol. 2011 129 1312 1319 10.1001/archophthalmol.2011.310 21987674 \n15 Tugal-Tutkun I. Urgancioglu M. Bilateral acute depigmentation of the iris. Graefes Arch. Clin. Exp. Ophthalmol. 2006 244 742 746 10.1007/s00417-005-0137-x 16205935 \n16 Hariprasad S.M. Shah G.K. Mieler W.F. Vitreous and aqueous penetration of orally administered moxifloxacin in humans. Arch. Ophthalmol. 2006 124 178 182 10.1001/archopht.124.2.178 16476886 \n17 Kernt M. Neubauer A.S. Ulbig M.W. In vitro safety of intravitreal moxifloxacin for endophthalmitis treatment. J. Cataract Refract. Surg. 2008 34 480 488 10.1016/j.jcrs.2007.10.046 18299076 \n18 Sullivan J.T. Woodruff M. Lettieri J. Pharmacokinetics of a once-daily oral dose of moxifloxacin (Bay 12-8039), a new enantiomerically pure 8-methoxy quinolone. Antimicrob. Agents Chemother. 1999 43 2793 2797 10543767 \n19 Knape R.M. Sayyad F.E. Davis J.L. Moxifloxacin and bilateral acute iris transillumination. J. Ophthalmic Inflamm. Infect. 2013 3 10 10.1186/1869-5760-3-10 23514193 \n20 Bennet M.D. Yee W. Bryan J.S. Pegaptanib combined with intravitreal injection of moxifloxacin as treatment of wet macular degeneration. Retina 2008 28 976 980 10.1097/IAE.0b013e3181733733 18698300 \n21 Aydin E. Kazi A.A. Peyman G.A. Esfahani M.R. Intravitreal toxicity of moxifloxacin. Retina 2006 26 187 190 10.1097/00006982-200602000-00011 16467676 \n22 Kernt M. Neubauer A.S. Liegl R.G. Intracameral moxifloxacin: in vitro safety on human ocular cells. Cornea 2009 28 553 561 10.1097/ICO.0b013e318191447b 19421040 \n23 Gao H. Pennesi M.E. Qiao X. Intravitreal moxifloxacin: retinal safety study with electroretinography and histopathology in animal models. Invest. Ophthalmol. Vis. Sci. 2006 47 1606 1611 10.1167/iovs.05-0702 16565399 \n24 Man I. Murphy J. Fergusn J. Fluoroquinolones phototoxicity: a comparison of moxifloxacin and lomefloxacin in normal volunteers. J. Antimicrob. Chemother. 1999 43 77 82 10.1093/jac/43.suppl_2.77 \n25 Richardson M.R. Price M.O. Price F.W. Proteomic analysis of human aqueous humor using multidimensional protein identification technology. Mol. Vis. 2009 11 15 2740 2750 \n26 Chowdhury U.R. Madden B.J. Charlesworth M.C. Faustsh M.P. Proteome analysis of human aqueous humor. Invest Opthalmol Vis Sci 2010 51 4921 4931 \n27 Nesvizhskii A.I. Aebersold R. Interpretation of shotgun proteomic data: the protein inference problem. Mol. Cell. Proteomics 2005 4 1419 1440 10.1074/mcp.R500012-MCP200 16009968\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1874-3641",
"issue": "11()",
"journal": "The open ophthalmology journal",
"keywords": null,
"medline_ta": "Open Ophthalmol J",
"mesh_terms": null,
"nlm_unique_id": "101480505",
"other_id": null,
"pages": "107-116",
"pmc": null,
"pmid": "28694894",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "15286907;23876164;20019884;19851342;21981449;16467676;12408886;16205935;10382879;16476886;25275293;10543767;19843560;18299076;20379213;21085642;16565399;18698300;10612281;20463327;19421040;14632076;17939991;16009968;23514193;21987674",
"title": "Moxifloxacin Concentration and Proteomic Analysis of Aqueous Humor in Human Uveitis Associated with Oral Moxifloxacin Therapy.",
"title_normalized": "moxifloxacin concentration and proteomic analysis of aqueous humor in human uveitis associated with oral moxifloxacin therapy"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/17/0092560",
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MOXIFLOXACIN"
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"drugadditional": null,... |
{
"abstract": "Low dose pulse MTX was associated with the development of pancytopenia in six patients with RA. Two patients died. Factors implicated in the occurrence of this complication were renal impairment in five patients, medication errors by two patients, preexisting marrow injury from occult alcoholism in one patient, and an apparent idiosyncratic reaction to the drug in another. Medication errors were associated with the use of five or more medications, and the unusual schedule of administration of low dose MTX may also have been contributory. From a consideration of the clinical pharmacokinetics of MTX, we suggest other factors that may predispose to the occurrence of marrow toxicity: the presence of hypoalbuminemia, interactions between MTX and other protein bound or weakly acidic drugs, and the repetitive dosing schedule of low dose MTX. Based on our experience, patients with impaired renal function (creatinine greater than or equal to 2.0 mg/dL) should not receive MTX. Renal function should be monitored regularly during treatment with MTX, and blood counts should be observed carefully if a new drug is added or substituted. A 5 mg test dose of MTX before initiating weekly therapy may identify patients with severe hypersensitivity to the drug. The potential risks of using MTX in a patient unwilling to accept blood products should be acknowledged and discussed with the patient. Furthermore, we recommend the use of leucovorin if pancytopenia occurs, even if low or undetectable serum levels of MTX are present.",
"affiliations": null,
"authors": "MacKinnon|S K|SK|;Starkebaum|G|G|;Willkens|R F|RF|",
"chemical_list": "D002955:Leucovorin; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1016/0049-0172(85)90029-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0049-0172",
"issue": "15(2)",
"journal": "Seminars in arthritis and rheumatism",
"keywords": null,
"medline_ta": "Semin Arthritis Rheum",
"mesh_terms": "D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid; D001853:Bone Marrow; D005260:Female; D006801:Humans; D002955:Leucovorin; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D010198:Pancytopenia; D012306:Risk",
"nlm_unique_id": "1306053",
"other_id": null,
"pages": "119-26",
"pmc": null,
"pmid": "3877983",
"pubdate": "1985-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pancytopenia associated with low dose pulse methotrexate in the treatment of rheumatoid arthritis.",
"title_normalized": "pancytopenia associated with low dose pulse methotrexate in the treatment of rheumatoid arthritis"
} | [
{
"companynumb": "US-VALIDUS PHARMACEUTICALS LLC-US-2020VAL000864",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
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{
"abstract": "Pemphigoid gestationis is considered to be a rare pregnancy exclusive bullous disease, which modifies the course of the pregnancy, with difficulties in the management of the pruritus and skin lesions as well as a possible change in the neonatal outcome. Differential diagnosis of skin lesions and pruritus in pregnancy is challenging, and complementary investigations such as skin biopsy or laboratory tests are indispensable. The correct diagnosis and proper treatment could change the natural course of a pregnancy at risk and could improve maternal and fetal morbidity. We present the case of a patient with pemfigoid gestationis with the aim to highlight: i) the management of this pregnancy-associated skin disorder which transfers this pregnancy into a category of high obstetrical risk pregnancy; ii) the particularities of the course of the pregnancy; and iii) the importance in the differential diagnosis of pregnancy dermatoses. The particularity of this case of pemphigoid gestationis was the acute fetal distress in the absence of intrauterine growth restriction that is frequently found in this pathology, and the management of a rare pregnancy skin condition that currently has no standard treatment.",
"affiliations": "Department of Obstetrics and Gynecology, Life Memorial Hospital, 012244 Bucharest, Romania.;Department of Obstetrics and Gynecology, Life Memorial Hospital, 012244 Bucharest, Romania.;Department of Obstetrics and Gynecology, University Emergency Hospital Bucharest, 050098 Bucharest, Romania.;Department of Obstetrics and Gynecology, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania.;Department of Pathology, Onco Team Diagnostic, 030138 Bucharest, Romania.;Department of Dermatology, 'Carol Davila' Central Military University Emergency Hospital, 010825 Bucharest, Romania.;Department of Food Hygiene and Nutrition, 'Carol Davila' University of Medicine and Pharmacy, 050463 Bucharest, Romania.;Department of Obstetrics and Gynecology, Life Memorial Hospital, 012244 Bucharest, Romania.",
"authors": "Parfene|Caliopia Gavril|CG|;Bohiltea|Roxana Elena|RE|;Mihai|Bianca Margareta|BM|;Grigoriu|Corina|C|;Margaritescu|Irina|I|;Chirita|Aurel Doru|AD|;Zugravu|Corina Aurelia|CA|;Pelinescu-Onciul|Dimitrie|D|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/etm.2021.10945",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-0981",
"issue": "23(1)",
"journal": "Experimental and therapeutic medicine",
"keywords": "dermatoses of pregnancy; fetal growth restriction; pemphigoid gestationis; premature delivery; skin lesions",
"medline_ta": "Exp Ther Med",
"mesh_terms": null,
"nlm_unique_id": "101531947",
"other_id": null,
"pages": "23",
"pmc": null,
"pmid": "34815775",
"pubdate": "2022-01",
"publication_types": "D002363:Case Reports",
"references": "9759674;30773280;27265076;32765726;19298272;27175516;10457123;22309336;16488288;18781114;22137226;33197417;11821508;28212762;25758329;21909194;20927731;17068480;8565245;8002643;8915153;16487882;21923615;28338110;1732338;25765353;17875879",
"title": "Influence of pemphigoid gestationis on pregnancy outcome: A case report and review of the literature.",
"title_normalized": "influence of pemphigoid gestationis on pregnancy outcome a case report and review of the literature"
} | [
{
"companynumb": "RO-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-327191",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"d... |
{
"abstract": "A 21-year-old man developed progressive and bilateral lower limb numbness, gait impairment and urinary incontinence over 10 days. He had received intrathecal methotrexate 20 days previously for acute lymphoblastic B-cell leukaemia, following 7 months of systemic chemotherapy. MR scan of the spinal cord showed bilateral symmetric and extensive T2/fluid attenuated inversion recovery (FLAIR) increased signal involving the dorsal columns in the thoracic cord. His serum folate concentration was at the lower end of the normal range. We stopped the intrathecal chemotherapy and gave folate; after a few days, he progressively improved. Myelopathy is an important adverse effect of intrathecal methotrexate, which may cause clinical and imaging features resembling subacute combined degeneration of the spinal cord. CNS infiltration must be excluded, intrathecal chemotherapy stopped and deficiency of folate or vitamin B12 treated as appropriate.",
"affiliations": "Division of Neurology, Department of Clinical Medicine, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil gustavo.rodrigues675@hotmail.com.;Department of Clinical Medicine, Hospital Universitário Lauro Wanderley, João Pessoa, Paraíba, Brazil.;Department of Surgery, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil.;Division of Neurology, Department of Clinical Medicine, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil.",
"authors": "Rodrigues|Pedro Gustavo Barros|PGB|http://orcid.org/0000-0001-7706-9610;Lima|Talles Tavares de|TT|;Duarte|Fernando Barroso|FB|;Nóbrega|Paulo Ribeiro|PR|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/practneurol-2021-003154",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1474-7758",
"issue": null,
"journal": "Practical neurology",
"keywords": "clinical neurology; haematology; myelopathy; neurooncology",
"medline_ta": "Pract Neurol",
"mesh_terms": null,
"nlm_unique_id": "101130961",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34716225",
"pubdate": "2021-10-29",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Myelopathy associated with intrathecal methotrexate.",
"title_normalized": "myelopathy associated with intrathecal methotrexate"
} | [
{
"companynumb": "BR-AZURITY PHARMACEUTICALS, INC.-BR-2022ARB000932",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"dru... |
{
"abstract": "We describe a patient with paraneoplastic autoimmune multiorgan syndrome (PAMS) secondary to a lymphoblastic T- cell lymphoma who presented with a lichenoid dermatitis and vitiligo, later developing bronchiolitis obliterans and autoimmune hepatitis. Notably, he had no detectable autoantibodies. The development of vitiligo and autoimmune hepatic involvement probably indicate a role for cytotoxic T- cell lymphocytes in the pathogenesis of this syndrome.",
"affiliations": "Department of Dermatology, 12 de Octubre University Hospital, Madrid, Spain.",
"authors": "Sanz-Bueno|Jimena|J|;Cullen|Daniella|D|;Zarco|Carlos|C|;Vanaclocha|Francisco|F|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D001323:Autoantibodies; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.4103/0378-6323.136898",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0378-6323",
"issue": "80(4)",
"journal": "Indian journal of dermatology, venereology and leprology",
"keywords": null,
"medline_ta": "Indian J Dermatol Venereol Leprol",
"mesh_terms": "D018931:Antineoplastic Agents, Hormonal; D001323:Autoantibodies; D001327:Autoimmune Diseases; D006801:Humans; D015458:Leukemia, T-Cell; D008297:Male; D010257:Paraneoplastic Syndromes; D010392:Pemphigus; D011241:Prednisone; D055815:Young Adult",
"nlm_unique_id": "7701852",
"other_id": null,
"pages": "328-30",
"pmc": null,
"pmid": "25035358",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Paraneoplastic autoimmune multiorgan syndrome (paraneoplastic pemphigus) with unusual manifestations and without detectable autoantibodies.",
"title_normalized": "paraneoplastic autoimmune multiorgan syndrome paraneoplastic pemphigus with unusual manifestations and without detectable autoantibodies"
} | [
{
"companynumb": "PHHY2014ES110673",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IMMUNE GLOBULIN NOS"
},
"drugadditional": null,
... |
{
"abstract": "Second-generation antipsychotics (SGAs), valproate, and sulpiride are related to significant weight gain and risk of metabolic syndrome (MetS). Among SGAs, olanzapine and clozapine are associated with the highest metabolic risk while ziprasidone is among one of the SGAs with the lowest risk. Several reports suggest that weight loss is observed in switching other antipsychotics to ziprasidone. Here we describe a female patient with chronic paranoid schizophrenia who had an unexpected weight gain and developed MetS during a cross-switch from a polypharmacy of olanzapine, valproate and sulpiride to ziprasidone monotherapy.",
"affiliations": null,
"authors": "Lee|Chin-Pang|CP|;Chen|Alice Pei-Jung|AP|;Juang|Yeong-Yuh|YY|",
"chemical_list": "D014150:Antipsychotic Agents; D010879:Piperazines; D013844:Thiazoles; C092292:ziprasidone",
"country": "United States",
"delete": false,
"doi": "10.3371/CSRP.LECH.043013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1232",
"issue": "9(3)",
"journal": "Clinical schizophrenia & related psychoses",
"keywords": "Polypharmacy; Schizophrenia; Weight Gain; Ziprasidone",
"medline_ta": "Clin Schizophr Relat Psychoses",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D005260:Female; D006801:Humans; D024821:Metabolic Syndrome; D010879:Piperazines; D019338:Polypharmacy; D012563:Schizophrenia, Paranoid; D013844:Thiazoles; D015430:Weight Gain",
"nlm_unique_id": "101312513",
"other_id": null,
"pages": "141-4",
"pmc": null,
"pmid": "23644168",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Weight Gain While Switching from Polypharmacy to Ziprasidone: A Case Report.",
"title_normalized": "weight gain while switching from polypharmacy to ziprasidone a case report"
} | [
{
"companynumb": "TW-WATSON-2015-25028",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "Graft versus host disease (GVHD) usually have involvement of classical target organs. Manifestations of Chronic GVHD (cGVHD) are much more protean than acute GVHD. NIH consensus criterion for cGVHD proposes different diagnostic and distinctive features of cGVHD. It acknowledges certain uncommon manifestations that can be attributed to cGVHD only when they are associated with more specific features. Patients rarely may develop such manifestations which are not diagnostic of cGVHD themselves. In the absence of more specific features of cGVHD, they may pose diagnostic challenge. Amongst the rare reported manifestations of cGVHD is serositis manifesting as pleural effusion, pericardial effusion or ascites. We report two patients developing ascites as an isolated manifestation of cGVHD.",
"affiliations": "Department of Medical Oncology, ACTREC, Tata Memorial Center, Mumbai, India.;Department of Pathology, Tata Memorial Center, Mumbai, India.;Department of Medical Oncology, ACTREC, Tata Memorial Center, Mumbai, India.",
"authors": "Bagal|Bhausaheb|B|;Ramadwar|Mukta|M|;Khattry|Navin|N|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1007/s12288-014-0477-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0971-4502",
"issue": "32(Suppl 1)",
"journal": "Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion",
"keywords": "Allogeneic Transplantation; Ascites; Graft versus Host Disease; Serositis",
"medline_ta": "Indian J Hematol Blood Transfus",
"mesh_terms": null,
"nlm_unique_id": "9425818",
"other_id": null,
"pages": "189-91",
"pmc": null,
"pmid": "27408388",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports",
"references": "9384488;8640168;10905062;3332169;14562000;16338616",
"title": "Ascites as a Manifestation of GVHD: a Rare Phenomenon.",
"title_normalized": "ascites as a manifestation of gvhd a rare phenomenon"
} | [
{
"companynumb": "PHHY2016IN098676",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"d... |
{
"abstract": "Atrial electromechanical delay (EMD) is used to predict atrial fibrillation, measured by echocardiography.\nThe aim of this study was to assess atrial EMD and mechanical function after anthracycline-containing chemotherapy.\nFifty-three patients with breast cancer (48 ± 8 years old) who received 240 mg/m2of Adriamycin, 2400 mg/m2 of cyclophosphamide, and 960 mg/m2 of paclitaxel were included in this retrospective study, as were 42 healthy subjects (47 ± 9 years old). Echocardiographic measurements were performed 11 ± 7 months (median 9 months) after treatment with anthracyclines.\nLeft intra-atrial EMD (11.4 ± 6.0 vs. 8.1 ± 4.9, p=0.008) and inter-atrial EMD (19.7 ± 7.4 vs. 14.7 ± 6.5, p=0.001) were prolonged; LA passive emptying volume and fraction were decreased (p=0.0001 and p=0.0001); LA active emptying volume and fraction were increased (p=0.0001 and p=0.0001); Mitral A velocity (0.8 ± 0.2 vs. 0.6 ± 0.2, p=0.0001) and mitral E-wave deceleration time (201.2 ± 35.6 vs. 163.7 ± 21.8, p=0.0001) were increased; Mitral E/A ratio (1.0 ± 0.3 vs. 1.3 ± 0.3, p=0.0001) and mitral Em (0.09 ± 0.03 vs. 0.11 ± 0.03, p=0.001) were decreased; Mitral Am (0.11 ± 0.02 vs. 0.09 ± 0.02, p=0.0001) and mitral E/Em ratio (8.8 ± 3.2 vs. 7.6 ± 2.6, p=0.017) were increased in the patients.\nIn patients with breast cancer after anthracycline therapy: Left intra-atrial, inter-atrial electromechanical intervals were prolonged. Diastolic function was impaired. Impaired left ventricular relaxation and left atrial electrical conduction could be contributing to the development of atrial arrhythmias.\nAtraso eletromecânico atrial (AEA) é utilizado para prever fibrilação atrial, medido pela ecocardiografia.\nO propósito deste estudo era verificar o AEA e a função mecânica após quimioterapia com antraciclinas.\nCinquenta e três pacientes com câncer de mama (48 ± 8 anos) que receberam 240 mg/m2 de adriamicina, 2400 mg/m2 de ciclofosfamida, e 960 mg/m2 de paclitaxel foram incluídas neste estudo retrospectivo, além de 42 indivíduos saudáveis (47 ± 9 anos). Medidas ecocardiográficas foram realizadas por aproximadamente 11 ± 7 meses (média de 9 meses) após tratamento com antraciclinas.\nAEA esquerdo intra-atrial (11,4 ± 6,0 vs. 8,1 ± 4,9, p=0,008) e AEA interarterial (19,7 ± 7,4 vs. 14,7 ± 6,5, p=0,001) foram prolongados; Volume de esvaziamento passivo e fracionamento de AE diminuíram (p=0,0001 e p=0,0001); Volume de esvaziamento ativo e fracionamento de AE (p=0,0001 e p=0,0001); Tempo de aceleração mitral A (0,8 ± 0,2 vs. 0,6 ± 0,2, p=0,0001) e de desaceleração de onda-E mitral (201,2 ± 35,6 vs. 163,7 ± 21,8, p=0,0001) aumentarão; Razão mitral E/A (1,0 ± 0,3 vs. 1,3 ± 0,3, p=0,0001) e mitral Em (0,09 ± 0,03 vs. 0,11 ± 0,03, p=0,001) diminuíram; Razão mitral Am (0,11 ± 0,02 vs. 0,09 ± 0,02, p=0,0001) e mitral E/Em (8,8 ± 3,2 vs. 7,6 ± 2,6, p=0,017) aumentaram nos pacientes.\nEm pacientes com câncer de mama após terapia com antraciclina: intervalos eletromecânicos intra-atriais esquerdos, intra-atriais foram prolongados. A função diastólica foi prejudicada. O relaxamento ventricular esquerdo foi prejudicado, e a condução elétrica atrial esquerda pode estar contribuindo para o desenvolvimento de arritmias atriais.",
"affiliations": "Pamukkale University Faculty of Medicine, Cardiology Denizli; - Turkey.;Pamukkale University Faculty of Medicine, Cardiology Denizli; - Turkey.;Balikesir Sevgi Hospital; - Turkey.;Pamukkale University Dept of Biostatistics; - Turkey.;Pamukkale University Medical Oncology - Turkey.",
"authors": "Yaylali|Yalin Tolga|YT|;Saricopur|Ahmet|A|;Yurtdas|Mustafa|M|;Senol|Hande|H|;Gokoz-Dogu|Gamze|G|",
"chemical_list": "D018943:Anthracyclines; D004317:Doxorubicin; D003520:Cyclophosphamide; D017239:Paclitaxel",
"country": "Brazil",
"delete": false,
"doi": "10.5935/abc.20160146",
"fulltext": "\n==== Front\nArq Bras CardiolArq. Bras. CardiolabcArquivos Brasileiros de Cardiologia0066-782X1678-4170Sociedade Brasileira de Cardiologia - SBC 10.5935/abc.20160146Cardiac Surgery - AdultsAtrial Function in Patients with Breast Cancer After Treatment with\nAnthracyclines Yaylali Yalin Tolga 1Saricopur Ahmet 1Yurtdas Mustafa 2Senol Hande 3Gokoz-Dogu Gamze 41 Pamukkale University Faculty of Medicine, Cardiology\nDenizli; - Turkey2 Balikesir Sevgi Hospital; - Turkey3 Pamukkale University Dept of Biostatistics; -\nTurkey4 Pamukkale University Medical Oncology - TurkeyMailing Address: Yalin Tolga Yaylali, Pamukkale\nUniversity, Cardiology Department. Çamlaralti Mah. Fakülte Cad.\nNo13 Kinikli. Postal Code 20070, Denizli - Turkey. E-mail:\nyaylalimd@gmail.com11 2016 11 2016 107 5 411 419 11 1 2016 22 7 2016 29 7 2016 This is an Open Access article distributed under the terms of the\nCreative Commons Attribution License, which permits unrestricted use,\ndistribution, and reproduction in any medium, provided the original work is\nproperly cited.Background\nAtrial electromechanical delay (EMD) is used to predict atrial fibrillation,\nmeasured by echocardiography.\n\nObjectives\nThe aim of this study was to assess atrial EMD and mechanical function after\nanthracycline-containing chemotherapy.\n\nMethods\nFifty-three patients with breast cancer (48 ± 8 years old) who\nreceived 240 mg/m2of Adriamycin, 2400 mg/m2 of\ncyclophosphamide, and 960 mg/m2 of paclitaxel were included in\nthis retrospective study, as were 42 healthy subjects (47 ± 9 years\nold). Echocardiographic measurements were performed 11 ± 7 months\n(median 9 months) after treatment with anthracyclines.\n\nResults\nLeft intra-atrial EMD (11.4 ± 6.0 vs. 8.1 ± 4.9, p=0.008) and\ninter-atrial EMD (19.7 ± 7.4 vs. 14.7 ± 6.5, p=0.001) were\nprolonged; LA passive emptying volume and fraction were decreased (p=0.0001\nand p=0.0001); LA active emptying volume and fraction were increased\n(p=0.0001 and p=0.0001); Mitral A velocity (0.8 ± 0.2 vs. 0.6\n± 0.2, p=0.0001) and mitral E-wave deceleration time (201.2 ±\n35.6 vs. 163.7 ± 21.8, p=0.0001) were increased; Mitral E/A ratio\n(1.0 ± 0.3 vs. 1.3 ± 0.3, p=0.0001) and mitral Em (0.09\n± 0.03 vs. 0.11 ± 0.03, p=0.001) were decreased; Mitral Am\n(0.11 ± 0.02 vs. 0.09 ± 0.02, p=0.0001) and mitral E/Em ratio\n(8.8 ± 3.2 vs. 7.6 ± 2.6, p=0.017) were increased in the\npatients.\n\nConclusions\nIn patients with breast cancer after anthracycline therapy: Left\nintra-atrial, inter-atrial electromechanical intervals were prolonged.\nDiastolic function was impaired. Impaired left ventricular relaxation and\nleft atrial electrical conduction could be contributing to the development\nof atrial arrhythmias.\n\nAtrial FunctionArrhythmias, CardiacUnilateral Breast NeoplasmsAntrhacyclinesDrug TherapyCardiotoxicity\n==== Body\nIntroduction\nThe anthracyclines (AC), which are a key component of many chemotherapy regimens, are\nclearly the most cardiotoxic chemotherapeutic agents producing left ventricular\ndysfunction and arrhythmias.1\nAtrial conduction system abnormalities play a major role in the genesis of\nre-entrant atrial arrhythmias. Left atrial (LA) volume and mechanical function have\nrecently been identified as a potential indicator of cardiac dysfunction and\narrhythmias.2,3 Intra- and inter-atrial\nelectromechanical delays are well-known electrophysiological features of the atrium\nprone to fibrillation.4\nEchocardiography is a sensitive and reproducible technique for the assessment of\natrial mechanical and electromechanical features.5,6 Atrial\nelectromechanical delay had been shown to be prolonged in patients with nonrheumatic\nparoxysmal atrial fibrillation, obesity, hyperthyroidism, and celiac\ndisease.7-10 The pathophysiology and predictors of arrhythmias\nafter treatment with AC are poorly defined. The hypothesis of the present study was\nthat atrial mechanical and electromechanical features might be affected in patients\ntreated with AC. Therefore, we aimed to assess atrial mechanical and\nelectromechanical features in patients after the administration of anthracycline\nchemotherapy and to compare them with healthy controls and then to evaluate their\nrelationship with parameters of left ventricular function on echocardiography.\n\nMethods\nStudy population\nThe study design was retrospective. Fifty-three women with breast cancer were\nselected from consecutive patients who received 240 mg/m2 of\nAdriamycin, 2400 mg/m2 of cyclophosphamide, and 960 mg/m2\nof paclitaxel at our institution between January 1, 2013 and December 31, 2013.\nA power analysis was performed before the study. Accordingly, when a reference\nstudy was considered, 28 subjects (14 in each group) would have resulted in 95%\nconfidence and 90% power. We included 95 subjects (53 patients and 42 controls)\nin the present study. The power analysis showed that our results, when examined\nfor inter-atrial EMD values, reached 95% confidence and 94% power. These women\nhad a comprehensive echocardiographic examination before the treatment, which\nshowed truly normal LV systolic and diastolic function. The control group was\ncomprised by 42 age-and sex-matched healthy female office staff. Exclusion\ncriteria were ischemic heart disease, moderate-to-severe valvular heart disease,\nheart failure, hypertension, diabetes mellitus, obesity, systolic and/or\ndiastolic dysfunction, atrial fibrillation, bundle branch block,\natrioventricular conduction abnormalities on electrocardiogram, acute or chronic\nrenal failure, collagen tissue disease, thyroid dysfunction, electrolyte\nimbalance, pulmonary disease, anemia, chronic liver disease, prior history of\nradiation therapy, life expectancy< 1 year, and insufficient\nechocardiographic imaging. None of the participants were taking any\nantiarrhythmics, tricyclic antidepressants, antihistaminics,\nangiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and\nantipsychotics. Heart rate, blood pressure, and routine biochemistry were\nmeasured in all participants. Exercise tolerance test to exclude ischemic heart\ndisease was performed in all subjects. A total of 750 women with breast cancer\nwere examined as to their eligibility for our study.\n\nThe institution's Medical Ethics Review Committee approved the study protocol\n(registration number: 60116787-020/7763, date of issue: 06.02.2014). Informed\nconsent was obtained from all participants. The study protocol conforms to the\nethical guidelines of the 1975 Declaration of Helsinki.\n\nTransthoracic echocardiography\nEchocardiographic examinations were carried out by using Vivid-7 echocardiography\ndevice with a 2.5-4 MHz probe (GE VingmedUltrasound, Horten, Norway). All\nparticipants were examined in the left lateral decubitus position by 2-D,\nM-mode, pulsed and color flow Doppler, and tissue Doppler echocardiography.\nContinuous 1-lead ECG recording was performed during the examination. LV\nejection fraction was obtained from two- or apical four-chamber views through\nthe modified Simpson method. To obtain maximum filling velocities, the\npulsed-Doppler sampling volume was placed between the tips of the mitral valve\nleaflets in the apical four-chamberview. Myocardial velocity profiles of the\nlateral and septal mitral annuli were obtained. Tissue Doppler measurements were\nobtained by placing the sample volume at the junction of the mitral annulus and\nthe septum, and lateral wall. All measurements were recorded as an average of 3\ncardiac cycles. Left atrial volumes (LA V) were obtained from apical\nfour-chamber view through the discs method and indexed for body surface area\n(BSA). LA V measurements were performed at the mitral valve opening (maximal,\nVmax), the onset of atrial systole (P wave on electrocardiogram, Vp), and the\nmitral valve closure (minimal, Vmin) (Figure 1\nA-C). The following LA emptying\nfunction parameters were calculated: LA passive emptying volume = Vmax-Vp, LA\npassive emptying fraction = (Vmax-Vp)/Vmax, LA active emptying volume = Vp-Vmin,\nLA active emptying fraction = (Vp-Vmin)/Vp.10 All volumes were indexed to BSA and expressed in\nml/m2. Atrial electromechanical coupling (PA) was defined as the\ntime interval from the onset of the P wave on surface electrocardiogram to the\nbeginning of the late diastolic wave (Am wave). PA was obtained from the lateral\nmitral annulus (PA lateral), septal mitral annulus (PA septum), and right\nventricular tricuspid annulus (PA tricuspid) (Figure 2 A-C). Values were\naveraged over 3 consecutive beats. The difference between PA lateral and PA\ntricuspid was defined as inter-atrial electromechanical delay, the difference\nbetween PA lateral and PA septum was defined as left intra-atrial\nelectromechanical delay, and the difference between PA septum and PA tricuspid\nwas defined as right intra-atrial electromechanical delay.10\n\n\nFigure 1 LA volumes are measured in the A4C views by means of 2D Echo at the\nmitral valve opening (A), at the onset of atrial systole (B), and at\nthe mitral valve closure (C).\n\n\n\n\n\nFigure 2 Measurements of time interval from the onset of P wave to the\nbeginning of Am wave (PA) are obtained at the lateral mitral annulus\n(A), septal mitral annulus (B), and RV tricuspid annulus (C).\n\n\n\n\nReproducibility\nOne experienced operator blinded to clinical and laboratory characteristics of\nthe participants analyzed all echocardiographic data. Intraobserver variability\nwas assessed in 30 selected subjects randomly from the both groups by repeating\nthe measurements. Measurements were repeated 1 week apart. Only one reader\nconducted this analysis. The reader was allowed to select the best measurement\neach time and was blinded to previous measurements. Intraobserver variability\nwas calculated as the difference between two measurements of the same patient by\na single cardiologist divided by the mean value.\n\nStatistical analysis\nCategorical variables are expressed as percentages and continuous variables as\nmean ± standard deviation and median with minimum-maximum values.\nContinuous variables were compared between groups using independent t tests (for\nnormally distributed variables) or a Mann-Whitney U test (for variables not\nnormally distributed). Categorical data were compared with the chi-square test.\nA multiple linear regression analysis was used to identify independent\npredictors of LA mechanical function impairment and electromechanical delays. P\nvalues < 0.05 were considered to indicate statistical significance. All\nanalyses were performed using SPSS version 15.0 (SPSS, Inc., Chicago, IL).\n\nResults\nClinical and echocardiographic findings of the patients (53 women, 48 ± 8\nyears) and controls (42 women, 47 ± 9 years) are listed in Table 1. None of the patients had developed\ncardiac complications including atrial fibrillation. Age, weight, body mass index,\nbody surface area, systolic and diastolic blood pressures, heart rate, and LV EF\nwere similar between the 2 groups. The mean duration of time elapsed from the\ncompletion of chemotherapy to the performance of echocardiography was 11 ± 7\nmonths (median 9 months). The mitral A-wave velocity, E-wave deceleration time, Am\nvelocities, E/Em ratio were significantly higher in the patients. The mitral Em\nvelocities, E/A ratio were significantly lower in the patients. The other\nconventional echocardiographic parameters such as LV EF, IVS and PW thickness, LA\ndiameter, LVEDD, LVESD, and systolic pulmonary artery values were within normal\nreference ranges, with no significant differences between the 2 groups (data not\nshown).\n\nTable 1 Characteristics of the study subjects\n\n \tPatients (n=53)\tControls (n=42)\t \t\n \tMean ± SD\tMed. (Min. – Max.)\tMean ± SD\tMed. (Min. – Max.)\tp Value\t\nDemographic And clinical\ncharacteristics\t \t\nAge, years\t48 ± 8\t49(29 - 65)\t46 ± 9\t47(30 - 65)\t0.419\t\nBody Mass Index, kg/m2\t23.98 ± 2.41\t23.8 (19.5 – 28.1)\t23.72 ± 2.33\t23.8 (20.3 – 28.5)\t0.603\t\nBody Surface Area, m2\t1.77 ± 0.14\t1.8(1.5 – 2.1)\t1.74 ± 0.13\t1.7(1.5 – 2.1)\t0.142\t\nSystolic Blood Pressure, mmHg\t118 ± 9\t120 (100 – 135)\t120 ± 9\t120 (100 – 135)\t0.396\t\nDiastolic Blood Pressure, mmHg\t71 ± 5\t70 (60 – 85)\t73 ± 5\t73 (60 – 85)\t0.064\t\nHeart rate, beats/min\t72 ±11\t70 (64-90)\t74 ± 11\t72 (62-88)\t0.104\t\nLV Ejection Fraction, %\t63 ± 5\t63 (49 - 74)\t64 ± 5\t62(57-78)\t0.958\t\nEffect of chemotherapy on Doppler\nparameters\t \t\nMitral E velocity, m/s\t0.8 ± 0.2\t0.8 (0.5-1.1)\t0.8 ± 0.2\t0.7 (0.4-1.2)\t0.223\t\nMitral A velocity, m/s\t0.8 ± 0.2\t0.8 (0.5–1.2)\t0.7 ± 0.2\t0.6 (0.4-1.0)\t0.0001*\t\nMitral E deceleration time, m/s\t201.3 ± 35.6\t196.3 (126-291.1)\t163.7 ± 21.8\t166.2 (109.9-203.7)\t0.0001*\t\nMitral E/A ratio\t1.0 ± 0.3\t0.9 (0.5-1.9)\t1.3 ± 0.3\t1.3 (0.7-2.3)\t0.0001*\t\nMitral Mean Em, m/s\t0.09 ± 0.03\t0.09 (0.05-0.16)\t0.11 ± 0.03\t0.11 (0.05-0.2)\t0.001*\t\nMitral Mean Am, m/s\t0.11 ± 0.02\t0.11(0.06 – 0.14)\t0.09 ± 0.02\t0.09 (0.06-0.12)\t0.0001*\t\nMitral E/Mean Em ratio\t8.8 ± 3.2\t8.7 (3.9-23.1)\t7.6 ± 2.6\t7.1 (4.1-16.8)\t0.017*\t\n* p<0,05 statistically significant; SD: standard deviation; Med: median;\nMin-Max: minimum - Maximum Values\n\nLeft atrial mechanical functions\nLA volume measurements of the study subjects are presented in Table 2. Maximum LA volume, Vp, LA active\nemptying volume (LAAEV) and fraction were significantly increased in the\npatients. LA passive emptying volume (LAPEV) and fraction were significantly\ndecreased in the patients. The mitral E-wave deceleration time was weakly\nassociated with LA passive emptying fraction (LAPEF), LA active emptying volume,\nand fraction. The reservoir function and total LA emptying did not change in the\npatients (data not shown).\n\nTable 2 Left atrial volume measurements of the study subjects\n\n \tPatients (n=53)\tControls (n=42)\t \t\n \tMean ± SD\tMed. (Min. – Max.)\tMean ± SD\tMed. (Min. – Max.)\tp Value\t\nEffect of chemotherapy on atrial function\t \t\nVmax1, ml/m2\t23.76 ± 5.2\t22.82 (16.54 – 38.81)\t20.71 ± 3.22\t20.6 (14.71 – 28.61)\t0.001*\t\nVp2, ml/m2\t16.34 ± 4.55\t15.65 (10.41 – 31.57)\t11.07 ± 2.19\t11.29 (6.27 – 14.88)\t0.0001*\t\nVmin3, ml/m2\t8.78 ± 2.98\t8.33 (4.66 – 18.95)\t7.7 ± 1.79\t7.96 (4 – 10.31)\t0.153\t\nLA passive emptying volume, ml/m2\t7.41 ± 2.01\t7.42 (3.01 – 12.32)\t9.64 ± 2\t9.71(4.92 – 14.54)\t0.0001*\t\nLA passive emptying fraction, %\t31.6 ± 7.37\t31.02 (15.8 – 45.49)\t46.53 ± 7.03\t45.34 (31.33-67.51)\t0.0001*\t\nLA active emptying volume, ml/m2\t7.56 ± 2.21\t7.25 (4.66-16.04)\t3.41 ± 0.74\t3.45 (2.15-4.75)\t0.0001*\t\nLA active emptying fraction, %\t46.67 ± 7.04\t45.45 (33-63.19)\t31.19 ± 5.24\t31.66 (19.73-44.77)\t0.0001*\t\n* p<0,05 statistically significant; SD: standard deviation; Med:\nmedian; Min-Max: minimum - Maximum Values.\n\n1Vmax: Volume measurements were performed at the mitral valve\nopening; 2Vp: Volume measurements were performed at the onset of\natrial systole; 3Vmin: Volume measurements were performed at the\nmitral valve closure. LA: Left atrial.\n\nAtrial electromechanical coupling\nThe atrial electromechanical coupling intervals measured from different sites are\nshown in Table 3. PA lateral,\ninter-atrial, and left intra-atrial electromechanical delays were significantly\nhigher in the patients. However, PA septum, PA tricuspid, and right intra-atrial\nelectromechanical delays did not differ significantly between the groups. E/A\nratio was weakly associated with left intra-atrial and inter-atrial\nelectromechanical delays (data not shown).\n\nTable 3 Atrial electromechanical coupling findings measured by tissue Doppler\nimaging\n\n \tPatients (n=53)\tControls (n=42)\tp Value\t\n \tMean ± SD\tMed. (Min. – Max.)\tMean ± SD\tMed. (Min. – Max.)\t\nEffect of chemotherapy on atrial function\t \t\nPA lateral, ms\t59.12 ± 8.91\t59.15 (36.97-78.82)\t54.04 ± 9.43\t51.76 (36.97-73.94)\t0.008*\t\nPA septum, ms\t47.72 ± 9.1\t48.06 (29.57-69.54)\t45.91 ± 9.5\t44.36 (25.88-66.85)\t0.348\t\nPA tricuspid, ms\t39.18 ± 8.36\t40.67 (22-57.3)\t39.35 ± 8.71\t37.9 (22.18-62.85)\t0.921\t\nInter-atrial EMD, ms\t19.73 ± 7.38\t18.49 (8.06-38.82)\t14.69 ± 6.51\t13.7 (7.39-29.58)\t0.001*\t\nLeft intra-atrial EMD, ms\t11.4 ± 5.98\t10.76 (1.85-25.88)\t8.13 ± 4.87\t7.39 (1.84-22.18)\t0.008*\t\nRight intra-atrial EMD, ms\t8.52 ± 5.48\t7.39 (1.85-25.18)\t6.56 ± 4.09\t4.77 (2.61 – 22.18)\t0.194\t\n* p<0,05 statistically significant; SD: Standard Deviation; Med:\nMedian; Min-Max: Minimum - Maximum Values.\n\nEMD: Electromechanical delay; PA: The time interval from the onset of\nP wave on surface electrocardiogram to the beginning of Am wave with\nTDI.\n\nAmong patients, the body mass index, diastolic blood pressure, mitral E\ndeceleration time were independent predictors for LAPEF. The systolic blood\npressure, diastolic blood pressure, mitral E deceleration time were independent\npredictors for LAAEV. Among controls, age, mitral E/A ratio were independent\npredictors for LAAEF (Table 4).\n\nTable 4 Multiple linear regression analysis of subject characteristics\ninfluencing LA mechanical function impairment\n\nPatient Group Dependent Variable: LAPEF\t Standardized Beta\tsig. (p)\t95,0% CI Lower - Upper\t\nAge\t-0,098\t0,505\t-0,334 - 0,167\t\nBMI\t0,292\t0,037*\t0,054 - 1,733\t\nSBP\t-0,312\t0,058\t-0,491 - 0,008\t\nDBP\t0,575\t0,001*\t0,303 - 1,118\t\nMitral E/A ratio\t-0,009\t0,949\t-6,964 - 6,53\t\nMitral E deceleration time\t-0,271\t0,039*\t-0,109 - -0,003\t\nMitral E/Mean Em ratio\t0,053\t0,696\t-0,507 - 0,752\t\nR2=0,321; model p=0,01; BMI: body mass index; CI:\nconfidence interval; DBP: diastolic blood pressure; LAPEF: left\natrial passive emptying fraction; SBP: systolic blood\npressure;\n\n* statistically significant.\n\nPatient Group Dependent Variable: LAAEV\t Standardized Beta\tsig. (p)\t95,0% CI Lower - Upper\t\nAge\t-0,042\t0,783\t-0,089 - 0,067\t\nBMI\t-0,186\t0,196\t-0,432 - 0,091\t\nSBP\t0,461\t0,008*\t0,029 - 0,184\t\nDBP\t-0,576\t0,001*\t-0,341 - -0,086\t\nMitral E/A ratio\t-0,010\t0,948\t-2,17 - 2,034\t\nMitral E deceleration time\t0,285\t0,036*\t0,001 - 0,034\t\nMitral E/Mean Em ratio\t0,076\t0,587\t-0,143 - 0,249\t\nR2=0,152; model p=0,041; BMI: body mass index; CI:\nConfidence Interval; DBP: diastolic blood pressure; LAAEV: left\natrial active emptying volume; SBP: systolic blood pressure;\n\n* statistically significant.\n\nControl Group Dependent Variable: LAPEF\t Standardized Beta\tsig. (p)\t95,0% CI Lower - Upper\t\nAge\t-0,541\t0,005*\t-0,509 - -0,101\t\nBMI\t-0,311\t0,065\t-1,445 - 0,045\t\nSBP\t0,189\t0,213\t-0,065 - 0,283\t\nDBP\t-0,100\t0,508\t-0,359 - 0,181\t\nMitral E/A ratio\t-0,437\t0,017*\t-12,325 - -1,293\t\nMitral E deceleration time\t-0,103\t0,493\t-0,098 - 0,048\t\nMitral E/Mean Em ratio\t0,221\t0,168\t-0,199 - 1,1\t\nR2=0,243; model p=0,018; BMI: body mass index; CI:\nConfidence Interval; DBP: diastolic blood pressure; LAPEF: left\natrial passive emptying fraction; SBP: systolic blood\npressure;\n\n* statistically significant.\n\nIntra-observer variability was less than 5% for all echocardiographic\nmeasurements.\n\nDiscussion\nThe present study showed that left intra-atrial and inter-atrial EM intervals were\nprolonged; LV diastolic function was impaired in patients with breast cancer treated\nwith AC, despite preservation of LA mechanical functions.\n\nThis study suggests that proarrhythmogenic mechanisms could be the result of changes\nin cardiac function, including LV diastolic dysfunction and delayed electrical\nconduction, which create an arrhythmogenic substrate. This arrhythmogenic substrate\nleads to a decrease in intracardiac conduction and to a heterogeneous dispersion of\nrepolarization, two effects that facilitate the genesis of cardiac arrhythmias in\nthose patients. This study also showed that diastolic function parameters were\nsignificantly impaired in the patients. We were not able to demonstrate systolic\ndysfunction in our patients because we could not perform global strain evaluation.\nThe most common cardiotoxicity of AC is left ventricular systolic dysfunction with\npossible arrhythmias. Studies examining the occurrence of arrhythmia in patients\ntreated with AC are scarce. Atrial fibrillation appears to be a rather common\ncomplication of AC and in one study, it was described in 2-10% of the\npatients.11 There are a\nlimited number of studies investigating diastolic function in patients treated with\nAC. There is no consensus regarding whether diastolic function is impaired in those\npatients.\n\nIn this study, patients with breast cancer after AC did not display any significant\nchange in total LA emptying, despite the fact that we showed that LA active emptying\nvolume and LA active emptying fraction were increased in those patients. This may\nsuggest preservation of atrial mechanical function early in the course of breast\ncancer survivors treated with AC. Yet it is possible to consider that the decrease\nin LA passive emptying volume is related to elevated end-diastolic LV pressure at\nleast due to LV diastolic dysfunction. The shift in early and late diastolic\nventricular filling might have occurred secondary to impaired relaxation. LA\nmechanical function plays a significant role to maintain cardiac output in patients\nwith DD.12 LA mechanical function\nis an important determinant of LV filling, especially in patients with end-stage\nsystolic or diastolic ventricular dysfunction.12 It consists of reservoir, conduit, and booster pump\nfunctions. In previous studies, it was demonstrated that LA mechanical functions\nwere impaired in patients with hypertension, chronic obstructive lung disease, and\ntype 1 diabetes mellitus.4,13,14 In addition, LA volume has been shown to be a powerful\nprognostic variable in a variety of cardiac disease states. Compared with AP\ndiameter, LA volume has a stronger association with outcomes in cardiac\npatients.15 Left atrial\ntotal emptying fraction was reported to be an independent and strong predictor for\nthe development of AF.10\n\nThe present study revealed that left intra- and interatrial EMD were significantly\nprolonged in the patients. Only mitral E/A ratio was weakly associated with LA EMD.\nIncreased EM delay was found to assist in the identification of subjects at\nincreased risk of AF. Atrial conduction time reflects both electrical and structural\natrial remodeling. Atrial EMD has been reported to be associated with low-grade\ninflammation, insulin resistance, LA enlargement, early LV diastolic dysfunction,\nand oxidative stress.4,16-18 Therefore, the impaired conduction observed in the present\nstudy could be associated with an increased risk of AF.\n\nThe prolonged EM intervals observed in this study could be explained by\nanthracycline-induced oxidative stress, which has been associated with autonomic\ndysfunction.18,19 Prolonged EM intervals may also\nindicate atrial remodeling during arrythmogenic process and may be a predictor of\nAF.7,20 Autonomic nervous system may play a role in the\ndevelopment of atrial fibrillation by its effects on atrial conduction time\n(heterogeneity).21,22 Studies looking at atrial function\nin patients treated with cardiotoxic chemotherapy are limited. Our results are\nconsistent with a previous study by Ceyhan et al., which reported that intra- and\ninter-atrial conductions were delayed in patients treated with\n5-florouracil.23\n\nThe results of our multiple linear regression analysis are inconclusive due to low R²\nvalues. They may suggest that risk factors for diastolic dysfunction such as blood\npressure, BMI, age, and diastolic dysfunction itself may play role in LA mechanical\nfunction impairment.\n\nClinical implications\nThese alterations may be an early form of subclinical cardiac involvement in\nbreast cancer survivors treated with AC and with no cardiovascular risk factors.\nWe can speculate that these patients may be at a higher risk to develop new or\nrecurrent atrial arrhythmias particularly atrial fibrillation. Monitoring could\nbe prudent in those patients to guide additional interventions such as\nanti-arrhythmic and/or anti-coagulant therapy. This could lead to a better\nclinical management and improved patient outcome.\n\nStudy limitations\nIn this study, patients also received cyclophosphamide and paclitaxel\nsimultaneously, which makes it difficult to decide which one caused these\nadverse effects. Pretreatment evaluation with comprehensive echocardiography\nincluding assessment of atrial mechanical and electromechanical features had not\nbeen done. However, the patients were selected among the ones who had truly\nnormal LV systolic and diastolic function on the baseline studies. These\nalterations might have been attributed incorrectly to the adverse effects of\nchemotherapeutic agents. LA volume should be measured using the disk summation\nalgorithm in both the apical four- and two- chamber views. We had measured them\nfrom a single-plane apical four-chamber approach, which is typically 1 to 2\nmL/m2 smaller than apical two-chamber volumes.15 However, we used the same\ntechnique for both patients and controls. We excluded patients with\ncardiovascular risk factors that can create an arrhythmogenic substrate. We\ncannot rule out systolic dysfunction, as we could not study global strain.\nFurther research is needed to define a true incidence and clinical relevance of\natrial arrhythmias in those patients and to determine the role of Holter\nmonitoring for the early diagnosis, intervention and surveillance of those\npatients more susceptible to develop arrhythmia.\n\nConclusions\nOur study revealed that left intra- and inter-atrial EM were prolonged and that LV\ndiastolic function was impaired in breast cancer survivors treated with AC. Impaired\nelectrical conduction in those patients may be associated with the development of\narrhythmias.\n\nAuthor contributions\n\nConception and design of the research, Analysis and interpretation of the data\nand Critical revision of the manuscript for intellectual content: Yaylali YT,\nSaricopur A, Yurtdas M, Senol H, Gokoz-Dogu G; Acquisition of data: Saricopur A,\nGokoz-Dogu G; Statistical analysis: Senol H; Writing of the manuscript: Yaylalı\nYT, Saricopur A.\n\nPotential Conflict of Interest\n\nNo potential conflict of interest relevant to this article was reported.\n\nSources of Funding\n\nThere were no external funding sources for this study.\n\nStudy Association\n\nThis article is a part of the residency thesis by Ahmet Saricopur, from Pamukkale\nUniversity Faculty of Medicine.\n==== Refs\nReferences\n1 Chen MH Force T Cardiovascular complications of cancer therapeutic\nagents Mann DL Zipes DP Libby P Bonow RO Braunwald's heart disease: a textbook of cardiovscular medicine 10th ed Philadelphia Elsevier 2015 1613 1623 \n2 Abecasis J Dourado R Ferreira A Saraiva C Cavaco D Santos KR Left atrial volume calculated by multi-detector computed\ntomography may predict successful pulmonary vein isolation in catheter\nablation of atrial fibrillation Europace 2009 11 10 1289 1294 19632980 \n3 Hof I Chilukuri K Arbab-Zadeh A Scherr D Dalal D Nazarian S Does left atrial volume e Pulmonary venous anatomy predict the\noutcome of catheter ablation of atrial fibrillation? J Cardiovasc Electrophysiol 2009 20 9 1005 1010 19493152 \n4 Acar G Akcay A Sokmen A Ozkaya M Guler E Sokmen G Assessment of atrial electromechanical delay, diastolic\nfunctions, and left atrial mechanical functions in patients with type 1\ndiabetes mellitus J Am Soc Echocardiogr 2009 22 6 732 738 19423291 \n5 Deniz A Yavuz B Aytemir K Hayran M Kose S Okutucu S Intra-left atrial mechanical delay detected by tissue Doppler\nechocardiography can be a useful marker for paroxysmal atrial\nfibrillation Echocardiography 2009 26 7 779 784 19486122 \n6 Omi W Nagai H Takamura M Okura S Okajima M Furusho H Doppler tissue analysis of atrial electromechanical coupling in\nparoxysmal atrial fibrillation J Am Soc Echocardiogr 2005 18 1 39 44 15637487 \n7 Cui QQ Zhang W Wang H Sun X Wang R Yang HY Assessment of atrial electromechanical coupling and influential\nfactors in nonrheumatic paroxysmal atrial fibrillation Clin Cardiol 2008 31 2 74 78 18257022 \n8 Yagmur J Cansel M Acikgoz N Ermis N Yagmur M Atas H Assessment of atrial electromechanical delay by tissue Doppler\nechocardiography in obese subjects Obesity (Silver Spring) 2011 19 4 779 783 20829801 \n9 Sokmen A Acar G Sokmen G Akcay A Akkoyun M Koroglu S Evaluation of atrial electromechanical delay and diastolic\nfunctions in patients with hyperthyroidism Echocardiography 2013 30 10 1194 1201 23742676 \n10 Bayar N Çekin AH Arslan Ş Çağırcı G Erkal Z Çay S Assessment of left atrial function in patients with celiac\ndisease Echocardiography 2015 32 12 1802 1808 25923824 \n11 Guglin M Aljayeh M Saiyad S Ali R Curtis AB Introducing a new entity: chemotherapy-induced\narrhythmia Europace 2009 11 12 1579 1586 19801562 \n12 Prioli A Marino P Lanzoni L Zardini P Increasing degrees of left ventricular filling impairment\nmodulate left atrial function in humans Am J Cardiol 1998 82 6 756 761 9761086 \n13 Aydin M Ozeren A Bilge M Dursun A Cam F Elbey MA Effects of dipper and non-dipper status of essential hypertension\non left atrial mechanical functions Int J Cardiol 2004 96 3 419 424 15301896 \n14 Acikel M Yilmaz M Gurlertop Y Kaynar H Bozkurt E Erol MK The effect of pulmonary hypertension on left atrial mechanical\nfunctions in chronic obstructive lung disease Int J Cardiol 2004 97 2 187 192 15458682 \n15 Lang RM Badano LP Mor-Avi V Afilalo J Armstrong A Ernande L Recommendations for cardiac chamber quantification by\nechocardiography in adults: an update from the American Society of\nEchocardiography and the European Association of Cardiovascular\nImaging J Am Soc Echocardiogr 2015 28 1 1 39 e14 25559473 \n16 Zehir R Karabay CY Kocabay G Kalayci A Kaymaz O Aykan AC Assessment of atrial conduction time in patients with polycystic\novary syndrome J Interv Card Electrophysiol 2014 41 2 137 143 25005453 \n17 Yagmur J Yetkin O Cansel M Acikgoz N Ermis N Karakus Y Assessment of atrial electromechanical delay and influential\nfactors in patients with obstructive sleep apnea Sleep Breath 2012 16 1 83 88 21221821 \n18 Acar G Sayarlioğlu M Akçay A Sökmen A Sökmen G Yalçintaş S Evaluation of atrial electromechanical delay and left atrial\nmechanical functions in patients with rheumatoid arthritis Turk Kardiyol Dern Ars 2009 37 7 447 453 20098037 \n19 Minotti G Cairo G Monti E Role of iron in antraciclina cardiotoxicity: new tunes for an old\nsong? FASEB J 1999 13 2 199 212 9973309 \n20 Aktoz M Yilmaztepe M Tatli E Turan FN Umit EG Altun A Assessment of ventricular and left atrial mechanical functions,\natrial electromechanical delay e P wave dispersion in patients with\nscleroderma Cardiol J 2011 18 3 261 269 21660915 \n21 Roshanali F Mandegar MH Yousefnia MA Alaeddini F Saidi B Prevention of atrial fibrillation after coronary artery bypass\ngrafting via atrial electromechanical interval and use of amiodarone\nprophylaxis Interact Cardiovasc Thorac Surg 2009 8 4 421 425 19144672 \n22 Workman AJ Cardiac adrenergic control and atrial\nfibrillation Naunyn Schmiedebergs Arch Pharmacol 2010 381 3 235 249 19960186 \n23 Ceyhan C Meydan N Barutca S Tekten T Onbasili AO Ozturk B Ultrasound tissue characterization by integrated backscatter for\nanalyzing Fluorouracil induced myocardial damage Echocardiography 2005 22 3 233 238 15725158\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0066-782X",
"issue": "107(5)",
"journal": "Arquivos brasileiros de cardiologia",
"keywords": null,
"medline_ta": "Arq Bras Cardiol",
"mesh_terms": "D000328:Adult; D018943:Anthracyclines; D000971:Antineoplastic Combined Chemotherapy Protocols; D001145:Arrhythmias, Cardiac; D001281:Atrial Fibrillation; D001794:Blood Pressure; D001943:Breast Neoplasms; D016022:Case-Control Studies; D003520:Cyclophosphamide; D003971:Diastole; D004317:Doxorubicin; D004452:Echocardiography; D005260:Female; D006801:Humans; D008875:Middle Aged; D017239:Paclitaxel; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D013599:Systole; D018487:Ventricular Dysfunction, Left; D016277:Ventricular Function, Left",
"nlm_unique_id": "0421031",
"other_id": null,
"pages": "411-419",
"pmc": null,
"pmid": "27812678",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": "20098037;21221821;19144672;15725158;9761086;25923824;18257022;15458682;20829801;19960186;19801562;9973309;19486122;15301896;19423291;25005453;23742676;19632980;19493152;15637487;21660915;25559473",
"title": "Atrial Function in Patients with Breast Cancer After Treatment with Anthracyclines.",
"title_normalized": "atrial function in patients with breast cancer after treatment with anthracyclines"
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{
"abstract": "The association of granulomatosis with polyangiitis and pregnancy is rare and therapeutic options are limited by the risk of teratogenicity and fetotoxicity. There is a paucity of published literature to guide clinical decision-making in these cases. We report the case of a 26-year-old woman with no medical history who presented at 21 weeks of gestation with a bilateral sudden loss of hearing and erosive rhinitis. The diagnosis of granulomatosis with polyangiitis was confirmed radiologically and biologically. Corticosteroids were not enough to stabilize the disease and she received intravenous immunoglobulins with remission. A successful delivery of a healthy male newborn was done at 36 weeks. A review of all published literature on granulomatosis with polyangiitis in pregnancy between 1970 and 2017 is presented. Trial registration: Not applicable.",
"affiliations": "Internal Medicine Department, CHU de Rouen, Rouen, France.;Internal Medicine Department, CHU de Rouen, Rouen, France.;Internal Medicine Department, CHU de Rouen, Rouen, France.;Obstetric and Gynecology Department, CHU de Rouen, Rouen, France.;Internal Medicine Department, CHU de Rouen, Rouen, France.;Internal Medicine Department, CHU de Rouen, Rouen, France.",
"authors": "Daher|A|A|https://orcid.org/0000-0002-5240-5160;Sauvetre|G|G|;Girszyn|N|N|;Verspyck|E|E|;Levesque|H|H|;Le Besnerais|M|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1753495X18822581",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1753-495X",
"issue": "13(2)",
"journal": "Obstetric medicine",
"keywords": "ANCA-associated vasculitis; Granulomatosis with polyangiitis; Wegener’s granulomatosis",
"medline_ta": "Obstet Med",
"mesh_terms": null,
"nlm_unique_id": "101464191",
"other_id": null,
"pages": "76-82",
"pmc": null,
"pmid": "32714439",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": "16570714;27733943;17011946;18850433;2202308;16570081;26214766;19054820;19646353;10435900;25272233;23758808;21200183;21098742;6497926;28623488;15384037;22892004;9515867;16753694;1200877;22270373;8883770;27582817;23168958;15089769;27293925;22170192;6691851;7932434;2145995;7668907;11005781;25858351;8953123;17517407;21183452;23608146;18299958;9566676;25256787;3958596;16242573;1857528;9214438;22242076;28154726;15496568;25832613",
"title": "Granulomatosis with polyangiitis and pregnancy: A case report and review of the literature.",
"title_normalized": "granulomatosis with polyangiitis and pregnancy a case report and review of the literature"
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"abstract": "Streptococcus mitis is a common pathogen causing infections in oncological patients. However, cases of abscesses caused by Streptococcus mitis in oncological patients have not been reported so far. We report on 5-year-old child with nephroblastoma and pulmonary and hepatic metastases at diagnosis who went into complete remission undergoing chemotherapy and nephrectomy, and who developed new round lesions in liver and lungs under continuous chemotherapy suggestive of new metastases. Biopsy of the lesions revealed abscesses with detection of Streptococcus mitis. The child was successfully treated with antibiotics, finished chemotherapy per protocol and has been in complete remission for 14 months. Infectious lesions involving organs of typical metastatic dissemination can easily be misdiagnosed as metastases, especially in the absence of symptoms. Histologic proof of lesions suspicious of metastases is mandatory if it leads to a change of prognosis and therapy. Streptococcus mitis can be a causative organism of pulmonary and hepatic abscesses in oncological patients.",
"affiliations": "Departments of Pediatrics.;Radiology.;Pathology.;General, Visceral, and Transplantation Surgery.;Thoracic and Cardiovascular Surgery.;Department of Pediatric Hematology and Oncology, Center of Pediatrics and Adolescent Medicine, Albert-Ludwigs-University Freiburg, Freiburg, Germany.;Pediatrics, Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, University Hospital Aachen, RWTH Aachen University, Aachen.;Pediatrics, Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, University Hospital Aachen, RWTH Aachen University, Aachen.",
"authors": "Imhof|Lara|L|;Schrading|Simone|S|;Braunschweig|Till|T|;Steinau|Gerhard|G|;Spillner|Jan Wilhelm|JW|;Puzik|Alexander|A|;Lassay|Lisa|L|;Kontny|Udo|U|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000992",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "40(7)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000038:Abscess; D002675:Child, Preschool; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008100:Liver Abscess; D008169:Lung Abscess; D009362:Neoplasm Metastasis; D013290:Streptococcal Infections; D034361:Streptococcus mitis; D009396:Wilms Tumor",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e429-e431",
"pmc": null,
"pmid": "29135843",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Abscessing Infection by Streptococcus mitis Mimicking Metastatic Lesions in a 5-Year-Old Girl With Nephroblastoma: A Case Report.",
"title_normalized": "abscessing infection by streptococcus mitis mimicking metastatic lesions in a 5 year old girl with nephroblastoma a case report"
} | [
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"companynumb": "DE-INGENUS PHARMACEUTICALS, LLC-INF201810-001022",
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"activesubstancename": "DOXORUBICIN"
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"abstract": "Abiraterone acetate is a potent and irreversible inhibitor of cytochrome p450 17A1 that suppresses androgen synthesis. It is approved for chemotherapy-naive and docetaxel-treated patients with metastatic castration-resistant prostate cancer. We describe the protocol for use of abiraterone in metastatic castration-resistant prostate cancer chemotherapy naive patients has been implanted in our centre and we review the cases of those patients whose adverse effects have forced the discontinuation of treatment. The side effects fit the safety profile of abiraterone, speed of their appearance and severity indicate that you should perform a thorough follow-up of these patients especially in the early phases of treatment.",
"affiliations": "Servicio de Farmacia, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), As Xubias, Spain.;Servicio de Farmacia, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), As Xubias, Spain.;Servicio de Farmacia, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), As Xubias, Spain.;Servicio de Farmacia, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), As Xubias, Spain.",
"authors": "Ramudo-Cela|Luis|L|;Balea-Filgueiras|Jesús|J|;Vizoso-Hermida|José Ramón|JR|;Martín-Herranz|Isabel|I|",
"chemical_list": "D000736:Androstenes; D043823:Taxoids; D000077143:Docetaxel; D000069501:Abiraterone Acetate; C089740:abiraterone",
"country": "England",
"delete": false,
"doi": "10.1177/1078155216674354",
"fulltext": null,
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"issn_linking": "1078-1552",
"issue": "23(8)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Abiraterone; clinical management; metastatic castration-resistant prostate cancer; prostate cancer; safety",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000069501:Abiraterone Acetate; D000369:Aged, 80 and over; D000736:Androstenes; D018450:Disease Progression; D000077143:Docetaxel; D006801:Humans; D008297:Male; D008875:Middle Aged; D064129:Prostatic Neoplasms, Castration-Resistant; D056737:Safety-Based Drug Withdrawals; D043823:Taxoids; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "615-619",
"pmc": null,
"pmid": "27753628",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Study of cases of abiraterone discontinuation due to toxicity in pre-chemotherapy after 1 year's experience.",
"title_normalized": "study of cases of abiraterone discontinuation due to toxicity in pre chemotherapy after 1 year s experience"
} | [
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"companynumb": "ES-JNJFOC-20171217037",
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"activesubstance": {
"activesubstancename": "ABIRATERONE ACETATE"
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"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nThe aim was to investigate the RAS discordance between initial and recurrent metastasectomy specimens in metastatic colorectal cancer (mCRC) patients treated with chemotherapy (CT) plus biological agents in a first-line setting.\n\n\nMETHODS\nPatients who had been treated with CT plus bevacizumab or cetuximab or panitumumab followed by R0 resection for potentially resectable colorectal cancer liver metastases were scanned. Among these, patients who developed resectable new metastases after a disease-free interval longer than 6 months were included in the study. We compared the RAS mutation status between the first biopsy and the second metastasectomy specimen.\n\n\nRESULTS\nA total of 82 mCRC patients treated with CT plus biological agents in a first-line setting were included in the study. The first biopsy assessment showed wild-type RAS tumours in 39 (47.6%) patients and mutant RAS tumours in 43 (52.4%) patients. The mean time for new operable liver metastasis after R0 resection was 15.5 months. In the second metastasectomy specimens, the numbers of wild-type and mutant RAS tumours were 30 (36.6%) and 52 (63.4%), respectively. The comparison with the first biopsy specimens showed RAS status conversions in 17 (20.7%) patients. Univariate comparison between patients with and without RAS status conversion revealed that grade, pathological T stage, wild-type RAS tumour and longer biological agent use time in the first-line treatment were significant factors for RAS conversion.\n\n\nCONCLUSIONS\nOur results suggest that re-biopsy is needed for an optimal second-line treatment decision in mCRC patients regardless of backbone biological agent, especially in patients with wild-type RAS mCRC.",
"affiliations": "Department of Medical Oncology, University of Health Sciences, Okmeydani Training and Research Hospital, Istanbul, Turkey.;Department of Medical Oncology, Faculty of Medicine, Medipol University, Istanbul, Turkey.;Department of Medical Oncology, Yuzuncu Yil University Medical School, Van, Turkey.;Department of Pathology, University of Health Sciences, Okmeydani Training and Research Hospital, Istanbul, Turkey.;Department of Medical Oncology, University of Health Sciences, Okmeydani Training and Research Hospital, Istanbul, Turkey.;Department of Medical Oncology, University of Health Sciences, Okmeydani Training and Research Hospital, Istanbul, Turkey.;Department of Pathology, Faculty of Medicine, Medipol University, Istanbul, Turkey.;Department of Surgery, University of Health Sciences, Okmeydani Training and Research Hospital, Istanbul, Turkey.;Department of Surgery, University of Health Sciences, Okmeydani Training and Research Hospital, Istanbul, Turkey.;Department of Medical Oncology, University of Health Sciences, Okmeydani Training and Research Hospital, Istanbul, Turkey.;Department of Medical Oncology, University of Health Sciences, Okmeydani Training and Research Hospital, Istanbul, Turkey.;Department of Medical Oncology, Faculty of Medicine, Medipol University, Istanbul, Turkey.",
"authors": "Arici|Serdar|S|https://orcid.org/0000-0003-2018-6554;Hamdard|Jamshid|J|;Sakin|Abdullah|A|;Sengiz Erhan|Selma|S|;Atci|Muhammed Mustafa|MM|;Cekin|Ruhper|R|;Saka|Burcu|B|;Köse|Emin|E|;Saydam|Tuba|T|;Geredeli|Caglayan|C|;Cihan|Sener|S|;Bilici|Ahmet|A|",
"chemical_list": "D001685:Biological Factors; D000068258:Bevacizumab; D000077544:Panitumumab; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1111/codi.15389",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-8910",
"issue": "23(1)",
"journal": "Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland",
"keywords": "RAS mutations; biological agents; colorectal cancer",
"medline_ta": "Colorectal Dis",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001685:Biological Factors; D000068818:Cetuximab; D015179:Colorectal Neoplasms; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D000077544:Panitumumab",
"nlm_unique_id": "100883611",
"other_id": null,
"pages": "206-212",
"pmc": null,
"pmid": "33002301",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The conversion of RAS status in metastatic colorectal cancer patients after first-line biological agent treatment.",
"title_normalized": "the conversion of ras status in metastatic colorectal cancer patients after first line biological agent treatment"
} | [
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"companynumb": "TR-AMGEN-TURSP2021086056",
"fulfillexpeditecriteria": "2",
"occurcountry": "TR",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
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{
"abstract": "BACKGROUND Central nervous system complications after transplantation occur in up to 40% of recipients and these complications are associated with increased length of hospital stay and mortality. Catatonia is a neuropsychiatric clinical syndrome which has been described in case reports and in a small case series as occurring in the immediate post-solid organ transplantation (SOT) period, and it has been attributed to calcineurin inhibitor neurotoxicity, psychological vulnerability, and depression. Among transplant recipients, the incidence of catatonia is unknown; it may be under diagnosed in part due to a broad differential diagnosis in the post-transplantation setting, which includes hypoactive delirium, non-convulsive status epilepticus, drug toxicity, conversion disorder, and volitional uncooperativeness. CASE REPORT We present 2 cases of catatonia diagnosed in liver allograft recipients. We also reviewed current literature for cases of catatonia among SOT recipients. We provide provisional evaluation and management strategies of recipients with clinical concern for catatonia. Catatonia generally occurs within the few first days after liver transplantation, and presents with staring, immobility, or mutism, but is also associated with other neurological and psychiatric symptoms. Catatonia can be successfully treated with intravenous lorazepam, and thus, modifying immunosuppressive regimens may be avoidable. Medications to treat catatonia are generally tapered over weeks to months, and psychiatric follow-up is indicated. The early post-liver transplantation period may be a state of relative deficiency in GABA (gamma-aminobutyric acid) signaling, predisposing liver transplant recipients in particular to post-transplantation catatonia. CONCLUSIONS Despite difficulties in establishing the diagnosis, catatonia after liver transplantation was rapidly responsive to intravenous lorazepam, indicating that changing immunosuppressants may be avoidable.",
"affiliations": "Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.;Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.;Department of Surgery, Division of Abdominal Transplant, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.",
"authors": "Tatreau|Jason R|JR|;Laughon|Sarah L|SL|;Kozlowski|Tomasz|T|",
"chemical_list": "D018757:GABA Modulators; D008140:Lorazepam",
"country": "United States",
"delete": false,
"doi": "10.12659/AOT.910298",
"fulltext": "\n==== Front\nAnn TransplantAnn. TransplantAnnals of TransplantationAnnals of Transplantation1425-95242329-0358International Scientific Literature, Inc. 3015060610.12659/AOT.910298910298Case ReportCatatonia After Liver Transplantation Tatreau Jason R. 1ABCDEFLaughon Sarah L. 1ABCDEFKozlowski Tomasz 2ABCDEF\n1 Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, U.S.A.\n2 Department of Surgery, Division of Abdominal Transplant, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, U.S.A.Corresponding Author: Tomasz Kozlowski, e-mail: tomasz_kozlowski@med.unc.eduA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\n2018 28 8 2018 23 608 614 29 3 2018 28 4 2018 © Ann Transplant, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Background\nCentral nervous system complications after transplantation occur in up to 40% of recipients and these complications are associated with increased length of hospital stay and mortality. Catatonia is a neuropsychiatric clinical syndrome which has been described in case reports and in a small case series as occurring in the immediate post-solid organ transplantation (SOT) period, and it has been attributed to calcineurin inhibitor neurotoxicity, psychological vulnerability, and depression. Among transplant recipients, the incidence of catatonia is unknown; it may be under diagnosed in part due to a broad differential diagnosis in the post-transplantation setting, which includes hypoactive delirium, non-convulsive status epilepticus, drug toxicity, conversion disorder, and volitional uncooperativeness.\n\nCase Report\nWe present 2 cases of catatonia diagnosed in liver allograft recipients. We also reviewed current literature for cases of catatonia among SOT recipients. We provide provisional evaluation and management strategies of recipients with clinical concern for catatonia.\n\nConclusions\nDespite difficulties in establishing the diagnosis, catatonia after liver transplantation was rapidly responsive to intravenous lorazepam, indicating that changing immunosuppressants may be avoidable.\n\nMeSH Keywords\nCatatoniaDeliriumGABA AgentsLiver TransplantationNeurotoxicity SyndromesPsychiatry\n==== Body\nBackground\nCentral nervous system complications after liver transplantation occur in up to 40% of recipients, and these complications are associated with increased length of hospital stay and mortality [1]. Catatonia is a neuropsychiatric syndrome with motor, speech, and behavioral abnormalities that has been described in several case reports of transplant recipients. However, among transplant recipients, the incidence of catatonia is unknown. Many potential transplant-related factors have been associated with catatonia syndromes in non-transplanted patients, including infection, posterior reversible encephalopathy syndrome [2,3], akinetic mutism [4], uremic encephalopathy [5], hyponatremia [6], and osmotic demyelination syndrome [7]. Immunosuppressants have specifically been implicated in catatonia among transplant recipients [8–10]. While the pathophysiology of catatonia remains unclear, proposed mechanisms involve neuronal decreases of GABA (gamma-aminobutyric acid) and dopamine and increases in glutamate [11].\n\nCatatonia is challenging to diagnose due to varying severity, symptom fluctuation, and lack of objective diagnostic testing. Additional difficulty in diagnosis is related to its broad differential diagnosis in the post-transplantation setting, including hypoactive delirium, non-convulsive status epilepticus, drug toxicity, conversion disorder, and volitional uncooperativeness [9,10,12,13].\n\nWe present 2 cases of catatonia diagnosed in the early post-operative period among liver allograft recipients at our institution. That we identified 2 cases within a 6-month period prompted a literature review of all known cases of catatonia after solid organ transplantation (SOT), which has not been described before. In this paper, we also discuss provisional evaluation and management strategies of transplant recipients with clinical concern for catatonia. We believe this short series, literature review, and recommendations will increase awareness and management of catatonia among transplant recipients.\n\nCase Report\nWe present 2 case reports and a review of the literature for known cases of catatonia in transplant recipients. On March 7, 2017, we systematically reviewed PubMed, EMBASE, and PsyINFO by cross-referencing the search terms “catatoni*” AND “transplant*”. Abstracts from EMBASE (35), PubMed (18), and PsyINFO (12) were reviewed for cases of catatonia in the context of SOT. Individual articles were also reviewed for additional references. Symptoms of catatonia were variably described among the cases identified, and only 4 articles quantified the severity of catatonia with a rating scale: the Bush-Francis Catatonia Rating Scale (BFCRS) was used in 3 cases and the Northoff Catatonia scale was used in 1 case. We reviewed each article for mention of any of the symptoms described in the BFCRS screening questions 1–14 and noted them as present or absent.\n\nCase 1\nA 52-year-old male with cirrhosis secondary to hepatitis C virus (HCV) infection and alcoholism (in remission greater than 1 year) with chronic ascites, hepatic encephalopathy, and a calculated MELD (Model for End-Stage Liver Disease) score of 16 received orthotopic ABO-compatible liver transplant (OLT) complicated by intra-operative large volume ascites loss and acute kidney injury on post-operative day (POD) 1, temporarily necessitating hemodialysis. The patient’s allograft function was good throughout the post-operative course. The immunosuppressive regimen consisted of tacrolimus (TAC), mycophenolate mofetil (MMF), and methylprednisolone. Psychiatric history consisted of bipolar disorder with multiple prior psychiatric hospitalizations in remission, with the patient on 20 mg nightly of olanzapine. Psychiatry was consulted on POD 1 for recommendations on restarting olanzapine. Psychiatry evaluation revealed no evidence of delirium, mania, psychosis, or other behavioral abnormalities, and given the absence of any recent mood symptoms and out of caution given his transplant, the recommendation was to restart olanzapine at a lower 5 mg dose with a plan to titrate to his prior home dose. He continued hemodialysis and physical therapy for the next 3 days without issue. On POD 4, he refused to get out of bed to work with Physical Therapy and didn’t answer questions asked by the surgical team, who became concerned that he was depressed. He was reassessed by Psychiatry on POD 6 and was noted to be alternating between staring blankly and looking around the room as though he was paranoid or confused, sometimes holding his head sideways for several seconds. He reported auditory hallucinations but would not discuss the nature of this. His speech alternated between periods of whispering, pausing for extended periods before answering, and not answering questions at all. His BFCRS score was 2. Neurological examination was remarkable for a mild bilateral upper extremity resting tremor. Electroencephalogram (EEG) was without epileptiform activity or diffuse background slowing. Blood work, including infectious workup, were all unremarkable. His TAC trough level was 1.4 ng/mL. Psychiatry was primarily concerned for psychosis or possible delirium and recommended increasing olanzapine to 10 mg nightly. The next day (POD 7), he had an episode of non-responsiveness and Neurology was consulted. His neurological examination was non-focal. The only signs of catatonia appreciated were mutism and head turning sideways at times, and the Neurology team was concerned for delirium and recommended a magnetic resonance imaging (MRI) to rule out intracranial pathology. Later that day (POD 7), he had another episode of unresponsiveness, including not moving his extremities. Repeated blood work and a head computed tomography (CT) were normal. Neurology was concerned for non-convulsive seizures and he received 2 mg of intravenous (IV) lorazepam, shortly after which he began moving his extremities and became fully aroused. Hours later, he again became non-responsive, but also was hypotensive, hypoxic, and required transfer to the intensive care unit. Repeat EEG showed only diffuse background slowing. Serial neurological examinations revealed the onset of immobility, negativism, waxy flexibility, catalepsy, posturing, staring, and mutism; BFCRS score was 18. Psychiatry recommended, and Neurology agreed, with administration of another dose of IV lorazepam, though a lower dose of 0.5 mg given his prior poor tolerance of 2 mg. He did not respond to a 0.5 mg dose, but after another 0.5 mg dose, he began smiling, making eye contact, and answering questions within 30 minutes. Based on this clinical scenario and his response to lorazepam, catatonia was diagnosed. Lorazepam was scheduled at 1 mg IV twice daily. In an abundance of caution, TAC was changed to cyclosporine (CyA) on POD 8. Due to ongoing staring and immobility, lorazepam was titrated over 6 days to 4 mg IV every 4 hours. Sedation and low normal blood pressures precluded further dose increase, so memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, was added at 5 mg twice daily for catatonia. His catatonia gradually improved over several days. Lorazepam was converted to oral formulation. With lorazepam 4 mg 4 times daily and memantine 10 mg twice daily catatonia resolved by POD 22 (BFCRS score was 0). He was discharged home on this regimen, which was tapered over 3 months by his outpatient transplant psychiatrist. Catatonia symptoms did not return.\n\nCase 2\nA 66-year-old female with cryptogenic cirrhosis and a calculated MELD score of 35 received an OLT without intra-operative complications. The immediate post-operative course was unremarkable, and her allograft functioning was good. The immunosuppressive regimen consisted of TAC, MMF, and methylprednisolone. She had no psychiatric history. On POD 3, she was seen for routine post-operative follow-up by the Transplant Psychologist, and was noted to be alert and fully oriented, but with new-onset communication difficulties including poor word-finding, speech latency, and dysarthria. She was fixated on her urine output to the exclusion of being able to hold a conversation. On POD 4, she began staring at the ceiling and reported visual hallucinations. Head CT and repeat blood work were non-contributory. Despite desired therapeutic levels, TAC was discontinued out of concern for neurotoxicity, and she was started on CyA. Her speech difficulties fluctuated over the next few days, and Neurology was consulted. Her brain MRI was without evidence of acute stroke and her 24-hour EEG was without epileptiform activity, diffuse background slowing, or other abnormalities, and routine non-pharmacologic delirium precautions were recommended. On POD 10 she was noted by Physical Therapy to have “freezing episodes” where she would stop moving and appear “stuck”, would not talk, and had an episode of urinary incontinence while standing. She became paranoid that the “devil” was coming for her, refused her immunosuppressive medications, and exhibited verbigeration, repeating (over 40 times according to her nurse) “I don’t think I’m supposed to take this”. Psychiatry was consulted and noted that she was mute, continuously pointing towards the ceiling, staring upwards without blinking, and resisting attempts at moving her arms. She also demonstrated mitgehen, positive grasp reflex, and withdrawal. Her BFCRS was 21 and Psychiatry recommended a trial of lorazepam. Within 15 minutes of receiving 2 mg IV lorazepam she became interactive, conversed appropriately, and acted without abnormal behaviors. Catatonia was diagnosed, and she was started on scheduled IV lorazepam. After a second dose of lorazepam the next morning, she became sedated and was without any residual evidence of catatonia. In light of her improvement, lorazepam was stopped. She was without evidence of catatonia for 3 days when on POD 14 she became “frozen” again and refused her medications. At that time, her vitals were within normal limits. Labs including CBC, complete metabolic panel, and CyA levels were unremarkable. She was given a third dose of 2 mg IV lorazepam and again her catatonia symptoms completely resolved. To reduce the likelihood of catatonia symptoms returning while not over sedating her, she was started on standing lorazepam 1 mg by mouth 3 times daily on POD 16, which she tolerated well without sedation or return of catatonia. She was discharged on POD 17. Lorazepam was tapered over the next several weeks by Psychiatry, and her catatonia symptoms did not return.\n\nDiscussion\nOur literature search identified 11 additional cases of post-transplantation catatonia among liver (8), heart (1), kidney (1), and kidney/pancreas (1) recipients [9,10,13–20]. Including our 2 cases, a total of 13 cases of post-transplantation catatonia are now described in the literature. Mean age of all patients was 53 years, ranging from 21–66 years of age. Sixty-two percent of cases were male. Psychiatric histories were described for 12 recipients, of which 9 recipients had significant psychiatric histories (Table 1). Only 3 recipients were reported to be taking psychotropics at the time of transplantation, 2 for depression and 1 for bipolar disorder.\n\nOverall, 10 out of 13 cases (77%) of post-SOT catatonia are among liver recipients; 9 received liver transplants and 1 received liver and kidney transplants. Liver recipients had a variety of primary hepatic diseases, including HCV cirrhosis (3 out of 10), alcoholic cirrhosis (2 out of 10), primary biliary cirrhosis (1 out of 10), non-alcoholic steatohepatitis (1 out of 10), and non-alcoholic fatty liver disease (1 out of 10). Underlying hepatic diseases were not reported in 2 cases. A minority of recipients (2 out of 10) developed transient complications in the early post-transplantation period, and there were no deaths.\n\nThe onset of catatonia was specified in 12 of the published cases. In 58% of cases (7 out of 12), catatonia was noted within 4 days of transplantation, and 6 of these 7 were among liver recipients. None of the non-liver recipients developed catatonia within the first week after transplantation (Table 1). The most common symptoms of catatonia among all cases were immobility (77%), staring (77%), withdrawal (77%), mutism (69%), negativism (61%), posturing (46%), echolalia (38%), and stereotypy (38%). The average number of catatonia symptoms was 6 (range 2–8). Concurrent psychiatric or neurologic symptoms were observed in all 13 cases, most commonly paranoia (46%), agitation (23%), hallucinations (23%), myoclonus (23%), and tremor (23%). For all 13 cases, once symptoms were recognized, early psychiatric consultation was requested, resulting in a diagnosis of catatonia.\n\nOf the 11 cases in which blood work was discussed, there were no blood work abnormalities described with any regularity. Hypomagnesemia was noted in only 4 cases (31%), and no patients had a magnesium level less than 1.5 mg/dL. Brain imaging was performed in 62% of cases, and none showed acute pathology. EEG was obtained in 54% of cases, and 5 EEGs showed diffuse slowing or generalized dysrhythmias. None showed epileptiform activity.\n\nImmunosuppressive regimens were reported in 10 patients. Immunosuppressive regimens were adjusted following the onset of catatonic symptoms in 7 cases despite therapeutic trough levels in 6 patients, of which 3 were before benzodiazepines were given. For our 2 cases, this reflected a reactive response of the medical team before we were able to reach a comfort level in taking care of these patients with suspicion of catatonia. In Brown et al. [13], a supratherapeutic TAC level (30.4 ng/mL) and MRI consistent with atypical posterior reversible encephalopathy syndrome (PRES), not the management of catatonia, triggered modification of immunosuppressive regimen [13]. In UNC Case 2, TAC was changed to CyA 8 days prior to catatonia treatment.\n\nBenzodiazepines were the most common initial treatment (9 cases), followed by zolpidem (1 case), sertraline plus methylphenidate (1 case), olanzapine (1 case), and mirtazapine (1 case). Seven cases showed significant reduction in catatonia symptoms within 60 minutes of the first treatment dose, and another 2 cases improved within 24 hours. In each of these 9 cases with rapid resolution of catatonia, benzodiazepines were used at the equivalent of at least 1 mg IV lorazepam. Dosing of lorazepam was increased in 2 cases due to incomplete resolution of catatonia: in 1 case to a total of 24 mg daily, and in another case from 0.5 mg every 6 hours, which gave a modest response after 24 hours, to 1 mg every 6 hours, which improved the response. Lorazepam dosing was decreased after the initial dose in 2 cases, both out of concern for over-sedation. Neuroleptics were used at some point in 38% of cases, and no cases of conversion to malignant catatonia or neuroleptic malignant syndrome occurred. Catatonia was successfully and completely treated in all 13 cases. Notably, psychopharmacologic agents started during catatonia were continued for at least 2 weeks in 77% of cases, including benzodiazepines (6 cases), antipsychotics (5 cases), memantine (1 case), methylphenidate (1 case), and mirtazapine (1 case).\n\nCatatonia in the early post-transplantation setting generally presents as a clinical syndrome of behavioral, motor, and speech abnormalities. Behavioral disturbances can include not working with physical and occupational therapists (immobility), poor oral intake or refusing medications (withdrawal), not making eye contact, or staring. Motor abnormalities vary but may be most noticeable during assessment of range of motion of upper extremities, when resistance to movement (negativism or waxy flexibility), exaggerated movements, or posturing may be evident. Speech abnormalities may include delayed or slowed responses, copy-catting (echolalia), repeating phrases (verbigeration), returning to the same topic (perseveration), or complete mutism. Without further investigation, these symptoms could potentially be attributed to hypoactive delirium, medication sedation, depression, volitional uncooperativeness, non-convulsive status epilepticus, or conversion disorder. While the majority had a positive psychiatric or substance abuse history, only a minority (3 out of 13 patients) were taking psychotropics for active psychiatric symptoms at the time of transplantation, and active psychiatric symptoms, such as anxiety, paranoia, and hallucinations, do not preclude a diagnosis of catatonia.\n\nSimilar to catatonia associated with other medical and psychiatric etiologies, post-transplantation catatonia is rapidly responsive to benzodiazepines, most commonly IV lorazepam. Effective dosing generally ameliorates catatonia symptoms within 60 minutes, though symptoms commonly remerge, and repeated dosing is often necessary. Dosing intervals should be frequent enough to prevent symptom reemergence. Initial dosing of 1–2 mg given 3 to 4 times daily is reasonable. IV lorazepam was the initial treatment in 8 recipients and was successful in all 7 cases where the dose was at least equivalent to 1 mg lorazepam. Paradoxical agitation was reported in 1 case after a single 0.5 mg IV dose [17]. This could arguably represent a positive response that unmasked an underlying agitated delirium. Some patients may be susceptible to sedation, hypotension, or worsening underlying delirium, and augmentation with non-benzodiazepines should be considered. Initial treatment with zolpidem was used successfully in 1 case and then switched to oxazepam [15]; memantine was used in 2 cases successfully (in 1 case to avoid benzodiazepine in order to avoid exacerbation of an underlying delirium [13], and in our Case 2 to augment lorazepam when dose increases were precluded by sedation and hypotension. IV dosing may be converted to oral dosing after symptoms have been effectively treated for 1 to 2 days.\n\nNeuroleptics used post-operatively for delirium and agitation are generally avoided in catatonia. While dopamine-blocking neuroleptics, generally high potency typical antipsychotics, have been linked to malignant catatonia or neuroleptic malignant syndrome [21,22], these cases showed that atypical antipsychotics may be prudently considered for concurrent symptoms of delirium (paranoia, hallucinations, agitation).\n\nThat the majority of cases did not involve changing immunosuppressive regimens indicates that changing regimens is potentially avoidable in post-transplantation catatonia, and based on these cases, switching to a non-calcineurin inhibitor agent such as sirolimus may be avoidable. For the 6 patients in whom immunosuppressants were changed, 5 were continued on a calcineurin inhibitor (from TAC to cyclosporine) and 1 was switched to sirolimus, suggesting that if either TAC or cyclosporine does contribute to catatonia, the mechanism is not through a class effect. Importantly, immunosuppressant serum levels were only supratherapeutic in 1 case, in which atypical PRES was also diagnosed. Therefore, it cannot be said that a therapeutic immunosuppressant level precludes a diagnosis of catatonia.\n\nCatatonia in the post-transplantation setting is surprisingly common among liver recipients and occurs early in the post-operative setting. While precise mechanisms for the development of catatonia are poorly understood, neuronal deficiencies in GABA are likely involved as evidenced by the efficacy of GABA agonists, such as benzodiazepines, in treating catatonia regardless of its etiology [12]. That the onset of catatonia is generally abrupt, within days after transplantation, supports the hypothesis that abrupt changes in neurotransmitter balance may occur in patients with newly transplanted livers and may be contributing to post-transplantation catatonia. Several lines of evidence implicate a relative deficiency in GABA-dependent signaling after liver transplantation specifically. Chronic liver failure is linked to neurochemical adaptations, including upregulation of GABA signaling [23–25]. Lack of effective hepatic metabolism of endogenous GABA-ergic neurotransmitters may lead to their accumulation and enhanced neuronal activity. Ammonia has been shown to modulate GABA receptors, further increasing GABA-ergic signaling in liver failure [26]. Reversal of this condition by liver allograft may lead to an acute state of relative GABA deficiency in the early post-operative period. TAC and CyA [27] are postulated to inhibit GABA activity as well as potentiate NMDA receptor activity, another mechanism implicated in the causality of catatonia [8,28]. Increasing GABA-ergic signaling with GABA agonists, such as benzodiazepines, may correct rapid changes in GABA signaling brought about by liver exchange, whereas memantine may treat catatonia through NMDA-receptor antagonism.\n\nGiven the variable presentation, symptom overlap, and effectiveness of early treatment, a low index of suspicion for catatonia in the early post-transplant liver recipient should be considered. Pre-transplantation ammonia levels have not been described among liver allograft recipients that develop catatonia, but it would be of clinical interest to determine whether pre-transplantation hyperammonemia is associated with catatonia after liver transplantation. Increased awareness and understanding of catatonia in the early post-transplantation period may shorten the length of hospital stay and decrease mortality. Early involvement of consult-liaison psychiatry can aid with diagnosis, treatment, and outpatient psychiatric care that may be indicated following hospital discharge.\n\nConclusions\nCatatonia in the early post-transplantation setting is a clinical syndrome of behavioral, motor, and speech abnormalities that with careful consideration could potentially be attributed to hypoactive delirium, medication sedation, depression, volitional uncooperativeness, non-convulsive status epilepticus, or conversion disorder. Post-transplantation catatonia is rapidly responsive to IV lorazepam, and neuroleptics may be prudently considered for concurrent symptoms of delirium. Changing immunosuppressive regimens is potentially avoidable in a post-transplantation catatonia. Catatonia in the post-transplantation setting is surprisingly common among liver recipients and occurs early in the post-operative setting. We hypothesize that it may be related to an acute state of relative GABA deficiency in the early post-operative period induced by liver explantation rapidly correcting a state of elevated GABA-ergic neurotransmission in chronic liver failure. Increased awareness and understanding of catatonia in the early post-transplantation period may shorten the length of hospital stay and decrease mortality. Early involvement of consult-liaison Psychiatry can aid with diagnosis, treatment, and outpatient psychiatric care that may be indicated following hospital discharge.\n\nAcknowledgments\nAuthors thank Dr. Kenneth Andreoni, University of Florida for the critical review of the manuscript.\n\nConflicts of interest.\n\nNone.\n\nSource of support: None\n\nTable 1 Case reports of catatonia after solid organ transplantation.\n\n\tAge/ sex\tPsychiatric history\tTrans-plant\tOnset (post-operative day)\tImmuno-suppressants\tChanges to immuno-suppressants\tInitial treatment\tResponse\tAgents used to lyse catatonia\tNeuroleptic\tProposed etiology\t\nUNC Case 1\t52/M\tBipolar\tLiver\t4\tTac, MMF, Pred\tTac to CyA (after positive Ativan challenge\tAtivan 2 mg IV\t60′\tAtivan 4 mg IV every 4 h + Namenda 10 mg BID\tZyprexa (bipolar)\tGABA deficiency\t\nUNC Case 2\t66/F\tnone\tLiver\t3\tTac, MMF, Pred\tTac to CyA (8 days before Ativan)\tAtivan 2 mg IV\t15′\tSingle dose, then Ativan 1 mg PO TID\tNone\tGABA deficiency\t\nCotteincin et al. [15]\t50/F\tnone\tLiver\t3\t?\tNo\tAmbien 10 mg PO\t30′\tSerax 40 mg daily\tNone\tPsycho-logical vulnerability\t\nHuang et al. [16]\t50/M\t?\tLiver\t3\t?\t?\tAtivan 1 mg IV\t60′\tAtivan 1 mg IV\tSeroquel\tPsycho-logical vulnerability\t\nSeetheram et al. [17]\t49/M\tAUD (remission)\tLiver\t3\tCyA, MMF, Pred\tStopped CyA (before oxazepam)\tZyprexa\tnone\tSerax + Ambien\tNone\tGABA deficiency\t\nO’Donnell et al. [9]\t54/M\tnone\tLiver\t7\tTac, MMF, Pred\tNo\tAtivan 1 mg IV\t60′\tAtivan 0.5 mg IV BID\tHaldol\tTac neurotoxicity (akinetic mutism)\t\nKalivas et al. [18]\t52/M\tAUD (remission)\tLiver + kidney\t2\t?\t?\tAtivan 1 mg IV\t24 h\tAtivan 0.5 mg IV QID\tZyprexa\tnone\t\nCorchs et al. [19]\t55/M\t?\tHeart\t11\t?\t?\tZoloft + Ritalin\t4 d\tRitalin\tNone\tCatatonic depression\t\nChopra et al. [10]\t57/F\tAUD (remission)\tKidney + pancreas\t?\tTac, MMF, Pred\tNo\tAtivan 1 mg PO\tNone\tNo meds\tNone\tTac neurotoxicity\t\nChopra et al. [10]\t60/M\tPTSD\tLiver\t8\tTac, MMF, Pred\tTac to CyA (after Ativan challenge)\tAtivan 0.5 mg IV\tNone\tNo meds\tNone\tTac neurotoxicity\t\nChung et al. [14]\t59/F\tMDD\tLiver\t2\tMMF, Pred\tNo\tAtivan 1 mg IV\t30′\tAtivan 1 mg IV QID\tNone\tSteroid – induced psychosis w/catatonic features\t\nKusztal et al. [20]\t21/F\tnone\tKidney\t9\tTac, MMF, Pred\tTac to CyA (before Valium)\tValium 2.5 mg IV\tNone\tECT\tZyprexa (psychosis)\tAnti-LG1 Antibody encephalitis + Tac neurotoxicity\t\nBrown et al. [13]\t59/M\tMDD\tLiver\t89\tTac, MMF, Pred\tTac to Sirolimus (Tac 30.4)\tRemeron\tNone\tNamenda 10 mg BID\tNone\tTac neurotoxicity (PRES)\t\nUNC – University of North Carolina Hospitals; AUD – alcohol use disorder; Tac – tacrolimus; MMF – mycophenolate mofetil; CyA – cyclosporine A; Pred – prednisolone/prednisone; Neurotox – neurotoxicity; PRES – posterior reversible encephalopathy syndrome; GABA – gamma-aminobutyric acid.\n==== Refs\nReferences\n1 Bernhardt M Pfugrad H Goldbecker A Central nervous system complications after liver transplantation: Common but mostly transient phenomena Liver Transpl 2007 13 465 66 17396292 \n2 Spiegel DR Varnell C Jr A case of catatonia due to posterior reversible encephalopathy syndrome treated successfully with antihypertensives and adjunctive olanzapine Gen Hosp Psychiatry 2011 33 3 302.e3 5 \n3 Kitabayashi Y Hamamoto Y Hirosawa R Postpartum catatonia associated with atypical posterior reversible encephalopathy syndrome J Neuropsychiatry Clin Neurosci 2007 19 1 91 92 \n4 Najera JE Alousi A De Lima M Ciurea SO Akinetic mutism-a serious complication to tacrolimus-based GVHD prophylaxis Bone Marrow Transplant 2013 48 1 157 58 22705799 \n5 Desai NG Patil NM Gangadhar BN Catatonia associated with uraemic encephalopathy Indian J Psychiatry 1984 26 1 95 96 21965965 \n6 Jaimes-Albornoz W Serra-Mestres J Prevalence and clinical correlations of catatonia in older adults referred to a liaison psychiatry service in a general hospital Gen Hosp Psychiatry 2013 35 5 512 16 23684045 \n7 Koussa S Nasnas R Catatonia and parkinsonism due to extrapontine myelinolysis following rapid correction of hyponatremia: A case report J Neurol 2003 250 103 5 12528003 \n8 Bernstein L Levin R Catatonia responsive to intravenous lorazepam in a patient with cyclosporine neurotoxicity and hypomagnesemia Psychosomatics 1994 34 1 102 3 \n9 O’Donnell MM Williams JP Weinrieb R Denysenko L Catatonic mutism after liver transplant rapidly reversed with lorazepam Gen Hosp Psychiatry 2007 29 280 81 17484951 \n10 Chopra A Das P Rai A Catatonia as a manifestation of tacrolimus-induced neurotoxicity in organ transplant patients: A case series Gen Hosp Psychiatry 2012 34 209.e9 11 \n11 Northoff G What catatonia can tell us about “top-down modulation”: A neuropsychiatric hypothesis Behav Brain Sci 2002 25 555 604 12958742 \n12 Denysenko L Freudenreich O Philbrick K Clinical monograph: Catatonia in medically ill patients an evidence-based medicine (EBM) Monograph for Psychosomatic Medicine Practice 2015 \n13 Brown GD Muzyk AJ Preud’homme XA Prolonged delirium with catatonia following orthotopic liver transplant responsive to memantine J Psychiatr Pract 2016 22 128 32 27138082 \n14 Chung I Weber GM Cuffy MC A 59-year-old woman who is awake yet unresponsive and stuporous after liver transplantation Chest 2013 143 1163 65 23546491 \n15 Cottencin O Debien C Vaiva G Catatonia and liver transplant Psychosomatics 2002 43 338 39 12189264 \n16 Huang AS Schwartz EH Travis TS Bourgeois JA Catatonia after liver transplantation Psychosomatics 2006 47 451 52 16959938 \n17 Seetheram P Akerman RR Postoperative echolalia and catatonia responsive to gamma aminobutyric acid receptor agonists in a liver transplant patient Anesth Analg 2006 103 785 86 \n18 Kalivas KK Bourgeois JA Catatonia after liver and kidney transplantation Gen Hosp Psychiatry 2009 31 196 98 19269546 \n19 Corchs F Teng CT Amphetamine, catatonic depression, and heart transplant: A case report Rev Bras Psiquiatr 2010 32 324 26 20945029 \n20 Kusztal M Piotrowski P Mazanowska O Catatonic episode after kidney transplantation Gen Hosp Psychiatry 2014 36 5 7 \n21 Cremona-Barbaro A Neuroleptic-induced catatonic symptoms Br J Psychiatry 1983 142 98 99 6831138 \n22 Johnson GC Manning DE Neuroleptic-induced catatonia: Case report J Clin Psychiatry 1983 44 310 12 6874654 \n23 Ahboucha S Gamrani H Baker G GABAergic neurosteroids: The “endogenous benzodiazepines” of acute liver failure Neurochem Int 201 60 707 14 \n24 Frederick RT Extent of reversibility of hepatic encephalopathy following liver transplantation Clin Liver Dis 2012 16 147 58 22321470 \n25 Jones EA Schafer DF Ferenci P Pappas SC The GABA hypothesis of the pathogenesis of hepatic encephalopathy: Current status Yale J Biol Med 1984 57 301 16 6093394 \n26 Jones EA Ammonia, the GABA neurotransmitter system, and hepatic encephalopathy Metab Brain Dis 2002 17 275 81 12602504 \n27 Shuto H Kataoka Y Fujisaki K Inhibition of GABA system involved in cyclosporine-induced convulsions Life Sci 1999 65 879 87 10465348 \n28 Chen S-R Hu Y-M Chen H Pan H-L Calcineurin inhibitor induces pain hypersensitivity by potentiating pre- and postsynaptic NMDA receptor activity in spinal cords J Physiol 2014 592 215 27 24081160\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1425-9524",
"issue": "23()",
"journal": "Annals of transplantation",
"keywords": null,
"medline_ta": "Ann Transplant",
"mesh_terms": "D000368:Aged; D002389:Catatonia; D005260:Female; D018757:GABA Modulators; D006801:Humans; D016031:Liver Transplantation; D008140:Lorazepam; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D016896:Treatment Outcome",
"nlm_unique_id": "9802544",
"other_id": null,
"pages": "608-614",
"pmc": null,
"pmid": "30150606",
"pubdate": "2018-08-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17308241;23684045;6093394;17484951;20945029;21965965;23546491;16959938;27138082;16931705;6874654;25369566;24559791;12528003;6831138;12602504;24081160;22705799;19269546;21601735;21937118;12189264;12958742;22321470;8426885;10465348;22041164",
"title": "Catatonia After Liver Transplantation.",
"title_normalized": "catatonia after liver transplantation"
} | [
{
"companynumb": "US-ACCORD-098091",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nLate-onset neutropenia (LON) is a known adverse effect to rituximab therapy. Information about its real incidence and clinical implications comes from case reports and few retrospective studies specifically designed to study LON. However, large prospective studies of LON are lacking in the literature. We aimed to determine the incidence of LON in a group of non-Hodgkin lymphoma patients treated with rituximab and to analyze the clinical course, complications, and risk factors associated with LON.\n\n\nMETHODS\nWe retrospectively reviewed 183 patients with a diagnosis of non-Hodgkin lymphoma consecutively treated with rituximab alone or in combination with chemotherapy.\n\n\nRESULTS\nWe identified 11 patients with grade 3/4 LON (13 episodes) out of 183 patients (6%). The median time to onset of LON was 75 days, and the median time to recovery from neutropenia was 100 days. The median neutrophil count nadir was 0.55 × 10(9)/L (range, 0.06-0.9 × 10(9)/L). Two patients presented infectious complications, one with fatal outcome.\n\n\nCONCLUSIONS\nIn our experience, the incidence of recognized LON is low (6%), although its real incidence may be greater because of the asymptomatic course and quick recovery in most cases. Infectious complications are unusual, but life-threatening complications can emerge. A careful evaluation of all cases of LON is warranted.",
"affiliations": "Department of Medical Oncology, Hospital Universitario de Gran Canaria Dr Negrin, Las Palmas de Gran Canaria, Spain. Electronic address: dagubuj@gobiernodecanarias.org.;Department of Medical Oncology, Hospital Universitario de Gran Canaria Dr Negrin, Las Palmas de Gran Canaria, Spain.;Department of Medical Oncology, Hospital Universitario de Gran Canaria Dr Negrin, Las Palmas de Gran Canaria, Spain.;Department of Medical Oncology, Hospital Universitario de Gran Canaria Dr Negrin, Las Palmas de Gran Canaria, Spain.;Department of Medical Oncology, Hospital Universitario de Gran Canaria Dr Negrin, Las Palmas de Gran Canaria, Spain.;Department of Medical Oncology, Hospital Universitario de Gran Canaria Dr Negrin, Las Palmas de Gran Canaria, Spain.;Department of Medical Oncology, Hospital Universitario de Gran Canaria Dr Negrin, Las Palmas de Gran Canaria, Spain.",
"authors": "Aguiar-Bujanda|David|D|;Blanco-Sánchez|María Jesús|MJ|;Hernández-Sosa|María|M|;Galván-Ruíz|Saray|S|;Hernández-Sarmiento|Samuel|S|;Saura-Grau|Salvador|S|;Bohn-Sarmiento|Uriel|U|",
"chemical_list": "D000970:Antineoplastic Agents; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "15(12)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Anti-CD20; Anticancer therapy; Chemoimmunotherapy; Haematological toxicity; Secondary effects",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D012189:Retrospective Studies; D000069283:Rituximab",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "761-5",
"pmc": null,
"pmid": "26319620",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Late-Onset Neutropenia After Rituximab-Containing Therapy for Non-Hodgkin Lymphoma.",
"title_normalized": "late onset neutropenia after rituximab containing therapy for non hodgkin lymphoma"
} | [
{
"companynumb": "PHHY2016ES009396",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"drug... |
{
"abstract": "OBJECTIVE\nTo report a case of herpes zoster keratitis in a patient undergoing treatment for herpetic acute retinal necrosis.\n\n\nMETHODS\nCase report.\n\n\nRESULTS\nA 71 year old male presented with acute retinal necrosis of the left eye due to herpes zoster and was treated with intravitreal foscarnet and oral valcyclovir. He developed a retinal detachment and underwent surgical repair. After four weeks, he developed an ipsilateral herpetic zoster keratitis demonstrated by Rose-Bengal staining that was responsive to topical ganciclovir gel.\n\n\nCONCLUSIONS\nThis case report describes the unusual development of herpes zoster keratitis after the development of unilateral acute retinal necrosis (ARN) in a patient on antiviral treatment.",
"affiliations": "Cleveland Clinic Foundation, Cole Eye Institute, 9500 Euclid Avenue Mail Code i13, Cleveland, OH, 44195, USA. Ansariw@ccf.org.;Cleveland Clinic Foundation, Cole Eye Institute, 9500 Euclid Avenue Mail Code i13, Cleveland, OH, 44195, USA.;Department of Ophthalmology, University of Colorado School of Medicine, 1675 Aurora Court, F731, Aurora, CO, 80045, USA.;Cleveland Clinic Foundation, Cole Eye Institute, 9500 Euclid Avenue Mail Code i13, Cleveland, OH, 44195, USA.;Cleveland Clinic Foundation, Cole Eye Institute, 9500 Euclid Avenue Mail Code i13, Cleveland, OH, 44195, USA.",
"authors": "Ansari|Waseem H|WH|;Pichi|Francesco|F|;Pecen|Paula E|PE|;Lowder|Careen Y|CY|;Srivistava|Sunil K|SK|",
"chemical_list": "D000998:Antiviral Agents; D015774:Ganciclovir",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10792-017-0521-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-5701",
"issue": "38(2)",
"journal": "International ophthalmology",
"keywords": "Acute retinal necrosis; Acyclovir resistance; Herpes zoster keratitis",
"medline_ta": "Int Ophthalmol",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D015774:Ganciclovir; D006563:Herpes Zoster Ophthalmicus; D006801:Humans; D007634:Keratitis; D008297:Male; D012163:Retinal Detachment; D015882:Retinal Necrosis Syndrome, Acute",
"nlm_unique_id": "7904294",
"other_id": null,
"pages": "829-832",
"pmc": null,
"pmid": "28434069",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21595539;22621210;11033138;23756055;17317412;7973122;6097854;2787629",
"title": "Herpes zoster keratitis development after acute retinal necrosis.",
"title_normalized": "herpes zoster keratitis development after acute retinal necrosis"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2017US-140028",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VALACYCLOVIR HYDROCHLORIDE"
},... |
{
"abstract": "Metastatic melanoma is a donor-derived malignancy that has rarely been reported in liver allograft recipients. We present a case of a transmitted donor-derived melanoma to a liver allograft recipient in whom the diagnosis was established by polymerase chain reaction-based DNA fingerprinting. A 52-year-old African-American man underwent a successful orthotropic liver transplant for alcohol-induced cirrhosis. One year after the orthotropic liver transplant, he presented at our institution with diffuse abdominal pain, and a computed tomography scan of the abdomen and chest showed innumerable masses diffusely involving the liver and multiple subcutaneous nodules in the abdominal and chest wall. A liver biopsy confirmed the diagnosis of metastatic melanoma. The origin of melanoma was traced to the donor by DNA fingerprinting of the native liver, the donor liver, and the donor gallbladder. Chemotherapy was initiated with temozolomide (75 mg/m² daily) and thalidomide (50 mg daily), to which he responded within 8 weeks with radiologic improvement in metastatic lesions. Tacrolimus was switched to sirolimus because of renal insufficiency as well as reported effectiveness against melanoma. Our patient survived for 9 months after the diagnosis of metastatic melanoma. He ultimately died of brain metastases. Donor-derived metastatic melanoma is a rare cancer with the highest transmission and mortality rates, which requires better recognition. Prompt diagnosis of donor-derived melanoma is critical and can be achieved reliably with polymerase chain reaction-based DNA analysis. Management options after diagnosis include de-escalation of immunosuppression, with or without urgent organ removal or retransplant. The roles of chemotherapy, immunotherapy, and radiotherapy require further study.",
"affiliations": "Department of Gastroenterology, University of Tennessee Health Science Center, Memphis, TN, USA.",
"authors": "Bilal|Muhammad|M|;Eason|James D|JD|;Das|Kanak|K|;Sylvestre|Pamela B|PB|;Dean|Amanda G|AG|;Vanatta|Jason M|JM|",
"chemical_list": "D014408:Biomarkers, Tumor; D007166:Immunosuppressive Agents",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2012.0243",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "11(5)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D014408:Biomarkers, Tumor; D001706:Biopsy; D001932:Brain Neoplasms; D016172:DNA Fingerprinting; D018450:Disease Progression; D017809:Fatal Outcome; D006801:Humans; D007166:Immunosuppressive Agents; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D011237:Predictive Value of Tests; D012878:Skin Neoplasms; D013997:Time Factors; D014019:Tissue Donors; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "458-63",
"pmc": null,
"pmid": "23534438",
"pubdate": "2013-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Donor-derived metastatic melanoma in a liver transplant recipient established by DNA fingerprinting.",
"title_normalized": "donor derived metastatic melanoma in a liver transplant recipient established by dna fingerprinting"
} | [
{
"companynumb": "US-ACTAVIS-2014-24094",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Hepatotoxicity may occasionally develop over the course of treatment with proton pump inhibitors (PPIs). Although skin reactions, interstitial nephritis, pancytopenia, anaphylaxis, and generalized edema have been reported to be associated with PPIs, hepatotoxicity associated with oral pantoprazole is very rare. In this report, we present a case of hepatotoxicity in a 35-year-old man who received pantoprazole (40 mg/day) for acute gastritis. One week after discontinuation of pantoprazole, his liver function began to improve, and the patient gradually fully recovered. Although this toxicity occurs only infrequently, pantoprazole should be considered as a rare hepatotoxic agent in the literature.",
"affiliations": "Medical Faculty, Department of Internal Medicine, Yuzuncu Yil University, 65000, Van, Turkey, m.aslan301@mynet.com.",
"authors": "Aslan|Mehmet|M|;Celik|Yilmaz|Y|;Karadas|Sevdegul|S|;Olmez|Sehmus|S|;Cifci|Adem|A|",
"chemical_list": "D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; D054328:Proton Pump Inhibitors; D000077402:Pantoprazole",
"country": "Austria",
"delete": false,
"doi": "10.1007/s00508-014-0535-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0043-5325",
"issue": "126(11-12)",
"journal": "Wiener klinische Wochenschrift",
"keywords": null,
"medline_ta": "Wien Klin Wochenschr",
"mesh_terms": "D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D015746:Abdominal Pain; D000897:Anti-Ulcer Agents; D056486:Chemical and Drug Induced Liver Injury; D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D000077402:Pantoprazole; D054328:Proton Pump Inhibitors; D035583:Rare Diseases; D016896:Treatment Outcome",
"nlm_unique_id": "21620870R",
"other_id": null,
"pages": "390-2",
"pmc": null,
"pmid": "24652021",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24310148;16416223;8897077;12016546;12649798;23350044;10677134;16144190;11434801;9165689;12840780;20586518;21298607;21626263;11341670;18655432;20374223;14535868;11558857;11421865",
"title": "Liver hepatotoxicity associated with pantoprazole: a rare case report.",
"title_normalized": "liver hepatotoxicity associated with pantoprazole a rare case report"
} | [
{
"companynumb": "TR-ACTAVIS-2015-09053",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PANTOPRAZOLE SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Xylazine is an emerging adulterant with fentanyl in fatal drug intoxications, which has public health, safety, and criminal investigative implications. Xylazine is a nonnarcotic sedative used for analgesia and muscle relaxation exclusively in veterinary medicine. Its chemical structure is similar to clonidine and acts as a central α-2 agonist which may cause bradycardia and transient hypertension followed by hypotension. We report the detection of xylazine in 42 deaths in Connecticut from March to August 2019. Xylazine combined with an opioid or stimulant may affect the toxicity of these drugs. Detection of xylazine may help the forensic pathologist distinguish illicit from prescribed fentanyl, and law enforcement agents track the illicit drugs to a specific drug supplier. Because of its lack of response to naloxone, emergency medicine physicians need to be aware of its potential presence as it may affect therapy.",
"affiliations": "From the Office of the Chief Medical Examiner, Farmington, CT.",
"authors": "Nunez|Jacqueline|J|;DeJoseph|Maura E|ME|;Gill|James R|JR|",
"chemical_list": "D000701:Analgesics, Opioid; D006993:Hypnotics and Sedatives; D013287:Illicit Drugs; D014991:Xylazine; D005283:Fentanyl",
"country": "United States",
"delete": false,
"doi": "10.1097/PAF.0000000000000622",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0195-7910",
"issue": "42(1)",
"journal": "The American journal of forensic medicine and pathology",
"keywords": null,
"medline_ta": "Am J Forensic Med Pathol",
"mesh_terms": "D000059:Accidents; D000328:Adult; D000701:Analgesics, Opioid; D002853:Chromatography, Liquid; D003237:Connecticut; D003334:Coroners and Medical Examiners; D062787:Drug Overdose; D005260:Female; D005283:Fentanyl; D006801:Humans; D006993:Hypnotics and Sedatives; D013287:Illicit Drugs; D008297:Male; D008875:Middle Aged; D019966:Substance-Related Disorders; D053719:Tandem Mass Spectrometry; D014991:Xylazine; D055815:Young Adult",
"nlm_unique_id": "8108948",
"other_id": null,
"pages": "9-11",
"pmc": null,
"pmid": "33031124",
"pubdate": "2021-03-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Xylazine, a Veterinary Tranquilizer, Detected in 42 Accidental Fentanyl Intoxication Deaths.",
"title_normalized": "xylazine a veterinary tranquilizer detected in 42 accidental fentanyl intoxication deaths"
} | [
{
"companynumb": "US-PFIZER INC-2020419706",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional": null,
... |
{
"abstract": "Multi-agent chemotherapy is recognized as the most common and effective treatment for Burkitt lymphoma, and intestinal mucosal injury is a common gastrointestinal complication following intensive chemotherapy. The aim of the present study was to describe a case of non-Hodgkin lymphoma with intestinal obstruction after chemotherapy in a young adult. The patient presented with aggravated vomiting during the second session of chemotherapy, which was initially attributed to superior mesenteric artery syndrome. However, following surgical intervention, the symptom was proven to be due to extreme intestinal stenosis in the ascending part of the duodenum. The patient underwent duodenojejunectomy and end-to-side anastomosis, and he recovered well from the operation. Although intestinal perforation and hemorrhage induced by chemotherapy have been previously reported sporadically, to the best of our knowledge, this is the first case report of distal duodenal obstruction due to intestinal atresia induced by polychemotherapy for lymphoma. We herein analyze the possible underlying reasons for the intestinal atresia and review the clinical and pathological characteristics of previously published relevant studies. The present findings may be helpful for increasing clinical awareness of this type of complication, as well as improving the management of patients treated with cytotoxic chemotherapeutic agents.",
"affiliations": "Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China.;Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China.;Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China.;Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China.;Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China.;Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China.",
"authors": "Wang|Xing|X|;Li|Jian-Zhong|JZ|;Yang|Ying-Hui|YH|;Huang|Xiao-Li|XL|;Wang|Yu|Y|;Wu|Bin|B|",
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"doi": "10.3892/mco.2017.1353",
"fulltext": "\n==== Front\nMol Clin OncolMol Clin OncolMCOMolecular and Clinical Oncology2049-94502049-9469D.A. Spandidos 10.3892/mco.2017.1353MCO-0-0-1353ArticlesIntestinal atresia following chemotherapy, presenting as superior mesenteric artery syndrome: A case report Wang Xing 1*Li Jian-Zhong 1*Yang Ying-Hui 1Huang Xiao-Li 1Wang Yu 2Wu Bin 11 Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China2 Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. ChinaCorrespondence to: Professor Bin Wu, Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Road, Guangzhou, Guangdong 510630, P.R. China, E-mail: wubin6@mail.sysu.edu.cn* Contributed equally\n\n10 2017 28 7 2017 28 7 2017 7 4 543 546 19 1 2017 24 7 2017 Copyright: © Wang et al.2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Multi-agent chemotherapy is recognized as the most common and effective treatment for Burkitt lymphoma, and intestinal mucosal injury is a common gastrointestinal complication following intensive chemotherapy. The aim of the present study was to describe a case of non-Hodgkin lymphoma with intestinal obstruction after chemotherapy in a young adult. The patient presented with aggravated vomiting during the second session of chemotherapy, which was initially attributed to superior mesenteric artery syndrome. However, following surgical intervention, the symptom was proven to be due to extreme intestinal stenosis in the ascending part of the duodenum. The patient underwent duodenojejunectomy and end-to-side anastomosis, and he recovered well from the operation. Although intestinal perforation and hemorrhage induced by chemotherapy have been previously reported sporadically, to the best of our knowledge, this is the first case report of distal duodenal obstruction due to intestinal atresia induced by polychemotherapy for lymphoma. We herein analyze the possible underlying reasons for the intestinal atresia and review the clinical and pathological characteristics of previously published relevant studies. The present findings may be helpful for increasing clinical awareness of this type of complication, as well as improving the management of patients treated with cytotoxic chemotherapeutic agents.\n\nintestinal obstructionnon-Hodgkin lymphomachemotherapyatresiasuperior mesenteric artery syndrome\n==== Body\nIntroduction\nBurkitt lymphoma is a highly aggressive type of B-cell non-Hodgkin lymphoma (NHL) and is characterized by a translocation involving the c-MYC oncogene. Burkitt lymphoma is internationally recognized to comprise three clinical variants, namely endemic, sporadic and immunodeficiency-related. The endemic type is associated with Epstein-Barr virus infection and is most prevalent in Africa and the Middle East; the sporadic type occurs throughout the rest of the world and constitutes 1–2% of adult and 30–40% of childhood NHL cases in Europe and North America; the immunodeficiency-related type is associated with infection by the human immunodeficiency virus (1,2). Due to its chemosensitive nature, specific regimens of intensive chemotherapy have been developed for the treatment of Burkitt lymphoma, and a regimen of cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate ifosfamide, etoposide and high-dose cytarabine (CODOX-M/IVAC) has been established as the standard therapy with a relatively high event-free survival (EFS) and overall survival (OS), particularly in patients aged <65 years (2). Moreover, several studies have reported that adding anti-CD20 monoclonal antibody (rituximab) to the therapy may achieve superior outcomes compared with controls. The CODOX-M/IVAC regimen has been reported to be associated with 2-year OS rates of 64–82% and an EFS rate of 92% (2,3).\n\nIntestinal atresia affects neonates in the majority of the cases. Primary small intestinal atresia mostly affects the duodenum (>50%), and is usually associated with chromosomal anomalies, such as trisomy 21, as well as other factors, including race, maternal age and birthweight (4). Secondary atresia rarely occurs after necrotizing enteritis, intussusception, meconium peritonitis and abdominal surgeries (5). Although chemotherapy-induced intestinal mucositis has been broadly reported, and intestinal hemorrhage and spontaneous perforation have been considered as complications of NHL following intensive chemotherapy in children, intestinal atresia secondary to chemotherapy is uncommon (6–9). We herein describe a case of NHL in a young adult who developed extreme intestinal stenosis, likely triggered by chemotherapy, but presenting as superior mesenteric artery syndrome (SMAS).\n\nCase report\nA 22-year-old male patient presented to a community hospital with a 4-month history of fatigue, paleness and intermittent melena in July 2015. The patient reported suffering from anorexia for 1 month prior to the onset of the abovementioned symptoms. The patient had no history of hair coloring and no exposure to radioactive substances or oil-based paints. The white blood cell count was 17.5×109/l (normal range, 4.0–10.0×109/l) and the hemoglobin level was 55 g/l (normal range, 120–160 g/l). Baseline abdominal computed tomography (CT) detected multiple intestinal lesions in the epigastric and umbilical region, with extensive retroperitoneal lymphadenopathy. Biopsy of the descending part of the duodenum revealed the presence of diffuse large B-cell lymphoma. One month later, the patient presented with cramping pain and abdominal bloating, with edema of the bilateral lower limbs, and was transferred to a tertiary care hospital for further assessment. On physical examination, severe anemic appearance was noted. No superficial lymph nodes were palpated, and the findings of the cardiovascular and pulmonary examinations were unremarkable. There was a slight protuberance over the abdomen, but there was no tenderness or organomegaly.\n\nThe patient received one course of chemotherapy with rituximab, vincristine, epirubicin, etoposide, dexamethasone and cyclophosphamide (R-EPOCH regimen). The definitive diagnosis after the first course was Burkitt lymphoma and the patient received cyclophosphamide, doxorubicin, rituximab and vincristine, with intrathecal injection of cytarabine and methotrexate (modified CODOX-M regimen with rituximab). During the period of chemotherapy, the patient presented with repeated vomiting, which was relieved by administration of antiemetic drugs. On January 4, 2016, sudden onset of aggravated vomiting ensued, with palpitations and weakness of the limbs, which could not be relieved by antiemetic therapy. The patient reported no epigastric pain, abdominal distension or headache, but on physical examination, tenderness over the epigastric region and positive succussion splash were noted. The subsequent esophagogastroduodenoscopy (EGD) detected a large amount of fluid retention in the gastric cavity and the duodenum. There was no residual lymphoma or stenosis observed in the descending part of the duodenum detected on EGD (Fig. 1). Abdominal plain X-ray and alimentary tract radiography with barium revealed duodenal obstruction, raising the suspicion of superior mesenteric artery syndrome (Figs. 2 and 3). Ultrasound revealed a narrow angle of 10° between the superior mesenteric artery and the abdominal aorta. The patient was primarily diagnosed with superior mesenteric artery syndrome and treated with proton pump inhibitors, somatostatin, nasogastric drainage and sufficient parenteral nutritional supply, but the symptoms continued. On February 21, 2016, the patient was transferred to the Department of Surgery for exploratory laparotomy. During surgery, a focal ‘band-like’ narrowing was observed at the junction between the ascending part of the duodenum and the proximal part of the jejunum, with a gross appearance of occluded intestinal lumen at the site of lesion. Of note, mild dilation was observed in the part of the duodenum posterior to the superior mesenteric artery (Fig. 4). Duodenojejunectomy and end-to-side anastomosis were performed during the surgery. The histopathology of the resected specimen revealed atrophy of the epithelium and severe structural disturbance of the submucosa and muscularis propria at the site of atresia (Fig. 5).\n\nThe patient recovered well from the procedure, with resolution of the symptoms, and further chemotherapies were well-tolerated.\n\nWritten informed consent was obtained from the patient authorizing use and disclosure of his protected health information.\n\nDiscussion\nWe herein describe a case of secondary intestinal atresia, possibly induced by chemotherapy, in a young adult diagnosed with Burkitt lymphoma. The case is interesting, as the onset and progression of the symptoms were highly suggestive of SMAS. Although the present case included lymphomatous involvement of the duodenum prior to treatment, the microscopic examination of the surgical specimen detected no signs of neoplasia after chemotherapy.\n\nNausea, vomiting and diarrhea are most common gastrointestinal complications of cancer chemotherapy, and mucositis due to the damage of the proliferating cells at the base of the mucosal squamous epithelia or in the intestinal crypts usually involves the gastrointestinal tract (10). Hemorrhage and perforation of the small intestine have been reported in the previous literature as complications associated with chemotherapy for NHL; however, in the majority of the cases, evidence of the tumor is found on histological examination of the specimen. Coward et al reported a case of suspected chemotherapy-induced bowel obstruction in small-cell lung cancer, in which pathological examination of the excised bowel specimen revealed severe ulceration, transmural necrosis and extensive fibrosis (6). Kehoe et al reported that >100 patients developed intestinal obstruction following intraperitoneal chemotherapy and concluded that the majority of the obstructions were associated with the progression of the primary malignancy, whereas only 12% of the patients developed mechanical obstruction due to adhesions. The adhesions were described as ‘coating or encasing the bowels’ intraoperatively, but no apparent stenosis of the intestine was observed (7).\n\nSeveral factors may contribute to the intestinal obstruction after chemotherapy. The administration of antiemetic drugs of 5-HT receptor antagonists may greatly decrease peristalsis and result in paralytic ileus; furthermore, constipation may occasionally develop secondary to prolonged bed rest. However, tumor cell necrosis under chemotherapy is hypothesized to be a prominent factor in the development of intestinal obstruction. Microtubular toxins, such as vincristine, are commonly associated with autonomic bowel dysfunction, and etoposide, as a podophyllotoxin derivative that interferes with microtubular binding, may cause paralytic ileus (6). Burkitt lymphoma as a highly proliferative hemotological malignancy usually involving several organs. The tumor cells infiltrating the wall of the small intestine are destroyed during chemotherapy, causing inflammation, necrosis, fibrosis of the adjacent tissue, and even perforation and hemorrhage (9,11,12). In addition, it is widely known that chemotherapy may interrupt the DNA synthesis of intestinal mucosal cells and cause atrophy of epithelia (13). The transmural necrosis and fibrosis were not prominent on histological examination in the present case, but extensive tissue degeneration was observed in the submucosa and muscularis propria, with an extensive tissue cell response. The necrosis of lymphoma cells occurred in the submucosa and muscularis propria, and the space was replaced by large numbers of foam-like cells, which were likely derived from macrophages. Therefore, it is possible that the intestinal atresia observed in this case is attributable to the altered structure of the intestinal wall.\n\nThe diagnosis of SMAS is primarily based on clinical suspicion, with additional upper gastrointestinal barium examination, ultrosonography and/or CT angiography. The diagnosis is most probable when radiography detects a decreased aortomesenteric angle (<25°) and an aortomesenteric distance of <10 mm (14,15). The case was misdiagnosed prior to surgery, since the clinical manifestations with acute weight loss, and the supportive findings on barium contrast examination, with an extremely narrow angle between the superior mesenteric artery and abdominal aorta, constituted strong evidence supporting the diagnosis of SMAS. Furthermore, the short distance between the predicted compression site of the superior mesenteric artery and the actual site of obstruction, also contributed to the misdiagnosis. Unfortunately, abdominal CT scan, which may have enabled identification of the exact obstruction site prior to surgery, was not performed in this case. However, regardless of intestinal necrosis, atresia or perforation, surgical intervention is considered to be a necessary intervention.\n\nIn summary, the present study describes a case of NHL, with post-chemotherapeutic intestinal atresia originally misdiagnosed as SMAS. This case indicates the importance of an abdominal CT scan in confirming the cause of the intestinal obstruction, and may also remind physicians to be aware of rare bowel complications associated with polychemotherapeutic regimens, and take measures for the protection of the intestinal mucosa during chemotherapy.\n\nFigure 1. Findings on esophagogastroduodenoscopy: A large amount of fluid retention was observed in (A) the gastric body and (B) the descending part of the duodenum. No stenosis or neoplasms were identified.\n\nFigure 2. Plain abdominal X-ray. At 7 days after the previous barium radiography, residual barium remained mainly in the stomach and duodenal bulb (arrows).\n\nFigure 3. Barium radiography of the upper gastrointestinal tract: The barium filling was interrupted at the horizontal (3rd) part of the duodenum. A sharply vertical margin was noted as the compression of the superior mesenteric artery (arrow).\n\nFigure 4. Macroscopic view of the resected intestine: The specimen exhibited a markedly thickened intestinal wall at the obstruction site in the junction of the duodenum and jejunum. (A) The left, middle and right arrows indicate the proximal dilated part, the site of the atresia and the distal part, respectively. (B) The apparent obstruction of the intestinal lumen was identified with a forceps exploration (arrow).\n\nFigure 5. Histological examination of the site of the atresia: (A and B) Low-power magnification (×50) of the site of the atresia. Twisted villi and atrophy of the mucosal epithelium are observed. Low-level fibrosis was observed in the submucosa, with a large number of foam-like cells interrupting the muscularis propria. (C) High-power magnification (×200) of the submucosa. The muscularis propria of the site of the atresia is interrupted by foam-like cells (arrow). There is no evidence of neoplasia.\n==== Refs\nReferences\n1 Molyneux EM Rochford R Griffin B Newton R Jackson G Menon G Harrison CJ Israels T Bailey S Burkitt's lymphoma Lancet 379 1234 1244 2012 10.1016/S0140-6736(11)61177-X 22333947 \n2 Casulo C Friedberg J Treating Burkitt lymphoma in adults Curr Hematol Malig Rep 10 266 271 2015 10.1007/s11899-015-0263-4 26013028 \n3 Wasterlid T Brown PN Hagberg O Hagberg H Pedersen LM D'Amore F Jerkeman M Impact of chemotherapy regimen and rituximab in adult Burkitt lymphoma: A retrospective population-based study from the Nordic Lymphoma Group Ann Oncol 24 1879 1886 2013 10.1093/annonc/mdt058 23446093 \n4 Takahashi D Hiroma T Takamizawa S Nakamura T Population-based study of esophageal and small intestinal atresia/stenosis Pediatr Int 56 838 844 2014 10.1111/ped.12359 24730728 \n5 Yu KC Wu XJ Feng JX Wei MF Experienes of managing children with acquired intestinal stenosis and atresia Chin J Pediatr Surg 36 211 214 2015 (In Chinese) \n6 Coward JI Ding NL Feakins R Kocher H Popat S Szlosarek PW Chemotherapy-induced bowel obstruction in small cell lung cancer: A case report Med Oncol 29 2623 2625 2012 10.1007/s12032-011-0150-3 22203382 \n7 Kehoe SM Williams NL Yakubu R Levine DA Chi DS Sabbatini PJ Aghajanian CA Barakat RR Abu-Rustum NR Incidence of intestinal obstruction following intraperitoneal chemotherapy for ovarian tubal and peritoneal malignancies Gynecol Oncol 113 228 232 2009 10.1016/j.ygyno.2009.01.016 19254808 \n8 Hata S Pietsch J Shankar S Intestinal complications in children undergoing chemotherapy for mediastinal non-Hodgkin's lymphoma Pediatr Hematol Oncol 21 707 710 2004 10.1080/08880010490514804 15739625 \n9 Fallon SC Redell MS El-Bietar J Lopez ME Vasudevan SA Brandt ML Intestinal perforation after treatment of Burkitt's lymphoma: Case report and review of the literature J Pediatr Surg 48 436 440 2013 10.1016/j.jpedsurg.2012.12.002 23414881 \n10 Sausville EA Longo DL Principles of cancer treatment. In: Harrison's principles of internal medicine Longo DL Fauci AS McGraw-Hill Companies New York, NY 708 709 2011 \n11 Howarth GS Tooley KL Davidson GP Butler RN A non-invasive method for detection of intestinal mucositis induced by different classes of chemotherapy drugs in the rat Cancer Biol Ther 5 1189 1195 2006 10.4161/cbt.5.9.3117 16931906 \n12 Ara C Coban S Kayaalp C Yilmaz S Kirimlioglu V Spontaneous intestinal perforation due to non-Hodgkin's lymphoma: Evaluation of eight cases Dig Dis Sci 52 1752 1756 2007 10.1007/s10620-006-9279-x 17420936 \n13 Abel E Ekman T Warnhammar E Hultborn R Jennische E Lange S Early disturbance of microvascular function precedes chemotherapy-induced intestinal injury Dig Dis Sci 50 1729 1733 2005 10.1007/s10620-005-2926-9 16133980 \n14 Pottorf BJ Husain FA Hollis HJ Lin E Laparoscopic management of duodenal obstruction resulting from superior mesenteric artery syndrome JAMA Surg 149 1319 1322 2014 10.1001/jamasurg.2014.1409 25353279 \n15 Merrett ND Wilson RB Cosman P Biankin AV Superior mesenteric artery syndrome: Diagnosis and treatment strategies J Gastrointest Surg 13 287 292 2009 10.1007/s11605-008-0695-4 18810558\n\n",
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"issue": "7(4)",
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"keywords": "atresia; chemotherapy; intestinal obstruction; non-Hodgkin lymphoma; superior mesenteric artery syndrome",
"medline_ta": "Mol Clin Oncol",
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"nlm_unique_id": "101613422",
"other_id": null,
"pages": "543-546",
"pmc": null,
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"pubdate": "2017-10",
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"title": "Intestinal atresia following chemotherapy, presenting as superior mesenteric artery syndrome: A case report.",
"title_normalized": "intestinal atresia following chemotherapy presenting as superior mesenteric artery syndrome a case report"
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"abstract": "A 64-year-old woman discovered a mass in her left breast and visited our hospital. A thorough examination resulted in a diagnosis of left, locally advanced breast cancer (cT4bN3, M0, cStage Ⅲc) with muscle invasion and Level Ⅲ lymph node metastases. Because of drug-induced lung disease following 4 courses of adriamycin and cyclophosphamide, the chemotherapy had to be stopped. Halsted's operation and postoperative radiotherapy (50 Gy) were performed. The patient was alive with no evidence of recurrence 9 months after surgery. Although multidisciplinary therapy is recommended in locally advanced breast cancer, chemotherapy sometimes cannot be performed due to factors such as age and physical status. Halsted's operation could be considered as a treatment of choice in patients with locally advanced breast cancer. It is important to choose the treatment strategy based on the condition of the patient.",
"affiliations": "Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences.",
"authors": "Moro|Kazuki|K|;Nagahashi|Masayuki|M|;Tsuchida|Junko|J|;Tatsuda|Kumiko|K|;Toshikawa|Chie|C|;Hasegawa|Miki|M|;Ishikawa|Takashi|T|;Shimada|Yoshifumi|Y|;Sakata|Jun|J|;Kameyama|Hitoshi|H|;Kobayashi|Takashi|T|;Minagawa|Masahiro|M|;Kosugi|Shin-ichi|S|;Koyama|Yu|Y|;Wakai|Toshifumi|T|",
"chemical_list": "D004317:Doxorubicin; D003520:Cyclophosphamide",
"country": "Japan",
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"issue": "42(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D055370:Lung Injury; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D064726:Triple Negative Breast Neoplasms",
"nlm_unique_id": "7810034",
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"pages": "1803-5",
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"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Locally Advanced Breast Cancer Treated with Halsted's Operation Because of Drug-Induced Lung Injury Caused by Neoadjuvant Chemotherapy--A Case Report.",
"title_normalized": "locally advanced breast cancer treated with halsted s operation because of drug induced lung injury caused by neoadjuvant chemotherapy a case report"
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"companynumb": "JP-PFIZER INC-2016492741",
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"abstract": "There is growing concern regarding the emergence of visceral leishmaniasis (VL), a disseminated parasitic disease caused by protozoa of the genus Leishmania, as an opportunistic infection in immunocompromised patients. This association has been principally studied in the context of human immunodeficiency virus infection, but VL has also been reported in patients undergoing treatment with immunosuppressive medication for various indications. Here a case of VL in a patient with rheumatoid arthritis undergoing treatment with methotrexate and corticosteroid is presented. Despite the rarity of such incidents, physicians should include VL in the differential diagnosis because this infection, if left untreated, is characterized by significant mortality.",
"affiliations": "Evangelismos General Hospital, Athens, Greece.;Evangelismos General Hospital, Athens, Greece.;Evangelismos General Hospital, Athens, Greece.;Evangelismos General Hospital, Athens, Greece.",
"authors": "Trigkidis|Kyriakos|K|;Geladari|Eleni|E|;Kokkinakis|Evangelos|E|;Vallianou|Natalia|N|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.5152/eurjrheum.2017.16066",
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"issn_linking": "2147-9720",
"issue": "4(2)",
"journal": "European journal of rheumatology",
"keywords": "Visceral leishmaniasis; corticosteroids; immunocompromised patients; methotrexate; rheumatoid arthritis",
"medline_ta": "Eur J Rheumatol",
"mesh_terms": null,
"nlm_unique_id": "101656068",
"other_id": null,
"pages": "139-141",
"pmc": null,
"pmid": "28638689",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": "20927287;19026580;22693548;23744570;24833919;23380419;18291340;24450618;22198490;15815883",
"title": "Visceral Leishmaniasis in a patient with rheumatoid arthritis undergoing treatment with methotrexate: Case report and review of the literature.",
"title_normalized": "visceral leishmaniasis in a patient with rheumatoid arthritis undergoing treatment with methotrexate case report and review of the literature"
} | [
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"companynumb": "GR-ACCORD-053229",
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"activesubstancename": "METHOTREXATE"
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{
"abstract": "Lamotrigine has been repeatedly reported to cause hematologic toxicities, which may be associated with high initial doses or excessive escalation. A 29-year-old lady experienced profound neutropenia after two weeks of lamotrigine high initial dose, started within two days of phenytoin. The too-early dose intensification may have produced lamotrigine-induced blood dyscrasia.",
"affiliations": "Department of Clinical Pharmacy Hamad General Hospital Doha Qatar.;Department of Clinical Pharmacy Hamad General Hospital Doha Qatar.",
"authors": "Salem|Muhammad|M|https://orcid.org/0000-0002-1639-0491;El-Bardissy|Ahmed|A|",
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"country": "England",
"delete": false,
"doi": "10.1002/ccr3.5136",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.5136\nCCR35136\nCase Report\nCase Report\nLamotrigine‐induced neutropenia after high‐dose concomitant initiation with phenytoin\nSALEM and EL‐BARDISSY\nSalem Muhammad https://orcid.org/0000-0002-1639-0491\n1 msalem02@qub.ac.uk\n\nEl‐Bardissy Ahmed 1\n1 Department of Clinical Pharmacy Hamad General Hospital Doha Qatar\n* Correspondence\nMuhammad Salem, Department of Clinical Pharmacy, Hamad General Hospital, PO box 3050, Doha, Qatar.\nEmail: msalem02@qub.ac.uk\n\n22 11 2021\n11 2021\n9 11 10.1002/ccr3.v9.11 e0513606 11 2021\n22 6 2021\n10 11 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nLamotrigine has been repeatedly reported to cause hematologic toxicities, which may be associated with high initial doses or excessive escalation. A 29‐year‐old lady experienced profound neutropenia after two weeks of lamotrigine high initial dose, started within two days of phenytoin. The too‐early dose intensification may have produced lamotrigine‐induced blood dyscrasia.\n\nThis graph represents the daily lamotrigine dose, white blood cell count (WBC) and absolute neutrophil count (ANC) over time. The bottom x‐axis represents days of the second admission. The left y‐axis represents the daily lamotrigine dose in milligrams and is shown by the vertical bars. The right y‐axis represents the WBC and ANC and is shown by the black circles and diamond points, respectively. The neutropenia cutoff is indicated by the dotted line (1.5 × 109/L). Phenytoin and filgrastim therapy days are shown by the two double‐arrowed lines in the plot area.\n\nlamotrigine\nleucopenia\nneutropenia\nphenytoin\nUGT1A4\nQatar National Library (QNL) source-schema-version-number2.0\ncover-dateNovember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.9 mode:remove_FC converted:22.11.2021\nSalem M , El‐Bardissy A . Lamotrigine‐induced neutropenia after high‐dose concomitant initiation with phenytoin. Clin Case Rep. 2021;9 :e05136. doi:10.1002/ccr3.5136\n\nFunding information\n\nThe publication of this article was funded by Qatar National Library (QNL)\n==== Body\npmc1 INTRODUCTION\n\nLamotrigine, originally manufactured as a dihydrofolate reductase inhibitor, is a phenyltriazine‐based antiepileptic drug (AED) which blocks voltage‐gated sodium and calcium channels and is approved by the US Food and Drug Administration (FDA) for focal, generalized tonic‐clonic (GTC), and Lennox‐Gastaut syndrome seizures, as well as type‐1 bipolar disorder. 1 While dermatologic toxicity is the most common reaction to lamotrigine, it has been repeatedly reported to cause blood dyscrasias, including thrombocytopenia, pancytopenia, 2 , 3 , 4 , 5 and various extents of neutropenia. 3 , 6 , 7 , 8 These hematologic changes could be explained by multiple postulated mechanisms, like dihydrofolate reductase inhibition, direct medullary toxicity, 3 or as a part of the spectrum of drug hypersensitivity syndrome (DHS), a disease of iatrogenic etiology, presumed to be induced by a minor‐pathway cytochrome P450‐based metabolite, lamotrigine‐arene‐oxide intermediate, 1 , 9 , 10 which may produce cutaneous, hepatic, and hematologic toxicity. 11 Lamotrigine‐induced DHS may be associated with abrupt high initial exposure or increments, rather than the dose itself. 12 , 13 , 14 Therefore, the recommended gradual dose increase in lamotrigine labels aims to induce adaptive metabolic, detoxifying, and immunologic changes to achieve desensitization. 11 Lamotrigine‐induced neutropenia has been reported mostly within the onset of a few days after initiation or dose increase, 6 , 7 , 15 , 16 , 17 and mainly associated with doses above the recommended. 3 , 8 , 11 , 15 , 18\n\nUridine diphosphate‐glucuronosyltransferase 1A4 (UGT1A4) extensively metabolizes lamotrigine to the inactive 2‐N‐glucuronide, predominantly, and 5‐N‐glucuronide. 1 , 19 Therefore, concomitant use with UGT1A4 inhibitors or inducers necessitates dose reduction or increase, respectively. The US Food and Drug Administration (FDA) label recommends different dosing schedules according to concomitant medications. 20 Phenytoin, an enzyme‐inducing antiepileptic drug (EIAED), is a prototypical activator of constitutive androstane receptor (CAR), a nuclear receptor, which, with pregnane × receptor (PXR) and aryl hydrocarbon receptor (AhR), regulates UGT1A4 gene expression. 1 Consequently, it induces UGT1A4 production and has been shown to decrease lamotrigine half‐life by around 40%–50%. 21 Hence, the recommended initial lamotrigine dose for patients on phenytoin and other enzyme inducers is generally double that for patients not on enzyme inhibiting or inducing agents. 20 However, the onset of the interaction from the time of the inducer's commencement till it becomes significant is not addressed in dosing recommendations.\n\nThis report aims to describe a case who has been added a high initial lamotrigine dose within two days of phenytoin initiation, and developed profound neutropenia, which was reversed after lamotrigine cessation.\n\n2 CASE REPORT\n\nA 29‐year‐old Kenyan woman presented to the emergency of Hamad General Hospital (HGH), Doha, Qatar, on January 27, 2019, with a history of severe headache, cough, and an episode of seizure. Her laboratories showed leukocytosis with a left shift and a hemoglobin of 6.7 g/dl. Upon waiting in a wheelchair, she abruptly developed a GTC seizure. She was injected immediately with intravenous lorazepam 4 mg, and ordered electroencephalogram (EEG), lumbar puncture (LP), and computed tomography (CT) of the head. While LP and CT were unremarkable, EEG showed diffuse theta background superimposed by left anterior temporal delta slowing, underlying structural versus anemic hypoxic encephalopathy with no specific epileptiform discharges. After the patient returned to baseline, the neurology team started her oral levetiracetam 500 mg twice daily. On the next day, her hemoglobin dropped to 5.8 g/dl. Anemia workup revealed low vitamin B12 and iron, and microcytic anemia in the peripheral smear. Two units packed RBCs were transfused to the patient. The next day, her hemoglobin raised above 8 g/dl. Since the patient was stabilized, the seizure was suspected to be due to anemic hypoxia/iron deficiency anemia. Over eight days, her liver enzymes increased from an admission baseline of alanine transaminase (ALT) and aspartate transaminase (AST) of 33 and 111 U/L to 252 and 241 U/L, respectively. Levetiracetam was alleged to be the reason for the liver function test derangement and was tapered to 250 mg BID since Day 4 of hospitalization, then stopped on Day 9. The patient was discharged with a hemoglobin of 11.2 g/dl on iron, cyanocobalamin, and folic acid.\n\nOn March 11, the ambulance brought the patient to the emergency with fever, severe headache, nausea, and general weakness since the morning. A summary of the second admission is demonstrated in Figure 1. Upon admission, the white blood cell count (WBC) was 9.3 × 109/L, and absolute neutrophil count (ANC) was 8 × 109/L. She developed a GTC seizure at the emergency department, which was aborted by giving IV diazepam 5 mg and loading with IV phenytoin 1000 mg. She was started on IV acyclovir and ceftriaxone for possible meningoencephalitis. Twelve hours later, phenytoin was continued as oral 100 mg thrice daily. Emergency CT head and magnetic resonance imaging (MRI) did not show any acute intracranial insult. Since the patient became stable on Day 2 of the second admission, the neurology team recommended stopping acyclovir and ceftriaxone and adding lamotrigine 50 mg twice daily as an anti‐seizure and mood stabilizer for anxiety and erratic agitative behavior. Two days later, the lamotrigine dose was escalated to 150 mg/day with a plan to decrease phenytoin gradually when reaching 250 mg. The plan was adjusted on Day 7 to reduce the lamotrigine dose back to 100 mg/day and increase weekly by 50 mg increments. On Day 13, phenytoin was stopped, and the lamotrigine dose was increased to 150 mg. The patient became febrile, and ceftriaxone was initiated. On the next day, WBC and ANC dropped to 1.7 × 109/L and 0.8 × 109/L, respectively. Autoimmune disease profile came negative, including anti–double‐stranded DNA, antineutrophil cytoplasmic antibody, antinuclear antibodies, and rheumatoid factor. Peripheral smear showed leukopenia with marked neutropenia and lymphocytopenia, and peripheral blood flow cytometry ruled out paroxysmal nocturnal hemoglobinuria. Vitamin B12 came out high (1431 pmol/L). Parasites, brucella, parvovirus, hepatitis, and HIV serology came negative, as well as virology PCR panel, including cytomegalovirus, Epstein‐Barr virus, adenovirus, influenza A and influenza B, and respiratory syncytial virus.\n\nFIGURE 1 This graph represents the daily lamotrigine dose, white blood cell count (WBC) and absolute neutrophil count (ANC) over time. The bottom x‐axis represents days of the second admission. The left y‐axis represents the daily lamotrigine dose in milligrams and is shown by the vertical bars. The right y‐axis represents the WBC and ANC and is shown by the black circles and diamond points, respectively. The neutropenia cutoff is indicated by the dotted line (1.5 × 109/L). Phenytoin and filgrastim therapy days are shown by the two double‐arrowed lines in the plot area\n\nSince other possible causes of cytopenia had been ruled out, lamotrigine was suspected to be the cause, and the dose was reduced to 50 mg twice daily. Two days later, while WBC and ANC continued to decrease, the patient continued to spike, so she was shifted to the febrile neutropenic dose of cefepime. Lamotrigine was stopped, and phenytoin was resumed. Blood and urine cultures came negative, and fever subsided since Day 16. However, on Day 21, fever re‐emerged while WBC and ANC reached 0.4 × 109/L and 0.0 × 109/L, respectively. The medical team escalated cefepime to meropenem. The hematology team initiated filgrastim and advised to stop any medication potentially inducing leukopenia. Therefore, phenytoin was changed to levetiracetam on Day 22. Fever subsided, cultures came negative, and WBC count showed signs of recovery on Day 24 with a WBC of 0.9 × 109/L and ANC of 0.02 × 109/L. Three days later, filgrastim was stopped after WBC reached 17.2 × 109/L and ANC 8.4 × 109/L. On Day 33, being seizure‐free and with normal liver function tests, WBC of 5.2 × 109/L, and ANC of 2.2 × 109/L, the patient was discharged on levetiracetam 750 mg twice daily, risperidone 4 mg at bedtime, vitamin B12, and iron supplementation. Consent was obtained from the patient for the publication of this case report.\n\n3 DISCUSSION\n\nIn this case report, leukopenia and neutropenia developed eleven days after lamotrigine commencement and declined to agranulocytosis two days after discontinuation. Both lamotrigine and phenytoin have been reported rarely to induce blood dyscrasia. 3 , 8 , 11 , 15 , 18 , 22 , 23 , 24 , 25 However, it is unlikely to connect our case's neutropenia to phenytoin, given the intensive lamotrigine initial dose and phenytoin's cessation only two days before signs of recovery. The WBC and ANC showed signs of recovery on the seventh day of lamotrigine discontinuation, indicating a sufficient restoration time after the offending drug removal.\n\nMultiple reports have demonstrated lamotrigine‐induced severe neutropenia following initial intensive doses, as in an 11‐year‐old girl with seizures who received twofold the optimal starting dose, 22 rapid dose titration, as in a 19‐year‐old woman who developed Stevens‐Johnson syndrome followed by severe neutropenia after early escalation on the tenth day, 17 or higher than recommended doses given with the UGT1A4 inhibitor, valproate. 3 , 6 , 8 , 15 , 18 Two separate cases, 62‐ and 35‐year‐old females with epilepsy and bipolar disorder, respectively, developed moderate and severe neutropenia few days after adding lamotrigine to valproate, at the double, then escalated to four times the recommended initial dose, with regard to the interaction. 6 , 15 Another case, a 48‐year‐old female patient with bipolar disorder, developed diffuse maculopapular rashes, leucopenia, and thrombocytopenia after seven days of lamotrigine added to valproate, four doses of 50 mg and three doses of 100 mg, which were four and eight times the recommended during the first two weeks, respectively. 3\n\nAs appropriate initial dosing and escalation can minimize the risks of toxicity, inappropriate lamotrigine de‐escalation after discontinuing concomitant EIAEDs may abruptly expose the patient to higher increments that can raise the risks to DHS. When discontinuing an inducer, the current FDA label recommendation is to remain on the same dose for a week and then half the dose over two weeks till a maximum maintenance daily dose of 200 mg. 20 A 59‐year‐old female patient received lamotrigine added to chronic phenobarbital for seizures control. While tapering the latter, lamotrigine daily dose was increased over four weeks up to 250 mg, continued for additional five weeks, and then stopped because of agranulocytosis. 23 A similar scenario occurred to a 24‐year‐old female patient with epilepsy who was added lamotrigine on chronic carbamazepine. 26 The initial lamotrigine dose and escalation rate were half the recommended, in case of concomitant inducer, for the first 4 weeks. However, after stopping carbamazepine at the beginning of Week 4, the dose remained the same and doubled at the beginning of Week 6. The neutrophils dropped to 0.6 × 109/L and then recovered to normal two weeks following lamotrigine cessation. 26\n\nAfter three years of its use in the UK, in 1994, the initial lamotrigine dose recommendation was halved to reduce the incidence of rash. 13 For patients on EIAEDs and no valproate, the current initial recommended dose is 50 mg/day for the first two weeks, 20 however, that is assuming the UGT1A4 is already induced. The time course to maximal enzyme induction is dependent on both the inducer and the enzyme half‐lives. 27 The full impact will require the enzyme accumulation to a new steady state based on its turnover as the rate‐limiting step. 28 Since lamotrigine was initially intended as adjunctive therapy, pharmacokinetic studies, upon which dosing recommendations were based, have only evaluated its concentrations when added to chronic EIAEDs. 29 , 30 In a recent study, lamotrigine concentrations were measured twenty‐one days after its addition to EIAEDs. 31 The few days apart, commencement sequence or adding an inducer to chronic lamotrigine was not studied sufficiently to suggest an initial dosing schedule based on the expected interaction time course. Unlike cytochromes P‐450 enzymes, studies are lacking for UGT primary substrates induction time course. 27 One randomized crossover study on 20 healthy volunteers showed that five days of rifampin decreased the sixth‐day single‐dose lamotrigine mean AUC and half‐life by 44 and 30%, respectively. 32 A recent case report showed decreased lamotrigine serum concentration by 73% after a month and a half of rifampin initiation. 33 Given the short rifampin half‐life, 1.5 to 5 h, 28 , 34 the time required to induce UGT1A4 after rifampin reaches a steady state would be more than five days. Since phenytoin's average half‐life is 22 h, it would take no less than five days to attain steady‐state serum concentrations, 19 then activate CAR to increase the UGT1A4 De novo synthesis through increasing its mRNA expression rate. 1 Therefore, in the case of phenytoin, reaching UGT1A4 induction status requiring lamotrigine dose escalation would need more than ten days, indicating that our patient should not have been considered on an EIAED while dosing lamotrigine initially. She should have been initiated on the standard dose of 25 mg per day as recommended in patients not on inducers nor inhibitors. Instead, our patient received fourfold the initial recommended dose with up to sixfold on Days 3 to 5 and 12 to 13 (Figure 1), that may have caused extreme initial exposure, which was not adequately adapted, resulted in a DHS, and manifested as profound hematologic toxicity. It is not possible to predict the outcome if the patient had received twofold instead, which is recommended in case of concomitant use with EIAEDs. However, restricting the dose to 25 mg per day would have been the optimum, as UGT1A4 was not yet induced to a level requiring high lamotrigine initial dose.\n\n4 CONCLUSION\n\nThis case report demonstrated that lamotrigine dose increase must take the estimated time course to the interaction onset into consideration when given with an inducer. Therefore, lamotrigine dose should be normal with no drug interaction‐based escalation until 10–14 days from the inducer's commencement. That is vital to avoid initial or escalated dose‐related toxicities.\n\nCONFLICT OF INTEREST\n\nThe authors declare that they have no competing interests in this work.\n\nAUTHOR CONTRIBUTIONS\n\nMS interpreted the patient's data, conceptualized, and wrote the original draft. AE participated in the literature review and reviewed the manuscript. All authors read and approved the final manuscript.\n\nETHICS APPROVAL\n\nEthics approval for this case report was provided by the Medical Research Committee (MRC) of Hamad Medical Corporation (HMC) (#MRC‐04–21–285).\n\nCONSENT\n\nWritten informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.\n\nDATA AVAILABILITY STATEMENT\n\nThe data that support the findings of this report are available from authors, MS and AE, upon reasonable request.\n==== Refs\nREFERENCES\n\n1 Mitra‐Ghosh T , Callisto SP , Lamba JK , et al. PharmGKB summary: lamotrigine pathway, pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics. 2020;30 (4 ):81‐90. doi:10.1097/FPC.0000000000000397 32187155\n2 Ural AU , Avcu F , Gokcil Z , Nevruz O , Cetin T . Leucopenia and thrombocytopenia possibly associated with lamotrigine use in a patient. Epileptic Disord. 2005;7 (1 ):33‐35.15741138\n3 Chang C‐C , Shiah I‐S , Yeh C‐B , Wang T‐S , Chang H‐A . Lamotrigine‐associated anticonvulsant hypersensitivity syndrome in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30 (4 ):741‐744. doi:10.1016/j.pnpbp.2005.11.033 16442685\n4 Okur M , Kaya A , Çaksen H , Taşkın G . Lamotrigine‐associated thrombocytopenia and leukopenia. J Emerg Med. 2012;42 (5 ):584‐585. doi:10.1016/j.jemermed.2010.05.060 20656445\n5 Chang CF , Chung KH . Lamotrigine‐induced pancytopenia in bipolar disorder. J Formos Med Assoc. 2018;117 (12 ):1128‐1129. doi:10.1016/j.jfma.2018.07.004 30033033\n6 Damiani JT , Christensen RC . Lamotrigine‐associated neutropenia in a geriatric patient. Am J Geriatr Psychiatry. 2000;8 (4 ):346.11069275\n7 LeDrew K , Phillips L , Hogan M , MacCallum A . Lamotrigine‐induced neutropenia. Can J Psychiatry. 2005;50 (4 ):242. doi:10.1177/070674370505000412 15898467\n8 Sawant NS , Parka SR , Singh RV , Nachane HB . Lamotrigine‐induced agranulocytosis in a case of schizoaffective disorder. Ann Indian Psychiatry. 2017;1 :49. doi:10.4103/aip.aip_5_17\n9 Maggs JL , Naisbitt DJ , Tettey JN , Pirmohamed M , Park BK . Metabolism of lamotrigine to a reactive arene oxide intermediate. Chem Res Toxicol. 2000;13 (11 ):1075‐1081. doi:10.1021/tx0000825 11087428\n10 Vázquez M , Maldonado C , Guevara N , et al. Lamotrigine‐valproic acid interaction leading to Stevens‐Johnson syndrome. Case Rep Med. 2018;2018 :1‐5. doi:10.1155/2018/5371854\n11 Sullivan JR , Shear NH . The drug hypersensitivity syndrome: what is the pathogenesis? Arch Dermatol. 2001;137 (3 ):357‐364.11255340\n12 Schlienger RG , Shapiro LE , Shear NH . Lamotrigine‐induced severe cutaneous adverse reactions. Epilepsia. 1998;39 (Suppl 7 ):S22‐S26. doi:10.1111/j.1528-1157.1998.tb01681.x 9798758\n13 Wong IC , Mawer GE , Sander JW . Factors influencing the incidence of lamotrigine‐related skin rash. Ann Pharmacother. 1999;33 (10 ):1037‐1042. doi:10.1345/aph.18422 10534214\n14 Messenheimer JA , Giorgi L , Risner ME . The tolerability of lamotrigine in children. Drug Saf. 2000;22 (4 ):303‐312. doi:10.2165/00002018-200022040-00003 10789824\n15 Nicholson RJ , Kelly KP , Grant IS . Leucopenia associated with lamotrigine. BMJ. 1995;310 (6978 ):504. doi:10.1136/bmj.310.6978.504b\n16 Ahn YM , Kim K , Kim YS . Three cases of reversible agranulocytosis after treatment with lamotrigine. Psychiatry Investig. 2008;5 (2 ):121‐123. doi:10.4306/pi.2008.5.2.121\n17 Yasui‐Furukori N , Hashimoto K , Tsuruga K , Nakamura K . Comorbidity of Stevens‐Johnson syndrome and neutropenia associated with lamotrigine: a case report. Gen Hosp Psychiatry. 2014;36 (6 ). doi:10.1016/j.genhosppsych.2014.07.010\n18 Solvason HB . Agranulocytosis associated with lamotrigine. Am J Psychiatry. 2000;157 (10 ):1704. doi:10.1176/appi.ajp.157.10.1704\n19 Bauer LA . Applied clinical pharmacokinetics, 3rd ed. McGraw‐Hill; 2015.\n20 Jubilant Cadista Pharmaceuticals USA, Inc. (Lamotrigine) tablet . DailyMed [Internet]; 2021. National Library of Medicine (US); 2019. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=0b0f0209‐edbd‐46f3‐9bed‐762cbea0d737&type=pdf Accessed February 1, 2021\n21 Jawad S , Yuen WC , Peck AW , Hamilton MJ , Oxley JR , Richens A . Lamotrigine: single‐dose pharmacokinetics and initial 1 week experience in refractory epilepsy. Epilepsy Res. 1987;1 (3 ):194‐201. doi:10.1016/0920-1211(87)90041-6 3504397\n22 de Camargo OA , Bode H . Agranulocytosis associated with lamotrigine. BMJ. 1999;318 (7192 ):1179. doi:10.1136/bmj.318.7192.1179a\n23 Fadul CE , Meyer LP , Jobst BC , Cornell CJ , Lewis LD . Agranulocytosis associated with lamotrigine in a patient with low‐grade glioma. Epilepsia. 2002;43 (2 ):199‐200. doi:10.1046/j.1528-1157.2002.31801.x 11903469\n24 Sharafuddin MJ , Spanheimer RG , McClune GL . Phenytoin‐induced agranulocytosis: a nonimmunologic idiosyncratic reaction? Acta Haematol. 1991;86 (4 ):212‐213. doi:10.1159/000204838 1805490\n25 Verrotti A , Scaparrotta A , Grosso S , Chiarelli F , Coppola G . Anticonvulsant drugs and hematological disease. Neurol Sci. 2014;35 (7 ):983‐993. doi:10.1007/s10072-014-1701-0 24619070\n26 Kilbas S . Lamotrigine‐induced leucopenia. Epileptic Disord. 2006;8 (4 ):317.17191364\n27 Anderson GD , Gidal BE , Messenheimer JA , Gilliam FG . Time course of lamotrigine de‐induction: impact of step‐wise withdrawal of carbamazepine or phenytoin. Epilepsy Res. 2002;49 (3 ):211‐217. doi:10.1016/s0920-1211(02)00033-5 12076842\n28 Brodie MJ , Mintzer S , Pack AM , Gidal BE , Vecht CJ , Schmidt D . Enzyme induction with antiepileptic drugs: cause for concern? Epilepsia. 2013;54 (1 ):11‐27. doi:10.1111/j.1528-1167.2012.03671.x\n29 Ramsay RE , Pellock JM , Garnett WR , et al. Pharmacokinetics and safety of lamotrigine (Lamictal) in patients with epilepsy. Epilepsy Res. 1991;10 (2–3 ):191‐200. doi:10.1016/0920-1211(91)90012-5 1817959\n30 Matsuo F , Gay P , Madsen J , et al. Lamotrigine high‐dose tolerability and safety in patients with epilepsy: a double‐blind, placebo‐controlled, eleven‐week study. Epilepsia. 1996;37 (9 ):857‐862. doi:10.1111/j.1528-1157.1996.tb00038.x 8814098\n31 Lovrić M , Čajić I , Petelin Gadže Ž , Klarica Domjanović I , Božina N . Effect of antiepileptic drug comedication on lamotrigine concentrations. Croat Med J. 2018;59 (1 ):13‐19. doi:10.3325/cmj.2018.59.13 29498493\n32 Ebert U , Thong NQ , Oertel R , Kirch W . Effects of rifampicin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects. Eur J Clin Pharmacol. 2000;56 (4 ):299‐304. doi:10.1007/s002280000146 10954343\n33 Wimpelmann J , Høvik H , Riedel B , Slørdal L . The interaction between rifampicin and lamotrigine: a case report. Br J Clin Pharmacol. 2019;85 (8 ):1859‐1860. doi:10.1111/bcp.13973 31144345\n34 Rifampin . IBM Micromedex Solutions. Truven Health Analytics, Inc; 2021. http://www.micromedexsolutions.com\n\n",
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"title": "Lamotrigine-induced neutropenia after high-dose concomitant initiation with phenytoin.",
"title_normalized": "lamotrigine induced neutropenia after high dose concomitant initiation with phenytoin"
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"abstract": "Mesalazine is a 5-aminosalicylic acid derivative that has been widely used to treat patients with inflammatory bowel disease. Accumulating evidence indicates that mesalazine has a very low rate of adverse drug reactions and is well tolerated by patients. However, a few cases of pulmonary and cardiac disease related to mesalazine have been reported in the past, though infrequently, preventing clinicians from diagnosing the conditions early. We describe the case of a 32-year-old man with ulcerative colitis who was admitted with a two-month history of persistent fever following mesalazine treatment initiated 14 mo earlier. At the time of admission, mesalazine dose was increased from 1.5 to 3.0 g/d, and antibiotic therapy was started with no improvement. Three weeks after admission, the patient developed dyspnea, non-productive cough, and chest pain. Severe eosinophilia was detected in laboratory tests, and a computed tomography scan revealed interstitial infiltrates in both lungs, as well as a large pericardial effusion. The bronchoalveolar lavage reported a CD4/CD8 ratio of 0.5, and an increased eosinophil count. Transbronchial biopsy examination showed a severe eosinophilic infiltrate of the lung tissue. Mesalazine-induced cardiopulmonary hypersensitivity was suspected after excluding other possible etiologies. Consequently, mesalazine treatment was suspended, and corticosteroid therapy was initiated, resulting in resolution of symptoms and radiologic abnormalities. We conclude that mesalazine-induced pulmonary and cardiac hypersensitivity should always be considered in the differential diagnosis of unexplained cardiopulmonary symptoms and radiographic abnormalities in patients with inflammatory bowel disease.",
"affiliations": "José Ferrusquía, Isabel Pérez-Martínez, Ruth de Francisco, Luis Rodrigo, Sabino Riestra, Department of Gastroenterology, Central University Hospital of Asturias, 33011 Oviedo, Asturias, Spain.;José Ferrusquía, Isabel Pérez-Martínez, Ruth de Francisco, Luis Rodrigo, Sabino Riestra, Department of Gastroenterology, Central University Hospital of Asturias, 33011 Oviedo, Asturias, Spain.;José Ferrusquía, Isabel Pérez-Martínez, Ruth de Francisco, Luis Rodrigo, Sabino Riestra, Department of Gastroenterology, Central University Hospital of Asturias, 33011 Oviedo, Asturias, Spain.;José Ferrusquía, Isabel Pérez-Martínez, Ruth de Francisco, Luis Rodrigo, Sabino Riestra, Department of Gastroenterology, Central University Hospital of Asturias, 33011 Oviedo, Asturias, Spain.;José Ferrusquía, Isabel Pérez-Martínez, Ruth de Francisco, Luis Rodrigo, Sabino Riestra, Department of Gastroenterology, Central University Hospital of Asturias, 33011 Oviedo, Asturias, Spain.;José Ferrusquía, Isabel Pérez-Martínez, Ruth de Francisco, Luis Rodrigo, Sabino Riestra, Department of Gastroenterology, Central University Hospital of Asturias, 33011 Oviedo, Asturias, Spain.;José Ferrusquía, Isabel Pérez-Martínez, Ruth de Francisco, Luis Rodrigo, Sabino Riestra, Department of Gastroenterology, Central University Hospital of Asturias, 33011 Oviedo, Asturias, Spain.",
"authors": "Ferrusquía|José|J|;Pérez-Martínez|Isabel|I|;Gómez de la Torre|Ricardo|R|;Fernández-Almira|María Luisa|ML|;de Francisco|Ruth|R|;Rodrigo|Luis|L|;Riestra|Sabino|S|",
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"issue": "21(13)",
"journal": "World journal of gastroenterology",
"keywords": "Eosinophilia; Lung hypersensitivity; Mesalazine; Pericardial effusion; Ulcerative colitis",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001706:Biopsy; D003093:Colitis, Ulcerative; D057915:Drug Substitution; D006801:Humans; D008297:Male; D019804:Mesalamine; D010490:Pericardial Effusion; D011237:Predictive Value of Tests; D011657:Pulmonary Eosinophilia; D012074:Remission Induction; D012130:Respiratory Hypersensitivity; D012307:Risk Factors; D012720:Severity of Illness Index; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "4069-77",
"pmc": null,
"pmid": "25852295",
"pubdate": "2015-04-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1827746;23667838;15168457;19237838;9013348;9101017;10189017;12643224;11687866;1582327;9952222;15726390;17574528;9973695;11418451;18074739;20005014;11687867;8633548;18223370;16205520;20151072;10959271;20237787;1682668;21761513;20299168;7555145;14723609;17226917;8502168;9825882;11579953;21172186;24461446;23185660;20441247;18480972;7249508;8166873;23964037;9046901;21165365;8041994;16573787;14555914;21857821;16633055;1411390;16469680;19601534;21686567;19423137;15770345;23361575;17339311;10468004;24333139",
"title": "Gastroenterology case report of mesalazine-induced cardiopulmonary hypersensitivity.",
"title_normalized": "gastroenterology case report of mesalazine induced cardiopulmonary hypersensitivity"
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"abstract": "Catheter-directed thrombolysis (CDT) for the treatment of acute pulmonary embolism (PE) has gained popularity in recent years, but potential complications during the procedure and their management are not frequently discussed in the literature. In this case report, we describe the clinical dilemma regarding the postoperative anticoagulation management of a 60-year-old male who developed cardiac perforation during a CDT of an acute saddle PE. Early resumption of systemic heparin in such cases may help in clot resolution; however, it can worsen the hemopericardium. On the other hand, delaying restarting heparin may help in healing of the cardiac perforation but can lead to clot propagation. As the chest tube output was minimal initially, anticoagulation was started, which, however, led to disastrous outcome. With limited published medical literature to help guide such a complex situation, it may be prudent to carefully weigh the risks and benefits of resuming systemic heparin versus delaying it for 1-2 days to allow for definitive resolution of the cardiac perforation.",
"affiliations": "Department of Radiology, Medical College of Georgia, Augusta University, Augusta, GA, USA.;Department of Radiology, Medical College of Georgia, Augusta University, Augusta, GA, USA.;Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.;Department of Radiology, Medical College of Georgia, Augusta University, Augusta, GA, USA.",
"authors": "Li|Hanzhou|H|;Jen|Serena|S|;Agarwal|Shvetank|S|;Rotem|Eran|E|",
"chemical_list": null,
"country": "India",
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"doi": "10.4103/lungindia.lungindia_383_17",
"fulltext": "\n==== Front\nLung IndiaLung IndiaLILung India : Official Organ of Indian Chest Society0970-21130974-598XMedknow Publications & Media Pvt Ltd India 29970775LI-35-33610.4103/lungindia.lungindia_383_17Case ReportManagement of cardiac tamponade during catheter-directed thrombolysis of saddle pulmonary embolism: A clinical dilemma Li Hanzhou Jen Serena Agarwal Shvetank 1Rotem Eran Department of Radiology, Medical College of Georgia, Augusta University, Augusta, GA, USA1 Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USAAddress for correspondence: Mr. Hanzhou Li, Department of Radiology, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA 30912, USA. E-mail: hanli@augusta.eduJul-Aug 2018 35 4 336 338 Copyright: © 2018 Indian Chest Society2018This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Catheter-directed thrombolysis (CDT) for the treatment of acute pulmonary embolism (PE) has gained popularity in recent years, but potential complications during the procedure and their management are not frequently discussed in the literature. In this case report, we describe the clinical dilemma regarding the postoperative anticoagulation management of a 60-year-old male who developed cardiac perforation during a CDT of an acute saddle PE. Early resumption of systemic heparin in such cases may help in clot resolution; however, it can worsen the hemopericardium. On the other hand, delaying restarting heparin may help in healing of the cardiac perforation but can lead to clot propagation. As the chest tube output was minimal initially, anticoagulation was started, which, however, led to disastrous outcome. With limited published medical literature to help guide such a complex situation, it may be prudent to carefully weigh the risks and benefits of resuming systemic heparin versus delaying it for 1–2 days to allow for definitive resolution of the cardiac perforation.\n\nKEY WORDS:\nCardiac tamponadecatheter-directed thrombolysissaddle pulmonary embolism\n==== Body\nINTRODUCTION\nSymptomatic saddle pulmonary embolism (PE) is a relatively uncommon (1%–5%) type of acute PE that represents a large clot burden at the bifurcation of the pulmonary artery and has a potential for acute and severe hemodynamic deterioration.[1] Current treatment options include systemic unfractionated heparin and/or thrombolytics, surgical thrombectomy, and catheter-directed thrombolysis (CDT). CDT has gained popularity in recent years for treating acute PE in patients in whom surgery or high-dose systemic thrombolytics are contraindicated. This approach allows for targeted clot removal with considerably lower doses of thrombolytics, in turn leading to reduced rates of associated in-hospital mortality and intracranial hemorrhage.[234] However, there is a paucity of information related to the potential complications from CDT and their management in the medical literature. In this case report, we describe the dilemma in the postoperative anticoagulation management of a patient with saddle PE who developed cardiac tamponade during CDT.\n\nCASE REPORT\nA 60-year-old, caucasian male with a body mass index of 32, who sustained multiple musculoskeletal and vascular injuries from a motor vehicle accident presented 3 weeks later with sudden, worsening dyspnea and sinus tachycardia. Computed tomography angiography (CTA) demonstrated a large saddle PE extending bilaterally into subsequent lobar and segmental pulmonary arteries (PAs) [Figure 1]. Due to a high risk for bleeding, an emergent CDT was to be performed through the right internal jugular vein with an EKOS™ Acoustic Pulse Thrombolysis system (EKOS Corporation, Bothell, WA, USA) by the interventional radiology team. The patient decompensated during catheter manipulation before the insertion of the EKOS catheter, requiring vasopressin and norepinephrine boluses as well as endotracheal intubation. An arteriogram of the main PA revealed contrast extravasation into the pericardium, suggestive of an acute cardiac tamponade [Figure 2]. CDT was abandoned, and heparin therapy was discontinued. A total of 100 cc of dark, sanguineous fluid was drained from the posterior aspect of the pericardium using an 8 French (F) Dawson-Mueller subxiphoid drain (Cook Medical, Bloomington, IN, USA). After the patient was hemodynamically stabilized, he was transferred to the Intensive Care Unit (ICU) where the pericardial drain was exchanged for a 14F percutaneous drainage catheter (Cook Group, Bloomington, IN, USA) and an additional 75 cc of serosanguinous fluid was drained.\n\nFigure 1 Contrast-enhanced computed tomography angiogram demonstrates a large saddle pulmonary embolism extending bilaterally into subsequent lobar and segmental pulmonary arteries\n\nFigure 2 An arteriogram of the main pulmonary artery revealed contrast extravasation into the pericardium\n\nAs the perforation occurred before the saddle PE could be dissolved and as the pericardial drain output was minimal, the ICU team restarted the patient on intravenous (IV) heparin to prevent clot progression and hopefully achieve some clot dissolution. The patient was evaluated by the cardiothoracic team and was deemed as a poor surgical candidate. Although hemodynamically stable, the patient continued to have persistent serosanguineous pericardial drainage through the night. The next morning, there was a sharp rise in serum creatinine to 4.49 mg/dL and a decrease in urine output to 55 mL in the past 12 h, which was probably due to a combination of inotropic drugs, IV contrast from the CTA as well as the CDT procedure, along with inadequate renal perfusion. The patient was placed on continuous renal replacement therapy, despite which his acidosis and hyperkalemia continued to worsen overnight. On day 2 in the ICU, the patient deteriorated requiring increasing infusions of norepinephrine and vasopressin while the pericardial drainage reduced acutely. Urgent transthoracic echocardiogram showed worsening pericardial effusion with tamponade physiology. Given the low drainage from the pericardium, a clot in the drain was suspected. The drain was replaced with a 14F Wayne pigtail catheter (Cook Medical, Bloomington, IN, USA) with immediate improvement in drainage. However, the patient's coagulation profile became deranged with a platelet count of 47 thousand/mm,[3] international normalized ratio (INR) of 2.2, D-Dimer of >5250 ng/mL, and adjusted partial thromboplastin time of 107.7 s – all suggestive of disseminated intravascular coagulopathy. A subsequent ultrasound showed multiple occlusive thrombi of the patient's femoral and popliteal veins. Furthermore, the patient remained intubated and sedated without response to verbal or painful stimuli. Given the patient's declining condition, the patient's family decided to withdraw care, and the patient passed away on the third postoperative day.\n\nDISCUSSION\nThe use of CDT has recently gained popularity as the first-line treatment for patients with PE who are at risk for bleeding. In a 2009 review of the literature, the collective success rate for CDT was >82.2%; the minor complication risk (requiring at most an overnight observation) was < 11.3%; and the major complication risk (requiring major therapy, prolonged hospitalization, or resulting in death) was < 4.3%.[3]\n\nThis case highlights the clinical challenges associated with an accidental cardiac perforation during CDT. Interventional radiologists should be aware of risk factors for cardiac perforations such as old age, female sex, vessel abnormalities, and prior cardiac interventions.[5] Although our patient did not have any of these risk factors, the emergent nature of the procedure may have contributed to this complication.\n\nEffective management comprises prompt recognition of the perforation, pericardiocentesis, intubation, vasopressors, and atropine.[67] Should pericardiocentesis prove ineffective, a surgery would be required.[8] However, because of the extremely high risk for bleeding, surgery is generally contraindicated. Furthermore, such situations bring with them the ever-present dilemma about whether systemic anticoagulation should be resumed and if so, then when? On the one hand, heparin infusion can aid in the resolution of PE and improve right heart and pulmonary function, whereas, on the other hand, it can place the patient at a higher risk of continued bleeding at the perforation site. In addition, renal dysfunction and other causes of coagulopathy may synergistically worsen the heparin effect. In the limited number of case studies with concurrent acute PE and hemorrhagic cardiac tamponade, clinicians have taken varying courses of action. In one case in which metastatic cancer caused cardiac tamponade and acute PE, the patient received an inferior vena cava filter, and heparin infusion was started 4 days after the removal of the pericardiocentesis drain.[9] In another case, a patient with a traumatic hemopericardium and acute PE was monitored for 2 days before starting the heparin infusion at a target PTT of 1.5–2.3 times the normal range. This patient also received warfarin for a target INR of 2.0–3.0.[10] Reversal agents such as protamine sulfate and Vitamin K or prothrombin complex concentrates are commonly used to reverse the effects of heparin and warfarin, respectively, in cardiac perforation cases;[611] however, this approach is not feasible in patients with unresolved saddle PE as it would worsen the hypercoagulable state and cause more clot progression.\n\nCONCLUSION\nAlthough CDT remains an effective treatment for acute PE in patients with a high risk of bleeding, there is a potential for life-threatening complications. Awareness of the risk factors for cardiac perforations as well as quick recognition and prompt pericardiocentesis will yield the most optimal outcome. If systemic anticoagulation is warranted for continued clot dissolution, the risks and benefits of resuming systemic heparin versus delaying it for 1–2 days to allow for definitive resolution of the cardiac perforation must be considered.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nAcknowledgment\nWe would like to acknowledge Dr. Hoang Anh Vo and Dr. Gregory Bowers for their clinical insight into this case.\n==== Refs\nREFERENCES\n1 Ryu JH Pellikka PA Froehling DA Peters SG Aughenbaugh GL Saddle pulmonary embolism diagnosed by CT angiography: Frequency, clinical features and outcome Respir Med 2007 101 1537 42 17254761 \n2 Patel N Patel NJ Agnihotri K Panaich SS Thakkar B Patel A Utilization of catheter-directed thrombolysis in pulmonary embolism and outcome difference between systemic thrombolysis and catheter-directed thrombolysis Catheter Cardiovasc Interv 2015 86 1219 27 26308961 \n3 Kuo WT Gould MK Louie JD Rosenberg JK Sze DY Hofmann LV Catheter-directed therapy for the treatment of massive pulmonary embolism: Systematic review and meta-analysis of modern techniques J Vasc Interv Radiol 2009 20 1431 40 19875060 \n4 Sista AK Kearon C Catheter-directed thrombolysis for pulmonary embolism: Where do we stand? JACC Cardiovasc Interv 2015 8 1393 5 26315744 \n5 Fasseas P Orford JL Panetta CJ Bell MR Denktas AE Lennon RJ Incidence, correlates, management, and clinical outcome of coronary perforation: Analysis of 16,298 procedures Am Heart J 2004 147 140 5 14691432 \n6 Friedrich SP Berman AD Baim DS Diver DJ Myocardial perforation in the cardiac catheterization laboratory: Incidence, presentation, diagnosis, and management Cathet Cardiovasc Diagn 1994 32 99 107 8062380 \n7 Tokuda M Kojodjojo P Epstein LM Koplan BA Michaud GF Tedrow UB Outcomes of cardiac perforation complicating catheter ablation of ventricular arrhythmias Circ Arrhythm Electrophysiol 2011 4 660 6 21753037 \n8 Tsang TS Freeman WK Barnes ME Reeder GS Packer DL Seward JB Rescue echocardiographically guided pericardiocentesis for cardiac perforation complicating catheter-based procedures. The mayo clinic experience J Am Coll Cardiol 1998 32 1345 50 9809946 \n9 Thomas C Lane K Cecconi M Pulmonary embolism with haemorrhagic pericardial effusion and tamponade: A clinical dilemma BMJ Case Rep 2014 2014 pii: bcr2013202285 \n10 Han JY Seon HJ Choi IS Ahn Y Jeong MH Lee SG Simultaneously diagnosed pulmonary thromboembolism and hemopericardium in a man with thoracic spinal cord injury J Spinal Cord Med 2012 35 178 81 22507028 \n11 Lin T Bai R Chen YW Yu RH Tang RB Sang CH Periprocedural anticoagulation of patients undergoing pericardiocentesis for cardiac tamponade complicating catheter ablation of atrial fibrillation Int Heart J 2015 56 56 61 25503659\n\n",
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"issue": "35(4)",
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"keywords": "Cardiac tamponade; catheter-directed thrombolysis; saddle pulmonary embolism",
"medline_ta": "Lung India",
"mesh_terms": null,
"nlm_unique_id": "8405380",
"other_id": null,
"pages": "336-338",
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"title": "Management of cardiac tamponade during catheter-directed thrombolysis of saddle pulmonary embolism: A clinical dilemma.",
"title_normalized": "management of cardiac tamponade during catheter directed thrombolysis of saddle pulmonary embolism a clinical dilemma"
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"abstract": "Bedaquiline and delamanid are newly available drugs for treating multidrug-resistant tuberculosis (MDR-TB); however, there are limited data guiding their use and no comparison studies.\n\n\n\nWe conducted a prospective, observational study among patients with MDR-TB in Georgia who were receiving a bedaquiline- or delamanid-based treatment regimen. Monthly sputum cultures, minimal inhibitory concentration testing, and adverse event monitoring were performed. Primary outcomes were culture conversion rates and clinical outcomes. Targeted maximum likelihood estimation and super learning were utilized to produce a covariate-adjusted proportion of outcomes for each regimen.\n\n\n\nAmong 156 patients with MDR-TB, 100 were enrolled and 95 were receiving a bedaquiline-based (n = 64) or delamanid-based (n = 31) regimen. Most were male (82%) and the median age was 38 years. Rates of previous treatment (56%) and cavitary disease (61%) were high. The most common companion drugs included linezolid, clofazimine, cycloserine, and a fluoroquinolone. The median numbers of effective drugs received among patients on bedaquiline-based (4; interquartile range [IQR], 4-4) and delamanid-based (4; IQR, 3.5-5) regimens were similar. Rates of acquired drug resistance were significantly higher among patients receiving delamanid versus bedaquiline (36% vs 10%, respectively; P < .01). Adjusted rates of sputum culture conversion at 2 months (67% vs 47%, respectively; P = .10) and 6 months (95% vs 74%, respectively; P < .01), as well as more favorable clinical outcomes (96% vs 72%, respectively; P < .01), were higher among patients receiving bedaquiline versus delamanid.\n\n\n\nAmong patients with MDR-TB, bedaquiline-based regimens were associated with higher rates of sputum culture conversion, more favorable outcomes, and a lower rate of acquired drug resistance versus delamanid-based regimens.",
"affiliations": "Department of Medicine, Division of Infectious Disease, Emory University School of Medicine, Atlanta, Georgia, USA.;National Center for Tuberculosis and Lung Disease, Tbilisi, Georgia.;Department of Biostatistics and Bioinformatics, Emory Rollins School of Public Health, Atlanta, Georgia, USA.;Department of Biostatistics and Bioinformatics, Emory Rollins School of Public Health, Atlanta, Georgia, USA.;National Center for Tuberculosis and Lung Disease, Tbilisi, Georgia.;National Center for Tuberculosis and Lung Disease, Tbilisi, Georgia.;National Center for Tuberculosis and Lung Disease, Tbilisi, Georgia.;Department of Pharmacy, University of Florida, Gainesville, Florida, USA.;Department of Medicine, Division of Infectious Disease, Emory University School of Medicine, Atlanta, Georgia, USA.;National Center for Tuberculosis and Lung Disease, Tbilisi, Georgia.",
"authors": "Kempker|R R|RR|;Mikiashvili|L|L|;Zhao|Y|Y|;Benkeser|D|D|;Barbakadze|K|K|;Bablishvili|N|N|;Avaliani|Z|Z|;Peloquin|C A|CA|;Blumberg|H M|HM|;Kipiani|M|M|",
"chemical_list": "D000995:Antitubercular Agents; D064687:Diarylquinolines; D009593:Nitroimidazoles; C516022:OPC-67683; D010080:Oxazoles; C493870:bedaquiline",
"country": "United States",
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"issue": "71(9)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "bedaquiline; culture conversion; delamanid; multidrug-resistant; tuberculosis",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000328:Adult; D000995:Antitubercular Agents; D064687:Diarylquinolines; D005260:Female; D005845:Georgia; D006801:Humans; D008297:Male; D009593:Nitroimidazoles; D010080:Oxazoles; D011446:Prospective Studies; D018088:Tuberculosis, Multidrug-Resistant",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "2336-2344",
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"pubdate": "2020-12-03",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "28221108;28234080;24100497;29122917;29430041;29562988;26976868;22670901;30215381;29126225;25140958;31315696;22347495;26293803;24392698;17910531;31002070;30630778;28693043;29724920;19494215",
"title": "Clinical Outcomes Among Patients With Drug-resistant Tuberculosis Receiving Bedaquiline- or Delamanid-Containing Regimens.",
"title_normalized": "clinical outcomes among patients with drug resistant tuberculosis receiving bedaquiline or delamanid containing regimens"
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"abstract": "To increase power or reduce the number of patients needed in trials studying treatments for psychiatric or mental disorders with a high placebo response rate, we may consider use of the sequential parallel comparison design proposed elsewhere. Because statistical significance does not necessarily imply that the difference between treatment and placebo is of clinical importance, it is always of importance to quantify the treatment effect in clinical trials. When the patient responses are dichotomous, the treatment and other covariates effects are not likely additive. Thus, using a weighted average of the risk differences over two phases may not be a meaningful summary index to measure the treatment effect. To alleviate this concern, we consider use of the relative difference or relative risk reduction to measure the treatment effect. We derive both point and interval estimators for the relative difference by use of the weighted-least-squares estimator and Mantel-Haenszel type estimator. We employ Monte Carlo simulation to evaluate the finite-sample performance of these estimators in a variety of situations. We also include a procedure for testing the homogeneity of the relative difference between phases under the sequential parallel comparison design. We use the placebo-controlled study to assess the efficacy of a low dose of aripiprazole adjunctive to antidepressant therapy in the treatment of patients with major depressive disorder to illustrate the use of estimators developed here.",
"affiliations": "Department of Mathematics and Statistics, San Diego State University, San Diego, CA, USA.",
"authors": "Lui|Kung-Jong|KJ|0000-0002-5413-2514",
"chemical_list": "D000928:Antidepressive Agents; D000068180:Aripiprazole",
"country": "England",
"delete": false,
"doi": "10.1177/0962280217748486",
"fulltext": null,
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"issn_linking": "0962-2802",
"issue": "28(7)",
"journal": "Statistical methods in medical research",
"keywords": "Relative difference; interval estimation; point estimation; relative risk reduction; sequential parallel comparison design",
"medline_ta": "Stat Methods Med Res",
"mesh_terms": "D000928:Antidepressive Agents; D000068180:Aripiprazole; D003865:Depressive Disorder, Major; D004359:Drug Therapy, Combination; D006801:Humans; D015233:Models, Statistical; D009010:Monte Carlo Method; D016032:Randomized Controlled Trials as Topic; D012107:Research Design",
"nlm_unique_id": "9212457",
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"publication_types": "D016428:Journal Article",
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"title": "Estimation of the relative difference (or relative risk reduction) under the sequential parallel comparison design.",
"title_normalized": "estimation of the relative difference or relative risk reduction under the sequential parallel comparison design"
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"abstract": "Disseminated adenovirus infection can result in high mortality and morbidity in immunocompromised patients. Here, we report the case of a 10-year-old renal allograft recipient who presented with hematuria and dysuria. Adenovirus was isolated from his urine. His urinary symptoms decreased after intravenous hydration and reduction of immunosuppressants. However, 2 weeks later he presented with general weakness and laboratory tests indicated renal failure necessitating emergency hemodialysis. Adenovirus was detected in his sputum; therefore, intravenous ganciclovir and immunoglobulin therapy were initiated. Renal biopsy revealed diffuse necrotizing granulomatous tubulointerstitial nephritis compatible with renal involvement of the viral infection. Adenovirus was detected in his serum. Despite cidofovir administration for 2 weeks, adenovirus was also detected in the cerebrospinal fluid, resulting in generalized tonic-clonic seizure. The patient died 7 weeks after the onset of urinary symptoms. Adenovirus should be considered in screening tests for post-renal transplantation patients who present with hemorrhagic cystitis.",
"affiliations": "Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.;Department of Pediatrics, Hallym University Medical Center, Seoul, Korea.;Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.;Division of Nephrology, Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.;Division of Nephrology, Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.;Division of Nephrology, Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.",
"authors": "Lee|Bora|B|;Park|Eujin|E|;Ha|Jongwon|J|;Ha|Il Soo|IS|;Il Cheong|Hae|H|;Kang|Hee Gyung|HG|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.23876/j.krcp.18.0048",
"fulltext": "\n==== Front\nKidney Res Clin PractKidney Res Clin PractKidney Research and Clinical Practice2211-91322211-9140Korean Society of Nephrology 10.23876/j.krcp.18.0048krcp-37-414Case ReportDisseminated adenovirus infection in a 10-year-old renal allograft recipient Lee Bora 1Park Eujin 2Ha Jongwon 3Ha Il Soo 4Il Cheong Hae 4Kang Hee Gyung 4\n1 Department of Pediatrics, Seoul National University College of Medicine, Seoul, \nKorea\n2 Department of Pediatrics, Hallym University Medical Center, Seoul, \nKorea\n3 Department of Surgery, Seoul National University College of Medicine, Seoul, \nKorea\n4 Division of Nephrology, Department of Pediatrics, Seoul National University College of Medicine, Seoul, \nKoreaCorrespondence: Hee Gyung Kang, Division of Nephrology, Department of Pediatrics, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea. E-mail: kanghg@snu.ac.kr. ORCID: https://orcid.org/0000-0001-8323-532012 2018 31 12 2018 37 4 414 417 28 5 2018 06 8 2018 16 8 2018 Copyright © 2018 by The Korean Society of Nephrology2018This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Disseminated adenovirus infection can result in high mortality and morbidity in immunocompromised patients. Here, we report the case of a 10-year-old renal allograft recipient who presented with hematuria and dysuria. Adenovirus was isolated from his urine. His urinary symptoms decreased after intravenous hydration and reduction of immunosuppressants. However, 2 weeks later he presented with general weakness and laboratory tests indicated renal failure necessitating emergency hemodialysis. Adenovirus was detected in his sputum; therefore, intravenous ganciclovir and immunoglobulin therapy were initiated. Renal biopsy revealed diffuse necrotizing granulomatous tubulointerstitial nephritis compatible with renal involvement of the viral infection. Adenovirus was detected in his serum. Despite cidofovir administration for 2 weeks, adenovirus was also detected in the cerebrospinal fluid, resulting in generalized tonic-clonic seizure. The patient died 7 weeks after the onset of urinary symptoms. Adenovirus should be considered in screening tests for post-renal transplantation patients who present with hemorrhagic cystitis.\n\nAdenoviridaeKidney transplantationOpportunistic infectionsPediatrics\n==== Body\nIntroduction\nAdenoviruses are one of the most common pathogens that cause febrile illness in the young population. They commonly infect the epithelium of the respiratory system but can also cause genitourinary, gastrointestinal, ophthalmologic, neurologic, and disseminated diseases. Most adenoviral infections are self-limiting and are resolved within 2 weeks; however, immunocompromised hosts are more susceptible to adenoviral infections and show a significantly higher mortality rate than healthy patients [1].\n\nAlthough potent immunosuppressive agents have helped reduce the incidence of transplant organ rejection, they increase the patient’s susceptibility to opportunistic infections as well as cancer [2]. Opportunistic infections are more likely to occur between the first and sixth month after organ transplantation [3]. Adenovirus infection is a well-known cause of mortality after bone marrow transplantation [4]. However, limited data are available regarding adenovirus infections following solid organ transplantations, such as renal allograft transplantation. This report describes the case of a pediatric patient with fatal disseminated adenovirus infection after renal transplantation.\n\nCase report\nThe patient was a 10-year-old boy who was born pre-term at a gestational age of 33 weeks and 2 days. He exhibited developmental delays in growth and motor function. He first visited our center for evaluation of short stature at the age of 6 years. He was clinically diagnosed with Russell–Silver syndrome, and proteinuria was incidentally found along with hypoalbuminemia. Conventional treatment for nephrotic syndrome, including high-dose steroid and calcineurin inhibitor, had been ineffective and his renal function had deteriorated. At the age of 8 years, he suffered from right renal vein thrombosis and pulmonary embolism for which he had been treated with anticoagulants. Despite treatment, he developed persistent pulmonary hypertension, which was managed with sildenafil. He underwent living donor kidney transplantation at the age of 9 years, with his mother as the donor. His renal function was well maintained with immunosuppression using prednisolone, mycophenolate mofetil (MMF), and tacrolimus. He discontinued MMF about 70 days after the transplantation and steroid was tapered. Tacrolimus was continued with blood levels maintained at approximately 10 ng/mL. About 3 months after the transplantation, he developed pneumocystis pneumonia that necessitated mechanical ventilation and was treated with intravenous sulfamethoxazole/trimethoprim for 14 days. Steroid was increased (from 2.5 mg to 20 mg prednisolone) and continued at the same dose after discharge. On the 135th postoperative day, he presented with dysuria and gross hematuria. Biochemistry showed the following: blood urea nitrogen (BUN), 24 mg/dL; creatinine (Cr), 0.56 mg/dL; and C-reactive protein (CRP), 0.42 mg/dL. Urinalysis revealed a red blood cell (RBC) count > 100/high power fields (HPF) and a white blood cell (WBC) count > 100/HPF. Urine culture for bacteria and BK virus were negative; however, urine John Cunningham (JC) virus polymerase chain reaction (PCR) and urine adenovirus culture were positive (1–9 cells/HPF). He was diagnosed with hemorrhagic cystitis and was managed with hydration and pain control because of tolerable dysuria and absence of fever. After a week, dysuria and hematuria persisted with a RBC count > 100/HPF and WBC count 1 to 4/HPF; however, his immunosuppression was maintained.\n\nThree weeks later, he visited the emergency room with fever, general weakness, chest tightness, mild cough with persistent dysuria, and hematuria. Laboratory tests revealed BUN at 175 mg/dL, Cr at 8.29 mg/dL, and CRP at 30.23 mg/dL (Table 1). He underwent emergent hemodialysis and was empirically treated with piperacillin/tazobactam considering the possibility of urosepsis. Sputum, blood, and urine culture results were negative; however, the adenovirus real-time PCR of sputum and blood cytomegalovirus (CMV) antigen were positive. He was presumed to have disseminated adenovirus infection and was treated with immunosuppression reduction and ganciclovir. Renal allograft biopsy showed diffuse necrotizing granulomatous tubulointerstitial nephritis (Fig. 1), indicating infectious tubulointerstitial nephritis rather than rejection. Staining for CD3 and C4d was negative, indicating negativity for cellular and humoral rejection, respectively. He also tested positive for JC virus PCR and serum CMV PCR, suggesting coinfection. He was treated with ganciclovir targeting CMV, antibiotic therapy with renal impairment dose for CMV infection, granulocyte colony-stimulating factor, immunoglobulin, transfusion, and hemodialysis; however, the inflammatory marker and fever remained consistently high.\n\nCidofovir is known to be more effective than other antiviral agents against adenovirus infection [5]. Therefore, despite its well-known nephrotoxicity, we initiated cidofovir treatment on the 167th postoperative day because of persistent infection. The patient was given cidofovir (1 mg/kg/day, 3 times/week without probenecid), a renal impairment dose of post-hematopoietic stem cell transplant adenovirus infection induction treatment, with on-going hemodialysis. After administration of 4 doses, we changed the regimen to 2 mg/kg every 2 weeks as a renal impairment dose for maintenance therapy, of which 3 treatments were completed. However, serum adenovirus PCR and cerebrospinal fluid adenovirus PCR were positive, his renal function was not recovered, and he presented generalized tonic-clonic seizure. Although treatment with vancomycin, meropenem, and acyclovir was initiated to control meningitis, his general condition continued to deteriorate. Anemia, leukopenia, and thrombocytopenia developed; these could be attributed to bone marrow suppression associated with severe infection. Despite intensive care, including mechanical ventilation and continuous renal replacement therapy, he died on the 215th day post-renal transplantation. Fig. 2 shows the summary of his clinical course and treatment.\n\nDiscussion\nAdenovirus infection is defined as detection of adenovirus by immunofluorescence, culture, histology or PCR from any site. Asymptomatic adenovirus infection refers to the absence of clinical symptoms whereas adenovirus disease is defined as anatomically corresponding symptoms in the absence of any other identifiable cause. Disseminated adenovirus disease is an adenovirus infection affecting two or more organs or systems [6]. Adenovirus infections after solid-organ transplantation may be asymptomatic or manifested as disseminated and severe infection with prolonged viral propagation and significant mortality and morbidity, including graft dysfunction and rejection [7]. This was the first case of disseminated adenovirus infection that led to mortality among all cases of pediatric renal transplantation treated at our center. Infection may be associated with the reactivation of a latent infection in the graft or the recipient or with a novel infection. Pre-transplant infection screening does not include adenovirus screening; therefore, we do not have information regarding the presence of a potential preexisting adenovirus infection in our patient.\n\nEstablishing a diagnosis of adenovirus infection can be challenging; infection is diagnosed when a culture or PCR is positive but it may be 3 weeks before the cytopathic changes become detectable. Quantitative real-time PCR is useful during follow-up because the presence of > 1 × 106 copies is associated with increased mortality [8].\n\nAdenovirus infection in solid organ transplantation recipients usually involves the donor organ. In renal transplantation recipients, the primary clinical presentation is acute hemorrhagic cystitis, sometimes complicated with interstitial nephritis [9]. To our knowledge, no controlled trials highlighting the benefit of any antiviral agent in human adenoviral disease have been conducted. So far, cidofovir appears to be more effective against adenovirus in vitro than any other antiviral agent; however, nephrotoxicity is a major adverse effect of cidofovir. In this patient, cidofovir was given at least a week after the infection became disseminated; however, earlier administration of cidofovir might have been more effective. In addition, it would have been useful to measure the serum viral load of adenovirus to assess the disease activity and the effect of medication.\n\nAdenoviral infections in organ transplantation patients can result in fatal complications and mortality. Therefore, adenovirus should be considered and included in all laboratory screening tests for post-renal transplantation patients with hemorrhagic cystitis. Prospective studies are warranted to better understand the pathogenesis and to develop appropriate screening and therapeutic guidelines for adenovirus infections in transplant recipients.\n\nConflicts of interest\n\nAll authors have no conflicts of interest to declare.\n\nFigure 1 Renal allograft biopsy\n(A) Alternating necrotizing granulomatous tubulointerstitial nephritis (×20). (B) Necrosis of glomerular and tubular system (H&E stain, ×200). (C) No CD3 deposition which means negative for cellular rejection (immunoperoxidase stain, ×200). (D) No C4d deposition which means negative for humoral rejection (immunoperoxidase stain, ×200).\n\nFigure 2 Time line and clinical course after transplantation\nPositive (closed symbols) and negative (open symbols) results of culture (Cx) and polymerase chain reaction (PCR) of urine (U), serum (S), throat swab (T), and cerebrospinal fluid (C) specimens for detection of adenovirus (AdV). The white and black arrows indicate intravenous immunoglobulin and cidofovir, respectively.\n\nA, admission; CMV, cytomegalovirus; CRRT, continuous renal replacement therapy; FK, tacrolimus; GTC seizure, generalized tonic-clonic seizure; HD, hemodialysis; MMF, mycophenolate mofetil; PCP, pneumocystis pneumonia.\n\nTable 1 Clinical characteristics of each admission\n\nTime after transplantation\t135th day\t159th day\t\nTacrolimus level (ng/mL)\t3.7\t16.3\t\nBUN (mg/dL)\t24\t175\t\nCreatinine (mg/dL)\t0.56\t8.29\t\nAST/ALT (IU/L)\t31/50\t30/24\t\nBilirubin, total (mg/dL)\t0.4\t0.2\t\nCRP (mg/dL)\t0.42\t30.23\t\nTotal CO2 (mmol/L)\t16\t15\t\nPT (INR)\t-\t0.92\t\naPTT (sec)\t-\t33.1\t\nALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CRP, C-reactive protein; PT, prothrombin time; aPTT, activated partial thromboplastin time.\n==== Refs\nReferences\n1 Hierholzer JC Adenoviruses in the immunocompromised host Clinl Microbiol Rev 5 262 274 1992 10.1128/CMR.5.3.262 \n2 Halloran PF Immunosuppressive drugs for kidney transplantation N Eng J Med 351 2715 2729 2004 10.1056/NEJMra033540 \n3 Fishman JA Rubin RH Infection in organ-transplant recipients N Engl J Med 338 1741 1751 1998 10.1056/NEJM199806113382407 9624195 \n4 Howard DS Phillips GL II Reece DE Adenovirus infections in hematopoietic stem cell transplant recipients Clin Infect Dis 29 1494 1501 1999 10.1086/313514 10585802 \n5 Neofytos D Ojha A Mookerjee B Treatment of adenovirus disease in stem cell transplant recipients with cidofovir Biol Blood Marrow Transplant 13 74 81 2007 10.1016/j.bbmt.2006.08.040 17222755 \n6 Tebruegge M Curtis N Adenovirus infection in the immunocompromised host Adv Exp Med Biol 659 153 174 2010 10.1007/978-1-4419-0981-7_13 20204763 \n7 Florescu D Hoffman J Adenovirus in solid organ transplantation Am J Transplant 13 Suppl 4 206 211 2013 10.1111/ajt.12112 23465013 \n8 Claas EC Schilham MW de Brouwer CS Internally controlled real-time PCR monitoring of adenovirus DNA load in serum or plasma of transplant recipients J Clin Microbiol 43 1738 1744 2005 10.1128/JCM.43.4.1738-1744.2005 15814994 \n9 Ito M Hirabayashi N Uno Y Nakayama A Asai J Necrotizing tubulointerstitial nephritis associated with adenovirus infection Hum Pathol 22 1225 1231 1991 10.1016/0046-8177(91)90104-W 1660851\n\n",
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"issue": "37(4)",
"journal": "Kidney research and clinical practice",
"keywords": "Adenoviridae; Kidney transplantation; Opportunistic infections; Pediatrics",
"medline_ta": "Kidney Res Clin Pract",
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"pages": "414-417",
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"pubdate": "2018-12",
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"title": "Disseminated adenovirus infection in a 10-year-old renal allograft recipient.",
"title_normalized": "disseminated adenovirus infection in a 10 year old renal allograft recipient"
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"abstract": "Objectives: To study the genetic and clinical characteristics of Chinese children with pathogenic proline-rich transmembrane protein 2 (PRRT2) gene-associated disorders. Methods: Targeted next generation sequencing (NGS) was used to identify pathogenic PRRT2 variations in Chinese children with epilepsy and/or kinesigenic dyskinesia. Patients with confirmed PRRT2-associated disorders were monitored and their clinical data were analyzed. Results: Forty-four patients with pathogenic PRRT2 variants were recruited. Thirty-five of them (79.5%) had heterozygous mutations, including 30 frameshifts, three missenses, one nonsense, and one splice site variant. The c.649dupC was the most common variant (56.8%). Eight patients (18.2%) showed whole gene deletions, and one patient (2.3%) had 16p11.2 microdeletion. Thirty-four cases (97.1%) were inherited and one case (2.9%) was de novo. Forty patients were diagnosed with benign familial infantile epilepsy (BFIE), two patients had paroxysmal kinesigenic dyskinesia (PKD) and two had infantile convulsions and choreoathetosis (ICCA). Patients with whole gene deletions had a later remission than patients with heterozygous mutations (13.9 vs. 7.1 months, P = 0.001). Forty-two patients were treated with antiseizure medications (ASMs). At last follow-up, 35 patients, including one who did not receive therapy, were asymptomatic, and one patient without ASMs died of status epilepticus at 12 months of age. One patient developed autism, and one patient showed mild developmental delay/intellectual disability. Conclusion: Our data suggested that patients with whole gene deletions could have more severe manifestations in PRRT2-associated disorders. Conventional ASMs, especially Oxcarbazepine, showed a good treatment response.",
"affiliations": "Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.;Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.;Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.;Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.;Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.;Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.;Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.;Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.;Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.;Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.;Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.;Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.",
"authors": "Luo|Han-Yu|HY|;Xie|Ling-Ling|LL|;Hong|Si-Qi|SQ|;Li|Xiu-Juan|XJ|;Li|Mei|M|;Hu|Yue|Y|;Ma|Jian-Nan|JN|;Wu|Peng|P|;Zhong|Min|M|;Cheng|Min|M|;Li|Ting-Song|TS|;Jiang|Li|L|",
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"doi": "10.3389/fped.2021.676616",
"fulltext": "\n==== Front\nFront Pediatr\nFront Pediatr\nFront. Pediatr.\nFrontiers in Pediatrics\n2296-2360\nFrontiers Media S.A.\n\n10.3389/fped.2021.676616\nPediatrics\nOriginal Research\nThe Genotype and Phenotype of Proline-Rich Transmembrane Protein 2 Associated Disorders in Chinese Children\nLuo Han-yu 12†\n\nXie Ling-ling 12†\n\nHong Si-qi 12\nLi Xiu-juan 12\nLi Mei 12\nHu Yue 12\n\nMa Jian-nan 12\n\nWu Peng 12\nZhong Min 12\nCheng Min 12\nLi Ting-song 12\n\nJiang Li 12*\n1Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China\n2Chongqing Key Laboratory of Pediatrics, Chongqing, China\nEdited by: Pasquale Striano, University of Genoa, Italy\n\nReviewed by: Ganna Balagura, Giannina Gaslini Institute (IRCCS), Italy; Alberto Spalice, Sapienza University of Rome, Italy; Aglaia Vignoli, University of Milan, Italy\n\n*Correspondence: Li Jiang dr_jiangcqmu@163.com\nThis article was submitted to Pediatric Neurology, a section of the journal Frontiers in Pediatrics\n\n†These authors have contributed equally to this work and share first authorship\n\n10 5 2021\n2021\n9 67661605 3 2021\n13 4 2021\nCopyright © 2021 Luo, Xie, Hong, Li, Li, Hu, Ma, Wu, Zhong, Cheng, Li and Jiang.\n2021\nLuo, Xie, Hong, Li, Li, Hu, Ma, Wu, Zhong, Cheng, Li and Jiang\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nObjectives: To study the genetic and clinical characteristics of Chinese children with pathogenic proline-rich transmembrane protein 2 (PRRT2) gene-associated disorders.\n\nMethods: Targeted next generation sequencing (NGS) was used to identify pathogenic PRRT2 variations in Chinese children with epilepsy and/or kinesigenic dyskinesia. Patients with confirmed PRRT2-associated disorders were monitored and their clinical data were analyzed.\n\nResults: Forty-four patients with pathogenic PRRT2 variants were recruited. Thirty-five of them (79.5%) had heterozygous mutations, including 30 frameshifts, three missenses, one nonsense, and one splice site variant. The c.649dupC was the most common variant (56.8%). Eight patients (18.2%) showed whole gene deletions, and one patient (2.3%) had 16p11.2 microdeletion. Thirty-four cases (97.1%) were inherited and one case (2.9%) was de novo. Forty patients were diagnosed with benign familial infantile epilepsy (BFIE), two patients had paroxysmal kinesigenic dyskinesia (PKD) and two had infantile convulsions and choreoathetosis (ICCA). Patients with whole gene deletions had a later remission than patients with heterozygous mutations (13.9 vs. 7.1 months, P = 0.001). Forty-two patients were treated with antiseizure medications (ASMs). At last follow-up, 35 patients, including one who did not receive therapy, were asymptomatic, and one patient without ASMs died of status epilepticus at 12 months of age. One patient developed autism, and one patient showed mild developmental delay/intellectual disability.\n\nConclusion: Our data suggested that patients with whole gene deletions could have more severe manifestations in PRRT2-associated disorders. Conventional ASMs, especially Oxcarbazepine, showed a good treatment response.\n\nPRRT2\ngenotype\nphenotype\nbenign familial infantile epilepsy\ntreatment\nprognosis\n==== Body\nIntroduction\n\nPathogenic mutations in the proline-rich transmembrane protein 2 (PRRT2) gene have recently been identified in a series of disorders. Among these PRRT2-associated disorders, a majority of patients have benign familial infantile epilepsy (BFIE), characterized by self-limiting seizures, which usually onset before the age of 6 months, and normal psychomotor development (1), paroxysmal kinesigenic dyskinesia (PKD), characterized by short attacks of dyskinesia triggered by sudden voluntary movements (2), or infantile convulsions with choreoathetosis (ICCA), presenting paroxysmal movement disorders during childhood after remission of infantile convulsions (3). Other rare cases, including hemiplegic migraine and episodic ataxia, have rapidly expanded the boundary of this spectrum (4). Most patients have a tendency to natural remission and favorable outcome. The diverse clinical manifestations caused by variants in the same gene indicate a conventional spectrum that share similar clinical and genetic features, although the pathophysiology of variants in PRRT2 is not entirely understood.\n\nIn this study, we aimed to describe clinical and genetic features of a selected cohort of Chinese children with PRRT2-associated disorders and discuss the treatment strategies and prognosis of these patients.\n\nMaterials and Methods\n\nPatients\n\nA total of 44 children who were diagnosed and treated at the Children's Hospital of Chongqing Medical University were recruited between April 2016 and May 2019. Inclusion criteria for the study were: (I) children (age < 18 years) receiving a new diagnosis of epilepsy or children presenting with paroxysmal movement disorders; (II) patients with pathogenic PRRT2 variants. Clinical data, including demographic information, family history, clinical manifestation, electroencephalogram (EEG), brain magnetic resonance imaging (MRI), treatment, and follow-up were collected and analyzed. BFIE was defined when patients met the following conditions: (I) onset of seizures between the age of 3 and 12 months; (II) focal seizures with or without secondary generalization; (III) normal interictal EEGs and brain MRI; (IV) normal psychomotor development; (V) positive family history; (VI) seizure-free before 2 years of age; and (VII) exclusion of other metabolic disorders (5). The diagnostic criteria of PKD were revised from Bruno et al. (6) as follows: (I) an identified kinesigenic trigger for attacks; (II) duration of attacks <1 minute; (III) attacks without loss of consciousness or pain; (IV) response to antiseizure medications (ASMs); (V) age of onset 1-20 years old; and (VI) exclusion of other organic diseases. ICCA was diagnosed when patients presented with both BFIE and PKD. All patients participated in a follow up at least 3 months after inclusion in the study, including number of seizure episodes, developmental milestones, mental conditions, and therapeutic regimes.\n\nGenetic Analysis\n\nWritten informed consent was obtained from legal guardians of patient. This study was approved by the Children's Hospital of Chongqing Medical University Ethics Committee. Genomic DNA from each individual and 50 normal controls without epilepsy or any related history were extracted from peripheral blood leukocytes. A custom-designed panel that captured the coding exons of 535 genes associated with epilepsy, including PRRT2, was synthetized using the Agilent SureSelect Target Enrichment System which contained a total of 12,000 probes covering 1.285 Mbp. Then, targeted next generation sequencing (NGS) was performed following previously reported experimental procedures (7). Sequencing results were aligned to the Genome Reference Consortium Homo sapiens (human) genome assembly GRCh37 (GRCh37/hg19) and compared with the established human PRRT2 sequences (NM_145239). Sanger sequencing was performed to validate variants identified by NGS and for segregation analysis. We used PolyPhen-2, SIFT, MutationTaster, and FATHMM-MKL to predict the pathogenicity of the missense variants.\n\nStatistical Analysis\n\nContinuous variables were expressed as mean ± SD. Differences were tested using Student's t-test or the Mann–Whitney U-test. Categorical variables were summarized as percentages, and compared byχ2 test or by Fisher's exact test. A P-value ≤ 0.05 in a two-tailed test was considered statistically significant. Statistical analyses were performed using SPSS version 23.0 (IBM, Armonk, NY).\n\nResults\n\nIdentification of Pathogenic PRRT2 Variants\n\nForty-four patients (29 males and 15 females) with pathogenic PRRT2 variants were identified (Table 1). Nine patients (20.5%) showed PRRT2 deletions (eight patients with PRRT2 whole gene deletions, and one with 16p11.2 microdeletion). The remaining 35 patients (79.5%) were PRRT2 heterozygous variants, including 30 frameshift mutations, three missense mutations, one nonsense mutation, and one splice site change. Of the 35 variants, 32 (91.4%) coded the proline-rich domain and extracellular domain, including 25 c.649dupC mutations, three c.649delC mutations, one c.224C>T mutation, one c.2484C>G mutation, one c.439G>C mutation, and one c.615dupA mutation (Figure 1). Based on the Human Gene Mutation Database (HGMD), four patients displayed novel variants (c.284C>G, c.883_884insGGAA, c.879+4A>G, and c.914G>A). The nonsense variant c.284C>G (p.S95X) resulted in a premature stop codon. The c.883_884insGGAA (p.N296Kfs*45) produced a frameshift variant with a premature stop codon 45 amino acids downstream. Both of them were classified as “pathogenetic” according to the ACMG criteria. The c.879+4A>G variant affected the splice site. According to the ACMG criteria, it was classified as “variant of unknown significance.” The missense variant c.914G>A (p.G305E) affected highly conserved residues of the cytoplasmic domain toward the C terminus of PRRT2, which was considered “variant of unknown significance” according to the ACMG criteria. All missense variants were predicted to be damaging to protein function by prediction tools used (Table 2). Thirty-four (97.1%) of the frameshift mutations were inherited, and only one c.649dupC mutation (2.9%) was de novo.\n\nTable 1 Genotypes of 44 patients with pathogenic PRRT2 mutations.\n\nPatient\tPosition:chr16\tExon\tVariant\tProtein\tNovel/reported\tParental derivation\t\nP1\t29824599\t2\tc.224C>T\tp.P75L\tR\tM\t\nP2\t29824659\t2\tc.284C>G\tp.S95X\tN\tM\t\nP3\t29824814\t2\tc.439G>C\tp.D147H\tR\tM\t\nP4\t29824990\t2\tc.615dupA\tp.S208Ifs*17\tR\tF\t\nP5\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tF\t\nP6\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tF\t\nP7\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tM\t\nP8\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tM\t\nP9\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tF\t\nP10\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tF\t\nP11\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tM\t\nP12\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tF\t\nP13\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tM\t\nP14\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tM\t\nP15\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tM\t\nP16\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tM\t\nP17\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tM\t\nP18\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tM\t\nP19\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tF\t\nP20\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tM\t\nP21\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tM\t\nP22\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tM\t\nP23\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tF\t\nP24\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tF\t\nP25\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tDe novo\t\nP26\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tF\t\nP27\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tF\t\nP28\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tM\t\nP29\t29825024\t2\tc.649dupC\tp.R217Pfs*8\tR\tF\t\nP30\t29825024\t2\tc.649delC\tp.R217Efs*12\tR\tM\t\nP31\t29825024\t2\tc.649delC\tp.R217Efs*12\tR\tF\t\nP32\t29825024\t2\tc.649delC\tp.R217Efs*12\tR\tF\t\nP33\t29825657\t3\tc.883_884insGGAA\tp.N296Kfs*45\tN\tF\t\nP34\t29825258\tSplicing\tc.879+4A>G\t-\tN\tF\t\nP35\t29825688\t3\tc.914G>A\tp.G305E\tN\tM\t\nP36\t29802081-30199897\t16p11.2 Microdeletion\t\t\tR\tF\t\nP37\t-\tWhole gene deletion\t\t\tR\tNA*\t\nP38\t-\tWhole gene deletion\t\t\tR\tNA*\t\nP39\t-\tWhole gene deletion\t\t\tR\tNA*\t\nP40\t-\tWhole gene deletion\t\t\tR\tNA*\t\nP41\t-\tWhole gene deletion\t\t\tR\tNA*\t\nP42\t-\tWhole gene deletion\t\t\tR\tNA*\t\nP43\t-\tWhole gene deletion\t\t\tR\tNA*\t\nP44\t-\tWhole gene deletion\t\t\tR\tNA*\t\n* The patient's parents did not accept gene sequencing. NA, not available; R, reported; N, Novel; M, mother; F, father.\n\nFigure 1 PRRT2 gene structure and locations of PRRT2 mutations in the PRRT2 gene sequence. The PRRT2 gene contains four exons that encode a 340 amino acid protein, including a protein-rich domain (amino acids 131-216) in its extracellular region (amino acids 1-268), one cytoplasmic region (amino acids 290-317), and two transmembrane regions (amino acids 269-289 and 318-338). The positions of the 35 heterozygous mutations identified in this study are shown.\n\nTable 2 Pathogenicity prediction of three missense mutations.\n\nVariant\tSIFT\tPolyPhen 2\tMutation Taster\tFATHMM-MKL\t\nc.224C>T, p.P75L\tdamaging\tBenign\tdisease causing\tDeleterious\t\nc.439G>C, p.D147H\tdamaging\tBenign\tpolymorphism\tTolerated\t\nc.914G>A, p.G305E\tdamaging\tprobably damaging\tdisease causing\tDeleterious\t\n\nClinical Findings\n\nPatients' detailed clinical information was gathered from 3 months to 2 years following PRRT2 mutation diagnosis (Table 3). No specific perinatal history or abnormal physical examination were noted in any patients when admitted. Figure 2 presented three patients' pedigrees (Patients 8, 9, and 35) that showed segregation of PRRT2 variants in more than two generations.\n\nTable 3 Clinical characteristics of patients harboring pathogenic PRRT2 mutations.\n\nPatient, Gender\tPheno-type\tVariant\tFamily history†\tAge of onset\tSeizure Type\tIctal EEG\tAge at treatment\tInitial ASMs\tEffective ASMs\tAge at remission\tAge at last follow up\tDevelopment\t\nP1, M\tBFIE\tc.224C>T\t+/–\t11 m\tFBTC\tNA\t18 m\tLEV\tLEV\t18 m\t4 y\tNormal\t\nP2, M\tBFIE\tc.284C>G\t+/–\t4.5 m\tFT\tNA\t5 m\tLEV\tLEV\t5 m\t4 y 3 m\tNormal\t\nP3, M\tPKD\tc.439G>C\t+/–\t13 y\tDystonia\tNA\t15 y\tLTG\tOXC\t17 y\t17 y\tNormal\t\nP4, M\tBFIE\tc.615dupA\t–/–\t5 m\tFT, FBTC\tNA\t5.5 m\tLEV\tLEV+PB\tLost to follow up\t\nP5, M\tBFIE\tc.649dupC\t–/+\t3.5 m\tFT\tNA\t4 m\tLEV\tOXC\t4.5 m\t4 y 9 m\tNormal\t\nP6, F\tBFIE\tc.649dupC\t+/–\t4.5 m\tFBTC\tNA\t5 m\tLEV\tLEV\t5 m\t4 y 1 m\tNormal\t\nP7, F\tBFIE\tc.649dupC\t+/–\t3.5 m\tFT, GTC\tNA\t4 m\tLEV\tLEV+TPM\t12 m\t3 y 8 m\tNormal\t\nP8, F\tBFIE\tc.649dupC\t+/–\t3.5 m\tFBTC\tNA\t4 m\tLEV\tLEV\t5 m\t3 y 8 m\tNormal\t\nP9, F\tBFIE\tc.649dupC\t+/–\t3.5 m\tFT\tNA\t4 m\tLEV\tOXC\t5.5 m\t3 y 7 m\tNormal\t\nP10, F\tBFIE\tc.649dupC\t+/–\t4 m\tFT\tNA\t4.5 m\tLEV\tLEV\t4.5 m\t3 y 5 m\tNormal\t\nP11, F\tBFIE\tc.649dupC\t–/–\t5.5 m\tFBTC\tNA\t7 m\tLEV\tLEV\t7 m\t3 y 6 m\tNormal\t\nP12, M\tBFIE\tc.649dupC\t–/+\t5 m\tFT\tNA\t6 m\tLEV\tLEV\t8 m\t3 y 1 m\tNormal\t\nP13, F\tBFIE\tc.649dupC\t–/–\t4.5 m\tFT, FBTC\tNA\t5 m\tLEV\tLEV\t5.5 m\t2 y 9 m\tNormal\t\nP14, M\tBFIE\tc.649dupC\t+/–\t4 m\tFT\tNA\t4.5 m\tLEV\tLEV+VPA\t8 m\t2 y 9 m\tNormal\t\nP15, M\tBFIE\tc.649dupC\t+/–\t3.5 m\tFBTC\tTemporal\t4 m\tLEV\tVPA\t4.5 m\t2 y 9 m\tAutism\t\nP16, F\tBFIE\tc.649dupC\t+/–\t3.5 m\tFT\tTemporal\t4 m\tVPA\tVPA\t4 m\t2 y 9 m\tNormal\t\nP17, M\tBFIE\tc.649dupC\t+/–\t3.5 m\tFT, GTC\tFrontal\t4 m\tLEV\tLEV\tLost to follow up\t\nP18, M\tBFIE\tc.649dupC\t–/–\t5.5 m\tFT, GTC\tNA\t5.5 m\tLEV\tLEV+VPA\t8 m\t2 y 8 m\tNormal\t\nP19, F\tBFIE\tc.649dupC\t+/–\t4.5 m\tFBTC\tNA\t5 m\tLEV\tLEV\t6 m\t2 y 7 m\tNormal\t\nP20, M\tBFIE\tc.649dupC\t+/+\t4 m\tFT, GTC\tFrontal\t4.5 m\tLEV\tLEV\tLost to follow up\t\nP21, M\tBFIE\tc.649dupC\t+/–\t5.5 m\tFBTC\tTem\t6 m\tOXC\tOXC\t6 m\t1 y 8 m\tNormal\t\nP22, M\tBFIE\tc.649dupC\t+/–\t5 m\tFT\tNA\t6 m\tOXC\tOXC\t6 m\t1 y 8 m\tNormal\t\nP23, F\tBFIE\tc.649dupC\t+/–\t4.5 m\tFBTC\tFrontal\t5 m\tLEV\tOXC\t5.5 m\t7 m\tNormal\t\nP24, F\tBFIE\tc.649dupC\t+/–\t4 m\tFT\tNA\t4.5 m\tLEV\tLEV+PB\t5.5 m\t4 y 5 m\tNormal\t\nP25, M\tBFIE\tc.649dupC\t–/–\t5 m\tFT\tNA\t5.5 m\tLEV\tLEV\tLost to follow up\t\nP26, M\tBFIE\tc.649dupC\t+/–\t5 m\tFBTC\tNA\t5.5 m\tLEV\tLEV\tLost to follow up\t\nP27, M\tBFIE\tc.649dupC\t–/–\t7.5 m\tFT\tNA\t8 m\tOXC\tOXC\tLost to follow up\t\nP28, M\tPKD\tc.649dupC\t–/+\t9 y\tChoreo-athetosis\tNA\t9.5 y\tOXC\tOXC\tLost to follow up\t\nP29, M\tBFIE\tc.649dupC\t–/+\t4.5 m\tFT, GTC\tFrontal\t5.5 m\tLEV\tOXC\t6 m\t2 y 1 m\tNormal\t\nP30, M\tBFIE\tc.649delC\t+/–\t4.5 m\tFT, GTC\tTempotal\t5 m\tLEV\tOXC\t11 m\t1 y 6 m\tNormal\t\nP31, M\tBFIE\tc.649delC\t+/–\t6 m\tFT\tNA\t6.5 m\tLEV\tOXC\t7 m\t1 y 6 m\tNormal\t\nP32, M\tBFIE\tc.649delC\t+/–\t4 m\tFT\tNA\t4.5 m\tVPA\tVPA\t6 m\t4 y\tNormal\t\nP33, F\tBFIE\tc.883_884insGGAA\t+/–\t4.5 m\tFBTC\tNA\t5 m\tLEV\tLEV\t14 m\t3 y 1 m\tNormal\t\nP34, M\tBFIE\tc.879+4A>G\t+/+\t3.5 m\tFBTC\tNA\t4 m\tOXC\tOXC\tLost to follow up\t\nP35, M\tICCA\tc.914G>A\t–/+\t6 y\tChoreo-athetosis\tNA\t6 y\tOXC\tOXC\t6.5 y\t8 y\tNormal\t\nP36, M\tICCA\t16p11.2 Microdeletion\t–/–\t10 y\tChoreo-athetosis\tNA\t12.5 y\tOXC\tOXC\t12.5 y\t13 y 9 m\tDDID\t\nP37, M\tBFIE\tWGD\t+/–\t12 m\tFBTC\tNA\tNone\tNone\tNone\t14 m\t4 y 5 y\tNormal\t\nP38, F\tBFIE\tWGD\t–/–\t3.5 m\tFBTC\tNA\t4 m\tLEV\tLEV\t8 m\t3 y 6 m\tNormal\t\nP39, M\tBFIE\tWGD\t–/–\t3 m\tFBTC\tNA\t4 m\tLEV\tLEV+VPA\t5 m\t3 y 5 m\tNormal\t\nP40, F\tBFIE\tWGD\t–/–\t8.5 m\tFT\tNA\t16 m\tLEV\tOXC\t26 m\t4 y\tNormal\t\nP41, F\tBFIE\tWGD\t+/–\t4 m\tFT\tOccipital\t4.5 m\tLEV\tLEV+VPA\t12 m\t4 y 6 m\tNormal\t\nP42, M\tBFIE\tWGD\t–/–\t5 m\tFT\tNA\t5 m\tLEV\tLEV\t14 m\t3 y\tNormal\t\nP43, M\tBFIE\tWGD\t–/–\t8.5 m\tFT, GTC\tNA\t18 m\tOXC\tOXC\t18 m\t2 y 11 m\tNormal\t\nP44, M\tBFIE\tWGD\t+/–\t8 m\tFBTC\tNA\tNone\tNone\tNone\t12 m\t-\tDeath\t\n† Self-limited non-febrile seizures during infantile period/paroxysmal kinesigenic dyskinesia. EEG, electroencephalogram; ASMs, antiseizure medications; M, male; F, female; BFIE, benign familial infantile epilepsy; PKD, paroxysmal kinesigenic dyskinesia; ICCA, infantile convulsions with choreoathetosis; m, month; y, year; GTC, generalized tonic-clonic seizure; FBTC, focal to bilateral tonic-clonic seizure; FT, focal tonic seizure; LEV, levetiracetam; OXC, oxcarbazepine; VPA, valproic acid; LTG, lamotrigine; DDID, developmental delay/intellectual disability. WGD, whole gene deletion.\n\nFigure 2 Pedigrees from three families with PRRT2 mutations. Arrow, proband; BFIE, benign familial infantile epilepsy; PKD, paroxysmal kinesigenic dyskinesia; ICCA, infantile convulsions with choreoathetosis. Individuals who underwent genetic sequencing are indicated by + and –. Individuals with a PRRT2 heterozygous mutation are shown using +/–, and individuals that tested negative for a PRRT2 mutation are shown using +/+. The c.649dupC mutation was identified in family 8 and family 9. The c.914G>A mutation was identified in Family 35.\n\nForty patients (25 males and 15 females) with pathogenic PRRT2 variants were diagnosed with BFIE, and 29 of them had a family history of seizures or PKD. The average age of onset was 5.1 ± 2.0 months. There was no significant difference (4.7 vs. 6.6 months, P = 0.143) in age of onset between patients with heterozygous mutations (n = 32) and patients with whole gene deletions (n = 8). All the patients presented with focal motor seizures. Twenty-three patients had focal to bilateral tonic-clonic seizures. Twenty-eight patients presented seizures in clusters (2-20 attacks per day). Status epilepticus was noted in one patient (Patient 44). Ictal EEG showed that discharges originated from temporal lobe (Patients 15, 16, 21, and 30), frontal lobe (Patients 17, 20, 23, and 29) and occipital lobe (Patient 41).The interictal EEGs were normal in 35 patients, whereas 4 patients showed interictal spike waves that originated from the frontal lobe (Patients 38 and 42), temporal lobe (Patient 33), or occipital lobe (Patient 14) during frequent attacks, which disappeared during subsequent follow-up. All patients demonstrated a normal brain MRI.\n\nTwo patients were diagnosed with PKD (Patients 3 and 28). Both of them had a family history of movement disorders. The age of symptoms onset was 9 and 13 years old, respectively. Patient 3 presented with dystonia triggered by standing up suddenly, and patient 28 presented with bilateral choreoathetosis triggered by sudden movement. The attacks occurred several times per day and usually lasted <1 min without loss of consciousness. Both patients showed normal interictal EEG and brain MRI.\n\nTwo patients (Patients 35 and 36) were diagnosed with ICCA. Patient 35 had manifested self-limited clusters of non-febrile focal motor seizures since the age of 5 months and developed bilateral dyskinesia at the age of 6 years. Patient 36 had focal to bilateral tonic-clonic seizures from 8 to 18 months of age, and presented with unilateral choreoathetosis at 10 years old. These two ICCA patients had normal brain MRI and EEG.\n\nTreatment and Outcome\n\nA total of 38 patients with BFIE initiated ASMs at the average age of 5.9 ± 3.5 months (Table 4). Thirty-one patients received levetiracetam (LEV; 10 mg/kg/day), and 16 (51.6%) patients were seizure free while using a dose between 15 and 40 mg/kg/d. However, the remaining 15 (48.4%) patients still experienced seizures after the LEV dosage was gradually increased to 30-40 mg/kg/d. Of these 15 patients, seven reached seizure freedom after the addition of phenobarbital (PB), topiramate (TPM), or valproic acid (VPA), respectively. Another seven patients were switched to oxcarbazepine (OXC; 10-20 mg/kg) and the seizures were completely controlled. The remaining one patient became seizure free after switching to VPA. Meanwhile, five patients were initially treated with OXC (10 mg/kg/d), and all of them reached seizure freedom at 15-20 mg/kg/d OXC. Two patients with BFIE initially received VPA (20 mg/kg/d), and their symptoms were controlled.\n\nTable 4 Treatment of PRRT2-associated disorders.\n\n\tBFIE (n = 40)\tPKD/ICCA (n = 4)\t\nAge of onset\t5.1 ± 2.0m\t9.5 ± 2.9y\t\nAge at treatment\t5.9 ± 3.5m\t10.8 ± 3.9y\t\nInitial ASMs\tLEV (77.5%)\nVPA (5.0%) OXC\n(12.5%) None\n(5.0%)\tOXC (75.0%)\nLTG (25.0%)\t\nResponse to initial ASMs\tLEV (51.6%)\nVPA (100%)\nOXC (100%)\tOXC (100%)\nLTG (0%)\t\nEffective ASMs\tLEV (42.1%)\nVPA (7.9%) OXC\n(31.6%)\nCombination\n(18.4%)\tOXC (100%)\t\nm, months; y, years; ASMs, antiseizure medications;\n\nLEV, levetiracetam; OXC, oxcarbazepine; VPA, valproic acid;\n\nLTG, lamotrigine.\n\nTwo patients (Patient 37 and 44) with BFIE did not receive treatment due to their parents' personal decision. Patient 37 was seizure free 2 months after the first seizure. Patient 44 presented with focal to bilateral tonic-clonic seizures in clusters since the age of 8 months. Interictal EEG during hospitalization once showed bilateral centro-frontal epileptic activity. Unfortunately, he died of status epilepticus (duration unknown) at home without any emergency aids at the age of 12 months.\n\nThe average age of seizure remission in the 32 patients with BFIE that received follow-up was 8.5 ± 5.0 months. Compared with patients with heterozygous mutations (n = 25), patients with whole gene deletions (n = 7) had a significantly later remission (13.9 vs. 7.1 months, P = 0.001). All patients had normal developmental milestones during follow-up except Patient 15 who developed autism at 2 years old.\n\nOne patient with PKD and two patients with ICCA were initially administered OXC. Patient 28 was lost to follow up, and the remaining two patients remitted from dyskinesia at a dose of 10-20 mg/kg/d. Patient 3 with PKD was initially administered lamotrigine (LTG, dosage unavailable) with no response. The attacks were controlled after switching to OXC (10 mg/kg/day). The average age at last episode was 12 ± 5.3 years. One patient with 16p11.2 microdeletion (Patient 36) showed mild developmental delay/intellectual disability. The remaining patients had normal cognitive outcome.\n\nDiscussion\n\nPRRT2 gene locates on chromosome 16p11.2, and encodes the proline-rich transmembrane protein 2 that is mainly expressed in the cerebral cortex, basal ganglia, and cerebellum (Figure 1). The function of the PRRT2 gene remains unclear, but current findings indicate that it is involved in the process of Ca2+-related presynaptic neurotransmitter release (8). A recent study demonstrated that PRRT2 also interacts with the voltage-gated Na+ channels Nav1.2 and Nav1.6 to negatively modulate neural activity (9). Thus, pathogenic mutations in the PRRT2 gene may lead to a state of neuronal hyper-excitability, which clinically presents a series of paroxysmal disorders. In this study, we reported 44 children with PRRT2 pathogenic mutations. In line with current data, the most common variant was the c.649dupC frameshift mutation, which was identified in 56.8% of patients in our study (4). We also reported four novel variants. The c.284C>G (p.S95X) and the c.883_884insGGAA (p.N296Kfs*45) led to a truncated PRRT2 protein and were classified as “pathogenetic” according to the ACMG criteria. The splice site variant (c.879+4A>G) was inherited from patient's father with cosegregation consistence which suggested its pathogenicity, although it was classified as “variant of unknown significance” according to the ACMG criteria. But further studies are needed to confirm its pathogenicity. The missense variant c.914G>A (p.G305E) was predicted to be damaging by Mutation Taster, Polyphen2, SIFT and FATHMM-MKL (Table 2). According to the study from Tsai et al., pathogenic missense variants at the C terminus often lead to failure of protein targeting to the plasma membrane that could be an important mechanism for PRRT2-associated disorders (10).\n\nSeveral studies have reported the existence of homozygous mutations, compound heterozygous mutations, and 16p11.2 microdeletion of PRRT2 in a small group of cases (11–14). In 2015, Ebrahimi-Fakhari et al. summarized that these rare cases accounted for 1.5% (21/1,444) of all PRRT2-associated cases (4). Meanwhile, only 3.7% of patients were identified with a whole deletion of PRRT2 gene in a recent Italian cohort study (15). In this study, the proportion (20.5%) of patients with whole gene deletions or 16p11.2 microdeletion was significantly higher than previous data. This could be explained by the selective bias due to different standards for accepting genetic testing in clinical practice. The biallelic mutation or complete deletion of the PRRT2 gene led to total impairment of function of the PRRT2 protein, possibly resulting in the patient's severe clinical presentation. In our cohort, one patient suffered status epilepticus, and one patient showed mild developmental delay/intellectual disability. Both of them had complete deletions of the PRRT2 gene. In addition, we found that patients with whole gene deletions had a later remission in PRRT2-associated BFIE. Previous study have revealed that patients with homozygous, compound heterozygous and microdeletion mutation more frequently presented with more severe phenotypes including intellectual/development disorders when comparing with heterozygous mutations cases (16–18). However, evidences remain insufficient to prove the existence of genotype-phenotype correlations among PRRT2-associated disorders. The “gene-dosage effect” that causes severe impairment or total loss of the PRRT2 protein that leads to clinical presentations still require further validation.\n\nYang et al. found that the whole PRRT2 gene mutation and the 16p11.2 microdeletion were more likely be de novo (19). Unfortunately, the parental derivation of eight patients with whole gene deletions was not available. Five of them had no family history, which could possibly serve as potential indirect evidence. However, seven family members carried a pathogenic mutation without clinical symptoms although PRRT2-associated disorders are autosomal dominant inherited, which suggested the phenomenon of incomplete penetrance. Balagura et al. reported that the penetrance of PRRT2 pathogenic mutation was 89% (15). Schubert et al. estimated an 82% penetrance of PRRT2 mutations in BFIE (20). Meanwhile, the penetrance of PRRT2 mutations in PKD was estimated to be 61%, which was raised to nearly 90% when ICCA cases were taken into account (21).\n\nAll patients in this study were diagnosed with BFIE, PKD, or ICCA due to inclusion criteria, and their clinical characteristics were similar with previous studies. BFIE, PKD, and ICCA are main phenotypes of PRRT2-associated disorders, accounting for more than 90% of all cases (4). In addition, several studies have reported that other disorders, including hemiplegic migraine and episodic ataxia, could be a PRRT2-associated phenotype (4). In a recent study, migraine occurred as a concomitant diagnosis of BFIE in 10% of PRRT2-associated patients, suggesting an increased risk for migraine in younger patients with PRRT2-associated BFIE (22). PRRT2-associated disorders are relatively benign. However, recent studies suggested that pathogenic PRRT2 mutation could be responsible for some severe epileptic syndromes. Döring et al. reported a case who presented BFIE at the age of 4 months and developed continuous spikes and waves during sleep at the age of 4 years (22). Only an inherited c.649dupC variant was identified through whole gene sequencing. Furthermore, Jafarpour and Desai reported that infantile spams could also be a PRRT2-associated phenotype (23). In addition, PRRT2 mutations could be responsible for early childhood myoclonic epilepsy according to a recent research (18). These findings suggested that this evolving spectrum has a more widely boundary. However, further studies are needed to establish whether PPRT2 mutations play an important role in these situations.\n\nSymptoms of PRRT2-associated disorders are readily controlled by conventional ASMs (4). Monotherapy was effective in a majority of patients with BFIE in our study. Considering both the efficacy and safety, LEV is one of the first-line choices for clinical treatment of pediatric epilepsy, especially for infantile patients. Most patients in our study were initially treated with LEV. Experiences from Zhao et al. suggested that OXC seems to be more effective than LEV (24). Similarly, half of patients in our study had no response to LEV, whereas all patients treated with OXC quickly became seizure free. These results revealed that OXC seems to be superior to LEV for patients with PRRT2-associated BFIE. OXC is a derivative of carbamazepine (CBZ) that has fewer side effects and drug interactions (25). Pan et al. suggested that OXC had a significant effect on pediatric PKD (26). Moreover, compared with non-PRRT2 mutations cases, CBZ seemed to be more effective in patients with PRRT2-associated PKD (27). A recent study revealed that PRRT2 could serve as a negative modulator of sodium channels (9). Therefore, as sodium channel blockers, CBZ and OXC probably have specific mechanisms for controlling symptoms in PRRT2-associated disorders. In addition, Symonds et al. recently reported that PRRT2-associated BFIE was the most frequent single-gene epilepsy, with an incidence of 1 per 9,970 live births (28). Thus, early genetic testing for patients with suspected BFIE is helpful to clinical treatment. Nevertheless, considering the self-limited course of PRRT2-associated diseases, whether ASMs play an essential role is ambiguous. However, one patient without ASMs suffered status epilepticus and died of delayed treatment, suggesting that the appropriate treatment is still necessary. Thus, comprehensive evaluation should be individualized when planning the treatment regime for patients with PRRT2-associated disorders.\n\nOutcome of patients with PRRT2-associated disorders is usually favorable. In the present study, the average age of remission of patients with BFIE was 8.5 ± 5.0 months, which was similar to previously published data (29). Most patients had normal psychomotor development at last follow-up. Interestingly, one patient carrying the c.649dupC variant showed language retardation that was diagnosed with autism after seizure remission. Although microdeletions and duplications at 16p11.2, where the PRRT2 gene is located, have been observed in patients with autism (30, 31). Current studies have found no clear relationship between PRRT2 pathogenic mutation and autism (32). Thus, we postulated that PRRT2 mutations play no pathological role in the development of autism in this patient. However, the function of the PRRT2 gene during the psychomotor development period needs further study.\n\nThis study has several limitations. Firstly, patients with BFIE may not yet develop movement disorders during the relatively short follow-up. Meanwhile, considering the self-limited course of PRRT2-associated disorders, some patients did not accept gene tests. Moreover, we did not include patients with other rare phenotypes. Thus, our results may not reflect the accurate phenotype distribution. Secondly, pedigree analysis was limited due to insufficient data of family members. Thus, continuous follow-up and detailed information of probands and family members are needed to better understand the characteristics of PRRT2-associated disorders.\n\nIn conclusion, pathogenic PRRT2 mutations are responsible for a series of paroxysmal diseases, mainly including BFIE, PKD, and ICCA. Patients with whole gene deletions could have more severe phenotypes. Conventional antiseizure medications, especially OXC, could be the first-line choice. Further long-term cohort studies and pedigree analysis are needed to fully illuminate characteristics of PRRT2-associated diseases.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by the ethics committee of Children's Hospital of Chongqing Medical University. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.\n\nAuthor Contributions\n\nLJ and L-lX designed the study. S-qH, X-jL, ML, YH, J-nM, PW, MZ, MC, and T-sL collected the patients' information. H-yL performed the statistical analysis. H-yL and L-lX drafted first version of the manuscript. All authors participated in the critical review of the manuscript, contributed to the article, and approved the submitted version.\n\nConflict of Interest\n\nThe 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.\n\nThe authors thank the patients and their families for participating in this study.\n==== Refs\nReferences\n\n1. Caraballo RH Cersosimo RO Amartino H Szepetowski P Fejerman N . Benign familial infantile seizures: further delineation of the syndrome. J Child Neurol. (2002) 17 :696-9. 10.1177/088307380201700909 12503648\n2. Bennett LB Roach ES Bowcock AM . A locus for paroxysmal kinesigenic dyskinesia maps to human chromosome 16. Neurology. (2000) 54 :125-30. 10.1212/WNL.54.1.125 10636137\n3. Szepetowski P Rochette J Berquin P Piussan C Lathrop GM Monaco AP . Familial infantile convulsions and paroxysmal choreoathetosis: a new neurological syndrome linked to the pericentromeric region of human chromosome 16. Am J Hum Genet. (1997) 61 :889-98. 10.1086/514877 9382100\n4. Ebrahimi-Fakhari D Saffari A Westenberger A Klein C . The evolving spectrum of PRRT2-associated paroxysmal diseases. Brain. (2015) 138 :3476-95. 10.1093/brain/awv317 26598493\n5. Vigevano F . Benign familial infantile seizures. Brain Dev. (2005) 27 :172-7. 10.1016/j.braindev.2003.12.012 15737697\n6. Bruno MK Hallett M Gwinn-Hardy K Sorensen B Considine E Tucker S . Clinical evaluation of idiopathic paroxysmal kinesigenic dyskinesia: new diagnostic criteria. Neurology. (2004) 63 :2280-7. 10.1212/01.WNL.0000147298.05983.50 15623687\n7. Fang ZX Zhang M Xie LL Jiang L Hong SQ Li XJ . KCNQ2 related early-onset epileptic encephalopathies in Chinese children. J Neurol. (2019) 266 :2224-32. 10.1007/s00415-019-09404-y 31152295\n8. Valtorta F Benfenati F Zara F Meldolesi J . PRRT2: from paroxysmal disorders to regulation of synaptic function. Trends Neurosci. (2016) 39 :668-79. 10.1016/j.tins.2016.08.005 27624551\n9. Fruscione F Valente P Sterlini B Romei A Baldassari S Fadda M . PRRT2 controls neuronal excitability by negatively modulating Na+ channel 1.2/1.6 activity. Brain. (2018) 141 :1000-16. 10.1093/brain/awy051 29554219\n10. Tsai MH Nian FS Hsu MH Liu WS Liu YT Liu C . PRRT2 missense mutations cluster near C-terminus and frequently lead to protein mislocalization. Epilepsia. (2019) 60 :807-17. 10.1111/epi.14725 30980674\n11. Delcourt M Riant F Mancini J Milh M Navarro V Roze E . Severe phenotypic spectrum of biallelic mutations in PRRT2 gene. J Neurol Neurosurg Psychiatry. (2015) 86 :782-5. 25595153\n12. Chen YP Song W Yang J Zheng ZZ Huang R Chen K . PRRT2 mutation screening in patients with paroxysmal kinesigenic dyskinesia from Southwest China. Eur J Neurol. (2014) 21 :174-6. 10.1111/ene.12122 23496026\n13. Labate A Tarantino P Viri M Mumoli L Gagliardi M Romeo A . Homozygous c.649dupC mutation in PRRT2 worsens the BFIS/PKD phenotype with mental retardation, episodic ataxia, and absences. Epilepsia. (2012) 53 :e196-9. 10.1111/epi.12009 23126439\n14. Dale RC Grattan-Smith P Nicholson M Peters GB . Microdeletions detected using chromosome microarray in children with suspected genetic movement disorders: a single-centre study. Dev Med Child Neurol. (2012) 54 :618-23. 10.1111/j.1469-8749.2012.04287.x 22515636\n15. Balagura G Riva A Marchese F Iacomino M Madia F Giacomini T . Clinical spectrum and genotype-phenotype correlations in PRRT2 Italian patients. Eur J Paediatr Neurol. (2020) 28 :193-7. 10.1016/j.ejpn.2020.06.005 32651081\n16. Guerrero-Lopez R Ortega-Moreno L Giraldez BG Alarcon-Morcillo C Sanchez-Martin G Nieto-Barrera M . Atypical course in individuals from Spanish families with benign familial infantile seizures and mutations in the PRRT2 gene. Epilepsy Res. (2014) 108 :1274-8. 10.1016/j.eplepsyres.2014.06.011 25060993\n17. Weber A Kohler A Hahn A Neubauer B Muller U . Benign infantile convulsions (IC) and subsequent paroxysmal kinesigenic dyskinesia (PKD) in a patient with 16p11.2 microdeletion syndrome. Neurogenetics. (2013) 14 :251-3. 10.1007/s10048-013-0376-7 24100940\n18. Vlaskamp DRM Callenbach PMC Rump P Giannini LAA Brilstra EH Dijkhuizen T . PRRT2-related phenotypes in patients with a 16p11.2 deletion. Eur J Med Genet. (2019) 62 :265-9. 10.1016/j.ejmg.2018.08.002 30125676\n19. Yang L You C Qiu S Yang X Li Y Liu F . Novel and de novo point and large microdeletion mutation in PRRT2-related epilepsy. Brain Behav. (2020) 10 :e01597. 10.1002/brb3.1597 32237035\n20. Schubert J Paravidino R Becker F Berger A Bebek N Bianchi A . PRRT2 mutations are the major cause of benign familial infantile seizures. Hum Mutat. (2012) 33 :1439-43. 10.1002/humu.22126 22623405\n21. van Vliet R Breedveld G de Rijk-van Andel J Brilstra E Verbeek N Verschuuren-Bemelmans C . PRRT2 phenotypes and penetrance of paroxysmal kinesigenic dyskinesia and infantile convulsions. Neurology. (2012) 79 :777-84. 10.1212/WNL.0b013e3182661fe3 22875091\n22. Döring JH Saffari A Bast T Brockmann K Ehrhardt L Fazeli W . The phenotypic spectrum of PRRT2-associated paroxysmal neurologic disorders in childhood. Biomedicines. (2020) 8 :456. 10.3390/biomedicines8110456 33126500\n23. Jafarpour S Desai J . Infantile spasms associated with a pathogenic PRRT2 variant. Pediatr Neurol. (2021) 115 :41. 10.1016/j.pediatrneurol.2020.10.010 33321212\n24. Zhao Q Liu Z Hu Y Fang S Zheng F Li X . Different experiences of two PRRT2-associated self-limited familial infantile epilepsy. Acta Neurol Belg. (2020) 120 :1025-8. 10.1007/s13760-020-01348-9 32246320\n25. Schmidt D Elger CE . What is the evidence that oxcarbazepine and carbamazepine are distinctly different antiepileptic drugs? Epilepsy Behav. (2004) 5 :627-35. 10.1016/j.yebeh.2004.07.004 15380112\n26. Pan G Zhang L Zhou S . Clinical features of patients with paroxysmal kinesigenic dyskinesia, mutation screening of PRRT2 and the effects of morning draughts of oxcarbazepine. BMC Pediatr. (2019) 19 :439. 10.1186/s12887-019-1798-7 31722684\n27. Li HF Chen WJ Ni W Wang KY Liu GL Wang N . PRRT2 mutation correlated with phenotype of paroxysmal kinesigenic dyskinesia and drug response. Neurology. (2013) 80 :1534-5. 10.1212/WNL.0b013e31828cf7e1 23535490\n28. Symonds JD Zuberi SM Stewart K McLellan A O'Regan M MacLeod S . Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort. Brain. (2019) 142 :2303-18. 10.1093/brain/awz195 31302675\n29. Okumura A Shimojima K Kurahashi H Numoto S Shimada S Ishii A . PRRT2 mutations in Japanese patients with benign infantile epilepsy and paroxysmal kinesigenic dyskinesia. Seizure. (2019) 71 :1-5. 10.1016/j.seizure.2019.05.017 31154286\n30. Weiss LA Shen Y Korn JM Arking DE Miller DT Fossdal R . Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med. (2008) 358 :667-75. 10.1056/NEJMoa075974 18184952\n31. Kumar RA KaraMohamed S Sudi J Conrad DF Brune C Badner JA . Recurrent 16p11.2 microdeletions in autism. Hum Mol Genet. (2008) 17 :628-38. 10.1093/hmg/ddm376 18156158\n32. Huguet G Nava C Lemiere N Patin E Laval G Ey E . Heterogeneous pattern of selective pressure for PRRT2 in human populations, but no association with autism spectrum disorders. PLoS ONE. (2014) 9 :e88600. 10.1371/journal.pone.0088600 24594579\n\n",
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"keywords": "PRRT2; benign familial infantile epilepsy; genotype; phenotype; prognosis; treatment",
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"title": "The Genotype and Phenotype of Proline-Rich Transmembrane Protein 2 Associated Disorders in Chinese Children.",
"title_normalized": "the genotype and phenotype of proline rich transmembrane protein 2 associated disorders in chinese children"
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"abstract": "A 76-year-old woman was referred to our hospital because of anemia. The laboratory findings revealed hemolysis. Although a direct Coombs test was negative, a high titer of RBC-bound IgG was detected, and a diagnosis of Coombs-negative autoimmune hemolytic anemia was made. She was successfully treated with prednisolone. One year and five months later, she again presented anemia and was diagnosed with pure red cell aplasia. Anti-erythropoietin receptor antibody was detected in the serum. She was treated with cyclosporine and obtained prompt recovery. We herein report this rare case and review the pertinent literature.",
"affiliations": "Department of Hematology, Mitsui Memorial Hospital, Japan.",
"authors": "Yoshimi|Mayumi|M|;Kadowaki|Yutaka|Y|;Kikuchi|Yuji|Y|;Takahashi|Tsuyoshi|T|",
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"mesh_terms": "D000368:Aged; D000744:Anemia, Hemolytic, Autoimmune; D003298:Coombs Test; D016572:Cyclosporine; D004921:Erythropoietin; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D011239:Prednisolone; D017467:Receptors, Erythropoietin; D012010:Red-Cell Aplasia, Pure; D016896:Treatment Outcome",
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"title": "Coombs-negative Autoimmune Hemolytic Anemia Followed by Anti-erythropoetin Receptor Antibody-associated Pure Red Cell Aplasia: A Case Report and Review of Literature.",
"title_normalized": "coombs negative autoimmune hemolytic anemia followed by anti erythropoetin receptor antibody associated pure red cell aplasia a case report and review of literature"
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"abstract": "A 17-year-old male received allogeneic transplantation for acute lymphoblastic leukemia, and presented with generalized seizures due to a solitary brain lesion with massive necrosis on day +621. Epstein-Barr virus (EBV) DNA copies were below the cut-off value in plasma. Stereotactic biopsy of the cerebral lesion confirmed the diagnosis of post-transplant lymphoproliferative disorder (PTLD) with large atypical cells positive for CD20 and EBER. In order to diagnose primary central nervous system PTLD, the biopsy should be applied as early as possible when brain lesion with necrosis develops in post-transplant patients regardless of EBV-DNA in plasma.",
"affiliations": "Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan.;Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan.;Department of Hematology, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japan.;Department of Hematology, National Hospital Organization Nagasaki Medical Center, Omura, Japan.;Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan.;Department of Pathology, Nagasaki Prefecture Shimabara Hospital, Shimabara, Japan.;Department of Neurosurgery, Nagasaki University Hospital, Nagasaki, Japan.;Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Japan.;Department of Pathology, School of Medicine, Kurume University, Kurume, Japan.;Department of Hematology, National Hospital Organization Nagasaki Medical Center, Omura, Japan.;Department of Hematology, Sasebo City General Hospital, Sasebo, Japan.;Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan.",
"authors": "Sakamoto|Hikaru|H|;Itonaga|Hidehiro|H|;Taguchi|Jun|J|;Kato|Takeharu|T|;Sawayama|Yasushi|Y|;Hayashi|Tomayoshi|T|;Baba|Shiro|S|;Moriuchi|Masako|M|;Ohshima|Koichi|K|;Yoshida|Shinichiro|S|;Moriuchi|Yukiyoshi|Y|;Miyazaki|Yasushi|Y|",
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"fulltext": "\n==== Front\nLeuk Res RepLeuk Res RepLeukemia Research Reports2213-0489Elsevier S2213-0489(18)30064-510.1016/j.lrr.2019.04.003ArticleCentral nervous system post-transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation: The Nagasaki transplant group experience Sakamoto Hikaru Writing - original draftMethodologyWriting - review & editingValidationaItonaga Hidehiro Writing - original draftMethodologyWriting - review & editingValidationitonaga-ngs@umin.ac.jpa⁎Taguchi Jun MethodologyWriting - review & editingValidationbKato Takeharu MethodologyWriting - review & editingValidationcSawayama Yasushi MethodologyWriting - review & editingValidationaHayashi Tomayoshi MethodologyWriting - review & editingValidationdBaba Shiro MethodologyWriting - review & editingValidationeMoriuchi Masako Formal analysisMethodologyWriting - review & editingValidationfOhshima Koichi MethodologyWriting - review & editingValidationgYoshida Shinichiro MethodologyWriting - review & editingValidationcMoriuchi Yukiyoshi Writing - original draftMethodologyWriting - review & editingValidationhMiyazaki Yasushi Writing - original draftMethodologyWriting - review & editingValidationaia Department of Hematology, Nagasaki University Hospital, Nagasaki, Japanb Department of Hematology, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japanc Department of Hematology, National Hospital Organization Nagasaki Medical Center, Omura, Japand Department of Pathology, Nagasaki Prefecture Shimabara Hospital, Shimabara, Japane Department of Neurosurgery, Nagasaki University Hospital, Nagasaki, Japanf Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Japang Department of Pathology, School of Medicine, Kurume University, Kurume, Japanh Department of Hematology, Sasebo City General Hospital, Sasebo, Japani Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan⁎ Correspondence to: Department of Hematology, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. itonaga-ngs@umin.ac.jp22 4 2019 2019 22 4 2019 11 27 30 17 10 2018 21 4 2019 © 2019 The Authors. Published by Elsevier Ltd.2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).A 17-year-old male received allogeneic transplantation for acute lymphoblastic leukemia, and presented with generalized seizures due to a solitary brain lesion with massive necrosis on day +621. Epstein–Barr virus (EBV) DNA copies were below the cut-off value in plasma. Stereotactic biopsy of the cerebral lesion confirmed the diagnosis of post-transplant lymphoproliferative disorder (PTLD) with large atypical cells positive for CD20 and EBER. In order to diagnose primary central nervous system PTLD, the biopsy should be applied as early as possible when brain lesion with necrosis develops in post-transplant patients regardless of EBV-DNA in plasma.\n\nKeywords\nPost-transplant lymphoproliferative disorderCentral nervous systemEpstein–Barr virusAllogeneic hematopoietic stem cell transplantation\n==== Body\n1 Introduction\nPost-transplant lymphoproliferative disorder (PTLD) is characterized by lymphoid or plasmacytic proliferation in a recipient after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or solid organ transplantation. PTLD is regarded as one of the most serious post-transplant complications due to its high mortality [1]; therefore, an early diagnosis is important for the initiation of optimal interventions. In most cases, the outgrowth of donor-derived Epstein–Barr virus (EBV)-infected B cells results in the development of PTLD. EBV DNA monitoring using the quantitative polymerase chain reaction (qPCR) method was previously reported to be a sensitive modality for the early diagnosis of EBV-positive PTLD [1], [2] because patients at an increased risk of overt PTLD development presented with EBV reactivation. Although different assays using whole blood, plasma, and peripheral blood mononuclear cells (PBMC) have been used to monitor EBV-positive PTLD, the qPCR method for EBV DNA in plasma is regarded as a more reliable assay than that in PBMC [3].\n\nPTLD is a rare complication with an incidence of 1–3% among recipients after allo-HSCT [2], [4] and represents a clinical heterogeneous manifestation. Due to the limited amount of information on primary central nervous system PTLD (CNS-PTLD) after allo-HSCT, the diagnostic value of EBV DNA copies in post-transplant patients with CNS-PTLD remains poorly understood.\n\nWe herein report a case of CNS-PTLD after allo-HSCT for which the qPCR method in PBMC, plasma, and cerebrospinal fluid (CSF) showed less evidence of EBV reactivation.\n\n2 Case report\nA 17-year-old male was diagnosed with acute T cell lymphoblastic leukemia (ALL) with the normal karyotype and SIL-TAL1 chimeric transcription. A CSF examination showed no evidence of CNS involvement. The patient achieved complete remission after induction therapy; however, due to allergies to methotrexate and L-asparaginase, he was unable to receive the standard consolidation program. Human leukocyte antigen 7/8 allele-matched (Cw-mismatched) unrelated bone marrow transplantation from a female donor without any T-cell depletion was performed using a myeloablative conditioning regimen (cyclophosphamide 120 mg/kg and total body irradiation 12 Gy/6 fr.). Tacrolimus and mycophenolate mofetil (MMF) were used as graft-versus-host disease (GVHD) prophylaxis. Neutrophil engraftment was achieved on day +12 and an XY-fluorescence in situ hybridization analysis revealed complete donor chimerism. He developed acute GVHD grade II on day +32, and the administration of prednisolone at 1.0 mg/kg was initiated.\n\nThe patient presented with the disturbance of consciousness due to generalized seizures during the GVHD treatment with tacrolimus 1.5 mg, prednisolone 7.5 mg, and MMF 2000 mg daily on day +621 after allo-HSCT. A peripheral blood count yielded a leukocyte count of 3.7 × 109/L, consisting of 26% neutrophils, 49% lymphocytes, and 25% monocytes; hemoglobin level, 13.6 g/dL; platelet count, 181 × 109/L. A lymphocyte subset analysis by flow cytometry showed that the percentages of CD22-positive cells, CD3-positive cells, and CD56-positive cells were 9.1, 81.3, and 12.1%, respectively. Magnetic resonance imaging (MRI) of the brain revealed a space-occupying lesion with ring enhancement and perifocal edema in the left front-parietal lobe (Fig. 1A, B), indicating several differential diagnoses, including opportunistic infections, PTLD, and the extramedullary relapse of ALL. Routine microbiological tests to detect bacteria, fungi, toxoplasma IgG, and interferon-gamma in blood samples were negative. The cell count in CSF was 4/mm3 with small mononuclear cells. The EBV serostatus was as follows: anti-EA-DR IgG < × 10; anti-VCA IgM < × 10, anti-VCA IgG × 20, and anti-EBNA-IgG < × 10.Fig. 1 MRI findings of CNS-PTLD and histopathological features of CNS-PTLD.\n\nAxial gadolinium-enhanced T1-weighted imaging (A), and fluid-attenuated inversion recovery (FLAIR) on magnetic resonance images (MRI) (B). MRI showed an approximately 20-mm ring-enhanced lesion in the left front-parietal lobe with perifocal edema.\n\nCerebral biopsy showed extensive necrosis (C; H&E stain, ×100) and the infiltration of large atypical lymphocytes (D; H&E stain, ×400). Atypical cells were positive for CD20 (E; ×400). A small number of Epstein–Barr virus (EBV)-encoded small RNA-positive cells were detected (F: ×600).\n\nFig. 1\n\nPBMC were separated after a Ficoll-Hypaque density gradient; and CD19-, CD3-, and CD56-positive cells were selected using immunomagnetic beads (Dynabeads M-450, Veritas, Tokyo, Japan.). DNA was extracted from PBMC, selected cells, whole blood, the plasma fraction, and CSF. A PCR assay was performed using the Taq-Man PCR kit (PE Applied Biosystems, Foster City, Calif.), as previously described [5]. EBV DNA copy numbers in plasma and CSF were below the cut-off value (1.0 × 102 copies/ml) (Table 1). The EBV DNA copy number was 1.1 × 102 copies/105 PBMC. The qPCR assay revealed that the EBV DNA copy number in the CD19-positive cell fraction was elevated (2.8 × 103 copies/105 cells), whereas those in the CD3- and CD56-positive cell fractions were not. A bone marrow examination showed complete donor chimerism and no evidence of ALL relapse due to the absence of SIL-TAL1 chimeric transcription. Stereotactic biopsy of the cerebral lesion confirmed the diagnosis of monomorphic PTLD with massive necrosis and large atypical cell proliferation. Immunohistochemical staining showed that large atypical cells were positive for CD20 and negative for CD3. A small number of EBV-encoded small RNA (EBER)-positive cells were detected (Fig. 1C–F). The biopsy sample was too small to evaluate the origin of PTLD cells by XY-fluorescence in situ hybridization.Table 1 Results of the qPCR assay for EBV DNA.\n\nTable 1Specimen\tResults\t\nWhole blood\t5.0 × 10³\tcopies/ml\t\nPlasma\t<1.0 × 10²\tcopies/ml\t\nPBMC\t1.1 × 102\tcopies/105 cells\t\nCD3+ cells\t9.2\tcopies/105 cells\t\nCD19+ cells\t2.8 × 103\tcopies/105 cells\t\nCD56+ cells\t8.2\tcopies/105 cells\t\nCSF\t<1.0 × 10²\tcopies/ml\t\nAbbreviations; EBV, Epstein–Barr virus; qPCR, quantitative polymerase chain reaction; PBMC, peripheral blood mononuclear cells; CSF, cerebrospinal fluid.\n\n\n\nTo treat CNS-PTLD, tacrolimus was reduced, whereas difficulties were associated with the cessation of immune suppressants because of the progression of chronic GVHD. MRI of the brain showed an enlarged tumor on day +840, which indicated the progression of CNS-PTLD. He did not respond to three courses of the weekly administration of rituximab (375 mg/m2). Local irradiation therapy (20 Gy/10 fr.) for CNS-PTLD was subsequently initiated on day +931, but was stopped after 5 fractions because of sepsis and progressive GVHD, and the patient died of multiorgan dysfunction on day +1018.\n\n3 Discussion\nThe present case developed CNS-PTLD from day 620 after allo-HSCT, with the use of an unrelated bone marrow graft and the prolonged administration of immunosuppressive agents being risk factors for PTLD [1]. Among 580 patients who underwent their first allo-HSCT at the Nagasaki Transplant Group between January 1, 1990 and April 31, 2018, we encountered the first case of CNS-PTLD (0.17%), which was in line with its rarity after allo-HSCT, as previously reported [6]. In terms of a detailed analysis to detect EBV DNA and MRI findings, our results provided important insights into diagnostic modalities for CNS-PTLD.\n\nThe most interesting result of this case was that EBV DNA copy numbers in plasma and CSF remained below the cut-off value. This result was not consistent with the findings of a previous study on a large cohort showing that the EBV DNA copy number in plasma was a more sensitive marker to diagnose EBV-related diseases, including PTLD [1], [3]. One possible reason for the present results was that EBV DNA in plasma was insufficient to reflect virus shedding from the CNS lesion. This has also been reported in cases of CNS-PTLD after solid organ transplantation [7]. Therefore, our results suggest that the careful interpretation of EBV DNA in plasma is needed when attempting to diagnose CNS-PTLD among post-transplant patients.\n\nEBV DNA copy numbers in PBMC in the present case were lower than those in cases of EBV-positive PTLD without CNS lesions, although the early symptom of EBV-positive PTLD is frequently increasing levels of EBV DNA copies in PBMC [3]. This result of the present case was, at least in part, due to the lower percentage of the B-cell fraction in the lymphocyte subset during intensive immunosuppressive treatment for active GVHD. Based on these results in the present case, the monitoring assays for EBV DNA in plasma and PBMC using qPCR may be insufficient to establish a probable diagnosis of CNS-PTLD after allo-HSCT.\n\nRing enhancement on MRI was observed in between 4 and 11% of patients with primary CNS lymphoma, and in approximately 75% of PCNSL in immunocompromised patients, such as post-transplant and human immunodeficiency virus (HIV)-infected patients [8]. These MRI findings reflect pathological findings that CNS-PTLD may have necrotic lesions [9]. We also considered differential diagnoses, such as toxoplasmosis, abscess, tuberculosis, relapsed ALL, and PTLD. Based on the diagnostic value of EBV DNA in plasma and PBMC, it is important to note that early biopsy of brain lesions needs to be considered for post-transplant patients who developed brain mass lesions with ring enhancement in order to accurately diagnose CNS-PTLD. Since recent studies reported that the intrathecal administration of rituximab was effective for CNS-PTLD [10], early biopsy after MRI may be a promising diagnostic modality for the provision of specific therapy.\n\nIn conclusion, CNS-PTLD needs to be considered in post-transplant patients who present with brain mass lesions with ring enhancement as well as the early biopsy of cerebral lesions regardless of the EBV DNA copy number. Further clinical and experimental investigations are required to develop optimal monitoring methods and diagnostic modalities for CNS-PTLD.\n\nConflict of interest\nThe authors declare no conflicts of interest associated with this manuscript.\n\nAcknowledgments\nI deeply appreciate that Prof. Hiroyuki Moriuchi (Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences.) provide an advice about the evaluation of EBV DNA.\n==== Refs\nReferences\n1 Dierickx D. Habermann T.M. Post-transplantation lymphoproliferative disorders in adults N. Engl. J. Med. 378 Feb (6) 2018 549 562 29414277 \n2 Reddy N. Rezvani K. Barrett A.J. Savani B.N. Strategies to prevent EBV reactivation and posttransplant lymphoproliferative disorders (PTLD) after allogeneic stem cell transplantation in high-risk patients Biol. Blood Marrow Transpl. 17 May (5) 2011 591 597 \n3 Kanakry J.A. Hegde A.M. Durand C.M. The clinical significance of EBV DNA in the plasma and peripheral blood mononuclear cells of patients with or without EBV diseases Blood 127 Apr (16) 2016 2007 2017 26744460 \n4 Styczynski J. Gil L. Tridello G. Response to rituximab-based therapy and risk factor analysis in Epstein Barr Virus-related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation Clin. Infect. Dis. 57 Sep (6) 2013 794 802 23771985 \n5 Kawashiri S. Nakamura H. Kawakami A. Emergence of Epstein-Barr virus-associated haemophagocytic syndrome upon treatment of systemic lupus erythematosus Lupus 15 1 2006 51 53 16482747 \n6 Lieberman F. Yazbeck V. Raptis A. Primary central nervous system post-transplant lymphoproliferative disorders following allogeneic hematopoietic stem cell transplantation J. Neurooncol. 107 Apr (2) 2012 225 232 22037801 \n7 Evens A.M. Choquet S. Kroll-Desrosiers A.R. Primary CNS posttransplant lymphoproliferative disease (PTLD): an international report of 84 cases in the modern era Am. J. Transpl. 13 Jun (6) 2013 1512 1522 \n8 Yap K.K. Sutherland T. Liew E. Tartaglia C.J. Pang M. Trost N. Magnetic resonance features of primary central nervous system lymphoma in the immunocompetent patient: a pictorial essay J. Med. Imaging Radiat. Oncol. 56 Apr (2) 2012 179 186 22498191 \n9 Castellano-Sanchez A.A. Li S. Qian J. Lagoo A. Weir E. Brat D.J. Primary central nervous system posttransplant lymphoproliferative disorders Am. J. Clin. Pathol. 121 Feb (2) 2004 246 253 14983939 \n10 Wu M. Sun J. Zhang Y. Intrathecal rituximab for EBV-associated post-transplant lymphoproliferative disorder with central nervous system involvement unresponsive to intravenous rituximab-based treatments: a prospective study Bone Marrow Transpl. 51 3 2016 456 458 Mar\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0489",
"issue": "11()",
"journal": "Leukemia research reports",
"keywords": "Allogeneic hematopoietic stem cell transplantation; Central nervous system; Epstein–Barr virus; Post-transplant lymphoproliferative disorder",
"medline_ta": "Leuk Res Rep",
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"references": "14983939;16482747;20732435;22037801;22498191;23721553;23771985;26595071;26744460;29414277",
"title": "Central nervous system post-transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation: The Nagasaki transplant group experience.",
"title_normalized": "central nervous system post transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation the nagasaki transplant group experience"
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"abstract": ": The aim of the study was to investigate whether treatment with non-vitamin K antagonist oral anticoagulants (NOACs) is effective and well tolerated in real-life patients following venous thromboembolism (VTE) associated with severe inherited thrombophilia. We evaluated 33 consecutive patients with severe inherited thrombophilia, defined as the presence of deficiencies in protein C, protein S, or anti-thrombin, homozygous factor V Leiden and prothrombin G20210A mutations, or combined defects. The patients were recruited from March 2010 to December 2015 and followed till July 2016. Rivaroxaban was used in 23 patients (70%), whereas dabigatran and apixaban were used in 4 patients each. During a median 21 (range 8-34) months' follow-up, three recurrent VTE episodes (9%) were observed. Deep vein thrombosis recurred after 6 months on rivaroxaban in a protein S-deficient 32-year-old woman who had heavy menstrual bleeding resulting in interruptions of therapy. A long journey preceded deep vein thrombosis recurrence after 12 months of rivaroxaban use in a 59-year-old obese man homozygous for prothrombin 20210A mutation. The third recurrent VTE following anticoagulation withdrawal prior to surgery and during hospitalization was observed in a 56-year-old woman with protein S deficiency and heterozygous factor V Leiden. The three patients continued use of NOACs, apixaban, dabigatran, and rivaroxaban, respectively. This largest real-life series of patients with severe thrombophilia receiving NOACs indicates that such patients could be safely and effectively treated with NOACs. Lower efficacy was observed in protein S deficiency. Recurrent VTE was mostly related with nonadherence, which highlights an important role of regular intake of NOACs in high-risk patients.",
"affiliations": "aInstitute of Cardiology, Jagiellonian University Medical College bJohn Paul II Hospital, Cracow, Poland.",
"authors": "Undas|Anetta|A|;Goralczyk|Tadeusz|T|",
"chemical_list": "D000925:Anticoagulants; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D000069552:Rivaroxaban; D000069604:Dabigatran",
"country": "England",
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"issue": "28(6)",
"journal": "Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis",
"keywords": null,
"medline_ta": "Blood Coagul Fibrinolysis",
"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D000069604:Dabigatran; D005260:Female; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D011720:Pyrazoles; D011728:Pyridones; D012008:Recurrence; D000069552:Rivaroxaban; D019851:Thrombophilia; D054556:Venous Thromboembolism; D055815:Young Adult",
"nlm_unique_id": "9102551",
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"pages": "438-442",
"pmc": null,
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"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Non-vitamin K antagonist oral anticoagulants in patients with severe inherited thrombophilia: a series of 33 patients.",
"title_normalized": "non vitamin k antagonist oral anticoagulants in patients with severe inherited thrombophilia a series of 33 patients"
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"abstract": "Neutrophilic eccrine hidradenitis (NEH) is an unusual self-limited skin disorder characterized by an inflammatory cell infiltrate in the deep dermis involving the eccrine sweat glands, commonly presenting as painful cutaneous nodules. NEH occurs most frequently in patients receiving chemotherapy for haematologic malignancies. We report a case of NEH masquerading as cutaneous vasculitis in a woman receiving cyclophosphamide for lupus nephritis. The association of NEH and the use of cytotoxic agents for SLE or other autoimmune diseases has not been reported previously. NEH must be considered in lupus patients receiving cytotoxic agents to avoid inappropriate use of corticosteroids or antibiotics in this self-limited condition.",
"affiliations": "Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA. lienesd@ucmail.uc.edu",
"authors": "Lienesch|D W|DW|;Mutasim|D F|DF|;Singh|R R|RR|",
"chemical_list": "D007166:Immunosuppressive Agents; D003520:Cyclophosphamide",
"country": "England",
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"mesh_terms": "D000328:Adult; D003520:Cyclophosphamide; D003937:Diagnosis, Differential; D005260:Female; D016575:Hidradenitis; D006801:Humans; D007166:Immunosuppressive Agents; D008181:Lupus Nephritis; D018366:Vasculitis, Leukocytoclastic, Cutaneous",
"nlm_unique_id": "9204265",
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"pages": "707-9",
"pmc": null,
"pmid": "14514135",
"pubdate": "2003",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Neutrophilic eccrine hidradenitis mimicking cutaneous vasculitis in a lupus patient: a complication of cyclophosphamide.",
"title_normalized": "neutrophilic eccrine hidradenitis mimicking cutaneous vasculitis in a lupus patient a complication of cyclophosphamide"
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"abstract": "Rheumatic heart disease (RHD) is a disease of disparity most prevalent in developing countries and among immigrant populations. Mitral stenosis (MS) is a common sequalae of RHD and affects females disproportionately more than males. Rheumatic MS remains a significant management challenge as severe MS is usually poorly tolerated in pregnancy due to haemodynamic changes and increased cardiovascular demands of progressing pregnancy. Pregnancy remains contraindicated in current management guidelines based on expert consensus, due to a paucity of evidence-based literature.\nA 28-year-old aboriginal woman with known severe MS was found to be pregnant during routine health review, despite contraceptive efforts. Echocardiography demonstrated mean mitral valve (MV) gradient 14 mmHg; stress echocardiography demonstrated increased MV gradient 28-32 mmHg at peak exercise and post-exercise pulmonary artery pressure 56 + 3 mmHg with marked dynamic D-shaped septal flattening. Left ventricular systolic function remained preserved. She remained remarkably asymptomatic and underwent successful elective induction of labour at 34 weeks. Postpartum, she remained euvolaemic despite worsening MV gradients and new atrial fibrillation (AF). She subsequently underwent balloon mitral valvuloplasty with good result.\nSevere rheumatic MS in pregnancy carries significant morbidity and mortality, due to an already fragile predisposition towards heart failure development compounded by altered haemodynamics. Pregnancy avoidance and valvular intervention prior to conception or in the second trimester remain the mainstay of MS management; however, we present an encouraging case of successful near-term pregnancy with minimal complications in a medically managed asymptomatic patient with critical MS, who subsequently underwent valvular intervention post-partum.",
"affiliations": "Department of Cardiology, Level 6, Flinders Medical Centre, Flinders Drive, Bedford Park, SA 5042, Australia.;Department of Cardiology, Level 6, Flinders Medical Centre, Flinders Drive, Bedford Park, SA 5042, Australia.;Department of Cardiology, Royal Darwin Hospital, 105 Rocklands Drive, Tiwi, NT 0810, Australia.;Department of Cardiology, Royal Darwin Hospital, 105 Rocklands Drive, Tiwi, NT 0810, Australia.",
"authors": "Eng-Frost|Joanne|J|https://orcid.org/0000-0002-7526-2078;Sinhal|Ajay|A|;Ilton|Marcus|M|https://orcid.org/0000-0002-8576-4661;Wing-Lun|Edwina|E|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ehjcr/ytab010",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n10.1093/ehjcr/ytab010\nytab010\nCase Report\nAcademicSubjects/MED00200\nManaging asymptomatic severe rheumatic mitral stenosis in pregnancy: a case report\nhttps://orcid.org/0000-0002-7526-2078\nEng-Frost Joanne 1\nSinhal Ajay 1\nhttps://orcid.org/0000-0002-8576-4661\nIlton Marcus 2\nWing-Lun Edwina 23\n1 Department of Cardiology, Level 6, Flinders Medical Centre, Flinders Drive, Bedford Park, SA 5042, Australia\n2 Department of Cardiology, Royal Darwin Hospital, 105 Rocklands Drive, Tiwi, NT 0810, Australia\n3 Faculty of Health and Medicine, University of Sydney, Science Road, Camperdown, NSW 2050, Australia\nCavaretta Elena Handling Editor\ncan de Sande Danny Editor\nHaertel Miglioranza Marcelo Editor\nParollo Matteo Editor\nChakir Mariame Editor\nCorresponding author. Tel: +61 437 627 914, Email: joanne.eng-frost@sa.gov.au\n3 2021\n28 2 2021\n28 2 2021\n5 3 ytab01024 7 2020\n24 8 2021\n07 1 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2021\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nBackground\n\nRheumatic heart disease (RHD) is a disease of disparity most prevalent in developing countries and among immigrant populations. Mitral stenosis (MS) is a common sequalae of RHD and affects females disproportionately more than males. Rheumatic MS remains a significant management challenge as severe MS is usually poorly tolerated in pregnancy due to haemodynamic changes and increased cardiovascular demands of progressing pregnancy. Pregnancy remains contraindicated in current management guidelines based on expert consensus, due to a paucity of evidence-based literature.\n\nCase summary\n\nA 28-year-old aboriginal woman with known severe MS was found to be pregnant during routine health review, despite contraceptive efforts. Echocardiography demonstrated mean mitral valve (MV) gradient 14 mmHg; stress echocardiography demonstrated increased MV gradient 28–32 mmHg at peak exercise and post-exercise pulmonary artery pressure 56 + 3 mmHg with marked dynamic D-shaped septal flattening. Left ventricular systolic function remained preserved. She remained remarkably asymptomatic and underwent successful elective induction of labour at 34 weeks. Postpartum, she remained euvolaemic despite worsening MV gradients and new atrial fibrillation (AF). She subsequently underwent balloon mitral valvuloplasty with good result.\n\nDiscussion\n\nSevere rheumatic MS in pregnancy carries significant morbidity and mortality, due to an already fragile predisposition towards heart failure development compounded by altered haemodynamics. Pregnancy avoidance and valvular intervention prior to conception or in the second trimester remain the mainstay of MS management; however, we present an encouraging case of successful near-term pregnancy with minimal complications in a medically managed asymptomatic patient with critical MS, who subsequently underwent valvular intervention post-partum.\n\nRheumatic heart disease\nMitral stenosis\nPregnancy\nBalloon valvuloplasty\nHeart failure\nPulmonary hypertension\nCase report\n==== Body\nLearning points\n\nThere is limited information regarding the management of severe mitral stenosis (MS) in women of childbearing age or who are pregnant, particularly if they remain asymptomatic.\n\nSerial echocardiography combined with stress testing and physiological assessment for surveillance of mitral valve gradients, symptoms, and overall function during pregnancy may be utilized in asymptomatic patients to guide optimization of medical therapy, and timing of percutaneous balloon mitral valvuloplasty (BMV).\n\nPercutaneous BMV may be safely deferred until postpartum in women with severe MS who remain asymptomatic, to minimize procedural risks for mother and developing foetus.\n\nIntroduction\n\nLeft-sided stenotic valvulopathies, including mitral stenosis (MS), remain a feared entity in pregnancy due to the effects of altered physiology including increased intravascular volume, cardiac output and heart rate, and decreased systemic vascular resistance and systolic blood pressure1 which increases MS complication risks. Maternal complications include pulmonary oedema, arrhythmias, and increased mortality, whilst foetal complications include preterm delivery, intrauterine growth restriction, and foetal death.1\n\nThe risk of developing heart failure corresponds with MS severity.2 Severe MS is usually poorly tolerated in pregnancy, with 67% of women developing peripartum heart failure even if previously asymptomatic.2–4 This is contributed to by increased heart rates antepartum, resulting in shortened diastolic filling time, increased left atrial pressure, and pulmonary venous pressures predisposing to heart failure.4 Pregnancy is contraindicated in current guidelines, which recommend percutaneous valvular intervention in women with moderate or severe MS contemplating pregnancy5 (Figure 1).\n\nFigure 1 Managing severe rheumatic mitral stenosis in pregnancy.\n\nWe present our management of a remarkably asymptomatic patient with critical MS, who presented 13 weeks antepartum despite contraceptive efforts and without preconception valve intervention. The valvular intervention occurred postpartum, with good outcomes for both mother and child.\n\nTimeline\n\nCase presentation\n\nA 28-year-old aboriginal Australian woman from a remote community with known severe MS was found to be 13 weeks pregnant despite contraceptive depot injections, after presenting for routine review at the local community clinic.\n\nShe had a previous episode of acute rheumatic fever aged 10. She had been adherent with standard secondary prophylaxis regimen since but subsequently developed severe mitral stenosis necessitating balloon mitral valvuloplasty (BMV) aged 14. Prior to pregnancy, her last echocardiogram in 2018 demonstrated severe rheumatic MS with mean pressure gradient (mPG) 17 mmHg, mitral valve area (MVA) 0.9 cm2, and mild pulmonary hypertension with estimated pulmonary artery pressure (EPAP) 30 mmHg + right atrial pressure (RAP) 3 mmHg. Left ventricular systolic function was preserved. She remained clinically asymptomatic and was therefore managed conservatively. Additionally, she received pregnancy-avoidance counselling and agreed to commence 3-monthly contraceptive depot injections. She did not have other medical conditions or regular medications.\n\nDue to the cultural significance of pregnancy within her community, she elected to continue her pregnancy fully cognisant of the increased risks of adverse outcomes secondary to her valvulopathy. She was subsequently referred for Cardiology Specialist input.\n\nShe remained remarkably asymptomatic despite critical MS. Physical examination demonstrated dual heart sounds with an additional soft diastolic murmur. There was no evidence of pulmonary congestion of peripheral oedema. Her NTproBNP level was 136 ng/L. She had mild normocytic anaemia (Hb 106 g/L; mean cell volume 85.8 fL); electrolytes and creatinine levels were normal (sodium 135 mmol/L, potassium 3.8 mmol/L, creatinine 54 µmol/L, estimated glomerular filtrate rate >90 mL/min/1.73 m2). Transthoracic echocardiography (TTE) at 13 weeks antepartum demonstrated a doming hockey stick appearance of the anterior mitral valve leaflet, thickened immobile posterior mitral leaflet with markedly restricted excursion resulting in severe mitral stenosis (mPG 14 mmHg), mitral valve area 0.4 cm2, severely dilated left atrium (indexed volume 50 mL/m2), mild pulmonary hypertension (EPAP 34 + 3 mmHg). Stress echocardiogram performed at 20 weeks antepartum demonstrated mitral valve (MV) mPG 28–32 mmHg at peak exercise, and post-exercise EPAP 56 + 3 mmHg with development of D-shaped septal flattening (Figure 2). She did not desaturate during this test. Given her minimal symptoms, she was successfully managed in a culturally sensitive manner in her remote community until the early third trimester, where she was electively admitted to a local tertiary hospital before transfer to a tertiary centre with cardiothoracic services for valve intervention prior to delivery.\n\nFigure 2 Exercise stress echocardiogram demonstrating (A) left ventricular at rest and (B) marked septal D-shape flattening with peak exercise.\n\nSerial TTEs during antepartum demonstrated critical but stable MV gradients (mPG 19–21 mmHg; Figure 3). She was also commenced on beta-blocker therapy to minimize maternal tachycardia. She remained clinically and haemodynamically stable until the planned induction of labour at 34 weeks. This was subsequently converted to caesarean section due to abnormal foetal cardiotocography, with the delivery of a healthy male baby.\n\nFigure 3 Transthoracic echocardiogram demonstrating (A) severe mitral stenosis and (B) pulmonary hypertension.\n\nBeta-blocker therapy was held for 24 h post-partum. The reason for this was unclear however was re-initiated together with digoxin due to worsening MV gradients (mPG 29 mmHg), EPAP 57 ± 3 mmHg (Figure 4), and development of palpitations secondary to new atrial fibrillation (AF) Day 2 postpartum. She remained clinically euvolaemic, and following consultation with her treating teams, she underwent elective BMV Day 8 postpartum with improved MV gradients and MVA (Figure 5). She remained well and was discharged Day 10 post-partum post-contraceptive implantation. She remained well on telephone review Day 2 post-discharge, prior to return to her local community.\n\nFigure 4 First postpartum transthoracic echocardiogram demonstrating (A) critical mitral stenosis and (B) pulmonary hypertension.\n\nFigure 5 Balloon inflation during balloon mitral valvuloplasty. (A) Distal balloon inflation. (B) Inflation of proximal and middle balloon, with waist in mid-portion of balloon demonstrating mitral stenosis. (C) Full balloon inflation. Post-balloon mitral valvuloplasty transthoracic echocardiogram demonstrating (D) moderate mitral stenosis and (E) mild pulmonary hypertension.\n\nDiscussion\n\nWhilst not common in developed countries, MS accounts for 9.5% of all valvular heart disease in Europe. Rheumatic heart disease (RHD) remains the most common aetiology.6 In Australia, RHD is a striking disease of disparity, where 89% of affected Australians identify as Aboriginal or Torres Strait Islander, representing a rate 6.6 times higher than non-Indigenous Australians.7 47% of Aboriginal or Torres Strait Islanders affected are aged under 20 years.7 Women account for 61% of the total indigenous RHD burden,7 attracting the greatest risk of poor outcomes, especially during pregnancy.\n\nPregnancy remains a World Health Organisation (WHO) Class IV contraindication in severe MS, due to maternal and foetal morbidity and mortality;5 however, there is a paucity of information regarding the management of severe MS in women of childbearing age or who are pregnant, particularly if they remain asymptomatic. The current guidelines are based on expert consensus which strongly recommends pregnancy avoidance or consideration of pregnancy termination, and do not address or acknowledge cultural sensitivities, varying levels of medical literacy or socioeconomic constraints of patient populations where RHD is likely more prevalent. Management of an already pregnant patient focuses on a combination of pharmacological agents including beta-blockers and diuretics, and clinical monitoring to identify the development of intervention indications.5,8 Percutaneous valvular intervention is recommended preconception. The intrapartum intervention has been reported but only in persistently symptomatic patients between second and third trimesters9 to consider organogenesis of the foetus. This does not take into account the hyperactive mammary tissue exposed to radiation, or the longer-term risk of childhood malignancy. Current guidelines do not account for many of these issues, or the timing and utility of serial echocardiographic assessments to guide percutaneous intervention as pregnancy develops.\n\nThis case demonstrates a number of important points. Achievement of pregnancy avoidance may not always be achieved despite its prescription. Serial echocardiography in combination with stress testing and physiological assessment for the surveillance of MV gradients, symptoms, and overall function during pregnancy may be utilized in asymptomatic patients to guide optimization of medical therapy, as well as the timing of percutaneous BMV. We have also demonstrated the safe and successful deferral of percutaneous BMV until post-partum in asymptomatic patients, protecting both the developing foetus and also maternal mammary tissue which remains increasingly active postpartum from potentially harmful radiation.\n\nOur case highlights the importance of patient-specific care and that further understanding of severe MS management in women of childbearing age and intrapartum is required to improve maternal and foetal outcomes.\n\nLead author biography\n\nJoanne M. H. Eng-Frost is a Cardiology Advanced Trainee at Flinders Medical Centre in Adelaide, Australia. She completed a Bachelor of Science (Biomedical Science) degree with Honours in Physiology at the University of Adelaide, Australia before earning a Doctor of Medicine (MD) degree at Flinders University, Australia. Her clinical interests include structural heart disease and interventional cardiology.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\nSlide sets: A fully edited slide set detailing these cases and suitable for local presentation is available online as Supplementary data.\n\nConsent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.\n\nConflict of interest: None declared.\n\nFunding: None declared.\n\nSupplementary Material\n\nytab010_Supplementary_Data Click here for additional data file.\n==== Refs\nReferences\n\n1 Tsiaras S , PoppasA. Mitral valve disease in pregnancy: outcomes and management. Obstet Med 2009;2 :6–10.27582798\n2 Silversides C , ColmanJ, SermerM, SiuS. Cardiac risk in pregnant women with rheumatic mitral stenosis. Am J Cardiol 2003;91 :1382–1385.12767443\n3 Van Hagen I , ThorneS, TahaN, YoussefG, ElnagarA, GabrielH et al Pregnancy outcomes in women with rheumatic mitral valve disease. Results from the Registry of Pregnancy and Cardiac Disease. Circulation 2018;137 :806–816.29459466\n4 Youssef G . Mitral stenosis in pregnant patients. E-J Cardiol Pract 2018;16 : 1–6.\n5 Regitz-Zagrosek V , LundqvistC, BorghiC, CifkovaR, FerreiraR, FoidartJ, et al Endorsed by the European Society of Gynecology (ESG), the Association for European Paediatric Cardiology (AEPC), and the German Society for Gender Medicine (DGesGM). ESC Guidelines on the management of cardiovascular disease during pregnancy. Eur Heart J 2011;32 :3147–3197.21873418\n6 Iung B , BaronG, ButchartE, DelahayeF, Gohlke-BarwolfC, LevangO et al A prospective survey of patients with valvular heart diseases in Europe: the Euro Heart Survey on Valvular Heart Disease. Eur Heart J 2003;24 :1231–1243.12831818\n7 Australian Institute of Health and Welfare. Acute rheumatic fever and rheumatic heart disease in Australia. Viewed 20th July 2020 (updated 11th October 2019). https://www.aihw.gov.au/getmedia/209d7b91-cba8-4882-9f79-720af1a090b3/Acute-rheumatic-fever-and-rheumatic-heart-disease-in-Australia-2014-2018.pdf.aspx?inline=true.\n8 Russell E , WalshW, CostelloB, McLellanA, BrownA, ReidC et al Medical management of rheumatic heart disease: a systematic review of evidence. Cardiol Rev 2018;26 :187–195.29608495\n9 Elkayam U , BitarF. Valvular heart disease and pregnancy: Part I: Native valves. J Am Coll Cardiol 2005;46 :223–230.16022946\n\n",
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"keywords": "Balloon valvuloplasty; Case report; Heart failure; Mitral stenosis; Pregnancy; Pulmonary hypertension; Rheumatic heart disease",
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"title": "Managing asymptomatic severe rheumatic mitral stenosis in pregnancy: a case report.",
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"abstract": "BACKGROUND\nEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are tolerable drugs used for patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). Serious adverse reactions are uncommon compared with cytotoxic drugs.\n\n\nMETHODS\nA 52-year-old man presented with general weakness and cytopenia. He had been taking erlotinib for 11 mo to treat NSCLC. The pathological diagnosis from the right upper lobe mass was adenocarcinoma with an EGFR mutation in exon 21 (L858R). He had previously received paclitaxel/carboplatin, gemcitabin/ vinorelbine chemotherapy, stereotactic radiosurgery for brain metastasis, and whole-brain radiotherapy as treatment for NSCLC. We diagnosed the patient with acute myeloid leukemia (AML). During the induction and consolidation chemotherapy for AML, the erlotinib was discontinued. When complete remission of the AML was achieved, since the lung masses were increased, pemetrexed/ cisplatin for the NSCLC was initiated. After two cycles of chemotherapy, the cytopenia was prolonged. AML relapse occurred with the same karyotype.\n\n\nCONCLUSIONS\nTherapy-related acute myeloid neoplasm (t-MN) is a rare but fatal late complication. Although a patient may be taking EGFR-TKIs, the possibility of t-MN should be considered. Further studies are needed to determine whether EGFR-TKI usage is a predisposing factor for t-MN.",
"affiliations": "Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul 04401, South Korea.;Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul 04401, South Korea. kukim@schmc.ac.kr.;Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul 04401, South Korea.;Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul 04401, South Korea.",
"authors": "Koo|So-My|SM|;Kim|Ki-Up|KU|;Kim|Yang-Ki|YK|;Uh|Soo-Taek|ST|",
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"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960\nBaishideng Publishing Group Inc\n\njWJCC.v9.i24.pg7205\n10.12998/wjcc.v9.i24.7205\nCase Report\nTherapy-related myeloid leukemia during erlotinib treatment in a non-small cell lung cancer patient: A case report\nKoo SM et al. T-AML during erlotinib treatment\nKoo So-My Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul 04401, South Korea\n\nKim Ki-Up Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul 04401, South Korea. kukim@schmc.ac.kr\n\nKim Yang-Ki Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul 04401, South Korea\n\nUh Soo-Taek Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul 04401, South Korea\n\nAuthor contributions: Koo SM and Kim KU designed research; Koo SM, Kim KU, Kim YK, and Uh ST performed research, analyzed data, and wrote the paper; all authors have read and approve the final manuscript.\n\nSupported by Soonchunhyang University Research Fund.\n\nCorresponding author: Ki-Up Kim, MD, Professor, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, 59 Daesakwan-Ro, Yongsan-Ku, Seoul 04401, South Korea. kukim@schmc.ac.kr\n\n26 8 2021\n26 8 2021\n9 24 72057211\n5 3 2021\n27 4 2021\n15 7 2021\n©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.\nBACKGROUND\n\nEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are tolerable drugs used for patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). Serious adverse reactions are uncommon compared with cytotoxic drugs.\n\nCASE SUMMARY\n\nA 52-year-old man presented with general weakness and cytopenia. He had been taking erlotinib for 11 mo to treat NSCLC. The pathological diagnosis from the right upper lobe mass was adenocarcinoma with an EGFR mutation in exon 21 (L858R). He had previously received paclitaxel/carboplatin, gemcitabin/ vinorelbine chemotherapy, stereotactic radiosurgery for brain metastasis, and whole-brain radiotherapy as treatment for NSCLC. We diagnosed the patient with acute myeloid leukemia (AML). During the induction and consolidation chemotherapy for AML, the erlotinib was discontinued. When complete remission of the AML was achieved, since the lung masses were increased, pemetrexed/ cisplatin for the NSCLC was initiated. After two cycles of chemotherapy, the cytopenia was prolonged. AML relapse occurred with the same karyotype.\n\nCONCLUSION\n\nTherapy-related acute myeloid neoplasm (t-MN) is a rare but fatal late complication. Although a patient may be taking EGFR-TKIs, the possibility of t-MN should be considered. Further studies are needed to determine whether EGFR-TKI usage is a predisposing factor for t-MN.\n\nAcute myeloid leukemia\nErlotinib\nNeoplasm, second primary\nNon-small cell lung cancer\nCase report\n==== Body\npmcCore Tip: Therapy-related acute myeloid leukemia (t-AML) developed during erlotinib treatment in a patient with epidermal growth factor receptor (EGFR)–mutant advanced non-small cell lung cancer (NSCLC). Alkylating cytotoxic drugs and radiotherapy are common treatments for patients with NSCLC. Cases of t-AML related to alkylating agents typically have a long latency period. Since it was 20 mo in this case, EGFR–tyrosine kinase inhibitor (EGFR-TKI) usage may be related to or hasten AML development in patients who previously received cytotoxic chemotherapy. Although the mechanism remains unclear, when a patient takes an EGFR-TKI, t-AML development should be considered, especially if cytopenia persists.\n\nINTRODUCTION\n\nTherapy-related acute myeloid leukemia (t-AML) is a rare but fatal late complication of cytotoxic chemotherapy. According to Surveillance, Epidemiology, and End Results data in United States cancer registries, 18 patients with t-AML were identified in 2001–2008 among 37008 non-small cell lung cancer (NSCLC) patients who received initial chemotherapy in adulthood[1]. Since patients with NSCLC receive multiple lines of treatment, it is difficult to determine which of the cytotoxic drugs are related to the AML that occurs several years later.\n\nEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the target therapy for patients with EGFR-mutant NSCLC. EGFR-TKIs are known to be relatively tolerable drugs for patients and less toxic than cytotoxic agents. Moreover, serious adverse reactions to them are uncommon[2].\n\nWe identified a case of AML that developed during erlotinib treatment and reviewed cases of myeloid neoplasms that occurred during EGFR-TKI treatment in the literature.\n\nCASE PRESENTATION\n\nChief complaints\n\nA 52-year-old man presented with general weakness. His symptoms had waxed and waned during the past several months.\n\nHistory of present illness\n\nHe was under lung cancer treatment consisting of erlotinib 100 mg/d, levetiracetam 1000 mg/d, and prednisolone 10 mg/d to control his symptoms and prevent seizure that related with brain metastasis.\n\nHistory of past illness\n\nHe had a medical history of chemotherapy and radiotherapy for NSCLC diagnosed as adenocarcinoma, T2bN2M1a by the International Association for the Study of Lung Cancer seventh edition guidelines 20 mo prior. The pathological diagnosis of the right upper lobe mass was adenocarcinoma with an EGFR mutation in exon 21(L858R). As first-line chemotherapy, he received six cycles of combination paclitaxel (175 mg/m2) and carboplatin (AUC 4). At that time, EGFR-TKI was not covered by medical insurance benefits as the first-line therapy, so cytotoxic chemotherapy was administered. After disease progression occurred, he received three cycles of gemcitabine (1000 mg/m2) and vinorelbine (25 mg/m2) chemotherapy. He then developed memory problems and gait difficulties. Brain magnetic resonance imaging revealed a brain metastasis. We decided to perform stereotactic radiosurgery using a Cyberknife to resect multiple metastatic lesions (total 23 Gy). Six months later, the size and number of brain metastatic lesions had increased. He subsequently received whole-brain radiotherapy (total 30 cGy).\n\nPersonal and family history\n\nOur patient, who ran a flower shop, was a former smoker with a 26 pack-years history of smoking. He had quit smoking a year prior.\n\nPhysical examination\n\nHis vital signs and physical examination findings were unremarkable except for a chronic ill-looking appearance.\n\nLaboratory examinations\n\nA complete blood count revealed a white blood cell count of 7600 (absolute neutrophil count, 500), hemoglobin level of 12.4 g/dL, and platelet count of 83000/μL. A leukocyte differential count revealed an absolute neutrophil count of 500/μL, lymphocyte count of 2400/μL, and monocyte count of 1000/μL. Immature cells were observed in the peripheral blood (Figure 1A). The chemistry results were normal except for a lactate dehydrogenase level of 293 U/L (reference interval, 106–211 U/L).\n\nFigure 1 Blood smear and bone marrow aspiration results. A: The blood smear shows 44% blast cells (× 1000); B: The bone marrow aspiration showed 77.3% myoblasts (× 1000).\n\nImaging examinations\n\nIn the initial diagnosis, chest computed tomography revealed a 61 mm × 44 mm lobulated mass in the right upper lobe and another 31 mm × 23 mm spiculated mass in the left upper lobe. As the third-line therapy, we started erlotinib, an EGFR-TKI, at a dose of 150 mg/d 11 mo prior. During erlotinib treatment, the mass in the right upper lung became markedly improved (Figure 2A and B).\n\nFigure 2 Contrast-enhanced chest computed tomography findings. A: Before erlotinib treatment, a 59 mm × 42 mm heterogenous enhancing lobulated mass in the right upper lobe (RUL) is closely abutting the adjacent costal pleura with focal thickening and retraction; B: During erlotinib treatment, the mass in the RUL is markedly improved; C: Four months after discontinuing the erlotinib due to leukemia induction chemotherapy, the mass in the RUL is enlarged, and a spiculated mass is visible in the left upper lobe (LUL) (24 mm × 17 mm); D: Two months after pemetrexed/cisplatin treatment, no remarkable changes in the RUL and LUL masses are noted.\n\nFINAL DIAGNOSIS\n\nBone marrow aspirate smears revealed a monocytic blast rate of 77.3% (Figure 1B). Eosinophil levels in the bone marrow were increased (14.4%). A bone marrow biopsy revealed 80% cellularity. While megakaryocytes were decreased, immature cells diffusely infiltrated the bone marrow. CBFB/MYH11 rearrangement was observed by fluorescence in situ hybridization analysis. On a chromosome analysis, inv(1) and inv(16) were detected. The patient’s karyotype was 46, XY, inv(1) (p22q32), inv(16) (p13.1q22).\n\nTREATMENT\n\nAfter receiving the diagnosis of AML, the patient started induction chemotherapy with daunorubicin/cytarabine and consolidation chemotherapy with high-dose cytarabine. During AML treatment, the erlotinib treatment was stopped.\n\nOUTCOME AND FOLLOW-UP\n\nAt the time that complete remission of the AML was achieved, both upper lobe masses had increased in size (Figure 2C and D). Fourth-line chemotherapy with pemetrexed/cisplatin for NSCLC was initiated. After two cycles of chemotherapy, the cytopenia persisted. The complete blood count revealed a white blood cell count of 1800 (absolute neutrophil count, 972), hemoglobin level of 9.6 g/dL, and platelet count of 88000/μL. Immature cells were observed in the peripheral blood. The result of the bone marrow study was AML relapse with the same karyotype. Re-induction chemotherapy with mitoxantrone/etoposide did not achieve remission. We administered low-dose cytarabine chemotherapy; the patient was exhausted with poor performance status and died of respiratory failure 10 mo after receiving the AML diagnosis.\n\nDISCUSSION\n\nThis case involved t-AML that developed during erlotinib treatment in a patient with NSCLC. The case was considered a therapy-related myeloid neoplasm rather than de novo AML because the patient had a clinical history of antecedent cytotoxic therapy and radiotherapy. Carboplatin and radiotherapy in this patient were risk factors for t-AML[3]. Patients with t-AML related to alkylating agents generally experience a longer latency period (5–7 years) than those with t-AML related to topoisomerase-2 inhibitors (2–3 years) between therapy and myeloid neoplasm development[4]. This can predict the long interval between alkylating chemotherapy and an AML diagnosis. However, in the present case, the interval between the initiation of carboplatin treatment and AML development was 20 mo, which was relatively short.\n\nDifferentiating therapy-related acute myeloid neoplasm (t-MN) from de novo myelodysplastic syndrome (MDS)/AML is difficult because mutation profiling has demonstrated similar abnormalities for both conditions. Common patterns in recurrent mutations and chromosomal abnormalities are chromosome 5 and 7 loss with alkylating agent exposure and MLL translocations at 11q23 or RUNX1/AML1 at 21q22 with topoisomerase-2 inhibitor exposure[4,5]. However, de novo and therapy-related MDS/AML can share genetic features (especially the 11q23 anomaly). There are no pathognomonic morphologic or genetic features of t-MN[5].\n\nEGFR-TKIs are the current first-line treatment for patients with EGFR mutation-positive advanced NSCLC. There have been a few reports related to leukemia and EGFR-TKIs[6-9]. In the literature review (Table 1), we identified eight patients with t-MN after EGFR-TKI treatment for antecedent NSCLC. The mean interval from the first-line NSCLC treatment to AML development was 40.7 (range, 11–120) months. None of the patients who were diagnosed with t-MN after EGFR-TKI treatment for NSCLC had taken topoisomerase II inhibitors. Since the latency period for these patients was not longer than expected, we considered the possibility that EGFR-TKI might be associated with the development of myeloid neoplasms.\n\nTable 1 Literature review findings of therapy-related myeloid neoplasms after epidermal growth factor receptor tyrosine kinase inhibitor treatment in non-small cell lung cancer patients\n\nPatients number\tRef.\tAge/sex\tPathological type of NSCLC\tInitial stage\tEGFR mutation\tPrior chemotherapy\tInterval from first line treatment\tPrior radiotherapy\tDuration of EGFR-TKI treatment\tInterval from EGFR-TKI treatment until leukemia\tCBC profiles at leukemia presentation: WBC (ANC) (μL)-hemoglobin (g/dL)/hematocrit (%)-platelets (mL)\tCharacteristics (Karyotype) of leukemia/MDS\tSurvival after diagnosis of leukemia\t\n1\tUchida et al[8], 2005\t49/M\tAdenocarinoma\tIV (T1N0M1)\tNA\tCisplatin/docetaxel/ irinotecan 2 cycles\t36 mo\tCyberknife for brain metastasis (22.993Gy)\tGefitinib, 15 mo\t15 mo\tNA\tAPL, normal karyotype, PML RARα positive\tNA\t\n2\tUchida et al[8], 2005\t65/M\tSquamous cell carcinoma\tIIIB (T4N3M0)\tNA\tCisplatin/mitomycin/ vinorelbine 2 cycles, Uracil/tegafur for 2 mo in adjuvant setting\t48 mo\tFractionated radiotherapy (2Gy* 25)\tGefitinib, 25 mo\t25 mo\tNA\tAPL, normal karyotype, PML RARα positive\tNA\t\n3\tUchida et al[8], 2005\t72/M\tAdenocarinoma\tIA (T1N0M0)\tNA\tCarboplatin/paclitaxel 1 cycle, Cisplatin, carboplatin, irinotecan, docetaxel, gemcitabine, vinorelbine, paclitaxel, amrubicin\t69 mo\tNone\tGefitinib, 5 mo + 4 mo (discontinued and restarted)\t26 mo\tNA\tAPL, normal karyotype, PML RARα positive\tNA\t\n4\tEnnishi et al[9], 2006\t51/F\tAdenocarcinoma\tRecurrence after LLL lobectomy, mediastinal LN metastasis\tNA\tCarboplatin/paclitaxel 6 cycles\tNA\tRadiotherapy at a total dosage of 60 Gy\tGefitinib, 14 mo\t14 mo\t2300-13.2/-15200\tAPL, t(15;17)(q22;q21), PML/RARα positive\tNA\t\n5\tStathopoulos et al[6], 2010\t67/M\tAdenocarinoma\tIIIB\tNA\tCisplatin/gemcitabine 6 cycles\t11 mo\tNone\tErlotinib, 4 mo\t8 mo\tGrade 4 thrombocytopenia\tMDS, 46, XY, del(20)(q11)[15]/47, idem, + 21(7)/48,idem, 21, + 21[-3]\tNA\t\n6\tStathopoulos et al[6], 2010\t70/M\tAdenocarinoma\tIIIB\tNA-\tCisplatin/paclitaxel 6 cycles\t12 mo\tNone\tErlotinib, 8 mo\t8 mo\tWBC 92000\tCML, BCR-ABL+\tNA\t\n7\tStathopoulos et al[6], 2010\t60/F\tAdenocarinoma\tIIIB\tNA\tCisplatin/vinorelbine 6 cycles. Carboplatin/etoposide 3 cycles\t36 mo\tRadiotherapy (RT) of the primary lung lesions and of themediastinum\tErlotinib, 8.5 mo\t8.5 mo\t2500-/28.8-72000\tMDS, RAEB-T/t-AML, 46, XX, del(7)(q22), add(21)(q22)\tDied 3.5 mo later\t\n8\tStathopoulos et al[6], 2010\t59/F\tSquamous cell carcinoma\tIV\tNA\tCarboplatin/etoposide 6 cycles\t14 mo\t\tErlotinib, 5.5 mo\t5.5 mo\t3200-/25.7\tMDS, RAEB 47, XX, +8, t(5;9)(q13;q34)\tDied 8 mo later\t\n9\tMoon et al[7], 2014\t72/M\tSquamous cell carcinoma\tII (T2N1M0)\tNA\tA combination of radiotherapy and a repeated chemotherapy regimen (4 trials, 13 cycles) consisting of docetaxel, cisplatin, gemcitabine, vinorelbine, gefitinib, irinotecan, and carboplatin\t10 yr\tCombination of radiotherapy and a repeated chemotherapy regimen\tGefitinib, Duration:NA\tNA\t1700 (780)-5.2/-34000\tT-AML (Acute megakaryoblastic leukemia)-5,-7,+2mar\tBeing followed up\t\n10\tPresent case\t52/M\tAdenocarcinoma\tIV (T2bN2M1a)\tL858R\tPaclitaxel/carboplatin 6 cycles, gemcitabin/vinorelbine 3 cycles\t20 mo\tCyberknife for brain metastasis (23Gy), WBRT (30Gy)\tErlotinib, 11 mo\t11 mo\t7600(500)-12.4/-83000\tAML, 46, XY, inv(1) (p22q32), inv(16)(p13.1q22)\tDied 10 mo later\t\nAPL: Acute promyelocytic leukemia; ANC: Absolute neutrophil count; CML: Chronic myeloid leukemia; EGFR: Epidermal growth factor receptor; EGFR-TKI: Epidermal growth factor receptor tyrosine kinase inhibitor; MDS: Myelodysplastic syndrome; NA: Not applicable; NSCLC: Non-small cell lung cancer; RAEB-T: Refractory anemia with excess blasts in transformation; t-AML: Therapy-related acute myeloid leukemia; WBC: White blood cell.\n\nThe duration of EGFR-TKI therapy before AML was relatively short (mean, 13.4 mo; range, 5.5–26 mo). However, since cytotoxic chemotherapy drugs were administered prior to EGFR-TKI in all of these patients, the development of myeloid neoplasm may be related to both classes of drugs. It was not known whether the occurrence of t-MN was different depending on the type of EGFR mutation. This is because out of the 8 reported cases, only our case (L858R) provided the type of EGFR mutation.\n\nSeveral case reports have shown that EGFR-TKIs might have leukemogenic effects in patients with t-MN after the administration of EGFR-TKIs[6,8,10]. However, after EGFR-TKIs were commercially approved, to the best of our knowledge, no cases of myeloid neoplasms after the administration of EGFR-TKI alone for NSCLC treatment have been reported in the literature. All patients of case reports with t-MN received chemotherapy or radiotherapy for NSCLC treatment before receiving EGFR-TKIs. We suggest that EGFR-TKI may be related to or shorten the interval to AML development when patients previously received cytotoxic chemotherapy. According to the historical concept, cytotoxic drugs such as topoisomerase II inhibitors or radiotherapy induce DNA damage that leads to translocation. In the model for the role of clonal selection[4], clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the absence of morphological evidence of disease and the presence of a clonal population of hematopoietic cells with somatic mutations in the genes associated with hematologic malignancies[11].\n\nToxins, drugs, oligoclonality with aging, chemoradiation, chemical exposure, immune destruction, or dysfunctional hematopoiesis may be selected for mutant clones and induce CHIP. Additional somatic alterations in CHIP can promote high-risk myeloid neoplasms. We considered the possibility that certain effects of EGFR-TKI on the tyrosine kinase pathway could play a role in CHIP.\n\nLong-term epidemiological research is needed to clarify whether there is a relationship between EGFR-TKI treatment and the rare but serious events noted here. If the incidence of this complication in the EGFR-TKI-treated cohort is beyond that expected on the basis of patients with NSCLC before EGFR-TKIs are commercially available, we must consider EGFR-TKIs as the predisposing factor of t-MN.\n\nCONCLUSION\n\nIn summary, if cytopenia persists in patients treated with EGFR-TKIs for NSCLC, the possibility of t-MN should be considered. Further studies are needed to determine whether the administration of EGFR-TKIs is a predisposing factor for t-MN.\n\nInformed consent statement: The author provided informed consent.\n\nConflict-of-interest statement: Dr. Koo has nothing to disclose.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: March 5, 2021\n\nFirst decision: April 24, 2021\n\nArticle in press: July 15, 2021\n\nSpecialty type: Medicine, research and experimental\n\nCountry/Territory of origin: South Korea\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B\n\nGrade C (Good): C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Neninger E, Yang TY S-Editor: Fan JR L-Editor: A P-Editor: Li X\n==== Refs\n1 Morton LM Dores GM Tucker MA Kim CJ Onel K Gilbert ES Fraumeni JF Jr Curtis RE Evolving risk of therapy-related acute myeloid leukemia following cancer chemotherapy among adults in the United States, 1975-2008 Blood 2013 121 2996 3004 23412096\n2 Shepherd FA Rodrigues Pereira J Ciuleanu T Tan EH Hirsh V Thongprasert S Campos D Maoleekoonpiroj S Smylie M Martins R van Kooten M Dediu M Findlay B Tu D Johnston D Bezjak A Clark G Santabárbara P Seymour L National Cancer Institute of Canada Clinical Trials Group Erlotinib in previously treated non-small-cell lung cancer N Engl J Med 2005 353 123 132 16014882\n3 Beaumont M Sanz M Carli PM Maloisel F Thomas X Detourmignies L Guerci A Gratecos N Rayon C San Miguel J Odriozola J Cahn JY Huguet F Vekhof A Stamatoulas A Dombret H Capote F Esteve J Stoppa AM Fenaux P Therapy-related acute promyelocytic leukemia J Clin Oncol 2003 21 2123 2137 12775738\n4 McNerney ME Godley LA Le Beau MM Therapy-related myeloid neoplasms: when genetics and environment collide Nat Rev Cancer 2017 17 513 527 28835720\n5 Klimek VM Tray NJ Therapy-related myeloid neoplasms: what's in a name? Curr Opin Hematol 2016 23 161 166 26779614\n6 Stathopoulos GP Trafalis D Athanasiou A Bardi G Chandrinou H Serious hematologic complications following erlotinib treatment Anticancer Res 2010 30 973 976 20393022\n7 Moon JJ Nam MH Lim CS Lee CK Cho Y Yoon SY Therapy-related acute megakaryoblastic leukemia in a lung cancer patient Ann Lab Med 2014 34 155 158 24624354\n8 Uchida A Matsuo K Tanimoto M APL during gefitinib treatment for non-small-cell lung cancer N Engl J Med 2005 352 843 15728826\n9 Ennishi D Sezaki N Senoo T Terui Y Hatake K Hino N A case of acute promyelocytic leukemia during gefitinib treatment Int J Hematol 2006 84 284 285 17020873\n10 Hotta K Kiura K Takigawa N Matsuo K Tabata M Fujiwara Y Tanimoto M Paradoxical clinical effects of epidermal growth factor receptor-tyrosine kinase inhibitors for acute myelogenous leukemia J Clin Oncol 2008 26 5826 5827; author reply 5827 19001344\n11 Steensma DP Bejar R Jaiswal S Lindsley RC Sekeres MA Hasserjian RP Ebert BL Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes Blood 2015 126 9 16 25931582\n\n",
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"journal": "World journal of clinical cases",
"keywords": "Acute myeloid leukemia; Case report; Erlotinib; Neoplasm, second primary; Non-small cell lung cancer",
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"title": "Therapy-related myeloid leukemia during erlotinib treatment in a non-small cell lung cancer patient: A case report.",
"title_normalized": "therapy related myeloid leukemia during erlotinib treatment in a non small cell lung cancer patient a case report"
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{
"abstract": "Polyethylene glycosylated (PEG)-asparaginase is a cornerstone of treatment for acute lymphoblastic leukemia (ALL), and effective administration is associated with better outcomes. PEG-asparaginase is associated with a uniphasic hypersensitivity reaction in ∼10% to 20% of patients. We present a 17-year-old male individual diagnosed with very high-risk pre-B-ALL, who experienced protracted anaphylaxis 1 hour following administration of his second PEG-asparaginase dose. This type of allergic reaction has yet to be described in ALL patients treated with PEG-asparaginase. Here, we outline the time course and successful management of protracted anaphylaxis in an ALL patient.",
"affiliations": "Department of Pediatrics, University of Vermont.;Department of Pediatrics, University of Vermont.;Department of Pediatrics, University of Vermont.;Department of Pediatrics, University of Vermont.",
"authors": "Fertal|Shelby A|SA|;Bradeen|Heather A|HA|;Friesen|Elizabeth|E|;Heath|Jessica L|JL|",
"chemical_list": "D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; C042705:pegaspargase; D001215:Asparaginase",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001906",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "43(3)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D000707:Anaphylaxis; D000970:Antineoplastic Agents; D001215:Asparaginase; D019468:Disease Management; D006801:Humans; D008297:Male; D011092:Polyethylene Glycols; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e385-e387",
"pmc": null,
"pmid": "32815880",
"pubdate": "2021-04-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Time Course and Management of Protracted Anaphylaxis Due to PEG-Asparaginase.",
"title_normalized": "time course and management of protracted anaphylaxis due to peg asparaginase"
} | [
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"companynumb": "US-SERVIER-S21005521",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEGASPARGASE"
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"drugadditional": "1",
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{
"abstract": "Medication errors recently became the focus of regulatory guidance in pharmacovigilance to support reporting, evaluation and prevention of medication errors.\n\n\n\nThis study aims to characterise spontaneously reported cases of medication errors in EudraVigilance over the period 2002-2015 before the release of EU good practice guidance.\n\n\n\nCase reports were identified through the adverse reaction section where a Medical Dictionary for Regulatory Activities (MedDRA®) term is reported and included in the Standardised MedDRA® Query (SMQ) for medication errors. These case reports were further categorised by MedDRA® terms, geographical region, patient age group and Anatomical Therapeutic Chemical classification system of suspect medicinal product(s).\n\n\n\nA total of 147,824 case reports were retrieved, 41,355 of which were from the European Economic Area (EEA). Approximately 60% of these case reports were retrieved with the narrow SMQ. The absolute number of medication error case reports and the proportion to the total number of reports in EudraVigilance increased during the study period, with peaks seen around 2005 and 2012 for cases with EEA origin. Fifty-two percent of case reports in which age was provided occurred in adults, 30% in the elderly and 18% in children, with almost half of these in children aged 2 months to 2 years.\n\n\n\nCase reports of medication errors in EudraVigilance steadily increased between 2005 and 2015, the reasons for which may be multifactorial, including increased awareness, changes to the MedDRA® terminology and the 2012 EU pharmacovigilance legislation and associated guidance for stakeholders, or a generally increased risk for errors as more medications become available.",
"affiliations": "Inspections, Human Medicines Pharmacovigilance and Committees Division, Pharmacovigilance and Epidemiology Department, European Medicines Agency (EMA), London, E14 5EU, UK. victoria.newbould@ema.europa.eu.;Information Management Division, Business Data and Analytics Department, European Medicines Agency (EMA), London, E14 5EU, UK.;Inspections, Human Medicines Pharmacovigilance and Committees Division, Pharmacovigilance and Epidemiology Department, European Medicines Agency (EMA), London, E14 5EU, UK.;Inspections, Human Medicines Pharmacovigilance and Committees Division, Pharmacovigilance and Epidemiology Department, European Medicines Agency (EMA), London, E14 5EU, UK.",
"authors": "Newbould|Victoria|V|;Le Meur|Steven|S|;Goedecke|Thomas|T|;Kurz|Xavier|X|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40264-017-0569-3",
"fulltext": "\n==== Front\nDrug SafDrug SafDrug Safety0114-59161179-1942Springer International Publishing Cham 2869898856910.1007/s40264-017-0569-3Original Research ArticleMedication Errors: A Characterisation of Spontaneously Reported Cases in EudraVigilance Newbould Victoria victoria.newbould@ema.europa.eu 1Le Meur Steven 2Goedecke Thomas 1Kurz Xavier 11 grid.452397.eInspections, Human Medicines Pharmacovigilance and Committees Division, Pharmacovigilance and Epidemiology Department, European Medicines Agency (EMA), London, E14 5EU UK 2 grid.452397.eInformation Management Division, Business Data and Analytics Department, European Medicines Agency (EMA), London, E14 5EU UK 11 7 2017 11 7 2017 2017 40 12 1241 1248 © The Author(s) 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, a link is provided to the Creative Commons license and any changes made are indicated.\nIntroduction\nMedication errors recently became the focus of regulatory guidance in pharmacovigilance to support reporting, evaluation and prevention of medication errors.\n\nObjective\nThis study aims to characterise spontaneously reported cases of medication errors in EudraVigilance over the period 2002–2015 before the release of EU good practice guidance.\n\nMethods\nCase reports were identified through the adverse reaction section where a Medical Dictionary for Regulatory Activities (MedDRA®) term is reported and included in the Standardised MedDRA® Query (SMQ) for medication errors. These case reports were further categorised by MedDRA® terms, geographical region, patient age group and Anatomical Therapeutic Chemical classification system of suspect medicinal product(s).\n\nResults\nA total of 147,824 case reports were retrieved, 41,355 of which were from the European Economic Area (EEA). Approximately 60% of these case reports were retrieved with the narrow SMQ. The absolute number of medication error case reports and the proportion to the total number of reports in EudraVigilance increased during the study period, with peaks seen around 2005 and 2012 for cases with EEA origin. Fifty-two percent of case reports in which age was provided occurred in adults, 30% in the elderly and 18% in children, with almost half of these in children aged 2 months to 2 years.\n\nConclusion\nCase reports of medication errors in EudraVigilance steadily increased between 2005 and 2015, the reasons for which may be multifactorial, including increased awareness, changes to the MedDRA® terminology and the 2012 EU pharmacovigilance legislation and associated guidance for stakeholders, or a generally increased risk for errors as more medications become available.\n\nissue-copyright-statement© Springer International Publishing AG, part of Springer Nature 2017\n==== Body\nKey Points\n\nEU pharmacovigilance legislation focuses on medication errors and increased error reporting to EudraVigilance\t\nA new Standardised MedDRA® Query for medication errors facilitates data retrieval and analysis in this first comprehensive review\t\nFurther research to assess the impact of EU regulatory guidance on error prevention strategies is required\t\n\n\n\nIntroduction\nThe EU pharmacovigilance legislation [1] has put an increased emphasis on medication errors and the regulatory requirement for national drug regulatory authorities and the pharmaceutical industry to report adverse drug reactions (ADRs) caused by a medication error. Hence, medication errors are explicitly included in the ADR definition of Directive 2001/83/EC. In November 2015, the EU regulatory network published a Good Practice Guide (GPG) [2] to support the recording, coding, reporting and assessment of medication errors associated with suspected serious and non-serious adverse reactions to national pharmacovigilance databases and/or EudraVigilance, as applicable. EudraVigilance is the centralised European database for reporting and evaluating suspected adverse reactions of medicines and is maintained by the European Medicines Agency (EMA) on behalf of the EU regulatory network. The database contains electronic Individual Case Safety Reports (ICSRs), hereafter referred to as case reports from within and outside the EEA1, in line with the reporting rules defined in the guideline on good pharmacovigilance practices (GVP) Module VI [3]. Unlike medication errors associated with adverse reactions, errors with the potential for harm and those not resulting in adverse reactions (including intercepted errors) are recorded in the Periodic Safety Update Report (PSUR) and are not reportable to EudraVigilance as ICSRs.\n\nThe GPG aims to define and classify medication errors for pharmacovigilance purposes, to increase awareness of the reporting requirements among stakeholders, and to improve the quality of error reports in EudraVigilance. It includes supporting key pharmacovigilance activities ranging from detecting and evaluating signals of medication errors to implementation of risk minimisation and error prevention strategies [4]. The objective of this descriptive study was to investigate the frequency and patterns of case reports in EudraVigilance associated with medication errors during the period 2002–2015, before the release of the GPG. This is the first comprehensive quantitative review of medication errors in EudraVigilance and will thereby serve as a basis to further evaluate the implementation of the GPG recommendations and measure its impact on the reporting and prevention of medication errors. For the purpose of this study, we refer to the definition of a medication error provided in the GPG: “a medication error is an unintended failure in the drug treatment process that leads to, or has the potential to lead to harm to the patient”. The GPG further explains that a failure in the drug treatment process does not refer to lack of efficacy of the drug but rather to human- or process-mediated failures.\n\nMethods\nData Source\nFor this study, spontaneous case reports in the EudraVigilance Post-Authorisation Module were used. The criteria for a valid case report and definitions of the ICSR data elements are specified in the International Conference on Harmonization (ICH) guidelines [5]. Valid case reports include, at a minimum, an identifiable reporter, an identifiable patient, and at least one drug and one ADR. The ICSR reaction section is coded with the Medical Dictionary for Regulatory Activities2 (MedDRA®) terminology, but free text in the case summary narrative section may also provide a rich source of information on medication errors. MedDRA® is organised into a hierarchy of five levels arranged by granularity, from very specific ‘Low-Level Term’ (LLT) to an entire ‘System Organ Class’ (SOC). EudraVigilance data can be retrieved and analysed using Standardised MedDRA® Queries (SMQs) developed by the Council for International Organisations of Medical Sciences (CIOMS), which combines terms related to a defined medical condition or area of interest that may be contained across different areas of the hierarchy [6, 7]. For our analysis, all case reports associated with a medication error were identified, where at least one MedDRA® LLT from the SMQ for medication errors (released in March 2016 with MedDRA® version 19.0) has been coded in the adverse reaction section.\n\nData Extraction\nThe narrow SMQ for medication errors has 89 terms; additional terms are available to form the broad SMQ. Whereas the narrow terms are highly likely to represent the condition of interest (a ‘narrow’ scope), broad terms provide for retrieving additional potential cases of interest, although those cases may, on closer, inspection prove to be irrelevant for a particular condition. For example, there are several product-quality terms in the broad SMQ, which could possibly be associated with medication errors. Data were retrieved with both the narrow and broad SMQ for medication errors. The possibility of retrieving duplicate cases was mitigated through semi-automated checks for duplicate case reports performed by the EMA according to a defined algorithm, and managed through a process of merging duplicate cases [8]. Data were retrieved for cases reported between 1 January 2002 and 31 December 2015 using EudraVigilance ‘ICSR message type’ based on the gateway date, and for serious and non-serious reports. Non-serious PSUR reports submitted in the past on a voluntary basis were excluded. Case reports were filtered by narrow or broad SMQ and by region of occurrence, i.e. European Economic Area (EEA) versus non-EEA origin, and by United Nations geo-scheme, which divides the countries of the world into regional and subregional groups [9]. The Anatomical Therapeutic Chemical (ATC) Classification System code of the suspect medicinal products in the reports was also retrieved. The full ICSR data extraction pathway is shown in Fig. 1.Fig. 1 EudraVigilance ICSR data extraction pathway using the broad and narrow SMQ for medication errors. Non-serious PSUR cases were excluded. ICSR individual case safety reports, SMQ standardised MedDRA® Query, EVPM eudravigilance post-authorisation module, PT preferred terms, EEA European economic area, ATC anatomical therapeutic classification, PSUR periodic safety update report, UN United Nations, MedDRA\n® medical dictionary for regulatory activities\n\n\n\n\nResults\nA total of 147,824 case reports were retrieved, of which 41,355 refer to cases occurring within the EEA. Approximately 60% of these are narrow SMQ cases. A case report may contain more than one MedDRA® term related to a medication error. The absolute number of medication error case reports has been increasing over time between 2002 and 2015, as shown in Fig. 2. The proportion of medication errors to total number of ADR reports has also been increasing, with peaks seen around 2005 and 2012 for cases with EEA origin (Fig. 3). There have also been increases over time in the proportion of medication error reports compared with the total number for non-EEA cases, although the proportion is lower, and no peak was seen in 2012. Using the narrow SMQ and looking at absolute numbers, 59% of medication error cases in EudraVigilance are from North and South America. For Europe, 60% are from Western Europe, 24% from Northern Europe, 12% from Southern Europe, and 4% from Eastern Europe. In the EEA, the most frequently reported MedDRA® Preferred Term (PT) is ‘Medication error’, followed by ‘Accidental overdose’, ‘Inappropriate schedule of drug administration’ and ‘Incorrect dose administered’ (Fig. 5). Eight percent of cases are from Asia, and only 2 and 1% are from Oceania and Africa, respectively (Fig. 6). Despite the low numbers from Oceania and Africa, the cumulative total proportions of medication errors versus all reported cases are higher than in Europe. The proportion of errors of all reported ADRs is approximately 3% for Eastern, Western and Southern Africa, although this figure is lower for Northern Africa (1.5%) and much lower for Middle Africa (0.7%). The patterns of errors in Africa vary with respect to the general global pattern, and also across the African regions.Fig. 2 Number of ICSRs retrieved with the narrow SMQ for medication errors reported in the EEA and globally (includes both EEA and non-EEA cases) to EudraVigilance between 2002 and 2015. ICSRs individual case safety reports, SMQ Standardised MedDRA® Query, EEA European economic area, MedDRA\n® medical dictionary for regulatory activities\n\n\nFig. 3 Proportion of medication error ICSRs with EEA origin retrieved with the broad and narrow SMQ to the total number of ICSRs reported to EudraVigilance between 2002 and 2015. The broad SMQ includes the terms from the narrow SMQ. ICSRs Individual Case Safety Reports, EEA European Economic Area, SMQ Standardised MedDRA® Query, MedDRA\n® Medical Dictionary for Regulatory Activities\n\n\n\n\nAs shown in Table 1, the ranking for ATC codes associated with medication errors reported inside and outside the EEA is largely similar, with vaccines ranking higher in the EEA (vaccines rank at number 12 outside the EEA). The most commonly reported PT for vaccines is ‘Inappropriate schedule of drug administration’. Drilling down into further detail of the most reported errors inside and outside the EEA combined, accidental overdoses occurred most frequently with paracetamol, opiates and benzodiazepines, while drug administration errors were most frequently reported with cisapride, insulin, fluticasone/salmeterol, fentanyl and salbutamol. Incorrect dose administered was highly associated with rivaroxaban, insulin, mifepristone, misoprostol and paracetamol .Table 1 Ranking of ATC codes most frequently reported with medication errors by EEA and non-EEA origin\n\nRanking\tEEA\tNon-EEA\t\n1\n2\n3\n4\n5\n6\n7\n8\n9\n10\tJ07 (Vaccines)\nN05 (Psycholeptics)\nN02 (Analgesics)\nB01 (Antithrombotics)\nG03 (Sex hormones)\nN06 (Psychoanaleptics)\nA10 (Drugs used in diabetes)\nN03 (Antiepileptics)\nL01 (Antineoplastics)\nJ01 (Antibacterials for systemic use)\tN02 (Analgesics)\nN05 (Psycholeptics)\nA10 (Drugs used in diabetes)\nB01 (Antithrombotics)\nL04 (Immunosupressants)\nR03 (Obstructive airways disease)\nN06 (Psychoanaleptics)\nG03 (Sex hormones)\nN03 (Antiepileptics)\nN07 (Other nervous system drugs)\t\n\nATC anatomical therapeutic chemical, EEA European economic area\n\n\n\n\nIn the EEA, for case reports where an age was provided, 30% of errors occurred in the elderly (over 64 years of age), 52% were in the age category 18–64 years, and 18% occurred in children (<17 years of age), with almost half of these in the age category 2 months to 2 years.\n\nDiscussion\nOur study demonstrates that reporting of cases of medication errors has been steadily increasing between 2005 and 2015, both in absolute numbers and proportion to all other case reports in EudraVigilance. The observed reporting trends may be explained by multiple factors. First, there have been significant transformations to the MedDRA® hierarchy since 2005, expanding from a single term for medication error, to a fully conceptual approach, to coding a broad range of medication errors, including coding examples and a clear distinction from product quality issues. Relevant guidance for MedDRA® coders [10] was updated accordingly, which may have contributed to more accurate coding of ADR reports associated with medication errors, where previously the error may have just been mentioned in the free-text narrative. Secondly, stakeholder awareness of the need to code medication errors in ADR reports for pharmacovigilance purposes has increased, which appears to be substantiated by the 2005 peak in reporting of both narrow and broad SMQ terms (Fig. 3). However, the 2005 peak is not seen for non-EEA cases (Fig. 4), and it is also known that EEA reporting trends generally peaked in 2005 after the EU enlargement and after mandatory electronic ADR reporting to EudraVigilance coming into effect. Another reporting peak in 2012 (Fig. 4), for EEA cases only, may be explained by the ADR definition of the 2012 pharmacovigilance legislation explicitly including medication errors. Alternatively, actual error rates may have increased as new medicinal products in the same indications, but different strengths or formulations compared with established treatment options, became available (e.g. novel high-strength insulin products or fixed-combination insulin products), or due to more medicines with complex methods of use (e.g. requiring drug delivery devices).Fig. 4 Proportion of medication error ICSRs retrieved with the narrow SMQ to the total number of ICSRs reported to EudraVigilance between 2002 and 2015 with EEA and non-EEA origin. ICSRs individual case safety reports, SMQ Standardised MedDRA® Query, EEA European Economic Area, MedDRA\n® Medical Dictionary for Regulatory Activities\n\n\n\n\nThe results of our study serve as a baseline to further evaluate the impact of the changes in regulatory requirements for medication errors and the GPG recommendations, including a reference for future trends with a potential to prevent errors for the benefit of public health, as shown by the ATC codes with the highest medication error rates reported in Table 1.\n\nThe reporting incidence of specific MedDRA® PTs requires careful interpretation. As shown in Fig. 5, the most frequently reported PT is ‘Medication error’, and, considering the gradual expansion of the terminology described earlier, this observation may be attributable to cases reported at the time when only this single term was available. Changing reporting practices and refined coding concepts also need to be taken into account. For example, in the EEA, the frequently reported PT ‘Inappropriate schedule of drug administration’ refers predominantly to non-reportable case reports formally sent as expedited spontaneous cases to EudraVigilance instead of ‘PSUR-type’ cases. Despite medication errors without adverse reaction(s) not being reportable to EudraVigilance, approximately 7% of the retrieved case reports have no adverse reaction included, although we did not perform an assessment of the report quality. The quality of coding is monitored as part of the data quality checking procedures referred to in the guideline on GVP Module VI [3].Fig. 5 Top 20 reported MedDRA® Preferred Terms from the narrow Standardised MedDRA® Query in Individual Case Safety Reports with European Economic Area origin (n = 25,865). MedDRA\n® Medical Dictionary for Regulatory Activities\n\n\n\n\nThe distribution of medication error reports across geographical regions is shown in Fig. 6. The interpretation needs to take into account different regional pharmacovigilance practices and reporting requirements for medication errors that are likely to follow general ADR reporting trends in these ICH regions. Although the focus of this study is on European data, the African cases are noteworthy given a fairly high proportion of 2.23% of all reported cases are medication errors, but overall reporting is significantly lower compared with other regions, and different types of errors predominate compared with global patterns. Preparation and storage errors are most frequent in Middle Africa, whereas in Eastern Africa labelled interactions (monitoring errors) dominate. A survey in Nigeria [11] concluded that the prevalence of medication errors is high among healthcare professionals due to knowledge gaps and practice deficiencies that require interventions.Fig. 6 Distribution of medication error Individual Case Safety Reports with narrow Standardised MedDRA® Query by geographic region (n = 88,318), at 31 December 2015. MedDRA\n® Medical Dictionary for Regulatory Activities\n\n\n\n\nThe breakdown in Western, Eastern, Northern and Southern Europe follows reporting trends in EudraVigilance as a whole, where ADR reporting is generally higher in Western Europe given the higher population numbers and longer duration of EU/EEA membership. However, adjustment for population size still indicates a wide variance in reporting rates across EU Member States during the most recent reporting period.\n\nAn analysis of age categories associated with medication errors is expected to show higher rates in the elderly or in children compared with the general population, but differences from general ADR reporting trends in these populations warrant further research, including, for particular products, increasing the risk of errors, e.g. vaccines for infants or commonly co-prescribed medicines in the elderly.\n\nTable 1 shows the ranking of medication errors by ATC code. For therapeutic classes such as analgesics, psycholeptics and antidiabetics, ranking among the top 10 most error-prone medicines would be expected, but not for other therapeutic classes. The fact that medication errors with vaccines rank top for EEA data should be interpreted with caution. The reporting patterns for vaccines are largely similar for EEA and non-EEA cases, with ‘Inappropriate schedule of drug administration’ most frequently reported, followed by ‘Incorrect route of drug administration’ and ‘Drug administered to patient of inappropriate age’. It appears that ‘Expired product administered’ and ‘Incomplete course of vaccination’ are reported more frequently in the EEA, although further analysis is required as this classification is based on the ATC code, where it may not always have been provided in the medicinal product dictionary. Any differences in EEA and non-EEA reporting of vaccine cases may have various explanations, e.g. vaccination uptake and reporting programmes are different across the Member States in the EEA, and different compared with the rest of the world. It is challenging to compare data from the EEA with non-EEA as the drug utilisation patterns vary. In addition, miscoding and incorrectly reported cases need to be taken into account.\n\nThe high numbers of case reports of ‘Drug administration error’ with cisapride are noteworthy in the context of signal detection and assessment of medication error reports. Measures of disproportionality of reporting to detect safety signals in EudraVigilance are not applicable to medication errors and alternative methods such as root cause analysis are warranted to assess the causes and circumstances in clinical practice. Most of the administration errors reported for cisapride were litigation cases in relation to QT prolongation, where, in addition to QT prolongation, a term referring to medication errors had been coded, implying liability aspects. The potential for litigation cases to skew data sets for signal detection purposes is recognised and proposals were made to exclude these cases from analyses [12] which may be particularly relevant for medication errors.\n\nAnother example is the high number of case reports with ‘Incorrect dose administered’ for rivaroxaban, which is marketed in different dosing schedules for different indications, including loading and maintenance doses for one indication and the need for dose adjustment in patients with renal impairment. In some case reports the dose had been adjusted when it should not have been, or vice versa, and in some cases patients had taken the wrong dose. We also found mixed approaches to coding, with some cases misclassified as off-label use or misuse, and this product is a good example for a potential error due to complicated dosing schedules. To adequately manage the risk of medication errors with rivaroxaban, a prescriber guide and patient alert card have been introduced to ensure correct administration, and these measures were also subject to effectiveness evaluation.\n\nWe did not assess whether individual case reports were truly medication errors or potentially miscoded, and no analysis of the root causes or associated harms could be performed given the large amount of data. In the context of routine EU pharmacovigilance activities for medication errors included in this review, regulatory actions may have been taken as appropriate, either at a national or EU level. Pharmacovigilance Risk Assessment Committee (PRAC) recommendations for any additional measures to prevent medication errors for centrally authorised medicines are regularly published on the EMA website to raise awareness among patients, carers and healthcare professionals [13]; however, the long-term impact of the GPG on pharmacovigilance, regulatory decision making and error-prevention strategies remains to be further investigated.\n\nConclusions\nReporting of medication errors has increased over the analysis period 2002 to end 2015. The release of the MedDRA® SMQ for medication errors has been an important milestone to improve the detection and retrieval of medication errors in EudraVigilance. In Europe, the number of reports have steadily increased since 2008, with a peak around 2012. Several factors could be responsible for this increase: expanded MedDRA® terminology and guidance; increased awareness of the need to report medication errors for pharmacovigilance purposes; and the public consultation and release of EU guidance on coding, recoding, reporting and assessment of medication errors, and the guidance on risk minimisation and prevention of medication errors. In addition, in 2015 the EMA launched a dedicated webpage to communicate to patients and healthcare professionals, as well as the general public, important risk minimisation activities in relation to medication errors for centrally authorised medicinal products. The synergy of these initiatives at EU regulatory level, and globally at ICH level, seem likely to have contributed to this increase and also to the granularity of coding of medication error reports associated with adverse reactions to EudraVigilance. Besides these likely effects, there is a possibility that actual error rates have increased as more generic medicines are launched, and novel medicines with increasingly complex instructions for use. This study is intended to provide a baseline for the reporting of medication errors to EudraVigilance. The impact of the GPG on the pharmacovigilance of medication errors and data quality to allow for complementary analysis (e.g. of the root causes) remain to be further explored.\n\n1 Pharmaceutical companies that hold the marketing authorisation of a medicine, as well as national medicines regulatory authorities, are legally required to submit reports of suspected side effects that occurred in the EEA to EudraVigilance, including reports received from healthcare professionals and patients. Pharmaceutical companies that hold the marketing authorisation for a medicine in the EEA are also legally required to submit to EudraVigilance all reports of suspected unexpected adverse reactions that are serious and that occurred in a third country (non-EEA) where they hold a marketing authorisation.\n\n2 MedDRA®, the Medical Dictionary for Regulatory Activities, is the international medical terminology developed under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The MedDRA® trademark is owned by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) on behalf of the ICH.\n\nThe original version of this article was revised due to a retrospective Open Access Order.\n\nA correction to this article is available online at https://doi.org/10.1007/s40264-018-0700-0.\n\nA correction to this article is available online at https://doi.org/10.1007/s40264-017-0609-z.\n\nChange history\n\n7/20/2018\n\nIn the original publication of the article, the trend line for non-EEA cases in figure 4 is incorrect. In this correction, the original Fig. 4 (Fig. 1) and the correct Fig. 4 (Fig. 2) are published.\n\nChange history\n\n11/7/2017\n\nCorrection to: Drug Saf DOI 10.1007/s40264-017-0569-3.\n\nCompliance with Ethical Standards\nFunding\nNo sources of funding were used to assist in the preparation of this article.\n\nConflicts of interest\nVictoria Newbould, Steven Le Meur, Thomas Goedecke and Xavier Kurz have no conflicts of interest that are directly relevant to the content of this study.\n\nDisclaimer\nThe views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the EMA or one of its committees or working parties.\n==== Refs\nReferences\n1. Union European Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use OJ. 2001 44 L311 67 128 \n2. Pharmacovigilance Risk Assessment Committee. Good practice guide on recording, coding, reporting and assessment of medication errors (EMA/762563/2014). http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2015/11/WC500196979.pdf (2015). Accessed 15 Jun 2017.\n3. European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) Module VI—management and reporting of adverse reactions to medicinal products (Rev 1) (EMA/873138/2011 Rev 1). http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/09/WC500172402.pdf (2014). Accessed 15 Jun 2017.\n4. Goedecke T Ord K Newbould V Brosch S Arlett P Medication errors: new EU good practice guide on risk minimisation and error prevention Drug Saf 2016 39 6 491 500 10.1007/s40264-016-0410-4 26940903 \n5. E2B(R3) Individual Case Safety Report (ICSR). Specification and related files. http://estri.ich.org/e2br3/index.htm. Accessed 19 Jun 2017.\n6. International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Medical dictionary for regulatory activities (MedDRA®). Standardised MedDRA® Queries. http://www.meddra.org/standardised-meddra-queries (2016). Accessed 15 Jun 2017.\n7. Development and rational use of Standardised MedDRA Queries (SMQs): retrieving adverse drug reactions with MedDRA. 2nd ed. Geneva: Council for International Organisations of Medical Sciences (CIOMS); 2016.\n8. Committee for Medicinal Products for Human Use. CHMP guideline on detection and management of duplicate individual cases and Individual Case Safety Reports (ICSRs) (EMA/13432/2009). http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/06/WC500129037.pdf (2009). Accessed 15 Jun 2017.\n9. United Nations Statistics Division. Composition of macro geographical (continental) regions, geographical sub-regions, and selected economic and other groupings. http://unstats.un.org/unsd/methods/m49/m49regin.htm (2017). Accessed 15 Jun 2017.\n10. International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). MedDRA® Term selection: points to consider. ICH-endorsed guide for MedDRA® Users. Release 4.12 based on MedDRA® Version 19.1. http://www.meddra.org/sites/default/files/guidance/file/9491-1910_termselptc_r4_12_sep2016.pdf (2016). Accessed 15 Jun 2017.\n11. Ogunleye O Oreagba IA Falade C Isah A Enwere O Olayemi S Medication errors among health professionals in Nigeria: a national survey Int J Risk Saf Med. 2016 28 2 77 91 10.3233/JRS-160721 27567765 \n12. European Medicines Agency. Screening for adverse reactions in EudraVigilance (EMA/849944/2016). http://www.ema.europa.eu/docs/en_GB/document_library/Other/2016/12/WC500218606.pdf (2016). Accessed 15 Jun 2017.\n13. European Medicines Agency. Recommendations on medication errors. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000398.jsp&mid=WC0b01ac058098f1c0 (2016). Accessed 15 Jun 2017.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0114-5916",
"issue": "40(12)",
"journal": "Drug safety",
"keywords": null,
"medline_ta": "Drug Saf",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000367:Age Factors; D000368:Aged; D002648:Child; D002675:Child, Preschool; D005060:Europe; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008508:Medication Errors; D008875:Middle Aged; D060735:Pharmacovigilance; D055815:Young Adult",
"nlm_unique_id": "9002928",
"other_id": null,
"pages": "1241-1248",
"pmc": null,
"pmid": "28698988",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": "26940903;27567765",
"title": "Medication Errors: A Characterisation of Spontaneously Reported Cases in EudraVigilance.",
"title_normalized": "medication errors a characterisation of spontaneously reported cases in eudravigilance"
} | [
{
"companynumb": "GB-JNJFOC-20171219992",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISAPRIDE"
},
"drugadditional": "3",
"d... |
{
"abstract": "Thrombotic microangiopathies are rare diseases characterized by an initial endothelial injury and the formation of thrombi in the microcirculation. Several types of thrombotic microangiopathies can be distinguished: the thrombotic thrombocytopenic purpura; the hemolytic and uremic syndrome, mainly \"typical\" following a shiga toxin-producing Escherichia coli infection or \"atypical\" due to a dysregulation of the alternative complement pathway; and \"secondary\" thrombotic microangiopathies. The use of drug treatments is reported as a frequent cause in this last category and requires stopping the offending drug. We report the case of a patient who developed \"secondary\" hemolytic and uremic syndrome associated with carfilzomib, a proteasome inhibitor which is used in case of multiple myeloma relapses. Besides stopping the treatment, the patient still showed signs of hemolysis and renal failure with anuria requiring hemodialysis. An eculizumab treatment was therefore initiated. The overall evolution was favorable and an improvement of the renal function promptly allowed the discontinuation of hemodialysis. We discuss the mechanisms that may activate the alternative complement pathway and the potential interest of a transient use of eculizumab in case of carfilzomib-induced hemolytic and uremic syndrome.",
"affiliations": "Service de néphrologie-dialyse, centre hospitalier Métropole Savoie, place Lucien Biset, 73000 Chambéry, France. Electronic address: casiez_catherine@live.fr.;Service d'hématologie, centre hospitalier Métropole Savoie, place Lucien Biset, 73000 Chambéry, France.;Service de néphrologie-dialyse, centre hospitalier Métropole Savoie, place Lucien Biset, 73000 Chambéry, France.",
"authors": "Casiez|Catherine|C|;Pica|Gian Matteo|GM|;Bally|Stéphane|S|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D009842:Oligopeptides; C524865:carfilzomib; C481642:eculizumab",
"country": "France",
"delete": false,
"doi": "10.1016/j.nephro.2020.03.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1769-7255",
"issue": "16(4)",
"journal": "Nephrologie & therapeutique",
"keywords": "Carfilzomib; Eculizumab; Hemolytic-uremic syndrome; Inhibiteurs du protéasome; Microangiopathies thrombotiques; Proteasome inhibitors; Syndrome hémolytique et urémique; Thrombotic microangiopathy",
"medline_ta": "Nephrol Ther",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D006463:Hemolytic-Uremic Syndrome; D006801:Humans; D008297:Male; D009842:Oligopeptides; D012074:Remission Induction",
"nlm_unique_id": "101248950",
"other_id": null,
"pages": "221-224",
"pmc": null,
"pmid": "32571738",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Carfilzomib-induced haemolytic and uremic syndrome: Favorable outcome with eculizumab.",
"title_normalized": "carfilzomib induced haemolytic and uremic syndrome favorable outcome with eculizumab"
} | [
{
"companynumb": "FR-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-331813",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drug... |
{
"abstract": "In this report, we present an unusual case of jaundice in a patient with advanced colorectal cancer due to intraductal tumour invasion of the intra- and extrahepatic biliary tree. This complication proved to be fatal despite aggressive therapeutic management. A correct diagnosis of this type of involvement was achieved by a combination of diagnostic and therapeutic cholangiography. Despite adequate biliary decompression, the patient died from liver failure and biliary sepsis.",
"affiliations": "Attendig Oncologist, Clinical Oncology Department, Hospital Universitario Montepríncipe , Boadilla Del Monte, Madrid, Spain .;Resident, Department of Radiology, University of Illinois at Chicago Hospital , Chicago, Illinois, USA .;Attending Radiologist, Department of Radiology, Hospital Universitario Montepríncipe , Boadilla Del Monte, Madrid, Spain .;Attending Gastroenterologist, Department of Gastrointestinal, Hospital Universitario Montepríncipe , Boadilla Del Monte, Madrid, Spain .;Department of Pathology, Hospital Universitario Montepríncipe , Boadilla Del Monte, Madrid, Spain .",
"authors": "Rodriguez-Pascual|Jesus|J|;Abbitt|Michael Tyler B|MT|;Fernádez|Marisol|M|;Camuñez|Fernando|F|;Pérez-Rodríguez|Francisco José|FJ|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2016/16951.7681",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-709X",
"issue": "10(4)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Colorectal cancer; Contrast enhanced computed tomography; Intrabiliary metastases",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "XD04-XD05",
"pmc": null,
"pmid": "27190935",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports",
"references": "19294464;15144404;10568181;23797727;10613721;9298879;6280834;25818370;7826164;24059396;26293132;12366810",
"title": "Massive Intrabile Duct Invasion Caused by a Fatal Progression of Colonic Adenocarcinoma: Abdominal Computed Tomography Findings and Cholangiography Correlation.",
"title_normalized": "massive intrabile duct invasion caused by a fatal progression of colonic adenocarcinoma abdominal computed tomography findings and cholangiography correlation"
} | [
{
"companynumb": "ES-ACCORD-040961",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
"dr... |
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