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What was the outcome of reaction 'Erythema'? | Dermatological manifestations during COVID-19 infection: a case series and discussion on the problem of differential diagnosis.
On March 11, 2019 the World Health Organization (WHO) declared Coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, as a pandemic. As of 15/01/2021, more than ninety million cases of infections have been confirmed, with almost two million related deaths. SARS-CoV-2 causes bilateral interstitial pneumonia, which can responsible of respiratory failure in the most severe cases, but the virus has also a wide range of other manifestations, including gastrointestinal, cardiovascular, neurological, and cutaneous signs and symptoms. Cutaneous manifestations are an important matter of study for allergy specialists, as they can be specific signs of the infection, but also manifestations of adverse reactions to the medical therapy in use. In this case series, we report four different cases of dermatological manifestations in COVID patients, two in hospitalised patients and two in patients with mild disease, treated at home. The first case reported is a woman, who develops urticaria while being treated at home with mild COVID-infection; the second and the third one case reported are drug- hypersensivity reaction to remdesevir and low molecular weight heparin. The last case reported is a man with mild covid with vasculitic sacral lesions. Key words: COVID pandemic, SARS-CoV-2, dermatological manifestation in covid infections, remdesevir hypersensitivity, covid and urticaria, covid and vasculitic lesions.
Introduction
On March 11, 2019 the World Health Organization (WHO) declared Coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, as a pandemic. Until 15/01/2021, more than ninety million cases of infections have been confirmed, with almost two millions related deaths (1).
SARS-CoV-2, a novel coronavirus first reported in December 2019 in the city of Wuhan in the Hubei province of China (2), infects human cells through the bond of its surface protein, the so-called spike (S) protein, to the angiotensin-converting enzyme 2 (ACE2), a transmembrane protein expressed mainly by the lung type II alveolar cells, but also by other cellular lines like endothelial cells, small intestinal epithelial cells and nasal epithelia(3).
Clinical features of SARS-CoV-2 infections are extremely variable: some patients can remain completely asymptomatic or have a fever for a few days, in some cases associated with the characteristic feature of anosmia and ageusia (loss of smell and taste), while others could develop interstitial pneumonia, ranging from mild to severe grade, requiring oxygen-therapy or mechanical ventilation.
While the initial reports of the infections did not mention COVID-related dermatologic manifestations or defined them as very rare, more recent studies defined the incidence of these manifestation between 5 and 20%(4, 5).
The most characteristic are the vasculitic lesions, such as chill-blade like lesions on hands and foots, livedo reticularis and truncal or acral petechiae or purpura; less common are the reports of urticaria, maculopapular erythema and vesicular eruption (6, 7).
Urticaria accounts for almost 20% of the dermatologic manifestations of COVID-19, and affects patients with respiratory involvement as patients with no pulmonary symptoms; it usually appears at the same time as the other symptoms, but it can also be later, while less frequently is the onset symptom of the infection. It usually affects the trunk eventually in association with arms and legs, while the head, hands and feet are commonly spared (8).
Maculopapular rash represent over 40% of cutaneous manifestations in COVID-19 patients; the erythematous lesions, which sometimes flows into larger erythematous patches, are usually located in the trunk and limbs, usually sparing palmoplantar skin and mucosa. This condition is commonly associated with a more severe course of the disease (8).
Vesicular rash, accounting for less than 10% of COVID-19 manifestations, tend to appear in the early stages of the infection, sometimes before all the other symptoms. The typical lesions, affecting mainly the trunk and the limbs, are monomorphic and can have haemorrhagic content. It seems to be associated with intermedium severity of the disease (8).
While vasculitic manifestations are caused by the pro-thrombotic effects of the viral infection, remains to be clarified how the virus can cause the other cutaneous manifestations. It is known that any viral infections can be a trigger for urticarial (9), but in the case of COVID-19 the immune upregulation, typical of this infection, could lead to an aberrant activation and degranulation of the dormant mast cells caused by the activated complement system and the altered cytokine-chemokine activity.
As of today, none of the dermatological manifestations of COVID has a specific treatment; they seem to respond well to steroid therapy, which has become one of the main treatment in COVID patients, and for urticaria the response the antihistamine therapy is similar to other causes of urticarial (10, 11).
Since all of the mentioned manifestations can develop before, in conjunction or after the beginning of the respiratory symptoms and possibly after the administration of medical therapy, a differential diagnosis between dermatological manifestation of COVID-19 and adverse reaction to drugs must be evaluated.
In this case series we report four different cases of dermatological manifestations in COVID patients, two in hospitalised patients, and the other in patients with mild disease, treated at home.
First case
A woman with fever, asthenia and cough for three days, subsequently developing anosmia and ageusia. The general practitioner (GP) prescribed COVID swab, which resulted positive. Because the symptoms were mild and the peripheral saturation was steadily over 95-96%, the GP started at home therapy with paracetamol and low molecular weight heparin. A couple of days later, as the woman reported feeling of shortness of breath, steroid therapy with methylprednisolone was prescribed. After four days of steroid therapy the fever was gone, and the dyspnea had improved, but the woman called the GP, reporting acute onset of urticaria, with itching hives on the belly and the back. The GP replaced methylprednisolone with prednisone, deeming urticaria as an allergic reaction to the steroid therapy. After a couple of days of antihistamine therapy, the woman reported complete resolution of urticaria, which eventually relapsed after a couple of days, urticaria, this time affecting all over the trunk, arms and legs. The GP did not change the medications, carrying on the steroid therapy and prescribing a longer antihistamine therapy, which was enough to treat the acute presentation of urticaria without another relapse. After a total of twelve days since the beginning of the therapy, the women was apyretic and regained the sense of taste; after three weeks the COVID swab became negative. The antihistamine therapy was suspended after a total of two consecutive weeks, with no subsequent episodes of urticaria.
Figure 1. Hives during the first day of urticaria
Figure 2 and 3. Hives during the relapse of urticaria
Figure 4. Maculopapular rash after one hour of remdersivir administration.
Figure 5. Maculopapular rash the day after.
Second case
Allergological consultation was requested for a man hospitalized for bilateral interstitial pneumonia COVID-related, with moderate acute respiratory distress syndrome (PaO2/FiO2 < 200 mmHg), treated HFNOT (high-flow nasal oxygen therapy).
The patient was obese, smoker and suffering from arterial hypertension. After two days of therapy with dexamethasone 6 mg/die and low molecular weight heparin with no improvement in the PaO2/FiO2 ratio, antiviral therapy with remdesevir was started. One hour after the administration of the first dose of the drug, he developed an itching maculo-papular rash under the neck, which later expanded on the upper trunk. Subsequent blood test revealed no eosinophilia nor elevated tryptase; the consultant decided to withdraw remdesevir therapy and prescribed antihistamine therapy with intramuscular chlorphenamine, continuing steroid and LMWH therapy. The rash did not expand further, and disappeared in the subsequent days.
Third case
A woman, overweight, smoker and suffering from diabetes was hospitalized with a diagnosis of bilateral interstitial pneumonia with severe respiratory failure, initially treated with HFNOT and then with c-PAP. Initial medical therapy included azithromycin, lopinavir/ritonavir and LMWH, followed by tocilizumab. During the 35th day of hospitalization, the patient developed a fixed erythema on the trunk and the limbs; since antiviral and the anti-IL6 mAb have been suspended from more than ten days, the reaction was attributed to enoxaparin. The doctors decided to stop the treatment with enoxaparin, replacing it with fondaparinux, as the patient had important thrombotic risk factor. A brief course of methylprednisolone 40 mg/die was done, with subsequent resolution of the rash in the course of a few days.
Figure 6 and 7. Fixed erythema on the trunk and belly.
Fourth case
Man, 45 years of age, overweight (99 kg), non-smoker, with a positive COVID-19 swab, with episodes of dyspnea and desaturation (91-92%). The man was treated at home after refusal of hospitalization, with steroid therapy (desamethasone 6 mg/die), azithromycin 500 mg/die and LMWH (enoxaparin 6000 UI/die).
After twelve days since the diagnosis of SARS-CoV-2 infection, the man developed sacral vasculitic lesions, without pain or itching; as the respiratory symptoms was improving and no other vasculitic lesion were found, the general practitioner decided not to modify the treatment. After an initial increase in the extension of the lesion, in two weeks the doctor observed a complete spontaneous resolution.
Figure 8. Sacral vasculitic manifestations.
Discussion and conclusions
Dermatological and allergic manifestation during COVID-19 infection are not very common, but not as rare as the first studies have reported. As of today, the presence of dermatological manifestations of COVID-19 has not been related to more severe disease or has been defined as a clinical subtype of the disease.
Vascular and thrombotic lesion are more characteristic of the SARS-CoV-2 infection and they are more easily recognisable, but the early use of heparin in hospitalized patient and in patients treated at home with known risk factors for thrombotic events may have lowered their global frequency since the initial reports. In the case of our patient, it is possible that the daily dose of heparin was too low to prevent the development of thrombotic lesions.
Less typical cutaneous rash, such as urticarial, vesicular or maculo-papular rash, can also appear in these patients, in some cases associated with more common symptoms, such as cough, dyspnea and fever, but also as one of the main features of the infection, in patients without respiratory symptoms. In these time of pandemic is therefore important for clinicians to be familiar with these cutaneous manifestations and, in regards to urticaria, to evaluate unusual cases of acute onset in subjects without previous history of urticaria, as it can be the first symptom of the infection. An early diagnosis is important not only for a timely treatment of the patients, but also to limit the viral spread. In these patients urticaria is as important to be properly treated as the other symptoms, as it can be bothersome or cause of concern. As the response to antihistamine therapy is good, a normal route of antihistamine therapy is always recommended as these drugs are usually well tolerated, while in patients with concomitant respiratory symptoms, a brief cycle of steroid therapy can have a positive impact on the cutaneous manifestation as on the respiratory ones. These patients have to be re-evaluated in the long term after the infection’s resolution, to define any cases of chronic urticaria if the symptoms last longer than six weeks.
It is also important to keep in mind that in COVID patients multiple drugs are often used in the same time. They include antibiotics, usually azithromycin or a beta-lactam, associated with low molecular weight heparin, sometimes with concomitant steroid therapy and/or an antiviral drug and eventually with monoclonal antibodies. In case of an adverse dermatological reaction, is therefore important the presence of an allergy consultant, not only to treat the acute cutaneous manifestation, but also to define a follow up path to complete the eventual diagnosis of drug hypersensitivity; in the case we reported of fixed erythema associated to enoxaparin, the woman was referred to allergist consultation to better defined the diagnosis of drug hypersensitivity.
Conflict of Interest:
Each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article | Recovered | ReactionOutcome | CC BY-NC-SA | 33682815 | 19,169,148 | 2021-02-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Basal cell carcinoma'. | A phase Ib, open label, dose escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia.
BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a transmembrane protein expressed on normal and malignant B cells. This open-label, phase Ib, dose-escalation study was conducted to determine the recommended phase II dose (RP2D) of BI 836826 + ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Eligible patients received 420 mg/day of ibrutinib with escalating doses of BI 836826. BI 836826 was administered in 4-week cycles. After Cycle 12, patients achieving complete response (CR), CR with incomplete marrow recovery, or minimal residual disease-negative partial response could continue to receive BI 836826 + ibrutinib every 4 weeks for ≤ 12 additional cycles. Patients received either 100 mg (n = 3) or 200 mg (n = 3) BI 836826 + ibrutinib. In the 100 mg BI 836826 cohort, one patient received two cycles and two patients received 22 cycles of BI 836826. In the 200 mg BI 836826 cohort, patients received 12, 16 and 20 cycles of BI 836826, respectively. All patients discontinued BI 836826 and continued ibrutinib outside the trial. No dose-limiting toxicities were reported in the maximum tolerated dose (MTD) evaluation period. As the trial was discontinued before the MTD was reached, the RP2D was not determined. Grade 3/4 adverse events (AEs) were predominantly hematological. Pseudomonal bacteremia was the only drug-related AE of special interest. BI 836826 + ibrutinib did not exceed the MTD at doses up to 200 mg in patients with CLL. However, RP2D and MTD were not formally established, as the sponsor discontinued the trial.
Introduction
The Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, is well established in the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia (CLL) [1–3]. While ibrutinib monotherapy is associated with impressive response rates in CLL patients, including those with del(17p) [1, 4], deep responses are rare, thus necessitating continuous use. This can result in cumulative toxicities, leading to treatment discontinuation [5]. Furthermore, patients often become resistant to long-term treatment, potentially leading to disease progression or transformation [6]. Therefore, there is clinical rationale for combining ibrutinib with other agents that could increase depth of response and delay development of resistance.
Preclinical and clinical studies have demonstrated that CD37, a tetraspanin B cell surface molecule, is a potential drug target in patients with CLL [7–10].
BI 836826 is a chimeric mouse–human anti-CD37 monoclonal antibody engineered to enhance binding and effector function that mediates direct antibody-dependent cell-mediated cytotoxicity (ADCC) against CLL cells [11]. A phase I, dose escalation study of BI 836826 in patients with relapsed/refractory CLL demonstrated acceptable tolerability and notable efficacy, particularly in patients with poor-risk features such as del(17p) and TP53 mutations [12]. In this phase Ib, dose-escalation study, we investigated the combination of ibrutinib and BI 836826 in patients with relapsed/refractory CLL.
Patients and methods
Patients
Eligible patients were ≤ 18 years old with relapsed/refractory CLL according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria [13]. All patients had received at least one prior line of systemic treatment. Prior BTK inhibitors were not allowed. Other eligibility criteria included Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0–2; clinically quantifiable disease burden (absolute lymphocyte count > 10,000/µL, measurable lymphadenopathy, or quantifiable bone marrow infiltration); adequate organ function; and residual non-hematological toxicity from prior treatment of grade ≤ 1.
Key exclusion criteria were: any CD37-targeting antibody or CD37 antibody-drug conjugate; allogeneic stem cell transplant within 1 year or active graft-versus-host disease; known transformation of CLL to an aggressive B-cell malignancy at the time of screening; history of non-CLL malignancy except for adequately treated in-situ, stage I or II carcinoma in complete response (CR) or any other cancer that had been in CR for ≥ 2 years after the end of cancer treatment; and active uncontrolled autoimmune cytopenia.
The trial was carried out in accordance with the Declaration of Helsinki, Good Clinical Practice Guidelines, applicable regulatory requirements and Boehringer Ingelheim standard operating procedures. The study protocol was approved by the Institutional Review Boards of all participating institutions. Written informed consent was obtained from all patients.
Study design and treatment
The primary objectives of this single arm, open-label, dose escalation phase Ib study were to determine the recommended phase II dose (RP2D) of BI 836826 plus ibrutinib in patients with relapsed/refractory CLL, and the number of patients with dose-limiting toxicities (DLTs) during the maximum tolerated dose (MTD) evaluation period (Cycle 1). Other objectives were the determination of the MTD, safety and efficacy of the combination.
Eligible patients underwent a two-week run-in phase with ibrutinib and remained on ibrutinib throughout the trial at a constant dose of 420 mg daily. BI 836826 was planned at dose levels of 100, 200, 400, 600, 800 and 1400 mg. Mandatory pre-medication (antihistamine, analgesic and glucocorticoid) to mitigate the risk of infusion-related reactions (IRRs) was given 30–120 min prior to BI 836826 administration. BI 836826 was then administered via rate-controlled intravenous infusion in Cycle 1 as a 10 mg dose on Day 1, on Days 2 and 8 at 50% of the assigned dose on each day, and on Day 15 at 100% of the assigned dose. In Cycles 2–4, BI 836826 was administered at the assigned dose on Days 1 and 15 of each cycle. In Cycles 5–12, BI 836826 was administered at the assigned dose on Day 1 only. BI 836826 was administered in 4-week cycles. At the end of Cycle 12, bone marrow biopsies were performed to evaluate response. Patients with a CR, CR with incomplete marrow recovery (CRi), or minimal residual disease (MRD)-negative partial response (PR) could choose to receive 12 additional treatment cycles of the combination. Following completion of 12 or 24 cycles, or discontinuation due to disease progression, unacceptable toxicity, or withdrawal of consent, patients could continue to receive ibrutinib outside of the study at the discretion of the treating investigator.
Study assessments
Safety was assessed by determining the incidence and severity of adverse events, graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Assessment of laboratory parameters, vital signs, physical examination and ECG was also undertaken. DLTs were defined as: any non-hematologic adverse event of grade ≥ 3 related to BI 836826 or ibrutinib, except IRRs and grade 3 alanine aminotransferase and/or aspartate aminotransferase elevation without concomitant bilirubin elevation or any other asymptomatic grade 3 laboratory abnormality with spontaneous recovery within 1 week; hematologic adverse events related to BI 836826 or ibrutinib including grade 4 neutropenia with concomitant infection; grade 4 febrile neutropenia, and grade 3 febrile neutropenia not resolving within 72 hours; grade 4 thrombocytopenia with clinically significant bleeding; grade 4 anemia; any grade 5 hematologic adverse event. Adverse events of special interest (AESIs) included DLTs, infusion-related reactions of grade ≥ 3, late-onset infections, events indicative of drug-induced liver injury, and tumor lysis syndrome. Adverse events consistent with the definition of a DLT but occurring after the MTD evaluation period were also considered AESIs.
Overall response, duration of response, MRD and reduction in size of tumor lymph nodes were exploratory endpoints. Overall response was defined as patients who achieved CR, CRi, PR or PR with lymphocytosis (PR-L) according to modified IWCLL guidelines [13]. MRD was evaluated in both blood and bone marrow samples and was defined as < 1 leukemic cell per 10,000 leukocytes detected by multi-parameter flow cytometry.
Statistical methods
All analyses were descriptive and exploratory. No formal statistical analysis was conducted. Dose escalation was guided by a Bayesian 5-parameter logistic regression model (BLRM) with overdose control [14, 15] that was fitted to binary toxicity outcomes.
Results
Patients and treatment exposure
Between July 7, 2016 and July 9, 2019, 10 patients were screened, of whom 7 entered the run-in period with ibrutinib. Six patients were treated with BI 836826 plus ibrutinib across three sites in the United States (100 mg BI 836826: n = 3; 200 mg BI 836826: n = 3). The median age among treated patients was 71.0 years (range 57–76 years); all patients were Caucasian (Table 1).
Table 1 Patient demographics
BI 836826 dosea
100 mg
(n = 3) 200 mg
(n = 3) Total
(N = 6)
Male, n (%) 1 (33) 2 (67) 3 (50)
Race, n (%)
White 3 (100) 3 (100) 6 (100)
Ethnicity, n (%)
Not Hispanic/Latino 2 (67) 3 (100) 5 (83)
Hispanic/Latino 1 (33) 0 1 (17)
Median age, years (range) 75.0 (68–76) 67.0 (57–74) 71.0 (57–76)
ECOG PS at baseline, n (%)
0 1 (33) 1 (33) 2 (33)
1 2 (67) 2 (67) 4 (67)
RAI stage at diagnosis, n (%)
0
I
II
III
IV
1 (33)
0
1 (33)
0
1 (33)
1 (33)
1 (33)
0
1 (33)
0
2 (33)
1 (17)
1 (17)
1 (17)
1 (17)
Mean time from first diagnosis, years (SD) 10.4 (4.9) 11.1 (5.1) 10.7 (4.5)
Median number of previous CLL therapies (range) 1 (1–1) 4 (1–5) 1 (1–5)
Status after prior treatment
Relapsed
Refractory
2 (67)
1 (33)
2 (67)
1 (33)
4 (67)
2 (33)
aGiven in combination with ibrutinib 420 mg/day
CLL chronic lymphocytic leukemia, ECOG PS Eastern Cooperative Oncology Group Performance Status, RAI staging system for CLL [16], SD standard deviation
In the 100 mg BI 836826 cohort, one patient received two cycles and two patients received 22 cycles of BI 836826. The patients in the 200 mg cohort received 12, 16 and 20 cycles of BI 836826, respectively. All six patients discontinued treatment with BI 836826 (disease progression, n = 1; investigator discretion, n = 3; lack of response by cycle 12, n = 2). Mean duration of BI 836826 exposure was 440.2 days. There were no dose reductions. Two patients in the 100 mg BI 836826 cohort had at least one important protocol deviation. Both patients continued treatment with BI 836826 beyond cycle 12 without having a CR, CRi, or MRD-negative PR. One of these patients did not receive pre-medication with glucocorticoid in Cycle 3, as required per protocol.
DLTs during the MTD evaluation period, MTD and RP2D
No DLTs were reported during the MTD evaluation period with 100 or 200 mg BI 836826. However, the trial was discontinued before patients were treated with 400 mg BI 836826, and the MTD and RP2D were therefore not determined.
Safety
All six patients had at least one adverse event that was considered by the investigator to be related to BI 836826. The most common BI 836826-related adverse events (any grade/grade ≥ 33) were IRR (67%/17%), neutropenia (50%/33%), anemia (33%/33%), lymphopenia (33%/33%) and fatigue (33%/0%; Table 2). All IRRs (ten in four patients) were grade ≤ 2 except for one grade 3 IRR. The majority of IRRs occurred within the first two cycles and were resolved within a day.
Table 2 Adverse events considered related to BI 836826 occurring in > 2 patients
Any-grade
n (%) Grade 3/4
n (%)
Infusion-related reactions 4 (67) 1 (17)
Neutropenia 3 (50) 2 (33)
Anemia 2 (33) 2 (33)
Lymphopenia 2 (33) 2 (33)
Fatigue 2 (33) 0
Five patients had serious adverse events (considered related to study drug in 4 patients), including neutropenia, acute coronary syndrome, cellulitis, pseudomonal bacteremia and Bowen’s disease. No serious adverse event was experienced by more than one patient. There were no fatal adverse events, and no dose reductions or permanent discontinuations of BI 836826 due to adverse events. One patient had an ibrutinib dose reduction due to grade 2 neutropenia. After the MTD evaluation period, two patients in the 200 mg cohort reported grade 3 DLTs: a duodenal ulcer occurring on Day 325 and pseudomonal bacteremia (considered as related to study drug) on Day 280.
Three AESIs were recorded: the two DLTs reported after the MTD evaluation period and grade 2 basal cell carcinoma (Day 622).
Based on laboratory data, grade 4 neutropenia was reported for two patients (one patient in each dose cohort). Neither episode was associated with a concomitant infection. One patient in the 100 mg dose cohort had an episode of grade 4 thrombocytopenia, which was not associated with concomitant bleeding. Two patients (one in each dose cohort) had an episode of grade ≥ 3 decreased CD4 + T-cell count but there were no concomitant CD4+-related specific infections.
Efficacy
Overall response rate was 83% among the 6 evaluable patients (one CR and four PRs; Table 3) The ORR in the 200 mg cohort was 100% (one CR, two PR). Of five patients who underwent peripheral blood-based MRD analysis, two were MRD-negative, one in each cohort including the patient who achieved CR. Three patients had bone marrow aspirate samples analyzed for MRD. None were MRD-negative but one patient developed MRD-negative CR a month after study completion.
Table 3 Best overall response in patients receiving BI 836826 plus ibrutinib
BI 836826 dose
Patients with response, n (%) 100 mg
n = 3 200 mg
n = 3 Total
N = 6
Overall response 2 (67) 3 (100) 5 (83)
CR 0 1 (33) 1 (17)
CRi 0 0 0
PR 2 (67) 2 (67) 4 (67)
PR-L 0 0 0
Stable disease
Progressive disease 1 (33) 0 1 (17)
CR complete response, CRi complete response with incomplete marrow recovery, OR overall response (CR + CRi + PR + PR-L), PR partial response; PR-L partial response with lymphocytosis
All five patients were censored for the analysis of duration of overall response since they had discontinued before progression or death was observed. Mean (standard deviation [SD]) duration of response was 538.0 (31.1) days and 312.0 (143.96) days in the 100 mg and 200 mg BI 836826 cohorts, respectively. The median best percentage change from baseline in the SPD of lymph nodes was -81.2% (range -84% to -51%) in the 100 mg dose group and -79.2% (range -92% to -59%) in the 200 mg dose group (Fig. 1). Tumor size was reduced in all six patients.Fig. 1 Maximum change in SPD of lymph node lesions at best response
Discussion
In this phase Ib, dose-escalation study of BI 836826 plus ibrutinib in patients with relapsed/refractory CLL, no DLTs were observed during the MTD evaluation period in either the 100 mg or 200 mg BI 836320 cohorts. Despite these promising findings, the sponsor took the strategic decision to discontinue the clinical development of BI 836826, due to the rapidly evolving CLL treatment landscape. Accordingly, the MTD was not reached and the RP2D was not determined. There were no safety reasons to terminate the program. Nevertheless, the results from this study suggest that BI 836826 can be safely combined with ibrutinib, with no apparent additive toxicity. Adverse events associated with the combination were consistent with previous clinical experience with BI 836826 [12] or ibrutinib monotherapy [4].
The efficacy of ibrutinib in relapsed/refractory CLL is well established [4, 17, 18], with an objective response rate of 63% observed in the phase III study, RESONATE [4]. Of note, overall response rate to ibrutinib generally deepens over time [17, 19], and had increased to 91% by the final analysis of RESONATE [2, 20]. Our preliminary findings (83% overall response rate) suggest that the addition of anti-CD37 agents to ibrutinib could potentially improve efficacy. While the sample size is limited, the promising efficacy of this combination especially at the 200 mg dose (100%), supports ongoing exploration of agents, including those that target CD37, for fixed-duration therapy in CLL.
A number of CD37-based therapeutics are currently undergoing investigation in CLL, including otlertuzumab, an anti-CD37 mono-specific ADAPTIR therapeutic protein [8]. Notably, in phase II studies, the addition of otlertuzumab to bendamustine greatly enhanced response compared with bendamustine alone in relapsed CLL patients [21]. Additionally, 212Pb-NNV003, a CD37-targeted radioimmunotherapy, has demonstrated notable anti-tumor effects in an animal model of CLL [22].
In conclusion, BI 836826 plus ibrutinib did not exceed the MTD at doses up to 200 mg in patients with CLL, and no DLTs were reported in the MTD evaluation period. While the RPTD and MTD were not formally established, our findings suggest that an anti-CD37 antibody may be combined with ibrutinib, or potentially other BTK inhibitors, for the treatment of relapsed/refractory CLL. Since continuous therapy with BTK inhibitors leads to toxicities, therapeutic resistance and is associated with high costs, exploration of novel combinations involving active agents with different therapeutic targets remains an unmet medical need.
Acknowledgements
We thank the patients, their families, and all the investigators who participated in these studies. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version.
Funding
The conduct of this research, study design, data collection, and analysis was financially supported by Boehringer Ingelheim. Medical writing assistance, funded by Boehringer Ingelheim, was provided by Lynn Pritchard, DPhil, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this manuscript.
Data availability
The clinical study report (including appendices, but without line listings) and other clinical documents related to this study may be accessed on request. Prior to providing access, the documents and data will be examined, and, if necessary, redacted and de-identified to protect the personal data of study participants and personnel, and to respect the boundaries of the informed consent of the study participants. See https://trials.boehringer-ingelheim.com/data_sharing/sharing.html#accordion-1-2 for further details. Bona fide, qualified scientific and medical researchers may request access to de-identified, analyzable patient-level study data, together with documentation describing the structure and content of the datasets. Researchers should use https://clinicalstudydatarequest.com/ to request access to raw data from this study.
Compliance with ethical standards
Conflict of interest
AVD has received consulting fees from AstraZeneca, Abbvie, BeiGene, Genentech, TG Therapeutics, Janssen, Rigel Pharmaceutical, Nurix, Bayer Oncology, Karyopharm and Pharmacyclics and has ongoing research funding from AstraZeneca, Takeda Oncology, Gilead Sciences, Bayer Oncology, Genentech, Verastem Oncology, MEI and Bristol Myers Squibb.
SES reports grants from Boehringer Ingelheim during the conduct of the study and personal fees from Pharmacyclics outside the submitted work.
TS reports institutional funds fees from Boehringer Ingelheim during the conduct of the study; personal fees from AstraZeneca, PCYC, Janssen, Juno, Celgene, BeiGene and Kite Pharma outside the submitted work.
AMQ, DM and DS are employees of Boehringer Ingelheim.
JRB reports personal fees from Abbvie, Acerta/AstraZeneca, Astellas, BeiGene, Catapult Therapeutics, Dynamo Therapeutics, Genentech/Roche, Janssen, Juno/Celgene, Kite, MEI Pharma, Nextcea, Novartis, Octapharma, Pfizer, Pharmacyclics, Redx, Rigel, Sun, Sunesis, Teva, and TG Therapeutics; grants and personal fees from Gilead, Loxo/Lilly and Verastem outside the submitted work. She has sat on Data Safety Monitoring Boards for Invectys and Morphosys.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | IBRUTINIB | DrugsGivenReaction | CC BY | 33683501 | 19,065,111 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'CD4 lymphocytes decreased'. | A phase Ib, open label, dose escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia.
BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a transmembrane protein expressed on normal and malignant B cells. This open-label, phase Ib, dose-escalation study was conducted to determine the recommended phase II dose (RP2D) of BI 836826 + ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Eligible patients received 420 mg/day of ibrutinib with escalating doses of BI 836826. BI 836826 was administered in 4-week cycles. After Cycle 12, patients achieving complete response (CR), CR with incomplete marrow recovery, or minimal residual disease-negative partial response could continue to receive BI 836826 + ibrutinib every 4 weeks for ≤ 12 additional cycles. Patients received either 100 mg (n = 3) or 200 mg (n = 3) BI 836826 + ibrutinib. In the 100 mg BI 836826 cohort, one patient received two cycles and two patients received 22 cycles of BI 836826. In the 200 mg BI 836826 cohort, patients received 12, 16 and 20 cycles of BI 836826, respectively. All patients discontinued BI 836826 and continued ibrutinib outside the trial. No dose-limiting toxicities were reported in the maximum tolerated dose (MTD) evaluation period. As the trial was discontinued before the MTD was reached, the RP2D was not determined. Grade 3/4 adverse events (AEs) were predominantly hematological. Pseudomonal bacteremia was the only drug-related AE of special interest. BI 836826 + ibrutinib did not exceed the MTD at doses up to 200 mg in patients with CLL. However, RP2D and MTD were not formally established, as the sponsor discontinued the trial.
Introduction
The Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, is well established in the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia (CLL) [1–3]. While ibrutinib monotherapy is associated with impressive response rates in CLL patients, including those with del(17p) [1, 4], deep responses are rare, thus necessitating continuous use. This can result in cumulative toxicities, leading to treatment discontinuation [5]. Furthermore, patients often become resistant to long-term treatment, potentially leading to disease progression or transformation [6]. Therefore, there is clinical rationale for combining ibrutinib with other agents that could increase depth of response and delay development of resistance.
Preclinical and clinical studies have demonstrated that CD37, a tetraspanin B cell surface molecule, is a potential drug target in patients with CLL [7–10].
BI 836826 is a chimeric mouse–human anti-CD37 monoclonal antibody engineered to enhance binding and effector function that mediates direct antibody-dependent cell-mediated cytotoxicity (ADCC) against CLL cells [11]. A phase I, dose escalation study of BI 836826 in patients with relapsed/refractory CLL demonstrated acceptable tolerability and notable efficacy, particularly in patients with poor-risk features such as del(17p) and TP53 mutations [12]. In this phase Ib, dose-escalation study, we investigated the combination of ibrutinib and BI 836826 in patients with relapsed/refractory CLL.
Patients and methods
Patients
Eligible patients were ≤ 18 years old with relapsed/refractory CLL according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria [13]. All patients had received at least one prior line of systemic treatment. Prior BTK inhibitors were not allowed. Other eligibility criteria included Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0–2; clinically quantifiable disease burden (absolute lymphocyte count > 10,000/µL, measurable lymphadenopathy, or quantifiable bone marrow infiltration); adequate organ function; and residual non-hematological toxicity from prior treatment of grade ≤ 1.
Key exclusion criteria were: any CD37-targeting antibody or CD37 antibody-drug conjugate; allogeneic stem cell transplant within 1 year or active graft-versus-host disease; known transformation of CLL to an aggressive B-cell malignancy at the time of screening; history of non-CLL malignancy except for adequately treated in-situ, stage I or II carcinoma in complete response (CR) or any other cancer that had been in CR for ≥ 2 years after the end of cancer treatment; and active uncontrolled autoimmune cytopenia.
The trial was carried out in accordance with the Declaration of Helsinki, Good Clinical Practice Guidelines, applicable regulatory requirements and Boehringer Ingelheim standard operating procedures. The study protocol was approved by the Institutional Review Boards of all participating institutions. Written informed consent was obtained from all patients.
Study design and treatment
The primary objectives of this single arm, open-label, dose escalation phase Ib study were to determine the recommended phase II dose (RP2D) of BI 836826 plus ibrutinib in patients with relapsed/refractory CLL, and the number of patients with dose-limiting toxicities (DLTs) during the maximum tolerated dose (MTD) evaluation period (Cycle 1). Other objectives were the determination of the MTD, safety and efficacy of the combination.
Eligible patients underwent a two-week run-in phase with ibrutinib and remained on ibrutinib throughout the trial at a constant dose of 420 mg daily. BI 836826 was planned at dose levels of 100, 200, 400, 600, 800 and 1400 mg. Mandatory pre-medication (antihistamine, analgesic and glucocorticoid) to mitigate the risk of infusion-related reactions (IRRs) was given 30–120 min prior to BI 836826 administration. BI 836826 was then administered via rate-controlled intravenous infusion in Cycle 1 as a 10 mg dose on Day 1, on Days 2 and 8 at 50% of the assigned dose on each day, and on Day 15 at 100% of the assigned dose. In Cycles 2–4, BI 836826 was administered at the assigned dose on Days 1 and 15 of each cycle. In Cycles 5–12, BI 836826 was administered at the assigned dose on Day 1 only. BI 836826 was administered in 4-week cycles. At the end of Cycle 12, bone marrow biopsies were performed to evaluate response. Patients with a CR, CR with incomplete marrow recovery (CRi), or minimal residual disease (MRD)-negative partial response (PR) could choose to receive 12 additional treatment cycles of the combination. Following completion of 12 or 24 cycles, or discontinuation due to disease progression, unacceptable toxicity, or withdrawal of consent, patients could continue to receive ibrutinib outside of the study at the discretion of the treating investigator.
Study assessments
Safety was assessed by determining the incidence and severity of adverse events, graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Assessment of laboratory parameters, vital signs, physical examination and ECG was also undertaken. DLTs were defined as: any non-hematologic adverse event of grade ≥ 3 related to BI 836826 or ibrutinib, except IRRs and grade 3 alanine aminotransferase and/or aspartate aminotransferase elevation without concomitant bilirubin elevation or any other asymptomatic grade 3 laboratory abnormality with spontaneous recovery within 1 week; hematologic adverse events related to BI 836826 or ibrutinib including grade 4 neutropenia with concomitant infection; grade 4 febrile neutropenia, and grade 3 febrile neutropenia not resolving within 72 hours; grade 4 thrombocytopenia with clinically significant bleeding; grade 4 anemia; any grade 5 hematologic adverse event. Adverse events of special interest (AESIs) included DLTs, infusion-related reactions of grade ≥ 3, late-onset infections, events indicative of drug-induced liver injury, and tumor lysis syndrome. Adverse events consistent with the definition of a DLT but occurring after the MTD evaluation period were also considered AESIs.
Overall response, duration of response, MRD and reduction in size of tumor lymph nodes were exploratory endpoints. Overall response was defined as patients who achieved CR, CRi, PR or PR with lymphocytosis (PR-L) according to modified IWCLL guidelines [13]. MRD was evaluated in both blood and bone marrow samples and was defined as < 1 leukemic cell per 10,000 leukocytes detected by multi-parameter flow cytometry.
Statistical methods
All analyses were descriptive and exploratory. No formal statistical analysis was conducted. Dose escalation was guided by a Bayesian 5-parameter logistic regression model (BLRM) with overdose control [14, 15] that was fitted to binary toxicity outcomes.
Results
Patients and treatment exposure
Between July 7, 2016 and July 9, 2019, 10 patients were screened, of whom 7 entered the run-in period with ibrutinib. Six patients were treated with BI 836826 plus ibrutinib across three sites in the United States (100 mg BI 836826: n = 3; 200 mg BI 836826: n = 3). The median age among treated patients was 71.0 years (range 57–76 years); all patients were Caucasian (Table 1).
Table 1 Patient demographics
BI 836826 dosea
100 mg
(n = 3) 200 mg
(n = 3) Total
(N = 6)
Male, n (%) 1 (33) 2 (67) 3 (50)
Race, n (%)
White 3 (100) 3 (100) 6 (100)
Ethnicity, n (%)
Not Hispanic/Latino 2 (67) 3 (100) 5 (83)
Hispanic/Latino 1 (33) 0 1 (17)
Median age, years (range) 75.0 (68–76) 67.0 (57–74) 71.0 (57–76)
ECOG PS at baseline, n (%)
0 1 (33) 1 (33) 2 (33)
1 2 (67) 2 (67) 4 (67)
RAI stage at diagnosis, n (%)
0
I
II
III
IV
1 (33)
0
1 (33)
0
1 (33)
1 (33)
1 (33)
0
1 (33)
0
2 (33)
1 (17)
1 (17)
1 (17)
1 (17)
Mean time from first diagnosis, years (SD) 10.4 (4.9) 11.1 (5.1) 10.7 (4.5)
Median number of previous CLL therapies (range) 1 (1–1) 4 (1–5) 1 (1–5)
Status after prior treatment
Relapsed
Refractory
2 (67)
1 (33)
2 (67)
1 (33)
4 (67)
2 (33)
aGiven in combination with ibrutinib 420 mg/day
CLL chronic lymphocytic leukemia, ECOG PS Eastern Cooperative Oncology Group Performance Status, RAI staging system for CLL [16], SD standard deviation
In the 100 mg BI 836826 cohort, one patient received two cycles and two patients received 22 cycles of BI 836826. The patients in the 200 mg cohort received 12, 16 and 20 cycles of BI 836826, respectively. All six patients discontinued treatment with BI 836826 (disease progression, n = 1; investigator discretion, n = 3; lack of response by cycle 12, n = 2). Mean duration of BI 836826 exposure was 440.2 days. There were no dose reductions. Two patients in the 100 mg BI 836826 cohort had at least one important protocol deviation. Both patients continued treatment with BI 836826 beyond cycle 12 without having a CR, CRi, or MRD-negative PR. One of these patients did not receive pre-medication with glucocorticoid in Cycle 3, as required per protocol.
DLTs during the MTD evaluation period, MTD and RP2D
No DLTs were reported during the MTD evaluation period with 100 or 200 mg BI 836826. However, the trial was discontinued before patients were treated with 400 mg BI 836826, and the MTD and RP2D were therefore not determined.
Safety
All six patients had at least one adverse event that was considered by the investigator to be related to BI 836826. The most common BI 836826-related adverse events (any grade/grade ≥ 33) were IRR (67%/17%), neutropenia (50%/33%), anemia (33%/33%), lymphopenia (33%/33%) and fatigue (33%/0%; Table 2). All IRRs (ten in four patients) were grade ≤ 2 except for one grade 3 IRR. The majority of IRRs occurred within the first two cycles and were resolved within a day.
Table 2 Adverse events considered related to BI 836826 occurring in > 2 patients
Any-grade
n (%) Grade 3/4
n (%)
Infusion-related reactions 4 (67) 1 (17)
Neutropenia 3 (50) 2 (33)
Anemia 2 (33) 2 (33)
Lymphopenia 2 (33) 2 (33)
Fatigue 2 (33) 0
Five patients had serious adverse events (considered related to study drug in 4 patients), including neutropenia, acute coronary syndrome, cellulitis, pseudomonal bacteremia and Bowen’s disease. No serious adverse event was experienced by more than one patient. There were no fatal adverse events, and no dose reductions or permanent discontinuations of BI 836826 due to adverse events. One patient had an ibrutinib dose reduction due to grade 2 neutropenia. After the MTD evaluation period, two patients in the 200 mg cohort reported grade 3 DLTs: a duodenal ulcer occurring on Day 325 and pseudomonal bacteremia (considered as related to study drug) on Day 280.
Three AESIs were recorded: the two DLTs reported after the MTD evaluation period and grade 2 basal cell carcinoma (Day 622).
Based on laboratory data, grade 4 neutropenia was reported for two patients (one patient in each dose cohort). Neither episode was associated with a concomitant infection. One patient in the 100 mg dose cohort had an episode of grade 4 thrombocytopenia, which was not associated with concomitant bleeding. Two patients (one in each dose cohort) had an episode of grade ≥ 3 decreased CD4 + T-cell count but there were no concomitant CD4+-related specific infections.
Efficacy
Overall response rate was 83% among the 6 evaluable patients (one CR and four PRs; Table 3) The ORR in the 200 mg cohort was 100% (one CR, two PR). Of five patients who underwent peripheral blood-based MRD analysis, two were MRD-negative, one in each cohort including the patient who achieved CR. Three patients had bone marrow aspirate samples analyzed for MRD. None were MRD-negative but one patient developed MRD-negative CR a month after study completion.
Table 3 Best overall response in patients receiving BI 836826 plus ibrutinib
BI 836826 dose
Patients with response, n (%) 100 mg
n = 3 200 mg
n = 3 Total
N = 6
Overall response 2 (67) 3 (100) 5 (83)
CR 0 1 (33) 1 (17)
CRi 0 0 0
PR 2 (67) 2 (67) 4 (67)
PR-L 0 0 0
Stable disease
Progressive disease 1 (33) 0 1 (17)
CR complete response, CRi complete response with incomplete marrow recovery, OR overall response (CR + CRi + PR + PR-L), PR partial response; PR-L partial response with lymphocytosis
All five patients were censored for the analysis of duration of overall response since they had discontinued before progression or death was observed. Mean (standard deviation [SD]) duration of response was 538.0 (31.1) days and 312.0 (143.96) days in the 100 mg and 200 mg BI 836826 cohorts, respectively. The median best percentage change from baseline in the SPD of lymph nodes was -81.2% (range -84% to -51%) in the 100 mg dose group and -79.2% (range -92% to -59%) in the 200 mg dose group (Fig. 1). Tumor size was reduced in all six patients.Fig. 1 Maximum change in SPD of lymph node lesions at best response
Discussion
In this phase Ib, dose-escalation study of BI 836826 plus ibrutinib in patients with relapsed/refractory CLL, no DLTs were observed during the MTD evaluation period in either the 100 mg or 200 mg BI 836320 cohorts. Despite these promising findings, the sponsor took the strategic decision to discontinue the clinical development of BI 836826, due to the rapidly evolving CLL treatment landscape. Accordingly, the MTD was not reached and the RP2D was not determined. There were no safety reasons to terminate the program. Nevertheless, the results from this study suggest that BI 836826 can be safely combined with ibrutinib, with no apparent additive toxicity. Adverse events associated with the combination were consistent with previous clinical experience with BI 836826 [12] or ibrutinib monotherapy [4].
The efficacy of ibrutinib in relapsed/refractory CLL is well established [4, 17, 18], with an objective response rate of 63% observed in the phase III study, RESONATE [4]. Of note, overall response rate to ibrutinib generally deepens over time [17, 19], and had increased to 91% by the final analysis of RESONATE [2, 20]. Our preliminary findings (83% overall response rate) suggest that the addition of anti-CD37 agents to ibrutinib could potentially improve efficacy. While the sample size is limited, the promising efficacy of this combination especially at the 200 mg dose (100%), supports ongoing exploration of agents, including those that target CD37, for fixed-duration therapy in CLL.
A number of CD37-based therapeutics are currently undergoing investigation in CLL, including otlertuzumab, an anti-CD37 mono-specific ADAPTIR therapeutic protein [8]. Notably, in phase II studies, the addition of otlertuzumab to bendamustine greatly enhanced response compared with bendamustine alone in relapsed CLL patients [21]. Additionally, 212Pb-NNV003, a CD37-targeted radioimmunotherapy, has demonstrated notable anti-tumor effects in an animal model of CLL [22].
In conclusion, BI 836826 plus ibrutinib did not exceed the MTD at doses up to 200 mg in patients with CLL, and no DLTs were reported in the MTD evaluation period. While the RPTD and MTD were not formally established, our findings suggest that an anti-CD37 antibody may be combined with ibrutinib, or potentially other BTK inhibitors, for the treatment of relapsed/refractory CLL. Since continuous therapy with BTK inhibitors leads to toxicities, therapeutic resistance and is associated with high costs, exploration of novel combinations involving active agents with different therapeutic targets remains an unmet medical need.
Acknowledgements
We thank the patients, their families, and all the investigators who participated in these studies. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version.
Funding
The conduct of this research, study design, data collection, and analysis was financially supported by Boehringer Ingelheim. Medical writing assistance, funded by Boehringer Ingelheim, was provided by Lynn Pritchard, DPhil, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this manuscript.
Data availability
The clinical study report (including appendices, but without line listings) and other clinical documents related to this study may be accessed on request. Prior to providing access, the documents and data will be examined, and, if necessary, redacted and de-identified to protect the personal data of study participants and personnel, and to respect the boundaries of the informed consent of the study participants. See https://trials.boehringer-ingelheim.com/data_sharing/sharing.html#accordion-1-2 for further details. Bona fide, qualified scientific and medical researchers may request access to de-identified, analyzable patient-level study data, together with documentation describing the structure and content of the datasets. Researchers should use https://clinicalstudydatarequest.com/ to request access to raw data from this study.
Compliance with ethical standards
Conflict of interest
AVD has received consulting fees from AstraZeneca, Abbvie, BeiGene, Genentech, TG Therapeutics, Janssen, Rigel Pharmaceutical, Nurix, Bayer Oncology, Karyopharm and Pharmacyclics and has ongoing research funding from AstraZeneca, Takeda Oncology, Gilead Sciences, Bayer Oncology, Genentech, Verastem Oncology, MEI and Bristol Myers Squibb.
SES reports grants from Boehringer Ingelheim during the conduct of the study and personal fees from Pharmacyclics outside the submitted work.
TS reports institutional funds fees from Boehringer Ingelheim during the conduct of the study; personal fees from AstraZeneca, PCYC, Janssen, Juno, Celgene, BeiGene and Kite Pharma outside the submitted work.
AMQ, DM and DS are employees of Boehringer Ingelheim.
JRB reports personal fees from Abbvie, Acerta/AstraZeneca, Astellas, BeiGene, Catapult Therapeutics, Dynamo Therapeutics, Genentech/Roche, Janssen, Juno/Celgene, Kite, MEI Pharma, Nextcea, Novartis, Octapharma, Pfizer, Pharmacyclics, Redx, Rigel, Sun, Sunesis, Teva, and TG Therapeutics; grants and personal fees from Gilead, Loxo/Lilly and Verastem outside the submitted work. She has sat on Data Safety Monitoring Boards for Invectys and Morphosys.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | IBRUTINIB | DrugsGivenReaction | CC BY | 33683501 | 19,065,111 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenia'. | A phase Ib, open label, dose escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia.
BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a transmembrane protein expressed on normal and malignant B cells. This open-label, phase Ib, dose-escalation study was conducted to determine the recommended phase II dose (RP2D) of BI 836826 + ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Eligible patients received 420 mg/day of ibrutinib with escalating doses of BI 836826. BI 836826 was administered in 4-week cycles. After Cycle 12, patients achieving complete response (CR), CR with incomplete marrow recovery, or minimal residual disease-negative partial response could continue to receive BI 836826 + ibrutinib every 4 weeks for ≤ 12 additional cycles. Patients received either 100 mg (n = 3) or 200 mg (n = 3) BI 836826 + ibrutinib. In the 100 mg BI 836826 cohort, one patient received two cycles and two patients received 22 cycles of BI 836826. In the 200 mg BI 836826 cohort, patients received 12, 16 and 20 cycles of BI 836826, respectively. All patients discontinued BI 836826 and continued ibrutinib outside the trial. No dose-limiting toxicities were reported in the maximum tolerated dose (MTD) evaluation period. As the trial was discontinued before the MTD was reached, the RP2D was not determined. Grade 3/4 adverse events (AEs) were predominantly hematological. Pseudomonal bacteremia was the only drug-related AE of special interest. BI 836826 + ibrutinib did not exceed the MTD at doses up to 200 mg in patients with CLL. However, RP2D and MTD were not formally established, as the sponsor discontinued the trial.
Introduction
The Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, is well established in the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia (CLL) [1–3]. While ibrutinib monotherapy is associated with impressive response rates in CLL patients, including those with del(17p) [1, 4], deep responses are rare, thus necessitating continuous use. This can result in cumulative toxicities, leading to treatment discontinuation [5]. Furthermore, patients often become resistant to long-term treatment, potentially leading to disease progression or transformation [6]. Therefore, there is clinical rationale for combining ibrutinib with other agents that could increase depth of response and delay development of resistance.
Preclinical and clinical studies have demonstrated that CD37, a tetraspanin B cell surface molecule, is a potential drug target in patients with CLL [7–10].
BI 836826 is a chimeric mouse–human anti-CD37 monoclonal antibody engineered to enhance binding and effector function that mediates direct antibody-dependent cell-mediated cytotoxicity (ADCC) against CLL cells [11]. A phase I, dose escalation study of BI 836826 in patients with relapsed/refractory CLL demonstrated acceptable tolerability and notable efficacy, particularly in patients with poor-risk features such as del(17p) and TP53 mutations [12]. In this phase Ib, dose-escalation study, we investigated the combination of ibrutinib and BI 836826 in patients with relapsed/refractory CLL.
Patients and methods
Patients
Eligible patients were ≤ 18 years old with relapsed/refractory CLL according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria [13]. All patients had received at least one prior line of systemic treatment. Prior BTK inhibitors were not allowed. Other eligibility criteria included Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0–2; clinically quantifiable disease burden (absolute lymphocyte count > 10,000/µL, measurable lymphadenopathy, or quantifiable bone marrow infiltration); adequate organ function; and residual non-hematological toxicity from prior treatment of grade ≤ 1.
Key exclusion criteria were: any CD37-targeting antibody or CD37 antibody-drug conjugate; allogeneic stem cell transplant within 1 year or active graft-versus-host disease; known transformation of CLL to an aggressive B-cell malignancy at the time of screening; history of non-CLL malignancy except for adequately treated in-situ, stage I or II carcinoma in complete response (CR) or any other cancer that had been in CR for ≥ 2 years after the end of cancer treatment; and active uncontrolled autoimmune cytopenia.
The trial was carried out in accordance with the Declaration of Helsinki, Good Clinical Practice Guidelines, applicable regulatory requirements and Boehringer Ingelheim standard operating procedures. The study protocol was approved by the Institutional Review Boards of all participating institutions. Written informed consent was obtained from all patients.
Study design and treatment
The primary objectives of this single arm, open-label, dose escalation phase Ib study were to determine the recommended phase II dose (RP2D) of BI 836826 plus ibrutinib in patients with relapsed/refractory CLL, and the number of patients with dose-limiting toxicities (DLTs) during the maximum tolerated dose (MTD) evaluation period (Cycle 1). Other objectives were the determination of the MTD, safety and efficacy of the combination.
Eligible patients underwent a two-week run-in phase with ibrutinib and remained on ibrutinib throughout the trial at a constant dose of 420 mg daily. BI 836826 was planned at dose levels of 100, 200, 400, 600, 800 and 1400 mg. Mandatory pre-medication (antihistamine, analgesic and glucocorticoid) to mitigate the risk of infusion-related reactions (IRRs) was given 30–120 min prior to BI 836826 administration. BI 836826 was then administered via rate-controlled intravenous infusion in Cycle 1 as a 10 mg dose on Day 1, on Days 2 and 8 at 50% of the assigned dose on each day, and on Day 15 at 100% of the assigned dose. In Cycles 2–4, BI 836826 was administered at the assigned dose on Days 1 and 15 of each cycle. In Cycles 5–12, BI 836826 was administered at the assigned dose on Day 1 only. BI 836826 was administered in 4-week cycles. At the end of Cycle 12, bone marrow biopsies were performed to evaluate response. Patients with a CR, CR with incomplete marrow recovery (CRi), or minimal residual disease (MRD)-negative partial response (PR) could choose to receive 12 additional treatment cycles of the combination. Following completion of 12 or 24 cycles, or discontinuation due to disease progression, unacceptable toxicity, or withdrawal of consent, patients could continue to receive ibrutinib outside of the study at the discretion of the treating investigator.
Study assessments
Safety was assessed by determining the incidence and severity of adverse events, graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Assessment of laboratory parameters, vital signs, physical examination and ECG was also undertaken. DLTs were defined as: any non-hematologic adverse event of grade ≥ 3 related to BI 836826 or ibrutinib, except IRRs and grade 3 alanine aminotransferase and/or aspartate aminotransferase elevation without concomitant bilirubin elevation or any other asymptomatic grade 3 laboratory abnormality with spontaneous recovery within 1 week; hematologic adverse events related to BI 836826 or ibrutinib including grade 4 neutropenia with concomitant infection; grade 4 febrile neutropenia, and grade 3 febrile neutropenia not resolving within 72 hours; grade 4 thrombocytopenia with clinically significant bleeding; grade 4 anemia; any grade 5 hematologic adverse event. Adverse events of special interest (AESIs) included DLTs, infusion-related reactions of grade ≥ 3, late-onset infections, events indicative of drug-induced liver injury, and tumor lysis syndrome. Adverse events consistent with the definition of a DLT but occurring after the MTD evaluation period were also considered AESIs.
Overall response, duration of response, MRD and reduction in size of tumor lymph nodes were exploratory endpoints. Overall response was defined as patients who achieved CR, CRi, PR or PR with lymphocytosis (PR-L) according to modified IWCLL guidelines [13]. MRD was evaluated in both blood and bone marrow samples and was defined as < 1 leukemic cell per 10,000 leukocytes detected by multi-parameter flow cytometry.
Statistical methods
All analyses were descriptive and exploratory. No formal statistical analysis was conducted. Dose escalation was guided by a Bayesian 5-parameter logistic regression model (BLRM) with overdose control [14, 15] that was fitted to binary toxicity outcomes.
Results
Patients and treatment exposure
Between July 7, 2016 and July 9, 2019, 10 patients were screened, of whom 7 entered the run-in period with ibrutinib. Six patients were treated with BI 836826 plus ibrutinib across three sites in the United States (100 mg BI 836826: n = 3; 200 mg BI 836826: n = 3). The median age among treated patients was 71.0 years (range 57–76 years); all patients were Caucasian (Table 1).
Table 1 Patient demographics
BI 836826 dosea
100 mg
(n = 3) 200 mg
(n = 3) Total
(N = 6)
Male, n (%) 1 (33) 2 (67) 3 (50)
Race, n (%)
White 3 (100) 3 (100) 6 (100)
Ethnicity, n (%)
Not Hispanic/Latino 2 (67) 3 (100) 5 (83)
Hispanic/Latino 1 (33) 0 1 (17)
Median age, years (range) 75.0 (68–76) 67.0 (57–74) 71.0 (57–76)
ECOG PS at baseline, n (%)
0 1 (33) 1 (33) 2 (33)
1 2 (67) 2 (67) 4 (67)
RAI stage at diagnosis, n (%)
0
I
II
III
IV
1 (33)
0
1 (33)
0
1 (33)
1 (33)
1 (33)
0
1 (33)
0
2 (33)
1 (17)
1 (17)
1 (17)
1 (17)
Mean time from first diagnosis, years (SD) 10.4 (4.9) 11.1 (5.1) 10.7 (4.5)
Median number of previous CLL therapies (range) 1 (1–1) 4 (1–5) 1 (1–5)
Status after prior treatment
Relapsed
Refractory
2 (67)
1 (33)
2 (67)
1 (33)
4 (67)
2 (33)
aGiven in combination with ibrutinib 420 mg/day
CLL chronic lymphocytic leukemia, ECOG PS Eastern Cooperative Oncology Group Performance Status, RAI staging system for CLL [16], SD standard deviation
In the 100 mg BI 836826 cohort, one patient received two cycles and two patients received 22 cycles of BI 836826. The patients in the 200 mg cohort received 12, 16 and 20 cycles of BI 836826, respectively. All six patients discontinued treatment with BI 836826 (disease progression, n = 1; investigator discretion, n = 3; lack of response by cycle 12, n = 2). Mean duration of BI 836826 exposure was 440.2 days. There were no dose reductions. Two patients in the 100 mg BI 836826 cohort had at least one important protocol deviation. Both patients continued treatment with BI 836826 beyond cycle 12 without having a CR, CRi, or MRD-negative PR. One of these patients did not receive pre-medication with glucocorticoid in Cycle 3, as required per protocol.
DLTs during the MTD evaluation period, MTD and RP2D
No DLTs were reported during the MTD evaluation period with 100 or 200 mg BI 836826. However, the trial was discontinued before patients were treated with 400 mg BI 836826, and the MTD and RP2D were therefore not determined.
Safety
All six patients had at least one adverse event that was considered by the investigator to be related to BI 836826. The most common BI 836826-related adverse events (any grade/grade ≥ 33) were IRR (67%/17%), neutropenia (50%/33%), anemia (33%/33%), lymphopenia (33%/33%) and fatigue (33%/0%; Table 2). All IRRs (ten in four patients) were grade ≤ 2 except for one grade 3 IRR. The majority of IRRs occurred within the first two cycles and were resolved within a day.
Table 2 Adverse events considered related to BI 836826 occurring in > 2 patients
Any-grade
n (%) Grade 3/4
n (%)
Infusion-related reactions 4 (67) 1 (17)
Neutropenia 3 (50) 2 (33)
Anemia 2 (33) 2 (33)
Lymphopenia 2 (33) 2 (33)
Fatigue 2 (33) 0
Five patients had serious adverse events (considered related to study drug in 4 patients), including neutropenia, acute coronary syndrome, cellulitis, pseudomonal bacteremia and Bowen’s disease. No serious adverse event was experienced by more than one patient. There were no fatal adverse events, and no dose reductions or permanent discontinuations of BI 836826 due to adverse events. One patient had an ibrutinib dose reduction due to grade 2 neutropenia. After the MTD evaluation period, two patients in the 200 mg cohort reported grade 3 DLTs: a duodenal ulcer occurring on Day 325 and pseudomonal bacteremia (considered as related to study drug) on Day 280.
Three AESIs were recorded: the two DLTs reported after the MTD evaluation period and grade 2 basal cell carcinoma (Day 622).
Based on laboratory data, grade 4 neutropenia was reported for two patients (one patient in each dose cohort). Neither episode was associated with a concomitant infection. One patient in the 100 mg dose cohort had an episode of grade 4 thrombocytopenia, which was not associated with concomitant bleeding. Two patients (one in each dose cohort) had an episode of grade ≥ 3 decreased CD4 + T-cell count but there were no concomitant CD4+-related specific infections.
Efficacy
Overall response rate was 83% among the 6 evaluable patients (one CR and four PRs; Table 3) The ORR in the 200 mg cohort was 100% (one CR, two PR). Of five patients who underwent peripheral blood-based MRD analysis, two were MRD-negative, one in each cohort including the patient who achieved CR. Three patients had bone marrow aspirate samples analyzed for MRD. None were MRD-negative but one patient developed MRD-negative CR a month after study completion.
Table 3 Best overall response in patients receiving BI 836826 plus ibrutinib
BI 836826 dose
Patients with response, n (%) 100 mg
n = 3 200 mg
n = 3 Total
N = 6
Overall response 2 (67) 3 (100) 5 (83)
CR 0 1 (33) 1 (17)
CRi 0 0 0
PR 2 (67) 2 (67) 4 (67)
PR-L 0 0 0
Stable disease
Progressive disease 1 (33) 0 1 (17)
CR complete response, CRi complete response with incomplete marrow recovery, OR overall response (CR + CRi + PR + PR-L), PR partial response; PR-L partial response with lymphocytosis
All five patients were censored for the analysis of duration of overall response since they had discontinued before progression or death was observed. Mean (standard deviation [SD]) duration of response was 538.0 (31.1) days and 312.0 (143.96) days in the 100 mg and 200 mg BI 836826 cohorts, respectively. The median best percentage change from baseline in the SPD of lymph nodes was -81.2% (range -84% to -51%) in the 100 mg dose group and -79.2% (range -92% to -59%) in the 200 mg dose group (Fig. 1). Tumor size was reduced in all six patients.Fig. 1 Maximum change in SPD of lymph node lesions at best response
Discussion
In this phase Ib, dose-escalation study of BI 836826 plus ibrutinib in patients with relapsed/refractory CLL, no DLTs were observed during the MTD evaluation period in either the 100 mg or 200 mg BI 836320 cohorts. Despite these promising findings, the sponsor took the strategic decision to discontinue the clinical development of BI 836826, due to the rapidly evolving CLL treatment landscape. Accordingly, the MTD was not reached and the RP2D was not determined. There were no safety reasons to terminate the program. Nevertheless, the results from this study suggest that BI 836826 can be safely combined with ibrutinib, with no apparent additive toxicity. Adverse events associated with the combination were consistent with previous clinical experience with BI 836826 [12] or ibrutinib monotherapy [4].
The efficacy of ibrutinib in relapsed/refractory CLL is well established [4, 17, 18], with an objective response rate of 63% observed in the phase III study, RESONATE [4]. Of note, overall response rate to ibrutinib generally deepens over time [17, 19], and had increased to 91% by the final analysis of RESONATE [2, 20]. Our preliminary findings (83% overall response rate) suggest that the addition of anti-CD37 agents to ibrutinib could potentially improve efficacy. While the sample size is limited, the promising efficacy of this combination especially at the 200 mg dose (100%), supports ongoing exploration of agents, including those that target CD37, for fixed-duration therapy in CLL.
A number of CD37-based therapeutics are currently undergoing investigation in CLL, including otlertuzumab, an anti-CD37 mono-specific ADAPTIR therapeutic protein [8]. Notably, in phase II studies, the addition of otlertuzumab to bendamustine greatly enhanced response compared with bendamustine alone in relapsed CLL patients [21]. Additionally, 212Pb-NNV003, a CD37-targeted radioimmunotherapy, has demonstrated notable anti-tumor effects in an animal model of CLL [22].
In conclusion, BI 836826 plus ibrutinib did not exceed the MTD at doses up to 200 mg in patients with CLL, and no DLTs were reported in the MTD evaluation period. While the RPTD and MTD were not formally established, our findings suggest that an anti-CD37 antibody may be combined with ibrutinib, or potentially other BTK inhibitors, for the treatment of relapsed/refractory CLL. Since continuous therapy with BTK inhibitors leads to toxicities, therapeutic resistance and is associated with high costs, exploration of novel combinations involving active agents with different therapeutic targets remains an unmet medical need.
Acknowledgements
We thank the patients, their families, and all the investigators who participated in these studies. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version.
Funding
The conduct of this research, study design, data collection, and analysis was financially supported by Boehringer Ingelheim. Medical writing assistance, funded by Boehringer Ingelheim, was provided by Lynn Pritchard, DPhil, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this manuscript.
Data availability
The clinical study report (including appendices, but without line listings) and other clinical documents related to this study may be accessed on request. Prior to providing access, the documents and data will be examined, and, if necessary, redacted and de-identified to protect the personal data of study participants and personnel, and to respect the boundaries of the informed consent of the study participants. See https://trials.boehringer-ingelheim.com/data_sharing/sharing.html#accordion-1-2 for further details. Bona fide, qualified scientific and medical researchers may request access to de-identified, analyzable patient-level study data, together with documentation describing the structure and content of the datasets. Researchers should use https://clinicalstudydatarequest.com/ to request access to raw data from this study.
Compliance with ethical standards
Conflict of interest
AVD has received consulting fees from AstraZeneca, Abbvie, BeiGene, Genentech, TG Therapeutics, Janssen, Rigel Pharmaceutical, Nurix, Bayer Oncology, Karyopharm and Pharmacyclics and has ongoing research funding from AstraZeneca, Takeda Oncology, Gilead Sciences, Bayer Oncology, Genentech, Verastem Oncology, MEI and Bristol Myers Squibb.
SES reports grants from Boehringer Ingelheim during the conduct of the study and personal fees from Pharmacyclics outside the submitted work.
TS reports institutional funds fees from Boehringer Ingelheim during the conduct of the study; personal fees from AstraZeneca, PCYC, Janssen, Juno, Celgene, BeiGene and Kite Pharma outside the submitted work.
AMQ, DM and DS are employees of Boehringer Ingelheim.
JRB reports personal fees from Abbvie, Acerta/AstraZeneca, Astellas, BeiGene, Catapult Therapeutics, Dynamo Therapeutics, Genentech/Roche, Janssen, Juno/Celgene, Kite, MEI Pharma, Nextcea, Novartis, Octapharma, Pfizer, Pharmacyclics, Redx, Rigel, Sun, Sunesis, Teva, and TG Therapeutics; grants and personal fees from Gilead, Loxo/Lilly and Verastem outside the submitted work. She has sat on Data Safety Monitoring Boards for Invectys and Morphosys.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | IBRUTINIB | DrugsGivenReaction | CC BY | 33683501 | 19,065,111 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thrombocytopenia'. | A phase Ib, open label, dose escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia.
BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a transmembrane protein expressed on normal and malignant B cells. This open-label, phase Ib, dose-escalation study was conducted to determine the recommended phase II dose (RP2D) of BI 836826 + ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Eligible patients received 420 mg/day of ibrutinib with escalating doses of BI 836826. BI 836826 was administered in 4-week cycles. After Cycle 12, patients achieving complete response (CR), CR with incomplete marrow recovery, or minimal residual disease-negative partial response could continue to receive BI 836826 + ibrutinib every 4 weeks for ≤ 12 additional cycles. Patients received either 100 mg (n = 3) or 200 mg (n = 3) BI 836826 + ibrutinib. In the 100 mg BI 836826 cohort, one patient received two cycles and two patients received 22 cycles of BI 836826. In the 200 mg BI 836826 cohort, patients received 12, 16 and 20 cycles of BI 836826, respectively. All patients discontinued BI 836826 and continued ibrutinib outside the trial. No dose-limiting toxicities were reported in the maximum tolerated dose (MTD) evaluation period. As the trial was discontinued before the MTD was reached, the RP2D was not determined. Grade 3/4 adverse events (AEs) were predominantly hematological. Pseudomonal bacteremia was the only drug-related AE of special interest. BI 836826 + ibrutinib did not exceed the MTD at doses up to 200 mg in patients with CLL. However, RP2D and MTD were not formally established, as the sponsor discontinued the trial.
Introduction
The Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, is well established in the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia (CLL) [1–3]. While ibrutinib monotherapy is associated with impressive response rates in CLL patients, including those with del(17p) [1, 4], deep responses are rare, thus necessitating continuous use. This can result in cumulative toxicities, leading to treatment discontinuation [5]. Furthermore, patients often become resistant to long-term treatment, potentially leading to disease progression or transformation [6]. Therefore, there is clinical rationale for combining ibrutinib with other agents that could increase depth of response and delay development of resistance.
Preclinical and clinical studies have demonstrated that CD37, a tetraspanin B cell surface molecule, is a potential drug target in patients with CLL [7–10].
BI 836826 is a chimeric mouse–human anti-CD37 monoclonal antibody engineered to enhance binding and effector function that mediates direct antibody-dependent cell-mediated cytotoxicity (ADCC) against CLL cells [11]. A phase I, dose escalation study of BI 836826 in patients with relapsed/refractory CLL demonstrated acceptable tolerability and notable efficacy, particularly in patients with poor-risk features such as del(17p) and TP53 mutations [12]. In this phase Ib, dose-escalation study, we investigated the combination of ibrutinib and BI 836826 in patients with relapsed/refractory CLL.
Patients and methods
Patients
Eligible patients were ≤ 18 years old with relapsed/refractory CLL according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria [13]. All patients had received at least one prior line of systemic treatment. Prior BTK inhibitors were not allowed. Other eligibility criteria included Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0–2; clinically quantifiable disease burden (absolute lymphocyte count > 10,000/µL, measurable lymphadenopathy, or quantifiable bone marrow infiltration); adequate organ function; and residual non-hematological toxicity from prior treatment of grade ≤ 1.
Key exclusion criteria were: any CD37-targeting antibody or CD37 antibody-drug conjugate; allogeneic stem cell transplant within 1 year or active graft-versus-host disease; known transformation of CLL to an aggressive B-cell malignancy at the time of screening; history of non-CLL malignancy except for adequately treated in-situ, stage I or II carcinoma in complete response (CR) or any other cancer that had been in CR for ≥ 2 years after the end of cancer treatment; and active uncontrolled autoimmune cytopenia.
The trial was carried out in accordance with the Declaration of Helsinki, Good Clinical Practice Guidelines, applicable regulatory requirements and Boehringer Ingelheim standard operating procedures. The study protocol was approved by the Institutional Review Boards of all participating institutions. Written informed consent was obtained from all patients.
Study design and treatment
The primary objectives of this single arm, open-label, dose escalation phase Ib study were to determine the recommended phase II dose (RP2D) of BI 836826 plus ibrutinib in patients with relapsed/refractory CLL, and the number of patients with dose-limiting toxicities (DLTs) during the maximum tolerated dose (MTD) evaluation period (Cycle 1). Other objectives were the determination of the MTD, safety and efficacy of the combination.
Eligible patients underwent a two-week run-in phase with ibrutinib and remained on ibrutinib throughout the trial at a constant dose of 420 mg daily. BI 836826 was planned at dose levels of 100, 200, 400, 600, 800 and 1400 mg. Mandatory pre-medication (antihistamine, analgesic and glucocorticoid) to mitigate the risk of infusion-related reactions (IRRs) was given 30–120 min prior to BI 836826 administration. BI 836826 was then administered via rate-controlled intravenous infusion in Cycle 1 as a 10 mg dose on Day 1, on Days 2 and 8 at 50% of the assigned dose on each day, and on Day 15 at 100% of the assigned dose. In Cycles 2–4, BI 836826 was administered at the assigned dose on Days 1 and 15 of each cycle. In Cycles 5–12, BI 836826 was administered at the assigned dose on Day 1 only. BI 836826 was administered in 4-week cycles. At the end of Cycle 12, bone marrow biopsies were performed to evaluate response. Patients with a CR, CR with incomplete marrow recovery (CRi), or minimal residual disease (MRD)-negative partial response (PR) could choose to receive 12 additional treatment cycles of the combination. Following completion of 12 or 24 cycles, or discontinuation due to disease progression, unacceptable toxicity, or withdrawal of consent, patients could continue to receive ibrutinib outside of the study at the discretion of the treating investigator.
Study assessments
Safety was assessed by determining the incidence and severity of adverse events, graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Assessment of laboratory parameters, vital signs, physical examination and ECG was also undertaken. DLTs were defined as: any non-hematologic adverse event of grade ≥ 3 related to BI 836826 or ibrutinib, except IRRs and grade 3 alanine aminotransferase and/or aspartate aminotransferase elevation without concomitant bilirubin elevation or any other asymptomatic grade 3 laboratory abnormality with spontaneous recovery within 1 week; hematologic adverse events related to BI 836826 or ibrutinib including grade 4 neutropenia with concomitant infection; grade 4 febrile neutropenia, and grade 3 febrile neutropenia not resolving within 72 hours; grade 4 thrombocytopenia with clinically significant bleeding; grade 4 anemia; any grade 5 hematologic adverse event. Adverse events of special interest (AESIs) included DLTs, infusion-related reactions of grade ≥ 3, late-onset infections, events indicative of drug-induced liver injury, and tumor lysis syndrome. Adverse events consistent with the definition of a DLT but occurring after the MTD evaluation period were also considered AESIs.
Overall response, duration of response, MRD and reduction in size of tumor lymph nodes were exploratory endpoints. Overall response was defined as patients who achieved CR, CRi, PR or PR with lymphocytosis (PR-L) according to modified IWCLL guidelines [13]. MRD was evaluated in both blood and bone marrow samples and was defined as < 1 leukemic cell per 10,000 leukocytes detected by multi-parameter flow cytometry.
Statistical methods
All analyses were descriptive and exploratory. No formal statistical analysis was conducted. Dose escalation was guided by a Bayesian 5-parameter logistic regression model (BLRM) with overdose control [14, 15] that was fitted to binary toxicity outcomes.
Results
Patients and treatment exposure
Between July 7, 2016 and July 9, 2019, 10 patients were screened, of whom 7 entered the run-in period with ibrutinib. Six patients were treated with BI 836826 plus ibrutinib across three sites in the United States (100 mg BI 836826: n = 3; 200 mg BI 836826: n = 3). The median age among treated patients was 71.0 years (range 57–76 years); all patients were Caucasian (Table 1).
Table 1 Patient demographics
BI 836826 dosea
100 mg
(n = 3) 200 mg
(n = 3) Total
(N = 6)
Male, n (%) 1 (33) 2 (67) 3 (50)
Race, n (%)
White 3 (100) 3 (100) 6 (100)
Ethnicity, n (%)
Not Hispanic/Latino 2 (67) 3 (100) 5 (83)
Hispanic/Latino 1 (33) 0 1 (17)
Median age, years (range) 75.0 (68–76) 67.0 (57–74) 71.0 (57–76)
ECOG PS at baseline, n (%)
0 1 (33) 1 (33) 2 (33)
1 2 (67) 2 (67) 4 (67)
RAI stage at diagnosis, n (%)
0
I
II
III
IV
1 (33)
0
1 (33)
0
1 (33)
1 (33)
1 (33)
0
1 (33)
0
2 (33)
1 (17)
1 (17)
1 (17)
1 (17)
Mean time from first diagnosis, years (SD) 10.4 (4.9) 11.1 (5.1) 10.7 (4.5)
Median number of previous CLL therapies (range) 1 (1–1) 4 (1–5) 1 (1–5)
Status after prior treatment
Relapsed
Refractory
2 (67)
1 (33)
2 (67)
1 (33)
4 (67)
2 (33)
aGiven in combination with ibrutinib 420 mg/day
CLL chronic lymphocytic leukemia, ECOG PS Eastern Cooperative Oncology Group Performance Status, RAI staging system for CLL [16], SD standard deviation
In the 100 mg BI 836826 cohort, one patient received two cycles and two patients received 22 cycles of BI 836826. The patients in the 200 mg cohort received 12, 16 and 20 cycles of BI 836826, respectively. All six patients discontinued treatment with BI 836826 (disease progression, n = 1; investigator discretion, n = 3; lack of response by cycle 12, n = 2). Mean duration of BI 836826 exposure was 440.2 days. There were no dose reductions. Two patients in the 100 mg BI 836826 cohort had at least one important protocol deviation. Both patients continued treatment with BI 836826 beyond cycle 12 without having a CR, CRi, or MRD-negative PR. One of these patients did not receive pre-medication with glucocorticoid in Cycle 3, as required per protocol.
DLTs during the MTD evaluation period, MTD and RP2D
No DLTs were reported during the MTD evaluation period with 100 or 200 mg BI 836826. However, the trial was discontinued before patients were treated with 400 mg BI 836826, and the MTD and RP2D were therefore not determined.
Safety
All six patients had at least one adverse event that was considered by the investigator to be related to BI 836826. The most common BI 836826-related adverse events (any grade/grade ≥ 33) were IRR (67%/17%), neutropenia (50%/33%), anemia (33%/33%), lymphopenia (33%/33%) and fatigue (33%/0%; Table 2). All IRRs (ten in four patients) were grade ≤ 2 except for one grade 3 IRR. The majority of IRRs occurred within the first two cycles and were resolved within a day.
Table 2 Adverse events considered related to BI 836826 occurring in > 2 patients
Any-grade
n (%) Grade 3/4
n (%)
Infusion-related reactions 4 (67) 1 (17)
Neutropenia 3 (50) 2 (33)
Anemia 2 (33) 2 (33)
Lymphopenia 2 (33) 2 (33)
Fatigue 2 (33) 0
Five patients had serious adverse events (considered related to study drug in 4 patients), including neutropenia, acute coronary syndrome, cellulitis, pseudomonal bacteremia and Bowen’s disease. No serious adverse event was experienced by more than one patient. There were no fatal adverse events, and no dose reductions or permanent discontinuations of BI 836826 due to adverse events. One patient had an ibrutinib dose reduction due to grade 2 neutropenia. After the MTD evaluation period, two patients in the 200 mg cohort reported grade 3 DLTs: a duodenal ulcer occurring on Day 325 and pseudomonal bacteremia (considered as related to study drug) on Day 280.
Three AESIs were recorded: the two DLTs reported after the MTD evaluation period and grade 2 basal cell carcinoma (Day 622).
Based on laboratory data, grade 4 neutropenia was reported for two patients (one patient in each dose cohort). Neither episode was associated with a concomitant infection. One patient in the 100 mg dose cohort had an episode of grade 4 thrombocytopenia, which was not associated with concomitant bleeding. Two patients (one in each dose cohort) had an episode of grade ≥ 3 decreased CD4 + T-cell count but there were no concomitant CD4+-related specific infections.
Efficacy
Overall response rate was 83% among the 6 evaluable patients (one CR and four PRs; Table 3) The ORR in the 200 mg cohort was 100% (one CR, two PR). Of five patients who underwent peripheral blood-based MRD analysis, two were MRD-negative, one in each cohort including the patient who achieved CR. Three patients had bone marrow aspirate samples analyzed for MRD. None were MRD-negative but one patient developed MRD-negative CR a month after study completion.
Table 3 Best overall response in patients receiving BI 836826 plus ibrutinib
BI 836826 dose
Patients with response, n (%) 100 mg
n = 3 200 mg
n = 3 Total
N = 6
Overall response 2 (67) 3 (100) 5 (83)
CR 0 1 (33) 1 (17)
CRi 0 0 0
PR 2 (67) 2 (67) 4 (67)
PR-L 0 0 0
Stable disease
Progressive disease 1 (33) 0 1 (17)
CR complete response, CRi complete response with incomplete marrow recovery, OR overall response (CR + CRi + PR + PR-L), PR partial response; PR-L partial response with lymphocytosis
All five patients were censored for the analysis of duration of overall response since they had discontinued before progression or death was observed. Mean (standard deviation [SD]) duration of response was 538.0 (31.1) days and 312.0 (143.96) days in the 100 mg and 200 mg BI 836826 cohorts, respectively. The median best percentage change from baseline in the SPD of lymph nodes was -81.2% (range -84% to -51%) in the 100 mg dose group and -79.2% (range -92% to -59%) in the 200 mg dose group (Fig. 1). Tumor size was reduced in all six patients.Fig. 1 Maximum change in SPD of lymph node lesions at best response
Discussion
In this phase Ib, dose-escalation study of BI 836826 plus ibrutinib in patients with relapsed/refractory CLL, no DLTs were observed during the MTD evaluation period in either the 100 mg or 200 mg BI 836320 cohorts. Despite these promising findings, the sponsor took the strategic decision to discontinue the clinical development of BI 836826, due to the rapidly evolving CLL treatment landscape. Accordingly, the MTD was not reached and the RP2D was not determined. There were no safety reasons to terminate the program. Nevertheless, the results from this study suggest that BI 836826 can be safely combined with ibrutinib, with no apparent additive toxicity. Adverse events associated with the combination were consistent with previous clinical experience with BI 836826 [12] or ibrutinib monotherapy [4].
The efficacy of ibrutinib in relapsed/refractory CLL is well established [4, 17, 18], with an objective response rate of 63% observed in the phase III study, RESONATE [4]. Of note, overall response rate to ibrutinib generally deepens over time [17, 19], and had increased to 91% by the final analysis of RESONATE [2, 20]. Our preliminary findings (83% overall response rate) suggest that the addition of anti-CD37 agents to ibrutinib could potentially improve efficacy. While the sample size is limited, the promising efficacy of this combination especially at the 200 mg dose (100%), supports ongoing exploration of agents, including those that target CD37, for fixed-duration therapy in CLL.
A number of CD37-based therapeutics are currently undergoing investigation in CLL, including otlertuzumab, an anti-CD37 mono-specific ADAPTIR therapeutic protein [8]. Notably, in phase II studies, the addition of otlertuzumab to bendamustine greatly enhanced response compared with bendamustine alone in relapsed CLL patients [21]. Additionally, 212Pb-NNV003, a CD37-targeted radioimmunotherapy, has demonstrated notable anti-tumor effects in an animal model of CLL [22].
In conclusion, BI 836826 plus ibrutinib did not exceed the MTD at doses up to 200 mg in patients with CLL, and no DLTs were reported in the MTD evaluation period. While the RPTD and MTD were not formally established, our findings suggest that an anti-CD37 antibody may be combined with ibrutinib, or potentially other BTK inhibitors, for the treatment of relapsed/refractory CLL. Since continuous therapy with BTK inhibitors leads to toxicities, therapeutic resistance and is associated with high costs, exploration of novel combinations involving active agents with different therapeutic targets remains an unmet medical need.
Acknowledgements
We thank the patients, their families, and all the investigators who participated in these studies. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version.
Funding
The conduct of this research, study design, data collection, and analysis was financially supported by Boehringer Ingelheim. Medical writing assistance, funded by Boehringer Ingelheim, was provided by Lynn Pritchard, DPhil, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this manuscript.
Data availability
The clinical study report (including appendices, but without line listings) and other clinical documents related to this study may be accessed on request. Prior to providing access, the documents and data will be examined, and, if necessary, redacted and de-identified to protect the personal data of study participants and personnel, and to respect the boundaries of the informed consent of the study participants. See https://trials.boehringer-ingelheim.com/data_sharing/sharing.html#accordion-1-2 for further details. Bona fide, qualified scientific and medical researchers may request access to de-identified, analyzable patient-level study data, together with documentation describing the structure and content of the datasets. Researchers should use https://clinicalstudydatarequest.com/ to request access to raw data from this study.
Compliance with ethical standards
Conflict of interest
AVD has received consulting fees from AstraZeneca, Abbvie, BeiGene, Genentech, TG Therapeutics, Janssen, Rigel Pharmaceutical, Nurix, Bayer Oncology, Karyopharm and Pharmacyclics and has ongoing research funding from AstraZeneca, Takeda Oncology, Gilead Sciences, Bayer Oncology, Genentech, Verastem Oncology, MEI and Bristol Myers Squibb.
SES reports grants from Boehringer Ingelheim during the conduct of the study and personal fees from Pharmacyclics outside the submitted work.
TS reports institutional funds fees from Boehringer Ingelheim during the conduct of the study; personal fees from AstraZeneca, PCYC, Janssen, Juno, Celgene, BeiGene and Kite Pharma outside the submitted work.
AMQ, DM and DS are employees of Boehringer Ingelheim.
JRB reports personal fees from Abbvie, Acerta/AstraZeneca, Astellas, BeiGene, Catapult Therapeutics, Dynamo Therapeutics, Genentech/Roche, Janssen, Juno/Celgene, Kite, MEI Pharma, Nextcea, Novartis, Octapharma, Pfizer, Pharmacyclics, Redx, Rigel, Sun, Sunesis, Teva, and TG Therapeutics; grants and personal fees from Gilead, Loxo/Lilly and Verastem outside the submitted work. She has sat on Data Safety Monitoring Boards for Invectys and Morphosys.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | IBRUTINIB | DrugsGivenReaction | CC BY | 33683501 | 19,065,111 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxicity to various agents'. | A phase Ib, open label, dose escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia.
BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a transmembrane protein expressed on normal and malignant B cells. This open-label, phase Ib, dose-escalation study was conducted to determine the recommended phase II dose (RP2D) of BI 836826 + ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Eligible patients received 420 mg/day of ibrutinib with escalating doses of BI 836826. BI 836826 was administered in 4-week cycles. After Cycle 12, patients achieving complete response (CR), CR with incomplete marrow recovery, or minimal residual disease-negative partial response could continue to receive BI 836826 + ibrutinib every 4 weeks for ≤ 12 additional cycles. Patients received either 100 mg (n = 3) or 200 mg (n = 3) BI 836826 + ibrutinib. In the 100 mg BI 836826 cohort, one patient received two cycles and two patients received 22 cycles of BI 836826. In the 200 mg BI 836826 cohort, patients received 12, 16 and 20 cycles of BI 836826, respectively. All patients discontinued BI 836826 and continued ibrutinib outside the trial. No dose-limiting toxicities were reported in the maximum tolerated dose (MTD) evaluation period. As the trial was discontinued before the MTD was reached, the RP2D was not determined. Grade 3/4 adverse events (AEs) were predominantly hematological. Pseudomonal bacteremia was the only drug-related AE of special interest. BI 836826 + ibrutinib did not exceed the MTD at doses up to 200 mg in patients with CLL. However, RP2D and MTD were not formally established, as the sponsor discontinued the trial.
Introduction
The Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, is well established in the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia (CLL) [1–3]. While ibrutinib monotherapy is associated with impressive response rates in CLL patients, including those with del(17p) [1, 4], deep responses are rare, thus necessitating continuous use. This can result in cumulative toxicities, leading to treatment discontinuation [5]. Furthermore, patients often become resistant to long-term treatment, potentially leading to disease progression or transformation [6]. Therefore, there is clinical rationale for combining ibrutinib with other agents that could increase depth of response and delay development of resistance.
Preclinical and clinical studies have demonstrated that CD37, a tetraspanin B cell surface molecule, is a potential drug target in patients with CLL [7–10].
BI 836826 is a chimeric mouse–human anti-CD37 monoclonal antibody engineered to enhance binding and effector function that mediates direct antibody-dependent cell-mediated cytotoxicity (ADCC) against CLL cells [11]. A phase I, dose escalation study of BI 836826 in patients with relapsed/refractory CLL demonstrated acceptable tolerability and notable efficacy, particularly in patients with poor-risk features such as del(17p) and TP53 mutations [12]. In this phase Ib, dose-escalation study, we investigated the combination of ibrutinib and BI 836826 in patients with relapsed/refractory CLL.
Patients and methods
Patients
Eligible patients were ≤ 18 years old with relapsed/refractory CLL according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria [13]. All patients had received at least one prior line of systemic treatment. Prior BTK inhibitors were not allowed. Other eligibility criteria included Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0–2; clinically quantifiable disease burden (absolute lymphocyte count > 10,000/µL, measurable lymphadenopathy, or quantifiable bone marrow infiltration); adequate organ function; and residual non-hematological toxicity from prior treatment of grade ≤ 1.
Key exclusion criteria were: any CD37-targeting antibody or CD37 antibody-drug conjugate; allogeneic stem cell transplant within 1 year or active graft-versus-host disease; known transformation of CLL to an aggressive B-cell malignancy at the time of screening; history of non-CLL malignancy except for adequately treated in-situ, stage I or II carcinoma in complete response (CR) or any other cancer that had been in CR for ≥ 2 years after the end of cancer treatment; and active uncontrolled autoimmune cytopenia.
The trial was carried out in accordance with the Declaration of Helsinki, Good Clinical Practice Guidelines, applicable regulatory requirements and Boehringer Ingelheim standard operating procedures. The study protocol was approved by the Institutional Review Boards of all participating institutions. Written informed consent was obtained from all patients.
Study design and treatment
The primary objectives of this single arm, open-label, dose escalation phase Ib study were to determine the recommended phase II dose (RP2D) of BI 836826 plus ibrutinib in patients with relapsed/refractory CLL, and the number of patients with dose-limiting toxicities (DLTs) during the maximum tolerated dose (MTD) evaluation period (Cycle 1). Other objectives were the determination of the MTD, safety and efficacy of the combination.
Eligible patients underwent a two-week run-in phase with ibrutinib and remained on ibrutinib throughout the trial at a constant dose of 420 mg daily. BI 836826 was planned at dose levels of 100, 200, 400, 600, 800 and 1400 mg. Mandatory pre-medication (antihistamine, analgesic and glucocorticoid) to mitigate the risk of infusion-related reactions (IRRs) was given 30–120 min prior to BI 836826 administration. BI 836826 was then administered via rate-controlled intravenous infusion in Cycle 1 as a 10 mg dose on Day 1, on Days 2 and 8 at 50% of the assigned dose on each day, and on Day 15 at 100% of the assigned dose. In Cycles 2–4, BI 836826 was administered at the assigned dose on Days 1 and 15 of each cycle. In Cycles 5–12, BI 836826 was administered at the assigned dose on Day 1 only. BI 836826 was administered in 4-week cycles. At the end of Cycle 12, bone marrow biopsies were performed to evaluate response. Patients with a CR, CR with incomplete marrow recovery (CRi), or minimal residual disease (MRD)-negative partial response (PR) could choose to receive 12 additional treatment cycles of the combination. Following completion of 12 or 24 cycles, or discontinuation due to disease progression, unacceptable toxicity, or withdrawal of consent, patients could continue to receive ibrutinib outside of the study at the discretion of the treating investigator.
Study assessments
Safety was assessed by determining the incidence and severity of adverse events, graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Assessment of laboratory parameters, vital signs, physical examination and ECG was also undertaken. DLTs were defined as: any non-hematologic adverse event of grade ≥ 3 related to BI 836826 or ibrutinib, except IRRs and grade 3 alanine aminotransferase and/or aspartate aminotransferase elevation without concomitant bilirubin elevation or any other asymptomatic grade 3 laboratory abnormality with spontaneous recovery within 1 week; hematologic adverse events related to BI 836826 or ibrutinib including grade 4 neutropenia with concomitant infection; grade 4 febrile neutropenia, and grade 3 febrile neutropenia not resolving within 72 hours; grade 4 thrombocytopenia with clinically significant bleeding; grade 4 anemia; any grade 5 hematologic adverse event. Adverse events of special interest (AESIs) included DLTs, infusion-related reactions of grade ≥ 3, late-onset infections, events indicative of drug-induced liver injury, and tumor lysis syndrome. Adverse events consistent with the definition of a DLT but occurring after the MTD evaluation period were also considered AESIs.
Overall response, duration of response, MRD and reduction in size of tumor lymph nodes were exploratory endpoints. Overall response was defined as patients who achieved CR, CRi, PR or PR with lymphocytosis (PR-L) according to modified IWCLL guidelines [13]. MRD was evaluated in both blood and bone marrow samples and was defined as < 1 leukemic cell per 10,000 leukocytes detected by multi-parameter flow cytometry.
Statistical methods
All analyses were descriptive and exploratory. No formal statistical analysis was conducted. Dose escalation was guided by a Bayesian 5-parameter logistic regression model (BLRM) with overdose control [14, 15] that was fitted to binary toxicity outcomes.
Results
Patients and treatment exposure
Between July 7, 2016 and July 9, 2019, 10 patients were screened, of whom 7 entered the run-in period with ibrutinib. Six patients were treated with BI 836826 plus ibrutinib across three sites in the United States (100 mg BI 836826: n = 3; 200 mg BI 836826: n = 3). The median age among treated patients was 71.0 years (range 57–76 years); all patients were Caucasian (Table 1).
Table 1 Patient demographics
BI 836826 dosea
100 mg
(n = 3) 200 mg
(n = 3) Total
(N = 6)
Male, n (%) 1 (33) 2 (67) 3 (50)
Race, n (%)
White 3 (100) 3 (100) 6 (100)
Ethnicity, n (%)
Not Hispanic/Latino 2 (67) 3 (100) 5 (83)
Hispanic/Latino 1 (33) 0 1 (17)
Median age, years (range) 75.0 (68–76) 67.0 (57–74) 71.0 (57–76)
ECOG PS at baseline, n (%)
0 1 (33) 1 (33) 2 (33)
1 2 (67) 2 (67) 4 (67)
RAI stage at diagnosis, n (%)
0
I
II
III
IV
1 (33)
0
1 (33)
0
1 (33)
1 (33)
1 (33)
0
1 (33)
0
2 (33)
1 (17)
1 (17)
1 (17)
1 (17)
Mean time from first diagnosis, years (SD) 10.4 (4.9) 11.1 (5.1) 10.7 (4.5)
Median number of previous CLL therapies (range) 1 (1–1) 4 (1–5) 1 (1–5)
Status after prior treatment
Relapsed
Refractory
2 (67)
1 (33)
2 (67)
1 (33)
4 (67)
2 (33)
aGiven in combination with ibrutinib 420 mg/day
CLL chronic lymphocytic leukemia, ECOG PS Eastern Cooperative Oncology Group Performance Status, RAI staging system for CLL [16], SD standard deviation
In the 100 mg BI 836826 cohort, one patient received two cycles and two patients received 22 cycles of BI 836826. The patients in the 200 mg cohort received 12, 16 and 20 cycles of BI 836826, respectively. All six patients discontinued treatment with BI 836826 (disease progression, n = 1; investigator discretion, n = 3; lack of response by cycle 12, n = 2). Mean duration of BI 836826 exposure was 440.2 days. There were no dose reductions. Two patients in the 100 mg BI 836826 cohort had at least one important protocol deviation. Both patients continued treatment with BI 836826 beyond cycle 12 without having a CR, CRi, or MRD-negative PR. One of these patients did not receive pre-medication with glucocorticoid in Cycle 3, as required per protocol.
DLTs during the MTD evaluation period, MTD and RP2D
No DLTs were reported during the MTD evaluation period with 100 or 200 mg BI 836826. However, the trial was discontinued before patients were treated with 400 mg BI 836826, and the MTD and RP2D were therefore not determined.
Safety
All six patients had at least one adverse event that was considered by the investigator to be related to BI 836826. The most common BI 836826-related adverse events (any grade/grade ≥ 33) were IRR (67%/17%), neutropenia (50%/33%), anemia (33%/33%), lymphopenia (33%/33%) and fatigue (33%/0%; Table 2). All IRRs (ten in four patients) were grade ≤ 2 except for one grade 3 IRR. The majority of IRRs occurred within the first two cycles and were resolved within a day.
Table 2 Adverse events considered related to BI 836826 occurring in > 2 patients
Any-grade
n (%) Grade 3/4
n (%)
Infusion-related reactions 4 (67) 1 (17)
Neutropenia 3 (50) 2 (33)
Anemia 2 (33) 2 (33)
Lymphopenia 2 (33) 2 (33)
Fatigue 2 (33) 0
Five patients had serious adverse events (considered related to study drug in 4 patients), including neutropenia, acute coronary syndrome, cellulitis, pseudomonal bacteremia and Bowen’s disease. No serious adverse event was experienced by more than one patient. There were no fatal adverse events, and no dose reductions or permanent discontinuations of BI 836826 due to adverse events. One patient had an ibrutinib dose reduction due to grade 2 neutropenia. After the MTD evaluation period, two patients in the 200 mg cohort reported grade 3 DLTs: a duodenal ulcer occurring on Day 325 and pseudomonal bacteremia (considered as related to study drug) on Day 280.
Three AESIs were recorded: the two DLTs reported after the MTD evaluation period and grade 2 basal cell carcinoma (Day 622).
Based on laboratory data, grade 4 neutropenia was reported for two patients (one patient in each dose cohort). Neither episode was associated with a concomitant infection. One patient in the 100 mg dose cohort had an episode of grade 4 thrombocytopenia, which was not associated with concomitant bleeding. Two patients (one in each dose cohort) had an episode of grade ≥ 3 decreased CD4 + T-cell count but there were no concomitant CD4+-related specific infections.
Efficacy
Overall response rate was 83% among the 6 evaluable patients (one CR and four PRs; Table 3) The ORR in the 200 mg cohort was 100% (one CR, two PR). Of five patients who underwent peripheral blood-based MRD analysis, two were MRD-negative, one in each cohort including the patient who achieved CR. Three patients had bone marrow aspirate samples analyzed for MRD. None were MRD-negative but one patient developed MRD-negative CR a month after study completion.
Table 3 Best overall response in patients receiving BI 836826 plus ibrutinib
BI 836826 dose
Patients with response, n (%) 100 mg
n = 3 200 mg
n = 3 Total
N = 6
Overall response 2 (67) 3 (100) 5 (83)
CR 0 1 (33) 1 (17)
CRi 0 0 0
PR 2 (67) 2 (67) 4 (67)
PR-L 0 0 0
Stable disease
Progressive disease 1 (33) 0 1 (17)
CR complete response, CRi complete response with incomplete marrow recovery, OR overall response (CR + CRi + PR + PR-L), PR partial response; PR-L partial response with lymphocytosis
All five patients were censored for the analysis of duration of overall response since they had discontinued before progression or death was observed. Mean (standard deviation [SD]) duration of response was 538.0 (31.1) days and 312.0 (143.96) days in the 100 mg and 200 mg BI 836826 cohorts, respectively. The median best percentage change from baseline in the SPD of lymph nodes was -81.2% (range -84% to -51%) in the 100 mg dose group and -79.2% (range -92% to -59%) in the 200 mg dose group (Fig. 1). Tumor size was reduced in all six patients.Fig. 1 Maximum change in SPD of lymph node lesions at best response
Discussion
In this phase Ib, dose-escalation study of BI 836826 plus ibrutinib in patients with relapsed/refractory CLL, no DLTs were observed during the MTD evaluation period in either the 100 mg or 200 mg BI 836320 cohorts. Despite these promising findings, the sponsor took the strategic decision to discontinue the clinical development of BI 836826, due to the rapidly evolving CLL treatment landscape. Accordingly, the MTD was not reached and the RP2D was not determined. There were no safety reasons to terminate the program. Nevertheless, the results from this study suggest that BI 836826 can be safely combined with ibrutinib, with no apparent additive toxicity. Adverse events associated with the combination were consistent with previous clinical experience with BI 836826 [12] or ibrutinib monotherapy [4].
The efficacy of ibrutinib in relapsed/refractory CLL is well established [4, 17, 18], with an objective response rate of 63% observed in the phase III study, RESONATE [4]. Of note, overall response rate to ibrutinib generally deepens over time [17, 19], and had increased to 91% by the final analysis of RESONATE [2, 20]. Our preliminary findings (83% overall response rate) suggest that the addition of anti-CD37 agents to ibrutinib could potentially improve efficacy. While the sample size is limited, the promising efficacy of this combination especially at the 200 mg dose (100%), supports ongoing exploration of agents, including those that target CD37, for fixed-duration therapy in CLL.
A number of CD37-based therapeutics are currently undergoing investigation in CLL, including otlertuzumab, an anti-CD37 mono-specific ADAPTIR therapeutic protein [8]. Notably, in phase II studies, the addition of otlertuzumab to bendamustine greatly enhanced response compared with bendamustine alone in relapsed CLL patients [21]. Additionally, 212Pb-NNV003, a CD37-targeted radioimmunotherapy, has demonstrated notable anti-tumor effects in an animal model of CLL [22].
In conclusion, BI 836826 plus ibrutinib did not exceed the MTD at doses up to 200 mg in patients with CLL, and no DLTs were reported in the MTD evaluation period. While the RPTD and MTD were not formally established, our findings suggest that an anti-CD37 antibody may be combined with ibrutinib, or potentially other BTK inhibitors, for the treatment of relapsed/refractory CLL. Since continuous therapy with BTK inhibitors leads to toxicities, therapeutic resistance and is associated with high costs, exploration of novel combinations involving active agents with different therapeutic targets remains an unmet medical need.
Acknowledgements
We thank the patients, their families, and all the investigators who participated in these studies. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version.
Funding
The conduct of this research, study design, data collection, and analysis was financially supported by Boehringer Ingelheim. Medical writing assistance, funded by Boehringer Ingelheim, was provided by Lynn Pritchard, DPhil, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this manuscript.
Data availability
The clinical study report (including appendices, but without line listings) and other clinical documents related to this study may be accessed on request. Prior to providing access, the documents and data will be examined, and, if necessary, redacted and de-identified to protect the personal data of study participants and personnel, and to respect the boundaries of the informed consent of the study participants. See https://trials.boehringer-ingelheim.com/data_sharing/sharing.html#accordion-1-2 for further details. Bona fide, qualified scientific and medical researchers may request access to de-identified, analyzable patient-level study data, together with documentation describing the structure and content of the datasets. Researchers should use https://clinicalstudydatarequest.com/ to request access to raw data from this study.
Compliance with ethical standards
Conflict of interest
AVD has received consulting fees from AstraZeneca, Abbvie, BeiGene, Genentech, TG Therapeutics, Janssen, Rigel Pharmaceutical, Nurix, Bayer Oncology, Karyopharm and Pharmacyclics and has ongoing research funding from AstraZeneca, Takeda Oncology, Gilead Sciences, Bayer Oncology, Genentech, Verastem Oncology, MEI and Bristol Myers Squibb.
SES reports grants from Boehringer Ingelheim during the conduct of the study and personal fees from Pharmacyclics outside the submitted work.
TS reports institutional funds fees from Boehringer Ingelheim during the conduct of the study; personal fees from AstraZeneca, PCYC, Janssen, Juno, Celgene, BeiGene and Kite Pharma outside the submitted work.
AMQ, DM and DS are employees of Boehringer Ingelheim.
JRB reports personal fees from Abbvie, Acerta/AstraZeneca, Astellas, BeiGene, Catapult Therapeutics, Dynamo Therapeutics, Genentech/Roche, Janssen, Juno/Celgene, Kite, MEI Pharma, Nextcea, Novartis, Octapharma, Pfizer, Pharmacyclics, Redx, Rigel, Sun, Sunesis, Teva, and TG Therapeutics; grants and personal fees from Gilead, Loxo/Lilly and Verastem outside the submitted work. She has sat on Data Safety Monitoring Boards for Invectys and Morphosys.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | IBRUTINIB | DrugsGivenReaction | CC BY | 33683501 | 19,065,111 | 2021-08 |
What was the administration route of drug 'IBRUTINIB'? | A phase Ib, open label, dose escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia.
BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a transmembrane protein expressed on normal and malignant B cells. This open-label, phase Ib, dose-escalation study was conducted to determine the recommended phase II dose (RP2D) of BI 836826 + ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Eligible patients received 420 mg/day of ibrutinib with escalating doses of BI 836826. BI 836826 was administered in 4-week cycles. After Cycle 12, patients achieving complete response (CR), CR with incomplete marrow recovery, or minimal residual disease-negative partial response could continue to receive BI 836826 + ibrutinib every 4 weeks for ≤ 12 additional cycles. Patients received either 100 mg (n = 3) or 200 mg (n = 3) BI 836826 + ibrutinib. In the 100 mg BI 836826 cohort, one patient received two cycles and two patients received 22 cycles of BI 836826. In the 200 mg BI 836826 cohort, patients received 12, 16 and 20 cycles of BI 836826, respectively. All patients discontinued BI 836826 and continued ibrutinib outside the trial. No dose-limiting toxicities were reported in the maximum tolerated dose (MTD) evaluation period. As the trial was discontinued before the MTD was reached, the RP2D was not determined. Grade 3/4 adverse events (AEs) were predominantly hematological. Pseudomonal bacteremia was the only drug-related AE of special interest. BI 836826 + ibrutinib did not exceed the MTD at doses up to 200 mg in patients with CLL. However, RP2D and MTD were not formally established, as the sponsor discontinued the trial.
Introduction
The Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, is well established in the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia (CLL) [1–3]. While ibrutinib monotherapy is associated with impressive response rates in CLL patients, including those with del(17p) [1, 4], deep responses are rare, thus necessitating continuous use. This can result in cumulative toxicities, leading to treatment discontinuation [5]. Furthermore, patients often become resistant to long-term treatment, potentially leading to disease progression or transformation [6]. Therefore, there is clinical rationale for combining ibrutinib with other agents that could increase depth of response and delay development of resistance.
Preclinical and clinical studies have demonstrated that CD37, a tetraspanin B cell surface molecule, is a potential drug target in patients with CLL [7–10].
BI 836826 is a chimeric mouse–human anti-CD37 monoclonal antibody engineered to enhance binding and effector function that mediates direct antibody-dependent cell-mediated cytotoxicity (ADCC) against CLL cells [11]. A phase I, dose escalation study of BI 836826 in patients with relapsed/refractory CLL demonstrated acceptable tolerability and notable efficacy, particularly in patients with poor-risk features such as del(17p) and TP53 mutations [12]. In this phase Ib, dose-escalation study, we investigated the combination of ibrutinib and BI 836826 in patients with relapsed/refractory CLL.
Patients and methods
Patients
Eligible patients were ≤ 18 years old with relapsed/refractory CLL according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria [13]. All patients had received at least one prior line of systemic treatment. Prior BTK inhibitors were not allowed. Other eligibility criteria included Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0–2; clinically quantifiable disease burden (absolute lymphocyte count > 10,000/µL, measurable lymphadenopathy, or quantifiable bone marrow infiltration); adequate organ function; and residual non-hematological toxicity from prior treatment of grade ≤ 1.
Key exclusion criteria were: any CD37-targeting antibody or CD37 antibody-drug conjugate; allogeneic stem cell transplant within 1 year or active graft-versus-host disease; known transformation of CLL to an aggressive B-cell malignancy at the time of screening; history of non-CLL malignancy except for adequately treated in-situ, stage I or II carcinoma in complete response (CR) or any other cancer that had been in CR for ≥ 2 years after the end of cancer treatment; and active uncontrolled autoimmune cytopenia.
The trial was carried out in accordance with the Declaration of Helsinki, Good Clinical Practice Guidelines, applicable regulatory requirements and Boehringer Ingelheim standard operating procedures. The study protocol was approved by the Institutional Review Boards of all participating institutions. Written informed consent was obtained from all patients.
Study design and treatment
The primary objectives of this single arm, open-label, dose escalation phase Ib study were to determine the recommended phase II dose (RP2D) of BI 836826 plus ibrutinib in patients with relapsed/refractory CLL, and the number of patients with dose-limiting toxicities (DLTs) during the maximum tolerated dose (MTD) evaluation period (Cycle 1). Other objectives were the determination of the MTD, safety and efficacy of the combination.
Eligible patients underwent a two-week run-in phase with ibrutinib and remained on ibrutinib throughout the trial at a constant dose of 420 mg daily. BI 836826 was planned at dose levels of 100, 200, 400, 600, 800 and 1400 mg. Mandatory pre-medication (antihistamine, analgesic and glucocorticoid) to mitigate the risk of infusion-related reactions (IRRs) was given 30–120 min prior to BI 836826 administration. BI 836826 was then administered via rate-controlled intravenous infusion in Cycle 1 as a 10 mg dose on Day 1, on Days 2 and 8 at 50% of the assigned dose on each day, and on Day 15 at 100% of the assigned dose. In Cycles 2–4, BI 836826 was administered at the assigned dose on Days 1 and 15 of each cycle. In Cycles 5–12, BI 836826 was administered at the assigned dose on Day 1 only. BI 836826 was administered in 4-week cycles. At the end of Cycle 12, bone marrow biopsies were performed to evaluate response. Patients with a CR, CR with incomplete marrow recovery (CRi), or minimal residual disease (MRD)-negative partial response (PR) could choose to receive 12 additional treatment cycles of the combination. Following completion of 12 or 24 cycles, or discontinuation due to disease progression, unacceptable toxicity, or withdrawal of consent, patients could continue to receive ibrutinib outside of the study at the discretion of the treating investigator.
Study assessments
Safety was assessed by determining the incidence and severity of adverse events, graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Assessment of laboratory parameters, vital signs, physical examination and ECG was also undertaken. DLTs were defined as: any non-hematologic adverse event of grade ≥ 3 related to BI 836826 or ibrutinib, except IRRs and grade 3 alanine aminotransferase and/or aspartate aminotransferase elevation without concomitant bilirubin elevation or any other asymptomatic grade 3 laboratory abnormality with spontaneous recovery within 1 week; hematologic adverse events related to BI 836826 or ibrutinib including grade 4 neutropenia with concomitant infection; grade 4 febrile neutropenia, and grade 3 febrile neutropenia not resolving within 72 hours; grade 4 thrombocytopenia with clinically significant bleeding; grade 4 anemia; any grade 5 hematologic adverse event. Adverse events of special interest (AESIs) included DLTs, infusion-related reactions of grade ≥ 3, late-onset infections, events indicative of drug-induced liver injury, and tumor lysis syndrome. Adverse events consistent with the definition of a DLT but occurring after the MTD evaluation period were also considered AESIs.
Overall response, duration of response, MRD and reduction in size of tumor lymph nodes were exploratory endpoints. Overall response was defined as patients who achieved CR, CRi, PR or PR with lymphocytosis (PR-L) according to modified IWCLL guidelines [13]. MRD was evaluated in both blood and bone marrow samples and was defined as < 1 leukemic cell per 10,000 leukocytes detected by multi-parameter flow cytometry.
Statistical methods
All analyses were descriptive and exploratory. No formal statistical analysis was conducted. Dose escalation was guided by a Bayesian 5-parameter logistic regression model (BLRM) with overdose control [14, 15] that was fitted to binary toxicity outcomes.
Results
Patients and treatment exposure
Between July 7, 2016 and July 9, 2019, 10 patients were screened, of whom 7 entered the run-in period with ibrutinib. Six patients were treated with BI 836826 plus ibrutinib across three sites in the United States (100 mg BI 836826: n = 3; 200 mg BI 836826: n = 3). The median age among treated patients was 71.0 years (range 57–76 years); all patients were Caucasian (Table 1).
Table 1 Patient demographics
BI 836826 dosea
100 mg
(n = 3) 200 mg
(n = 3) Total
(N = 6)
Male, n (%) 1 (33) 2 (67) 3 (50)
Race, n (%)
White 3 (100) 3 (100) 6 (100)
Ethnicity, n (%)
Not Hispanic/Latino 2 (67) 3 (100) 5 (83)
Hispanic/Latino 1 (33) 0 1 (17)
Median age, years (range) 75.0 (68–76) 67.0 (57–74) 71.0 (57–76)
ECOG PS at baseline, n (%)
0 1 (33) 1 (33) 2 (33)
1 2 (67) 2 (67) 4 (67)
RAI stage at diagnosis, n (%)
0
I
II
III
IV
1 (33)
0
1 (33)
0
1 (33)
1 (33)
1 (33)
0
1 (33)
0
2 (33)
1 (17)
1 (17)
1 (17)
1 (17)
Mean time from first diagnosis, years (SD) 10.4 (4.9) 11.1 (5.1) 10.7 (4.5)
Median number of previous CLL therapies (range) 1 (1–1) 4 (1–5) 1 (1–5)
Status after prior treatment
Relapsed
Refractory
2 (67)
1 (33)
2 (67)
1 (33)
4 (67)
2 (33)
aGiven in combination with ibrutinib 420 mg/day
CLL chronic lymphocytic leukemia, ECOG PS Eastern Cooperative Oncology Group Performance Status, RAI staging system for CLL [16], SD standard deviation
In the 100 mg BI 836826 cohort, one patient received two cycles and two patients received 22 cycles of BI 836826. The patients in the 200 mg cohort received 12, 16 and 20 cycles of BI 836826, respectively. All six patients discontinued treatment with BI 836826 (disease progression, n = 1; investigator discretion, n = 3; lack of response by cycle 12, n = 2). Mean duration of BI 836826 exposure was 440.2 days. There were no dose reductions. Two patients in the 100 mg BI 836826 cohort had at least one important protocol deviation. Both patients continued treatment with BI 836826 beyond cycle 12 without having a CR, CRi, or MRD-negative PR. One of these patients did not receive pre-medication with glucocorticoid in Cycle 3, as required per protocol.
DLTs during the MTD evaluation period, MTD and RP2D
No DLTs were reported during the MTD evaluation period with 100 or 200 mg BI 836826. However, the trial was discontinued before patients were treated with 400 mg BI 836826, and the MTD and RP2D were therefore not determined.
Safety
All six patients had at least one adverse event that was considered by the investigator to be related to BI 836826. The most common BI 836826-related adverse events (any grade/grade ≥ 33) were IRR (67%/17%), neutropenia (50%/33%), anemia (33%/33%), lymphopenia (33%/33%) and fatigue (33%/0%; Table 2). All IRRs (ten in four patients) were grade ≤ 2 except for one grade 3 IRR. The majority of IRRs occurred within the first two cycles and were resolved within a day.
Table 2 Adverse events considered related to BI 836826 occurring in > 2 patients
Any-grade
n (%) Grade 3/4
n (%)
Infusion-related reactions 4 (67) 1 (17)
Neutropenia 3 (50) 2 (33)
Anemia 2 (33) 2 (33)
Lymphopenia 2 (33) 2 (33)
Fatigue 2 (33) 0
Five patients had serious adverse events (considered related to study drug in 4 patients), including neutropenia, acute coronary syndrome, cellulitis, pseudomonal bacteremia and Bowen’s disease. No serious adverse event was experienced by more than one patient. There were no fatal adverse events, and no dose reductions or permanent discontinuations of BI 836826 due to adverse events. One patient had an ibrutinib dose reduction due to grade 2 neutropenia. After the MTD evaluation period, two patients in the 200 mg cohort reported grade 3 DLTs: a duodenal ulcer occurring on Day 325 and pseudomonal bacteremia (considered as related to study drug) on Day 280.
Three AESIs were recorded: the two DLTs reported after the MTD evaluation period and grade 2 basal cell carcinoma (Day 622).
Based on laboratory data, grade 4 neutropenia was reported for two patients (one patient in each dose cohort). Neither episode was associated with a concomitant infection. One patient in the 100 mg dose cohort had an episode of grade 4 thrombocytopenia, which was not associated with concomitant bleeding. Two patients (one in each dose cohort) had an episode of grade ≥ 3 decreased CD4 + T-cell count but there were no concomitant CD4+-related specific infections.
Efficacy
Overall response rate was 83% among the 6 evaluable patients (one CR and four PRs; Table 3) The ORR in the 200 mg cohort was 100% (one CR, two PR). Of five patients who underwent peripheral blood-based MRD analysis, two were MRD-negative, one in each cohort including the patient who achieved CR. Three patients had bone marrow aspirate samples analyzed for MRD. None were MRD-negative but one patient developed MRD-negative CR a month after study completion.
Table 3 Best overall response in patients receiving BI 836826 plus ibrutinib
BI 836826 dose
Patients with response, n (%) 100 mg
n = 3 200 mg
n = 3 Total
N = 6
Overall response 2 (67) 3 (100) 5 (83)
CR 0 1 (33) 1 (17)
CRi 0 0 0
PR 2 (67) 2 (67) 4 (67)
PR-L 0 0 0
Stable disease
Progressive disease 1 (33) 0 1 (17)
CR complete response, CRi complete response with incomplete marrow recovery, OR overall response (CR + CRi + PR + PR-L), PR partial response; PR-L partial response with lymphocytosis
All five patients were censored for the analysis of duration of overall response since they had discontinued before progression or death was observed. Mean (standard deviation [SD]) duration of response was 538.0 (31.1) days and 312.0 (143.96) days in the 100 mg and 200 mg BI 836826 cohorts, respectively. The median best percentage change from baseline in the SPD of lymph nodes was -81.2% (range -84% to -51%) in the 100 mg dose group and -79.2% (range -92% to -59%) in the 200 mg dose group (Fig. 1). Tumor size was reduced in all six patients.Fig. 1 Maximum change in SPD of lymph node lesions at best response
Discussion
In this phase Ib, dose-escalation study of BI 836826 plus ibrutinib in patients with relapsed/refractory CLL, no DLTs were observed during the MTD evaluation period in either the 100 mg or 200 mg BI 836320 cohorts. Despite these promising findings, the sponsor took the strategic decision to discontinue the clinical development of BI 836826, due to the rapidly evolving CLL treatment landscape. Accordingly, the MTD was not reached and the RP2D was not determined. There were no safety reasons to terminate the program. Nevertheless, the results from this study suggest that BI 836826 can be safely combined with ibrutinib, with no apparent additive toxicity. Adverse events associated with the combination were consistent with previous clinical experience with BI 836826 [12] or ibrutinib monotherapy [4].
The efficacy of ibrutinib in relapsed/refractory CLL is well established [4, 17, 18], with an objective response rate of 63% observed in the phase III study, RESONATE [4]. Of note, overall response rate to ibrutinib generally deepens over time [17, 19], and had increased to 91% by the final analysis of RESONATE [2, 20]. Our preliminary findings (83% overall response rate) suggest that the addition of anti-CD37 agents to ibrutinib could potentially improve efficacy. While the sample size is limited, the promising efficacy of this combination especially at the 200 mg dose (100%), supports ongoing exploration of agents, including those that target CD37, for fixed-duration therapy in CLL.
A number of CD37-based therapeutics are currently undergoing investigation in CLL, including otlertuzumab, an anti-CD37 mono-specific ADAPTIR therapeutic protein [8]. Notably, in phase II studies, the addition of otlertuzumab to bendamustine greatly enhanced response compared with bendamustine alone in relapsed CLL patients [21]. Additionally, 212Pb-NNV003, a CD37-targeted radioimmunotherapy, has demonstrated notable anti-tumor effects in an animal model of CLL [22].
In conclusion, BI 836826 plus ibrutinib did not exceed the MTD at doses up to 200 mg in patients with CLL, and no DLTs were reported in the MTD evaluation period. While the RPTD and MTD were not formally established, our findings suggest that an anti-CD37 antibody may be combined with ibrutinib, or potentially other BTK inhibitors, for the treatment of relapsed/refractory CLL. Since continuous therapy with BTK inhibitors leads to toxicities, therapeutic resistance and is associated with high costs, exploration of novel combinations involving active agents with different therapeutic targets remains an unmet medical need.
Acknowledgements
We thank the patients, their families, and all the investigators who participated in these studies. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version.
Funding
The conduct of this research, study design, data collection, and analysis was financially supported by Boehringer Ingelheim. Medical writing assistance, funded by Boehringer Ingelheim, was provided by Lynn Pritchard, DPhil, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this manuscript.
Data availability
The clinical study report (including appendices, but without line listings) and other clinical documents related to this study may be accessed on request. Prior to providing access, the documents and data will be examined, and, if necessary, redacted and de-identified to protect the personal data of study participants and personnel, and to respect the boundaries of the informed consent of the study participants. See https://trials.boehringer-ingelheim.com/data_sharing/sharing.html#accordion-1-2 for further details. Bona fide, qualified scientific and medical researchers may request access to de-identified, analyzable patient-level study data, together with documentation describing the structure and content of the datasets. Researchers should use https://clinicalstudydatarequest.com/ to request access to raw data from this study.
Compliance with ethical standards
Conflict of interest
AVD has received consulting fees from AstraZeneca, Abbvie, BeiGene, Genentech, TG Therapeutics, Janssen, Rigel Pharmaceutical, Nurix, Bayer Oncology, Karyopharm and Pharmacyclics and has ongoing research funding from AstraZeneca, Takeda Oncology, Gilead Sciences, Bayer Oncology, Genentech, Verastem Oncology, MEI and Bristol Myers Squibb.
SES reports grants from Boehringer Ingelheim during the conduct of the study and personal fees from Pharmacyclics outside the submitted work.
TS reports institutional funds fees from Boehringer Ingelheim during the conduct of the study; personal fees from AstraZeneca, PCYC, Janssen, Juno, Celgene, BeiGene and Kite Pharma outside the submitted work.
AMQ, DM and DS are employees of Boehringer Ingelheim.
JRB reports personal fees from Abbvie, Acerta/AstraZeneca, Astellas, BeiGene, Catapult Therapeutics, Dynamo Therapeutics, Genentech/Roche, Janssen, Juno/Celgene, Kite, MEI Pharma, Nextcea, Novartis, Octapharma, Pfizer, Pharmacyclics, Redx, Rigel, Sun, Sunesis, Teva, and TG Therapeutics; grants and personal fees from Gilead, Loxo/Lilly and Verastem outside the submitted work. She has sat on Data Safety Monitoring Boards for Invectys and Morphosys.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Oral | DrugAdministrationRoute | CC BY | 33683501 | 19,065,111 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Brain stem infarction'. | Emergent stenting after intravenous thrombolysis for isolated basilar artery dissection in a patient with acute ischemic stroke: a case report.
BACKGROUND
Isolated basilar artery dissection (IBAD) is a rare but important cause of ischemic stroke. Anti-thrombotic therapy is often used to treat IBAD-related ischemic stroke, but selected cases might need more aggressive treatment. There is no previous report of emergent stenting for IBAD-related ischemic stroke after intravenous thrombolysis.
METHODS
A 53-year-old Japanese woman was admitted to our hospital with disturbance of consciousness, right hemiplegia, severe dysarthria, and total gaze paralysis. Brain magnetic resonance imaging revealed no ischemic lesion, but magnetic resonance angiography showed stenosis in the basilar artery. After initiation of intravenous thrombolysis, her neurological symptoms dramatically improved. Five hours later, however, her symptoms deteriorated again. Cerebral angiography showed IBAD. Emergent stenting was successfully performed. At 90 days after stroke onset, she had no significant disability, with a modified Rankin scale score of 1.
CONCLUSIONS
Emergent stenting can be an effective treatment for patients with IBAD-related ischemic stroke who are resistant to IV-rtPA.
Background
Isolated basilar artery (BA) dissection (IBAD) is a rare but important cause of ischemic stroke (incidence, 1/400,000/year) [1]. It is known to have a poor prognosis, with a mortality rate ranging from 10 to 78.9% [2]. Anti-thrombotic therapy is often used to treat IBAD-related ischemic stroke, but selected cases might need more aggressive treatment [3]. Although some cases of endovascular stenting for IBAD have been reported, the procedures were performed electively for progressive ischemic symptoms despite adequate anti-thrombotic therapy [2–5]. To the best of our knowledge, there is no previous report of emergent stenting for IBAD-related ischemic stroke after intravenous thrombolysis. We report a case of IBAD in a patient with acute ischemic stroke who underwent emergent stenting for neurological deterioration after intravenous thrombolysis.
Case presentation
A 53-year-old Japanese woman with a medical history of diabetes mellitus and no other risk factors for arteriosclerosis was admitted to our hospital. Physical examination showed a Glasgow Coma Scale score of E3V3M4, right hemiplegia, severe dysarthria, and total gaze paralysis. The National Institute of Health Stroke Scale (NIHSS) score was 22. Brain magnetic resonance imaging (MRI) at 90 minutes from the onset of symptoms revealed no high-intensity area on diffusion-weighted imaging (Fig. 1a). Brain magnetic resonance angiography showed stenosis in the BA (Fig. 1b). After initiation of intravenous administration of recombinant tissue plasminogen activator (IV-rtPA), neurological symptoms improved with an NIHSS of 4; however, 5 hours after IV-rtPA, the symptoms deteriorated again with an NIHSS of 22. Cerebral angiography showed severe stenosis and double lumen in the BA (Fig. 1c–f). We deployed Enterprise Vascular Reconstruction Device (VRD) 4.5 × 22 mm2 and 4.5 × 28 mm2 (Johnson & Johnson Codman, Miami, FL, USA) from the right posterior cerebral artery to the left vertebral artery (Fig. 1g) after administration of 200 mg of aspirin and 300 mg of clopidogrel. On day 2, 100 mg/day aspirin and 75 mg/day clopidogrel were initiated. Although MRI revealed small pontine infarction (Fig. 1h), the patient’s neurological deficit gradually improved. She was transferred to the rehabilitation center on day 23 with an NIHSS of 3. At 90 days from stroke onset, she had no significant disability with an NIHSS of 0 and a modified Rankin scale score of 1.Fig. 1 a Brain magnetic resonance imaging (MRI) at 90 minutes from symptom onset showing no high-intensity area on diffusion-weighted imaging (DWI). b Brain magnetic resonance angiography showing stenosis in the middle portion of the basilar artery (BA). c Cerebral angiography (45° right-anterior oblique view) showing intimal flap and double lumen in the middle and distal portions of the BA. Maximum intensity projection images of 3D rotational angiography showing double lumen of the BA in the coronal view (d), sagittal view (e), and axial view (f). g Cerebral angiography (45° right-anterior oblique view) after stenting. Enterprise VRD 4.5 × 22 mm2 (arrow: distal and proximal marker) and 4.5 × 28 mm2 (arrowhead: distal and proximal marker) was deployed from the P1 portion of the right posterior cerebral artery to the V4 portion of the left vertebral artery. h Brain MRI on day 6 showing left-sided pontine infarction on DWI
Discussion and conclusions
This is the first case report of a patient with acute ischemic stroke due to IBAD who underwent emergent stenting for neurological deterioration after IV-rtPA. Although some cases of stenting for IBAD have been reported, most of the procedures in these cases were performed after at least 3 days of dual antiplatelet therapy [2–5], and there is only one report of stenting in the hyper-acute phase of ischemic stroke [3]. There is no previous report of emergent stenting after IV-rtPA for IBAD-related ischemic stroke. Our case suggests that even for patients with IBAD-related ischemic stroke who are resistant to IV-rtPA, stenting can be a safe and effective treatment option.
Optimal treatment for ischemic stroke with IBAD has not been established. In clinical practice, anticoagulant or antiplatelet therapies are usually used. However, conservative management occasionally results in a poor prognosis [3, 6]. Efficacy and safety of IV-rtPA for ischemic stroke due to intracranial artery dissection have not been established, and in some cases, neurological deterioration after IV-rtPA is noted [7]. For patients presenting with progressive ischemia despite adequate medical treatments including IV-rtPA, stenting can be an alternative treatment option with a relatively good prognosis.
The benefits of stenting for IBAD are not completely understood. Occlusion of perforating branches of the BA is reported to be the main mechanism underlying IBAD-related ischemic stroke [8]. We speculate that thrombus formation in the false lumen might obstruct the blood flow in perforating branches by compressing the origin of these branches, resulting in brainstem infarction. IV-rtPA can prevent thrombus formation, but its efficacy is transient. In contrast, stenting can repair the intimal flap, which is the inflow route of the false lumen. Reduced blood flow into the false lumen will lead to less thrombus formation in this structure.
In conclusion, emergent stenting can be an effective treatment for patients with IBAD-related ischemic stroke who are resistant to IV-rtPA.
Abbreviations
BA Basilar artery
IBAD Isolated basilar artery dissection
NIHSS National Institute of Health Stroke Scale
MRI Magnetic resonance imaging
IV-rtPA Intravenous recombinant tissue plasminogen activator
DWI Diffusion-weighted imaging
Acknowledgements
None.
Authors’ contributions
TG was responsible for the conception and design of the work as well as data analysis and interpretation. NO, TI, HT, SM, MU, and YY were responsible for data collection. TG drafted the article, which was critically revised by NO, TI, HT, SM, MU, and YY. TG, NO, TI, HT, SM, MU, and YY were responsible for the final approval of the version to be published.
Funding
The authors have no funding to declare.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written 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-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ALTEPLASE | DrugsGivenReaction | CC BY | 33685504 | 19,051,578 | 2021-03-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vertebral artery dissection'. | Emergent stenting after intravenous thrombolysis for isolated basilar artery dissection in a patient with acute ischemic stroke: a case report.
BACKGROUND
Isolated basilar artery dissection (IBAD) is a rare but important cause of ischemic stroke. Anti-thrombotic therapy is often used to treat IBAD-related ischemic stroke, but selected cases might need more aggressive treatment. There is no previous report of emergent stenting for IBAD-related ischemic stroke after intravenous thrombolysis.
METHODS
A 53-year-old Japanese woman was admitted to our hospital with disturbance of consciousness, right hemiplegia, severe dysarthria, and total gaze paralysis. Brain magnetic resonance imaging revealed no ischemic lesion, but magnetic resonance angiography showed stenosis in the basilar artery. After initiation of intravenous thrombolysis, her neurological symptoms dramatically improved. Five hours later, however, her symptoms deteriorated again. Cerebral angiography showed IBAD. Emergent stenting was successfully performed. At 90 days after stroke onset, she had no significant disability, with a modified Rankin scale score of 1.
CONCLUSIONS
Emergent stenting can be an effective treatment for patients with IBAD-related ischemic stroke who are resistant to IV-rtPA.
Background
Isolated basilar artery (BA) dissection (IBAD) is a rare but important cause of ischemic stroke (incidence, 1/400,000/year) [1]. It is known to have a poor prognosis, with a mortality rate ranging from 10 to 78.9% [2]. Anti-thrombotic therapy is often used to treat IBAD-related ischemic stroke, but selected cases might need more aggressive treatment [3]. Although some cases of endovascular stenting for IBAD have been reported, the procedures were performed electively for progressive ischemic symptoms despite adequate anti-thrombotic therapy [2–5]. To the best of our knowledge, there is no previous report of emergent stenting for IBAD-related ischemic stroke after intravenous thrombolysis. We report a case of IBAD in a patient with acute ischemic stroke who underwent emergent stenting for neurological deterioration after intravenous thrombolysis.
Case presentation
A 53-year-old Japanese woman with a medical history of diabetes mellitus and no other risk factors for arteriosclerosis was admitted to our hospital. Physical examination showed a Glasgow Coma Scale score of E3V3M4, right hemiplegia, severe dysarthria, and total gaze paralysis. The National Institute of Health Stroke Scale (NIHSS) score was 22. Brain magnetic resonance imaging (MRI) at 90 minutes from the onset of symptoms revealed no high-intensity area on diffusion-weighted imaging (Fig. 1a). Brain magnetic resonance angiography showed stenosis in the BA (Fig. 1b). After initiation of intravenous administration of recombinant tissue plasminogen activator (IV-rtPA), neurological symptoms improved with an NIHSS of 4; however, 5 hours after IV-rtPA, the symptoms deteriorated again with an NIHSS of 22. Cerebral angiography showed severe stenosis and double lumen in the BA (Fig. 1c–f). We deployed Enterprise Vascular Reconstruction Device (VRD) 4.5 × 22 mm2 and 4.5 × 28 mm2 (Johnson & Johnson Codman, Miami, FL, USA) from the right posterior cerebral artery to the left vertebral artery (Fig. 1g) after administration of 200 mg of aspirin and 300 mg of clopidogrel. On day 2, 100 mg/day aspirin and 75 mg/day clopidogrel were initiated. Although MRI revealed small pontine infarction (Fig. 1h), the patient’s neurological deficit gradually improved. She was transferred to the rehabilitation center on day 23 with an NIHSS of 3. At 90 days from stroke onset, she had no significant disability with an NIHSS of 0 and a modified Rankin scale score of 1.Fig. 1 a Brain magnetic resonance imaging (MRI) at 90 minutes from symptom onset showing no high-intensity area on diffusion-weighted imaging (DWI). b Brain magnetic resonance angiography showing stenosis in the middle portion of the basilar artery (BA). c Cerebral angiography (45° right-anterior oblique view) showing intimal flap and double lumen in the middle and distal portions of the BA. Maximum intensity projection images of 3D rotational angiography showing double lumen of the BA in the coronal view (d), sagittal view (e), and axial view (f). g Cerebral angiography (45° right-anterior oblique view) after stenting. Enterprise VRD 4.5 × 22 mm2 (arrow: distal and proximal marker) and 4.5 × 28 mm2 (arrowhead: distal and proximal marker) was deployed from the P1 portion of the right posterior cerebral artery to the V4 portion of the left vertebral artery. h Brain MRI on day 6 showing left-sided pontine infarction on DWI
Discussion and conclusions
This is the first case report of a patient with acute ischemic stroke due to IBAD who underwent emergent stenting for neurological deterioration after IV-rtPA. Although some cases of stenting for IBAD have been reported, most of the procedures in these cases were performed after at least 3 days of dual antiplatelet therapy [2–5], and there is only one report of stenting in the hyper-acute phase of ischemic stroke [3]. There is no previous report of emergent stenting after IV-rtPA for IBAD-related ischemic stroke. Our case suggests that even for patients with IBAD-related ischemic stroke who are resistant to IV-rtPA, stenting can be a safe and effective treatment option.
Optimal treatment for ischemic stroke with IBAD has not been established. In clinical practice, anticoagulant or antiplatelet therapies are usually used. However, conservative management occasionally results in a poor prognosis [3, 6]. Efficacy and safety of IV-rtPA for ischemic stroke due to intracranial artery dissection have not been established, and in some cases, neurological deterioration after IV-rtPA is noted [7]. For patients presenting with progressive ischemia despite adequate medical treatments including IV-rtPA, stenting can be an alternative treatment option with a relatively good prognosis.
The benefits of stenting for IBAD are not completely understood. Occlusion of perforating branches of the BA is reported to be the main mechanism underlying IBAD-related ischemic stroke [8]. We speculate that thrombus formation in the false lumen might obstruct the blood flow in perforating branches by compressing the origin of these branches, resulting in brainstem infarction. IV-rtPA can prevent thrombus formation, but its efficacy is transient. In contrast, stenting can repair the intimal flap, which is the inflow route of the false lumen. Reduced blood flow into the false lumen will lead to less thrombus formation in this structure.
In conclusion, emergent stenting can be an effective treatment for patients with IBAD-related ischemic stroke who are resistant to IV-rtPA.
Abbreviations
BA Basilar artery
IBAD Isolated basilar artery dissection
NIHSS National Institute of Health Stroke Scale
MRI Magnetic resonance imaging
IV-rtPA Intravenous recombinant tissue plasminogen activator
DWI Diffusion-weighted imaging
Acknowledgements
None.
Authors’ contributions
TG was responsible for the conception and design of the work as well as data analysis and interpretation. NO, TI, HT, SM, MU, and YY were responsible for data collection. TG drafted the article, which was critically revised by NO, TI, HT, SM, MU, and YY. TG, NO, TI, HT, SM, MU, and YY were responsible for the final approval of the version to be published.
Funding
The authors have no funding to declare.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written 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-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ALTEPLASE | DrugsGivenReaction | CC BY | 33685504 | 19,051,578 | 2021-03-09 |
What was the administration route of drug 'ALTEPLASE'? | Emergent stenting after intravenous thrombolysis for isolated basilar artery dissection in a patient with acute ischemic stroke: a case report.
BACKGROUND
Isolated basilar artery dissection (IBAD) is a rare but important cause of ischemic stroke. Anti-thrombotic therapy is often used to treat IBAD-related ischemic stroke, but selected cases might need more aggressive treatment. There is no previous report of emergent stenting for IBAD-related ischemic stroke after intravenous thrombolysis.
METHODS
A 53-year-old Japanese woman was admitted to our hospital with disturbance of consciousness, right hemiplegia, severe dysarthria, and total gaze paralysis. Brain magnetic resonance imaging revealed no ischemic lesion, but magnetic resonance angiography showed stenosis in the basilar artery. After initiation of intravenous thrombolysis, her neurological symptoms dramatically improved. Five hours later, however, her symptoms deteriorated again. Cerebral angiography showed IBAD. Emergent stenting was successfully performed. At 90 days after stroke onset, she had no significant disability, with a modified Rankin scale score of 1.
CONCLUSIONS
Emergent stenting can be an effective treatment for patients with IBAD-related ischemic stroke who are resistant to IV-rtPA.
Background
Isolated basilar artery (BA) dissection (IBAD) is a rare but important cause of ischemic stroke (incidence, 1/400,000/year) [1]. It is known to have a poor prognosis, with a mortality rate ranging from 10 to 78.9% [2]. Anti-thrombotic therapy is often used to treat IBAD-related ischemic stroke, but selected cases might need more aggressive treatment [3]. Although some cases of endovascular stenting for IBAD have been reported, the procedures were performed electively for progressive ischemic symptoms despite adequate anti-thrombotic therapy [2–5]. To the best of our knowledge, there is no previous report of emergent stenting for IBAD-related ischemic stroke after intravenous thrombolysis. We report a case of IBAD in a patient with acute ischemic stroke who underwent emergent stenting for neurological deterioration after intravenous thrombolysis.
Case presentation
A 53-year-old Japanese woman with a medical history of diabetes mellitus and no other risk factors for arteriosclerosis was admitted to our hospital. Physical examination showed a Glasgow Coma Scale score of E3V3M4, right hemiplegia, severe dysarthria, and total gaze paralysis. The National Institute of Health Stroke Scale (NIHSS) score was 22. Brain magnetic resonance imaging (MRI) at 90 minutes from the onset of symptoms revealed no high-intensity area on diffusion-weighted imaging (Fig. 1a). Brain magnetic resonance angiography showed stenosis in the BA (Fig. 1b). After initiation of intravenous administration of recombinant tissue plasminogen activator (IV-rtPA), neurological symptoms improved with an NIHSS of 4; however, 5 hours after IV-rtPA, the symptoms deteriorated again with an NIHSS of 22. Cerebral angiography showed severe stenosis and double lumen in the BA (Fig. 1c–f). We deployed Enterprise Vascular Reconstruction Device (VRD) 4.5 × 22 mm2 and 4.5 × 28 mm2 (Johnson & Johnson Codman, Miami, FL, USA) from the right posterior cerebral artery to the left vertebral artery (Fig. 1g) after administration of 200 mg of aspirin and 300 mg of clopidogrel. On day 2, 100 mg/day aspirin and 75 mg/day clopidogrel were initiated. Although MRI revealed small pontine infarction (Fig. 1h), the patient’s neurological deficit gradually improved. She was transferred to the rehabilitation center on day 23 with an NIHSS of 3. At 90 days from stroke onset, she had no significant disability with an NIHSS of 0 and a modified Rankin scale score of 1.Fig. 1 a Brain magnetic resonance imaging (MRI) at 90 minutes from symptom onset showing no high-intensity area on diffusion-weighted imaging (DWI). b Brain magnetic resonance angiography showing stenosis in the middle portion of the basilar artery (BA). c Cerebral angiography (45° right-anterior oblique view) showing intimal flap and double lumen in the middle and distal portions of the BA. Maximum intensity projection images of 3D rotational angiography showing double lumen of the BA in the coronal view (d), sagittal view (e), and axial view (f). g Cerebral angiography (45° right-anterior oblique view) after stenting. Enterprise VRD 4.5 × 22 mm2 (arrow: distal and proximal marker) and 4.5 × 28 mm2 (arrowhead: distal and proximal marker) was deployed from the P1 portion of the right posterior cerebral artery to the V4 portion of the left vertebral artery. h Brain MRI on day 6 showing left-sided pontine infarction on DWI
Discussion and conclusions
This is the first case report of a patient with acute ischemic stroke due to IBAD who underwent emergent stenting for neurological deterioration after IV-rtPA. Although some cases of stenting for IBAD have been reported, most of the procedures in these cases were performed after at least 3 days of dual antiplatelet therapy [2–5], and there is only one report of stenting in the hyper-acute phase of ischemic stroke [3]. There is no previous report of emergent stenting after IV-rtPA for IBAD-related ischemic stroke. Our case suggests that even for patients with IBAD-related ischemic stroke who are resistant to IV-rtPA, stenting can be a safe and effective treatment option.
Optimal treatment for ischemic stroke with IBAD has not been established. In clinical practice, anticoagulant or antiplatelet therapies are usually used. However, conservative management occasionally results in a poor prognosis [3, 6]. Efficacy and safety of IV-rtPA for ischemic stroke due to intracranial artery dissection have not been established, and in some cases, neurological deterioration after IV-rtPA is noted [7]. For patients presenting with progressive ischemia despite adequate medical treatments including IV-rtPA, stenting can be an alternative treatment option with a relatively good prognosis.
The benefits of stenting for IBAD are not completely understood. Occlusion of perforating branches of the BA is reported to be the main mechanism underlying IBAD-related ischemic stroke [8]. We speculate that thrombus formation in the false lumen might obstruct the blood flow in perforating branches by compressing the origin of these branches, resulting in brainstem infarction. IV-rtPA can prevent thrombus formation, but its efficacy is transient. In contrast, stenting can repair the intimal flap, which is the inflow route of the false lumen. Reduced blood flow into the false lumen will lead to less thrombus formation in this structure.
In conclusion, emergent stenting can be an effective treatment for patients with IBAD-related ischemic stroke who are resistant to IV-rtPA.
Abbreviations
BA Basilar artery
IBAD Isolated basilar artery dissection
NIHSS National Institute of Health Stroke Scale
MRI Magnetic resonance imaging
IV-rtPA Intravenous recombinant tissue plasminogen activator
DWI Diffusion-weighted imaging
Acknowledgements
None.
Authors’ contributions
TG was responsible for the conception and design of the work as well as data analysis and interpretation. NO, TI, HT, SM, MU, and YY were responsible for data collection. TG drafted the article, which was critically revised by NO, TI, HT, SM, MU, and YY. TG, NO, TI, HT, SM, MU, and YY were responsible for the final approval of the version to be published.
Funding
The authors have no funding to declare.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written 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-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33685504 | 19,051,578 | 2021-03-09 |
What was the outcome of reaction 'Vertebral artery dissection'? | Emergent stenting after intravenous thrombolysis for isolated basilar artery dissection in a patient with acute ischemic stroke: a case report.
BACKGROUND
Isolated basilar artery dissection (IBAD) is a rare but important cause of ischemic stroke. Anti-thrombotic therapy is often used to treat IBAD-related ischemic stroke, but selected cases might need more aggressive treatment. There is no previous report of emergent stenting for IBAD-related ischemic stroke after intravenous thrombolysis.
METHODS
A 53-year-old Japanese woman was admitted to our hospital with disturbance of consciousness, right hemiplegia, severe dysarthria, and total gaze paralysis. Brain magnetic resonance imaging revealed no ischemic lesion, but magnetic resonance angiography showed stenosis in the basilar artery. After initiation of intravenous thrombolysis, her neurological symptoms dramatically improved. Five hours later, however, her symptoms deteriorated again. Cerebral angiography showed IBAD. Emergent stenting was successfully performed. At 90 days after stroke onset, she had no significant disability, with a modified Rankin scale score of 1.
CONCLUSIONS
Emergent stenting can be an effective treatment for patients with IBAD-related ischemic stroke who are resistant to IV-rtPA.
Background
Isolated basilar artery (BA) dissection (IBAD) is a rare but important cause of ischemic stroke (incidence, 1/400,000/year) [1]. It is known to have a poor prognosis, with a mortality rate ranging from 10 to 78.9% [2]. Anti-thrombotic therapy is often used to treat IBAD-related ischemic stroke, but selected cases might need more aggressive treatment [3]. Although some cases of endovascular stenting for IBAD have been reported, the procedures were performed electively for progressive ischemic symptoms despite adequate anti-thrombotic therapy [2–5]. To the best of our knowledge, there is no previous report of emergent stenting for IBAD-related ischemic stroke after intravenous thrombolysis. We report a case of IBAD in a patient with acute ischemic stroke who underwent emergent stenting for neurological deterioration after intravenous thrombolysis.
Case presentation
A 53-year-old Japanese woman with a medical history of diabetes mellitus and no other risk factors for arteriosclerosis was admitted to our hospital. Physical examination showed a Glasgow Coma Scale score of E3V3M4, right hemiplegia, severe dysarthria, and total gaze paralysis. The National Institute of Health Stroke Scale (NIHSS) score was 22. Brain magnetic resonance imaging (MRI) at 90 minutes from the onset of symptoms revealed no high-intensity area on diffusion-weighted imaging (Fig. 1a). Brain magnetic resonance angiography showed stenosis in the BA (Fig. 1b). After initiation of intravenous administration of recombinant tissue plasminogen activator (IV-rtPA), neurological symptoms improved with an NIHSS of 4; however, 5 hours after IV-rtPA, the symptoms deteriorated again with an NIHSS of 22. Cerebral angiography showed severe stenosis and double lumen in the BA (Fig. 1c–f). We deployed Enterprise Vascular Reconstruction Device (VRD) 4.5 × 22 mm2 and 4.5 × 28 mm2 (Johnson & Johnson Codman, Miami, FL, USA) from the right posterior cerebral artery to the left vertebral artery (Fig. 1g) after administration of 200 mg of aspirin and 300 mg of clopidogrel. On day 2, 100 mg/day aspirin and 75 mg/day clopidogrel were initiated. Although MRI revealed small pontine infarction (Fig. 1h), the patient’s neurological deficit gradually improved. She was transferred to the rehabilitation center on day 23 with an NIHSS of 3. At 90 days from stroke onset, she had no significant disability with an NIHSS of 0 and a modified Rankin scale score of 1.Fig. 1 a Brain magnetic resonance imaging (MRI) at 90 minutes from symptom onset showing no high-intensity area on diffusion-weighted imaging (DWI). b Brain magnetic resonance angiography showing stenosis in the middle portion of the basilar artery (BA). c Cerebral angiography (45° right-anterior oblique view) showing intimal flap and double lumen in the middle and distal portions of the BA. Maximum intensity projection images of 3D rotational angiography showing double lumen of the BA in the coronal view (d), sagittal view (e), and axial view (f). g Cerebral angiography (45° right-anterior oblique view) after stenting. Enterprise VRD 4.5 × 22 mm2 (arrow: distal and proximal marker) and 4.5 × 28 mm2 (arrowhead: distal and proximal marker) was deployed from the P1 portion of the right posterior cerebral artery to the V4 portion of the left vertebral artery. h Brain MRI on day 6 showing left-sided pontine infarction on DWI
Discussion and conclusions
This is the first case report of a patient with acute ischemic stroke due to IBAD who underwent emergent stenting for neurological deterioration after IV-rtPA. Although some cases of stenting for IBAD have been reported, most of the procedures in these cases were performed after at least 3 days of dual antiplatelet therapy [2–5], and there is only one report of stenting in the hyper-acute phase of ischemic stroke [3]. There is no previous report of emergent stenting after IV-rtPA for IBAD-related ischemic stroke. Our case suggests that even for patients with IBAD-related ischemic stroke who are resistant to IV-rtPA, stenting can be a safe and effective treatment option.
Optimal treatment for ischemic stroke with IBAD has not been established. In clinical practice, anticoagulant or antiplatelet therapies are usually used. However, conservative management occasionally results in a poor prognosis [3, 6]. Efficacy and safety of IV-rtPA for ischemic stroke due to intracranial artery dissection have not been established, and in some cases, neurological deterioration after IV-rtPA is noted [7]. For patients presenting with progressive ischemia despite adequate medical treatments including IV-rtPA, stenting can be an alternative treatment option with a relatively good prognosis.
The benefits of stenting for IBAD are not completely understood. Occlusion of perforating branches of the BA is reported to be the main mechanism underlying IBAD-related ischemic stroke [8]. We speculate that thrombus formation in the false lumen might obstruct the blood flow in perforating branches by compressing the origin of these branches, resulting in brainstem infarction. IV-rtPA can prevent thrombus formation, but its efficacy is transient. In contrast, stenting can repair the intimal flap, which is the inflow route of the false lumen. Reduced blood flow into the false lumen will lead to less thrombus formation in this structure.
In conclusion, emergent stenting can be an effective treatment for patients with IBAD-related ischemic stroke who are resistant to IV-rtPA.
Abbreviations
BA Basilar artery
IBAD Isolated basilar artery dissection
NIHSS National Institute of Health Stroke Scale
MRI Magnetic resonance imaging
IV-rtPA Intravenous recombinant tissue plasminogen activator
DWI Diffusion-weighted imaging
Acknowledgements
None.
Authors’ contributions
TG was responsible for the conception and design of the work as well as data analysis and interpretation. NO, TI, HT, SM, MU, and YY were responsible for data collection. TG drafted the article, which was critically revised by NO, TI, HT, SM, MU, and YY. TG, NO, TI, HT, SM, MU, and YY were responsible for the final approval of the version to be published.
Funding
The authors have no funding to declare.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written 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-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33685504 | 19,051,578 | 2021-03-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Device dislocation'. | Levonorgestrel intrauterine system embedded within tubal ectopic pregnancy: a case report.
BACKGROUND
The presence of the levonorgestrel-releasing intrauterine system embedded within an ectopic pregnancy is a rare occurrence. Tubal migration of an intrauterine device is not well understood and has not been extensively studied in literature.
METHODS
A 34-year-old African woman, para 1, gravida 2, presented with symptoms of ruptured ectopic pregnancy. She underwent a laparoscopy where a ruptured left ectopic pregnancy was found with a levonorgestrel-releasing intrauterine system inserted 2 years prior embedded within the tube. A left salpingectomy was performed with removal of the levonorgestrel-releasing intrauterine system. The patient recovered well and proceeded to have an intrauterine pregnancy 3 months later.
CONCLUSIONS
Migration of the levonorgestrel-releasing intrauterine system into the fallopian tube is a rare occurrence that is not well understood. In the case presented, levonorgestrel-releasing intrauterine system was found embedded within the fimbrial end of the left fallopian tube, which had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal intrauterine device to prevent complications.
Background
An intrauterine contraceptive device (IUD) is a highly effective method of contraception [1]. Types of IUDs include the levonorgestrel releasing intrauterine system (LNG IUS), also commonly referred to as Mirena, and the copper IUD. They have a low failure rate of less than 1%, which is comparable to permanent sterilization [1]. The pearl index of the LNG IUS is 0.06 per 100 women years, while that of the copper IUD is 0.52 per 100 women years [2]. Even though the risk of ectopic pregnancy with IUDs is lower than with no contraception, if a pregnancy occurs with an IUD in situ, it is likely to be an ectopic pregnancy. The rate of ectopic pregnancy among LNG IUS users ranges from 0.02 to 0.2 per 100 women years, whereas the rate among copper IUD users ranges from 0.1 to 0.8 per 100 women years. In case of pregnancy, the risk of ectopic pregnancy is higher in LNG IUS users compared with copper IUD users (27% versus 15% respectively) [2]. Progesterone is known to cause ciliary dysfunction within the fallopian tube, subsequently predisposing LNG IUS users who conceive to ectopic pregnancy [3]. It is therefore important to rule out ectopic pregnancy in women with acute abdomen or positive pregnancy test among LNG IUS users [4]
A correctly positioned IUD is located within 3 mm of the uterine fundus, with both arms extending to the cornua, a vertically oriented stem in the uterine body, and the strings protruding through the cervical os into the vaginal canal [5]. Suboptimally placed IUDs are at a higher risk of malposition or expulsion and associated symptoms [5]. Malposition of IUDs is a common complication of this method of contraception, with a reported rate of up to 10% [6]. Malposition of an IUD includes displacement, expulsion, rotation, or embedment. Migration of IUDs is, however, an uncommon occurrence, with most cases of migration reported to the colon and the urinary tract [7–9]. The fallopian tube is an uncommon location for migration and embedment [7]. Having an IUD embedded within a tubal ectopic pregnancy is an even rarer phenomenon.
We describe a case of a patient who presented with ruptured ectopic pregnancy and was found to have a LNG IUS embedded in the fimbrial end of the affected fallopian tube.
Case presentation
A 34-year-old African female, para 1, gravida 2, presented to the Accident and Emergency Department, having had symptoms of vomiting and abdominal pain for 3 days. The symptoms had worsened on the day of presentation to the hospital. She reported several episodes of vomiting with associated loose stools and abdominal fullness. She also had ongoing vaginal bleeding that had started 5 days prior to presentation.
Two years prior, the patient had an uncomplicated insertion of LNG IUS by an obstetrician/gynecologist at the 8-week visit following a normal vaginal delivery. She had a normal pap smear done at the time of insertion. One year following insertion, she had a desire to conceive and was scheduled for removal of the LNG IUS device. The strings could not be seen, and the device could not be retrieved with alligator forceps. The patient was therefore sent for a pelvic ultrasound to locate the lost IUD. The device was not seen on ultrasound. The patient was, however, lost to follow-up until presentation with symptoms of ruptured ectopic pregnancy. She had no preexisting conditions or previous surgery.
On physical examination she was in fair general condition and not pale. Her vital signs were a temperature of 37.6 °C, a blood pressure of 120/66 mmHg, pulse rate of 99 beats per minute, respiration rate of 18 breaths per minute, and oxygen saturation of 100% on room air. On abdominal examination she had tenderness on the left iliac fossa and suprapubic regions with absent bowel sounds. The rest of the systemic examination was normal. An impression of acute abdomen was made at this point. As initial treatment she was given intravenous fluids (Ringer’s lactate solution) 1-L bolus, as well as intravenous paracetamol and ondansetron for pain and vomiting, respectively.
The initial investigations included a full blood count, which revealed a normal hemoglobin level of 13.2 g/dl, slightly elevated white cell count of 12.28 × 109 cells/L, and normal platelet count of 314 × 109 cells/L. She had a beta human chorionic gonadotropin (Hcg) level of 7721 mIU/ml. Urinalysis showed leucocytes 2+, nitrite negative, and blood 2+. Transvaginal ultrasound showed a 2.1 cm × 1.8 cm echogenic mass with central cystic area on the left adnexa. It had no internal or peripheral vascularity. There was marked pelvic echogenic free fluid with low internal echoes extending to the Morrison’s pouch. The uterus was anteverted and normal in size and shape with an endometrial thickness of 5.5 mm. A 1.9 cm cystic lesion was seen in the right ovary, which was likely a corpus luteum cyst. There was no gestational sac or intrauterine device seen within the endometrial cavity (Fig. 1). These features indicated ruptured ectopic pregnancy.Fig. 1 Ultrasound image of an empty uterus. The arrow points to the endometrial lining measuring 5.5 mm
The diagnosis at this point was a ruptured left tubal ectopic pregnancy. The plan was to admit the patient for an emergency laparoscopy with possible left salpingectomy. The diagnosis and plan were explained to the patient, who signed an informed consent for the procedure. Group and cross match of one unit of packed red cells was ordered in case a transfusion would be required.
The laparoscopy was done under general anesthesia in the Lloyd–Davis position. Cohen’s uterine manipulator was placed. Veress insufflation was performed, followed by insertion of a 10-mm primary trocar at the umbilicus. Entry and operating pressures were 20 mmHg and 15 mmHg, respectively. Two secondary ports were inserted under vision, 5 mm in the right iliac fossa and 12 mm in the left iliac fossa. On primary survey, LNG IUS was found embedded at the fimbrial end of the left fallopian tube (Fig. 2). The LNG IUS was retrieved whole under vision through the 12-mm port (Fig. 3). There was hemoperitoneum of 700 ml (Fig. 2). A ruptured left ampullary ectopic pregnancy was identified by left salpingectomy using bipolar coagulation and scissors (Fig. 4). A corpus luteum cyst was found on the right ovary with normal right fallopian tube. Suction and peritoneal lavage were performed, and hemostasis was confirmed (Fig. 5). The specimen was retrieved through the 12-mm port and taken for histology. There was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal. All trocars were removed under vision.Fig. 2 Body of the embedded LNG IUS (indicated by arrow), which is seen protruding from the left tubal pregnancy with hemoperitoneum
Fig. 3 LNG IUS (indicated by arrow) being retrieved from the left tubal pregnancy
Fig. 4 Left salpingectomy (indicated by arrow) performed using bipolar coagulation
Fig. 5 Pelvic view after completion of the procedure confirming hemostasis. Arrow points to an empty pouch of Douglas
The postoperative recovery of the patient was unremarkable. She was debriefed about the surgery and discharged the following morning. She went home on oral paracetamol and diclofenac for pain relief.
The patient was reviewed in the gynecology outpatient clinic 2 weeks later. She was asymptomatic and doing well. Histology report confirmed left ectopic tubal gestation. She reported that she desired conception. Preconception counseling was done. She was put on daily folic acid (400 µg). The patient was advised to come to the hospital as soon as she missed a period or tested positive for pregnancy for an early pregnancy ultrasound to rule out another ectopic pregnancy. Three months later she presented at the early pregnancy clinic following 5 weeks of amenorrhea. A pelvic ultrasound was done that showed intrauterine pregnancy at 5 weeks gestation.
Discussion
The above case documents a rare occurrence of a ruptured ectopic pregnancy with the LNG IUS embedded within the affected fallopian tube.
Levonorgestrel IUS (Mirena) is a safe, reversible, and highly effective contraceptive method [2]. It is known to have other therapeutic benefits such as reduction in menstrual bleeding, anemia, and dysmenorrhea, as well as management of endometrial hyperplasia [10]. In this patient, the use of the LNG IUS was purely for contraception purposes.
Ectopic pregnancies affect approximately 2% of all pregnancies. The most common presentation of an ectopic pregnancy is abdominal pain and abnormal uterine bleeding [11]. Even though the rate of ectopic pregnancy is lower in women using LNG IUS, if a pregnancy occurs while using this IUD, there is a high risk of it being an ectopic pregnancy [2]. Current IUD use is a known risk factor for ectopic pregnancy [12]. Other risk factors for ectopic pregnancy include pelvic inflammatory disease, previous tubal surgery, previous ectopic pregnancy, and smoking [12]. On examination, features of acute abdomen due to hemoperitoneum may be present [11, 12]. The patient in this case had a presentation suggestive of ectopic pregnancy with concurrent LNG IUS use as a risk factor. However, she had other unspecific presenting features of diarrhea, vomiting, and low-grade fever. It is important to note that some patients may be asymptomatic without specific risk factors for an ectopic pregnancy [12]
On the other hand, malposition of an IUD is one of its common complications, presenting with pelvic pain and bleeding or no symptoms [13]. Although malposition is associated with reduced contraceptive efficacy, this is mostly true for copper IUDs and not LNG IUS, which has local progesterone effects [6]. Malposition is diagnosed by ultrasound [13]. However, compared with copper IUDs, the LNG IUS is more likely to be missed by ultrasonography. LNG IUS is compounded with barium sulfate, which makes it radio opaque for X-ray recognition [14]. A plain X-ray can therefore be used as an adjunctive imaging modality in the case of a lost LNG IUS not seen on ultrasound [15]. The patient in this case had a lost LNG IUS not seen on ultrasound 1 year after insertion but was lost to follow-up for additional imaging.
Uterine perforation is uncommon, with an incidence of 1 in 1000 insertions. It is a serious complication of IUD use and is often asymptomatic [16]. There is increased risk of perforation if insertion is done less than 6 months postpartum or while breastfeeding. This period is associated with endometrial atrophy with accelerated uterine involution and hence has a high risk of perforation [6, 13]. The current patient was asymptomatic for malposition or perforation for 2 years prior to the ectopic pregnancy. The transvaginal ultrasound done at diagnosis of ectopic pregnancy did not visualize the device in the left adnexa. Her LNG IUS was inserted only 2 months postpartum while breastfeeding. This may have been a risk factor for possible unrecognized perforation.
Routine transvaginal ultrasound to monitor IUD position either immediately post insertion or after 6 weeks is not recommended without clinical suspicion of malposition according to de Kroon et al. [17]. It has been reported that IUDs take approximately 3 months to settle into their stable position. An initially malpositioned IUD can therefore assume the correct fundal position over time [18]. In asymptomatic women with uncomplicated IUD insertion, routine ultrasound lacks benefit over clinical evaluation with string check at 6 weeks [17]. The patient in this case was asymptomatic without complications at insertion. One year later, the LNG IUS device could not be seen on clinical examination nor on ultrasound.
The mechanism of device migration is not well understood, especially in the case of tubal migration. The fallopian tube is a rare site for dislocated IUD [19, 20]. This phenomenon has been described in few case reports. There are theories from case reports about the tubal migration of an IUD. The first possibility is placement of the device at the tubal ostium during insertion with subsequent migration into the tube due to uterine contractions and tubal peristalsis [21]. The other possibility is uterine perforation with migration of the device into the peritoneal cavity and subsequent perforation of a preexisting hydrosalpinx as described by Ozdemir et al. in a case report [19]. The patient in this case did not have any hydrosalpinx noted intraoperatively. Perforation can be due to either immediate traumatic perforation at insertion or delayed transmural migration [22, 23]. It is also possible that, following an unrecognized perforation, there was nestling of the IUD close to the fimbrial end of the fallopian tube, with the device being enveloped within the fimbria [7, 19]. This phenomenon could have occurred antecedent to conception of the ectopic pregnancy. In the patient in this case, there was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal.
The presence of an IUD within the fallopian tube is associated with an inflammatory reaction [19] interfering with tubal function and predisposing the patient to ectopic pregnancy. The tubal dysfunction is exacerbated by progesterone in the LNG IUS, which interferes with ciliary beating and tubal contractility [3]. It is possible that the embedment of LNG IUS at the fimbrial end of the fallopian tube occurred as a result of displacement from the proximal tube by the growing tubal pregnancy or its rupture.
Once an intraabdominal IUD is diagnosed, it should be removed whether it is symptomatic or not to avoid serious complications such as adhesion formation, bowel obstruction, and infertility [15, 19]. Laparoscopy is the surgical approach of choice as it is safe and effective. It provides good visualization to locate and remove a lost IUD [15]. In this case, the diagnosis of the LNG IUS within the fallopian tube and its removal were done laparoscopically.
Conclusion
Migration of the LNG IUS into the fallopian tube is a rare occurrence that is not well understood. In the case presented, a LNG IUS was found embedded within the fimbrial end of the fallopian tube that had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal IUD to prevent complications. The patient made a good recovery and proceeded to have an intrauterine pregnancy 3 months later, as desired.
Abbreviations
IUD Intrauterine device
LNG IUS Levonorgestrel intrauterine system
Acknowledgements
We would like to thank the patient for her permission to publish this manuscript.
Authors’ contributions
DM collected and analyzed the data and drafted the manuscript. IG and KW contributed to the manuscript writing and editing. All authors managed the patient and read and approved the final manuscript.
Funding
None.
Availability of data and materials
Clinical data and complementary examinations are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of the case and any accompanying images. A copy of the consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | LEVONORGESTREL | DrugsGivenReaction | CC BY | 33685513 | 19,041,622 | 2021-03-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Levonorgestrel intrauterine system embedded within tubal ectopic pregnancy: a case report.
BACKGROUND
The presence of the levonorgestrel-releasing intrauterine system embedded within an ectopic pregnancy is a rare occurrence. Tubal migration of an intrauterine device is not well understood and has not been extensively studied in literature.
METHODS
A 34-year-old African woman, para 1, gravida 2, presented with symptoms of ruptured ectopic pregnancy. She underwent a laparoscopy where a ruptured left ectopic pregnancy was found with a levonorgestrel-releasing intrauterine system inserted 2 years prior embedded within the tube. A left salpingectomy was performed with removal of the levonorgestrel-releasing intrauterine system. The patient recovered well and proceeded to have an intrauterine pregnancy 3 months later.
CONCLUSIONS
Migration of the levonorgestrel-releasing intrauterine system into the fallopian tube is a rare occurrence that is not well understood. In the case presented, levonorgestrel-releasing intrauterine system was found embedded within the fimbrial end of the left fallopian tube, which had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal intrauterine device to prevent complications.
Background
An intrauterine contraceptive device (IUD) is a highly effective method of contraception [1]. Types of IUDs include the levonorgestrel releasing intrauterine system (LNG IUS), also commonly referred to as Mirena, and the copper IUD. They have a low failure rate of less than 1%, which is comparable to permanent sterilization [1]. The pearl index of the LNG IUS is 0.06 per 100 women years, while that of the copper IUD is 0.52 per 100 women years [2]. Even though the risk of ectopic pregnancy with IUDs is lower than with no contraception, if a pregnancy occurs with an IUD in situ, it is likely to be an ectopic pregnancy. The rate of ectopic pregnancy among LNG IUS users ranges from 0.02 to 0.2 per 100 women years, whereas the rate among copper IUD users ranges from 0.1 to 0.8 per 100 women years. In case of pregnancy, the risk of ectopic pregnancy is higher in LNG IUS users compared with copper IUD users (27% versus 15% respectively) [2]. Progesterone is known to cause ciliary dysfunction within the fallopian tube, subsequently predisposing LNG IUS users who conceive to ectopic pregnancy [3]. It is therefore important to rule out ectopic pregnancy in women with acute abdomen or positive pregnancy test among LNG IUS users [4]
A correctly positioned IUD is located within 3 mm of the uterine fundus, with both arms extending to the cornua, a vertically oriented stem in the uterine body, and the strings protruding through the cervical os into the vaginal canal [5]. Suboptimally placed IUDs are at a higher risk of malposition or expulsion and associated symptoms [5]. Malposition of IUDs is a common complication of this method of contraception, with a reported rate of up to 10% [6]. Malposition of an IUD includes displacement, expulsion, rotation, or embedment. Migration of IUDs is, however, an uncommon occurrence, with most cases of migration reported to the colon and the urinary tract [7–9]. The fallopian tube is an uncommon location for migration and embedment [7]. Having an IUD embedded within a tubal ectopic pregnancy is an even rarer phenomenon.
We describe a case of a patient who presented with ruptured ectopic pregnancy and was found to have a LNG IUS embedded in the fimbrial end of the affected fallopian tube.
Case presentation
A 34-year-old African female, para 1, gravida 2, presented to the Accident and Emergency Department, having had symptoms of vomiting and abdominal pain for 3 days. The symptoms had worsened on the day of presentation to the hospital. She reported several episodes of vomiting with associated loose stools and abdominal fullness. She also had ongoing vaginal bleeding that had started 5 days prior to presentation.
Two years prior, the patient had an uncomplicated insertion of LNG IUS by an obstetrician/gynecologist at the 8-week visit following a normal vaginal delivery. She had a normal pap smear done at the time of insertion. One year following insertion, she had a desire to conceive and was scheduled for removal of the LNG IUS device. The strings could not be seen, and the device could not be retrieved with alligator forceps. The patient was therefore sent for a pelvic ultrasound to locate the lost IUD. The device was not seen on ultrasound. The patient was, however, lost to follow-up until presentation with symptoms of ruptured ectopic pregnancy. She had no preexisting conditions or previous surgery.
On physical examination she was in fair general condition and not pale. Her vital signs were a temperature of 37.6 °C, a blood pressure of 120/66 mmHg, pulse rate of 99 beats per minute, respiration rate of 18 breaths per minute, and oxygen saturation of 100% on room air. On abdominal examination she had tenderness on the left iliac fossa and suprapubic regions with absent bowel sounds. The rest of the systemic examination was normal. An impression of acute abdomen was made at this point. As initial treatment she was given intravenous fluids (Ringer’s lactate solution) 1-L bolus, as well as intravenous paracetamol and ondansetron for pain and vomiting, respectively.
The initial investigations included a full blood count, which revealed a normal hemoglobin level of 13.2 g/dl, slightly elevated white cell count of 12.28 × 109 cells/L, and normal platelet count of 314 × 109 cells/L. She had a beta human chorionic gonadotropin (Hcg) level of 7721 mIU/ml. Urinalysis showed leucocytes 2+, nitrite negative, and blood 2+. Transvaginal ultrasound showed a 2.1 cm × 1.8 cm echogenic mass with central cystic area on the left adnexa. It had no internal or peripheral vascularity. There was marked pelvic echogenic free fluid with low internal echoes extending to the Morrison’s pouch. The uterus was anteverted and normal in size and shape with an endometrial thickness of 5.5 mm. A 1.9 cm cystic lesion was seen in the right ovary, which was likely a corpus luteum cyst. There was no gestational sac or intrauterine device seen within the endometrial cavity (Fig. 1). These features indicated ruptured ectopic pregnancy.Fig. 1 Ultrasound image of an empty uterus. The arrow points to the endometrial lining measuring 5.5 mm
The diagnosis at this point was a ruptured left tubal ectopic pregnancy. The plan was to admit the patient for an emergency laparoscopy with possible left salpingectomy. The diagnosis and plan were explained to the patient, who signed an informed consent for the procedure. Group and cross match of one unit of packed red cells was ordered in case a transfusion would be required.
The laparoscopy was done under general anesthesia in the Lloyd–Davis position. Cohen’s uterine manipulator was placed. Veress insufflation was performed, followed by insertion of a 10-mm primary trocar at the umbilicus. Entry and operating pressures were 20 mmHg and 15 mmHg, respectively. Two secondary ports were inserted under vision, 5 mm in the right iliac fossa and 12 mm in the left iliac fossa. On primary survey, LNG IUS was found embedded at the fimbrial end of the left fallopian tube (Fig. 2). The LNG IUS was retrieved whole under vision through the 12-mm port (Fig. 3). There was hemoperitoneum of 700 ml (Fig. 2). A ruptured left ampullary ectopic pregnancy was identified by left salpingectomy using bipolar coagulation and scissors (Fig. 4). A corpus luteum cyst was found on the right ovary with normal right fallopian tube. Suction and peritoneal lavage were performed, and hemostasis was confirmed (Fig. 5). The specimen was retrieved through the 12-mm port and taken for histology. There was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal. All trocars were removed under vision.Fig. 2 Body of the embedded LNG IUS (indicated by arrow), which is seen protruding from the left tubal pregnancy with hemoperitoneum
Fig. 3 LNG IUS (indicated by arrow) being retrieved from the left tubal pregnancy
Fig. 4 Left salpingectomy (indicated by arrow) performed using bipolar coagulation
Fig. 5 Pelvic view after completion of the procedure confirming hemostasis. Arrow points to an empty pouch of Douglas
The postoperative recovery of the patient was unremarkable. She was debriefed about the surgery and discharged the following morning. She went home on oral paracetamol and diclofenac for pain relief.
The patient was reviewed in the gynecology outpatient clinic 2 weeks later. She was asymptomatic and doing well. Histology report confirmed left ectopic tubal gestation. She reported that she desired conception. Preconception counseling was done. She was put on daily folic acid (400 µg). The patient was advised to come to the hospital as soon as she missed a period or tested positive for pregnancy for an early pregnancy ultrasound to rule out another ectopic pregnancy. Three months later she presented at the early pregnancy clinic following 5 weeks of amenorrhea. A pelvic ultrasound was done that showed intrauterine pregnancy at 5 weeks gestation.
Discussion
The above case documents a rare occurrence of a ruptured ectopic pregnancy with the LNG IUS embedded within the affected fallopian tube.
Levonorgestrel IUS (Mirena) is a safe, reversible, and highly effective contraceptive method [2]. It is known to have other therapeutic benefits such as reduction in menstrual bleeding, anemia, and dysmenorrhea, as well as management of endometrial hyperplasia [10]. In this patient, the use of the LNG IUS was purely for contraception purposes.
Ectopic pregnancies affect approximately 2% of all pregnancies. The most common presentation of an ectopic pregnancy is abdominal pain and abnormal uterine bleeding [11]. Even though the rate of ectopic pregnancy is lower in women using LNG IUS, if a pregnancy occurs while using this IUD, there is a high risk of it being an ectopic pregnancy [2]. Current IUD use is a known risk factor for ectopic pregnancy [12]. Other risk factors for ectopic pregnancy include pelvic inflammatory disease, previous tubal surgery, previous ectopic pregnancy, and smoking [12]. On examination, features of acute abdomen due to hemoperitoneum may be present [11, 12]. The patient in this case had a presentation suggestive of ectopic pregnancy with concurrent LNG IUS use as a risk factor. However, she had other unspecific presenting features of diarrhea, vomiting, and low-grade fever. It is important to note that some patients may be asymptomatic without specific risk factors for an ectopic pregnancy [12]
On the other hand, malposition of an IUD is one of its common complications, presenting with pelvic pain and bleeding or no symptoms [13]. Although malposition is associated with reduced contraceptive efficacy, this is mostly true for copper IUDs and not LNG IUS, which has local progesterone effects [6]. Malposition is diagnosed by ultrasound [13]. However, compared with copper IUDs, the LNG IUS is more likely to be missed by ultrasonography. LNG IUS is compounded with barium sulfate, which makes it radio opaque for X-ray recognition [14]. A plain X-ray can therefore be used as an adjunctive imaging modality in the case of a lost LNG IUS not seen on ultrasound [15]. The patient in this case had a lost LNG IUS not seen on ultrasound 1 year after insertion but was lost to follow-up for additional imaging.
Uterine perforation is uncommon, with an incidence of 1 in 1000 insertions. It is a serious complication of IUD use and is often asymptomatic [16]. There is increased risk of perforation if insertion is done less than 6 months postpartum or while breastfeeding. This period is associated with endometrial atrophy with accelerated uterine involution and hence has a high risk of perforation [6, 13]. The current patient was asymptomatic for malposition or perforation for 2 years prior to the ectopic pregnancy. The transvaginal ultrasound done at diagnosis of ectopic pregnancy did not visualize the device in the left adnexa. Her LNG IUS was inserted only 2 months postpartum while breastfeeding. This may have been a risk factor for possible unrecognized perforation.
Routine transvaginal ultrasound to monitor IUD position either immediately post insertion or after 6 weeks is not recommended without clinical suspicion of malposition according to de Kroon et al. [17]. It has been reported that IUDs take approximately 3 months to settle into their stable position. An initially malpositioned IUD can therefore assume the correct fundal position over time [18]. In asymptomatic women with uncomplicated IUD insertion, routine ultrasound lacks benefit over clinical evaluation with string check at 6 weeks [17]. The patient in this case was asymptomatic without complications at insertion. One year later, the LNG IUS device could not be seen on clinical examination nor on ultrasound.
The mechanism of device migration is not well understood, especially in the case of tubal migration. The fallopian tube is a rare site for dislocated IUD [19, 20]. This phenomenon has been described in few case reports. There are theories from case reports about the tubal migration of an IUD. The first possibility is placement of the device at the tubal ostium during insertion with subsequent migration into the tube due to uterine contractions and tubal peristalsis [21]. The other possibility is uterine perforation with migration of the device into the peritoneal cavity and subsequent perforation of a preexisting hydrosalpinx as described by Ozdemir et al. in a case report [19]. The patient in this case did not have any hydrosalpinx noted intraoperatively. Perforation can be due to either immediate traumatic perforation at insertion or delayed transmural migration [22, 23]. It is also possible that, following an unrecognized perforation, there was nestling of the IUD close to the fimbrial end of the fallopian tube, with the device being enveloped within the fimbria [7, 19]. This phenomenon could have occurred antecedent to conception of the ectopic pregnancy. In the patient in this case, there was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal.
The presence of an IUD within the fallopian tube is associated with an inflammatory reaction [19] interfering with tubal function and predisposing the patient to ectopic pregnancy. The tubal dysfunction is exacerbated by progesterone in the LNG IUS, which interferes with ciliary beating and tubal contractility [3]. It is possible that the embedment of LNG IUS at the fimbrial end of the fallopian tube occurred as a result of displacement from the proximal tube by the growing tubal pregnancy or its rupture.
Once an intraabdominal IUD is diagnosed, it should be removed whether it is symptomatic or not to avoid serious complications such as adhesion formation, bowel obstruction, and infertility [15, 19]. Laparoscopy is the surgical approach of choice as it is safe and effective. It provides good visualization to locate and remove a lost IUD [15]. In this case, the diagnosis of the LNG IUS within the fallopian tube and its removal were done laparoscopically.
Conclusion
Migration of the LNG IUS into the fallopian tube is a rare occurrence that is not well understood. In the case presented, a LNG IUS was found embedded within the fimbrial end of the fallopian tube that had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal IUD to prevent complications. The patient made a good recovery and proceeded to have an intrauterine pregnancy 3 months later, as desired.
Abbreviations
IUD Intrauterine device
LNG IUS Levonorgestrel intrauterine system
Acknowledgements
We would like to thank the patient for her permission to publish this manuscript.
Authors’ contributions
DM collected and analyzed the data and drafted the manuscript. IG and KW contributed to the manuscript writing and editing. All authors managed the patient and read and approved the final manuscript.
Funding
None.
Availability of data and materials
Clinical data and complementary examinations are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of the case and any accompanying images. A copy of the consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | LEVONORGESTREL | DrugsGivenReaction | CC BY | 33685513 | 19,041,622 | 2021-03-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Embedded device'. | Levonorgestrel intrauterine system embedded within tubal ectopic pregnancy: a case report.
BACKGROUND
The presence of the levonorgestrel-releasing intrauterine system embedded within an ectopic pregnancy is a rare occurrence. Tubal migration of an intrauterine device is not well understood and has not been extensively studied in literature.
METHODS
A 34-year-old African woman, para 1, gravida 2, presented with symptoms of ruptured ectopic pregnancy. She underwent a laparoscopy where a ruptured left ectopic pregnancy was found with a levonorgestrel-releasing intrauterine system inserted 2 years prior embedded within the tube. A left salpingectomy was performed with removal of the levonorgestrel-releasing intrauterine system. The patient recovered well and proceeded to have an intrauterine pregnancy 3 months later.
CONCLUSIONS
Migration of the levonorgestrel-releasing intrauterine system into the fallopian tube is a rare occurrence that is not well understood. In the case presented, levonorgestrel-releasing intrauterine system was found embedded within the fimbrial end of the left fallopian tube, which had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal intrauterine device to prevent complications.
Background
An intrauterine contraceptive device (IUD) is a highly effective method of contraception [1]. Types of IUDs include the levonorgestrel releasing intrauterine system (LNG IUS), also commonly referred to as Mirena, and the copper IUD. They have a low failure rate of less than 1%, which is comparable to permanent sterilization [1]. The pearl index of the LNG IUS is 0.06 per 100 women years, while that of the copper IUD is 0.52 per 100 women years [2]. Even though the risk of ectopic pregnancy with IUDs is lower than with no contraception, if a pregnancy occurs with an IUD in situ, it is likely to be an ectopic pregnancy. The rate of ectopic pregnancy among LNG IUS users ranges from 0.02 to 0.2 per 100 women years, whereas the rate among copper IUD users ranges from 0.1 to 0.8 per 100 women years. In case of pregnancy, the risk of ectopic pregnancy is higher in LNG IUS users compared with copper IUD users (27% versus 15% respectively) [2]. Progesterone is known to cause ciliary dysfunction within the fallopian tube, subsequently predisposing LNG IUS users who conceive to ectopic pregnancy [3]. It is therefore important to rule out ectopic pregnancy in women with acute abdomen or positive pregnancy test among LNG IUS users [4]
A correctly positioned IUD is located within 3 mm of the uterine fundus, with both arms extending to the cornua, a vertically oriented stem in the uterine body, and the strings protruding through the cervical os into the vaginal canal [5]. Suboptimally placed IUDs are at a higher risk of malposition or expulsion and associated symptoms [5]. Malposition of IUDs is a common complication of this method of contraception, with a reported rate of up to 10% [6]. Malposition of an IUD includes displacement, expulsion, rotation, or embedment. Migration of IUDs is, however, an uncommon occurrence, with most cases of migration reported to the colon and the urinary tract [7–9]. The fallopian tube is an uncommon location for migration and embedment [7]. Having an IUD embedded within a tubal ectopic pregnancy is an even rarer phenomenon.
We describe a case of a patient who presented with ruptured ectopic pregnancy and was found to have a LNG IUS embedded in the fimbrial end of the affected fallopian tube.
Case presentation
A 34-year-old African female, para 1, gravida 2, presented to the Accident and Emergency Department, having had symptoms of vomiting and abdominal pain for 3 days. The symptoms had worsened on the day of presentation to the hospital. She reported several episodes of vomiting with associated loose stools and abdominal fullness. She also had ongoing vaginal bleeding that had started 5 days prior to presentation.
Two years prior, the patient had an uncomplicated insertion of LNG IUS by an obstetrician/gynecologist at the 8-week visit following a normal vaginal delivery. She had a normal pap smear done at the time of insertion. One year following insertion, she had a desire to conceive and was scheduled for removal of the LNG IUS device. The strings could not be seen, and the device could not be retrieved with alligator forceps. The patient was therefore sent for a pelvic ultrasound to locate the lost IUD. The device was not seen on ultrasound. The patient was, however, lost to follow-up until presentation with symptoms of ruptured ectopic pregnancy. She had no preexisting conditions or previous surgery.
On physical examination she was in fair general condition and not pale. Her vital signs were a temperature of 37.6 °C, a blood pressure of 120/66 mmHg, pulse rate of 99 beats per minute, respiration rate of 18 breaths per minute, and oxygen saturation of 100% on room air. On abdominal examination she had tenderness on the left iliac fossa and suprapubic regions with absent bowel sounds. The rest of the systemic examination was normal. An impression of acute abdomen was made at this point. As initial treatment she was given intravenous fluids (Ringer’s lactate solution) 1-L bolus, as well as intravenous paracetamol and ondansetron for pain and vomiting, respectively.
The initial investigations included a full blood count, which revealed a normal hemoglobin level of 13.2 g/dl, slightly elevated white cell count of 12.28 × 109 cells/L, and normal platelet count of 314 × 109 cells/L. She had a beta human chorionic gonadotropin (Hcg) level of 7721 mIU/ml. Urinalysis showed leucocytes 2+, nitrite negative, and blood 2+. Transvaginal ultrasound showed a 2.1 cm × 1.8 cm echogenic mass with central cystic area on the left adnexa. It had no internal or peripheral vascularity. There was marked pelvic echogenic free fluid with low internal echoes extending to the Morrison’s pouch. The uterus was anteverted and normal in size and shape with an endometrial thickness of 5.5 mm. A 1.9 cm cystic lesion was seen in the right ovary, which was likely a corpus luteum cyst. There was no gestational sac or intrauterine device seen within the endometrial cavity (Fig. 1). These features indicated ruptured ectopic pregnancy.Fig. 1 Ultrasound image of an empty uterus. The arrow points to the endometrial lining measuring 5.5 mm
The diagnosis at this point was a ruptured left tubal ectopic pregnancy. The plan was to admit the patient for an emergency laparoscopy with possible left salpingectomy. The diagnosis and plan were explained to the patient, who signed an informed consent for the procedure. Group and cross match of one unit of packed red cells was ordered in case a transfusion would be required.
The laparoscopy was done under general anesthesia in the Lloyd–Davis position. Cohen’s uterine manipulator was placed. Veress insufflation was performed, followed by insertion of a 10-mm primary trocar at the umbilicus. Entry and operating pressures were 20 mmHg and 15 mmHg, respectively. Two secondary ports were inserted under vision, 5 mm in the right iliac fossa and 12 mm in the left iliac fossa. On primary survey, LNG IUS was found embedded at the fimbrial end of the left fallopian tube (Fig. 2). The LNG IUS was retrieved whole under vision through the 12-mm port (Fig. 3). There was hemoperitoneum of 700 ml (Fig. 2). A ruptured left ampullary ectopic pregnancy was identified by left salpingectomy using bipolar coagulation and scissors (Fig. 4). A corpus luteum cyst was found on the right ovary with normal right fallopian tube. Suction and peritoneal lavage were performed, and hemostasis was confirmed (Fig. 5). The specimen was retrieved through the 12-mm port and taken for histology. There was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal. All trocars were removed under vision.Fig. 2 Body of the embedded LNG IUS (indicated by arrow), which is seen protruding from the left tubal pregnancy with hemoperitoneum
Fig. 3 LNG IUS (indicated by arrow) being retrieved from the left tubal pregnancy
Fig. 4 Left salpingectomy (indicated by arrow) performed using bipolar coagulation
Fig. 5 Pelvic view after completion of the procedure confirming hemostasis. Arrow points to an empty pouch of Douglas
The postoperative recovery of the patient was unremarkable. She was debriefed about the surgery and discharged the following morning. She went home on oral paracetamol and diclofenac for pain relief.
The patient was reviewed in the gynecology outpatient clinic 2 weeks later. She was asymptomatic and doing well. Histology report confirmed left ectopic tubal gestation. She reported that she desired conception. Preconception counseling was done. She was put on daily folic acid (400 µg). The patient was advised to come to the hospital as soon as she missed a period or tested positive for pregnancy for an early pregnancy ultrasound to rule out another ectopic pregnancy. Three months later she presented at the early pregnancy clinic following 5 weeks of amenorrhea. A pelvic ultrasound was done that showed intrauterine pregnancy at 5 weeks gestation.
Discussion
The above case documents a rare occurrence of a ruptured ectopic pregnancy with the LNG IUS embedded within the affected fallopian tube.
Levonorgestrel IUS (Mirena) is a safe, reversible, and highly effective contraceptive method [2]. It is known to have other therapeutic benefits such as reduction in menstrual bleeding, anemia, and dysmenorrhea, as well as management of endometrial hyperplasia [10]. In this patient, the use of the LNG IUS was purely for contraception purposes.
Ectopic pregnancies affect approximately 2% of all pregnancies. The most common presentation of an ectopic pregnancy is abdominal pain and abnormal uterine bleeding [11]. Even though the rate of ectopic pregnancy is lower in women using LNG IUS, if a pregnancy occurs while using this IUD, there is a high risk of it being an ectopic pregnancy [2]. Current IUD use is a known risk factor for ectopic pregnancy [12]. Other risk factors for ectopic pregnancy include pelvic inflammatory disease, previous tubal surgery, previous ectopic pregnancy, and smoking [12]. On examination, features of acute abdomen due to hemoperitoneum may be present [11, 12]. The patient in this case had a presentation suggestive of ectopic pregnancy with concurrent LNG IUS use as a risk factor. However, she had other unspecific presenting features of diarrhea, vomiting, and low-grade fever. It is important to note that some patients may be asymptomatic without specific risk factors for an ectopic pregnancy [12]
On the other hand, malposition of an IUD is one of its common complications, presenting with pelvic pain and bleeding or no symptoms [13]. Although malposition is associated with reduced contraceptive efficacy, this is mostly true for copper IUDs and not LNG IUS, which has local progesterone effects [6]. Malposition is diagnosed by ultrasound [13]. However, compared with copper IUDs, the LNG IUS is more likely to be missed by ultrasonography. LNG IUS is compounded with barium sulfate, which makes it radio opaque for X-ray recognition [14]. A plain X-ray can therefore be used as an adjunctive imaging modality in the case of a lost LNG IUS not seen on ultrasound [15]. The patient in this case had a lost LNG IUS not seen on ultrasound 1 year after insertion but was lost to follow-up for additional imaging.
Uterine perforation is uncommon, with an incidence of 1 in 1000 insertions. It is a serious complication of IUD use and is often asymptomatic [16]. There is increased risk of perforation if insertion is done less than 6 months postpartum or while breastfeeding. This period is associated with endometrial atrophy with accelerated uterine involution and hence has a high risk of perforation [6, 13]. The current patient was asymptomatic for malposition or perforation for 2 years prior to the ectopic pregnancy. The transvaginal ultrasound done at diagnosis of ectopic pregnancy did not visualize the device in the left adnexa. Her LNG IUS was inserted only 2 months postpartum while breastfeeding. This may have been a risk factor for possible unrecognized perforation.
Routine transvaginal ultrasound to monitor IUD position either immediately post insertion or after 6 weeks is not recommended without clinical suspicion of malposition according to de Kroon et al. [17]. It has been reported that IUDs take approximately 3 months to settle into their stable position. An initially malpositioned IUD can therefore assume the correct fundal position over time [18]. In asymptomatic women with uncomplicated IUD insertion, routine ultrasound lacks benefit over clinical evaluation with string check at 6 weeks [17]. The patient in this case was asymptomatic without complications at insertion. One year later, the LNG IUS device could not be seen on clinical examination nor on ultrasound.
The mechanism of device migration is not well understood, especially in the case of tubal migration. The fallopian tube is a rare site for dislocated IUD [19, 20]. This phenomenon has been described in few case reports. There are theories from case reports about the tubal migration of an IUD. The first possibility is placement of the device at the tubal ostium during insertion with subsequent migration into the tube due to uterine contractions and tubal peristalsis [21]. The other possibility is uterine perforation with migration of the device into the peritoneal cavity and subsequent perforation of a preexisting hydrosalpinx as described by Ozdemir et al. in a case report [19]. The patient in this case did not have any hydrosalpinx noted intraoperatively. Perforation can be due to either immediate traumatic perforation at insertion or delayed transmural migration [22, 23]. It is also possible that, following an unrecognized perforation, there was nestling of the IUD close to the fimbrial end of the fallopian tube, with the device being enveloped within the fimbria [7, 19]. This phenomenon could have occurred antecedent to conception of the ectopic pregnancy. In the patient in this case, there was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal.
The presence of an IUD within the fallopian tube is associated with an inflammatory reaction [19] interfering with tubal function and predisposing the patient to ectopic pregnancy. The tubal dysfunction is exacerbated by progesterone in the LNG IUS, which interferes with ciliary beating and tubal contractility [3]. It is possible that the embedment of LNG IUS at the fimbrial end of the fallopian tube occurred as a result of displacement from the proximal tube by the growing tubal pregnancy or its rupture.
Once an intraabdominal IUD is diagnosed, it should be removed whether it is symptomatic or not to avoid serious complications such as adhesion formation, bowel obstruction, and infertility [15, 19]. Laparoscopy is the surgical approach of choice as it is safe and effective. It provides good visualization to locate and remove a lost IUD [15]. In this case, the diagnosis of the LNG IUS within the fallopian tube and its removal were done laparoscopically.
Conclusion
Migration of the LNG IUS into the fallopian tube is a rare occurrence that is not well understood. In the case presented, a LNG IUS was found embedded within the fimbrial end of the fallopian tube that had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal IUD to prevent complications. The patient made a good recovery and proceeded to have an intrauterine pregnancy 3 months later, as desired.
Abbreviations
IUD Intrauterine device
LNG IUS Levonorgestrel intrauterine system
Acknowledgements
We would like to thank the patient for her permission to publish this manuscript.
Authors’ contributions
DM collected and analyzed the data and drafted the manuscript. IG and KW contributed to the manuscript writing and editing. All authors managed the patient and read and approved the final manuscript.
Funding
None.
Availability of data and materials
Clinical data and complementary examinations are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of the case and any accompanying images. A copy of the consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | LEVONORGESTREL | DrugsGivenReaction | CC BY | 33685513 | 19,041,622 | 2021-03-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ruptured ectopic pregnancy'. | Levonorgestrel intrauterine system embedded within tubal ectopic pregnancy: a case report.
BACKGROUND
The presence of the levonorgestrel-releasing intrauterine system embedded within an ectopic pregnancy is a rare occurrence. Tubal migration of an intrauterine device is not well understood and has not been extensively studied in literature.
METHODS
A 34-year-old African woman, para 1, gravida 2, presented with symptoms of ruptured ectopic pregnancy. She underwent a laparoscopy where a ruptured left ectopic pregnancy was found with a levonorgestrel-releasing intrauterine system inserted 2 years prior embedded within the tube. A left salpingectomy was performed with removal of the levonorgestrel-releasing intrauterine system. The patient recovered well and proceeded to have an intrauterine pregnancy 3 months later.
CONCLUSIONS
Migration of the levonorgestrel-releasing intrauterine system into the fallopian tube is a rare occurrence that is not well understood. In the case presented, levonorgestrel-releasing intrauterine system was found embedded within the fimbrial end of the left fallopian tube, which had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal intrauterine device to prevent complications.
Background
An intrauterine contraceptive device (IUD) is a highly effective method of contraception [1]. Types of IUDs include the levonorgestrel releasing intrauterine system (LNG IUS), also commonly referred to as Mirena, and the copper IUD. They have a low failure rate of less than 1%, which is comparable to permanent sterilization [1]. The pearl index of the LNG IUS is 0.06 per 100 women years, while that of the copper IUD is 0.52 per 100 women years [2]. Even though the risk of ectopic pregnancy with IUDs is lower than with no contraception, if a pregnancy occurs with an IUD in situ, it is likely to be an ectopic pregnancy. The rate of ectopic pregnancy among LNG IUS users ranges from 0.02 to 0.2 per 100 women years, whereas the rate among copper IUD users ranges from 0.1 to 0.8 per 100 women years. In case of pregnancy, the risk of ectopic pregnancy is higher in LNG IUS users compared with copper IUD users (27% versus 15% respectively) [2]. Progesterone is known to cause ciliary dysfunction within the fallopian tube, subsequently predisposing LNG IUS users who conceive to ectopic pregnancy [3]. It is therefore important to rule out ectopic pregnancy in women with acute abdomen or positive pregnancy test among LNG IUS users [4]
A correctly positioned IUD is located within 3 mm of the uterine fundus, with both arms extending to the cornua, a vertically oriented stem in the uterine body, and the strings protruding through the cervical os into the vaginal canal [5]. Suboptimally placed IUDs are at a higher risk of malposition or expulsion and associated symptoms [5]. Malposition of IUDs is a common complication of this method of contraception, with a reported rate of up to 10% [6]. Malposition of an IUD includes displacement, expulsion, rotation, or embedment. Migration of IUDs is, however, an uncommon occurrence, with most cases of migration reported to the colon and the urinary tract [7–9]. The fallopian tube is an uncommon location for migration and embedment [7]. Having an IUD embedded within a tubal ectopic pregnancy is an even rarer phenomenon.
We describe a case of a patient who presented with ruptured ectopic pregnancy and was found to have a LNG IUS embedded in the fimbrial end of the affected fallopian tube.
Case presentation
A 34-year-old African female, para 1, gravida 2, presented to the Accident and Emergency Department, having had symptoms of vomiting and abdominal pain for 3 days. The symptoms had worsened on the day of presentation to the hospital. She reported several episodes of vomiting with associated loose stools and abdominal fullness. She also had ongoing vaginal bleeding that had started 5 days prior to presentation.
Two years prior, the patient had an uncomplicated insertion of LNG IUS by an obstetrician/gynecologist at the 8-week visit following a normal vaginal delivery. She had a normal pap smear done at the time of insertion. One year following insertion, she had a desire to conceive and was scheduled for removal of the LNG IUS device. The strings could not be seen, and the device could not be retrieved with alligator forceps. The patient was therefore sent for a pelvic ultrasound to locate the lost IUD. The device was not seen on ultrasound. The patient was, however, lost to follow-up until presentation with symptoms of ruptured ectopic pregnancy. She had no preexisting conditions or previous surgery.
On physical examination she was in fair general condition and not pale. Her vital signs were a temperature of 37.6 °C, a blood pressure of 120/66 mmHg, pulse rate of 99 beats per minute, respiration rate of 18 breaths per minute, and oxygen saturation of 100% on room air. On abdominal examination she had tenderness on the left iliac fossa and suprapubic regions with absent bowel sounds. The rest of the systemic examination was normal. An impression of acute abdomen was made at this point. As initial treatment she was given intravenous fluids (Ringer’s lactate solution) 1-L bolus, as well as intravenous paracetamol and ondansetron for pain and vomiting, respectively.
The initial investigations included a full blood count, which revealed a normal hemoglobin level of 13.2 g/dl, slightly elevated white cell count of 12.28 × 109 cells/L, and normal platelet count of 314 × 109 cells/L. She had a beta human chorionic gonadotropin (Hcg) level of 7721 mIU/ml. Urinalysis showed leucocytes 2+, nitrite negative, and blood 2+. Transvaginal ultrasound showed a 2.1 cm × 1.8 cm echogenic mass with central cystic area on the left adnexa. It had no internal or peripheral vascularity. There was marked pelvic echogenic free fluid with low internal echoes extending to the Morrison’s pouch. The uterus was anteverted and normal in size and shape with an endometrial thickness of 5.5 mm. A 1.9 cm cystic lesion was seen in the right ovary, which was likely a corpus luteum cyst. There was no gestational sac or intrauterine device seen within the endometrial cavity (Fig. 1). These features indicated ruptured ectopic pregnancy.Fig. 1 Ultrasound image of an empty uterus. The arrow points to the endometrial lining measuring 5.5 mm
The diagnosis at this point was a ruptured left tubal ectopic pregnancy. The plan was to admit the patient for an emergency laparoscopy with possible left salpingectomy. The diagnosis and plan were explained to the patient, who signed an informed consent for the procedure. Group and cross match of one unit of packed red cells was ordered in case a transfusion would be required.
The laparoscopy was done under general anesthesia in the Lloyd–Davis position. Cohen’s uterine manipulator was placed. Veress insufflation was performed, followed by insertion of a 10-mm primary trocar at the umbilicus. Entry and operating pressures were 20 mmHg and 15 mmHg, respectively. Two secondary ports were inserted under vision, 5 mm in the right iliac fossa and 12 mm in the left iliac fossa. On primary survey, LNG IUS was found embedded at the fimbrial end of the left fallopian tube (Fig. 2). The LNG IUS was retrieved whole under vision through the 12-mm port (Fig. 3). There was hemoperitoneum of 700 ml (Fig. 2). A ruptured left ampullary ectopic pregnancy was identified by left salpingectomy using bipolar coagulation and scissors (Fig. 4). A corpus luteum cyst was found on the right ovary with normal right fallopian tube. Suction and peritoneal lavage were performed, and hemostasis was confirmed (Fig. 5). The specimen was retrieved through the 12-mm port and taken for histology. There was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal. All trocars were removed under vision.Fig. 2 Body of the embedded LNG IUS (indicated by arrow), which is seen protruding from the left tubal pregnancy with hemoperitoneum
Fig. 3 LNG IUS (indicated by arrow) being retrieved from the left tubal pregnancy
Fig. 4 Left salpingectomy (indicated by arrow) performed using bipolar coagulation
Fig. 5 Pelvic view after completion of the procedure confirming hemostasis. Arrow points to an empty pouch of Douglas
The postoperative recovery of the patient was unremarkable. She was debriefed about the surgery and discharged the following morning. She went home on oral paracetamol and diclofenac for pain relief.
The patient was reviewed in the gynecology outpatient clinic 2 weeks later. She was asymptomatic and doing well. Histology report confirmed left ectopic tubal gestation. She reported that she desired conception. Preconception counseling was done. She was put on daily folic acid (400 µg). The patient was advised to come to the hospital as soon as she missed a period or tested positive for pregnancy for an early pregnancy ultrasound to rule out another ectopic pregnancy. Three months later she presented at the early pregnancy clinic following 5 weeks of amenorrhea. A pelvic ultrasound was done that showed intrauterine pregnancy at 5 weeks gestation.
Discussion
The above case documents a rare occurrence of a ruptured ectopic pregnancy with the LNG IUS embedded within the affected fallopian tube.
Levonorgestrel IUS (Mirena) is a safe, reversible, and highly effective contraceptive method [2]. It is known to have other therapeutic benefits such as reduction in menstrual bleeding, anemia, and dysmenorrhea, as well as management of endometrial hyperplasia [10]. In this patient, the use of the LNG IUS was purely for contraception purposes.
Ectopic pregnancies affect approximately 2% of all pregnancies. The most common presentation of an ectopic pregnancy is abdominal pain and abnormal uterine bleeding [11]. Even though the rate of ectopic pregnancy is lower in women using LNG IUS, if a pregnancy occurs while using this IUD, there is a high risk of it being an ectopic pregnancy [2]. Current IUD use is a known risk factor for ectopic pregnancy [12]. Other risk factors for ectopic pregnancy include pelvic inflammatory disease, previous tubal surgery, previous ectopic pregnancy, and smoking [12]. On examination, features of acute abdomen due to hemoperitoneum may be present [11, 12]. The patient in this case had a presentation suggestive of ectopic pregnancy with concurrent LNG IUS use as a risk factor. However, she had other unspecific presenting features of diarrhea, vomiting, and low-grade fever. It is important to note that some patients may be asymptomatic without specific risk factors for an ectopic pregnancy [12]
On the other hand, malposition of an IUD is one of its common complications, presenting with pelvic pain and bleeding or no symptoms [13]. Although malposition is associated with reduced contraceptive efficacy, this is mostly true for copper IUDs and not LNG IUS, which has local progesterone effects [6]. Malposition is diagnosed by ultrasound [13]. However, compared with copper IUDs, the LNG IUS is more likely to be missed by ultrasonography. LNG IUS is compounded with barium sulfate, which makes it radio opaque for X-ray recognition [14]. A plain X-ray can therefore be used as an adjunctive imaging modality in the case of a lost LNG IUS not seen on ultrasound [15]. The patient in this case had a lost LNG IUS not seen on ultrasound 1 year after insertion but was lost to follow-up for additional imaging.
Uterine perforation is uncommon, with an incidence of 1 in 1000 insertions. It is a serious complication of IUD use and is often asymptomatic [16]. There is increased risk of perforation if insertion is done less than 6 months postpartum or while breastfeeding. This period is associated with endometrial atrophy with accelerated uterine involution and hence has a high risk of perforation [6, 13]. The current patient was asymptomatic for malposition or perforation for 2 years prior to the ectopic pregnancy. The transvaginal ultrasound done at diagnosis of ectopic pregnancy did not visualize the device in the left adnexa. Her LNG IUS was inserted only 2 months postpartum while breastfeeding. This may have been a risk factor for possible unrecognized perforation.
Routine transvaginal ultrasound to monitor IUD position either immediately post insertion or after 6 weeks is not recommended without clinical suspicion of malposition according to de Kroon et al. [17]. It has been reported that IUDs take approximately 3 months to settle into their stable position. An initially malpositioned IUD can therefore assume the correct fundal position over time [18]. In asymptomatic women with uncomplicated IUD insertion, routine ultrasound lacks benefit over clinical evaluation with string check at 6 weeks [17]. The patient in this case was asymptomatic without complications at insertion. One year later, the LNG IUS device could not be seen on clinical examination nor on ultrasound.
The mechanism of device migration is not well understood, especially in the case of tubal migration. The fallopian tube is a rare site for dislocated IUD [19, 20]. This phenomenon has been described in few case reports. There are theories from case reports about the tubal migration of an IUD. The first possibility is placement of the device at the tubal ostium during insertion with subsequent migration into the tube due to uterine contractions and tubal peristalsis [21]. The other possibility is uterine perforation with migration of the device into the peritoneal cavity and subsequent perforation of a preexisting hydrosalpinx as described by Ozdemir et al. in a case report [19]. The patient in this case did not have any hydrosalpinx noted intraoperatively. Perforation can be due to either immediate traumatic perforation at insertion or delayed transmural migration [22, 23]. It is also possible that, following an unrecognized perforation, there was nestling of the IUD close to the fimbrial end of the fallopian tube, with the device being enveloped within the fimbria [7, 19]. This phenomenon could have occurred antecedent to conception of the ectopic pregnancy. In the patient in this case, there was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal.
The presence of an IUD within the fallopian tube is associated with an inflammatory reaction [19] interfering with tubal function and predisposing the patient to ectopic pregnancy. The tubal dysfunction is exacerbated by progesterone in the LNG IUS, which interferes with ciliary beating and tubal contractility [3]. It is possible that the embedment of LNG IUS at the fimbrial end of the fallopian tube occurred as a result of displacement from the proximal tube by the growing tubal pregnancy or its rupture.
Once an intraabdominal IUD is diagnosed, it should be removed whether it is symptomatic or not to avoid serious complications such as adhesion formation, bowel obstruction, and infertility [15, 19]. Laparoscopy is the surgical approach of choice as it is safe and effective. It provides good visualization to locate and remove a lost IUD [15]. In this case, the diagnosis of the LNG IUS within the fallopian tube and its removal were done laparoscopically.
Conclusion
Migration of the LNG IUS into the fallopian tube is a rare occurrence that is not well understood. In the case presented, a LNG IUS was found embedded within the fimbrial end of the fallopian tube that had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal IUD to prevent complications. The patient made a good recovery and proceeded to have an intrauterine pregnancy 3 months later, as desired.
Abbreviations
IUD Intrauterine device
LNG IUS Levonorgestrel intrauterine system
Acknowledgements
We would like to thank the patient for her permission to publish this manuscript.
Authors’ contributions
DM collected and analyzed the data and drafted the manuscript. IG and KW contributed to the manuscript writing and editing. All authors managed the patient and read and approved the final manuscript.
Funding
None.
Availability of data and materials
Clinical data and complementary examinations are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of the case and any accompanying images. A copy of the consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | LEVONORGESTREL | DrugsGivenReaction | CC BY | 33685513 | 19,041,622 | 2021-03-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Uterine perforation'. | Levonorgestrel intrauterine system embedded within tubal ectopic pregnancy: a case report.
BACKGROUND
The presence of the levonorgestrel-releasing intrauterine system embedded within an ectopic pregnancy is a rare occurrence. Tubal migration of an intrauterine device is not well understood and has not been extensively studied in literature.
METHODS
A 34-year-old African woman, para 1, gravida 2, presented with symptoms of ruptured ectopic pregnancy. She underwent a laparoscopy where a ruptured left ectopic pregnancy was found with a levonorgestrel-releasing intrauterine system inserted 2 years prior embedded within the tube. A left salpingectomy was performed with removal of the levonorgestrel-releasing intrauterine system. The patient recovered well and proceeded to have an intrauterine pregnancy 3 months later.
CONCLUSIONS
Migration of the levonorgestrel-releasing intrauterine system into the fallopian tube is a rare occurrence that is not well understood. In the case presented, levonorgestrel-releasing intrauterine system was found embedded within the fimbrial end of the left fallopian tube, which had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal intrauterine device to prevent complications.
Background
An intrauterine contraceptive device (IUD) is a highly effective method of contraception [1]. Types of IUDs include the levonorgestrel releasing intrauterine system (LNG IUS), also commonly referred to as Mirena, and the copper IUD. They have a low failure rate of less than 1%, which is comparable to permanent sterilization [1]. The pearl index of the LNG IUS is 0.06 per 100 women years, while that of the copper IUD is 0.52 per 100 women years [2]. Even though the risk of ectopic pregnancy with IUDs is lower than with no contraception, if a pregnancy occurs with an IUD in situ, it is likely to be an ectopic pregnancy. The rate of ectopic pregnancy among LNG IUS users ranges from 0.02 to 0.2 per 100 women years, whereas the rate among copper IUD users ranges from 0.1 to 0.8 per 100 women years. In case of pregnancy, the risk of ectopic pregnancy is higher in LNG IUS users compared with copper IUD users (27% versus 15% respectively) [2]. Progesterone is known to cause ciliary dysfunction within the fallopian tube, subsequently predisposing LNG IUS users who conceive to ectopic pregnancy [3]. It is therefore important to rule out ectopic pregnancy in women with acute abdomen or positive pregnancy test among LNG IUS users [4]
A correctly positioned IUD is located within 3 mm of the uterine fundus, with both arms extending to the cornua, a vertically oriented stem in the uterine body, and the strings protruding through the cervical os into the vaginal canal [5]. Suboptimally placed IUDs are at a higher risk of malposition or expulsion and associated symptoms [5]. Malposition of IUDs is a common complication of this method of contraception, with a reported rate of up to 10% [6]. Malposition of an IUD includes displacement, expulsion, rotation, or embedment. Migration of IUDs is, however, an uncommon occurrence, with most cases of migration reported to the colon and the urinary tract [7–9]. The fallopian tube is an uncommon location for migration and embedment [7]. Having an IUD embedded within a tubal ectopic pregnancy is an even rarer phenomenon.
We describe a case of a patient who presented with ruptured ectopic pregnancy and was found to have a LNG IUS embedded in the fimbrial end of the affected fallopian tube.
Case presentation
A 34-year-old African female, para 1, gravida 2, presented to the Accident and Emergency Department, having had symptoms of vomiting and abdominal pain for 3 days. The symptoms had worsened on the day of presentation to the hospital. She reported several episodes of vomiting with associated loose stools and abdominal fullness. She also had ongoing vaginal bleeding that had started 5 days prior to presentation.
Two years prior, the patient had an uncomplicated insertion of LNG IUS by an obstetrician/gynecologist at the 8-week visit following a normal vaginal delivery. She had a normal pap smear done at the time of insertion. One year following insertion, she had a desire to conceive and was scheduled for removal of the LNG IUS device. The strings could not be seen, and the device could not be retrieved with alligator forceps. The patient was therefore sent for a pelvic ultrasound to locate the lost IUD. The device was not seen on ultrasound. The patient was, however, lost to follow-up until presentation with symptoms of ruptured ectopic pregnancy. She had no preexisting conditions or previous surgery.
On physical examination she was in fair general condition and not pale. Her vital signs were a temperature of 37.6 °C, a blood pressure of 120/66 mmHg, pulse rate of 99 beats per minute, respiration rate of 18 breaths per minute, and oxygen saturation of 100% on room air. On abdominal examination she had tenderness on the left iliac fossa and suprapubic regions with absent bowel sounds. The rest of the systemic examination was normal. An impression of acute abdomen was made at this point. As initial treatment she was given intravenous fluids (Ringer’s lactate solution) 1-L bolus, as well as intravenous paracetamol and ondansetron for pain and vomiting, respectively.
The initial investigations included a full blood count, which revealed a normal hemoglobin level of 13.2 g/dl, slightly elevated white cell count of 12.28 × 109 cells/L, and normal platelet count of 314 × 109 cells/L. She had a beta human chorionic gonadotropin (Hcg) level of 7721 mIU/ml. Urinalysis showed leucocytes 2+, nitrite negative, and blood 2+. Transvaginal ultrasound showed a 2.1 cm × 1.8 cm echogenic mass with central cystic area on the left adnexa. It had no internal or peripheral vascularity. There was marked pelvic echogenic free fluid with low internal echoes extending to the Morrison’s pouch. The uterus was anteverted and normal in size and shape with an endometrial thickness of 5.5 mm. A 1.9 cm cystic lesion was seen in the right ovary, which was likely a corpus luteum cyst. There was no gestational sac or intrauterine device seen within the endometrial cavity (Fig. 1). These features indicated ruptured ectopic pregnancy.Fig. 1 Ultrasound image of an empty uterus. The arrow points to the endometrial lining measuring 5.5 mm
The diagnosis at this point was a ruptured left tubal ectopic pregnancy. The plan was to admit the patient for an emergency laparoscopy with possible left salpingectomy. The diagnosis and plan were explained to the patient, who signed an informed consent for the procedure. Group and cross match of one unit of packed red cells was ordered in case a transfusion would be required.
The laparoscopy was done under general anesthesia in the Lloyd–Davis position. Cohen’s uterine manipulator was placed. Veress insufflation was performed, followed by insertion of a 10-mm primary trocar at the umbilicus. Entry and operating pressures were 20 mmHg and 15 mmHg, respectively. Two secondary ports were inserted under vision, 5 mm in the right iliac fossa and 12 mm in the left iliac fossa. On primary survey, LNG IUS was found embedded at the fimbrial end of the left fallopian tube (Fig. 2). The LNG IUS was retrieved whole under vision through the 12-mm port (Fig. 3). There was hemoperitoneum of 700 ml (Fig. 2). A ruptured left ampullary ectopic pregnancy was identified by left salpingectomy using bipolar coagulation and scissors (Fig. 4). A corpus luteum cyst was found on the right ovary with normal right fallopian tube. Suction and peritoneal lavage were performed, and hemostasis was confirmed (Fig. 5). The specimen was retrieved through the 12-mm port and taken for histology. There was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal. All trocars were removed under vision.Fig. 2 Body of the embedded LNG IUS (indicated by arrow), which is seen protruding from the left tubal pregnancy with hemoperitoneum
Fig. 3 LNG IUS (indicated by arrow) being retrieved from the left tubal pregnancy
Fig. 4 Left salpingectomy (indicated by arrow) performed using bipolar coagulation
Fig. 5 Pelvic view after completion of the procedure confirming hemostasis. Arrow points to an empty pouch of Douglas
The postoperative recovery of the patient was unremarkable. She was debriefed about the surgery and discharged the following morning. She went home on oral paracetamol and diclofenac for pain relief.
The patient was reviewed in the gynecology outpatient clinic 2 weeks later. She was asymptomatic and doing well. Histology report confirmed left ectopic tubal gestation. She reported that she desired conception. Preconception counseling was done. She was put on daily folic acid (400 µg). The patient was advised to come to the hospital as soon as she missed a period or tested positive for pregnancy for an early pregnancy ultrasound to rule out another ectopic pregnancy. Three months later she presented at the early pregnancy clinic following 5 weeks of amenorrhea. A pelvic ultrasound was done that showed intrauterine pregnancy at 5 weeks gestation.
Discussion
The above case documents a rare occurrence of a ruptured ectopic pregnancy with the LNG IUS embedded within the affected fallopian tube.
Levonorgestrel IUS (Mirena) is a safe, reversible, and highly effective contraceptive method [2]. It is known to have other therapeutic benefits such as reduction in menstrual bleeding, anemia, and dysmenorrhea, as well as management of endometrial hyperplasia [10]. In this patient, the use of the LNG IUS was purely for contraception purposes.
Ectopic pregnancies affect approximately 2% of all pregnancies. The most common presentation of an ectopic pregnancy is abdominal pain and abnormal uterine bleeding [11]. Even though the rate of ectopic pregnancy is lower in women using LNG IUS, if a pregnancy occurs while using this IUD, there is a high risk of it being an ectopic pregnancy [2]. Current IUD use is a known risk factor for ectopic pregnancy [12]. Other risk factors for ectopic pregnancy include pelvic inflammatory disease, previous tubal surgery, previous ectopic pregnancy, and smoking [12]. On examination, features of acute abdomen due to hemoperitoneum may be present [11, 12]. The patient in this case had a presentation suggestive of ectopic pregnancy with concurrent LNG IUS use as a risk factor. However, she had other unspecific presenting features of diarrhea, vomiting, and low-grade fever. It is important to note that some patients may be asymptomatic without specific risk factors for an ectopic pregnancy [12]
On the other hand, malposition of an IUD is one of its common complications, presenting with pelvic pain and bleeding or no symptoms [13]. Although malposition is associated with reduced contraceptive efficacy, this is mostly true for copper IUDs and not LNG IUS, which has local progesterone effects [6]. Malposition is diagnosed by ultrasound [13]. However, compared with copper IUDs, the LNG IUS is more likely to be missed by ultrasonography. LNG IUS is compounded with barium sulfate, which makes it radio opaque for X-ray recognition [14]. A plain X-ray can therefore be used as an adjunctive imaging modality in the case of a lost LNG IUS not seen on ultrasound [15]. The patient in this case had a lost LNG IUS not seen on ultrasound 1 year after insertion but was lost to follow-up for additional imaging.
Uterine perforation is uncommon, with an incidence of 1 in 1000 insertions. It is a serious complication of IUD use and is often asymptomatic [16]. There is increased risk of perforation if insertion is done less than 6 months postpartum or while breastfeeding. This period is associated with endometrial atrophy with accelerated uterine involution and hence has a high risk of perforation [6, 13]. The current patient was asymptomatic for malposition or perforation for 2 years prior to the ectopic pregnancy. The transvaginal ultrasound done at diagnosis of ectopic pregnancy did not visualize the device in the left adnexa. Her LNG IUS was inserted only 2 months postpartum while breastfeeding. This may have been a risk factor for possible unrecognized perforation.
Routine transvaginal ultrasound to monitor IUD position either immediately post insertion or after 6 weeks is not recommended without clinical suspicion of malposition according to de Kroon et al. [17]. It has been reported that IUDs take approximately 3 months to settle into their stable position. An initially malpositioned IUD can therefore assume the correct fundal position over time [18]. In asymptomatic women with uncomplicated IUD insertion, routine ultrasound lacks benefit over clinical evaluation with string check at 6 weeks [17]. The patient in this case was asymptomatic without complications at insertion. One year later, the LNG IUS device could not be seen on clinical examination nor on ultrasound.
The mechanism of device migration is not well understood, especially in the case of tubal migration. The fallopian tube is a rare site for dislocated IUD [19, 20]. This phenomenon has been described in few case reports. There are theories from case reports about the tubal migration of an IUD. The first possibility is placement of the device at the tubal ostium during insertion with subsequent migration into the tube due to uterine contractions and tubal peristalsis [21]. The other possibility is uterine perforation with migration of the device into the peritoneal cavity and subsequent perforation of a preexisting hydrosalpinx as described by Ozdemir et al. in a case report [19]. The patient in this case did not have any hydrosalpinx noted intraoperatively. Perforation can be due to either immediate traumatic perforation at insertion or delayed transmural migration [22, 23]. It is also possible that, following an unrecognized perforation, there was nestling of the IUD close to the fimbrial end of the fallopian tube, with the device being enveloped within the fimbria [7, 19]. This phenomenon could have occurred antecedent to conception of the ectopic pregnancy. In the patient in this case, there was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal.
The presence of an IUD within the fallopian tube is associated with an inflammatory reaction [19] interfering with tubal function and predisposing the patient to ectopic pregnancy. The tubal dysfunction is exacerbated by progesterone in the LNG IUS, which interferes with ciliary beating and tubal contractility [3]. It is possible that the embedment of LNG IUS at the fimbrial end of the fallopian tube occurred as a result of displacement from the proximal tube by the growing tubal pregnancy or its rupture.
Once an intraabdominal IUD is diagnosed, it should be removed whether it is symptomatic or not to avoid serious complications such as adhesion formation, bowel obstruction, and infertility [15, 19]. Laparoscopy is the surgical approach of choice as it is safe and effective. It provides good visualization to locate and remove a lost IUD [15]. In this case, the diagnosis of the LNG IUS within the fallopian tube and its removal were done laparoscopically.
Conclusion
Migration of the LNG IUS into the fallopian tube is a rare occurrence that is not well understood. In the case presented, a LNG IUS was found embedded within the fimbrial end of the fallopian tube that had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal IUD to prevent complications. The patient made a good recovery and proceeded to have an intrauterine pregnancy 3 months later, as desired.
Abbreviations
IUD Intrauterine device
LNG IUS Levonorgestrel intrauterine system
Acknowledgements
We would like to thank the patient for her permission to publish this manuscript.
Authors’ contributions
DM collected and analyzed the data and drafted the manuscript. IG and KW contributed to the manuscript writing and editing. All authors managed the patient and read and approved the final manuscript.
Funding
None.
Availability of data and materials
Clinical data and complementary examinations are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of the case and any accompanying images. A copy of the consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | LEVONORGESTREL | DrugsGivenReaction | CC BY | 33685513 | 19,041,622 | 2021-03-09 |
What was the administration route of drug 'LEVONORGESTREL'? | Levonorgestrel intrauterine system embedded within tubal ectopic pregnancy: a case report.
BACKGROUND
The presence of the levonorgestrel-releasing intrauterine system embedded within an ectopic pregnancy is a rare occurrence. Tubal migration of an intrauterine device is not well understood and has not been extensively studied in literature.
METHODS
A 34-year-old African woman, para 1, gravida 2, presented with symptoms of ruptured ectopic pregnancy. She underwent a laparoscopy where a ruptured left ectopic pregnancy was found with a levonorgestrel-releasing intrauterine system inserted 2 years prior embedded within the tube. A left salpingectomy was performed with removal of the levonorgestrel-releasing intrauterine system. The patient recovered well and proceeded to have an intrauterine pregnancy 3 months later.
CONCLUSIONS
Migration of the levonorgestrel-releasing intrauterine system into the fallopian tube is a rare occurrence that is not well understood. In the case presented, levonorgestrel-releasing intrauterine system was found embedded within the fimbrial end of the left fallopian tube, which had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal intrauterine device to prevent complications.
Background
An intrauterine contraceptive device (IUD) is a highly effective method of contraception [1]. Types of IUDs include the levonorgestrel releasing intrauterine system (LNG IUS), also commonly referred to as Mirena, and the copper IUD. They have a low failure rate of less than 1%, which is comparable to permanent sterilization [1]. The pearl index of the LNG IUS is 0.06 per 100 women years, while that of the copper IUD is 0.52 per 100 women years [2]. Even though the risk of ectopic pregnancy with IUDs is lower than with no contraception, if a pregnancy occurs with an IUD in situ, it is likely to be an ectopic pregnancy. The rate of ectopic pregnancy among LNG IUS users ranges from 0.02 to 0.2 per 100 women years, whereas the rate among copper IUD users ranges from 0.1 to 0.8 per 100 women years. In case of pregnancy, the risk of ectopic pregnancy is higher in LNG IUS users compared with copper IUD users (27% versus 15% respectively) [2]. Progesterone is known to cause ciliary dysfunction within the fallopian tube, subsequently predisposing LNG IUS users who conceive to ectopic pregnancy [3]. It is therefore important to rule out ectopic pregnancy in women with acute abdomen or positive pregnancy test among LNG IUS users [4]
A correctly positioned IUD is located within 3 mm of the uterine fundus, with both arms extending to the cornua, a vertically oriented stem in the uterine body, and the strings protruding through the cervical os into the vaginal canal [5]. Suboptimally placed IUDs are at a higher risk of malposition or expulsion and associated symptoms [5]. Malposition of IUDs is a common complication of this method of contraception, with a reported rate of up to 10% [6]. Malposition of an IUD includes displacement, expulsion, rotation, or embedment. Migration of IUDs is, however, an uncommon occurrence, with most cases of migration reported to the colon and the urinary tract [7–9]. The fallopian tube is an uncommon location for migration and embedment [7]. Having an IUD embedded within a tubal ectopic pregnancy is an even rarer phenomenon.
We describe a case of a patient who presented with ruptured ectopic pregnancy and was found to have a LNG IUS embedded in the fimbrial end of the affected fallopian tube.
Case presentation
A 34-year-old African female, para 1, gravida 2, presented to the Accident and Emergency Department, having had symptoms of vomiting and abdominal pain for 3 days. The symptoms had worsened on the day of presentation to the hospital. She reported several episodes of vomiting with associated loose stools and abdominal fullness. She also had ongoing vaginal bleeding that had started 5 days prior to presentation.
Two years prior, the patient had an uncomplicated insertion of LNG IUS by an obstetrician/gynecologist at the 8-week visit following a normal vaginal delivery. She had a normal pap smear done at the time of insertion. One year following insertion, she had a desire to conceive and was scheduled for removal of the LNG IUS device. The strings could not be seen, and the device could not be retrieved with alligator forceps. The patient was therefore sent for a pelvic ultrasound to locate the lost IUD. The device was not seen on ultrasound. The patient was, however, lost to follow-up until presentation with symptoms of ruptured ectopic pregnancy. She had no preexisting conditions or previous surgery.
On physical examination she was in fair general condition and not pale. Her vital signs were a temperature of 37.6 °C, a blood pressure of 120/66 mmHg, pulse rate of 99 beats per minute, respiration rate of 18 breaths per minute, and oxygen saturation of 100% on room air. On abdominal examination she had tenderness on the left iliac fossa and suprapubic regions with absent bowel sounds. The rest of the systemic examination was normal. An impression of acute abdomen was made at this point. As initial treatment she was given intravenous fluids (Ringer’s lactate solution) 1-L bolus, as well as intravenous paracetamol and ondansetron for pain and vomiting, respectively.
The initial investigations included a full blood count, which revealed a normal hemoglobin level of 13.2 g/dl, slightly elevated white cell count of 12.28 × 109 cells/L, and normal platelet count of 314 × 109 cells/L. She had a beta human chorionic gonadotropin (Hcg) level of 7721 mIU/ml. Urinalysis showed leucocytes 2+, nitrite negative, and blood 2+. Transvaginal ultrasound showed a 2.1 cm × 1.8 cm echogenic mass with central cystic area on the left adnexa. It had no internal or peripheral vascularity. There was marked pelvic echogenic free fluid with low internal echoes extending to the Morrison’s pouch. The uterus was anteverted and normal in size and shape with an endometrial thickness of 5.5 mm. A 1.9 cm cystic lesion was seen in the right ovary, which was likely a corpus luteum cyst. There was no gestational sac or intrauterine device seen within the endometrial cavity (Fig. 1). These features indicated ruptured ectopic pregnancy.Fig. 1 Ultrasound image of an empty uterus. The arrow points to the endometrial lining measuring 5.5 mm
The diagnosis at this point was a ruptured left tubal ectopic pregnancy. The plan was to admit the patient for an emergency laparoscopy with possible left salpingectomy. The diagnosis and plan were explained to the patient, who signed an informed consent for the procedure. Group and cross match of one unit of packed red cells was ordered in case a transfusion would be required.
The laparoscopy was done under general anesthesia in the Lloyd–Davis position. Cohen’s uterine manipulator was placed. Veress insufflation was performed, followed by insertion of a 10-mm primary trocar at the umbilicus. Entry and operating pressures were 20 mmHg and 15 mmHg, respectively. Two secondary ports were inserted under vision, 5 mm in the right iliac fossa and 12 mm in the left iliac fossa. On primary survey, LNG IUS was found embedded at the fimbrial end of the left fallopian tube (Fig. 2). The LNG IUS was retrieved whole under vision through the 12-mm port (Fig. 3). There was hemoperitoneum of 700 ml (Fig. 2). A ruptured left ampullary ectopic pregnancy was identified by left salpingectomy using bipolar coagulation and scissors (Fig. 4). A corpus luteum cyst was found on the right ovary with normal right fallopian tube. Suction and peritoneal lavage were performed, and hemostasis was confirmed (Fig. 5). The specimen was retrieved through the 12-mm port and taken for histology. There was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal. All trocars were removed under vision.Fig. 2 Body of the embedded LNG IUS (indicated by arrow), which is seen protruding from the left tubal pregnancy with hemoperitoneum
Fig. 3 LNG IUS (indicated by arrow) being retrieved from the left tubal pregnancy
Fig. 4 Left salpingectomy (indicated by arrow) performed using bipolar coagulation
Fig. 5 Pelvic view after completion of the procedure confirming hemostasis. Arrow points to an empty pouch of Douglas
The postoperative recovery of the patient was unremarkable. She was debriefed about the surgery and discharged the following morning. She went home on oral paracetamol and diclofenac for pain relief.
The patient was reviewed in the gynecology outpatient clinic 2 weeks later. She was asymptomatic and doing well. Histology report confirmed left ectopic tubal gestation. She reported that she desired conception. Preconception counseling was done. She was put on daily folic acid (400 µg). The patient was advised to come to the hospital as soon as she missed a period or tested positive for pregnancy for an early pregnancy ultrasound to rule out another ectopic pregnancy. Three months later she presented at the early pregnancy clinic following 5 weeks of amenorrhea. A pelvic ultrasound was done that showed intrauterine pregnancy at 5 weeks gestation.
Discussion
The above case documents a rare occurrence of a ruptured ectopic pregnancy with the LNG IUS embedded within the affected fallopian tube.
Levonorgestrel IUS (Mirena) is a safe, reversible, and highly effective contraceptive method [2]. It is known to have other therapeutic benefits such as reduction in menstrual bleeding, anemia, and dysmenorrhea, as well as management of endometrial hyperplasia [10]. In this patient, the use of the LNG IUS was purely for contraception purposes.
Ectopic pregnancies affect approximately 2% of all pregnancies. The most common presentation of an ectopic pregnancy is abdominal pain and abnormal uterine bleeding [11]. Even though the rate of ectopic pregnancy is lower in women using LNG IUS, if a pregnancy occurs while using this IUD, there is a high risk of it being an ectopic pregnancy [2]. Current IUD use is a known risk factor for ectopic pregnancy [12]. Other risk factors for ectopic pregnancy include pelvic inflammatory disease, previous tubal surgery, previous ectopic pregnancy, and smoking [12]. On examination, features of acute abdomen due to hemoperitoneum may be present [11, 12]. The patient in this case had a presentation suggestive of ectopic pregnancy with concurrent LNG IUS use as a risk factor. However, she had other unspecific presenting features of diarrhea, vomiting, and low-grade fever. It is important to note that some patients may be asymptomatic without specific risk factors for an ectopic pregnancy [12]
On the other hand, malposition of an IUD is one of its common complications, presenting with pelvic pain and bleeding or no symptoms [13]. Although malposition is associated with reduced contraceptive efficacy, this is mostly true for copper IUDs and not LNG IUS, which has local progesterone effects [6]. Malposition is diagnosed by ultrasound [13]. However, compared with copper IUDs, the LNG IUS is more likely to be missed by ultrasonography. LNG IUS is compounded with barium sulfate, which makes it radio opaque for X-ray recognition [14]. A plain X-ray can therefore be used as an adjunctive imaging modality in the case of a lost LNG IUS not seen on ultrasound [15]. The patient in this case had a lost LNG IUS not seen on ultrasound 1 year after insertion but was lost to follow-up for additional imaging.
Uterine perforation is uncommon, with an incidence of 1 in 1000 insertions. It is a serious complication of IUD use and is often asymptomatic [16]. There is increased risk of perforation if insertion is done less than 6 months postpartum or while breastfeeding. This period is associated with endometrial atrophy with accelerated uterine involution and hence has a high risk of perforation [6, 13]. The current patient was asymptomatic for malposition or perforation for 2 years prior to the ectopic pregnancy. The transvaginal ultrasound done at diagnosis of ectopic pregnancy did not visualize the device in the left adnexa. Her LNG IUS was inserted only 2 months postpartum while breastfeeding. This may have been a risk factor for possible unrecognized perforation.
Routine transvaginal ultrasound to monitor IUD position either immediately post insertion or after 6 weeks is not recommended without clinical suspicion of malposition according to de Kroon et al. [17]. It has been reported that IUDs take approximately 3 months to settle into their stable position. An initially malpositioned IUD can therefore assume the correct fundal position over time [18]. In asymptomatic women with uncomplicated IUD insertion, routine ultrasound lacks benefit over clinical evaluation with string check at 6 weeks [17]. The patient in this case was asymptomatic without complications at insertion. One year later, the LNG IUS device could not be seen on clinical examination nor on ultrasound.
The mechanism of device migration is not well understood, especially in the case of tubal migration. The fallopian tube is a rare site for dislocated IUD [19, 20]. This phenomenon has been described in few case reports. There are theories from case reports about the tubal migration of an IUD. The first possibility is placement of the device at the tubal ostium during insertion with subsequent migration into the tube due to uterine contractions and tubal peristalsis [21]. The other possibility is uterine perforation with migration of the device into the peritoneal cavity and subsequent perforation of a preexisting hydrosalpinx as described by Ozdemir et al. in a case report [19]. The patient in this case did not have any hydrosalpinx noted intraoperatively. Perforation can be due to either immediate traumatic perforation at insertion or delayed transmural migration [22, 23]. It is also possible that, following an unrecognized perforation, there was nestling of the IUD close to the fimbrial end of the fallopian tube, with the device being enveloped within the fimbria [7, 19]. This phenomenon could have occurred antecedent to conception of the ectopic pregnancy. In the patient in this case, there was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal.
The presence of an IUD within the fallopian tube is associated with an inflammatory reaction [19] interfering with tubal function and predisposing the patient to ectopic pregnancy. The tubal dysfunction is exacerbated by progesterone in the LNG IUS, which interferes with ciliary beating and tubal contractility [3]. It is possible that the embedment of LNG IUS at the fimbrial end of the fallopian tube occurred as a result of displacement from the proximal tube by the growing tubal pregnancy or its rupture.
Once an intraabdominal IUD is diagnosed, it should be removed whether it is symptomatic or not to avoid serious complications such as adhesion formation, bowel obstruction, and infertility [15, 19]. Laparoscopy is the surgical approach of choice as it is safe and effective. It provides good visualization to locate and remove a lost IUD [15]. In this case, the diagnosis of the LNG IUS within the fallopian tube and its removal were done laparoscopically.
Conclusion
Migration of the LNG IUS into the fallopian tube is a rare occurrence that is not well understood. In the case presented, a LNG IUS was found embedded within the fimbrial end of the fallopian tube that had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal IUD to prevent complications. The patient made a good recovery and proceeded to have an intrauterine pregnancy 3 months later, as desired.
Abbreviations
IUD Intrauterine device
LNG IUS Levonorgestrel intrauterine system
Acknowledgements
We would like to thank the patient for her permission to publish this manuscript.
Authors’ contributions
DM collected and analyzed the data and drafted the manuscript. IG and KW contributed to the manuscript writing and editing. All authors managed the patient and read and approved the final manuscript.
Funding
None.
Availability of data and materials
Clinical data and complementary examinations are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of the case and any accompanying images. A copy of the consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Intra-uterine | DrugAdministrationRoute | CC BY | 33685513 | 19,041,622 | 2021-03-09 |
What was the outcome of reaction 'Device dislocation'? | Levonorgestrel intrauterine system embedded within tubal ectopic pregnancy: a case report.
BACKGROUND
The presence of the levonorgestrel-releasing intrauterine system embedded within an ectopic pregnancy is a rare occurrence. Tubal migration of an intrauterine device is not well understood and has not been extensively studied in literature.
METHODS
A 34-year-old African woman, para 1, gravida 2, presented with symptoms of ruptured ectopic pregnancy. She underwent a laparoscopy where a ruptured left ectopic pregnancy was found with a levonorgestrel-releasing intrauterine system inserted 2 years prior embedded within the tube. A left salpingectomy was performed with removal of the levonorgestrel-releasing intrauterine system. The patient recovered well and proceeded to have an intrauterine pregnancy 3 months later.
CONCLUSIONS
Migration of the levonorgestrel-releasing intrauterine system into the fallopian tube is a rare occurrence that is not well understood. In the case presented, levonorgestrel-releasing intrauterine system was found embedded within the fimbrial end of the left fallopian tube, which had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal intrauterine device to prevent complications.
Background
An intrauterine contraceptive device (IUD) is a highly effective method of contraception [1]. Types of IUDs include the levonorgestrel releasing intrauterine system (LNG IUS), also commonly referred to as Mirena, and the copper IUD. They have a low failure rate of less than 1%, which is comparable to permanent sterilization [1]. The pearl index of the LNG IUS is 0.06 per 100 women years, while that of the copper IUD is 0.52 per 100 women years [2]. Even though the risk of ectopic pregnancy with IUDs is lower than with no contraception, if a pregnancy occurs with an IUD in situ, it is likely to be an ectopic pregnancy. The rate of ectopic pregnancy among LNG IUS users ranges from 0.02 to 0.2 per 100 women years, whereas the rate among copper IUD users ranges from 0.1 to 0.8 per 100 women years. In case of pregnancy, the risk of ectopic pregnancy is higher in LNG IUS users compared with copper IUD users (27% versus 15% respectively) [2]. Progesterone is known to cause ciliary dysfunction within the fallopian tube, subsequently predisposing LNG IUS users who conceive to ectopic pregnancy [3]. It is therefore important to rule out ectopic pregnancy in women with acute abdomen or positive pregnancy test among LNG IUS users [4]
A correctly positioned IUD is located within 3 mm of the uterine fundus, with both arms extending to the cornua, a vertically oriented stem in the uterine body, and the strings protruding through the cervical os into the vaginal canal [5]. Suboptimally placed IUDs are at a higher risk of malposition or expulsion and associated symptoms [5]. Malposition of IUDs is a common complication of this method of contraception, with a reported rate of up to 10% [6]. Malposition of an IUD includes displacement, expulsion, rotation, or embedment. Migration of IUDs is, however, an uncommon occurrence, with most cases of migration reported to the colon and the urinary tract [7–9]. The fallopian tube is an uncommon location for migration and embedment [7]. Having an IUD embedded within a tubal ectopic pregnancy is an even rarer phenomenon.
We describe a case of a patient who presented with ruptured ectopic pregnancy and was found to have a LNG IUS embedded in the fimbrial end of the affected fallopian tube.
Case presentation
A 34-year-old African female, para 1, gravida 2, presented to the Accident and Emergency Department, having had symptoms of vomiting and abdominal pain for 3 days. The symptoms had worsened on the day of presentation to the hospital. She reported several episodes of vomiting with associated loose stools and abdominal fullness. She also had ongoing vaginal bleeding that had started 5 days prior to presentation.
Two years prior, the patient had an uncomplicated insertion of LNG IUS by an obstetrician/gynecologist at the 8-week visit following a normal vaginal delivery. She had a normal pap smear done at the time of insertion. One year following insertion, she had a desire to conceive and was scheduled for removal of the LNG IUS device. The strings could not be seen, and the device could not be retrieved with alligator forceps. The patient was therefore sent for a pelvic ultrasound to locate the lost IUD. The device was not seen on ultrasound. The patient was, however, lost to follow-up until presentation with symptoms of ruptured ectopic pregnancy. She had no preexisting conditions or previous surgery.
On physical examination she was in fair general condition and not pale. Her vital signs were a temperature of 37.6 °C, a blood pressure of 120/66 mmHg, pulse rate of 99 beats per minute, respiration rate of 18 breaths per minute, and oxygen saturation of 100% on room air. On abdominal examination she had tenderness on the left iliac fossa and suprapubic regions with absent bowel sounds. The rest of the systemic examination was normal. An impression of acute abdomen was made at this point. As initial treatment she was given intravenous fluids (Ringer’s lactate solution) 1-L bolus, as well as intravenous paracetamol and ondansetron for pain and vomiting, respectively.
The initial investigations included a full blood count, which revealed a normal hemoglobin level of 13.2 g/dl, slightly elevated white cell count of 12.28 × 109 cells/L, and normal platelet count of 314 × 109 cells/L. She had a beta human chorionic gonadotropin (Hcg) level of 7721 mIU/ml. Urinalysis showed leucocytes 2+, nitrite negative, and blood 2+. Transvaginal ultrasound showed a 2.1 cm × 1.8 cm echogenic mass with central cystic area on the left adnexa. It had no internal or peripheral vascularity. There was marked pelvic echogenic free fluid with low internal echoes extending to the Morrison’s pouch. The uterus was anteverted and normal in size and shape with an endometrial thickness of 5.5 mm. A 1.9 cm cystic lesion was seen in the right ovary, which was likely a corpus luteum cyst. There was no gestational sac or intrauterine device seen within the endometrial cavity (Fig. 1). These features indicated ruptured ectopic pregnancy.Fig. 1 Ultrasound image of an empty uterus. The arrow points to the endometrial lining measuring 5.5 mm
The diagnosis at this point was a ruptured left tubal ectopic pregnancy. The plan was to admit the patient for an emergency laparoscopy with possible left salpingectomy. The diagnosis and plan were explained to the patient, who signed an informed consent for the procedure. Group and cross match of one unit of packed red cells was ordered in case a transfusion would be required.
The laparoscopy was done under general anesthesia in the Lloyd–Davis position. Cohen’s uterine manipulator was placed. Veress insufflation was performed, followed by insertion of a 10-mm primary trocar at the umbilicus. Entry and operating pressures were 20 mmHg and 15 mmHg, respectively. Two secondary ports were inserted under vision, 5 mm in the right iliac fossa and 12 mm in the left iliac fossa. On primary survey, LNG IUS was found embedded at the fimbrial end of the left fallopian tube (Fig. 2). The LNG IUS was retrieved whole under vision through the 12-mm port (Fig. 3). There was hemoperitoneum of 700 ml (Fig. 2). A ruptured left ampullary ectopic pregnancy was identified by left salpingectomy using bipolar coagulation and scissors (Fig. 4). A corpus luteum cyst was found on the right ovary with normal right fallopian tube. Suction and peritoneal lavage were performed, and hemostasis was confirmed (Fig. 5). The specimen was retrieved through the 12-mm port and taken for histology. There was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal. All trocars were removed under vision.Fig. 2 Body of the embedded LNG IUS (indicated by arrow), which is seen protruding from the left tubal pregnancy with hemoperitoneum
Fig. 3 LNG IUS (indicated by arrow) being retrieved from the left tubal pregnancy
Fig. 4 Left salpingectomy (indicated by arrow) performed using bipolar coagulation
Fig. 5 Pelvic view after completion of the procedure confirming hemostasis. Arrow points to an empty pouch of Douglas
The postoperative recovery of the patient was unremarkable. She was debriefed about the surgery and discharged the following morning. She went home on oral paracetamol and diclofenac for pain relief.
The patient was reviewed in the gynecology outpatient clinic 2 weeks later. She was asymptomatic and doing well. Histology report confirmed left ectopic tubal gestation. She reported that she desired conception. Preconception counseling was done. She was put on daily folic acid (400 µg). The patient was advised to come to the hospital as soon as she missed a period or tested positive for pregnancy for an early pregnancy ultrasound to rule out another ectopic pregnancy. Three months later she presented at the early pregnancy clinic following 5 weeks of amenorrhea. A pelvic ultrasound was done that showed intrauterine pregnancy at 5 weeks gestation.
Discussion
The above case documents a rare occurrence of a ruptured ectopic pregnancy with the LNG IUS embedded within the affected fallopian tube.
Levonorgestrel IUS (Mirena) is a safe, reversible, and highly effective contraceptive method [2]. It is known to have other therapeutic benefits such as reduction in menstrual bleeding, anemia, and dysmenorrhea, as well as management of endometrial hyperplasia [10]. In this patient, the use of the LNG IUS was purely for contraception purposes.
Ectopic pregnancies affect approximately 2% of all pregnancies. The most common presentation of an ectopic pregnancy is abdominal pain and abnormal uterine bleeding [11]. Even though the rate of ectopic pregnancy is lower in women using LNG IUS, if a pregnancy occurs while using this IUD, there is a high risk of it being an ectopic pregnancy [2]. Current IUD use is a known risk factor for ectopic pregnancy [12]. Other risk factors for ectopic pregnancy include pelvic inflammatory disease, previous tubal surgery, previous ectopic pregnancy, and smoking [12]. On examination, features of acute abdomen due to hemoperitoneum may be present [11, 12]. The patient in this case had a presentation suggestive of ectopic pregnancy with concurrent LNG IUS use as a risk factor. However, she had other unspecific presenting features of diarrhea, vomiting, and low-grade fever. It is important to note that some patients may be asymptomatic without specific risk factors for an ectopic pregnancy [12]
On the other hand, malposition of an IUD is one of its common complications, presenting with pelvic pain and bleeding or no symptoms [13]. Although malposition is associated with reduced contraceptive efficacy, this is mostly true for copper IUDs and not LNG IUS, which has local progesterone effects [6]. Malposition is diagnosed by ultrasound [13]. However, compared with copper IUDs, the LNG IUS is more likely to be missed by ultrasonography. LNG IUS is compounded with barium sulfate, which makes it radio opaque for X-ray recognition [14]. A plain X-ray can therefore be used as an adjunctive imaging modality in the case of a lost LNG IUS not seen on ultrasound [15]. The patient in this case had a lost LNG IUS not seen on ultrasound 1 year after insertion but was lost to follow-up for additional imaging.
Uterine perforation is uncommon, with an incidence of 1 in 1000 insertions. It is a serious complication of IUD use and is often asymptomatic [16]. There is increased risk of perforation if insertion is done less than 6 months postpartum or while breastfeeding. This period is associated with endometrial atrophy with accelerated uterine involution and hence has a high risk of perforation [6, 13]. The current patient was asymptomatic for malposition or perforation for 2 years prior to the ectopic pregnancy. The transvaginal ultrasound done at diagnosis of ectopic pregnancy did not visualize the device in the left adnexa. Her LNG IUS was inserted only 2 months postpartum while breastfeeding. This may have been a risk factor for possible unrecognized perforation.
Routine transvaginal ultrasound to monitor IUD position either immediately post insertion or after 6 weeks is not recommended without clinical suspicion of malposition according to de Kroon et al. [17]. It has been reported that IUDs take approximately 3 months to settle into their stable position. An initially malpositioned IUD can therefore assume the correct fundal position over time [18]. In asymptomatic women with uncomplicated IUD insertion, routine ultrasound lacks benefit over clinical evaluation with string check at 6 weeks [17]. The patient in this case was asymptomatic without complications at insertion. One year later, the LNG IUS device could not be seen on clinical examination nor on ultrasound.
The mechanism of device migration is not well understood, especially in the case of tubal migration. The fallopian tube is a rare site for dislocated IUD [19, 20]. This phenomenon has been described in few case reports. There are theories from case reports about the tubal migration of an IUD. The first possibility is placement of the device at the tubal ostium during insertion with subsequent migration into the tube due to uterine contractions and tubal peristalsis [21]. The other possibility is uterine perforation with migration of the device into the peritoneal cavity and subsequent perforation of a preexisting hydrosalpinx as described by Ozdemir et al. in a case report [19]. The patient in this case did not have any hydrosalpinx noted intraoperatively. Perforation can be due to either immediate traumatic perforation at insertion or delayed transmural migration [22, 23]. It is also possible that, following an unrecognized perforation, there was nestling of the IUD close to the fimbrial end of the fallopian tube, with the device being enveloped within the fimbria [7, 19]. This phenomenon could have occurred antecedent to conception of the ectopic pregnancy. In the patient in this case, there was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal.
The presence of an IUD within the fallopian tube is associated with an inflammatory reaction [19] interfering with tubal function and predisposing the patient to ectopic pregnancy. The tubal dysfunction is exacerbated by progesterone in the LNG IUS, which interferes with ciliary beating and tubal contractility [3]. It is possible that the embedment of LNG IUS at the fimbrial end of the fallopian tube occurred as a result of displacement from the proximal tube by the growing tubal pregnancy or its rupture.
Once an intraabdominal IUD is diagnosed, it should be removed whether it is symptomatic or not to avoid serious complications such as adhesion formation, bowel obstruction, and infertility [15, 19]. Laparoscopy is the surgical approach of choice as it is safe and effective. It provides good visualization to locate and remove a lost IUD [15]. In this case, the diagnosis of the LNG IUS within the fallopian tube and its removal were done laparoscopically.
Conclusion
Migration of the LNG IUS into the fallopian tube is a rare occurrence that is not well understood. In the case presented, a LNG IUS was found embedded within the fimbrial end of the fallopian tube that had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal IUD to prevent complications. The patient made a good recovery and proceeded to have an intrauterine pregnancy 3 months later, as desired.
Abbreviations
IUD Intrauterine device
LNG IUS Levonorgestrel intrauterine system
Acknowledgements
We would like to thank the patient for her permission to publish this manuscript.
Authors’ contributions
DM collected and analyzed the data and drafted the manuscript. IG and KW contributed to the manuscript writing and editing. All authors managed the patient and read and approved the final manuscript.
Funding
None.
Availability of data and materials
Clinical data and complementary examinations are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of the case and any accompanying images. A copy of the consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33685513 | 19,041,622 | 2021-03-09 |
What was the outcome of reaction 'Embedded device'? | Levonorgestrel intrauterine system embedded within tubal ectopic pregnancy: a case report.
BACKGROUND
The presence of the levonorgestrel-releasing intrauterine system embedded within an ectopic pregnancy is a rare occurrence. Tubal migration of an intrauterine device is not well understood and has not been extensively studied in literature.
METHODS
A 34-year-old African woman, para 1, gravida 2, presented with symptoms of ruptured ectopic pregnancy. She underwent a laparoscopy where a ruptured left ectopic pregnancy was found with a levonorgestrel-releasing intrauterine system inserted 2 years prior embedded within the tube. A left salpingectomy was performed with removal of the levonorgestrel-releasing intrauterine system. The patient recovered well and proceeded to have an intrauterine pregnancy 3 months later.
CONCLUSIONS
Migration of the levonorgestrel-releasing intrauterine system into the fallopian tube is a rare occurrence that is not well understood. In the case presented, levonorgestrel-releasing intrauterine system was found embedded within the fimbrial end of the left fallopian tube, which had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal intrauterine device to prevent complications.
Background
An intrauterine contraceptive device (IUD) is a highly effective method of contraception [1]. Types of IUDs include the levonorgestrel releasing intrauterine system (LNG IUS), also commonly referred to as Mirena, and the copper IUD. They have a low failure rate of less than 1%, which is comparable to permanent sterilization [1]. The pearl index of the LNG IUS is 0.06 per 100 women years, while that of the copper IUD is 0.52 per 100 women years [2]. Even though the risk of ectopic pregnancy with IUDs is lower than with no contraception, if a pregnancy occurs with an IUD in situ, it is likely to be an ectopic pregnancy. The rate of ectopic pregnancy among LNG IUS users ranges from 0.02 to 0.2 per 100 women years, whereas the rate among copper IUD users ranges from 0.1 to 0.8 per 100 women years. In case of pregnancy, the risk of ectopic pregnancy is higher in LNG IUS users compared with copper IUD users (27% versus 15% respectively) [2]. Progesterone is known to cause ciliary dysfunction within the fallopian tube, subsequently predisposing LNG IUS users who conceive to ectopic pregnancy [3]. It is therefore important to rule out ectopic pregnancy in women with acute abdomen or positive pregnancy test among LNG IUS users [4]
A correctly positioned IUD is located within 3 mm of the uterine fundus, with both arms extending to the cornua, a vertically oriented stem in the uterine body, and the strings protruding through the cervical os into the vaginal canal [5]. Suboptimally placed IUDs are at a higher risk of malposition or expulsion and associated symptoms [5]. Malposition of IUDs is a common complication of this method of contraception, with a reported rate of up to 10% [6]. Malposition of an IUD includes displacement, expulsion, rotation, or embedment. Migration of IUDs is, however, an uncommon occurrence, with most cases of migration reported to the colon and the urinary tract [7–9]. The fallopian tube is an uncommon location for migration and embedment [7]. Having an IUD embedded within a tubal ectopic pregnancy is an even rarer phenomenon.
We describe a case of a patient who presented with ruptured ectopic pregnancy and was found to have a LNG IUS embedded in the fimbrial end of the affected fallopian tube.
Case presentation
A 34-year-old African female, para 1, gravida 2, presented to the Accident and Emergency Department, having had symptoms of vomiting and abdominal pain for 3 days. The symptoms had worsened on the day of presentation to the hospital. She reported several episodes of vomiting with associated loose stools and abdominal fullness. She also had ongoing vaginal bleeding that had started 5 days prior to presentation.
Two years prior, the patient had an uncomplicated insertion of LNG IUS by an obstetrician/gynecologist at the 8-week visit following a normal vaginal delivery. She had a normal pap smear done at the time of insertion. One year following insertion, she had a desire to conceive and was scheduled for removal of the LNG IUS device. The strings could not be seen, and the device could not be retrieved with alligator forceps. The patient was therefore sent for a pelvic ultrasound to locate the lost IUD. The device was not seen on ultrasound. The patient was, however, lost to follow-up until presentation with symptoms of ruptured ectopic pregnancy. She had no preexisting conditions or previous surgery.
On physical examination she was in fair general condition and not pale. Her vital signs were a temperature of 37.6 °C, a blood pressure of 120/66 mmHg, pulse rate of 99 beats per minute, respiration rate of 18 breaths per minute, and oxygen saturation of 100% on room air. On abdominal examination she had tenderness on the left iliac fossa and suprapubic regions with absent bowel sounds. The rest of the systemic examination was normal. An impression of acute abdomen was made at this point. As initial treatment she was given intravenous fluids (Ringer’s lactate solution) 1-L bolus, as well as intravenous paracetamol and ondansetron for pain and vomiting, respectively.
The initial investigations included a full blood count, which revealed a normal hemoglobin level of 13.2 g/dl, slightly elevated white cell count of 12.28 × 109 cells/L, and normal platelet count of 314 × 109 cells/L. She had a beta human chorionic gonadotropin (Hcg) level of 7721 mIU/ml. Urinalysis showed leucocytes 2+, nitrite negative, and blood 2+. Transvaginal ultrasound showed a 2.1 cm × 1.8 cm echogenic mass with central cystic area on the left adnexa. It had no internal or peripheral vascularity. There was marked pelvic echogenic free fluid with low internal echoes extending to the Morrison’s pouch. The uterus was anteverted and normal in size and shape with an endometrial thickness of 5.5 mm. A 1.9 cm cystic lesion was seen in the right ovary, which was likely a corpus luteum cyst. There was no gestational sac or intrauterine device seen within the endometrial cavity (Fig. 1). These features indicated ruptured ectopic pregnancy.Fig. 1 Ultrasound image of an empty uterus. The arrow points to the endometrial lining measuring 5.5 mm
The diagnosis at this point was a ruptured left tubal ectopic pregnancy. The plan was to admit the patient for an emergency laparoscopy with possible left salpingectomy. The diagnosis and plan were explained to the patient, who signed an informed consent for the procedure. Group and cross match of one unit of packed red cells was ordered in case a transfusion would be required.
The laparoscopy was done under general anesthesia in the Lloyd–Davis position. Cohen’s uterine manipulator was placed. Veress insufflation was performed, followed by insertion of a 10-mm primary trocar at the umbilicus. Entry and operating pressures were 20 mmHg and 15 mmHg, respectively. Two secondary ports were inserted under vision, 5 mm in the right iliac fossa and 12 mm in the left iliac fossa. On primary survey, LNG IUS was found embedded at the fimbrial end of the left fallopian tube (Fig. 2). The LNG IUS was retrieved whole under vision through the 12-mm port (Fig. 3). There was hemoperitoneum of 700 ml (Fig. 2). A ruptured left ampullary ectopic pregnancy was identified by left salpingectomy using bipolar coagulation and scissors (Fig. 4). A corpus luteum cyst was found on the right ovary with normal right fallopian tube. Suction and peritoneal lavage were performed, and hemostasis was confirmed (Fig. 5). The specimen was retrieved through the 12-mm port and taken for histology. There was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal. All trocars were removed under vision.Fig. 2 Body of the embedded LNG IUS (indicated by arrow), which is seen protruding from the left tubal pregnancy with hemoperitoneum
Fig. 3 LNG IUS (indicated by arrow) being retrieved from the left tubal pregnancy
Fig. 4 Left salpingectomy (indicated by arrow) performed using bipolar coagulation
Fig. 5 Pelvic view after completion of the procedure confirming hemostasis. Arrow points to an empty pouch of Douglas
The postoperative recovery of the patient was unremarkable. She was debriefed about the surgery and discharged the following morning. She went home on oral paracetamol and diclofenac for pain relief.
The patient was reviewed in the gynecology outpatient clinic 2 weeks later. She was asymptomatic and doing well. Histology report confirmed left ectopic tubal gestation. She reported that she desired conception. Preconception counseling was done. She was put on daily folic acid (400 µg). The patient was advised to come to the hospital as soon as she missed a period or tested positive for pregnancy for an early pregnancy ultrasound to rule out another ectopic pregnancy. Three months later she presented at the early pregnancy clinic following 5 weeks of amenorrhea. A pelvic ultrasound was done that showed intrauterine pregnancy at 5 weeks gestation.
Discussion
The above case documents a rare occurrence of a ruptured ectopic pregnancy with the LNG IUS embedded within the affected fallopian tube.
Levonorgestrel IUS (Mirena) is a safe, reversible, and highly effective contraceptive method [2]. It is known to have other therapeutic benefits such as reduction in menstrual bleeding, anemia, and dysmenorrhea, as well as management of endometrial hyperplasia [10]. In this patient, the use of the LNG IUS was purely for contraception purposes.
Ectopic pregnancies affect approximately 2% of all pregnancies. The most common presentation of an ectopic pregnancy is abdominal pain and abnormal uterine bleeding [11]. Even though the rate of ectopic pregnancy is lower in women using LNG IUS, if a pregnancy occurs while using this IUD, there is a high risk of it being an ectopic pregnancy [2]. Current IUD use is a known risk factor for ectopic pregnancy [12]. Other risk factors for ectopic pregnancy include pelvic inflammatory disease, previous tubal surgery, previous ectopic pregnancy, and smoking [12]. On examination, features of acute abdomen due to hemoperitoneum may be present [11, 12]. The patient in this case had a presentation suggestive of ectopic pregnancy with concurrent LNG IUS use as a risk factor. However, she had other unspecific presenting features of diarrhea, vomiting, and low-grade fever. It is important to note that some patients may be asymptomatic without specific risk factors for an ectopic pregnancy [12]
On the other hand, malposition of an IUD is one of its common complications, presenting with pelvic pain and bleeding or no symptoms [13]. Although malposition is associated with reduced contraceptive efficacy, this is mostly true for copper IUDs and not LNG IUS, which has local progesterone effects [6]. Malposition is diagnosed by ultrasound [13]. However, compared with copper IUDs, the LNG IUS is more likely to be missed by ultrasonography. LNG IUS is compounded with barium sulfate, which makes it radio opaque for X-ray recognition [14]. A plain X-ray can therefore be used as an adjunctive imaging modality in the case of a lost LNG IUS not seen on ultrasound [15]. The patient in this case had a lost LNG IUS not seen on ultrasound 1 year after insertion but was lost to follow-up for additional imaging.
Uterine perforation is uncommon, with an incidence of 1 in 1000 insertions. It is a serious complication of IUD use and is often asymptomatic [16]. There is increased risk of perforation if insertion is done less than 6 months postpartum or while breastfeeding. This period is associated with endometrial atrophy with accelerated uterine involution and hence has a high risk of perforation [6, 13]. The current patient was asymptomatic for malposition or perforation for 2 years prior to the ectopic pregnancy. The transvaginal ultrasound done at diagnosis of ectopic pregnancy did not visualize the device in the left adnexa. Her LNG IUS was inserted only 2 months postpartum while breastfeeding. This may have been a risk factor for possible unrecognized perforation.
Routine transvaginal ultrasound to monitor IUD position either immediately post insertion or after 6 weeks is not recommended without clinical suspicion of malposition according to de Kroon et al. [17]. It has been reported that IUDs take approximately 3 months to settle into their stable position. An initially malpositioned IUD can therefore assume the correct fundal position over time [18]. In asymptomatic women with uncomplicated IUD insertion, routine ultrasound lacks benefit over clinical evaluation with string check at 6 weeks [17]. The patient in this case was asymptomatic without complications at insertion. One year later, the LNG IUS device could not be seen on clinical examination nor on ultrasound.
The mechanism of device migration is not well understood, especially in the case of tubal migration. The fallopian tube is a rare site for dislocated IUD [19, 20]. This phenomenon has been described in few case reports. There are theories from case reports about the tubal migration of an IUD. The first possibility is placement of the device at the tubal ostium during insertion with subsequent migration into the tube due to uterine contractions and tubal peristalsis [21]. The other possibility is uterine perforation with migration of the device into the peritoneal cavity and subsequent perforation of a preexisting hydrosalpinx as described by Ozdemir et al. in a case report [19]. The patient in this case did not have any hydrosalpinx noted intraoperatively. Perforation can be due to either immediate traumatic perforation at insertion or delayed transmural migration [22, 23]. It is also possible that, following an unrecognized perforation, there was nestling of the IUD close to the fimbrial end of the fallopian tube, with the device being enveloped within the fimbria [7, 19]. This phenomenon could have occurred antecedent to conception of the ectopic pregnancy. In the patient in this case, there was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal.
The presence of an IUD within the fallopian tube is associated with an inflammatory reaction [19] interfering with tubal function and predisposing the patient to ectopic pregnancy. The tubal dysfunction is exacerbated by progesterone in the LNG IUS, which interferes with ciliary beating and tubal contractility [3]. It is possible that the embedment of LNG IUS at the fimbrial end of the fallopian tube occurred as a result of displacement from the proximal tube by the growing tubal pregnancy or its rupture.
Once an intraabdominal IUD is diagnosed, it should be removed whether it is symptomatic or not to avoid serious complications such as adhesion formation, bowel obstruction, and infertility [15, 19]. Laparoscopy is the surgical approach of choice as it is safe and effective. It provides good visualization to locate and remove a lost IUD [15]. In this case, the diagnosis of the LNG IUS within the fallopian tube and its removal were done laparoscopically.
Conclusion
Migration of the LNG IUS into the fallopian tube is a rare occurrence that is not well understood. In the case presented, a LNG IUS was found embedded within the fimbrial end of the fallopian tube that had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal IUD to prevent complications. The patient made a good recovery and proceeded to have an intrauterine pregnancy 3 months later, as desired.
Abbreviations
IUD Intrauterine device
LNG IUS Levonorgestrel intrauterine system
Acknowledgements
We would like to thank the patient for her permission to publish this manuscript.
Authors’ contributions
DM collected and analyzed the data and drafted the manuscript. IG and KW contributed to the manuscript writing and editing. All authors managed the patient and read and approved the final manuscript.
Funding
None.
Availability of data and materials
Clinical data and complementary examinations are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of the case and any accompanying images. A copy of the consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33685513 | 19,041,622 | 2021-03-09 |
What was the outcome of reaction 'Ruptured ectopic pregnancy'? | Levonorgestrel intrauterine system embedded within tubal ectopic pregnancy: a case report.
BACKGROUND
The presence of the levonorgestrel-releasing intrauterine system embedded within an ectopic pregnancy is a rare occurrence. Tubal migration of an intrauterine device is not well understood and has not been extensively studied in literature.
METHODS
A 34-year-old African woman, para 1, gravida 2, presented with symptoms of ruptured ectopic pregnancy. She underwent a laparoscopy where a ruptured left ectopic pregnancy was found with a levonorgestrel-releasing intrauterine system inserted 2 years prior embedded within the tube. A left salpingectomy was performed with removal of the levonorgestrel-releasing intrauterine system. The patient recovered well and proceeded to have an intrauterine pregnancy 3 months later.
CONCLUSIONS
Migration of the levonorgestrel-releasing intrauterine system into the fallopian tube is a rare occurrence that is not well understood. In the case presented, levonorgestrel-releasing intrauterine system was found embedded within the fimbrial end of the left fallopian tube, which had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal intrauterine device to prevent complications.
Background
An intrauterine contraceptive device (IUD) is a highly effective method of contraception [1]. Types of IUDs include the levonorgestrel releasing intrauterine system (LNG IUS), also commonly referred to as Mirena, and the copper IUD. They have a low failure rate of less than 1%, which is comparable to permanent sterilization [1]. The pearl index of the LNG IUS is 0.06 per 100 women years, while that of the copper IUD is 0.52 per 100 women years [2]. Even though the risk of ectopic pregnancy with IUDs is lower than with no contraception, if a pregnancy occurs with an IUD in situ, it is likely to be an ectopic pregnancy. The rate of ectopic pregnancy among LNG IUS users ranges from 0.02 to 0.2 per 100 women years, whereas the rate among copper IUD users ranges from 0.1 to 0.8 per 100 women years. In case of pregnancy, the risk of ectopic pregnancy is higher in LNG IUS users compared with copper IUD users (27% versus 15% respectively) [2]. Progesterone is known to cause ciliary dysfunction within the fallopian tube, subsequently predisposing LNG IUS users who conceive to ectopic pregnancy [3]. It is therefore important to rule out ectopic pregnancy in women with acute abdomen or positive pregnancy test among LNG IUS users [4]
A correctly positioned IUD is located within 3 mm of the uterine fundus, with both arms extending to the cornua, a vertically oriented stem in the uterine body, and the strings protruding through the cervical os into the vaginal canal [5]. Suboptimally placed IUDs are at a higher risk of malposition or expulsion and associated symptoms [5]. Malposition of IUDs is a common complication of this method of contraception, with a reported rate of up to 10% [6]. Malposition of an IUD includes displacement, expulsion, rotation, or embedment. Migration of IUDs is, however, an uncommon occurrence, with most cases of migration reported to the colon and the urinary tract [7–9]. The fallopian tube is an uncommon location for migration and embedment [7]. Having an IUD embedded within a tubal ectopic pregnancy is an even rarer phenomenon.
We describe a case of a patient who presented with ruptured ectopic pregnancy and was found to have a LNG IUS embedded in the fimbrial end of the affected fallopian tube.
Case presentation
A 34-year-old African female, para 1, gravida 2, presented to the Accident and Emergency Department, having had symptoms of vomiting and abdominal pain for 3 days. The symptoms had worsened on the day of presentation to the hospital. She reported several episodes of vomiting with associated loose stools and abdominal fullness. She also had ongoing vaginal bleeding that had started 5 days prior to presentation.
Two years prior, the patient had an uncomplicated insertion of LNG IUS by an obstetrician/gynecologist at the 8-week visit following a normal vaginal delivery. She had a normal pap smear done at the time of insertion. One year following insertion, she had a desire to conceive and was scheduled for removal of the LNG IUS device. The strings could not be seen, and the device could not be retrieved with alligator forceps. The patient was therefore sent for a pelvic ultrasound to locate the lost IUD. The device was not seen on ultrasound. The patient was, however, lost to follow-up until presentation with symptoms of ruptured ectopic pregnancy. She had no preexisting conditions or previous surgery.
On physical examination she was in fair general condition and not pale. Her vital signs were a temperature of 37.6 °C, a blood pressure of 120/66 mmHg, pulse rate of 99 beats per minute, respiration rate of 18 breaths per minute, and oxygen saturation of 100% on room air. On abdominal examination she had tenderness on the left iliac fossa and suprapubic regions with absent bowel sounds. The rest of the systemic examination was normal. An impression of acute abdomen was made at this point. As initial treatment she was given intravenous fluids (Ringer’s lactate solution) 1-L bolus, as well as intravenous paracetamol and ondansetron for pain and vomiting, respectively.
The initial investigations included a full blood count, which revealed a normal hemoglobin level of 13.2 g/dl, slightly elevated white cell count of 12.28 × 109 cells/L, and normal platelet count of 314 × 109 cells/L. She had a beta human chorionic gonadotropin (Hcg) level of 7721 mIU/ml. Urinalysis showed leucocytes 2+, nitrite negative, and blood 2+. Transvaginal ultrasound showed a 2.1 cm × 1.8 cm echogenic mass with central cystic area on the left adnexa. It had no internal or peripheral vascularity. There was marked pelvic echogenic free fluid with low internal echoes extending to the Morrison’s pouch. The uterus was anteverted and normal in size and shape with an endometrial thickness of 5.5 mm. A 1.9 cm cystic lesion was seen in the right ovary, which was likely a corpus luteum cyst. There was no gestational sac or intrauterine device seen within the endometrial cavity (Fig. 1). These features indicated ruptured ectopic pregnancy.Fig. 1 Ultrasound image of an empty uterus. The arrow points to the endometrial lining measuring 5.5 mm
The diagnosis at this point was a ruptured left tubal ectopic pregnancy. The plan was to admit the patient for an emergency laparoscopy with possible left salpingectomy. The diagnosis and plan were explained to the patient, who signed an informed consent for the procedure. Group and cross match of one unit of packed red cells was ordered in case a transfusion would be required.
The laparoscopy was done under general anesthesia in the Lloyd–Davis position. Cohen’s uterine manipulator was placed. Veress insufflation was performed, followed by insertion of a 10-mm primary trocar at the umbilicus. Entry and operating pressures were 20 mmHg and 15 mmHg, respectively. Two secondary ports were inserted under vision, 5 mm in the right iliac fossa and 12 mm in the left iliac fossa. On primary survey, LNG IUS was found embedded at the fimbrial end of the left fallopian tube (Fig. 2). The LNG IUS was retrieved whole under vision through the 12-mm port (Fig. 3). There was hemoperitoneum of 700 ml (Fig. 2). A ruptured left ampullary ectopic pregnancy was identified by left salpingectomy using bipolar coagulation and scissors (Fig. 4). A corpus luteum cyst was found on the right ovary with normal right fallopian tube. Suction and peritoneal lavage were performed, and hemostasis was confirmed (Fig. 5). The specimen was retrieved through the 12-mm port and taken for histology. There was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal. All trocars were removed under vision.Fig. 2 Body of the embedded LNG IUS (indicated by arrow), which is seen protruding from the left tubal pregnancy with hemoperitoneum
Fig. 3 LNG IUS (indicated by arrow) being retrieved from the left tubal pregnancy
Fig. 4 Left salpingectomy (indicated by arrow) performed using bipolar coagulation
Fig. 5 Pelvic view after completion of the procedure confirming hemostasis. Arrow points to an empty pouch of Douglas
The postoperative recovery of the patient was unremarkable. She was debriefed about the surgery and discharged the following morning. She went home on oral paracetamol and diclofenac for pain relief.
The patient was reviewed in the gynecology outpatient clinic 2 weeks later. She was asymptomatic and doing well. Histology report confirmed left ectopic tubal gestation. She reported that she desired conception. Preconception counseling was done. She was put on daily folic acid (400 µg). The patient was advised to come to the hospital as soon as she missed a period or tested positive for pregnancy for an early pregnancy ultrasound to rule out another ectopic pregnancy. Three months later she presented at the early pregnancy clinic following 5 weeks of amenorrhea. A pelvic ultrasound was done that showed intrauterine pregnancy at 5 weeks gestation.
Discussion
The above case documents a rare occurrence of a ruptured ectopic pregnancy with the LNG IUS embedded within the affected fallopian tube.
Levonorgestrel IUS (Mirena) is a safe, reversible, and highly effective contraceptive method [2]. It is known to have other therapeutic benefits such as reduction in menstrual bleeding, anemia, and dysmenorrhea, as well as management of endometrial hyperplasia [10]. In this patient, the use of the LNG IUS was purely for contraception purposes.
Ectopic pregnancies affect approximately 2% of all pregnancies. The most common presentation of an ectopic pregnancy is abdominal pain and abnormal uterine bleeding [11]. Even though the rate of ectopic pregnancy is lower in women using LNG IUS, if a pregnancy occurs while using this IUD, there is a high risk of it being an ectopic pregnancy [2]. Current IUD use is a known risk factor for ectopic pregnancy [12]. Other risk factors for ectopic pregnancy include pelvic inflammatory disease, previous tubal surgery, previous ectopic pregnancy, and smoking [12]. On examination, features of acute abdomen due to hemoperitoneum may be present [11, 12]. The patient in this case had a presentation suggestive of ectopic pregnancy with concurrent LNG IUS use as a risk factor. However, she had other unspecific presenting features of diarrhea, vomiting, and low-grade fever. It is important to note that some patients may be asymptomatic without specific risk factors for an ectopic pregnancy [12]
On the other hand, malposition of an IUD is one of its common complications, presenting with pelvic pain and bleeding or no symptoms [13]. Although malposition is associated with reduced contraceptive efficacy, this is mostly true for copper IUDs and not LNG IUS, which has local progesterone effects [6]. Malposition is diagnosed by ultrasound [13]. However, compared with copper IUDs, the LNG IUS is more likely to be missed by ultrasonography. LNG IUS is compounded with barium sulfate, which makes it radio opaque for X-ray recognition [14]. A plain X-ray can therefore be used as an adjunctive imaging modality in the case of a lost LNG IUS not seen on ultrasound [15]. The patient in this case had a lost LNG IUS not seen on ultrasound 1 year after insertion but was lost to follow-up for additional imaging.
Uterine perforation is uncommon, with an incidence of 1 in 1000 insertions. It is a serious complication of IUD use and is often asymptomatic [16]. There is increased risk of perforation if insertion is done less than 6 months postpartum or while breastfeeding. This period is associated with endometrial atrophy with accelerated uterine involution and hence has a high risk of perforation [6, 13]. The current patient was asymptomatic for malposition or perforation for 2 years prior to the ectopic pregnancy. The transvaginal ultrasound done at diagnosis of ectopic pregnancy did not visualize the device in the left adnexa. Her LNG IUS was inserted only 2 months postpartum while breastfeeding. This may have been a risk factor for possible unrecognized perforation.
Routine transvaginal ultrasound to monitor IUD position either immediately post insertion or after 6 weeks is not recommended without clinical suspicion of malposition according to de Kroon et al. [17]. It has been reported that IUDs take approximately 3 months to settle into their stable position. An initially malpositioned IUD can therefore assume the correct fundal position over time [18]. In asymptomatic women with uncomplicated IUD insertion, routine ultrasound lacks benefit over clinical evaluation with string check at 6 weeks [17]. The patient in this case was asymptomatic without complications at insertion. One year later, the LNG IUS device could not be seen on clinical examination nor on ultrasound.
The mechanism of device migration is not well understood, especially in the case of tubal migration. The fallopian tube is a rare site for dislocated IUD [19, 20]. This phenomenon has been described in few case reports. There are theories from case reports about the tubal migration of an IUD. The first possibility is placement of the device at the tubal ostium during insertion with subsequent migration into the tube due to uterine contractions and tubal peristalsis [21]. The other possibility is uterine perforation with migration of the device into the peritoneal cavity and subsequent perforation of a preexisting hydrosalpinx as described by Ozdemir et al. in a case report [19]. The patient in this case did not have any hydrosalpinx noted intraoperatively. Perforation can be due to either immediate traumatic perforation at insertion or delayed transmural migration [22, 23]. It is also possible that, following an unrecognized perforation, there was nestling of the IUD close to the fimbrial end of the fallopian tube, with the device being enveloped within the fimbria [7, 19]. This phenomenon could have occurred antecedent to conception of the ectopic pregnancy. In the patient in this case, there was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal.
The presence of an IUD within the fallopian tube is associated with an inflammatory reaction [19] interfering with tubal function and predisposing the patient to ectopic pregnancy. The tubal dysfunction is exacerbated by progesterone in the LNG IUS, which interferes with ciliary beating and tubal contractility [3]. It is possible that the embedment of LNG IUS at the fimbrial end of the fallopian tube occurred as a result of displacement from the proximal tube by the growing tubal pregnancy or its rupture.
Once an intraabdominal IUD is diagnosed, it should be removed whether it is symptomatic or not to avoid serious complications such as adhesion formation, bowel obstruction, and infertility [15, 19]. Laparoscopy is the surgical approach of choice as it is safe and effective. It provides good visualization to locate and remove a lost IUD [15]. In this case, the diagnosis of the LNG IUS within the fallopian tube and its removal were done laparoscopically.
Conclusion
Migration of the LNG IUS into the fallopian tube is a rare occurrence that is not well understood. In the case presented, a LNG IUS was found embedded within the fimbrial end of the fallopian tube that had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal IUD to prevent complications. The patient made a good recovery and proceeded to have an intrauterine pregnancy 3 months later, as desired.
Abbreviations
IUD Intrauterine device
LNG IUS Levonorgestrel intrauterine system
Acknowledgements
We would like to thank the patient for her permission to publish this manuscript.
Authors’ contributions
DM collected and analyzed the data and drafted the manuscript. IG and KW contributed to the manuscript writing and editing. All authors managed the patient and read and approved the final manuscript.
Funding
None.
Availability of data and materials
Clinical data and complementary examinations are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of the case and any accompanying images. A copy of the consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33685513 | 19,041,622 | 2021-03-09 |
What was the outcome of reaction 'Uterine perforation'? | Levonorgestrel intrauterine system embedded within tubal ectopic pregnancy: a case report.
BACKGROUND
The presence of the levonorgestrel-releasing intrauterine system embedded within an ectopic pregnancy is a rare occurrence. Tubal migration of an intrauterine device is not well understood and has not been extensively studied in literature.
METHODS
A 34-year-old African woman, para 1, gravida 2, presented with symptoms of ruptured ectopic pregnancy. She underwent a laparoscopy where a ruptured left ectopic pregnancy was found with a levonorgestrel-releasing intrauterine system inserted 2 years prior embedded within the tube. A left salpingectomy was performed with removal of the levonorgestrel-releasing intrauterine system. The patient recovered well and proceeded to have an intrauterine pregnancy 3 months later.
CONCLUSIONS
Migration of the levonorgestrel-releasing intrauterine system into the fallopian tube is a rare occurrence that is not well understood. In the case presented, levonorgestrel-releasing intrauterine system was found embedded within the fimbrial end of the left fallopian tube, which had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal intrauterine device to prevent complications.
Background
An intrauterine contraceptive device (IUD) is a highly effective method of contraception [1]. Types of IUDs include the levonorgestrel releasing intrauterine system (LNG IUS), also commonly referred to as Mirena, and the copper IUD. They have a low failure rate of less than 1%, which is comparable to permanent sterilization [1]. The pearl index of the LNG IUS is 0.06 per 100 women years, while that of the copper IUD is 0.52 per 100 women years [2]. Even though the risk of ectopic pregnancy with IUDs is lower than with no contraception, if a pregnancy occurs with an IUD in situ, it is likely to be an ectopic pregnancy. The rate of ectopic pregnancy among LNG IUS users ranges from 0.02 to 0.2 per 100 women years, whereas the rate among copper IUD users ranges from 0.1 to 0.8 per 100 women years. In case of pregnancy, the risk of ectopic pregnancy is higher in LNG IUS users compared with copper IUD users (27% versus 15% respectively) [2]. Progesterone is known to cause ciliary dysfunction within the fallopian tube, subsequently predisposing LNG IUS users who conceive to ectopic pregnancy [3]. It is therefore important to rule out ectopic pregnancy in women with acute abdomen or positive pregnancy test among LNG IUS users [4]
A correctly positioned IUD is located within 3 mm of the uterine fundus, with both arms extending to the cornua, a vertically oriented stem in the uterine body, and the strings protruding through the cervical os into the vaginal canal [5]. Suboptimally placed IUDs are at a higher risk of malposition or expulsion and associated symptoms [5]. Malposition of IUDs is a common complication of this method of contraception, with a reported rate of up to 10% [6]. Malposition of an IUD includes displacement, expulsion, rotation, or embedment. Migration of IUDs is, however, an uncommon occurrence, with most cases of migration reported to the colon and the urinary tract [7–9]. The fallopian tube is an uncommon location for migration and embedment [7]. Having an IUD embedded within a tubal ectopic pregnancy is an even rarer phenomenon.
We describe a case of a patient who presented with ruptured ectopic pregnancy and was found to have a LNG IUS embedded in the fimbrial end of the affected fallopian tube.
Case presentation
A 34-year-old African female, para 1, gravida 2, presented to the Accident and Emergency Department, having had symptoms of vomiting and abdominal pain for 3 days. The symptoms had worsened on the day of presentation to the hospital. She reported several episodes of vomiting with associated loose stools and abdominal fullness. She also had ongoing vaginal bleeding that had started 5 days prior to presentation.
Two years prior, the patient had an uncomplicated insertion of LNG IUS by an obstetrician/gynecologist at the 8-week visit following a normal vaginal delivery. She had a normal pap smear done at the time of insertion. One year following insertion, she had a desire to conceive and was scheduled for removal of the LNG IUS device. The strings could not be seen, and the device could not be retrieved with alligator forceps. The patient was therefore sent for a pelvic ultrasound to locate the lost IUD. The device was not seen on ultrasound. The patient was, however, lost to follow-up until presentation with symptoms of ruptured ectopic pregnancy. She had no preexisting conditions or previous surgery.
On physical examination she was in fair general condition and not pale. Her vital signs were a temperature of 37.6 °C, a blood pressure of 120/66 mmHg, pulse rate of 99 beats per minute, respiration rate of 18 breaths per minute, and oxygen saturation of 100% on room air. On abdominal examination she had tenderness on the left iliac fossa and suprapubic regions with absent bowel sounds. The rest of the systemic examination was normal. An impression of acute abdomen was made at this point. As initial treatment she was given intravenous fluids (Ringer’s lactate solution) 1-L bolus, as well as intravenous paracetamol and ondansetron for pain and vomiting, respectively.
The initial investigations included a full blood count, which revealed a normal hemoglobin level of 13.2 g/dl, slightly elevated white cell count of 12.28 × 109 cells/L, and normal platelet count of 314 × 109 cells/L. She had a beta human chorionic gonadotropin (Hcg) level of 7721 mIU/ml. Urinalysis showed leucocytes 2+, nitrite negative, and blood 2+. Transvaginal ultrasound showed a 2.1 cm × 1.8 cm echogenic mass with central cystic area on the left adnexa. It had no internal or peripheral vascularity. There was marked pelvic echogenic free fluid with low internal echoes extending to the Morrison’s pouch. The uterus was anteverted and normal in size and shape with an endometrial thickness of 5.5 mm. A 1.9 cm cystic lesion was seen in the right ovary, which was likely a corpus luteum cyst. There was no gestational sac or intrauterine device seen within the endometrial cavity (Fig. 1). These features indicated ruptured ectopic pregnancy.Fig. 1 Ultrasound image of an empty uterus. The arrow points to the endometrial lining measuring 5.5 mm
The diagnosis at this point was a ruptured left tubal ectopic pregnancy. The plan was to admit the patient for an emergency laparoscopy with possible left salpingectomy. The diagnosis and plan were explained to the patient, who signed an informed consent for the procedure. Group and cross match of one unit of packed red cells was ordered in case a transfusion would be required.
The laparoscopy was done under general anesthesia in the Lloyd–Davis position. Cohen’s uterine manipulator was placed. Veress insufflation was performed, followed by insertion of a 10-mm primary trocar at the umbilicus. Entry and operating pressures were 20 mmHg and 15 mmHg, respectively. Two secondary ports were inserted under vision, 5 mm in the right iliac fossa and 12 mm in the left iliac fossa. On primary survey, LNG IUS was found embedded at the fimbrial end of the left fallopian tube (Fig. 2). The LNG IUS was retrieved whole under vision through the 12-mm port (Fig. 3). There was hemoperitoneum of 700 ml (Fig. 2). A ruptured left ampullary ectopic pregnancy was identified by left salpingectomy using bipolar coagulation and scissors (Fig. 4). A corpus luteum cyst was found on the right ovary with normal right fallopian tube. Suction and peritoneal lavage were performed, and hemostasis was confirmed (Fig. 5). The specimen was retrieved through the 12-mm port and taken for histology. There was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal. All trocars were removed under vision.Fig. 2 Body of the embedded LNG IUS (indicated by arrow), which is seen protruding from the left tubal pregnancy with hemoperitoneum
Fig. 3 LNG IUS (indicated by arrow) being retrieved from the left tubal pregnancy
Fig. 4 Left salpingectomy (indicated by arrow) performed using bipolar coagulation
Fig. 5 Pelvic view after completion of the procedure confirming hemostasis. Arrow points to an empty pouch of Douglas
The postoperative recovery of the patient was unremarkable. She was debriefed about the surgery and discharged the following morning. She went home on oral paracetamol and diclofenac for pain relief.
The patient was reviewed in the gynecology outpatient clinic 2 weeks later. She was asymptomatic and doing well. Histology report confirmed left ectopic tubal gestation. She reported that she desired conception. Preconception counseling was done. She was put on daily folic acid (400 µg). The patient was advised to come to the hospital as soon as she missed a period or tested positive for pregnancy for an early pregnancy ultrasound to rule out another ectopic pregnancy. Three months later she presented at the early pregnancy clinic following 5 weeks of amenorrhea. A pelvic ultrasound was done that showed intrauterine pregnancy at 5 weeks gestation.
Discussion
The above case documents a rare occurrence of a ruptured ectopic pregnancy with the LNG IUS embedded within the affected fallopian tube.
Levonorgestrel IUS (Mirena) is a safe, reversible, and highly effective contraceptive method [2]. It is known to have other therapeutic benefits such as reduction in menstrual bleeding, anemia, and dysmenorrhea, as well as management of endometrial hyperplasia [10]. In this patient, the use of the LNG IUS was purely for contraception purposes.
Ectopic pregnancies affect approximately 2% of all pregnancies. The most common presentation of an ectopic pregnancy is abdominal pain and abnormal uterine bleeding [11]. Even though the rate of ectopic pregnancy is lower in women using LNG IUS, if a pregnancy occurs while using this IUD, there is a high risk of it being an ectopic pregnancy [2]. Current IUD use is a known risk factor for ectopic pregnancy [12]. Other risk factors for ectopic pregnancy include pelvic inflammatory disease, previous tubal surgery, previous ectopic pregnancy, and smoking [12]. On examination, features of acute abdomen due to hemoperitoneum may be present [11, 12]. The patient in this case had a presentation suggestive of ectopic pregnancy with concurrent LNG IUS use as a risk factor. However, she had other unspecific presenting features of diarrhea, vomiting, and low-grade fever. It is important to note that some patients may be asymptomatic without specific risk factors for an ectopic pregnancy [12]
On the other hand, malposition of an IUD is one of its common complications, presenting with pelvic pain and bleeding or no symptoms [13]. Although malposition is associated with reduced contraceptive efficacy, this is mostly true for copper IUDs and not LNG IUS, which has local progesterone effects [6]. Malposition is diagnosed by ultrasound [13]. However, compared with copper IUDs, the LNG IUS is more likely to be missed by ultrasonography. LNG IUS is compounded with barium sulfate, which makes it radio opaque for X-ray recognition [14]. A plain X-ray can therefore be used as an adjunctive imaging modality in the case of a lost LNG IUS not seen on ultrasound [15]. The patient in this case had a lost LNG IUS not seen on ultrasound 1 year after insertion but was lost to follow-up for additional imaging.
Uterine perforation is uncommon, with an incidence of 1 in 1000 insertions. It is a serious complication of IUD use and is often asymptomatic [16]. There is increased risk of perforation if insertion is done less than 6 months postpartum or while breastfeeding. This period is associated with endometrial atrophy with accelerated uterine involution and hence has a high risk of perforation [6, 13]. The current patient was asymptomatic for malposition or perforation for 2 years prior to the ectopic pregnancy. The transvaginal ultrasound done at diagnosis of ectopic pregnancy did not visualize the device in the left adnexa. Her LNG IUS was inserted only 2 months postpartum while breastfeeding. This may have been a risk factor for possible unrecognized perforation.
Routine transvaginal ultrasound to monitor IUD position either immediately post insertion or after 6 weeks is not recommended without clinical suspicion of malposition according to de Kroon et al. [17]. It has been reported that IUDs take approximately 3 months to settle into their stable position. An initially malpositioned IUD can therefore assume the correct fundal position over time [18]. In asymptomatic women with uncomplicated IUD insertion, routine ultrasound lacks benefit over clinical evaluation with string check at 6 weeks [17]. The patient in this case was asymptomatic without complications at insertion. One year later, the LNG IUS device could not be seen on clinical examination nor on ultrasound.
The mechanism of device migration is not well understood, especially in the case of tubal migration. The fallopian tube is a rare site for dislocated IUD [19, 20]. This phenomenon has been described in few case reports. There are theories from case reports about the tubal migration of an IUD. The first possibility is placement of the device at the tubal ostium during insertion with subsequent migration into the tube due to uterine contractions and tubal peristalsis [21]. The other possibility is uterine perforation with migration of the device into the peritoneal cavity and subsequent perforation of a preexisting hydrosalpinx as described by Ozdemir et al. in a case report [19]. The patient in this case did not have any hydrosalpinx noted intraoperatively. Perforation can be due to either immediate traumatic perforation at insertion or delayed transmural migration [22, 23]. It is also possible that, following an unrecognized perforation, there was nestling of the IUD close to the fimbrial end of the fallopian tube, with the device being enveloped within the fimbria [7, 19]. This phenomenon could have occurred antecedent to conception of the ectopic pregnancy. In the patient in this case, there was no sign of uterus perforation. The pouch of Douglas and rectum appeared normal.
The presence of an IUD within the fallopian tube is associated with an inflammatory reaction [19] interfering with tubal function and predisposing the patient to ectopic pregnancy. The tubal dysfunction is exacerbated by progesterone in the LNG IUS, which interferes with ciliary beating and tubal contractility [3]. It is possible that the embedment of LNG IUS at the fimbrial end of the fallopian tube occurred as a result of displacement from the proximal tube by the growing tubal pregnancy or its rupture.
Once an intraabdominal IUD is diagnosed, it should be removed whether it is symptomatic or not to avoid serious complications such as adhesion formation, bowel obstruction, and infertility [15, 19]. Laparoscopy is the surgical approach of choice as it is safe and effective. It provides good visualization to locate and remove a lost IUD [15]. In this case, the diagnosis of the LNG IUS within the fallopian tube and its removal were done laparoscopically.
Conclusion
Migration of the LNG IUS into the fallopian tube is a rare occurrence that is not well understood. In the case presented, a LNG IUS was found embedded within the fimbrial end of the fallopian tube that had a ruptured ectopic pregnancy. Surgical treatment with laparoscopy is recommended for intraabdominal IUD to prevent complications. The patient made a good recovery and proceeded to have an intrauterine pregnancy 3 months later, as desired.
Abbreviations
IUD Intrauterine device
LNG IUS Levonorgestrel intrauterine system
Acknowledgements
We would like to thank the patient for her permission to publish this manuscript.
Authors’ contributions
DM collected and analyzed the data and drafted the manuscript. IG and KW contributed to the manuscript writing and editing. All authors managed the patient and read and approved the final manuscript.
Funding
None.
Availability of data and materials
Clinical data and complementary examinations are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of the case and any accompanying images. A copy of the consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33685513 | 19,041,622 | 2021-03-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Aggression'. | Treatment with the direct oral anticoagulants (DOACs) apixaban and rivaroxaban associated with significant worsening of behavioural and psychological symptoms of dementia (BPSD).
We report the cases of two patients who developed worsening behavioural and psychological symptoms of dementia (BPSD), coinciding with starting the factor Xa inhibitor direct oral anticoagulant medications apixaban and rivaroxaban, respectively. Both patients required detaining under the Mental Health Act. Their symptoms improved significantly, within 2 weeks, on switching to alternative anticoagulant therapies and they were both discharged from the acute psychiatric ward. Front-line staff should partake in postmarketing surveillance of medications, completing the Medicines and Healthcare products Regulatory Agency yellow cards for example (UK). There is increasing evidence for an aetiological role of cerebral mitochondrial dysfunction in neuropsychiatric disorders. Development of a rating scale of drugs that are potentially less toxic to cerebral mitochondria could inform national prescribing guidelines and enable safer treatments to be offered to older people, reducing the likely hood of them experiencing apparent BPSD.
Background
Globally, the estimated proportion of the general population aged 60 and over with dementia is between 5% and 8% equating to around 50 million people. There are nearly 10 million new cases every year.1 Ischaemic heart disease and stroke are the biggest cause of death worldwide.2 Factor Xa inhibitor direct oral anticoagulants (DOACs) have become widely prescribed over recent years in the UK, being included as drugs recommended by the National Institute for Health and Care Excellence as achieving anticoagulation in prevention of systemic emboli in patients in atrial fibrillation (AF) or with deep vein thrombosis. A significant proportion of the population with mild cognitive impairment or dementia are, therefore, also treated with DOAC’s for these coexistent diagnoses. In our experience locally, reflecting changing practice throughout the developed world, many patients are being switched from warfarin to factor Xa inhibitor DOACs, which do not require close monitoring of blood levels. Despite no listed neuropsychiatric side effects in the British National Formulary (BNF) for these, we suspected that these two patients were experiencing iatrogenic worsening of their behavioural and psychological symptoms of dementia (BPSD). We hypothesise that similar factor Xa inhibitor side effects are experienced by many older people to a varying degree and wrongly attributed to BPSD.
Case presentation 1
A woman in her early 80s was admitted to her local District General Hospital (DGH) following a fall. She was found to have a pulmonary embolus (PE) and to be in AF. She was commenced on apixaban. During this admission, staff raised concerns about her memory and on discharge, referred her to the local memory assessment service (MAS). Following initial MAS assessment approximately 3 weeks later, the patient was commenced on the antidepressant mirtazapine for low mood and poor sleep. However, after a further 3 weeks, she was brought to the liaison department at the DGH following physically assaulting police officers and paramedics. Her husband confirmed a deterioration in his wife’s memory over 6 months with her becoming repetitive in conversation and forgetting who some of the neighbours were. She had also started to accuse him of having an affair and steeling her money over these months. He denied this saying that they spent nearly all their time together. However, he indicated that there had been a noticeable worsening of her presentation following her hospital admission 6 weeks before with a PE, with her becoming physically aggressive since, assaulting him on multiple occasions and calling the police frequently. He explained that he had had to lock himself in the bathroom that day for his own safety. At interview, the patient reported low mood and poor sleep since the alleged affair, saying that she had seen this person and found a slip in her husband’s pocket. Her mood was labile, alternating between irritability and tearfulness. She was noted to be repetitive in conversation with poor recall of recent events. Her insight was poor although she was aware of recent memory difficulties. She was assessed and admitted under section 2 of the Mental Health Act (MHA) with a provisional diagnosis of delusional jealousy in the context of likely dementia.
Investigations
Physical examination was unremarkable. Medications included apixaban (5 mg two times per day), bisoprolol (2.5 mg two times per day), digoxin (125 μg one time per day) and glyceryl trinitrate spray as required. A dementia blood screen was normal. An MRI head scan showed minor generalised cerebral atrophy with a few foci within the supratentorial white matter reported as likely age related ischaemic phenomena. The patient scored 70/100 on the Addenbrooke’s cognitive examination, losing marks in the memory domain and suggestive of at least mild dementia.
Management
Mirtazapine was stopped as the patient’s agitation and aggression had only worsened. Subsequent trials of medication to manage this included intramuscular lorazepam (0.5–1.0 mg), required on several occasions; quetiapine (125 mg daily) combined with citalopram (20 mg daily), both subsequently stopped as not effective; replaced by aripiprazole (15 mg daily), also ineffective and replaced by oral zuclopenthixol, (increased to 18 mg daily). After 2 weeks on this dose of zuclopenthixol and nearly 4 months on the acute psychiatric ward, although the patient was no longer expressing delusion ideas regarding, her husband having an affair her presentation had, if anything, worsened with regard to her agitation and aggression, throwing a chair, banging on the doors, hitting out at staff and asking for her mother. The decision was made to switch apixaban to dabigatran as an alternative DOAC. The rationale was that there had been no other obvious precipitating factors that might explain the relatively sudden and persistent deterioration in the patient’s mental state and the temporal relationship with starting apixaban. She became markedly more settled over the next 2 weeks, no longer banging on doors or wanting to leave. She acknowledged feeling more calm and relaxed. There were no longer concerns regarding her mood or sleep. This was in the absence of any other behavioural approach, medication or management changes.
Outcome and follow-up
The patient was discharged to a local care home, which would not have been considered possible prior to her switching anticoagulant medication and appearing far less agitated and aggressive. She was significantly more settled and her presentation was of mild dementia. Treatment with antipsychotic medication had been effective for her delusional beliefs throughout her admission and she continued treatment with clopixol (18 mg daily). The management plan was to reduce this while monitoring her mental state for any re-emergence of BPSD agitation and aggression. After a month, both she and her husband were enquiring about the possibility of her returning home.
Case presentation 2
The second case is of a man in his early 70s, described by his family as having some mild memory problems and confusion at times although managing his activities of daily living well enough. He did not think it severe enough to bother his general practitioner (GP). However, approximately a month after commencing rivaroxaban for AF, he became agitated and more confused. So much so that not only did he present to his GP, who referred him to our MAS, he was in turn referred to our older persons community mental health team, as his apparent BPSD had worsened rapidly. He had become physically threatening and aggressive towards his wife and daughters. He was assessed and admitted under the MHA and received a working diagnosis of advanced dementia. This led to trials of treatment with a variety of psychotropic medications. His apparent BPSD appeared to be treatment resistant and his presentation worsened.
At the time, in 2016, there were no side effects listed for rivaroxaban in the BNF which might have suggested the potential for worsening of mental state or cognition. However, in the absence of any other identifiable psychosocial or pathophysiological causes or changes to medication, we switched rivaroxaban to warfarin. We saw a significant improvement in the patient’s presentation within 2 weeks. Importantly, further improvements were noted on gradually reducing and discontinuing the psychotropic medications that were being prescribed in an attempt to manage his change in behaviour. This patient had also became settled sufficiently to be discharged. He caught the bus home, a fact he was able to recount to us in clinic a month later when his clinical presentation was also of mild dementia.
Discussion
Front-line healthcare staff in acute settings and the community manage a heavy workload. It is all too easy to overlook potential neuropsychiatric drug side effects, especially if they are not clearly listed. They may be easily missed among older patients and wrongly attributed to dementia.
Rivaroxaban is structurally related to the antibiotic linezolid, which has been reported to cause mitochondrial toxicity.3 Premarketing in vitro studies concluded the risk of mitochondrial toxicity associated with this anticoagulant to be low.4 However, a more recent in vitro study, using rat kidney mitochondria, reported evidence of mitochondrial swelling and a collapse of the membrane potential following exposure to low doses of rivaroxaban.5 The effect of apixaban, which is structurally related to rivaroxaban, has yet to be investigated on mitochondrial function.6
Recent research supports not only an association between reduced cerebral mitochondrial function and neuropsychiatric symptoms and disorders, but also the aetiological role it may play.7
There is a need for a far greater awareness and understanding of the potential cerebral mitochondrial toxicity of drugs commonly prescribed to our older populations. These are numerous and include, for example, some of the drugs prescribed for diabetes (metformin) and raised cholesterol (statins) as well as many of those prescribed for neuropsychiatric symptoms such as trazadone and sodium valproate.8
Asthenia (abnormal physical weakness or lack of energy) has more recently become listed as a common/very common side effect of rivaroxaban in the BNF. This is presumably as a result of the medicines and healthcare products regulatory agency (MHRA) yellow card reporting of suspected adverse reactions being submitted. This clinical symptom may be associated with mitochondrial toxicity.9 Interestingly, Karlsvik et al reported no increase in the level of fatigue after initiation of treatment with rivaroxaban.10
Further research could enable the compiling of a cerebral mitochondrial toxicity burden scale of drugs, similar to that as already exists for anticholinergic burden on cognitive functioning.11 There are research techniques that can assess cerebral mitochondrial dysfunction using non-invasive brain scanning of lactate levels, which are considered to be a good correlate of mitochondrial function.12 Such a scale could inform clinical decision making, switching patients to drugs that are potentially less toxic to cerebral mitochondria, when appropriate.
We may then be able to significantly improve quality of life and reduce the burden and cost for patients, their carers, psychiatric services and the social care system by potentially avoiding psychiatric admission and placement in dementia care homes with fees, in the UK of between £34 000 (residential) and £47 000 (nursing) per annum.13
Patient’s perspective
Something changed when I was in hospital after my fall, something wasn’t right. I feel calmer and much better now, ready to go back home with my husband.
Learning points
Consider drug-induced neuropsychiatric symptoms in older patients with suspected behavioural and psychological symptoms of dementia (BPSD). Avoid assuming that their worsening presentation is necessarily secondary to cerebral emboli because they have a degree of vascular pathology on brain imaging and are in atrial fibrillation.
Older patients are particularly prone to experiencing neuropsychiatric side effects of drugs that may not have been apparent during preclinical trials. Polypharmacy and associated drug interactions are also more common. All front-line staff should be encouraged to discuss with colleagues any medicine safety concerns, which can be particularly hard to unpick from BPSD, and to report these via the medicines and healthcare products regulatory agency yellow card system, for example.
Neuropsychiatric symptoms and disorders are known to be associated with reduced cerebral mitochondrial function. There is an increasing body of research supporting that this relationship is aetiological. If so, any further drug-induced impairment of cerebral mitochondrial function could, therefore, be expected to precipitate or exacerbate such symptoms or disorders already present potentially.
An increased awareness of which drugs are less toxic to cerebral mitochondria, with the development of a rating scale for example, could inform prescribing guidelines (National Institute for Health and Care Excellence) and safer treatments being offered to older people, reducing the likely hood of them experiencing apparent BPSD and requiring psychiatric detention.
Contributors: IPH, KMFP, SDS and RG conceived the case review article. KMFP, SDS and RG where directly involved in the clinical management of the two cases cited. IPH shared his expert knowledge of the potential mitochondrial toxicity of drugs. KMFP carried out the literature search. RG and KMFP drafted the first manuscript. All authors contributed to revising and approving the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | ARIPIPRAZOLE, BISOPROLOL, CITALOPRAM HYDROBROMIDE, DIGOXIN, MIRTAZAPINE, NITROGLYCERIN, QUETIAPINE FUMARATE | DrugsGivenReaction | CC BY-NC | 33685912 | 19,993,400 | 2021-03-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Agitation'. | Treatment with the direct oral anticoagulants (DOACs) apixaban and rivaroxaban associated with significant worsening of behavioural and psychological symptoms of dementia (BPSD).
We report the cases of two patients who developed worsening behavioural and psychological symptoms of dementia (BPSD), coinciding with starting the factor Xa inhibitor direct oral anticoagulant medications apixaban and rivaroxaban, respectively. Both patients required detaining under the Mental Health Act. Their symptoms improved significantly, within 2 weeks, on switching to alternative anticoagulant therapies and they were both discharged from the acute psychiatric ward. Front-line staff should partake in postmarketing surveillance of medications, completing the Medicines and Healthcare products Regulatory Agency yellow cards for example (UK). There is increasing evidence for an aetiological role of cerebral mitochondrial dysfunction in neuropsychiatric disorders. Development of a rating scale of drugs that are potentially less toxic to cerebral mitochondria could inform national prescribing guidelines and enable safer treatments to be offered to older people, reducing the likely hood of them experiencing apparent BPSD.
Background
Globally, the estimated proportion of the general population aged 60 and over with dementia is between 5% and 8% equating to around 50 million people. There are nearly 10 million new cases every year.1 Ischaemic heart disease and stroke are the biggest cause of death worldwide.2 Factor Xa inhibitor direct oral anticoagulants (DOACs) have become widely prescribed over recent years in the UK, being included as drugs recommended by the National Institute for Health and Care Excellence as achieving anticoagulation in prevention of systemic emboli in patients in atrial fibrillation (AF) or with deep vein thrombosis. A significant proportion of the population with mild cognitive impairment or dementia are, therefore, also treated with DOAC’s for these coexistent diagnoses. In our experience locally, reflecting changing practice throughout the developed world, many patients are being switched from warfarin to factor Xa inhibitor DOACs, which do not require close monitoring of blood levels. Despite no listed neuropsychiatric side effects in the British National Formulary (BNF) for these, we suspected that these two patients were experiencing iatrogenic worsening of their behavioural and psychological symptoms of dementia (BPSD). We hypothesise that similar factor Xa inhibitor side effects are experienced by many older people to a varying degree and wrongly attributed to BPSD.
Case presentation 1
A woman in her early 80s was admitted to her local District General Hospital (DGH) following a fall. She was found to have a pulmonary embolus (PE) and to be in AF. She was commenced on apixaban. During this admission, staff raised concerns about her memory and on discharge, referred her to the local memory assessment service (MAS). Following initial MAS assessment approximately 3 weeks later, the patient was commenced on the antidepressant mirtazapine for low mood and poor sleep. However, after a further 3 weeks, she was brought to the liaison department at the DGH following physically assaulting police officers and paramedics. Her husband confirmed a deterioration in his wife’s memory over 6 months with her becoming repetitive in conversation and forgetting who some of the neighbours were. She had also started to accuse him of having an affair and steeling her money over these months. He denied this saying that they spent nearly all their time together. However, he indicated that there had been a noticeable worsening of her presentation following her hospital admission 6 weeks before with a PE, with her becoming physically aggressive since, assaulting him on multiple occasions and calling the police frequently. He explained that he had had to lock himself in the bathroom that day for his own safety. At interview, the patient reported low mood and poor sleep since the alleged affair, saying that she had seen this person and found a slip in her husband’s pocket. Her mood was labile, alternating between irritability and tearfulness. She was noted to be repetitive in conversation with poor recall of recent events. Her insight was poor although she was aware of recent memory difficulties. She was assessed and admitted under section 2 of the Mental Health Act (MHA) with a provisional diagnosis of delusional jealousy in the context of likely dementia.
Investigations
Physical examination was unremarkable. Medications included apixaban (5 mg two times per day), bisoprolol (2.5 mg two times per day), digoxin (125 μg one time per day) and glyceryl trinitrate spray as required. A dementia blood screen was normal. An MRI head scan showed minor generalised cerebral atrophy with a few foci within the supratentorial white matter reported as likely age related ischaemic phenomena. The patient scored 70/100 on the Addenbrooke’s cognitive examination, losing marks in the memory domain and suggestive of at least mild dementia.
Management
Mirtazapine was stopped as the patient’s agitation and aggression had only worsened. Subsequent trials of medication to manage this included intramuscular lorazepam (0.5–1.0 mg), required on several occasions; quetiapine (125 mg daily) combined with citalopram (20 mg daily), both subsequently stopped as not effective; replaced by aripiprazole (15 mg daily), also ineffective and replaced by oral zuclopenthixol, (increased to 18 mg daily). After 2 weeks on this dose of zuclopenthixol and nearly 4 months on the acute psychiatric ward, although the patient was no longer expressing delusion ideas regarding, her husband having an affair her presentation had, if anything, worsened with regard to her agitation and aggression, throwing a chair, banging on the doors, hitting out at staff and asking for her mother. The decision was made to switch apixaban to dabigatran as an alternative DOAC. The rationale was that there had been no other obvious precipitating factors that might explain the relatively sudden and persistent deterioration in the patient’s mental state and the temporal relationship with starting apixaban. She became markedly more settled over the next 2 weeks, no longer banging on doors or wanting to leave. She acknowledged feeling more calm and relaxed. There were no longer concerns regarding her mood or sleep. This was in the absence of any other behavioural approach, medication or management changes.
Outcome and follow-up
The patient was discharged to a local care home, which would not have been considered possible prior to her switching anticoagulant medication and appearing far less agitated and aggressive. She was significantly more settled and her presentation was of mild dementia. Treatment with antipsychotic medication had been effective for her delusional beliefs throughout her admission and she continued treatment with clopixol (18 mg daily). The management plan was to reduce this while monitoring her mental state for any re-emergence of BPSD agitation and aggression. After a month, both she and her husband were enquiring about the possibility of her returning home.
Case presentation 2
The second case is of a man in his early 70s, described by his family as having some mild memory problems and confusion at times although managing his activities of daily living well enough. He did not think it severe enough to bother his general practitioner (GP). However, approximately a month after commencing rivaroxaban for AF, he became agitated and more confused. So much so that not only did he present to his GP, who referred him to our MAS, he was in turn referred to our older persons community mental health team, as his apparent BPSD had worsened rapidly. He had become physically threatening and aggressive towards his wife and daughters. He was assessed and admitted under the MHA and received a working diagnosis of advanced dementia. This led to trials of treatment with a variety of psychotropic medications. His apparent BPSD appeared to be treatment resistant and his presentation worsened.
At the time, in 2016, there were no side effects listed for rivaroxaban in the BNF which might have suggested the potential for worsening of mental state or cognition. However, in the absence of any other identifiable psychosocial or pathophysiological causes or changes to medication, we switched rivaroxaban to warfarin. We saw a significant improvement in the patient’s presentation within 2 weeks. Importantly, further improvements were noted on gradually reducing and discontinuing the psychotropic medications that were being prescribed in an attempt to manage his change in behaviour. This patient had also became settled sufficiently to be discharged. He caught the bus home, a fact he was able to recount to us in clinic a month later when his clinical presentation was also of mild dementia.
Discussion
Front-line healthcare staff in acute settings and the community manage a heavy workload. It is all too easy to overlook potential neuropsychiatric drug side effects, especially if they are not clearly listed. They may be easily missed among older patients and wrongly attributed to dementia.
Rivaroxaban is structurally related to the antibiotic linezolid, which has been reported to cause mitochondrial toxicity.3 Premarketing in vitro studies concluded the risk of mitochondrial toxicity associated with this anticoagulant to be low.4 However, a more recent in vitro study, using rat kidney mitochondria, reported evidence of mitochondrial swelling and a collapse of the membrane potential following exposure to low doses of rivaroxaban.5 The effect of apixaban, which is structurally related to rivaroxaban, has yet to be investigated on mitochondrial function.6
Recent research supports not only an association between reduced cerebral mitochondrial function and neuropsychiatric symptoms and disorders, but also the aetiological role it may play.7
There is a need for a far greater awareness and understanding of the potential cerebral mitochondrial toxicity of drugs commonly prescribed to our older populations. These are numerous and include, for example, some of the drugs prescribed for diabetes (metformin) and raised cholesterol (statins) as well as many of those prescribed for neuropsychiatric symptoms such as trazadone and sodium valproate.8
Asthenia (abnormal physical weakness or lack of energy) has more recently become listed as a common/very common side effect of rivaroxaban in the BNF. This is presumably as a result of the medicines and healthcare products regulatory agency (MHRA) yellow card reporting of suspected adverse reactions being submitted. This clinical symptom may be associated with mitochondrial toxicity.9 Interestingly, Karlsvik et al reported no increase in the level of fatigue after initiation of treatment with rivaroxaban.10
Further research could enable the compiling of a cerebral mitochondrial toxicity burden scale of drugs, similar to that as already exists for anticholinergic burden on cognitive functioning.11 There are research techniques that can assess cerebral mitochondrial dysfunction using non-invasive brain scanning of lactate levels, which are considered to be a good correlate of mitochondrial function.12 Such a scale could inform clinical decision making, switching patients to drugs that are potentially less toxic to cerebral mitochondria, when appropriate.
We may then be able to significantly improve quality of life and reduce the burden and cost for patients, their carers, psychiatric services and the social care system by potentially avoiding psychiatric admission and placement in dementia care homes with fees, in the UK of between £34 000 (residential) and £47 000 (nursing) per annum.13
Patient’s perspective
Something changed when I was in hospital after my fall, something wasn’t right. I feel calmer and much better now, ready to go back home with my husband.
Learning points
Consider drug-induced neuropsychiatric symptoms in older patients with suspected behavioural and psychological symptoms of dementia (BPSD). Avoid assuming that their worsening presentation is necessarily secondary to cerebral emboli because they have a degree of vascular pathology on brain imaging and are in atrial fibrillation.
Older patients are particularly prone to experiencing neuropsychiatric side effects of drugs that may not have been apparent during preclinical trials. Polypharmacy and associated drug interactions are also more common. All front-line staff should be encouraged to discuss with colleagues any medicine safety concerns, which can be particularly hard to unpick from BPSD, and to report these via the medicines and healthcare products regulatory agency yellow card system, for example.
Neuropsychiatric symptoms and disorders are known to be associated with reduced cerebral mitochondrial function. There is an increasing body of research supporting that this relationship is aetiological. If so, any further drug-induced impairment of cerebral mitochondrial function could, therefore, be expected to precipitate or exacerbate such symptoms or disorders already present potentially.
An increased awareness of which drugs are less toxic to cerebral mitochondria, with the development of a rating scale for example, could inform prescribing guidelines (National Institute for Health and Care Excellence) and safer treatments being offered to older people, reducing the likely hood of them experiencing apparent BPSD and requiring psychiatric detention.
Contributors: IPH, KMFP, SDS and RG conceived the case review article. KMFP, SDS and RG where directly involved in the clinical management of the two cases cited. IPH shared his expert knowledge of the potential mitochondrial toxicity of drugs. KMFP carried out the literature search. RG and KMFP drafted the first manuscript. All authors contributed to revising and approving the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | ARIPIPRAZOLE, BISOPROLOL, CITALOPRAM HYDROBROMIDE, DIGOXIN, MIRTAZAPINE, NITROGLYCERIN, QUETIAPINE FUMARATE | DrugsGivenReaction | CC BY-NC | 33685912 | 19,993,400 | 2021-03-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Memory impairment'. | Treatment with the direct oral anticoagulants (DOACs) apixaban and rivaroxaban associated with significant worsening of behavioural and psychological symptoms of dementia (BPSD).
We report the cases of two patients who developed worsening behavioural and psychological symptoms of dementia (BPSD), coinciding with starting the factor Xa inhibitor direct oral anticoagulant medications apixaban and rivaroxaban, respectively. Both patients required detaining under the Mental Health Act. Their symptoms improved significantly, within 2 weeks, on switching to alternative anticoagulant therapies and they were both discharged from the acute psychiatric ward. Front-line staff should partake in postmarketing surveillance of medications, completing the Medicines and Healthcare products Regulatory Agency yellow cards for example (UK). There is increasing evidence for an aetiological role of cerebral mitochondrial dysfunction in neuropsychiatric disorders. Development of a rating scale of drugs that are potentially less toxic to cerebral mitochondria could inform national prescribing guidelines and enable safer treatments to be offered to older people, reducing the likely hood of them experiencing apparent BPSD.
Background
Globally, the estimated proportion of the general population aged 60 and over with dementia is between 5% and 8% equating to around 50 million people. There are nearly 10 million new cases every year.1 Ischaemic heart disease and stroke are the biggest cause of death worldwide.2 Factor Xa inhibitor direct oral anticoagulants (DOACs) have become widely prescribed over recent years in the UK, being included as drugs recommended by the National Institute for Health and Care Excellence as achieving anticoagulation in prevention of systemic emboli in patients in atrial fibrillation (AF) or with deep vein thrombosis. A significant proportion of the population with mild cognitive impairment or dementia are, therefore, also treated with DOAC’s for these coexistent diagnoses. In our experience locally, reflecting changing practice throughout the developed world, many patients are being switched from warfarin to factor Xa inhibitor DOACs, which do not require close monitoring of blood levels. Despite no listed neuropsychiatric side effects in the British National Formulary (BNF) for these, we suspected that these two patients were experiencing iatrogenic worsening of their behavioural and psychological symptoms of dementia (BPSD). We hypothesise that similar factor Xa inhibitor side effects are experienced by many older people to a varying degree and wrongly attributed to BPSD.
Case presentation 1
A woman in her early 80s was admitted to her local District General Hospital (DGH) following a fall. She was found to have a pulmonary embolus (PE) and to be in AF. She was commenced on apixaban. During this admission, staff raised concerns about her memory and on discharge, referred her to the local memory assessment service (MAS). Following initial MAS assessment approximately 3 weeks later, the patient was commenced on the antidepressant mirtazapine for low mood and poor sleep. However, after a further 3 weeks, she was brought to the liaison department at the DGH following physically assaulting police officers and paramedics. Her husband confirmed a deterioration in his wife’s memory over 6 months with her becoming repetitive in conversation and forgetting who some of the neighbours were. She had also started to accuse him of having an affair and steeling her money over these months. He denied this saying that they spent nearly all their time together. However, he indicated that there had been a noticeable worsening of her presentation following her hospital admission 6 weeks before with a PE, with her becoming physically aggressive since, assaulting him on multiple occasions and calling the police frequently. He explained that he had had to lock himself in the bathroom that day for his own safety. At interview, the patient reported low mood and poor sleep since the alleged affair, saying that she had seen this person and found a slip in her husband’s pocket. Her mood was labile, alternating between irritability and tearfulness. She was noted to be repetitive in conversation with poor recall of recent events. Her insight was poor although she was aware of recent memory difficulties. She was assessed and admitted under section 2 of the Mental Health Act (MHA) with a provisional diagnosis of delusional jealousy in the context of likely dementia.
Investigations
Physical examination was unremarkable. Medications included apixaban (5 mg two times per day), bisoprolol (2.5 mg two times per day), digoxin (125 μg one time per day) and glyceryl trinitrate spray as required. A dementia blood screen was normal. An MRI head scan showed minor generalised cerebral atrophy with a few foci within the supratentorial white matter reported as likely age related ischaemic phenomena. The patient scored 70/100 on the Addenbrooke’s cognitive examination, losing marks in the memory domain and suggestive of at least mild dementia.
Management
Mirtazapine was stopped as the patient’s agitation and aggression had only worsened. Subsequent trials of medication to manage this included intramuscular lorazepam (0.5–1.0 mg), required on several occasions; quetiapine (125 mg daily) combined with citalopram (20 mg daily), both subsequently stopped as not effective; replaced by aripiprazole (15 mg daily), also ineffective and replaced by oral zuclopenthixol, (increased to 18 mg daily). After 2 weeks on this dose of zuclopenthixol and nearly 4 months on the acute psychiatric ward, although the patient was no longer expressing delusion ideas regarding, her husband having an affair her presentation had, if anything, worsened with regard to her agitation and aggression, throwing a chair, banging on the doors, hitting out at staff and asking for her mother. The decision was made to switch apixaban to dabigatran as an alternative DOAC. The rationale was that there had been no other obvious precipitating factors that might explain the relatively sudden and persistent deterioration in the patient’s mental state and the temporal relationship with starting apixaban. She became markedly more settled over the next 2 weeks, no longer banging on doors or wanting to leave. She acknowledged feeling more calm and relaxed. There were no longer concerns regarding her mood or sleep. This was in the absence of any other behavioural approach, medication or management changes.
Outcome and follow-up
The patient was discharged to a local care home, which would not have been considered possible prior to her switching anticoagulant medication and appearing far less agitated and aggressive. She was significantly more settled and her presentation was of mild dementia. Treatment with antipsychotic medication had been effective for her delusional beliefs throughout her admission and she continued treatment with clopixol (18 mg daily). The management plan was to reduce this while monitoring her mental state for any re-emergence of BPSD agitation and aggression. After a month, both she and her husband were enquiring about the possibility of her returning home.
Case presentation 2
The second case is of a man in his early 70s, described by his family as having some mild memory problems and confusion at times although managing his activities of daily living well enough. He did not think it severe enough to bother his general practitioner (GP). However, approximately a month after commencing rivaroxaban for AF, he became agitated and more confused. So much so that not only did he present to his GP, who referred him to our MAS, he was in turn referred to our older persons community mental health team, as his apparent BPSD had worsened rapidly. He had become physically threatening and aggressive towards his wife and daughters. He was assessed and admitted under the MHA and received a working diagnosis of advanced dementia. This led to trials of treatment with a variety of psychotropic medications. His apparent BPSD appeared to be treatment resistant and his presentation worsened.
At the time, in 2016, there were no side effects listed for rivaroxaban in the BNF which might have suggested the potential for worsening of mental state or cognition. However, in the absence of any other identifiable psychosocial or pathophysiological causes or changes to medication, we switched rivaroxaban to warfarin. We saw a significant improvement in the patient’s presentation within 2 weeks. Importantly, further improvements were noted on gradually reducing and discontinuing the psychotropic medications that were being prescribed in an attempt to manage his change in behaviour. This patient had also became settled sufficiently to be discharged. He caught the bus home, a fact he was able to recount to us in clinic a month later when his clinical presentation was also of mild dementia.
Discussion
Front-line healthcare staff in acute settings and the community manage a heavy workload. It is all too easy to overlook potential neuropsychiatric drug side effects, especially if they are not clearly listed. They may be easily missed among older patients and wrongly attributed to dementia.
Rivaroxaban is structurally related to the antibiotic linezolid, which has been reported to cause mitochondrial toxicity.3 Premarketing in vitro studies concluded the risk of mitochondrial toxicity associated with this anticoagulant to be low.4 However, a more recent in vitro study, using rat kidney mitochondria, reported evidence of mitochondrial swelling and a collapse of the membrane potential following exposure to low doses of rivaroxaban.5 The effect of apixaban, which is structurally related to rivaroxaban, has yet to be investigated on mitochondrial function.6
Recent research supports not only an association between reduced cerebral mitochondrial function and neuropsychiatric symptoms and disorders, but also the aetiological role it may play.7
There is a need for a far greater awareness and understanding of the potential cerebral mitochondrial toxicity of drugs commonly prescribed to our older populations. These are numerous and include, for example, some of the drugs prescribed for diabetes (metformin) and raised cholesterol (statins) as well as many of those prescribed for neuropsychiatric symptoms such as trazadone and sodium valproate.8
Asthenia (abnormal physical weakness or lack of energy) has more recently become listed as a common/very common side effect of rivaroxaban in the BNF. This is presumably as a result of the medicines and healthcare products regulatory agency (MHRA) yellow card reporting of suspected adverse reactions being submitted. This clinical symptom may be associated with mitochondrial toxicity.9 Interestingly, Karlsvik et al reported no increase in the level of fatigue after initiation of treatment with rivaroxaban.10
Further research could enable the compiling of a cerebral mitochondrial toxicity burden scale of drugs, similar to that as already exists for anticholinergic burden on cognitive functioning.11 There are research techniques that can assess cerebral mitochondrial dysfunction using non-invasive brain scanning of lactate levels, which are considered to be a good correlate of mitochondrial function.12 Such a scale could inform clinical decision making, switching patients to drugs that are potentially less toxic to cerebral mitochondria, when appropriate.
We may then be able to significantly improve quality of life and reduce the burden and cost for patients, their carers, psychiatric services and the social care system by potentially avoiding psychiatric admission and placement in dementia care homes with fees, in the UK of between £34 000 (residential) and £47 000 (nursing) per annum.13
Patient’s perspective
Something changed when I was in hospital after my fall, something wasn’t right. I feel calmer and much better now, ready to go back home with my husband.
Learning points
Consider drug-induced neuropsychiatric symptoms in older patients with suspected behavioural and psychological symptoms of dementia (BPSD). Avoid assuming that their worsening presentation is necessarily secondary to cerebral emboli because they have a degree of vascular pathology on brain imaging and are in atrial fibrillation.
Older patients are particularly prone to experiencing neuropsychiatric side effects of drugs that may not have been apparent during preclinical trials. Polypharmacy and associated drug interactions are also more common. All front-line staff should be encouraged to discuss with colleagues any medicine safety concerns, which can be particularly hard to unpick from BPSD, and to report these via the medicines and healthcare products regulatory agency yellow card system, for example.
Neuropsychiatric symptoms and disorders are known to be associated with reduced cerebral mitochondrial function. There is an increasing body of research supporting that this relationship is aetiological. If so, any further drug-induced impairment of cerebral mitochondrial function could, therefore, be expected to precipitate or exacerbate such symptoms or disorders already present potentially.
An increased awareness of which drugs are less toxic to cerebral mitochondria, with the development of a rating scale for example, could inform prescribing guidelines (National Institute for Health and Care Excellence) and safer treatments being offered to older people, reducing the likely hood of them experiencing apparent BPSD and requiring psychiatric detention.
Contributors: IPH, KMFP, SDS and RG conceived the case review article. KMFP, SDS and RG where directly involved in the clinical management of the two cases cited. IPH shared his expert knowledge of the potential mitochondrial toxicity of drugs. KMFP carried out the literature search. RG and KMFP drafted the first manuscript. All authors contributed to revising and approving the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | ARIPIPRAZOLE, BISOPROLOL, CITALOPRAM HYDROBROMIDE, DIGOXIN, MIRTAZAPINE, NITROGLYCERIN, QUETIAPINE FUMARATE | DrugsGivenReaction | CC BY-NC | 33685912 | 19,993,400 | 2021-03-08 |
What was the administration route of drug 'APIXABAN'? | Treatment with the direct oral anticoagulants (DOACs) apixaban and rivaroxaban associated with significant worsening of behavioural and psychological symptoms of dementia (BPSD).
We report the cases of two patients who developed worsening behavioural and psychological symptoms of dementia (BPSD), coinciding with starting the factor Xa inhibitor direct oral anticoagulant medications apixaban and rivaroxaban, respectively. Both patients required detaining under the Mental Health Act. Their symptoms improved significantly, within 2 weeks, on switching to alternative anticoagulant therapies and they were both discharged from the acute psychiatric ward. Front-line staff should partake in postmarketing surveillance of medications, completing the Medicines and Healthcare products Regulatory Agency yellow cards for example (UK). There is increasing evidence for an aetiological role of cerebral mitochondrial dysfunction in neuropsychiatric disorders. Development of a rating scale of drugs that are potentially less toxic to cerebral mitochondria could inform national prescribing guidelines and enable safer treatments to be offered to older people, reducing the likely hood of them experiencing apparent BPSD.
Background
Globally, the estimated proportion of the general population aged 60 and over with dementia is between 5% and 8% equating to around 50 million people. There are nearly 10 million new cases every year.1 Ischaemic heart disease and stroke are the biggest cause of death worldwide.2 Factor Xa inhibitor direct oral anticoagulants (DOACs) have become widely prescribed over recent years in the UK, being included as drugs recommended by the National Institute for Health and Care Excellence as achieving anticoagulation in prevention of systemic emboli in patients in atrial fibrillation (AF) or with deep vein thrombosis. A significant proportion of the population with mild cognitive impairment or dementia are, therefore, also treated with DOAC’s for these coexistent diagnoses. In our experience locally, reflecting changing practice throughout the developed world, many patients are being switched from warfarin to factor Xa inhibitor DOACs, which do not require close monitoring of blood levels. Despite no listed neuropsychiatric side effects in the British National Formulary (BNF) for these, we suspected that these two patients were experiencing iatrogenic worsening of their behavioural and psychological symptoms of dementia (BPSD). We hypothesise that similar factor Xa inhibitor side effects are experienced by many older people to a varying degree and wrongly attributed to BPSD.
Case presentation 1
A woman in her early 80s was admitted to her local District General Hospital (DGH) following a fall. She was found to have a pulmonary embolus (PE) and to be in AF. She was commenced on apixaban. During this admission, staff raised concerns about her memory and on discharge, referred her to the local memory assessment service (MAS). Following initial MAS assessment approximately 3 weeks later, the patient was commenced on the antidepressant mirtazapine for low mood and poor sleep. However, after a further 3 weeks, she was brought to the liaison department at the DGH following physically assaulting police officers and paramedics. Her husband confirmed a deterioration in his wife’s memory over 6 months with her becoming repetitive in conversation and forgetting who some of the neighbours were. She had also started to accuse him of having an affair and steeling her money over these months. He denied this saying that they spent nearly all their time together. However, he indicated that there had been a noticeable worsening of her presentation following her hospital admission 6 weeks before with a PE, with her becoming physically aggressive since, assaulting him on multiple occasions and calling the police frequently. He explained that he had had to lock himself in the bathroom that day for his own safety. At interview, the patient reported low mood and poor sleep since the alleged affair, saying that she had seen this person and found a slip in her husband’s pocket. Her mood was labile, alternating between irritability and tearfulness. She was noted to be repetitive in conversation with poor recall of recent events. Her insight was poor although she was aware of recent memory difficulties. She was assessed and admitted under section 2 of the Mental Health Act (MHA) with a provisional diagnosis of delusional jealousy in the context of likely dementia.
Investigations
Physical examination was unremarkable. Medications included apixaban (5 mg two times per day), bisoprolol (2.5 mg two times per day), digoxin (125 μg one time per day) and glyceryl trinitrate spray as required. A dementia blood screen was normal. An MRI head scan showed minor generalised cerebral atrophy with a few foci within the supratentorial white matter reported as likely age related ischaemic phenomena. The patient scored 70/100 on the Addenbrooke’s cognitive examination, losing marks in the memory domain and suggestive of at least mild dementia.
Management
Mirtazapine was stopped as the patient’s agitation and aggression had only worsened. Subsequent trials of medication to manage this included intramuscular lorazepam (0.5–1.0 mg), required on several occasions; quetiapine (125 mg daily) combined with citalopram (20 mg daily), both subsequently stopped as not effective; replaced by aripiprazole (15 mg daily), also ineffective and replaced by oral zuclopenthixol, (increased to 18 mg daily). After 2 weeks on this dose of zuclopenthixol and nearly 4 months on the acute psychiatric ward, although the patient was no longer expressing delusion ideas regarding, her husband having an affair her presentation had, if anything, worsened with regard to her agitation and aggression, throwing a chair, banging on the doors, hitting out at staff and asking for her mother. The decision was made to switch apixaban to dabigatran as an alternative DOAC. The rationale was that there had been no other obvious precipitating factors that might explain the relatively sudden and persistent deterioration in the patient’s mental state and the temporal relationship with starting apixaban. She became markedly more settled over the next 2 weeks, no longer banging on doors or wanting to leave. She acknowledged feeling more calm and relaxed. There were no longer concerns regarding her mood or sleep. This was in the absence of any other behavioural approach, medication or management changes.
Outcome and follow-up
The patient was discharged to a local care home, which would not have been considered possible prior to her switching anticoagulant medication and appearing far less agitated and aggressive. She was significantly more settled and her presentation was of mild dementia. Treatment with antipsychotic medication had been effective for her delusional beliefs throughout her admission and she continued treatment with clopixol (18 mg daily). The management plan was to reduce this while monitoring her mental state for any re-emergence of BPSD agitation and aggression. After a month, both she and her husband were enquiring about the possibility of her returning home.
Case presentation 2
The second case is of a man in his early 70s, described by his family as having some mild memory problems and confusion at times although managing his activities of daily living well enough. He did not think it severe enough to bother his general practitioner (GP). However, approximately a month after commencing rivaroxaban for AF, he became agitated and more confused. So much so that not only did he present to his GP, who referred him to our MAS, he was in turn referred to our older persons community mental health team, as his apparent BPSD had worsened rapidly. He had become physically threatening and aggressive towards his wife and daughters. He was assessed and admitted under the MHA and received a working diagnosis of advanced dementia. This led to trials of treatment with a variety of psychotropic medications. His apparent BPSD appeared to be treatment resistant and his presentation worsened.
At the time, in 2016, there were no side effects listed for rivaroxaban in the BNF which might have suggested the potential for worsening of mental state or cognition. However, in the absence of any other identifiable psychosocial or pathophysiological causes or changes to medication, we switched rivaroxaban to warfarin. We saw a significant improvement in the patient’s presentation within 2 weeks. Importantly, further improvements were noted on gradually reducing and discontinuing the psychotropic medications that were being prescribed in an attempt to manage his change in behaviour. This patient had also became settled sufficiently to be discharged. He caught the bus home, a fact he was able to recount to us in clinic a month later when his clinical presentation was also of mild dementia.
Discussion
Front-line healthcare staff in acute settings and the community manage a heavy workload. It is all too easy to overlook potential neuropsychiatric drug side effects, especially if they are not clearly listed. They may be easily missed among older patients and wrongly attributed to dementia.
Rivaroxaban is structurally related to the antibiotic linezolid, which has been reported to cause mitochondrial toxicity.3 Premarketing in vitro studies concluded the risk of mitochondrial toxicity associated with this anticoagulant to be low.4 However, a more recent in vitro study, using rat kidney mitochondria, reported evidence of mitochondrial swelling and a collapse of the membrane potential following exposure to low doses of rivaroxaban.5 The effect of apixaban, which is structurally related to rivaroxaban, has yet to be investigated on mitochondrial function.6
Recent research supports not only an association between reduced cerebral mitochondrial function and neuropsychiatric symptoms and disorders, but also the aetiological role it may play.7
There is a need for a far greater awareness and understanding of the potential cerebral mitochondrial toxicity of drugs commonly prescribed to our older populations. These are numerous and include, for example, some of the drugs prescribed for diabetes (metformin) and raised cholesterol (statins) as well as many of those prescribed for neuropsychiatric symptoms such as trazadone and sodium valproate.8
Asthenia (abnormal physical weakness or lack of energy) has more recently become listed as a common/very common side effect of rivaroxaban in the BNF. This is presumably as a result of the medicines and healthcare products regulatory agency (MHRA) yellow card reporting of suspected adverse reactions being submitted. This clinical symptom may be associated with mitochondrial toxicity.9 Interestingly, Karlsvik et al reported no increase in the level of fatigue after initiation of treatment with rivaroxaban.10
Further research could enable the compiling of a cerebral mitochondrial toxicity burden scale of drugs, similar to that as already exists for anticholinergic burden on cognitive functioning.11 There are research techniques that can assess cerebral mitochondrial dysfunction using non-invasive brain scanning of lactate levels, which are considered to be a good correlate of mitochondrial function.12 Such a scale could inform clinical decision making, switching patients to drugs that are potentially less toxic to cerebral mitochondria, when appropriate.
We may then be able to significantly improve quality of life and reduce the burden and cost for patients, their carers, psychiatric services and the social care system by potentially avoiding psychiatric admission and placement in dementia care homes with fees, in the UK of between £34 000 (residential) and £47 000 (nursing) per annum.13
Patient’s perspective
Something changed when I was in hospital after my fall, something wasn’t right. I feel calmer and much better now, ready to go back home with my husband.
Learning points
Consider drug-induced neuropsychiatric symptoms in older patients with suspected behavioural and psychological symptoms of dementia (BPSD). Avoid assuming that their worsening presentation is necessarily secondary to cerebral emboli because they have a degree of vascular pathology on brain imaging and are in atrial fibrillation.
Older patients are particularly prone to experiencing neuropsychiatric side effects of drugs that may not have been apparent during preclinical trials. Polypharmacy and associated drug interactions are also more common. All front-line staff should be encouraged to discuss with colleagues any medicine safety concerns, which can be particularly hard to unpick from BPSD, and to report these via the medicines and healthcare products regulatory agency yellow card system, for example.
Neuropsychiatric symptoms and disorders are known to be associated with reduced cerebral mitochondrial function. There is an increasing body of research supporting that this relationship is aetiological. If so, any further drug-induced impairment of cerebral mitochondrial function could, therefore, be expected to precipitate or exacerbate such symptoms or disorders already present potentially.
An increased awareness of which drugs are less toxic to cerebral mitochondria, with the development of a rating scale for example, could inform prescribing guidelines (National Institute for Health and Care Excellence) and safer treatments being offered to older people, reducing the likely hood of them experiencing apparent BPSD and requiring psychiatric detention.
Contributors: IPH, KMFP, SDS and RG conceived the case review article. KMFP, SDS and RG where directly involved in the clinical management of the two cases cited. IPH shared his expert knowledge of the potential mitochondrial toxicity of drugs. KMFP carried out the literature search. RG and KMFP drafted the first manuscript. All authors contributed to revising and approving the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Oral | DrugAdministrationRoute | CC BY-NC | 33685912 | 19,421,458 | 2021-03-08 |
What was the administration route of drug 'LORAZEPAM'? | Treatment with the direct oral anticoagulants (DOACs) apixaban and rivaroxaban associated with significant worsening of behavioural and psychological symptoms of dementia (BPSD).
We report the cases of two patients who developed worsening behavioural and psychological symptoms of dementia (BPSD), coinciding with starting the factor Xa inhibitor direct oral anticoagulant medications apixaban and rivaroxaban, respectively. Both patients required detaining under the Mental Health Act. Their symptoms improved significantly, within 2 weeks, on switching to alternative anticoagulant therapies and they were both discharged from the acute psychiatric ward. Front-line staff should partake in postmarketing surveillance of medications, completing the Medicines and Healthcare products Regulatory Agency yellow cards for example (UK). There is increasing evidence for an aetiological role of cerebral mitochondrial dysfunction in neuropsychiatric disorders. Development of a rating scale of drugs that are potentially less toxic to cerebral mitochondria could inform national prescribing guidelines and enable safer treatments to be offered to older people, reducing the likely hood of them experiencing apparent BPSD.
Background
Globally, the estimated proportion of the general population aged 60 and over with dementia is between 5% and 8% equating to around 50 million people. There are nearly 10 million new cases every year.1 Ischaemic heart disease and stroke are the biggest cause of death worldwide.2 Factor Xa inhibitor direct oral anticoagulants (DOACs) have become widely prescribed over recent years in the UK, being included as drugs recommended by the National Institute for Health and Care Excellence as achieving anticoagulation in prevention of systemic emboli in patients in atrial fibrillation (AF) or with deep vein thrombosis. A significant proportion of the population with mild cognitive impairment or dementia are, therefore, also treated with DOAC’s for these coexistent diagnoses. In our experience locally, reflecting changing practice throughout the developed world, many patients are being switched from warfarin to factor Xa inhibitor DOACs, which do not require close monitoring of blood levels. Despite no listed neuropsychiatric side effects in the British National Formulary (BNF) for these, we suspected that these two patients were experiencing iatrogenic worsening of their behavioural and psychological symptoms of dementia (BPSD). We hypothesise that similar factor Xa inhibitor side effects are experienced by many older people to a varying degree and wrongly attributed to BPSD.
Case presentation 1
A woman in her early 80s was admitted to her local District General Hospital (DGH) following a fall. She was found to have a pulmonary embolus (PE) and to be in AF. She was commenced on apixaban. During this admission, staff raised concerns about her memory and on discharge, referred her to the local memory assessment service (MAS). Following initial MAS assessment approximately 3 weeks later, the patient was commenced on the antidepressant mirtazapine for low mood and poor sleep. However, after a further 3 weeks, she was brought to the liaison department at the DGH following physically assaulting police officers and paramedics. Her husband confirmed a deterioration in his wife’s memory over 6 months with her becoming repetitive in conversation and forgetting who some of the neighbours were. She had also started to accuse him of having an affair and steeling her money over these months. He denied this saying that they spent nearly all their time together. However, he indicated that there had been a noticeable worsening of her presentation following her hospital admission 6 weeks before with a PE, with her becoming physically aggressive since, assaulting him on multiple occasions and calling the police frequently. He explained that he had had to lock himself in the bathroom that day for his own safety. At interview, the patient reported low mood and poor sleep since the alleged affair, saying that she had seen this person and found a slip in her husband’s pocket. Her mood was labile, alternating between irritability and tearfulness. She was noted to be repetitive in conversation with poor recall of recent events. Her insight was poor although she was aware of recent memory difficulties. She was assessed and admitted under section 2 of the Mental Health Act (MHA) with a provisional diagnosis of delusional jealousy in the context of likely dementia.
Investigations
Physical examination was unremarkable. Medications included apixaban (5 mg two times per day), bisoprolol (2.5 mg two times per day), digoxin (125 μg one time per day) and glyceryl trinitrate spray as required. A dementia blood screen was normal. An MRI head scan showed minor generalised cerebral atrophy with a few foci within the supratentorial white matter reported as likely age related ischaemic phenomena. The patient scored 70/100 on the Addenbrooke’s cognitive examination, losing marks in the memory domain and suggestive of at least mild dementia.
Management
Mirtazapine was stopped as the patient’s agitation and aggression had only worsened. Subsequent trials of medication to manage this included intramuscular lorazepam (0.5–1.0 mg), required on several occasions; quetiapine (125 mg daily) combined with citalopram (20 mg daily), both subsequently stopped as not effective; replaced by aripiprazole (15 mg daily), also ineffective and replaced by oral zuclopenthixol, (increased to 18 mg daily). After 2 weeks on this dose of zuclopenthixol and nearly 4 months on the acute psychiatric ward, although the patient was no longer expressing delusion ideas regarding, her husband having an affair her presentation had, if anything, worsened with regard to her agitation and aggression, throwing a chair, banging on the doors, hitting out at staff and asking for her mother. The decision was made to switch apixaban to dabigatran as an alternative DOAC. The rationale was that there had been no other obvious precipitating factors that might explain the relatively sudden and persistent deterioration in the patient’s mental state and the temporal relationship with starting apixaban. She became markedly more settled over the next 2 weeks, no longer banging on doors or wanting to leave. She acknowledged feeling more calm and relaxed. There were no longer concerns regarding her mood or sleep. This was in the absence of any other behavioural approach, medication or management changes.
Outcome and follow-up
The patient was discharged to a local care home, which would not have been considered possible prior to her switching anticoagulant medication and appearing far less agitated and aggressive. She was significantly more settled and her presentation was of mild dementia. Treatment with antipsychotic medication had been effective for her delusional beliefs throughout her admission and she continued treatment with clopixol (18 mg daily). The management plan was to reduce this while monitoring her mental state for any re-emergence of BPSD agitation and aggression. After a month, both she and her husband were enquiring about the possibility of her returning home.
Case presentation 2
The second case is of a man in his early 70s, described by his family as having some mild memory problems and confusion at times although managing his activities of daily living well enough. He did not think it severe enough to bother his general practitioner (GP). However, approximately a month after commencing rivaroxaban for AF, he became agitated and more confused. So much so that not only did he present to his GP, who referred him to our MAS, he was in turn referred to our older persons community mental health team, as his apparent BPSD had worsened rapidly. He had become physically threatening and aggressive towards his wife and daughters. He was assessed and admitted under the MHA and received a working diagnosis of advanced dementia. This led to trials of treatment with a variety of psychotropic medications. His apparent BPSD appeared to be treatment resistant and his presentation worsened.
At the time, in 2016, there were no side effects listed for rivaroxaban in the BNF which might have suggested the potential for worsening of mental state or cognition. However, in the absence of any other identifiable psychosocial or pathophysiological causes or changes to medication, we switched rivaroxaban to warfarin. We saw a significant improvement in the patient’s presentation within 2 weeks. Importantly, further improvements were noted on gradually reducing and discontinuing the psychotropic medications that were being prescribed in an attempt to manage his change in behaviour. This patient had also became settled sufficiently to be discharged. He caught the bus home, a fact he was able to recount to us in clinic a month later when his clinical presentation was also of mild dementia.
Discussion
Front-line healthcare staff in acute settings and the community manage a heavy workload. It is all too easy to overlook potential neuropsychiatric drug side effects, especially if they are not clearly listed. They may be easily missed among older patients and wrongly attributed to dementia.
Rivaroxaban is structurally related to the antibiotic linezolid, which has been reported to cause mitochondrial toxicity.3 Premarketing in vitro studies concluded the risk of mitochondrial toxicity associated with this anticoagulant to be low.4 However, a more recent in vitro study, using rat kidney mitochondria, reported evidence of mitochondrial swelling and a collapse of the membrane potential following exposure to low doses of rivaroxaban.5 The effect of apixaban, which is structurally related to rivaroxaban, has yet to be investigated on mitochondrial function.6
Recent research supports not only an association between reduced cerebral mitochondrial function and neuropsychiatric symptoms and disorders, but also the aetiological role it may play.7
There is a need for a far greater awareness and understanding of the potential cerebral mitochondrial toxicity of drugs commonly prescribed to our older populations. These are numerous and include, for example, some of the drugs prescribed for diabetes (metformin) and raised cholesterol (statins) as well as many of those prescribed for neuropsychiatric symptoms such as trazadone and sodium valproate.8
Asthenia (abnormal physical weakness or lack of energy) has more recently become listed as a common/very common side effect of rivaroxaban in the BNF. This is presumably as a result of the medicines and healthcare products regulatory agency (MHRA) yellow card reporting of suspected adverse reactions being submitted. This clinical symptom may be associated with mitochondrial toxicity.9 Interestingly, Karlsvik et al reported no increase in the level of fatigue after initiation of treatment with rivaroxaban.10
Further research could enable the compiling of a cerebral mitochondrial toxicity burden scale of drugs, similar to that as already exists for anticholinergic burden on cognitive functioning.11 There are research techniques that can assess cerebral mitochondrial dysfunction using non-invasive brain scanning of lactate levels, which are considered to be a good correlate of mitochondrial function.12 Such a scale could inform clinical decision making, switching patients to drugs that are potentially less toxic to cerebral mitochondria, when appropriate.
We may then be able to significantly improve quality of life and reduce the burden and cost for patients, their carers, psychiatric services and the social care system by potentially avoiding psychiatric admission and placement in dementia care homes with fees, in the UK of between £34 000 (residential) and £47 000 (nursing) per annum.13
Patient’s perspective
Something changed when I was in hospital after my fall, something wasn’t right. I feel calmer and much better now, ready to go back home with my husband.
Learning points
Consider drug-induced neuropsychiatric symptoms in older patients with suspected behavioural and psychological symptoms of dementia (BPSD). Avoid assuming that their worsening presentation is necessarily secondary to cerebral emboli because they have a degree of vascular pathology on brain imaging and are in atrial fibrillation.
Older patients are particularly prone to experiencing neuropsychiatric side effects of drugs that may not have been apparent during preclinical trials. Polypharmacy and associated drug interactions are also more common. All front-line staff should be encouraged to discuss with colleagues any medicine safety concerns, which can be particularly hard to unpick from BPSD, and to report these via the medicines and healthcare products regulatory agency yellow card system, for example.
Neuropsychiatric symptoms and disorders are known to be associated with reduced cerebral mitochondrial function. There is an increasing body of research supporting that this relationship is aetiological. If so, any further drug-induced impairment of cerebral mitochondrial function could, therefore, be expected to precipitate or exacerbate such symptoms or disorders already present potentially.
An increased awareness of which drugs are less toxic to cerebral mitochondria, with the development of a rating scale for example, could inform prescribing guidelines (National Institute for Health and Care Excellence) and safer treatments being offered to older people, reducing the likely hood of them experiencing apparent BPSD and requiring psychiatric detention.
Contributors: IPH, KMFP, SDS and RG conceived the case review article. KMFP, SDS and RG where directly involved in the clinical management of the two cases cited. IPH shared his expert knowledge of the potential mitochondrial toxicity of drugs. KMFP carried out the literature search. RG and KMFP drafted the first manuscript. All authors contributed to revising and approving the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Intramuscular | DrugAdministrationRoute | CC BY-NC | 33685912 | 19,421,458 | 2021-03-08 |
What was the administration route of drug 'RIVAROXABAN'? | Treatment with the direct oral anticoagulants (DOACs) apixaban and rivaroxaban associated with significant worsening of behavioural and psychological symptoms of dementia (BPSD).
We report the cases of two patients who developed worsening behavioural and psychological symptoms of dementia (BPSD), coinciding with starting the factor Xa inhibitor direct oral anticoagulant medications apixaban and rivaroxaban, respectively. Both patients required detaining under the Mental Health Act. Their symptoms improved significantly, within 2 weeks, on switching to alternative anticoagulant therapies and they were both discharged from the acute psychiatric ward. Front-line staff should partake in postmarketing surveillance of medications, completing the Medicines and Healthcare products Regulatory Agency yellow cards for example (UK). There is increasing evidence for an aetiological role of cerebral mitochondrial dysfunction in neuropsychiatric disorders. Development of a rating scale of drugs that are potentially less toxic to cerebral mitochondria could inform national prescribing guidelines and enable safer treatments to be offered to older people, reducing the likely hood of them experiencing apparent BPSD.
Background
Globally, the estimated proportion of the general population aged 60 and over with dementia is between 5% and 8% equating to around 50 million people. There are nearly 10 million new cases every year.1 Ischaemic heart disease and stroke are the biggest cause of death worldwide.2 Factor Xa inhibitor direct oral anticoagulants (DOACs) have become widely prescribed over recent years in the UK, being included as drugs recommended by the National Institute for Health and Care Excellence as achieving anticoagulation in prevention of systemic emboli in patients in atrial fibrillation (AF) or with deep vein thrombosis. A significant proportion of the population with mild cognitive impairment or dementia are, therefore, also treated with DOAC’s for these coexistent diagnoses. In our experience locally, reflecting changing practice throughout the developed world, many patients are being switched from warfarin to factor Xa inhibitor DOACs, which do not require close monitoring of blood levels. Despite no listed neuropsychiatric side effects in the British National Formulary (BNF) for these, we suspected that these two patients were experiencing iatrogenic worsening of their behavioural and psychological symptoms of dementia (BPSD). We hypothesise that similar factor Xa inhibitor side effects are experienced by many older people to a varying degree and wrongly attributed to BPSD.
Case presentation 1
A woman in her early 80s was admitted to her local District General Hospital (DGH) following a fall. She was found to have a pulmonary embolus (PE) and to be in AF. She was commenced on apixaban. During this admission, staff raised concerns about her memory and on discharge, referred her to the local memory assessment service (MAS). Following initial MAS assessment approximately 3 weeks later, the patient was commenced on the antidepressant mirtazapine for low mood and poor sleep. However, after a further 3 weeks, she was brought to the liaison department at the DGH following physically assaulting police officers and paramedics. Her husband confirmed a deterioration in his wife’s memory over 6 months with her becoming repetitive in conversation and forgetting who some of the neighbours were. She had also started to accuse him of having an affair and steeling her money over these months. He denied this saying that they spent nearly all their time together. However, he indicated that there had been a noticeable worsening of her presentation following her hospital admission 6 weeks before with a PE, with her becoming physically aggressive since, assaulting him on multiple occasions and calling the police frequently. He explained that he had had to lock himself in the bathroom that day for his own safety. At interview, the patient reported low mood and poor sleep since the alleged affair, saying that she had seen this person and found a slip in her husband’s pocket. Her mood was labile, alternating between irritability and tearfulness. She was noted to be repetitive in conversation with poor recall of recent events. Her insight was poor although she was aware of recent memory difficulties. She was assessed and admitted under section 2 of the Mental Health Act (MHA) with a provisional diagnosis of delusional jealousy in the context of likely dementia.
Investigations
Physical examination was unremarkable. Medications included apixaban (5 mg two times per day), bisoprolol (2.5 mg two times per day), digoxin (125 μg one time per day) and glyceryl trinitrate spray as required. A dementia blood screen was normal. An MRI head scan showed minor generalised cerebral atrophy with a few foci within the supratentorial white matter reported as likely age related ischaemic phenomena. The patient scored 70/100 on the Addenbrooke’s cognitive examination, losing marks in the memory domain and suggestive of at least mild dementia.
Management
Mirtazapine was stopped as the patient’s agitation and aggression had only worsened. Subsequent trials of medication to manage this included intramuscular lorazepam (0.5–1.0 mg), required on several occasions; quetiapine (125 mg daily) combined with citalopram (20 mg daily), both subsequently stopped as not effective; replaced by aripiprazole (15 mg daily), also ineffective and replaced by oral zuclopenthixol, (increased to 18 mg daily). After 2 weeks on this dose of zuclopenthixol and nearly 4 months on the acute psychiatric ward, although the patient was no longer expressing delusion ideas regarding, her husband having an affair her presentation had, if anything, worsened with regard to her agitation and aggression, throwing a chair, banging on the doors, hitting out at staff and asking for her mother. The decision was made to switch apixaban to dabigatran as an alternative DOAC. The rationale was that there had been no other obvious precipitating factors that might explain the relatively sudden and persistent deterioration in the patient’s mental state and the temporal relationship with starting apixaban. She became markedly more settled over the next 2 weeks, no longer banging on doors or wanting to leave. She acknowledged feeling more calm and relaxed. There were no longer concerns regarding her mood or sleep. This was in the absence of any other behavioural approach, medication or management changes.
Outcome and follow-up
The patient was discharged to a local care home, which would not have been considered possible prior to her switching anticoagulant medication and appearing far less agitated and aggressive. She was significantly more settled and her presentation was of mild dementia. Treatment with antipsychotic medication had been effective for her delusional beliefs throughout her admission and she continued treatment with clopixol (18 mg daily). The management plan was to reduce this while monitoring her mental state for any re-emergence of BPSD agitation and aggression. After a month, both she and her husband were enquiring about the possibility of her returning home.
Case presentation 2
The second case is of a man in his early 70s, described by his family as having some mild memory problems and confusion at times although managing his activities of daily living well enough. He did not think it severe enough to bother his general practitioner (GP). However, approximately a month after commencing rivaroxaban for AF, he became agitated and more confused. So much so that not only did he present to his GP, who referred him to our MAS, he was in turn referred to our older persons community mental health team, as his apparent BPSD had worsened rapidly. He had become physically threatening and aggressive towards his wife and daughters. He was assessed and admitted under the MHA and received a working diagnosis of advanced dementia. This led to trials of treatment with a variety of psychotropic medications. His apparent BPSD appeared to be treatment resistant and his presentation worsened.
At the time, in 2016, there were no side effects listed for rivaroxaban in the BNF which might have suggested the potential for worsening of mental state or cognition. However, in the absence of any other identifiable psychosocial or pathophysiological causes or changes to medication, we switched rivaroxaban to warfarin. We saw a significant improvement in the patient’s presentation within 2 weeks. Importantly, further improvements were noted on gradually reducing and discontinuing the psychotropic medications that were being prescribed in an attempt to manage his change in behaviour. This patient had also became settled sufficiently to be discharged. He caught the bus home, a fact he was able to recount to us in clinic a month later when his clinical presentation was also of mild dementia.
Discussion
Front-line healthcare staff in acute settings and the community manage a heavy workload. It is all too easy to overlook potential neuropsychiatric drug side effects, especially if they are not clearly listed. They may be easily missed among older patients and wrongly attributed to dementia.
Rivaroxaban is structurally related to the antibiotic linezolid, which has been reported to cause mitochondrial toxicity.3 Premarketing in vitro studies concluded the risk of mitochondrial toxicity associated with this anticoagulant to be low.4 However, a more recent in vitro study, using rat kidney mitochondria, reported evidence of mitochondrial swelling and a collapse of the membrane potential following exposure to low doses of rivaroxaban.5 The effect of apixaban, which is structurally related to rivaroxaban, has yet to be investigated on mitochondrial function.6
Recent research supports not only an association between reduced cerebral mitochondrial function and neuropsychiatric symptoms and disorders, but also the aetiological role it may play.7
There is a need for a far greater awareness and understanding of the potential cerebral mitochondrial toxicity of drugs commonly prescribed to our older populations. These are numerous and include, for example, some of the drugs prescribed for diabetes (metformin) and raised cholesterol (statins) as well as many of those prescribed for neuropsychiatric symptoms such as trazadone and sodium valproate.8
Asthenia (abnormal physical weakness or lack of energy) has more recently become listed as a common/very common side effect of rivaroxaban in the BNF. This is presumably as a result of the medicines and healthcare products regulatory agency (MHRA) yellow card reporting of suspected adverse reactions being submitted. This clinical symptom may be associated with mitochondrial toxicity.9 Interestingly, Karlsvik et al reported no increase in the level of fatigue after initiation of treatment with rivaroxaban.10
Further research could enable the compiling of a cerebral mitochondrial toxicity burden scale of drugs, similar to that as already exists for anticholinergic burden on cognitive functioning.11 There are research techniques that can assess cerebral mitochondrial dysfunction using non-invasive brain scanning of lactate levels, which are considered to be a good correlate of mitochondrial function.12 Such a scale could inform clinical decision making, switching patients to drugs that are potentially less toxic to cerebral mitochondria, when appropriate.
We may then be able to significantly improve quality of life and reduce the burden and cost for patients, their carers, psychiatric services and the social care system by potentially avoiding psychiatric admission and placement in dementia care homes with fees, in the UK of between £34 000 (residential) and £47 000 (nursing) per annum.13
Patient’s perspective
Something changed when I was in hospital after my fall, something wasn’t right. I feel calmer and much better now, ready to go back home with my husband.
Learning points
Consider drug-induced neuropsychiatric symptoms in older patients with suspected behavioural and psychological symptoms of dementia (BPSD). Avoid assuming that their worsening presentation is necessarily secondary to cerebral emboli because they have a degree of vascular pathology on brain imaging and are in atrial fibrillation.
Older patients are particularly prone to experiencing neuropsychiatric side effects of drugs that may not have been apparent during preclinical trials. Polypharmacy and associated drug interactions are also more common. All front-line staff should be encouraged to discuss with colleagues any medicine safety concerns, which can be particularly hard to unpick from BPSD, and to report these via the medicines and healthcare products regulatory agency yellow card system, for example.
Neuropsychiatric symptoms and disorders are known to be associated with reduced cerebral mitochondrial function. There is an increasing body of research supporting that this relationship is aetiological. If so, any further drug-induced impairment of cerebral mitochondrial function could, therefore, be expected to precipitate or exacerbate such symptoms or disorders already present potentially.
An increased awareness of which drugs are less toxic to cerebral mitochondria, with the development of a rating scale for example, could inform prescribing guidelines (National Institute for Health and Care Excellence) and safer treatments being offered to older people, reducing the likely hood of them experiencing apparent BPSD and requiring psychiatric detention.
Contributors: IPH, KMFP, SDS and RG conceived the case review article. KMFP, SDS and RG where directly involved in the clinical management of the two cases cited. IPH shared his expert knowledge of the potential mitochondrial toxicity of drugs. KMFP carried out the literature search. RG and KMFP drafted the first manuscript. All authors contributed to revising and approving the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Oral | DrugAdministrationRoute | CC BY-NC | 33685912 | 19,024,234 | 2021-03-08 |
What was the administration route of drug 'ZUCLOPENTHIXOL'? | Treatment with the direct oral anticoagulants (DOACs) apixaban and rivaroxaban associated with significant worsening of behavioural and psychological symptoms of dementia (BPSD).
We report the cases of two patients who developed worsening behavioural and psychological symptoms of dementia (BPSD), coinciding with starting the factor Xa inhibitor direct oral anticoagulant medications apixaban and rivaroxaban, respectively. Both patients required detaining under the Mental Health Act. Their symptoms improved significantly, within 2 weeks, on switching to alternative anticoagulant therapies and they were both discharged from the acute psychiatric ward. Front-line staff should partake in postmarketing surveillance of medications, completing the Medicines and Healthcare products Regulatory Agency yellow cards for example (UK). There is increasing evidence for an aetiological role of cerebral mitochondrial dysfunction in neuropsychiatric disorders. Development of a rating scale of drugs that are potentially less toxic to cerebral mitochondria could inform national prescribing guidelines and enable safer treatments to be offered to older people, reducing the likely hood of them experiencing apparent BPSD.
Background
Globally, the estimated proportion of the general population aged 60 and over with dementia is between 5% and 8% equating to around 50 million people. There are nearly 10 million new cases every year.1 Ischaemic heart disease and stroke are the biggest cause of death worldwide.2 Factor Xa inhibitor direct oral anticoagulants (DOACs) have become widely prescribed over recent years in the UK, being included as drugs recommended by the National Institute for Health and Care Excellence as achieving anticoagulation in prevention of systemic emboli in patients in atrial fibrillation (AF) or with deep vein thrombosis. A significant proportion of the population with mild cognitive impairment or dementia are, therefore, also treated with DOAC’s for these coexistent diagnoses. In our experience locally, reflecting changing practice throughout the developed world, many patients are being switched from warfarin to factor Xa inhibitor DOACs, which do not require close monitoring of blood levels. Despite no listed neuropsychiatric side effects in the British National Formulary (BNF) for these, we suspected that these two patients were experiencing iatrogenic worsening of their behavioural and psychological symptoms of dementia (BPSD). We hypothesise that similar factor Xa inhibitor side effects are experienced by many older people to a varying degree and wrongly attributed to BPSD.
Case presentation 1
A woman in her early 80s was admitted to her local District General Hospital (DGH) following a fall. She was found to have a pulmonary embolus (PE) and to be in AF. She was commenced on apixaban. During this admission, staff raised concerns about her memory and on discharge, referred her to the local memory assessment service (MAS). Following initial MAS assessment approximately 3 weeks later, the patient was commenced on the antidepressant mirtazapine for low mood and poor sleep. However, after a further 3 weeks, she was brought to the liaison department at the DGH following physically assaulting police officers and paramedics. Her husband confirmed a deterioration in his wife’s memory over 6 months with her becoming repetitive in conversation and forgetting who some of the neighbours were. She had also started to accuse him of having an affair and steeling her money over these months. He denied this saying that they spent nearly all their time together. However, he indicated that there had been a noticeable worsening of her presentation following her hospital admission 6 weeks before with a PE, with her becoming physically aggressive since, assaulting him on multiple occasions and calling the police frequently. He explained that he had had to lock himself in the bathroom that day for his own safety. At interview, the patient reported low mood and poor sleep since the alleged affair, saying that she had seen this person and found a slip in her husband’s pocket. Her mood was labile, alternating between irritability and tearfulness. She was noted to be repetitive in conversation with poor recall of recent events. Her insight was poor although she was aware of recent memory difficulties. She was assessed and admitted under section 2 of the Mental Health Act (MHA) with a provisional diagnosis of delusional jealousy in the context of likely dementia.
Investigations
Physical examination was unremarkable. Medications included apixaban (5 mg two times per day), bisoprolol (2.5 mg two times per day), digoxin (125 μg one time per day) and glyceryl trinitrate spray as required. A dementia blood screen was normal. An MRI head scan showed minor generalised cerebral atrophy with a few foci within the supratentorial white matter reported as likely age related ischaemic phenomena. The patient scored 70/100 on the Addenbrooke’s cognitive examination, losing marks in the memory domain and suggestive of at least mild dementia.
Management
Mirtazapine was stopped as the patient’s agitation and aggression had only worsened. Subsequent trials of medication to manage this included intramuscular lorazepam (0.5–1.0 mg), required on several occasions; quetiapine (125 mg daily) combined with citalopram (20 mg daily), both subsequently stopped as not effective; replaced by aripiprazole (15 mg daily), also ineffective and replaced by oral zuclopenthixol, (increased to 18 mg daily). After 2 weeks on this dose of zuclopenthixol and nearly 4 months on the acute psychiatric ward, although the patient was no longer expressing delusion ideas regarding, her husband having an affair her presentation had, if anything, worsened with regard to her agitation and aggression, throwing a chair, banging on the doors, hitting out at staff and asking for her mother. The decision was made to switch apixaban to dabigatran as an alternative DOAC. The rationale was that there had been no other obvious precipitating factors that might explain the relatively sudden and persistent deterioration in the patient’s mental state and the temporal relationship with starting apixaban. She became markedly more settled over the next 2 weeks, no longer banging on doors or wanting to leave. She acknowledged feeling more calm and relaxed. There were no longer concerns regarding her mood or sleep. This was in the absence of any other behavioural approach, medication or management changes.
Outcome and follow-up
The patient was discharged to a local care home, which would not have been considered possible prior to her switching anticoagulant medication and appearing far less agitated and aggressive. She was significantly more settled and her presentation was of mild dementia. Treatment with antipsychotic medication had been effective for her delusional beliefs throughout her admission and she continued treatment with clopixol (18 mg daily). The management plan was to reduce this while monitoring her mental state for any re-emergence of BPSD agitation and aggression. After a month, both she and her husband were enquiring about the possibility of her returning home.
Case presentation 2
The second case is of a man in his early 70s, described by his family as having some mild memory problems and confusion at times although managing his activities of daily living well enough. He did not think it severe enough to bother his general practitioner (GP). However, approximately a month after commencing rivaroxaban for AF, he became agitated and more confused. So much so that not only did he present to his GP, who referred him to our MAS, he was in turn referred to our older persons community mental health team, as his apparent BPSD had worsened rapidly. He had become physically threatening and aggressive towards his wife and daughters. He was assessed and admitted under the MHA and received a working diagnosis of advanced dementia. This led to trials of treatment with a variety of psychotropic medications. His apparent BPSD appeared to be treatment resistant and his presentation worsened.
At the time, in 2016, there were no side effects listed for rivaroxaban in the BNF which might have suggested the potential for worsening of mental state or cognition. However, in the absence of any other identifiable psychosocial or pathophysiological causes or changes to medication, we switched rivaroxaban to warfarin. We saw a significant improvement in the patient’s presentation within 2 weeks. Importantly, further improvements were noted on gradually reducing and discontinuing the psychotropic medications that were being prescribed in an attempt to manage his change in behaviour. This patient had also became settled sufficiently to be discharged. He caught the bus home, a fact he was able to recount to us in clinic a month later when his clinical presentation was also of mild dementia.
Discussion
Front-line healthcare staff in acute settings and the community manage a heavy workload. It is all too easy to overlook potential neuropsychiatric drug side effects, especially if they are not clearly listed. They may be easily missed among older patients and wrongly attributed to dementia.
Rivaroxaban is structurally related to the antibiotic linezolid, which has been reported to cause mitochondrial toxicity.3 Premarketing in vitro studies concluded the risk of mitochondrial toxicity associated with this anticoagulant to be low.4 However, a more recent in vitro study, using rat kidney mitochondria, reported evidence of mitochondrial swelling and a collapse of the membrane potential following exposure to low doses of rivaroxaban.5 The effect of apixaban, which is structurally related to rivaroxaban, has yet to be investigated on mitochondrial function.6
Recent research supports not only an association between reduced cerebral mitochondrial function and neuropsychiatric symptoms and disorders, but also the aetiological role it may play.7
There is a need for a far greater awareness and understanding of the potential cerebral mitochondrial toxicity of drugs commonly prescribed to our older populations. These are numerous and include, for example, some of the drugs prescribed for diabetes (metformin) and raised cholesterol (statins) as well as many of those prescribed for neuropsychiatric symptoms such as trazadone and sodium valproate.8
Asthenia (abnormal physical weakness or lack of energy) has more recently become listed as a common/very common side effect of rivaroxaban in the BNF. This is presumably as a result of the medicines and healthcare products regulatory agency (MHRA) yellow card reporting of suspected adverse reactions being submitted. This clinical symptom may be associated with mitochondrial toxicity.9 Interestingly, Karlsvik et al reported no increase in the level of fatigue after initiation of treatment with rivaroxaban.10
Further research could enable the compiling of a cerebral mitochondrial toxicity burden scale of drugs, similar to that as already exists for anticholinergic burden on cognitive functioning.11 There are research techniques that can assess cerebral mitochondrial dysfunction using non-invasive brain scanning of lactate levels, which are considered to be a good correlate of mitochondrial function.12 Such a scale could inform clinical decision making, switching patients to drugs that are potentially less toxic to cerebral mitochondria, when appropriate.
We may then be able to significantly improve quality of life and reduce the burden and cost for patients, their carers, psychiatric services and the social care system by potentially avoiding psychiatric admission and placement in dementia care homes with fees, in the UK of between £34 000 (residential) and £47 000 (nursing) per annum.13
Patient’s perspective
Something changed when I was in hospital after my fall, something wasn’t right. I feel calmer and much better now, ready to go back home with my husband.
Learning points
Consider drug-induced neuropsychiatric symptoms in older patients with suspected behavioural and psychological symptoms of dementia (BPSD). Avoid assuming that their worsening presentation is necessarily secondary to cerebral emboli because they have a degree of vascular pathology on brain imaging and are in atrial fibrillation.
Older patients are particularly prone to experiencing neuropsychiatric side effects of drugs that may not have been apparent during preclinical trials. Polypharmacy and associated drug interactions are also more common. All front-line staff should be encouraged to discuss with colleagues any medicine safety concerns, which can be particularly hard to unpick from BPSD, and to report these via the medicines and healthcare products regulatory agency yellow card system, for example.
Neuropsychiatric symptoms and disorders are known to be associated with reduced cerebral mitochondrial function. There is an increasing body of research supporting that this relationship is aetiological. If so, any further drug-induced impairment of cerebral mitochondrial function could, therefore, be expected to precipitate or exacerbate such symptoms or disorders already present potentially.
An increased awareness of which drugs are less toxic to cerebral mitochondria, with the development of a rating scale for example, could inform prescribing guidelines (National Institute for Health and Care Excellence) and safer treatments being offered to older people, reducing the likely hood of them experiencing apparent BPSD and requiring psychiatric detention.
Contributors: IPH, KMFP, SDS and RG conceived the case review article. KMFP, SDS and RG where directly involved in the clinical management of the two cases cited. IPH shared his expert knowledge of the potential mitochondrial toxicity of drugs. KMFP carried out the literature search. RG and KMFP drafted the first manuscript. All authors contributed to revising and approving the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Oral | DrugAdministrationRoute | CC BY-NC | 33685912 | 19,052,008 | 2021-03-08 |
What was the outcome of reaction 'Aggression'? | Treatment with the direct oral anticoagulants (DOACs) apixaban and rivaroxaban associated with significant worsening of behavioural and psychological symptoms of dementia (BPSD).
We report the cases of two patients who developed worsening behavioural and psychological symptoms of dementia (BPSD), coinciding with starting the factor Xa inhibitor direct oral anticoagulant medications apixaban and rivaroxaban, respectively. Both patients required detaining under the Mental Health Act. Their symptoms improved significantly, within 2 weeks, on switching to alternative anticoagulant therapies and they were both discharged from the acute psychiatric ward. Front-line staff should partake in postmarketing surveillance of medications, completing the Medicines and Healthcare products Regulatory Agency yellow cards for example (UK). There is increasing evidence for an aetiological role of cerebral mitochondrial dysfunction in neuropsychiatric disorders. Development of a rating scale of drugs that are potentially less toxic to cerebral mitochondria could inform national prescribing guidelines and enable safer treatments to be offered to older people, reducing the likely hood of them experiencing apparent BPSD.
Background
Globally, the estimated proportion of the general population aged 60 and over with dementia is between 5% and 8% equating to around 50 million people. There are nearly 10 million new cases every year.1 Ischaemic heart disease and stroke are the biggest cause of death worldwide.2 Factor Xa inhibitor direct oral anticoagulants (DOACs) have become widely prescribed over recent years in the UK, being included as drugs recommended by the National Institute for Health and Care Excellence as achieving anticoagulation in prevention of systemic emboli in patients in atrial fibrillation (AF) or with deep vein thrombosis. A significant proportion of the population with mild cognitive impairment or dementia are, therefore, also treated with DOAC’s for these coexistent diagnoses. In our experience locally, reflecting changing practice throughout the developed world, many patients are being switched from warfarin to factor Xa inhibitor DOACs, which do not require close monitoring of blood levels. Despite no listed neuropsychiatric side effects in the British National Formulary (BNF) for these, we suspected that these two patients were experiencing iatrogenic worsening of their behavioural and psychological symptoms of dementia (BPSD). We hypothesise that similar factor Xa inhibitor side effects are experienced by many older people to a varying degree and wrongly attributed to BPSD.
Case presentation 1
A woman in her early 80s was admitted to her local District General Hospital (DGH) following a fall. She was found to have a pulmonary embolus (PE) and to be in AF. She was commenced on apixaban. During this admission, staff raised concerns about her memory and on discharge, referred her to the local memory assessment service (MAS). Following initial MAS assessment approximately 3 weeks later, the patient was commenced on the antidepressant mirtazapine for low mood and poor sleep. However, after a further 3 weeks, she was brought to the liaison department at the DGH following physically assaulting police officers and paramedics. Her husband confirmed a deterioration in his wife’s memory over 6 months with her becoming repetitive in conversation and forgetting who some of the neighbours were. She had also started to accuse him of having an affair and steeling her money over these months. He denied this saying that they spent nearly all their time together. However, he indicated that there had been a noticeable worsening of her presentation following her hospital admission 6 weeks before with a PE, with her becoming physically aggressive since, assaulting him on multiple occasions and calling the police frequently. He explained that he had had to lock himself in the bathroom that day for his own safety. At interview, the patient reported low mood and poor sleep since the alleged affair, saying that she had seen this person and found a slip in her husband’s pocket. Her mood was labile, alternating between irritability and tearfulness. She was noted to be repetitive in conversation with poor recall of recent events. Her insight was poor although she was aware of recent memory difficulties. She was assessed and admitted under section 2 of the Mental Health Act (MHA) with a provisional diagnosis of delusional jealousy in the context of likely dementia.
Investigations
Physical examination was unremarkable. Medications included apixaban (5 mg two times per day), bisoprolol (2.5 mg two times per day), digoxin (125 μg one time per day) and glyceryl trinitrate spray as required. A dementia blood screen was normal. An MRI head scan showed minor generalised cerebral atrophy with a few foci within the supratentorial white matter reported as likely age related ischaemic phenomena. The patient scored 70/100 on the Addenbrooke’s cognitive examination, losing marks in the memory domain and suggestive of at least mild dementia.
Management
Mirtazapine was stopped as the patient’s agitation and aggression had only worsened. Subsequent trials of medication to manage this included intramuscular lorazepam (0.5–1.0 mg), required on several occasions; quetiapine (125 mg daily) combined with citalopram (20 mg daily), both subsequently stopped as not effective; replaced by aripiprazole (15 mg daily), also ineffective and replaced by oral zuclopenthixol, (increased to 18 mg daily). After 2 weeks on this dose of zuclopenthixol and nearly 4 months on the acute psychiatric ward, although the patient was no longer expressing delusion ideas regarding, her husband having an affair her presentation had, if anything, worsened with regard to her agitation and aggression, throwing a chair, banging on the doors, hitting out at staff and asking for her mother. The decision was made to switch apixaban to dabigatran as an alternative DOAC. The rationale was that there had been no other obvious precipitating factors that might explain the relatively sudden and persistent deterioration in the patient’s mental state and the temporal relationship with starting apixaban. She became markedly more settled over the next 2 weeks, no longer banging on doors or wanting to leave. She acknowledged feeling more calm and relaxed. There were no longer concerns regarding her mood or sleep. This was in the absence of any other behavioural approach, medication or management changes.
Outcome and follow-up
The patient was discharged to a local care home, which would not have been considered possible prior to her switching anticoagulant medication and appearing far less agitated and aggressive. She was significantly more settled and her presentation was of mild dementia. Treatment with antipsychotic medication had been effective for her delusional beliefs throughout her admission and she continued treatment with clopixol (18 mg daily). The management plan was to reduce this while monitoring her mental state for any re-emergence of BPSD agitation and aggression. After a month, both she and her husband were enquiring about the possibility of her returning home.
Case presentation 2
The second case is of a man in his early 70s, described by his family as having some mild memory problems and confusion at times although managing his activities of daily living well enough. He did not think it severe enough to bother his general practitioner (GP). However, approximately a month after commencing rivaroxaban for AF, he became agitated and more confused. So much so that not only did he present to his GP, who referred him to our MAS, he was in turn referred to our older persons community mental health team, as his apparent BPSD had worsened rapidly. He had become physically threatening and aggressive towards his wife and daughters. He was assessed and admitted under the MHA and received a working diagnosis of advanced dementia. This led to trials of treatment with a variety of psychotropic medications. His apparent BPSD appeared to be treatment resistant and his presentation worsened.
At the time, in 2016, there were no side effects listed for rivaroxaban in the BNF which might have suggested the potential for worsening of mental state or cognition. However, in the absence of any other identifiable psychosocial or pathophysiological causes or changes to medication, we switched rivaroxaban to warfarin. We saw a significant improvement in the patient’s presentation within 2 weeks. Importantly, further improvements were noted on gradually reducing and discontinuing the psychotropic medications that were being prescribed in an attempt to manage his change in behaviour. This patient had also became settled sufficiently to be discharged. He caught the bus home, a fact he was able to recount to us in clinic a month later when his clinical presentation was also of mild dementia.
Discussion
Front-line healthcare staff in acute settings and the community manage a heavy workload. It is all too easy to overlook potential neuropsychiatric drug side effects, especially if they are not clearly listed. They may be easily missed among older patients and wrongly attributed to dementia.
Rivaroxaban is structurally related to the antibiotic linezolid, which has been reported to cause mitochondrial toxicity.3 Premarketing in vitro studies concluded the risk of mitochondrial toxicity associated with this anticoagulant to be low.4 However, a more recent in vitro study, using rat kidney mitochondria, reported evidence of mitochondrial swelling and a collapse of the membrane potential following exposure to low doses of rivaroxaban.5 The effect of apixaban, which is structurally related to rivaroxaban, has yet to be investigated on mitochondrial function.6
Recent research supports not only an association between reduced cerebral mitochondrial function and neuropsychiatric symptoms and disorders, but also the aetiological role it may play.7
There is a need for a far greater awareness and understanding of the potential cerebral mitochondrial toxicity of drugs commonly prescribed to our older populations. These are numerous and include, for example, some of the drugs prescribed for diabetes (metformin) and raised cholesterol (statins) as well as many of those prescribed for neuropsychiatric symptoms such as trazadone and sodium valproate.8
Asthenia (abnormal physical weakness or lack of energy) has more recently become listed as a common/very common side effect of rivaroxaban in the BNF. This is presumably as a result of the medicines and healthcare products regulatory agency (MHRA) yellow card reporting of suspected adverse reactions being submitted. This clinical symptom may be associated with mitochondrial toxicity.9 Interestingly, Karlsvik et al reported no increase in the level of fatigue after initiation of treatment with rivaroxaban.10
Further research could enable the compiling of a cerebral mitochondrial toxicity burden scale of drugs, similar to that as already exists for anticholinergic burden on cognitive functioning.11 There are research techniques that can assess cerebral mitochondrial dysfunction using non-invasive brain scanning of lactate levels, which are considered to be a good correlate of mitochondrial function.12 Such a scale could inform clinical decision making, switching patients to drugs that are potentially less toxic to cerebral mitochondria, when appropriate.
We may then be able to significantly improve quality of life and reduce the burden and cost for patients, their carers, psychiatric services and the social care system by potentially avoiding psychiatric admission and placement in dementia care homes with fees, in the UK of between £34 000 (residential) and £47 000 (nursing) per annum.13
Patient’s perspective
Something changed when I was in hospital after my fall, something wasn’t right. I feel calmer and much better now, ready to go back home with my husband.
Learning points
Consider drug-induced neuropsychiatric symptoms in older patients with suspected behavioural and psychological symptoms of dementia (BPSD). Avoid assuming that their worsening presentation is necessarily secondary to cerebral emboli because they have a degree of vascular pathology on brain imaging and are in atrial fibrillation.
Older patients are particularly prone to experiencing neuropsychiatric side effects of drugs that may not have been apparent during preclinical trials. Polypharmacy and associated drug interactions are also more common. All front-line staff should be encouraged to discuss with colleagues any medicine safety concerns, which can be particularly hard to unpick from BPSD, and to report these via the medicines and healthcare products regulatory agency yellow card system, for example.
Neuropsychiatric symptoms and disorders are known to be associated with reduced cerebral mitochondrial function. There is an increasing body of research supporting that this relationship is aetiological. If so, any further drug-induced impairment of cerebral mitochondrial function could, therefore, be expected to precipitate or exacerbate such symptoms or disorders already present potentially.
An increased awareness of which drugs are less toxic to cerebral mitochondria, with the development of a rating scale for example, could inform prescribing guidelines (National Institute for Health and Care Excellence) and safer treatments being offered to older people, reducing the likely hood of them experiencing apparent BPSD and requiring psychiatric detention.
Contributors: IPH, KMFP, SDS and RG conceived the case review article. KMFP, SDS and RG where directly involved in the clinical management of the two cases cited. IPH shared his expert knowledge of the potential mitochondrial toxicity of drugs. KMFP carried out the literature search. RG and KMFP drafted the first manuscript. All authors contributed to revising and approving the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovering | ReactionOutcome | CC BY-NC | 33685912 | 19,993,400 | 2021-03-08 |
What was the outcome of reaction 'Agitation'? | Treatment with the direct oral anticoagulants (DOACs) apixaban and rivaroxaban associated with significant worsening of behavioural and psychological symptoms of dementia (BPSD).
We report the cases of two patients who developed worsening behavioural and psychological symptoms of dementia (BPSD), coinciding with starting the factor Xa inhibitor direct oral anticoagulant medications apixaban and rivaroxaban, respectively. Both patients required detaining under the Mental Health Act. Their symptoms improved significantly, within 2 weeks, on switching to alternative anticoagulant therapies and they were both discharged from the acute psychiatric ward. Front-line staff should partake in postmarketing surveillance of medications, completing the Medicines and Healthcare products Regulatory Agency yellow cards for example (UK). There is increasing evidence for an aetiological role of cerebral mitochondrial dysfunction in neuropsychiatric disorders. Development of a rating scale of drugs that are potentially less toxic to cerebral mitochondria could inform national prescribing guidelines and enable safer treatments to be offered to older people, reducing the likely hood of them experiencing apparent BPSD.
Background
Globally, the estimated proportion of the general population aged 60 and over with dementia is between 5% and 8% equating to around 50 million people. There are nearly 10 million new cases every year.1 Ischaemic heart disease and stroke are the biggest cause of death worldwide.2 Factor Xa inhibitor direct oral anticoagulants (DOACs) have become widely prescribed over recent years in the UK, being included as drugs recommended by the National Institute for Health and Care Excellence as achieving anticoagulation in prevention of systemic emboli in patients in atrial fibrillation (AF) or with deep vein thrombosis. A significant proportion of the population with mild cognitive impairment or dementia are, therefore, also treated with DOAC’s for these coexistent diagnoses. In our experience locally, reflecting changing practice throughout the developed world, many patients are being switched from warfarin to factor Xa inhibitor DOACs, which do not require close monitoring of blood levels. Despite no listed neuropsychiatric side effects in the British National Formulary (BNF) for these, we suspected that these two patients were experiencing iatrogenic worsening of their behavioural and psychological symptoms of dementia (BPSD). We hypothesise that similar factor Xa inhibitor side effects are experienced by many older people to a varying degree and wrongly attributed to BPSD.
Case presentation 1
A woman in her early 80s was admitted to her local District General Hospital (DGH) following a fall. She was found to have a pulmonary embolus (PE) and to be in AF. She was commenced on apixaban. During this admission, staff raised concerns about her memory and on discharge, referred her to the local memory assessment service (MAS). Following initial MAS assessment approximately 3 weeks later, the patient was commenced on the antidepressant mirtazapine for low mood and poor sleep. However, after a further 3 weeks, she was brought to the liaison department at the DGH following physically assaulting police officers and paramedics. Her husband confirmed a deterioration in his wife’s memory over 6 months with her becoming repetitive in conversation and forgetting who some of the neighbours were. She had also started to accuse him of having an affair and steeling her money over these months. He denied this saying that they spent nearly all their time together. However, he indicated that there had been a noticeable worsening of her presentation following her hospital admission 6 weeks before with a PE, with her becoming physically aggressive since, assaulting him on multiple occasions and calling the police frequently. He explained that he had had to lock himself in the bathroom that day for his own safety. At interview, the patient reported low mood and poor sleep since the alleged affair, saying that she had seen this person and found a slip in her husband’s pocket. Her mood was labile, alternating between irritability and tearfulness. She was noted to be repetitive in conversation with poor recall of recent events. Her insight was poor although she was aware of recent memory difficulties. She was assessed and admitted under section 2 of the Mental Health Act (MHA) with a provisional diagnosis of delusional jealousy in the context of likely dementia.
Investigations
Physical examination was unremarkable. Medications included apixaban (5 mg two times per day), bisoprolol (2.5 mg two times per day), digoxin (125 μg one time per day) and glyceryl trinitrate spray as required. A dementia blood screen was normal. An MRI head scan showed minor generalised cerebral atrophy with a few foci within the supratentorial white matter reported as likely age related ischaemic phenomena. The patient scored 70/100 on the Addenbrooke’s cognitive examination, losing marks in the memory domain and suggestive of at least mild dementia.
Management
Mirtazapine was stopped as the patient’s agitation and aggression had only worsened. Subsequent trials of medication to manage this included intramuscular lorazepam (0.5–1.0 mg), required on several occasions; quetiapine (125 mg daily) combined with citalopram (20 mg daily), both subsequently stopped as not effective; replaced by aripiprazole (15 mg daily), also ineffective and replaced by oral zuclopenthixol, (increased to 18 mg daily). After 2 weeks on this dose of zuclopenthixol and nearly 4 months on the acute psychiatric ward, although the patient was no longer expressing delusion ideas regarding, her husband having an affair her presentation had, if anything, worsened with regard to her agitation and aggression, throwing a chair, banging on the doors, hitting out at staff and asking for her mother. The decision was made to switch apixaban to dabigatran as an alternative DOAC. The rationale was that there had been no other obvious precipitating factors that might explain the relatively sudden and persistent deterioration in the patient’s mental state and the temporal relationship with starting apixaban. She became markedly more settled over the next 2 weeks, no longer banging on doors or wanting to leave. She acknowledged feeling more calm and relaxed. There were no longer concerns regarding her mood or sleep. This was in the absence of any other behavioural approach, medication or management changes.
Outcome and follow-up
The patient was discharged to a local care home, which would not have been considered possible prior to her switching anticoagulant medication and appearing far less agitated and aggressive. She was significantly more settled and her presentation was of mild dementia. Treatment with antipsychotic medication had been effective for her delusional beliefs throughout her admission and she continued treatment with clopixol (18 mg daily). The management plan was to reduce this while monitoring her mental state for any re-emergence of BPSD agitation and aggression. After a month, both she and her husband were enquiring about the possibility of her returning home.
Case presentation 2
The second case is of a man in his early 70s, described by his family as having some mild memory problems and confusion at times although managing his activities of daily living well enough. He did not think it severe enough to bother his general practitioner (GP). However, approximately a month after commencing rivaroxaban for AF, he became agitated and more confused. So much so that not only did he present to his GP, who referred him to our MAS, he was in turn referred to our older persons community mental health team, as his apparent BPSD had worsened rapidly. He had become physically threatening and aggressive towards his wife and daughters. He was assessed and admitted under the MHA and received a working diagnosis of advanced dementia. This led to trials of treatment with a variety of psychotropic medications. His apparent BPSD appeared to be treatment resistant and his presentation worsened.
At the time, in 2016, there were no side effects listed for rivaroxaban in the BNF which might have suggested the potential for worsening of mental state or cognition. However, in the absence of any other identifiable psychosocial or pathophysiological causes or changes to medication, we switched rivaroxaban to warfarin. We saw a significant improvement in the patient’s presentation within 2 weeks. Importantly, further improvements were noted on gradually reducing and discontinuing the psychotropic medications that were being prescribed in an attempt to manage his change in behaviour. This patient had also became settled sufficiently to be discharged. He caught the bus home, a fact he was able to recount to us in clinic a month later when his clinical presentation was also of mild dementia.
Discussion
Front-line healthcare staff in acute settings and the community manage a heavy workload. It is all too easy to overlook potential neuropsychiatric drug side effects, especially if they are not clearly listed. They may be easily missed among older patients and wrongly attributed to dementia.
Rivaroxaban is structurally related to the antibiotic linezolid, which has been reported to cause mitochondrial toxicity.3 Premarketing in vitro studies concluded the risk of mitochondrial toxicity associated with this anticoagulant to be low.4 However, a more recent in vitro study, using rat kidney mitochondria, reported evidence of mitochondrial swelling and a collapse of the membrane potential following exposure to low doses of rivaroxaban.5 The effect of apixaban, which is structurally related to rivaroxaban, has yet to be investigated on mitochondrial function.6
Recent research supports not only an association between reduced cerebral mitochondrial function and neuropsychiatric symptoms and disorders, but also the aetiological role it may play.7
There is a need for a far greater awareness and understanding of the potential cerebral mitochondrial toxicity of drugs commonly prescribed to our older populations. These are numerous and include, for example, some of the drugs prescribed for diabetes (metformin) and raised cholesterol (statins) as well as many of those prescribed for neuropsychiatric symptoms such as trazadone and sodium valproate.8
Asthenia (abnormal physical weakness or lack of energy) has more recently become listed as a common/very common side effect of rivaroxaban in the BNF. This is presumably as a result of the medicines and healthcare products regulatory agency (MHRA) yellow card reporting of suspected adverse reactions being submitted. This clinical symptom may be associated with mitochondrial toxicity.9 Interestingly, Karlsvik et al reported no increase in the level of fatigue after initiation of treatment with rivaroxaban.10
Further research could enable the compiling of a cerebral mitochondrial toxicity burden scale of drugs, similar to that as already exists for anticholinergic burden on cognitive functioning.11 There are research techniques that can assess cerebral mitochondrial dysfunction using non-invasive brain scanning of lactate levels, which are considered to be a good correlate of mitochondrial function.12 Such a scale could inform clinical decision making, switching patients to drugs that are potentially less toxic to cerebral mitochondria, when appropriate.
We may then be able to significantly improve quality of life and reduce the burden and cost for patients, their carers, psychiatric services and the social care system by potentially avoiding psychiatric admission and placement in dementia care homes with fees, in the UK of between £34 000 (residential) and £47 000 (nursing) per annum.13
Patient’s perspective
Something changed when I was in hospital after my fall, something wasn’t right. I feel calmer and much better now, ready to go back home with my husband.
Learning points
Consider drug-induced neuropsychiatric symptoms in older patients with suspected behavioural and psychological symptoms of dementia (BPSD). Avoid assuming that their worsening presentation is necessarily secondary to cerebral emboli because they have a degree of vascular pathology on brain imaging and are in atrial fibrillation.
Older patients are particularly prone to experiencing neuropsychiatric side effects of drugs that may not have been apparent during preclinical trials. Polypharmacy and associated drug interactions are also more common. All front-line staff should be encouraged to discuss with colleagues any medicine safety concerns, which can be particularly hard to unpick from BPSD, and to report these via the medicines and healthcare products regulatory agency yellow card system, for example.
Neuropsychiatric symptoms and disorders are known to be associated with reduced cerebral mitochondrial function. There is an increasing body of research supporting that this relationship is aetiological. If so, any further drug-induced impairment of cerebral mitochondrial function could, therefore, be expected to precipitate or exacerbate such symptoms or disorders already present potentially.
An increased awareness of which drugs are less toxic to cerebral mitochondria, with the development of a rating scale for example, could inform prescribing guidelines (National Institute for Health and Care Excellence) and safer treatments being offered to older people, reducing the likely hood of them experiencing apparent BPSD and requiring psychiatric detention.
Contributors: IPH, KMFP, SDS and RG conceived the case review article. KMFP, SDS and RG where directly involved in the clinical management of the two cases cited. IPH shared his expert knowledge of the potential mitochondrial toxicity of drugs. KMFP carried out the literature search. RG and KMFP drafted the first manuscript. All authors contributed to revising and approving the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovering | ReactionOutcome | CC BY-NC | 33685912 | 19,993,400 | 2021-03-08 |
What was the outcome of reaction 'Condition aggravated'? | Treatment with the direct oral anticoagulants (DOACs) apixaban and rivaroxaban associated with significant worsening of behavioural and psychological symptoms of dementia (BPSD).
We report the cases of two patients who developed worsening behavioural and psychological symptoms of dementia (BPSD), coinciding with starting the factor Xa inhibitor direct oral anticoagulant medications apixaban and rivaroxaban, respectively. Both patients required detaining under the Mental Health Act. Their symptoms improved significantly, within 2 weeks, on switching to alternative anticoagulant therapies and they were both discharged from the acute psychiatric ward. Front-line staff should partake in postmarketing surveillance of medications, completing the Medicines and Healthcare products Regulatory Agency yellow cards for example (UK). There is increasing evidence for an aetiological role of cerebral mitochondrial dysfunction in neuropsychiatric disorders. Development of a rating scale of drugs that are potentially less toxic to cerebral mitochondria could inform national prescribing guidelines and enable safer treatments to be offered to older people, reducing the likely hood of them experiencing apparent BPSD.
Background
Globally, the estimated proportion of the general population aged 60 and over with dementia is between 5% and 8% equating to around 50 million people. There are nearly 10 million new cases every year.1 Ischaemic heart disease and stroke are the biggest cause of death worldwide.2 Factor Xa inhibitor direct oral anticoagulants (DOACs) have become widely prescribed over recent years in the UK, being included as drugs recommended by the National Institute for Health and Care Excellence as achieving anticoagulation in prevention of systemic emboli in patients in atrial fibrillation (AF) or with deep vein thrombosis. A significant proportion of the population with mild cognitive impairment or dementia are, therefore, also treated with DOAC’s for these coexistent diagnoses. In our experience locally, reflecting changing practice throughout the developed world, many patients are being switched from warfarin to factor Xa inhibitor DOACs, which do not require close monitoring of blood levels. Despite no listed neuropsychiatric side effects in the British National Formulary (BNF) for these, we suspected that these two patients were experiencing iatrogenic worsening of their behavioural and psychological symptoms of dementia (BPSD). We hypothesise that similar factor Xa inhibitor side effects are experienced by many older people to a varying degree and wrongly attributed to BPSD.
Case presentation 1
A woman in her early 80s was admitted to her local District General Hospital (DGH) following a fall. She was found to have a pulmonary embolus (PE) and to be in AF. She was commenced on apixaban. During this admission, staff raised concerns about her memory and on discharge, referred her to the local memory assessment service (MAS). Following initial MAS assessment approximately 3 weeks later, the patient was commenced on the antidepressant mirtazapine for low mood and poor sleep. However, after a further 3 weeks, she was brought to the liaison department at the DGH following physically assaulting police officers and paramedics. Her husband confirmed a deterioration in his wife’s memory over 6 months with her becoming repetitive in conversation and forgetting who some of the neighbours were. She had also started to accuse him of having an affair and steeling her money over these months. He denied this saying that they spent nearly all their time together. However, he indicated that there had been a noticeable worsening of her presentation following her hospital admission 6 weeks before with a PE, with her becoming physically aggressive since, assaulting him on multiple occasions and calling the police frequently. He explained that he had had to lock himself in the bathroom that day for his own safety. At interview, the patient reported low mood and poor sleep since the alleged affair, saying that she had seen this person and found a slip in her husband’s pocket. Her mood was labile, alternating between irritability and tearfulness. She was noted to be repetitive in conversation with poor recall of recent events. Her insight was poor although she was aware of recent memory difficulties. She was assessed and admitted under section 2 of the Mental Health Act (MHA) with a provisional diagnosis of delusional jealousy in the context of likely dementia.
Investigations
Physical examination was unremarkable. Medications included apixaban (5 mg two times per day), bisoprolol (2.5 mg two times per day), digoxin (125 μg one time per day) and glyceryl trinitrate spray as required. A dementia blood screen was normal. An MRI head scan showed minor generalised cerebral atrophy with a few foci within the supratentorial white matter reported as likely age related ischaemic phenomena. The patient scored 70/100 on the Addenbrooke’s cognitive examination, losing marks in the memory domain and suggestive of at least mild dementia.
Management
Mirtazapine was stopped as the patient’s agitation and aggression had only worsened. Subsequent trials of medication to manage this included intramuscular lorazepam (0.5–1.0 mg), required on several occasions; quetiapine (125 mg daily) combined with citalopram (20 mg daily), both subsequently stopped as not effective; replaced by aripiprazole (15 mg daily), also ineffective and replaced by oral zuclopenthixol, (increased to 18 mg daily). After 2 weeks on this dose of zuclopenthixol and nearly 4 months on the acute psychiatric ward, although the patient was no longer expressing delusion ideas regarding, her husband having an affair her presentation had, if anything, worsened with regard to her agitation and aggression, throwing a chair, banging on the doors, hitting out at staff and asking for her mother. The decision was made to switch apixaban to dabigatran as an alternative DOAC. The rationale was that there had been no other obvious precipitating factors that might explain the relatively sudden and persistent deterioration in the patient’s mental state and the temporal relationship with starting apixaban. She became markedly more settled over the next 2 weeks, no longer banging on doors or wanting to leave. She acknowledged feeling more calm and relaxed. There were no longer concerns regarding her mood or sleep. This was in the absence of any other behavioural approach, medication or management changes.
Outcome and follow-up
The patient was discharged to a local care home, which would not have been considered possible prior to her switching anticoagulant medication and appearing far less agitated and aggressive. She was significantly more settled and her presentation was of mild dementia. Treatment with antipsychotic medication had been effective for her delusional beliefs throughout her admission and she continued treatment with clopixol (18 mg daily). The management plan was to reduce this while monitoring her mental state for any re-emergence of BPSD agitation and aggression. After a month, both she and her husband were enquiring about the possibility of her returning home.
Case presentation 2
The second case is of a man in his early 70s, described by his family as having some mild memory problems and confusion at times although managing his activities of daily living well enough. He did not think it severe enough to bother his general practitioner (GP). However, approximately a month after commencing rivaroxaban for AF, he became agitated and more confused. So much so that not only did he present to his GP, who referred him to our MAS, he was in turn referred to our older persons community mental health team, as his apparent BPSD had worsened rapidly. He had become physically threatening and aggressive towards his wife and daughters. He was assessed and admitted under the MHA and received a working diagnosis of advanced dementia. This led to trials of treatment with a variety of psychotropic medications. His apparent BPSD appeared to be treatment resistant and his presentation worsened.
At the time, in 2016, there were no side effects listed for rivaroxaban in the BNF which might have suggested the potential for worsening of mental state or cognition. However, in the absence of any other identifiable psychosocial or pathophysiological causes or changes to medication, we switched rivaroxaban to warfarin. We saw a significant improvement in the patient’s presentation within 2 weeks. Importantly, further improvements were noted on gradually reducing and discontinuing the psychotropic medications that were being prescribed in an attempt to manage his change in behaviour. This patient had also became settled sufficiently to be discharged. He caught the bus home, a fact he was able to recount to us in clinic a month later when his clinical presentation was also of mild dementia.
Discussion
Front-line healthcare staff in acute settings and the community manage a heavy workload. It is all too easy to overlook potential neuropsychiatric drug side effects, especially if they are not clearly listed. They may be easily missed among older patients and wrongly attributed to dementia.
Rivaroxaban is structurally related to the antibiotic linezolid, which has been reported to cause mitochondrial toxicity.3 Premarketing in vitro studies concluded the risk of mitochondrial toxicity associated with this anticoagulant to be low.4 However, a more recent in vitro study, using rat kidney mitochondria, reported evidence of mitochondrial swelling and a collapse of the membrane potential following exposure to low doses of rivaroxaban.5 The effect of apixaban, which is structurally related to rivaroxaban, has yet to be investigated on mitochondrial function.6
Recent research supports not only an association between reduced cerebral mitochondrial function and neuropsychiatric symptoms and disorders, but also the aetiological role it may play.7
There is a need for a far greater awareness and understanding of the potential cerebral mitochondrial toxicity of drugs commonly prescribed to our older populations. These are numerous and include, for example, some of the drugs prescribed for diabetes (metformin) and raised cholesterol (statins) as well as many of those prescribed for neuropsychiatric symptoms such as trazadone and sodium valproate.8
Asthenia (abnormal physical weakness or lack of energy) has more recently become listed as a common/very common side effect of rivaroxaban in the BNF. This is presumably as a result of the medicines and healthcare products regulatory agency (MHRA) yellow card reporting of suspected adverse reactions being submitted. This clinical symptom may be associated with mitochondrial toxicity.9 Interestingly, Karlsvik et al reported no increase in the level of fatigue after initiation of treatment with rivaroxaban.10
Further research could enable the compiling of a cerebral mitochondrial toxicity burden scale of drugs, similar to that as already exists for anticholinergic burden on cognitive functioning.11 There are research techniques that can assess cerebral mitochondrial dysfunction using non-invasive brain scanning of lactate levels, which are considered to be a good correlate of mitochondrial function.12 Such a scale could inform clinical decision making, switching patients to drugs that are potentially less toxic to cerebral mitochondria, when appropriate.
We may then be able to significantly improve quality of life and reduce the burden and cost for patients, their carers, psychiatric services and the social care system by potentially avoiding psychiatric admission and placement in dementia care homes with fees, in the UK of between £34 000 (residential) and £47 000 (nursing) per annum.13
Patient’s perspective
Something changed when I was in hospital after my fall, something wasn’t right. I feel calmer and much better now, ready to go back home with my husband.
Learning points
Consider drug-induced neuropsychiatric symptoms in older patients with suspected behavioural and psychological symptoms of dementia (BPSD). Avoid assuming that their worsening presentation is necessarily secondary to cerebral emboli because they have a degree of vascular pathology on brain imaging and are in atrial fibrillation.
Older patients are particularly prone to experiencing neuropsychiatric side effects of drugs that may not have been apparent during preclinical trials. Polypharmacy and associated drug interactions are also more common. All front-line staff should be encouraged to discuss with colleagues any medicine safety concerns, which can be particularly hard to unpick from BPSD, and to report these via the medicines and healthcare products regulatory agency yellow card system, for example.
Neuropsychiatric symptoms and disorders are known to be associated with reduced cerebral mitochondrial function. There is an increasing body of research supporting that this relationship is aetiological. If so, any further drug-induced impairment of cerebral mitochondrial function could, therefore, be expected to precipitate or exacerbate such symptoms or disorders already present potentially.
An increased awareness of which drugs are less toxic to cerebral mitochondria, with the development of a rating scale for example, could inform prescribing guidelines (National Institute for Health and Care Excellence) and safer treatments being offered to older people, reducing the likely hood of them experiencing apparent BPSD and requiring psychiatric detention.
Contributors: IPH, KMFP, SDS and RG conceived the case review article. KMFP, SDS and RG where directly involved in the clinical management of the two cases cited. IPH shared his expert knowledge of the potential mitochondrial toxicity of drugs. KMFP carried out the literature search. RG and KMFP drafted the first manuscript. All authors contributed to revising and approving the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovering | ReactionOutcome | CC BY-NC | 33685912 | 19,422,277 | 2021-03-08 |
What was the outcome of reaction 'Memory impairment'? | Treatment with the direct oral anticoagulants (DOACs) apixaban and rivaroxaban associated with significant worsening of behavioural and psychological symptoms of dementia (BPSD).
We report the cases of two patients who developed worsening behavioural and psychological symptoms of dementia (BPSD), coinciding with starting the factor Xa inhibitor direct oral anticoagulant medications apixaban and rivaroxaban, respectively. Both patients required detaining under the Mental Health Act. Their symptoms improved significantly, within 2 weeks, on switching to alternative anticoagulant therapies and they were both discharged from the acute psychiatric ward. Front-line staff should partake in postmarketing surveillance of medications, completing the Medicines and Healthcare products Regulatory Agency yellow cards for example (UK). There is increasing evidence for an aetiological role of cerebral mitochondrial dysfunction in neuropsychiatric disorders. Development of a rating scale of drugs that are potentially less toxic to cerebral mitochondria could inform national prescribing guidelines and enable safer treatments to be offered to older people, reducing the likely hood of them experiencing apparent BPSD.
Background
Globally, the estimated proportion of the general population aged 60 and over with dementia is between 5% and 8% equating to around 50 million people. There are nearly 10 million new cases every year.1 Ischaemic heart disease and stroke are the biggest cause of death worldwide.2 Factor Xa inhibitor direct oral anticoagulants (DOACs) have become widely prescribed over recent years in the UK, being included as drugs recommended by the National Institute for Health and Care Excellence as achieving anticoagulation in prevention of systemic emboli in patients in atrial fibrillation (AF) or with deep vein thrombosis. A significant proportion of the population with mild cognitive impairment or dementia are, therefore, also treated with DOAC’s for these coexistent diagnoses. In our experience locally, reflecting changing practice throughout the developed world, many patients are being switched from warfarin to factor Xa inhibitor DOACs, which do not require close monitoring of blood levels. Despite no listed neuropsychiatric side effects in the British National Formulary (BNF) for these, we suspected that these two patients were experiencing iatrogenic worsening of their behavioural and psychological symptoms of dementia (BPSD). We hypothesise that similar factor Xa inhibitor side effects are experienced by many older people to a varying degree and wrongly attributed to BPSD.
Case presentation 1
A woman in her early 80s was admitted to her local District General Hospital (DGH) following a fall. She was found to have a pulmonary embolus (PE) and to be in AF. She was commenced on apixaban. During this admission, staff raised concerns about her memory and on discharge, referred her to the local memory assessment service (MAS). Following initial MAS assessment approximately 3 weeks later, the patient was commenced on the antidepressant mirtazapine for low mood and poor sleep. However, after a further 3 weeks, she was brought to the liaison department at the DGH following physically assaulting police officers and paramedics. Her husband confirmed a deterioration in his wife’s memory over 6 months with her becoming repetitive in conversation and forgetting who some of the neighbours were. She had also started to accuse him of having an affair and steeling her money over these months. He denied this saying that they spent nearly all their time together. However, he indicated that there had been a noticeable worsening of her presentation following her hospital admission 6 weeks before with a PE, with her becoming physically aggressive since, assaulting him on multiple occasions and calling the police frequently. He explained that he had had to lock himself in the bathroom that day for his own safety. At interview, the patient reported low mood and poor sleep since the alleged affair, saying that she had seen this person and found a slip in her husband’s pocket. Her mood was labile, alternating between irritability and tearfulness. She was noted to be repetitive in conversation with poor recall of recent events. Her insight was poor although she was aware of recent memory difficulties. She was assessed and admitted under section 2 of the Mental Health Act (MHA) with a provisional diagnosis of delusional jealousy in the context of likely dementia.
Investigations
Physical examination was unremarkable. Medications included apixaban (5 mg two times per day), bisoprolol (2.5 mg two times per day), digoxin (125 μg one time per day) and glyceryl trinitrate spray as required. A dementia blood screen was normal. An MRI head scan showed minor generalised cerebral atrophy with a few foci within the supratentorial white matter reported as likely age related ischaemic phenomena. The patient scored 70/100 on the Addenbrooke’s cognitive examination, losing marks in the memory domain and suggestive of at least mild dementia.
Management
Mirtazapine was stopped as the patient’s agitation and aggression had only worsened. Subsequent trials of medication to manage this included intramuscular lorazepam (0.5–1.0 mg), required on several occasions; quetiapine (125 mg daily) combined with citalopram (20 mg daily), both subsequently stopped as not effective; replaced by aripiprazole (15 mg daily), also ineffective and replaced by oral zuclopenthixol, (increased to 18 mg daily). After 2 weeks on this dose of zuclopenthixol and nearly 4 months on the acute psychiatric ward, although the patient was no longer expressing delusion ideas regarding, her husband having an affair her presentation had, if anything, worsened with regard to her agitation and aggression, throwing a chair, banging on the doors, hitting out at staff and asking for her mother. The decision was made to switch apixaban to dabigatran as an alternative DOAC. The rationale was that there had been no other obvious precipitating factors that might explain the relatively sudden and persistent deterioration in the patient’s mental state and the temporal relationship with starting apixaban. She became markedly more settled over the next 2 weeks, no longer banging on doors or wanting to leave. She acknowledged feeling more calm and relaxed. There were no longer concerns regarding her mood or sleep. This was in the absence of any other behavioural approach, medication or management changes.
Outcome and follow-up
The patient was discharged to a local care home, which would not have been considered possible prior to her switching anticoagulant medication and appearing far less agitated and aggressive. She was significantly more settled and her presentation was of mild dementia. Treatment with antipsychotic medication had been effective for her delusional beliefs throughout her admission and she continued treatment with clopixol (18 mg daily). The management plan was to reduce this while monitoring her mental state for any re-emergence of BPSD agitation and aggression. After a month, both she and her husband were enquiring about the possibility of her returning home.
Case presentation 2
The second case is of a man in his early 70s, described by his family as having some mild memory problems and confusion at times although managing his activities of daily living well enough. He did not think it severe enough to bother his general practitioner (GP). However, approximately a month after commencing rivaroxaban for AF, he became agitated and more confused. So much so that not only did he present to his GP, who referred him to our MAS, he was in turn referred to our older persons community mental health team, as his apparent BPSD had worsened rapidly. He had become physically threatening and aggressive towards his wife and daughters. He was assessed and admitted under the MHA and received a working diagnosis of advanced dementia. This led to trials of treatment with a variety of psychotropic medications. His apparent BPSD appeared to be treatment resistant and his presentation worsened.
At the time, in 2016, there were no side effects listed for rivaroxaban in the BNF which might have suggested the potential for worsening of mental state or cognition. However, in the absence of any other identifiable psychosocial or pathophysiological causes or changes to medication, we switched rivaroxaban to warfarin. We saw a significant improvement in the patient’s presentation within 2 weeks. Importantly, further improvements were noted on gradually reducing and discontinuing the psychotropic medications that were being prescribed in an attempt to manage his change in behaviour. This patient had also became settled sufficiently to be discharged. He caught the bus home, a fact he was able to recount to us in clinic a month later when his clinical presentation was also of mild dementia.
Discussion
Front-line healthcare staff in acute settings and the community manage a heavy workload. It is all too easy to overlook potential neuropsychiatric drug side effects, especially if they are not clearly listed. They may be easily missed among older patients and wrongly attributed to dementia.
Rivaroxaban is structurally related to the antibiotic linezolid, which has been reported to cause mitochondrial toxicity.3 Premarketing in vitro studies concluded the risk of mitochondrial toxicity associated with this anticoagulant to be low.4 However, a more recent in vitro study, using rat kidney mitochondria, reported evidence of mitochondrial swelling and a collapse of the membrane potential following exposure to low doses of rivaroxaban.5 The effect of apixaban, which is structurally related to rivaroxaban, has yet to be investigated on mitochondrial function.6
Recent research supports not only an association between reduced cerebral mitochondrial function and neuropsychiatric symptoms and disorders, but also the aetiological role it may play.7
There is a need for a far greater awareness and understanding of the potential cerebral mitochondrial toxicity of drugs commonly prescribed to our older populations. These are numerous and include, for example, some of the drugs prescribed for diabetes (metformin) and raised cholesterol (statins) as well as many of those prescribed for neuropsychiatric symptoms such as trazadone and sodium valproate.8
Asthenia (abnormal physical weakness or lack of energy) has more recently become listed as a common/very common side effect of rivaroxaban in the BNF. This is presumably as a result of the medicines and healthcare products regulatory agency (MHRA) yellow card reporting of suspected adverse reactions being submitted. This clinical symptom may be associated with mitochondrial toxicity.9 Interestingly, Karlsvik et al reported no increase in the level of fatigue after initiation of treatment with rivaroxaban.10
Further research could enable the compiling of a cerebral mitochondrial toxicity burden scale of drugs, similar to that as already exists for anticholinergic burden on cognitive functioning.11 There are research techniques that can assess cerebral mitochondrial dysfunction using non-invasive brain scanning of lactate levels, which are considered to be a good correlate of mitochondrial function.12 Such a scale could inform clinical decision making, switching patients to drugs that are potentially less toxic to cerebral mitochondria, when appropriate.
We may then be able to significantly improve quality of life and reduce the burden and cost for patients, their carers, psychiatric services and the social care system by potentially avoiding psychiatric admission and placement in dementia care homes with fees, in the UK of between £34 000 (residential) and £47 000 (nursing) per annum.13
Patient’s perspective
Something changed when I was in hospital after my fall, something wasn’t right. I feel calmer and much better now, ready to go back home with my husband.
Learning points
Consider drug-induced neuropsychiatric symptoms in older patients with suspected behavioural and psychological symptoms of dementia (BPSD). Avoid assuming that their worsening presentation is necessarily secondary to cerebral emboli because they have a degree of vascular pathology on brain imaging and are in atrial fibrillation.
Older patients are particularly prone to experiencing neuropsychiatric side effects of drugs that may not have been apparent during preclinical trials. Polypharmacy and associated drug interactions are also more common. All front-line staff should be encouraged to discuss with colleagues any medicine safety concerns, which can be particularly hard to unpick from BPSD, and to report these via the medicines and healthcare products regulatory agency yellow card system, for example.
Neuropsychiatric symptoms and disorders are known to be associated with reduced cerebral mitochondrial function. There is an increasing body of research supporting that this relationship is aetiological. If so, any further drug-induced impairment of cerebral mitochondrial function could, therefore, be expected to precipitate or exacerbate such symptoms or disorders already present potentially.
An increased awareness of which drugs are less toxic to cerebral mitochondria, with the development of a rating scale for example, could inform prescribing guidelines (National Institute for Health and Care Excellence) and safer treatments being offered to older people, reducing the likely hood of them experiencing apparent BPSD and requiring psychiatric detention.
Contributors: IPH, KMFP, SDS and RG conceived the case review article. KMFP, SDS and RG where directly involved in the clinical management of the two cases cited. IPH shared his expert knowledge of the potential mitochondrial toxicity of drugs. KMFP carried out the literature search. RG and KMFP drafted the first manuscript. All authors contributed to revising and approving the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovering | ReactionOutcome | CC BY-NC | 33685912 | 19,993,400 | 2021-03-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acquired gene mutation'. | Monitoring epidermal growth factor receptor C797S mutation in Japanese non-small cell lung cancer patients with serial cell-free DNA evaluation using digital droplet PCR.
Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is effective in treating both naïve and T790M-mutated EGFR-TKI-resistant non-small cell lung cancer patients. The EGFR C797S mutation is the major osimertinib resistance mechanism. The present study monitored the EGFR C797S mutation during osimertinib treatment in Japanese patients using droplet digital PCR (ddPCR). In our first cohort, C797S detection was validated with tumor specimens and/or plasma samples from 26 patients using ddPCR with custom-designed probes detecting and discriminating T790M and C797S in cis and trans positions. In our second cohort, 18 patients with EGFR-T790M who were going to start osimertinib were analyzed using ddPCR by collecting the plasma samples every month from the beginning of the course of osimertinib. In the first cohort, C797S was detected in 15.4% of patients. C797S and T790M in cis and trans positions were distinguished using ddPCR. In the second cohort, serial cfDNA evaluation revealed that the rate of EGFR mutation changes with disease state. Increases of EGFR mutation were detected, including C797S several months before the diagnosis of disease progression. As with the first cohort, C797S and T790M in cis and trans position were distinguished by ddPCR at disease progression. Coincidentally, in the first cohort, next generation sequencing detected NRAS Q61K mutation and the resistance with NRAS Q61K mutation was overcome by trametinib. In the second cohort, serial cfDNA analysis was useful for evaluating bone oligo-progression and local radiation therapy.
1 INTRODUCTION
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKI) inhibit the EGFR and its downstream signaling pathways by binding to the adenosine triphosphate (ATP)‐binding pocket of the EGFR‐tyrosine kinase domain, which strongly suppresses the growth of EGFR‐mutant non–small cell lung cancer (NSCLC) cells. 1 EGFR‐TKI have been shown to prolong the progression‐free survival (PFS) of patients with EGFR‐mutant NSCLC. 2 , 3 However, cancer cells acquire resistance to EGFR‐TKI. One of the resistance mechanisms is via the secondary point mutation Thr790Met (T790M), which decreases the relative binding affinity of TKI to the ATP‐binding site of EGFR. 5 , 6
Osimertinib, a third‐generation EGFR‐TKI, was developed to overcome this resistance by covalently binding to T790M‐mutated EGFR. 7 Its efficacy in T790M‐positive patients with advanced NSCLC has been evaluated in a phase 3 clinical trial. The results showed that the median PFS was significantly longer with osimertinib than that with platinum‐based chemotherapy. 8 However, a wide variety of osimertinib‐resistant mechanisms have been reported (eg, C797S, G796D, L718Q, MET amplification, BRAF V600E mutation, and small‐cell lung cancer [SCLC] transformation). 9 , 10 , 11 , 12 , 13 , 14 C797S is one of the major resistance mechanisms that impair the covalent binding between EGFR and osimertinib. Preclinical model studies suggested some strategies to overcome resistance due to C797S. 15 Therefore, detection of C797S and understanding osimertinib resistance mechanisms are important.
Cell‐free DNA (cfDNA) from plasma samples contains the DNA of malignant tumors. Thus, it is possible to detect EGFR mutations, not only activating mutations but also resistance mutations like T790M from plasma cfDNA. A clinical trial confirmed the efficacy of osimertinib treatment based on EGFR mutation status in plasma cfDNA 16 . Moreover, the amount of cfDNA with EGFR mutation has been reported to change with treatment response and disease progression. 17 , 18 , 19 For example, after EGFR‐TKI treatment, the EGFR mutation becomes negative in plasma cfDNA, whereas after the disease progression, the EGFR mutation becomes positive again. However, EGFR mutation in cfDNA has not been fully evaluated during osimertinib treatment. For example, the mechanism of each EGFR mutation status change (activating mutation, T790M, and C797S) under osimertinib treatment beyond progression or after local radiation therapy remains unknown.
Therefore, in our first cohort we validated the C797S detection from plasma cfDNA using digital droplet PCR (ddPCR) by evaluating the concordance between tissue and plasma clinical samples. In addition to a commercially available independent ddPCR probe for C797S and T790M, a novel original probe set that could detect and distinguish C797S and T790M mutations in cis and trans positions was used. In the second cohort, we checked the EGFR mutation profile (exon 19 deletion, L858R, T790M, and C797S) in the plasma cfDNA during and after the osimertinib treatment in the serial analysis. Serial EGFR mutation examination with cfDNA in the plasma enables early detection of resistance mutation emergence, including EGFR C797S, some months earlier than the radiological progression. Thus, serial monitoring of the EGFR mutation status, including C797S, would be useful in developing an appropriate treatment strategy involving the administration of osimertinib.
2 MATERIALS AND METHODS
2.1 Patients and samples
The first cohort included 60 Japanese patients with NSCLC with EGFR T790M mutation who started osimertinib treatment after the first or second generation EGFR‐TKI treatment in the Department of Thoracic Medical Oncology at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR) from June 2014 to January 2018. Among these patients, 50.0% had EGFR exon 19 deletion, 48.3% had EGFR L858R, and 1.7% had EGFR L861Q. A total of 26 patients agreed to undergo a tumor specimen assay and/or plasma sample analysis after the disease progression.
In the second cohort, 18 Japanese patients with NSCLC with EGFR T790M mutation started osimertinib treatment after the first‐generation or second‐generation EGFR‐TKI treatment at the Cancer Institute Hospital of the JFCR from December 2017 to November 2018. Among them, 83.3% had EGFR exon 19 deletion, and 16.7% had EGFR L858R. Plasma samples were collected almost every month from the start to 6 months after the osimertinib treatment.
The systemic response to osimertinib was evaluated using RECIST v1.1. All patients underwent computed tomography every 2‐3 months, with a few exceptions. All patients provided written informed consent, and this study was approved by the Institutional Review Board of the Cancer Institute Hospital in the JFCR.
2.2 Nucleic acid extraction
DNA was extracted from cytology or histology samples using the cobas EGFR Mutation Test kit (Roche Molecular Systems), the RNeasy Mini Kit (Qiagen), or the DNeasy Blood & Tissue Kit (Qiagen) as per the manufacturer’s instructions. cfDNA was extracted from plasma samples using the Maxwell RSC ccfDNA Plasma Kit (Promega) or the QIAamp MinElute ccfDNA Kit (Qiagen) following the manufacturer’s instructions. DNA concentration was measured using the Qubit dsDNA HS Assay Kit (Invitrogen, Life Technologies) on a Qubit 2.0 Fluorometer (Invitrogen, Life Technologies).
2.3 Digital droplet PCR for detecting C797S
The method used in ddPCR for detecting EGFR exon 19 deletion, L858R, and T790M is described in our previously published report. 20 In brief, a probe was obtained from Riken Genesis to detect C797S. Cycling conditions for PCR were determined according to the manual. Assays were considered positive if ≥10 copies were observed per reaction (20 µL) based on false‐positive droplet counts from human reference genomic DNA (average C797S copies, 2.36). For the detection of cis/trans‐C797S with T790M, novel probes were designed. Forward primer: CATCTGCCTCACCTCCAC, reverse primer: CGTATCTCCCTTCCCTGATTAC. T790M mutation probe: FAM/IBFQ, CA+TC+A+T+GC+A+GC. C797S mutation probe‐1 (c.2390): FAM/IBFQ, CG+GC+T+C+CCTC. C797S mutation probe‐2 (c.2389): FAM/IBFQ, TCGG+C+A+GCCT+C. WT probe: HEX/IBFQ, TCA+TC+A+C+GC+A+GC.
2.4 Deep sequencing
A targeted amplicon sequencing library was prepared by amplifying exon 20 of EGFR by PCR. Paired‐end sequencing (2 × 150 bp) was performed using the MiSeq platform. To test whether the two mutations, T790M and C797S, were located in the same allele (cis) or different alleles (trans), four reference FASTA files with or without these mutations were prepared. The obtained sequence reads were then mapped to these four reference sequences using BLAT and the reads with lowest mismatches were counted.
For the target sequencing analysis, the library was prepared using a Haloplex custom panel (Agilent), which was designed to detect well‐known cancer‐associated somatic mutations. 21 Paired‐end sequencing (2 × 150 bp) was performed on the MiSeq platform. Sequence reads were aligned to the UCSC hg19 reference genome using the Burrows‐Wheeler Aligner (BWA) (version 0.7.10). Read pairs with a mapping quality of <30 and with mismatches of more than 5% of the read length were excluded. Somatic variants were called by in‐house pipeline.
2.5 Establishment of osimertinib‐resistant PC9 cells with NRAS Q61K
PC9 cells, harboring the EGFR del19 mutation, were treated with increasing concentrations of osimertinib for 6‐12 months and several osimertinib‐resistant PC9 cell lines were established. From the in‐house NGS analysis detecting cancer‐related 108 genes, 21 NRAS Q61K mutation was found in osimertinib‐resistant PC9 cells.
2.6 Cell viability assays
We carried out 3‐day cell viability assays by plating 2000 cells per well into black transparent‐bottom 96‐well plates. On the following day, the cells were treated with the indicated TKI across a 10‐dose range from 0.3 nmol/L to 10 μmol/L. After 72 hours of drug treatment, cell viability was measured using the CellTiter‐Glo assay (Promega).
2.7 Statistical analysis
Fisher’s exact and χ2 tests were used for categorical comparison of data, based on group number, and the Mann‐Whitney U‐test was used to compare differences in continuous data. Paired t tests were used to compare differences in continuous and paired data. All P‐values were based on a two‐sided hypothesis. We performed all statistical analyses using the JMP statistical software package 13 (SAS Institute).
3 RESULTS
3.1 Concordance of C797S, T790M mutation detection between tumor cell DNA and plasma cfDNA
Osimertinib‐resistant tumor cell DNA and/or plasma cfDNA of 26 patients was analyzed in the first cohort. Patient characteristics, a flow chart representing the availability of each examination, a summary of treatment history, and the resistance mechanism of 26 patients are shown in Table S1, Figures S1‐S3. C797S was detected by ddPCR in 15.4% (4/26) of patients, and T790M loss was detected in 65.4% (17/26) (Figure 1A). The concordance rate between tumor cell DNA and plasma cell‐free DNA was 88.9% (8/9) for detecting C797S and 100% (9/9) for detecting T790M (Figure 1B).
FIGURE 1 A, Frequency of C797S and T790M loss detected by droplet digital PCR (ddPCR). B, The concordance of T790M and C797S detection with ddPCR between tumor cell DNA and plasma cfDNA. Red: positive. Blue: negative
3.2 Validation to detect and discriminate EGFR‐T790M/C797S in cis and trans positions with droplet digital PCR
We validated the detection of C797S by ddPCR. JFCR163 is a cell line from the specimen of osimertinib‐resistant patient No. 20. The EGFR of this cell line was sequenced, and C797S was detected (Figure 2A). Using this sample, ddPCR was performed and showed “a positive” result in the cis position (Figure 2B). Next, we assayed the sample from patient No. 4 (JFCR‐129) using a custom probe that can distinguish between C797S in the cis and trans positions with T790M (Figure 2C). The results showed that C797S was in the trans position, which was validated by NGS (Figures 2D, 3E and Figure S4).
FIGURE 2 Detection of epidermal growth factor receptor (EGFR) T790M and C797S by droplet digital PCR (ddPCR). Detection of T790M and C797S in the trans position was possible using ddPCR. A, Detection of EGFR T790M and C797S with Sanger sequencing from JFCR163. B, Detection of EGFR C797S mutation with ddPCR from JFCR 163. Mutant positive template is depicted with blue dots. C, Example of our original ddPCR probe to distinguish cis or trans EGFR‐T790M and C797S mutations. T790M mutation was detected as FAM positive with low amplitude and depicted with blue dots. C797S and T790M in cis position was detected as FAM positive with high amplitude and depicted with blue dots. C797S in trans position was detected as both FAM and HEX positive and depicted with yellow dots. D, Sample from patient No. 4 (JFCR‐129‐2) showed yellow dots positive with ddPCR, which indicated the detection of T790M and C797S in the trans position. E, T790M and C797S in the trans position was also confirmed by NGS using the PCR amplified exon 20 of EGFR, the results of JFCR‐129‐2. (JFCR‐129‐1 as a comparison)
FIGURE 3 Detection of NRAS‐Q61K mutation in osimertinib‐resistant case. A, NRAS Q61K was detected from the clinical samples from patient No. 24 with NGS. B, Cell viability assay using osimertinib‐resistant PC9 with NRAS Q61K showed that trametinib and osimertinib combination can overcome the resistance with NRAS Q61K mutation
3.3 NRAS Q61K mutation is an osimertinib‐resistant mechanism, which is overcome with trametinib and osimertinib treatment
While we were analyzing the osimertinib resistance mechanism including C797S in the first cohort, coincidentally NGS sequencing detected the NRAS Q61K mutation in 1 patient (Figure 3A). As an independent experiment, we established osimertinib‐resistant PC9 cells that harbored the NRAS‐Q61K mutation; resistance was overcome with trametinib treatment combined with osimertinib (Figure 3B).
3.4 Fractional abundance of epidermal growth factor receptor mutation including C797S in cfDNA changes with osimertinib treatment response and disease progression
In the second cohort, 18 patients started osimertinib treatment after T790M detection. In 44.4% (8/18) of patients, EGFR‐activating mutation in the plasma cfDNA was positive with ddPCR at least once during the follow‐up period. All patients’ clinical backgrounds are shown in Table S2. The EGFR‐activating mutation tended to be negative, especially when disease was limited to the intrathoracic region and the number of metastatic organs was small.
The fractional abundance chart of the EGFR mutation in 8 patients is depicted in Figures 4 and 5. Pretreatment, EGFR‐activating mutation in the plasma cfDNA was positive in 7 patients, whereas posttreatment, the fractional abundance of EGFR‐activating mutation in plasma cfDNA decreased to almost zero in all 7 patients. Disease progression was confirmed in 6 patients, and 5 of them had EGFR‐activating mutations. EGFR C797S mutation was detected in cfDNA before disease progression in 3 cases. EGFR T790M/C797S in cis and trans positions was also discriminated with ddPCR using our original probes (both case A7 and case A19 harbored EGFR T790M/C797S in cis). Fractional abundance changes of EGFR‐activating mutation are significantly more correlated with the treatment response and disease progression than carcinoembryonic antigen (CEA), a major clinical tumor marker (Figure 6).
FIGURE 4 Fractional abundance chart of epidermal growth factor receptor (EGFR) mutation in 6 patients. Fractional abundance of EGFR mutation is shown on the vertical axis, whereas the days from osimertinib initiation is shown on the horizontal axis. C797S was detected in 1 patient (Case A7) at least once during the follow‐up period. RT, radiation therapy
FIGURE 5 A, Change of fractional abundance of epidermal growth factor receptor (EGFR) mutation in Case A17 is shown. After osimertinib treatment, multiple brain metastasis remained in remission. PET‐CT examination revealed disease progression of left femur bone metastasis. B, Change of fractional abundance of EGFR mutation in Case A19 is shown. After osimertinib treatment, primary lung tumor and other metastasis remained stable with CT examination. MRI examination revealed L5 vertebrae metastasis progression
FIGURE 6 A, Fractional abundance of epidermal growth factor receptor (EGFR)‐activating mutation and carcinoembryonic antigen (CEA) before the osimertinib treatment, best osimertinib response, and disease progression are described in the graph. The two types of vertical axis were shown to estimate the variation precisely. B, Fractional abundance of EGFR‐activating mutation was significantly different between pretreatment and at the time of best response
3.5 Fractional abundance changes of epidermal growth factor receptor mutation in cases of bone oligo‐progression and after a local radiation therapy
We focused on 2 patients. In both cases, EGFR mutation in the plasma cfDNA increased a few months before the radiological progression. It became negative after the local radiation therapy for bone oligo‐progression.
Case A17 was a 56‐year‐old woman with NSCLC with EGFR exon 19 deletion. She was treated with erlotinib; however, the disease progressed with multiple brain metastases. EGFR T790M mutation was confirmed in the plasma cfDNA, and she started osimertinib treatment. The EGFR mutation in the plasma cfDNA became negative and she continued osimertinib treatment. The EGFR mutation in the plasma cfDNA started to increase after 8 months of continuous treatment; however, her routine CT and brain MRI examination did not reveal disease progression. After that, she complained of left leg pain and PET‐CT examination revealed disease progression of left femur bone metastasis; however, the other metastases remained in remission. Local radiation therapy (30 Gy/10 Fr) was performed on the left femur bone for pain control. Consequently, the EGFR mutation in the plasma cfDNA became negative again. The patient continued osimertinib treatment beyond progression, and the disease remained stable for several months without disease progression (Figure 5A).
Case A19 was a 76‐year‐old woman with NSCLC with EGFR exon 19 deletion. Disease progression was confirmed as an S1 vertebrae metastasis under afatinib treatment. The patient started osimertinib after detection of T790M mutation in the plasma cfDNA. The EGFR mutation in the plasma cfDNA became negative but soon increased again. Routine CT scans did not detect disease progression at around 1‐year posttreatment. However, back pain occurred after 8 months of treatment, and repeat MRI examination revealed L5 vertebrae metastasis progression. Local radiation therapy (39 Gy/13 Fr) was performed on the L5 vertebrae for pain control. Consequently, EGFR mutation in the plasma cfDNA decreased to zero, and the patient continued osimertinib treatment beyond progression for 6 months without disease progression (Figure 5B).
4 DISCUSSION
We first validated the C797S detection from plasma cfDNA with ddPCR using clinical samples. The concordance rate between tumor cell DNA and plasma cfDNA was high at disease progression after osimertinib treatment. Then, ddPCR was used to distinguish cis and trans C797S from T790M using novel specific probes. Past reports also showed the efficacy of ddPCR in detecting C797S; 22 , 23 however, the efficacy of ddPCR in distinguishing EGFR‐T790M/C797S in cis and trans, validated with clinical samples, has not been reported. A difference in treatment strategies was observed between T790M and C797S in the cis and trans positions: while brigatinib with an anti–EGFR antibody has been a promising treatment option for tumors with cis‐C797S/T790M, osimertinib combined with gefitinib has been found to be effective against trans‐C797S and T790M. 15 , 24 , 25 Therefore, detection of C797S in the cis and trans positions using ddPCR would be useful in clinical practice. At present, treatment targeting C797S has not been approved in Japan; therefore, we are trying to include these patients in clinical trials. NGS has been widely used to detect multiple gene mutations. Although NGS can also distinguish EGFR T790M/C797S in cis and trans positions, ddPCR is cheaper to use and has a faster turnaround time than NGS. 26 , 27 Therefore, ddPCR would be useful, especially in serially monitoring EGFR mutations during osimertinib treatment.
Coincidentally, we found the NRAS Q61K mutation through the NGS in analyzing the osimertinib‐resistant tumor cells. Trametinib with osimertinib was effective against tumors with NRAS Q61K mutation in the cell line model. Therefore, a clinical trial to evaluate the effect of trametinib combination treatment for NSCLC patients resistant to osimertinib is expected.
After validating the detection of the EGFR C797S mutation in plasma cfDNA, serial evaluation of EGFR mutation (active mutation, T790M and C797S) was performed in the plasma cfDNA during and after osimertinib treatment in the second cohort. EGFR mutation in the plasma cfDNA has been reported to decrease with EGFR‐TKI treatment and to increase with disease progression, 17 , 18 , 19 but a serial evaluation of EGFR T790M and C797S status during the osimertinib treatment has not been fully reported. We found that C797S in cfDNA also changes with treatment response, and confirmed that the EGFR T790M and C797S in cis or trans position were detectable in plasma cfDNA some months before clinical disease progression. We further found that the fractional abundance of EGFR mutation in the plasma cfDNA might be a more reliable plasma biomarker of osimertinib response than CEA, a widely used tumor maker. While we were preparing this manuscript, Romero et al 28 reported on the EGFR mutation, including C797S monitoring during osimertinib treatment. The present study has some significance because we validated the detection of EGFR C797S mutation with clinical samples, showed C797S monitoring including cis/trans analysis, conducted closed and periodic monitoring, and illustrated the relationship between EGFR mutation and CEA in a Japanese cohort.
We focused on 2 patients who had disease progression with bone oligo‐progression, who were treated with local radiation therapy and continued osimertinib treatment. Several reports showed the usefulness of cfDNA for early detection of disease progression, and local radiation therapy decreases the amount of mutant EGFR DNA. 28 , 29 , 30 In some cases, early detection of bone metastasis is difficult with CT scans. 31 Indeed, not routine CT scans but PET‐CT and MRI successfully detected the bone metastasis in 2 patients. Therefore, the usefulness of cfDNA in detecting bone oligo progression should be emphasized. Second, the treatment strategy for oligo‐progression is still debatable. 32 There is no reliable biomarker to continue osimertinib treatment after local therapy. We clearly showed that EGFR mutation in the plasma cfDNA became negative after the local radiation therapy, and patients continued the osimertinib treatment over several months without disease progression. During the osimertinib treatment beyond progression, EGFR mutation in the plasma cfDNA was maintained at low levels, which might indicate that it could be a reliable biomarker to continue osimertinib beyond progression.
This study had certain limitations. First, the number of patients in this study is small, which decreases the importance of our results. Increasing the cohort size would be necessary in a future study. Second, the detection rate of EGFR mutation in the plasma cfDNA was not high, and the negative result in liquid biopsy can be a sensitivity issue and not a real negative. The technical improvement would be desirable to introduce it into clinical practice. A past report showed that the sensitivity of EGFR mutation detection in cfDNA is low when diseases are limited to the intrathoracic region. 33 Therefore, we also evaluated the disease state in the second cohort. We found that EGFR mutation in cfDNA tended not to be detected when the disease was in intrathoracic areas. Therefore, analysis of the cfDNA from patients with intrathoracic disease requires careful interpretation.
In conclusion, we found that EGFR‐T790M/C797S mutations in cis and trans positions are discriminately detectable, distinguished by ddPCR from plasma cfDNA. Serial evaluation of EGFR mutation in plasma cfDNA showed the emergence of EGFR mutations, including C797S, during osimertinib treatment before disease progression.
DISCLOSURE
M. Nishio received research funding from Novartis, ONO Pharmaceutical, Chugai Pharmaceutical, Bristol‐Myers Squibb, TAIHO Pharmaceutical, Eli Lilly, Pfizer, Astellas Pharma, and AstraZeneca and received honorarium from Pfizer, Bristol‐Myers Squibb, ONO Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, TAIHO Pharmaceutical, and AstraZeneca. N. Yanagitani is a consultant of Chugai Pharmaceutical. R. Katayama received research funding from Chugai, TAKEDA, Toppan Printing, and Daiichi‐Sankyo. T. Sasaki received research funding from Novartis, Pfizer, and Boehringer Ingelheim and received honorarium from AstraZeneca. All other authors declare no conflict of interest.
Supporting information
Supplementary Material
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Appendix S1
Click here for additional data file. | OSIMERTINIB | DrugsGivenReaction | CC BY-NC | 33686722 | 19,711,823 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug resistance'. | Monitoring epidermal growth factor receptor C797S mutation in Japanese non-small cell lung cancer patients with serial cell-free DNA evaluation using digital droplet PCR.
Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is effective in treating both naïve and T790M-mutated EGFR-TKI-resistant non-small cell lung cancer patients. The EGFR C797S mutation is the major osimertinib resistance mechanism. The present study monitored the EGFR C797S mutation during osimertinib treatment in Japanese patients using droplet digital PCR (ddPCR). In our first cohort, C797S detection was validated with tumor specimens and/or plasma samples from 26 patients using ddPCR with custom-designed probes detecting and discriminating T790M and C797S in cis and trans positions. In our second cohort, 18 patients with EGFR-T790M who were going to start osimertinib were analyzed using ddPCR by collecting the plasma samples every month from the beginning of the course of osimertinib. In the first cohort, C797S was detected in 15.4% of patients. C797S and T790M in cis and trans positions were distinguished using ddPCR. In the second cohort, serial cfDNA evaluation revealed that the rate of EGFR mutation changes with disease state. Increases of EGFR mutation were detected, including C797S several months before the diagnosis of disease progression. As with the first cohort, C797S and T790M in cis and trans position were distinguished by ddPCR at disease progression. Coincidentally, in the first cohort, next generation sequencing detected NRAS Q61K mutation and the resistance with NRAS Q61K mutation was overcome by trametinib. In the second cohort, serial cfDNA analysis was useful for evaluating bone oligo-progression and local radiation therapy.
1 INTRODUCTION
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKI) inhibit the EGFR and its downstream signaling pathways by binding to the adenosine triphosphate (ATP)‐binding pocket of the EGFR‐tyrosine kinase domain, which strongly suppresses the growth of EGFR‐mutant non–small cell lung cancer (NSCLC) cells. 1 EGFR‐TKI have been shown to prolong the progression‐free survival (PFS) of patients with EGFR‐mutant NSCLC. 2 , 3 However, cancer cells acquire resistance to EGFR‐TKI. One of the resistance mechanisms is via the secondary point mutation Thr790Met (T790M), which decreases the relative binding affinity of TKI to the ATP‐binding site of EGFR. 5 , 6
Osimertinib, a third‐generation EGFR‐TKI, was developed to overcome this resistance by covalently binding to T790M‐mutated EGFR. 7 Its efficacy in T790M‐positive patients with advanced NSCLC has been evaluated in a phase 3 clinical trial. The results showed that the median PFS was significantly longer with osimertinib than that with platinum‐based chemotherapy. 8 However, a wide variety of osimertinib‐resistant mechanisms have been reported (eg, C797S, G796D, L718Q, MET amplification, BRAF V600E mutation, and small‐cell lung cancer [SCLC] transformation). 9 , 10 , 11 , 12 , 13 , 14 C797S is one of the major resistance mechanisms that impair the covalent binding between EGFR and osimertinib. Preclinical model studies suggested some strategies to overcome resistance due to C797S. 15 Therefore, detection of C797S and understanding osimertinib resistance mechanisms are important.
Cell‐free DNA (cfDNA) from plasma samples contains the DNA of malignant tumors. Thus, it is possible to detect EGFR mutations, not only activating mutations but also resistance mutations like T790M from plasma cfDNA. A clinical trial confirmed the efficacy of osimertinib treatment based on EGFR mutation status in plasma cfDNA 16 . Moreover, the amount of cfDNA with EGFR mutation has been reported to change with treatment response and disease progression. 17 , 18 , 19 For example, after EGFR‐TKI treatment, the EGFR mutation becomes negative in plasma cfDNA, whereas after the disease progression, the EGFR mutation becomes positive again. However, EGFR mutation in cfDNA has not been fully evaluated during osimertinib treatment. For example, the mechanism of each EGFR mutation status change (activating mutation, T790M, and C797S) under osimertinib treatment beyond progression or after local radiation therapy remains unknown.
Therefore, in our first cohort we validated the C797S detection from plasma cfDNA using digital droplet PCR (ddPCR) by evaluating the concordance between tissue and plasma clinical samples. In addition to a commercially available independent ddPCR probe for C797S and T790M, a novel original probe set that could detect and distinguish C797S and T790M mutations in cis and trans positions was used. In the second cohort, we checked the EGFR mutation profile (exon 19 deletion, L858R, T790M, and C797S) in the plasma cfDNA during and after the osimertinib treatment in the serial analysis. Serial EGFR mutation examination with cfDNA in the plasma enables early detection of resistance mutation emergence, including EGFR C797S, some months earlier than the radiological progression. Thus, serial monitoring of the EGFR mutation status, including C797S, would be useful in developing an appropriate treatment strategy involving the administration of osimertinib.
2 MATERIALS AND METHODS
2.1 Patients and samples
The first cohort included 60 Japanese patients with NSCLC with EGFR T790M mutation who started osimertinib treatment after the first or second generation EGFR‐TKI treatment in the Department of Thoracic Medical Oncology at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR) from June 2014 to January 2018. Among these patients, 50.0% had EGFR exon 19 deletion, 48.3% had EGFR L858R, and 1.7% had EGFR L861Q. A total of 26 patients agreed to undergo a tumor specimen assay and/or plasma sample analysis after the disease progression.
In the second cohort, 18 Japanese patients with NSCLC with EGFR T790M mutation started osimertinib treatment after the first‐generation or second‐generation EGFR‐TKI treatment at the Cancer Institute Hospital of the JFCR from December 2017 to November 2018. Among them, 83.3% had EGFR exon 19 deletion, and 16.7% had EGFR L858R. Plasma samples were collected almost every month from the start to 6 months after the osimertinib treatment.
The systemic response to osimertinib was evaluated using RECIST v1.1. All patients underwent computed tomography every 2‐3 months, with a few exceptions. All patients provided written informed consent, and this study was approved by the Institutional Review Board of the Cancer Institute Hospital in the JFCR.
2.2 Nucleic acid extraction
DNA was extracted from cytology or histology samples using the cobas EGFR Mutation Test kit (Roche Molecular Systems), the RNeasy Mini Kit (Qiagen), or the DNeasy Blood & Tissue Kit (Qiagen) as per the manufacturer’s instructions. cfDNA was extracted from plasma samples using the Maxwell RSC ccfDNA Plasma Kit (Promega) or the QIAamp MinElute ccfDNA Kit (Qiagen) following the manufacturer’s instructions. DNA concentration was measured using the Qubit dsDNA HS Assay Kit (Invitrogen, Life Technologies) on a Qubit 2.0 Fluorometer (Invitrogen, Life Technologies).
2.3 Digital droplet PCR for detecting C797S
The method used in ddPCR for detecting EGFR exon 19 deletion, L858R, and T790M is described in our previously published report. 20 In brief, a probe was obtained from Riken Genesis to detect C797S. Cycling conditions for PCR were determined according to the manual. Assays were considered positive if ≥10 copies were observed per reaction (20 µL) based on false‐positive droplet counts from human reference genomic DNA (average C797S copies, 2.36). For the detection of cis/trans‐C797S with T790M, novel probes were designed. Forward primer: CATCTGCCTCACCTCCAC, reverse primer: CGTATCTCCCTTCCCTGATTAC. T790M mutation probe: FAM/IBFQ, CA+TC+A+T+GC+A+GC. C797S mutation probe‐1 (c.2390): FAM/IBFQ, CG+GC+T+C+CCTC. C797S mutation probe‐2 (c.2389): FAM/IBFQ, TCGG+C+A+GCCT+C. WT probe: HEX/IBFQ, TCA+TC+A+C+GC+A+GC.
2.4 Deep sequencing
A targeted amplicon sequencing library was prepared by amplifying exon 20 of EGFR by PCR. Paired‐end sequencing (2 × 150 bp) was performed using the MiSeq platform. To test whether the two mutations, T790M and C797S, were located in the same allele (cis) or different alleles (trans), four reference FASTA files with or without these mutations were prepared. The obtained sequence reads were then mapped to these four reference sequences using BLAT and the reads with lowest mismatches were counted.
For the target sequencing analysis, the library was prepared using a Haloplex custom panel (Agilent), which was designed to detect well‐known cancer‐associated somatic mutations. 21 Paired‐end sequencing (2 × 150 bp) was performed on the MiSeq platform. Sequence reads were aligned to the UCSC hg19 reference genome using the Burrows‐Wheeler Aligner (BWA) (version 0.7.10). Read pairs with a mapping quality of <30 and with mismatches of more than 5% of the read length were excluded. Somatic variants were called by in‐house pipeline.
2.5 Establishment of osimertinib‐resistant PC9 cells with NRAS Q61K
PC9 cells, harboring the EGFR del19 mutation, were treated with increasing concentrations of osimertinib for 6‐12 months and several osimertinib‐resistant PC9 cell lines were established. From the in‐house NGS analysis detecting cancer‐related 108 genes, 21 NRAS Q61K mutation was found in osimertinib‐resistant PC9 cells.
2.6 Cell viability assays
We carried out 3‐day cell viability assays by plating 2000 cells per well into black transparent‐bottom 96‐well plates. On the following day, the cells were treated with the indicated TKI across a 10‐dose range from 0.3 nmol/L to 10 μmol/L. After 72 hours of drug treatment, cell viability was measured using the CellTiter‐Glo assay (Promega).
2.7 Statistical analysis
Fisher’s exact and χ2 tests were used for categorical comparison of data, based on group number, and the Mann‐Whitney U‐test was used to compare differences in continuous data. Paired t tests were used to compare differences in continuous and paired data. All P‐values were based on a two‐sided hypothesis. We performed all statistical analyses using the JMP statistical software package 13 (SAS Institute).
3 RESULTS
3.1 Concordance of C797S, T790M mutation detection between tumor cell DNA and plasma cfDNA
Osimertinib‐resistant tumor cell DNA and/or plasma cfDNA of 26 patients was analyzed in the first cohort. Patient characteristics, a flow chart representing the availability of each examination, a summary of treatment history, and the resistance mechanism of 26 patients are shown in Table S1, Figures S1‐S3. C797S was detected by ddPCR in 15.4% (4/26) of patients, and T790M loss was detected in 65.4% (17/26) (Figure 1A). The concordance rate between tumor cell DNA and plasma cell‐free DNA was 88.9% (8/9) for detecting C797S and 100% (9/9) for detecting T790M (Figure 1B).
FIGURE 1 A, Frequency of C797S and T790M loss detected by droplet digital PCR (ddPCR). B, The concordance of T790M and C797S detection with ddPCR between tumor cell DNA and plasma cfDNA. Red: positive. Blue: negative
3.2 Validation to detect and discriminate EGFR‐T790M/C797S in cis and trans positions with droplet digital PCR
We validated the detection of C797S by ddPCR. JFCR163 is a cell line from the specimen of osimertinib‐resistant patient No. 20. The EGFR of this cell line was sequenced, and C797S was detected (Figure 2A). Using this sample, ddPCR was performed and showed “a positive” result in the cis position (Figure 2B). Next, we assayed the sample from patient No. 4 (JFCR‐129) using a custom probe that can distinguish between C797S in the cis and trans positions with T790M (Figure 2C). The results showed that C797S was in the trans position, which was validated by NGS (Figures 2D, 3E and Figure S4).
FIGURE 2 Detection of epidermal growth factor receptor (EGFR) T790M and C797S by droplet digital PCR (ddPCR). Detection of T790M and C797S in the trans position was possible using ddPCR. A, Detection of EGFR T790M and C797S with Sanger sequencing from JFCR163. B, Detection of EGFR C797S mutation with ddPCR from JFCR 163. Mutant positive template is depicted with blue dots. C, Example of our original ddPCR probe to distinguish cis or trans EGFR‐T790M and C797S mutations. T790M mutation was detected as FAM positive with low amplitude and depicted with blue dots. C797S and T790M in cis position was detected as FAM positive with high amplitude and depicted with blue dots. C797S in trans position was detected as both FAM and HEX positive and depicted with yellow dots. D, Sample from patient No. 4 (JFCR‐129‐2) showed yellow dots positive with ddPCR, which indicated the detection of T790M and C797S in the trans position. E, T790M and C797S in the trans position was also confirmed by NGS using the PCR amplified exon 20 of EGFR, the results of JFCR‐129‐2. (JFCR‐129‐1 as a comparison)
FIGURE 3 Detection of NRAS‐Q61K mutation in osimertinib‐resistant case. A, NRAS Q61K was detected from the clinical samples from patient No. 24 with NGS. B, Cell viability assay using osimertinib‐resistant PC9 with NRAS Q61K showed that trametinib and osimertinib combination can overcome the resistance with NRAS Q61K mutation
3.3 NRAS Q61K mutation is an osimertinib‐resistant mechanism, which is overcome with trametinib and osimertinib treatment
While we were analyzing the osimertinib resistance mechanism including C797S in the first cohort, coincidentally NGS sequencing detected the NRAS Q61K mutation in 1 patient (Figure 3A). As an independent experiment, we established osimertinib‐resistant PC9 cells that harbored the NRAS‐Q61K mutation; resistance was overcome with trametinib treatment combined with osimertinib (Figure 3B).
3.4 Fractional abundance of epidermal growth factor receptor mutation including C797S in cfDNA changes with osimertinib treatment response and disease progression
In the second cohort, 18 patients started osimertinib treatment after T790M detection. In 44.4% (8/18) of patients, EGFR‐activating mutation in the plasma cfDNA was positive with ddPCR at least once during the follow‐up period. All patients’ clinical backgrounds are shown in Table S2. The EGFR‐activating mutation tended to be negative, especially when disease was limited to the intrathoracic region and the number of metastatic organs was small.
The fractional abundance chart of the EGFR mutation in 8 patients is depicted in Figures 4 and 5. Pretreatment, EGFR‐activating mutation in the plasma cfDNA was positive in 7 patients, whereas posttreatment, the fractional abundance of EGFR‐activating mutation in plasma cfDNA decreased to almost zero in all 7 patients. Disease progression was confirmed in 6 patients, and 5 of them had EGFR‐activating mutations. EGFR C797S mutation was detected in cfDNA before disease progression in 3 cases. EGFR T790M/C797S in cis and trans positions was also discriminated with ddPCR using our original probes (both case A7 and case A19 harbored EGFR T790M/C797S in cis). Fractional abundance changes of EGFR‐activating mutation are significantly more correlated with the treatment response and disease progression than carcinoembryonic antigen (CEA), a major clinical tumor marker (Figure 6).
FIGURE 4 Fractional abundance chart of epidermal growth factor receptor (EGFR) mutation in 6 patients. Fractional abundance of EGFR mutation is shown on the vertical axis, whereas the days from osimertinib initiation is shown on the horizontal axis. C797S was detected in 1 patient (Case A7) at least once during the follow‐up period. RT, radiation therapy
FIGURE 5 A, Change of fractional abundance of epidermal growth factor receptor (EGFR) mutation in Case A17 is shown. After osimertinib treatment, multiple brain metastasis remained in remission. PET‐CT examination revealed disease progression of left femur bone metastasis. B, Change of fractional abundance of EGFR mutation in Case A19 is shown. After osimertinib treatment, primary lung tumor and other metastasis remained stable with CT examination. MRI examination revealed L5 vertebrae metastasis progression
FIGURE 6 A, Fractional abundance of epidermal growth factor receptor (EGFR)‐activating mutation and carcinoembryonic antigen (CEA) before the osimertinib treatment, best osimertinib response, and disease progression are described in the graph. The two types of vertical axis were shown to estimate the variation precisely. B, Fractional abundance of EGFR‐activating mutation was significantly different between pretreatment and at the time of best response
3.5 Fractional abundance changes of epidermal growth factor receptor mutation in cases of bone oligo‐progression and after a local radiation therapy
We focused on 2 patients. In both cases, EGFR mutation in the plasma cfDNA increased a few months before the radiological progression. It became negative after the local radiation therapy for bone oligo‐progression.
Case A17 was a 56‐year‐old woman with NSCLC with EGFR exon 19 deletion. She was treated with erlotinib; however, the disease progressed with multiple brain metastases. EGFR T790M mutation was confirmed in the plasma cfDNA, and she started osimertinib treatment. The EGFR mutation in the plasma cfDNA became negative and she continued osimertinib treatment. The EGFR mutation in the plasma cfDNA started to increase after 8 months of continuous treatment; however, her routine CT and brain MRI examination did not reveal disease progression. After that, she complained of left leg pain and PET‐CT examination revealed disease progression of left femur bone metastasis; however, the other metastases remained in remission. Local radiation therapy (30 Gy/10 Fr) was performed on the left femur bone for pain control. Consequently, the EGFR mutation in the plasma cfDNA became negative again. The patient continued osimertinib treatment beyond progression, and the disease remained stable for several months without disease progression (Figure 5A).
Case A19 was a 76‐year‐old woman with NSCLC with EGFR exon 19 deletion. Disease progression was confirmed as an S1 vertebrae metastasis under afatinib treatment. The patient started osimertinib after detection of T790M mutation in the plasma cfDNA. The EGFR mutation in the plasma cfDNA became negative but soon increased again. Routine CT scans did not detect disease progression at around 1‐year posttreatment. However, back pain occurred after 8 months of treatment, and repeat MRI examination revealed L5 vertebrae metastasis progression. Local radiation therapy (39 Gy/13 Fr) was performed on the L5 vertebrae for pain control. Consequently, EGFR mutation in the plasma cfDNA decreased to zero, and the patient continued osimertinib treatment beyond progression for 6 months without disease progression (Figure 5B).
4 DISCUSSION
We first validated the C797S detection from plasma cfDNA with ddPCR using clinical samples. The concordance rate between tumor cell DNA and plasma cfDNA was high at disease progression after osimertinib treatment. Then, ddPCR was used to distinguish cis and trans C797S from T790M using novel specific probes. Past reports also showed the efficacy of ddPCR in detecting C797S; 22 , 23 however, the efficacy of ddPCR in distinguishing EGFR‐T790M/C797S in cis and trans, validated with clinical samples, has not been reported. A difference in treatment strategies was observed between T790M and C797S in the cis and trans positions: while brigatinib with an anti–EGFR antibody has been a promising treatment option for tumors with cis‐C797S/T790M, osimertinib combined with gefitinib has been found to be effective against trans‐C797S and T790M. 15 , 24 , 25 Therefore, detection of C797S in the cis and trans positions using ddPCR would be useful in clinical practice. At present, treatment targeting C797S has not been approved in Japan; therefore, we are trying to include these patients in clinical trials. NGS has been widely used to detect multiple gene mutations. Although NGS can also distinguish EGFR T790M/C797S in cis and trans positions, ddPCR is cheaper to use and has a faster turnaround time than NGS. 26 , 27 Therefore, ddPCR would be useful, especially in serially monitoring EGFR mutations during osimertinib treatment.
Coincidentally, we found the NRAS Q61K mutation through the NGS in analyzing the osimertinib‐resistant tumor cells. Trametinib with osimertinib was effective against tumors with NRAS Q61K mutation in the cell line model. Therefore, a clinical trial to evaluate the effect of trametinib combination treatment for NSCLC patients resistant to osimertinib is expected.
After validating the detection of the EGFR C797S mutation in plasma cfDNA, serial evaluation of EGFR mutation (active mutation, T790M and C797S) was performed in the plasma cfDNA during and after osimertinib treatment in the second cohort. EGFR mutation in the plasma cfDNA has been reported to decrease with EGFR‐TKI treatment and to increase with disease progression, 17 , 18 , 19 but a serial evaluation of EGFR T790M and C797S status during the osimertinib treatment has not been fully reported. We found that C797S in cfDNA also changes with treatment response, and confirmed that the EGFR T790M and C797S in cis or trans position were detectable in plasma cfDNA some months before clinical disease progression. We further found that the fractional abundance of EGFR mutation in the plasma cfDNA might be a more reliable plasma biomarker of osimertinib response than CEA, a widely used tumor maker. While we were preparing this manuscript, Romero et al 28 reported on the EGFR mutation, including C797S monitoring during osimertinib treatment. The present study has some significance because we validated the detection of EGFR C797S mutation with clinical samples, showed C797S monitoring including cis/trans analysis, conducted closed and periodic monitoring, and illustrated the relationship between EGFR mutation and CEA in a Japanese cohort.
We focused on 2 patients who had disease progression with bone oligo‐progression, who were treated with local radiation therapy and continued osimertinib treatment. Several reports showed the usefulness of cfDNA for early detection of disease progression, and local radiation therapy decreases the amount of mutant EGFR DNA. 28 , 29 , 30 In some cases, early detection of bone metastasis is difficult with CT scans. 31 Indeed, not routine CT scans but PET‐CT and MRI successfully detected the bone metastasis in 2 patients. Therefore, the usefulness of cfDNA in detecting bone oligo progression should be emphasized. Second, the treatment strategy for oligo‐progression is still debatable. 32 There is no reliable biomarker to continue osimertinib treatment after local therapy. We clearly showed that EGFR mutation in the plasma cfDNA became negative after the local radiation therapy, and patients continued the osimertinib treatment over several months without disease progression. During the osimertinib treatment beyond progression, EGFR mutation in the plasma cfDNA was maintained at low levels, which might indicate that it could be a reliable biomarker to continue osimertinib beyond progression.
This study had certain limitations. First, the number of patients in this study is small, which decreases the importance of our results. Increasing the cohort size would be necessary in a future study. Second, the detection rate of EGFR mutation in the plasma cfDNA was not high, and the negative result in liquid biopsy can be a sensitivity issue and not a real negative. The technical improvement would be desirable to introduce it into clinical practice. A past report showed that the sensitivity of EGFR mutation detection in cfDNA is low when diseases are limited to the intrathoracic region. 33 Therefore, we also evaluated the disease state in the second cohort. We found that EGFR mutation in cfDNA tended not to be detected when the disease was in intrathoracic areas. Therefore, analysis of the cfDNA from patients with intrathoracic disease requires careful interpretation.
In conclusion, we found that EGFR‐T790M/C797S mutations in cis and trans positions are discriminately detectable, distinguished by ddPCR from plasma cfDNA. Serial evaluation of EGFR mutation in plasma cfDNA showed the emergence of EGFR mutations, including C797S, during osimertinib treatment before disease progression.
DISCLOSURE
M. Nishio received research funding from Novartis, ONO Pharmaceutical, Chugai Pharmaceutical, Bristol‐Myers Squibb, TAIHO Pharmaceutical, Eli Lilly, Pfizer, Astellas Pharma, and AstraZeneca and received honorarium from Pfizer, Bristol‐Myers Squibb, ONO Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, TAIHO Pharmaceutical, and AstraZeneca. N. Yanagitani is a consultant of Chugai Pharmaceutical. R. Katayama received research funding from Chugai, TAKEDA, Toppan Printing, and Daiichi‐Sankyo. T. Sasaki received research funding from Novartis, Pfizer, and Boehringer Ingelheim and received honorarium from AstraZeneca. All other authors declare no conflict of interest.
Supporting information
Supplementary Material
Click here for additional data file.
Appendix S1
Click here for additional data file. | OSIMERTINIB | DrugsGivenReaction | CC BY-NC | 33686722 | 19,711,823 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malignant transformation'. | Monitoring epidermal growth factor receptor C797S mutation in Japanese non-small cell lung cancer patients with serial cell-free DNA evaluation using digital droplet PCR.
Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is effective in treating both naïve and T790M-mutated EGFR-TKI-resistant non-small cell lung cancer patients. The EGFR C797S mutation is the major osimertinib resistance mechanism. The present study monitored the EGFR C797S mutation during osimertinib treatment in Japanese patients using droplet digital PCR (ddPCR). In our first cohort, C797S detection was validated with tumor specimens and/or plasma samples from 26 patients using ddPCR with custom-designed probes detecting and discriminating T790M and C797S in cis and trans positions. In our second cohort, 18 patients with EGFR-T790M who were going to start osimertinib were analyzed using ddPCR by collecting the plasma samples every month from the beginning of the course of osimertinib. In the first cohort, C797S was detected in 15.4% of patients. C797S and T790M in cis and trans positions were distinguished using ddPCR. In the second cohort, serial cfDNA evaluation revealed that the rate of EGFR mutation changes with disease state. Increases of EGFR mutation were detected, including C797S several months before the diagnosis of disease progression. As with the first cohort, C797S and T790M in cis and trans position were distinguished by ddPCR at disease progression. Coincidentally, in the first cohort, next generation sequencing detected NRAS Q61K mutation and the resistance with NRAS Q61K mutation was overcome by trametinib. In the second cohort, serial cfDNA analysis was useful for evaluating bone oligo-progression and local radiation therapy.
1 INTRODUCTION
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKI) inhibit the EGFR and its downstream signaling pathways by binding to the adenosine triphosphate (ATP)‐binding pocket of the EGFR‐tyrosine kinase domain, which strongly suppresses the growth of EGFR‐mutant non–small cell lung cancer (NSCLC) cells. 1 EGFR‐TKI have been shown to prolong the progression‐free survival (PFS) of patients with EGFR‐mutant NSCLC. 2 , 3 However, cancer cells acquire resistance to EGFR‐TKI. One of the resistance mechanisms is via the secondary point mutation Thr790Met (T790M), which decreases the relative binding affinity of TKI to the ATP‐binding site of EGFR. 5 , 6
Osimertinib, a third‐generation EGFR‐TKI, was developed to overcome this resistance by covalently binding to T790M‐mutated EGFR. 7 Its efficacy in T790M‐positive patients with advanced NSCLC has been evaluated in a phase 3 clinical trial. The results showed that the median PFS was significantly longer with osimertinib than that with platinum‐based chemotherapy. 8 However, a wide variety of osimertinib‐resistant mechanisms have been reported (eg, C797S, G796D, L718Q, MET amplification, BRAF V600E mutation, and small‐cell lung cancer [SCLC] transformation). 9 , 10 , 11 , 12 , 13 , 14 C797S is one of the major resistance mechanisms that impair the covalent binding between EGFR and osimertinib. Preclinical model studies suggested some strategies to overcome resistance due to C797S. 15 Therefore, detection of C797S and understanding osimertinib resistance mechanisms are important.
Cell‐free DNA (cfDNA) from plasma samples contains the DNA of malignant tumors. Thus, it is possible to detect EGFR mutations, not only activating mutations but also resistance mutations like T790M from plasma cfDNA. A clinical trial confirmed the efficacy of osimertinib treatment based on EGFR mutation status in plasma cfDNA 16 . Moreover, the amount of cfDNA with EGFR mutation has been reported to change with treatment response and disease progression. 17 , 18 , 19 For example, after EGFR‐TKI treatment, the EGFR mutation becomes negative in plasma cfDNA, whereas after the disease progression, the EGFR mutation becomes positive again. However, EGFR mutation in cfDNA has not been fully evaluated during osimertinib treatment. For example, the mechanism of each EGFR mutation status change (activating mutation, T790M, and C797S) under osimertinib treatment beyond progression or after local radiation therapy remains unknown.
Therefore, in our first cohort we validated the C797S detection from plasma cfDNA using digital droplet PCR (ddPCR) by evaluating the concordance between tissue and plasma clinical samples. In addition to a commercially available independent ddPCR probe for C797S and T790M, a novel original probe set that could detect and distinguish C797S and T790M mutations in cis and trans positions was used. In the second cohort, we checked the EGFR mutation profile (exon 19 deletion, L858R, T790M, and C797S) in the plasma cfDNA during and after the osimertinib treatment in the serial analysis. Serial EGFR mutation examination with cfDNA in the plasma enables early detection of resistance mutation emergence, including EGFR C797S, some months earlier than the radiological progression. Thus, serial monitoring of the EGFR mutation status, including C797S, would be useful in developing an appropriate treatment strategy involving the administration of osimertinib.
2 MATERIALS AND METHODS
2.1 Patients and samples
The first cohort included 60 Japanese patients with NSCLC with EGFR T790M mutation who started osimertinib treatment after the first or second generation EGFR‐TKI treatment in the Department of Thoracic Medical Oncology at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR) from June 2014 to January 2018. Among these patients, 50.0% had EGFR exon 19 deletion, 48.3% had EGFR L858R, and 1.7% had EGFR L861Q. A total of 26 patients agreed to undergo a tumor specimen assay and/or plasma sample analysis after the disease progression.
In the second cohort, 18 Japanese patients with NSCLC with EGFR T790M mutation started osimertinib treatment after the first‐generation or second‐generation EGFR‐TKI treatment at the Cancer Institute Hospital of the JFCR from December 2017 to November 2018. Among them, 83.3% had EGFR exon 19 deletion, and 16.7% had EGFR L858R. Plasma samples were collected almost every month from the start to 6 months after the osimertinib treatment.
The systemic response to osimertinib was evaluated using RECIST v1.1. All patients underwent computed tomography every 2‐3 months, with a few exceptions. All patients provided written informed consent, and this study was approved by the Institutional Review Board of the Cancer Institute Hospital in the JFCR.
2.2 Nucleic acid extraction
DNA was extracted from cytology or histology samples using the cobas EGFR Mutation Test kit (Roche Molecular Systems), the RNeasy Mini Kit (Qiagen), or the DNeasy Blood & Tissue Kit (Qiagen) as per the manufacturer’s instructions. cfDNA was extracted from plasma samples using the Maxwell RSC ccfDNA Plasma Kit (Promega) or the QIAamp MinElute ccfDNA Kit (Qiagen) following the manufacturer’s instructions. DNA concentration was measured using the Qubit dsDNA HS Assay Kit (Invitrogen, Life Technologies) on a Qubit 2.0 Fluorometer (Invitrogen, Life Technologies).
2.3 Digital droplet PCR for detecting C797S
The method used in ddPCR for detecting EGFR exon 19 deletion, L858R, and T790M is described in our previously published report. 20 In brief, a probe was obtained from Riken Genesis to detect C797S. Cycling conditions for PCR were determined according to the manual. Assays were considered positive if ≥10 copies were observed per reaction (20 µL) based on false‐positive droplet counts from human reference genomic DNA (average C797S copies, 2.36). For the detection of cis/trans‐C797S with T790M, novel probes were designed. Forward primer: CATCTGCCTCACCTCCAC, reverse primer: CGTATCTCCCTTCCCTGATTAC. T790M mutation probe: FAM/IBFQ, CA+TC+A+T+GC+A+GC. C797S mutation probe‐1 (c.2390): FAM/IBFQ, CG+GC+T+C+CCTC. C797S mutation probe‐2 (c.2389): FAM/IBFQ, TCGG+C+A+GCCT+C. WT probe: HEX/IBFQ, TCA+TC+A+C+GC+A+GC.
2.4 Deep sequencing
A targeted amplicon sequencing library was prepared by amplifying exon 20 of EGFR by PCR. Paired‐end sequencing (2 × 150 bp) was performed using the MiSeq platform. To test whether the two mutations, T790M and C797S, were located in the same allele (cis) or different alleles (trans), four reference FASTA files with or without these mutations were prepared. The obtained sequence reads were then mapped to these four reference sequences using BLAT and the reads with lowest mismatches were counted.
For the target sequencing analysis, the library was prepared using a Haloplex custom panel (Agilent), which was designed to detect well‐known cancer‐associated somatic mutations. 21 Paired‐end sequencing (2 × 150 bp) was performed on the MiSeq platform. Sequence reads were aligned to the UCSC hg19 reference genome using the Burrows‐Wheeler Aligner (BWA) (version 0.7.10). Read pairs with a mapping quality of <30 and with mismatches of more than 5% of the read length were excluded. Somatic variants were called by in‐house pipeline.
2.5 Establishment of osimertinib‐resistant PC9 cells with NRAS Q61K
PC9 cells, harboring the EGFR del19 mutation, were treated with increasing concentrations of osimertinib for 6‐12 months and several osimertinib‐resistant PC9 cell lines were established. From the in‐house NGS analysis detecting cancer‐related 108 genes, 21 NRAS Q61K mutation was found in osimertinib‐resistant PC9 cells.
2.6 Cell viability assays
We carried out 3‐day cell viability assays by plating 2000 cells per well into black transparent‐bottom 96‐well plates. On the following day, the cells were treated with the indicated TKI across a 10‐dose range from 0.3 nmol/L to 10 μmol/L. After 72 hours of drug treatment, cell viability was measured using the CellTiter‐Glo assay (Promega).
2.7 Statistical analysis
Fisher’s exact and χ2 tests were used for categorical comparison of data, based on group number, and the Mann‐Whitney U‐test was used to compare differences in continuous data. Paired t tests were used to compare differences in continuous and paired data. All P‐values were based on a two‐sided hypothesis. We performed all statistical analyses using the JMP statistical software package 13 (SAS Institute).
3 RESULTS
3.1 Concordance of C797S, T790M mutation detection between tumor cell DNA and plasma cfDNA
Osimertinib‐resistant tumor cell DNA and/or plasma cfDNA of 26 patients was analyzed in the first cohort. Patient characteristics, a flow chart representing the availability of each examination, a summary of treatment history, and the resistance mechanism of 26 patients are shown in Table S1, Figures S1‐S3. C797S was detected by ddPCR in 15.4% (4/26) of patients, and T790M loss was detected in 65.4% (17/26) (Figure 1A). The concordance rate between tumor cell DNA and plasma cell‐free DNA was 88.9% (8/9) for detecting C797S and 100% (9/9) for detecting T790M (Figure 1B).
FIGURE 1 A, Frequency of C797S and T790M loss detected by droplet digital PCR (ddPCR). B, The concordance of T790M and C797S detection with ddPCR between tumor cell DNA and plasma cfDNA. Red: positive. Blue: negative
3.2 Validation to detect and discriminate EGFR‐T790M/C797S in cis and trans positions with droplet digital PCR
We validated the detection of C797S by ddPCR. JFCR163 is a cell line from the specimen of osimertinib‐resistant patient No. 20. The EGFR of this cell line was sequenced, and C797S was detected (Figure 2A). Using this sample, ddPCR was performed and showed “a positive” result in the cis position (Figure 2B). Next, we assayed the sample from patient No. 4 (JFCR‐129) using a custom probe that can distinguish between C797S in the cis and trans positions with T790M (Figure 2C). The results showed that C797S was in the trans position, which was validated by NGS (Figures 2D, 3E and Figure S4).
FIGURE 2 Detection of epidermal growth factor receptor (EGFR) T790M and C797S by droplet digital PCR (ddPCR). Detection of T790M and C797S in the trans position was possible using ddPCR. A, Detection of EGFR T790M and C797S with Sanger sequencing from JFCR163. B, Detection of EGFR C797S mutation with ddPCR from JFCR 163. Mutant positive template is depicted with blue dots. C, Example of our original ddPCR probe to distinguish cis or trans EGFR‐T790M and C797S mutations. T790M mutation was detected as FAM positive with low amplitude and depicted with blue dots. C797S and T790M in cis position was detected as FAM positive with high amplitude and depicted with blue dots. C797S in trans position was detected as both FAM and HEX positive and depicted with yellow dots. D, Sample from patient No. 4 (JFCR‐129‐2) showed yellow dots positive with ddPCR, which indicated the detection of T790M and C797S in the trans position. E, T790M and C797S in the trans position was also confirmed by NGS using the PCR amplified exon 20 of EGFR, the results of JFCR‐129‐2. (JFCR‐129‐1 as a comparison)
FIGURE 3 Detection of NRAS‐Q61K mutation in osimertinib‐resistant case. A, NRAS Q61K was detected from the clinical samples from patient No. 24 with NGS. B, Cell viability assay using osimertinib‐resistant PC9 with NRAS Q61K showed that trametinib and osimertinib combination can overcome the resistance with NRAS Q61K mutation
3.3 NRAS Q61K mutation is an osimertinib‐resistant mechanism, which is overcome with trametinib and osimertinib treatment
While we were analyzing the osimertinib resistance mechanism including C797S in the first cohort, coincidentally NGS sequencing detected the NRAS Q61K mutation in 1 patient (Figure 3A). As an independent experiment, we established osimertinib‐resistant PC9 cells that harbored the NRAS‐Q61K mutation; resistance was overcome with trametinib treatment combined with osimertinib (Figure 3B).
3.4 Fractional abundance of epidermal growth factor receptor mutation including C797S in cfDNA changes with osimertinib treatment response and disease progression
In the second cohort, 18 patients started osimertinib treatment after T790M detection. In 44.4% (8/18) of patients, EGFR‐activating mutation in the plasma cfDNA was positive with ddPCR at least once during the follow‐up period. All patients’ clinical backgrounds are shown in Table S2. The EGFR‐activating mutation tended to be negative, especially when disease was limited to the intrathoracic region and the number of metastatic organs was small.
The fractional abundance chart of the EGFR mutation in 8 patients is depicted in Figures 4 and 5. Pretreatment, EGFR‐activating mutation in the plasma cfDNA was positive in 7 patients, whereas posttreatment, the fractional abundance of EGFR‐activating mutation in plasma cfDNA decreased to almost zero in all 7 patients. Disease progression was confirmed in 6 patients, and 5 of them had EGFR‐activating mutations. EGFR C797S mutation was detected in cfDNA before disease progression in 3 cases. EGFR T790M/C797S in cis and trans positions was also discriminated with ddPCR using our original probes (both case A7 and case A19 harbored EGFR T790M/C797S in cis). Fractional abundance changes of EGFR‐activating mutation are significantly more correlated with the treatment response and disease progression than carcinoembryonic antigen (CEA), a major clinical tumor marker (Figure 6).
FIGURE 4 Fractional abundance chart of epidermal growth factor receptor (EGFR) mutation in 6 patients. Fractional abundance of EGFR mutation is shown on the vertical axis, whereas the days from osimertinib initiation is shown on the horizontal axis. C797S was detected in 1 patient (Case A7) at least once during the follow‐up period. RT, radiation therapy
FIGURE 5 A, Change of fractional abundance of epidermal growth factor receptor (EGFR) mutation in Case A17 is shown. After osimertinib treatment, multiple brain metastasis remained in remission. PET‐CT examination revealed disease progression of left femur bone metastasis. B, Change of fractional abundance of EGFR mutation in Case A19 is shown. After osimertinib treatment, primary lung tumor and other metastasis remained stable with CT examination. MRI examination revealed L5 vertebrae metastasis progression
FIGURE 6 A, Fractional abundance of epidermal growth factor receptor (EGFR)‐activating mutation and carcinoembryonic antigen (CEA) before the osimertinib treatment, best osimertinib response, and disease progression are described in the graph. The two types of vertical axis were shown to estimate the variation precisely. B, Fractional abundance of EGFR‐activating mutation was significantly different between pretreatment and at the time of best response
3.5 Fractional abundance changes of epidermal growth factor receptor mutation in cases of bone oligo‐progression and after a local radiation therapy
We focused on 2 patients. In both cases, EGFR mutation in the plasma cfDNA increased a few months before the radiological progression. It became negative after the local radiation therapy for bone oligo‐progression.
Case A17 was a 56‐year‐old woman with NSCLC with EGFR exon 19 deletion. She was treated with erlotinib; however, the disease progressed with multiple brain metastases. EGFR T790M mutation was confirmed in the plasma cfDNA, and she started osimertinib treatment. The EGFR mutation in the plasma cfDNA became negative and she continued osimertinib treatment. The EGFR mutation in the plasma cfDNA started to increase after 8 months of continuous treatment; however, her routine CT and brain MRI examination did not reveal disease progression. After that, she complained of left leg pain and PET‐CT examination revealed disease progression of left femur bone metastasis; however, the other metastases remained in remission. Local radiation therapy (30 Gy/10 Fr) was performed on the left femur bone for pain control. Consequently, the EGFR mutation in the plasma cfDNA became negative again. The patient continued osimertinib treatment beyond progression, and the disease remained stable for several months without disease progression (Figure 5A).
Case A19 was a 76‐year‐old woman with NSCLC with EGFR exon 19 deletion. Disease progression was confirmed as an S1 vertebrae metastasis under afatinib treatment. The patient started osimertinib after detection of T790M mutation in the plasma cfDNA. The EGFR mutation in the plasma cfDNA became negative but soon increased again. Routine CT scans did not detect disease progression at around 1‐year posttreatment. However, back pain occurred after 8 months of treatment, and repeat MRI examination revealed L5 vertebrae metastasis progression. Local radiation therapy (39 Gy/13 Fr) was performed on the L5 vertebrae for pain control. Consequently, EGFR mutation in the plasma cfDNA decreased to zero, and the patient continued osimertinib treatment beyond progression for 6 months without disease progression (Figure 5B).
4 DISCUSSION
We first validated the C797S detection from plasma cfDNA with ddPCR using clinical samples. The concordance rate between tumor cell DNA and plasma cfDNA was high at disease progression after osimertinib treatment. Then, ddPCR was used to distinguish cis and trans C797S from T790M using novel specific probes. Past reports also showed the efficacy of ddPCR in detecting C797S; 22 , 23 however, the efficacy of ddPCR in distinguishing EGFR‐T790M/C797S in cis and trans, validated with clinical samples, has not been reported. A difference in treatment strategies was observed between T790M and C797S in the cis and trans positions: while brigatinib with an anti–EGFR antibody has been a promising treatment option for tumors with cis‐C797S/T790M, osimertinib combined with gefitinib has been found to be effective against trans‐C797S and T790M. 15 , 24 , 25 Therefore, detection of C797S in the cis and trans positions using ddPCR would be useful in clinical practice. At present, treatment targeting C797S has not been approved in Japan; therefore, we are trying to include these patients in clinical trials. NGS has been widely used to detect multiple gene mutations. Although NGS can also distinguish EGFR T790M/C797S in cis and trans positions, ddPCR is cheaper to use and has a faster turnaround time than NGS. 26 , 27 Therefore, ddPCR would be useful, especially in serially monitoring EGFR mutations during osimertinib treatment.
Coincidentally, we found the NRAS Q61K mutation through the NGS in analyzing the osimertinib‐resistant tumor cells. Trametinib with osimertinib was effective against tumors with NRAS Q61K mutation in the cell line model. Therefore, a clinical trial to evaluate the effect of trametinib combination treatment for NSCLC patients resistant to osimertinib is expected.
After validating the detection of the EGFR C797S mutation in plasma cfDNA, serial evaluation of EGFR mutation (active mutation, T790M and C797S) was performed in the plasma cfDNA during and after osimertinib treatment in the second cohort. EGFR mutation in the plasma cfDNA has been reported to decrease with EGFR‐TKI treatment and to increase with disease progression, 17 , 18 , 19 but a serial evaluation of EGFR T790M and C797S status during the osimertinib treatment has not been fully reported. We found that C797S in cfDNA also changes with treatment response, and confirmed that the EGFR T790M and C797S in cis or trans position were detectable in plasma cfDNA some months before clinical disease progression. We further found that the fractional abundance of EGFR mutation in the plasma cfDNA might be a more reliable plasma biomarker of osimertinib response than CEA, a widely used tumor maker. While we were preparing this manuscript, Romero et al 28 reported on the EGFR mutation, including C797S monitoring during osimertinib treatment. The present study has some significance because we validated the detection of EGFR C797S mutation with clinical samples, showed C797S monitoring including cis/trans analysis, conducted closed and periodic monitoring, and illustrated the relationship between EGFR mutation and CEA in a Japanese cohort.
We focused on 2 patients who had disease progression with bone oligo‐progression, who were treated with local radiation therapy and continued osimertinib treatment. Several reports showed the usefulness of cfDNA for early detection of disease progression, and local radiation therapy decreases the amount of mutant EGFR DNA. 28 , 29 , 30 In some cases, early detection of bone metastasis is difficult with CT scans. 31 Indeed, not routine CT scans but PET‐CT and MRI successfully detected the bone metastasis in 2 patients. Therefore, the usefulness of cfDNA in detecting bone oligo progression should be emphasized. Second, the treatment strategy for oligo‐progression is still debatable. 32 There is no reliable biomarker to continue osimertinib treatment after local therapy. We clearly showed that EGFR mutation in the plasma cfDNA became negative after the local radiation therapy, and patients continued the osimertinib treatment over several months without disease progression. During the osimertinib treatment beyond progression, EGFR mutation in the plasma cfDNA was maintained at low levels, which might indicate that it could be a reliable biomarker to continue osimertinib beyond progression.
This study had certain limitations. First, the number of patients in this study is small, which decreases the importance of our results. Increasing the cohort size would be necessary in a future study. Second, the detection rate of EGFR mutation in the plasma cfDNA was not high, and the negative result in liquid biopsy can be a sensitivity issue and not a real negative. The technical improvement would be desirable to introduce it into clinical practice. A past report showed that the sensitivity of EGFR mutation detection in cfDNA is low when diseases are limited to the intrathoracic region. 33 Therefore, we also evaluated the disease state in the second cohort. We found that EGFR mutation in cfDNA tended not to be detected when the disease was in intrathoracic areas. Therefore, analysis of the cfDNA from patients with intrathoracic disease requires careful interpretation.
In conclusion, we found that EGFR‐T790M/C797S mutations in cis and trans positions are discriminately detectable, distinguished by ddPCR from plasma cfDNA. Serial evaluation of EGFR mutation in plasma cfDNA showed the emergence of EGFR mutations, including C797S, during osimertinib treatment before disease progression.
DISCLOSURE
M. Nishio received research funding from Novartis, ONO Pharmaceutical, Chugai Pharmaceutical, Bristol‐Myers Squibb, TAIHO Pharmaceutical, Eli Lilly, Pfizer, Astellas Pharma, and AstraZeneca and received honorarium from Pfizer, Bristol‐Myers Squibb, ONO Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, TAIHO Pharmaceutical, and AstraZeneca. N. Yanagitani is a consultant of Chugai Pharmaceutical. R. Katayama received research funding from Chugai, TAKEDA, Toppan Printing, and Daiichi‐Sankyo. T. Sasaki received research funding from Novartis, Pfizer, and Boehringer Ingelheim and received honorarium from AstraZeneca. All other authors declare no conflict of interest.
Supporting information
Supplementary Material
Click here for additional data file.
Appendix S1
Click here for additional data file. | OSIMERTINIB | DrugsGivenReaction | CC BY-NC | 33686722 | 19,711,823 | 2021-06 |
What was the administration route of drug 'OSIMERTINIB'? | Monitoring epidermal growth factor receptor C797S mutation in Japanese non-small cell lung cancer patients with serial cell-free DNA evaluation using digital droplet PCR.
Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is effective in treating both naïve and T790M-mutated EGFR-TKI-resistant non-small cell lung cancer patients. The EGFR C797S mutation is the major osimertinib resistance mechanism. The present study monitored the EGFR C797S mutation during osimertinib treatment in Japanese patients using droplet digital PCR (ddPCR). In our first cohort, C797S detection was validated with tumor specimens and/or plasma samples from 26 patients using ddPCR with custom-designed probes detecting and discriminating T790M and C797S in cis and trans positions. In our second cohort, 18 patients with EGFR-T790M who were going to start osimertinib were analyzed using ddPCR by collecting the plasma samples every month from the beginning of the course of osimertinib. In the first cohort, C797S was detected in 15.4% of patients. C797S and T790M in cis and trans positions were distinguished using ddPCR. In the second cohort, serial cfDNA evaluation revealed that the rate of EGFR mutation changes with disease state. Increases of EGFR mutation were detected, including C797S several months before the diagnosis of disease progression. As with the first cohort, C797S and T790M in cis and trans position were distinguished by ddPCR at disease progression. Coincidentally, in the first cohort, next generation sequencing detected NRAS Q61K mutation and the resistance with NRAS Q61K mutation was overcome by trametinib. In the second cohort, serial cfDNA analysis was useful for evaluating bone oligo-progression and local radiation therapy.
1 INTRODUCTION
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKI) inhibit the EGFR and its downstream signaling pathways by binding to the adenosine triphosphate (ATP)‐binding pocket of the EGFR‐tyrosine kinase domain, which strongly suppresses the growth of EGFR‐mutant non–small cell lung cancer (NSCLC) cells. 1 EGFR‐TKI have been shown to prolong the progression‐free survival (PFS) of patients with EGFR‐mutant NSCLC. 2 , 3 However, cancer cells acquire resistance to EGFR‐TKI. One of the resistance mechanisms is via the secondary point mutation Thr790Met (T790M), which decreases the relative binding affinity of TKI to the ATP‐binding site of EGFR. 5 , 6
Osimertinib, a third‐generation EGFR‐TKI, was developed to overcome this resistance by covalently binding to T790M‐mutated EGFR. 7 Its efficacy in T790M‐positive patients with advanced NSCLC has been evaluated in a phase 3 clinical trial. The results showed that the median PFS was significantly longer with osimertinib than that with platinum‐based chemotherapy. 8 However, a wide variety of osimertinib‐resistant mechanisms have been reported (eg, C797S, G796D, L718Q, MET amplification, BRAF V600E mutation, and small‐cell lung cancer [SCLC] transformation). 9 , 10 , 11 , 12 , 13 , 14 C797S is one of the major resistance mechanisms that impair the covalent binding between EGFR and osimertinib. Preclinical model studies suggested some strategies to overcome resistance due to C797S. 15 Therefore, detection of C797S and understanding osimertinib resistance mechanisms are important.
Cell‐free DNA (cfDNA) from plasma samples contains the DNA of malignant tumors. Thus, it is possible to detect EGFR mutations, not only activating mutations but also resistance mutations like T790M from plasma cfDNA. A clinical trial confirmed the efficacy of osimertinib treatment based on EGFR mutation status in plasma cfDNA 16 . Moreover, the amount of cfDNA with EGFR mutation has been reported to change with treatment response and disease progression. 17 , 18 , 19 For example, after EGFR‐TKI treatment, the EGFR mutation becomes negative in plasma cfDNA, whereas after the disease progression, the EGFR mutation becomes positive again. However, EGFR mutation in cfDNA has not been fully evaluated during osimertinib treatment. For example, the mechanism of each EGFR mutation status change (activating mutation, T790M, and C797S) under osimertinib treatment beyond progression or after local radiation therapy remains unknown.
Therefore, in our first cohort we validated the C797S detection from plasma cfDNA using digital droplet PCR (ddPCR) by evaluating the concordance between tissue and plasma clinical samples. In addition to a commercially available independent ddPCR probe for C797S and T790M, a novel original probe set that could detect and distinguish C797S and T790M mutations in cis and trans positions was used. In the second cohort, we checked the EGFR mutation profile (exon 19 deletion, L858R, T790M, and C797S) in the plasma cfDNA during and after the osimertinib treatment in the serial analysis. Serial EGFR mutation examination with cfDNA in the plasma enables early detection of resistance mutation emergence, including EGFR C797S, some months earlier than the radiological progression. Thus, serial monitoring of the EGFR mutation status, including C797S, would be useful in developing an appropriate treatment strategy involving the administration of osimertinib.
2 MATERIALS AND METHODS
2.1 Patients and samples
The first cohort included 60 Japanese patients with NSCLC with EGFR T790M mutation who started osimertinib treatment after the first or second generation EGFR‐TKI treatment in the Department of Thoracic Medical Oncology at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR) from June 2014 to January 2018. Among these patients, 50.0% had EGFR exon 19 deletion, 48.3% had EGFR L858R, and 1.7% had EGFR L861Q. A total of 26 patients agreed to undergo a tumor specimen assay and/or plasma sample analysis after the disease progression.
In the second cohort, 18 Japanese patients with NSCLC with EGFR T790M mutation started osimertinib treatment after the first‐generation or second‐generation EGFR‐TKI treatment at the Cancer Institute Hospital of the JFCR from December 2017 to November 2018. Among them, 83.3% had EGFR exon 19 deletion, and 16.7% had EGFR L858R. Plasma samples were collected almost every month from the start to 6 months after the osimertinib treatment.
The systemic response to osimertinib was evaluated using RECIST v1.1. All patients underwent computed tomography every 2‐3 months, with a few exceptions. All patients provided written informed consent, and this study was approved by the Institutional Review Board of the Cancer Institute Hospital in the JFCR.
2.2 Nucleic acid extraction
DNA was extracted from cytology or histology samples using the cobas EGFR Mutation Test kit (Roche Molecular Systems), the RNeasy Mini Kit (Qiagen), or the DNeasy Blood & Tissue Kit (Qiagen) as per the manufacturer’s instructions. cfDNA was extracted from plasma samples using the Maxwell RSC ccfDNA Plasma Kit (Promega) or the QIAamp MinElute ccfDNA Kit (Qiagen) following the manufacturer’s instructions. DNA concentration was measured using the Qubit dsDNA HS Assay Kit (Invitrogen, Life Technologies) on a Qubit 2.0 Fluorometer (Invitrogen, Life Technologies).
2.3 Digital droplet PCR for detecting C797S
The method used in ddPCR for detecting EGFR exon 19 deletion, L858R, and T790M is described in our previously published report. 20 In brief, a probe was obtained from Riken Genesis to detect C797S. Cycling conditions for PCR were determined according to the manual. Assays were considered positive if ≥10 copies were observed per reaction (20 µL) based on false‐positive droplet counts from human reference genomic DNA (average C797S copies, 2.36). For the detection of cis/trans‐C797S with T790M, novel probes were designed. Forward primer: CATCTGCCTCACCTCCAC, reverse primer: CGTATCTCCCTTCCCTGATTAC. T790M mutation probe: FAM/IBFQ, CA+TC+A+T+GC+A+GC. C797S mutation probe‐1 (c.2390): FAM/IBFQ, CG+GC+T+C+CCTC. C797S mutation probe‐2 (c.2389): FAM/IBFQ, TCGG+C+A+GCCT+C. WT probe: HEX/IBFQ, TCA+TC+A+C+GC+A+GC.
2.4 Deep sequencing
A targeted amplicon sequencing library was prepared by amplifying exon 20 of EGFR by PCR. Paired‐end sequencing (2 × 150 bp) was performed using the MiSeq platform. To test whether the two mutations, T790M and C797S, were located in the same allele (cis) or different alleles (trans), four reference FASTA files with or without these mutations were prepared. The obtained sequence reads were then mapped to these four reference sequences using BLAT and the reads with lowest mismatches were counted.
For the target sequencing analysis, the library was prepared using a Haloplex custom panel (Agilent), which was designed to detect well‐known cancer‐associated somatic mutations. 21 Paired‐end sequencing (2 × 150 bp) was performed on the MiSeq platform. Sequence reads were aligned to the UCSC hg19 reference genome using the Burrows‐Wheeler Aligner (BWA) (version 0.7.10). Read pairs with a mapping quality of <30 and with mismatches of more than 5% of the read length were excluded. Somatic variants were called by in‐house pipeline.
2.5 Establishment of osimertinib‐resistant PC9 cells with NRAS Q61K
PC9 cells, harboring the EGFR del19 mutation, were treated with increasing concentrations of osimertinib for 6‐12 months and several osimertinib‐resistant PC9 cell lines were established. From the in‐house NGS analysis detecting cancer‐related 108 genes, 21 NRAS Q61K mutation was found in osimertinib‐resistant PC9 cells.
2.6 Cell viability assays
We carried out 3‐day cell viability assays by plating 2000 cells per well into black transparent‐bottom 96‐well plates. On the following day, the cells were treated with the indicated TKI across a 10‐dose range from 0.3 nmol/L to 10 μmol/L. After 72 hours of drug treatment, cell viability was measured using the CellTiter‐Glo assay (Promega).
2.7 Statistical analysis
Fisher’s exact and χ2 tests were used for categorical comparison of data, based on group number, and the Mann‐Whitney U‐test was used to compare differences in continuous data. Paired t tests were used to compare differences in continuous and paired data. All P‐values were based on a two‐sided hypothesis. We performed all statistical analyses using the JMP statistical software package 13 (SAS Institute).
3 RESULTS
3.1 Concordance of C797S, T790M mutation detection between tumor cell DNA and plasma cfDNA
Osimertinib‐resistant tumor cell DNA and/or plasma cfDNA of 26 patients was analyzed in the first cohort. Patient characteristics, a flow chart representing the availability of each examination, a summary of treatment history, and the resistance mechanism of 26 patients are shown in Table S1, Figures S1‐S3. C797S was detected by ddPCR in 15.4% (4/26) of patients, and T790M loss was detected in 65.4% (17/26) (Figure 1A). The concordance rate between tumor cell DNA and plasma cell‐free DNA was 88.9% (8/9) for detecting C797S and 100% (9/9) for detecting T790M (Figure 1B).
FIGURE 1 A, Frequency of C797S and T790M loss detected by droplet digital PCR (ddPCR). B, The concordance of T790M and C797S detection with ddPCR between tumor cell DNA and plasma cfDNA. Red: positive. Blue: negative
3.2 Validation to detect and discriminate EGFR‐T790M/C797S in cis and trans positions with droplet digital PCR
We validated the detection of C797S by ddPCR. JFCR163 is a cell line from the specimen of osimertinib‐resistant patient No. 20. The EGFR of this cell line was sequenced, and C797S was detected (Figure 2A). Using this sample, ddPCR was performed and showed “a positive” result in the cis position (Figure 2B). Next, we assayed the sample from patient No. 4 (JFCR‐129) using a custom probe that can distinguish between C797S in the cis and trans positions with T790M (Figure 2C). The results showed that C797S was in the trans position, which was validated by NGS (Figures 2D, 3E and Figure S4).
FIGURE 2 Detection of epidermal growth factor receptor (EGFR) T790M and C797S by droplet digital PCR (ddPCR). Detection of T790M and C797S in the trans position was possible using ddPCR. A, Detection of EGFR T790M and C797S with Sanger sequencing from JFCR163. B, Detection of EGFR C797S mutation with ddPCR from JFCR 163. Mutant positive template is depicted with blue dots. C, Example of our original ddPCR probe to distinguish cis or trans EGFR‐T790M and C797S mutations. T790M mutation was detected as FAM positive with low amplitude and depicted with blue dots. C797S and T790M in cis position was detected as FAM positive with high amplitude and depicted with blue dots. C797S in trans position was detected as both FAM and HEX positive and depicted with yellow dots. D, Sample from patient No. 4 (JFCR‐129‐2) showed yellow dots positive with ddPCR, which indicated the detection of T790M and C797S in the trans position. E, T790M and C797S in the trans position was also confirmed by NGS using the PCR amplified exon 20 of EGFR, the results of JFCR‐129‐2. (JFCR‐129‐1 as a comparison)
FIGURE 3 Detection of NRAS‐Q61K mutation in osimertinib‐resistant case. A, NRAS Q61K was detected from the clinical samples from patient No. 24 with NGS. B, Cell viability assay using osimertinib‐resistant PC9 with NRAS Q61K showed that trametinib and osimertinib combination can overcome the resistance with NRAS Q61K mutation
3.3 NRAS Q61K mutation is an osimertinib‐resistant mechanism, which is overcome with trametinib and osimertinib treatment
While we were analyzing the osimertinib resistance mechanism including C797S in the first cohort, coincidentally NGS sequencing detected the NRAS Q61K mutation in 1 patient (Figure 3A). As an independent experiment, we established osimertinib‐resistant PC9 cells that harbored the NRAS‐Q61K mutation; resistance was overcome with trametinib treatment combined with osimertinib (Figure 3B).
3.4 Fractional abundance of epidermal growth factor receptor mutation including C797S in cfDNA changes with osimertinib treatment response and disease progression
In the second cohort, 18 patients started osimertinib treatment after T790M detection. In 44.4% (8/18) of patients, EGFR‐activating mutation in the plasma cfDNA was positive with ddPCR at least once during the follow‐up period. All patients’ clinical backgrounds are shown in Table S2. The EGFR‐activating mutation tended to be negative, especially when disease was limited to the intrathoracic region and the number of metastatic organs was small.
The fractional abundance chart of the EGFR mutation in 8 patients is depicted in Figures 4 and 5. Pretreatment, EGFR‐activating mutation in the plasma cfDNA was positive in 7 patients, whereas posttreatment, the fractional abundance of EGFR‐activating mutation in plasma cfDNA decreased to almost zero in all 7 patients. Disease progression was confirmed in 6 patients, and 5 of them had EGFR‐activating mutations. EGFR C797S mutation was detected in cfDNA before disease progression in 3 cases. EGFR T790M/C797S in cis and trans positions was also discriminated with ddPCR using our original probes (both case A7 and case A19 harbored EGFR T790M/C797S in cis). Fractional abundance changes of EGFR‐activating mutation are significantly more correlated with the treatment response and disease progression than carcinoembryonic antigen (CEA), a major clinical tumor marker (Figure 6).
FIGURE 4 Fractional abundance chart of epidermal growth factor receptor (EGFR) mutation in 6 patients. Fractional abundance of EGFR mutation is shown on the vertical axis, whereas the days from osimertinib initiation is shown on the horizontal axis. C797S was detected in 1 patient (Case A7) at least once during the follow‐up period. RT, radiation therapy
FIGURE 5 A, Change of fractional abundance of epidermal growth factor receptor (EGFR) mutation in Case A17 is shown. After osimertinib treatment, multiple brain metastasis remained in remission. PET‐CT examination revealed disease progression of left femur bone metastasis. B, Change of fractional abundance of EGFR mutation in Case A19 is shown. After osimertinib treatment, primary lung tumor and other metastasis remained stable with CT examination. MRI examination revealed L5 vertebrae metastasis progression
FIGURE 6 A, Fractional abundance of epidermal growth factor receptor (EGFR)‐activating mutation and carcinoembryonic antigen (CEA) before the osimertinib treatment, best osimertinib response, and disease progression are described in the graph. The two types of vertical axis were shown to estimate the variation precisely. B, Fractional abundance of EGFR‐activating mutation was significantly different between pretreatment and at the time of best response
3.5 Fractional abundance changes of epidermal growth factor receptor mutation in cases of bone oligo‐progression and after a local radiation therapy
We focused on 2 patients. In both cases, EGFR mutation in the plasma cfDNA increased a few months before the radiological progression. It became negative after the local radiation therapy for bone oligo‐progression.
Case A17 was a 56‐year‐old woman with NSCLC with EGFR exon 19 deletion. She was treated with erlotinib; however, the disease progressed with multiple brain metastases. EGFR T790M mutation was confirmed in the plasma cfDNA, and she started osimertinib treatment. The EGFR mutation in the plasma cfDNA became negative and she continued osimertinib treatment. The EGFR mutation in the plasma cfDNA started to increase after 8 months of continuous treatment; however, her routine CT and brain MRI examination did not reveal disease progression. After that, she complained of left leg pain and PET‐CT examination revealed disease progression of left femur bone metastasis; however, the other metastases remained in remission. Local radiation therapy (30 Gy/10 Fr) was performed on the left femur bone for pain control. Consequently, the EGFR mutation in the plasma cfDNA became negative again. The patient continued osimertinib treatment beyond progression, and the disease remained stable for several months without disease progression (Figure 5A).
Case A19 was a 76‐year‐old woman with NSCLC with EGFR exon 19 deletion. Disease progression was confirmed as an S1 vertebrae metastasis under afatinib treatment. The patient started osimertinib after detection of T790M mutation in the plasma cfDNA. The EGFR mutation in the plasma cfDNA became negative but soon increased again. Routine CT scans did not detect disease progression at around 1‐year posttreatment. However, back pain occurred after 8 months of treatment, and repeat MRI examination revealed L5 vertebrae metastasis progression. Local radiation therapy (39 Gy/13 Fr) was performed on the L5 vertebrae for pain control. Consequently, EGFR mutation in the plasma cfDNA decreased to zero, and the patient continued osimertinib treatment beyond progression for 6 months without disease progression (Figure 5B).
4 DISCUSSION
We first validated the C797S detection from plasma cfDNA with ddPCR using clinical samples. The concordance rate between tumor cell DNA and plasma cfDNA was high at disease progression after osimertinib treatment. Then, ddPCR was used to distinguish cis and trans C797S from T790M using novel specific probes. Past reports also showed the efficacy of ddPCR in detecting C797S; 22 , 23 however, the efficacy of ddPCR in distinguishing EGFR‐T790M/C797S in cis and trans, validated with clinical samples, has not been reported. A difference in treatment strategies was observed between T790M and C797S in the cis and trans positions: while brigatinib with an anti–EGFR antibody has been a promising treatment option for tumors with cis‐C797S/T790M, osimertinib combined with gefitinib has been found to be effective against trans‐C797S and T790M. 15 , 24 , 25 Therefore, detection of C797S in the cis and trans positions using ddPCR would be useful in clinical practice. At present, treatment targeting C797S has not been approved in Japan; therefore, we are trying to include these patients in clinical trials. NGS has been widely used to detect multiple gene mutations. Although NGS can also distinguish EGFR T790M/C797S in cis and trans positions, ddPCR is cheaper to use and has a faster turnaround time than NGS. 26 , 27 Therefore, ddPCR would be useful, especially in serially monitoring EGFR mutations during osimertinib treatment.
Coincidentally, we found the NRAS Q61K mutation through the NGS in analyzing the osimertinib‐resistant tumor cells. Trametinib with osimertinib was effective against tumors with NRAS Q61K mutation in the cell line model. Therefore, a clinical trial to evaluate the effect of trametinib combination treatment for NSCLC patients resistant to osimertinib is expected.
After validating the detection of the EGFR C797S mutation in plasma cfDNA, serial evaluation of EGFR mutation (active mutation, T790M and C797S) was performed in the plasma cfDNA during and after osimertinib treatment in the second cohort. EGFR mutation in the plasma cfDNA has been reported to decrease with EGFR‐TKI treatment and to increase with disease progression, 17 , 18 , 19 but a serial evaluation of EGFR T790M and C797S status during the osimertinib treatment has not been fully reported. We found that C797S in cfDNA also changes with treatment response, and confirmed that the EGFR T790M and C797S in cis or trans position were detectable in plasma cfDNA some months before clinical disease progression. We further found that the fractional abundance of EGFR mutation in the plasma cfDNA might be a more reliable plasma biomarker of osimertinib response than CEA, a widely used tumor maker. While we were preparing this manuscript, Romero et al 28 reported on the EGFR mutation, including C797S monitoring during osimertinib treatment. The present study has some significance because we validated the detection of EGFR C797S mutation with clinical samples, showed C797S monitoring including cis/trans analysis, conducted closed and periodic monitoring, and illustrated the relationship between EGFR mutation and CEA in a Japanese cohort.
We focused on 2 patients who had disease progression with bone oligo‐progression, who were treated with local radiation therapy and continued osimertinib treatment. Several reports showed the usefulness of cfDNA for early detection of disease progression, and local radiation therapy decreases the amount of mutant EGFR DNA. 28 , 29 , 30 In some cases, early detection of bone metastasis is difficult with CT scans. 31 Indeed, not routine CT scans but PET‐CT and MRI successfully detected the bone metastasis in 2 patients. Therefore, the usefulness of cfDNA in detecting bone oligo progression should be emphasized. Second, the treatment strategy for oligo‐progression is still debatable. 32 There is no reliable biomarker to continue osimertinib treatment after local therapy. We clearly showed that EGFR mutation in the plasma cfDNA became negative after the local radiation therapy, and patients continued the osimertinib treatment over several months without disease progression. During the osimertinib treatment beyond progression, EGFR mutation in the plasma cfDNA was maintained at low levels, which might indicate that it could be a reliable biomarker to continue osimertinib beyond progression.
This study had certain limitations. First, the number of patients in this study is small, which decreases the importance of our results. Increasing the cohort size would be necessary in a future study. Second, the detection rate of EGFR mutation in the plasma cfDNA was not high, and the negative result in liquid biopsy can be a sensitivity issue and not a real negative. The technical improvement would be desirable to introduce it into clinical practice. A past report showed that the sensitivity of EGFR mutation detection in cfDNA is low when diseases are limited to the intrathoracic region. 33 Therefore, we also evaluated the disease state in the second cohort. We found that EGFR mutation in cfDNA tended not to be detected when the disease was in intrathoracic areas. Therefore, analysis of the cfDNA from patients with intrathoracic disease requires careful interpretation.
In conclusion, we found that EGFR‐T790M/C797S mutations in cis and trans positions are discriminately detectable, distinguished by ddPCR from plasma cfDNA. Serial evaluation of EGFR mutation in plasma cfDNA showed the emergence of EGFR mutations, including C797S, during osimertinib treatment before disease progression.
DISCLOSURE
M. Nishio received research funding from Novartis, ONO Pharmaceutical, Chugai Pharmaceutical, Bristol‐Myers Squibb, TAIHO Pharmaceutical, Eli Lilly, Pfizer, Astellas Pharma, and AstraZeneca and received honorarium from Pfizer, Bristol‐Myers Squibb, ONO Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, TAIHO Pharmaceutical, and AstraZeneca. N. Yanagitani is a consultant of Chugai Pharmaceutical. R. Katayama received research funding from Chugai, TAKEDA, Toppan Printing, and Daiichi‐Sankyo. T. Sasaki received research funding from Novartis, Pfizer, and Boehringer Ingelheim and received honorarium from AstraZeneca. All other authors declare no conflict of interest.
Supporting information
Supplementary Material
Click here for additional data file.
Appendix S1
Click here for additional data file. | Oral | DrugAdministrationRoute | CC BY-NC | 33686722 | 19,711,823 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'No adverse event'. | Use of endobronchial valve to treat COVID-19 adult respiratory distress syndrome-related alveolopleural fistula.
Coronavirus disease-2019 (COVID-19) pneumonia is one of the severe and most dreaded forms of illness caused by severe acute respiratory syndrome coronavirus 2. It often progresses to respiratory failure and acute respiratory distress syndrome (ARDS) requiring mechanical ventilation. ARDS can lead to multiple complications while on mechanical ventilation due to positive airway pressures in a fibrotic lung, one such complication is the development of alveolopleural fistula. Alveolopleural fistula has high morbidity and mortality. We used endobronchial valve in a patient with COVID-19-related ARDS with persistent air leak (alveolopleural fistula), which allowed us to remove the chest tube and wean the patient successfully off mechanical ventilation.
INTRODUCTION
Coronavirus disease-2019 (COVID-19) is a viral illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It can affect any organ and has wide range of manifestations but respiratory system is involved in majority of the patients. In some patients, it can lead to severe pneumonia followed by acute respiratory distress syndrome (ARDS).[12]
We report a patient with COVID-19 pneumonia leading to ARDS and subsequent development of an alveolopleural fistula who was successfully treated with multiple endobronchial valves (EBVs).
CASE REPORT
The patient was a 55-year-old hispanic male with no prior past medical history who presented with 2 days of dry cough and shortness of breath. Vital signs on admission showed an oxygen saturation of 68% on ambient air, respiratory rate of 30 breaths per min, heart rate of 95 beats per min with a temperature of 36.7°C. On physical examination, he was alert and oriented, in moderate respiratory distress with rales and mild expiratory wheezes, he was tachycardic in sinus rhythm, soft abdomen, and anxious mood. He was admitted with acute hypoxic respiratory failure. He was tested for SARS-Cov2 on admission and was found to be positive.
Initial computed tomography (CT) chest without contrast showed diffuse bilateral ground-glass opacities [Figure 1]. His oxygen requirement increased as well as his work of breathing requiring Bilevel Positive Airway Pressure, and was transferred to the medical intensive care unit (ICU) 1 day after admission requiring intubation. His inflammatory markers were elevated, with C-reactive protein 183 mg/L, ferritin 1723 ng/ml, lactate dehydrogenase 993 IU/L, and D-dimer >34 mg/L. He received 2 doses of tocilizumab, as well as a 5-day course of Remdesivir. He had worsening oxygenation, significant coughing paroxysms, and ventilator asynchrony, with PF ratio of 90, requiring high-dose sedation and neuromuscular blockade, as well as prone positioning. On day 4, he developed hemoptysis with >200 mL of bright red blood, and emergent bedside bronchoscopy was completed, which noted normal bronchial mucosa which do not appear to be friable or inflamed, no endobronchial lesions, and no active bleeding. On the 10th day of admission, he developed a right-sided pneumothorax, requiring chest tube placement, likely secondary to ongoing severe ARDS, and lung infection with Stenotrophomonas maltophilia. A tracheostomy was completed on day 14 for further ventilator weaning. On day 20, he developed persistent air leak concerning for a alveolopleural fistula, repeat CT chest concerning for a moderate-sized pneumothorax and findings concerning for post ARDS fibrotic lungs (particularly on the right side) [Figure 1]. He had difficulty with tracheostomy collar trial secondary to severe cough paroxysms. He continued to have a loculated pneumothorax despite chest tube, with persistent alveolopleural fistula. On day 34, he had a repeat chest CT scan small-to-medium size right pneumothorax with well-positioned chest tube in place. After interdisciplinary conference with cardiothoracic surgery, pulmonary, and the ICU team, it was decided that patient had fibrotic right lower and middle lobe from ARDS and the leak is from multiple lobe. He was not deemed to be a surgical candidate hence interventional pulmonology was consulted for EBV placement to facilitate chest tube removal and ventilator weaning.
Figure 1 Computed tomography chest: On the day of admission (a) and 4 weeks later (b)
Procedure details
Bronchoscopy was done on day 41 of admission. Pulmonary balloon was used to sequentially block the right mainstem, bronchus intermedius, and basilar segments. The air leak was recognized to be coming from right middle lobe (RML) and right lower lobe (RLL). Sequential EBV placement was planned to make sure the patient does not become hypoxic from multiple lobar blocks (RLL and RML), although both lobes were fibrotic on the CT scan. On day 41, he had a total 4 Spiration EBV placed. One each in RML lateral segment (9 mm), RML medial segment (9 mm), RLL superior segment (9 mm) and RLL medial basilar segment (7 mm) [Figures 2 and 3]. The air leak improved significantly but still had small leak. Bronchoscopy was repeated 4 days later, and two additional Spiration EBVs were placed, 9 mm each, one in anterolateral and another in posterior basilar segment. Over next few days, his leak completely resolved. The patient was weaned off of positive pressure a week later to trach collar, and the chest tube was subsequently removed. A week later, he was completely liberated from ventilator, tracheostomy tube was downsized and eventually decannulated. He was transferred out of the ICU to long-term acute care for rehabilitation, and then ultimately was discharged to home. Three months later, he followed up in the pulmonary clinic. His tracheostomy site was completely healed. He was able to walk without shortness of breath, saturating 96 on ambient air and 91% on 6-min walk test. Repeat imaging showed hydropneumothorax which was an expected finding.
Figure 2 Arrows showing endobronchial valves
Figure 3 Bronchoscopic view of endobronchial valves
DISCUSSION
Alveolopleural fistula is a communication or fistula between an alveoli and the pleural space. We called it alveolopleural fistula instead of bronchopleural fistula because the patient had lung parenchyma necrosis followed by fistula development; in addition, the fistula was distal to the segmental bronchi.[34] Patient's with ARDS secondary to COVID-19 requiring high amounts of positive end expiratory pressure (PEEP) and are at higher risk in developing a pneumothorax. Parenchymal necrosis followed by fibrotic lung can increase the risk when patient is on positive pressure ventilation for long time. Many patients with a prolonged ventilator course are at risk of developing a secondary bacterial infection, which also increases the risk of pneumothorax and bronchopleural and alveolopleural fistula.[5] Significant coughing paroxysms add additional risk of pneumothorax. Positive pressure and higher amounts of PEEP can make it challenging to heal a pneumothorax, allowing complications of alveolopleural fistula to arise.
EBVs have been used since 2005 to treat alveolopleural and bronchopleural fistula in patients who are not considered a good surgical candidates.[6] EBV can treat these fistulas by allowing air to exit through the valve but not enter the lower segment. This is the first documented use of an EBV in the setting of COVID-19 that we could find. The placement of the valves, allowed a significant reduction in the air leak. This assisted in the patient's breathing trials on the ventilator and tracheostomy collar trials by reducing the overall volume loss through the fistula, ultimately allowing the patient to successfully liberated from the ventilator and have his chest tubes removed.
CONCLUSION
EBV can safely be used in patients with alveolopleural fistula secondary to COVID-19 ARDS.
Declaration of patient consent
The 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.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | REMDESIVIR, TOCILIZUMAB | DrugsGivenReaction | CC BY-NC-SA | 33686984 | 20,932,243 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Use of endobronchial valve to treat COVID-19 adult respiratory distress syndrome-related alveolopleural fistula.
Coronavirus disease-2019 (COVID-19) pneumonia is one of the severe and most dreaded forms of illness caused by severe acute respiratory syndrome coronavirus 2. It often progresses to respiratory failure and acute respiratory distress syndrome (ARDS) requiring mechanical ventilation. ARDS can lead to multiple complications while on mechanical ventilation due to positive airway pressures in a fibrotic lung, one such complication is the development of alveolopleural fistula. Alveolopleural fistula has high morbidity and mortality. We used endobronchial valve in a patient with COVID-19-related ARDS with persistent air leak (alveolopleural fistula), which allowed us to remove the chest tube and wean the patient successfully off mechanical ventilation.
INTRODUCTION
Coronavirus disease-2019 (COVID-19) is a viral illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It can affect any organ and has wide range of manifestations but respiratory system is involved in majority of the patients. In some patients, it can lead to severe pneumonia followed by acute respiratory distress syndrome (ARDS).[12]
We report a patient with COVID-19 pneumonia leading to ARDS and subsequent development of an alveolopleural fistula who was successfully treated with multiple endobronchial valves (EBVs).
CASE REPORT
The patient was a 55-year-old hispanic male with no prior past medical history who presented with 2 days of dry cough and shortness of breath. Vital signs on admission showed an oxygen saturation of 68% on ambient air, respiratory rate of 30 breaths per min, heart rate of 95 beats per min with a temperature of 36.7°C. On physical examination, he was alert and oriented, in moderate respiratory distress with rales and mild expiratory wheezes, he was tachycardic in sinus rhythm, soft abdomen, and anxious mood. He was admitted with acute hypoxic respiratory failure. He was tested for SARS-Cov2 on admission and was found to be positive.
Initial computed tomography (CT) chest without contrast showed diffuse bilateral ground-glass opacities [Figure 1]. His oxygen requirement increased as well as his work of breathing requiring Bilevel Positive Airway Pressure, and was transferred to the medical intensive care unit (ICU) 1 day after admission requiring intubation. His inflammatory markers were elevated, with C-reactive protein 183 mg/L, ferritin 1723 ng/ml, lactate dehydrogenase 993 IU/L, and D-dimer >34 mg/L. He received 2 doses of tocilizumab, as well as a 5-day course of Remdesivir. He had worsening oxygenation, significant coughing paroxysms, and ventilator asynchrony, with PF ratio of 90, requiring high-dose sedation and neuromuscular blockade, as well as prone positioning. On day 4, he developed hemoptysis with >200 mL of bright red blood, and emergent bedside bronchoscopy was completed, which noted normal bronchial mucosa which do not appear to be friable or inflamed, no endobronchial lesions, and no active bleeding. On the 10th day of admission, he developed a right-sided pneumothorax, requiring chest tube placement, likely secondary to ongoing severe ARDS, and lung infection with Stenotrophomonas maltophilia. A tracheostomy was completed on day 14 for further ventilator weaning. On day 20, he developed persistent air leak concerning for a alveolopleural fistula, repeat CT chest concerning for a moderate-sized pneumothorax and findings concerning for post ARDS fibrotic lungs (particularly on the right side) [Figure 1]. He had difficulty with tracheostomy collar trial secondary to severe cough paroxysms. He continued to have a loculated pneumothorax despite chest tube, with persistent alveolopleural fistula. On day 34, he had a repeat chest CT scan small-to-medium size right pneumothorax with well-positioned chest tube in place. After interdisciplinary conference with cardiothoracic surgery, pulmonary, and the ICU team, it was decided that patient had fibrotic right lower and middle lobe from ARDS and the leak is from multiple lobe. He was not deemed to be a surgical candidate hence interventional pulmonology was consulted for EBV placement to facilitate chest tube removal and ventilator weaning.
Figure 1 Computed tomography chest: On the day of admission (a) and 4 weeks later (b)
Procedure details
Bronchoscopy was done on day 41 of admission. Pulmonary balloon was used to sequentially block the right mainstem, bronchus intermedius, and basilar segments. The air leak was recognized to be coming from right middle lobe (RML) and right lower lobe (RLL). Sequential EBV placement was planned to make sure the patient does not become hypoxic from multiple lobar blocks (RLL and RML), although both lobes were fibrotic on the CT scan. On day 41, he had a total 4 Spiration EBV placed. One each in RML lateral segment (9 mm), RML medial segment (9 mm), RLL superior segment (9 mm) and RLL medial basilar segment (7 mm) [Figures 2 and 3]. The air leak improved significantly but still had small leak. Bronchoscopy was repeated 4 days later, and two additional Spiration EBVs were placed, 9 mm each, one in anterolateral and another in posterior basilar segment. Over next few days, his leak completely resolved. The patient was weaned off of positive pressure a week later to trach collar, and the chest tube was subsequently removed. A week later, he was completely liberated from ventilator, tracheostomy tube was downsized and eventually decannulated. He was transferred out of the ICU to long-term acute care for rehabilitation, and then ultimately was discharged to home. Three months later, he followed up in the pulmonary clinic. His tracheostomy site was completely healed. He was able to walk without shortness of breath, saturating 96 on ambient air and 91% on 6-min walk test. Repeat imaging showed hydropneumothorax which was an expected finding.
Figure 2 Arrows showing endobronchial valves
Figure 3 Bronchoscopic view of endobronchial valves
DISCUSSION
Alveolopleural fistula is a communication or fistula between an alveoli and the pleural space. We called it alveolopleural fistula instead of bronchopleural fistula because the patient had lung parenchyma necrosis followed by fistula development; in addition, the fistula was distal to the segmental bronchi.[34] Patient's with ARDS secondary to COVID-19 requiring high amounts of positive end expiratory pressure (PEEP) and are at higher risk in developing a pneumothorax. Parenchymal necrosis followed by fibrotic lung can increase the risk when patient is on positive pressure ventilation for long time. Many patients with a prolonged ventilator course are at risk of developing a secondary bacterial infection, which also increases the risk of pneumothorax and bronchopleural and alveolopleural fistula.[5] Significant coughing paroxysms add additional risk of pneumothorax. Positive pressure and higher amounts of PEEP can make it challenging to heal a pneumothorax, allowing complications of alveolopleural fistula to arise.
EBVs have been used since 2005 to treat alveolopleural and bronchopleural fistula in patients who are not considered a good surgical candidates.[6] EBV can treat these fistulas by allowing air to exit through the valve but not enter the lower segment. This is the first documented use of an EBV in the setting of COVID-19 that we could find. The placement of the valves, allowed a significant reduction in the air leak. This assisted in the patient's breathing trials on the ventilator and tracheostomy collar trials by reducing the overall volume loss through the fistula, ultimately allowing the patient to successfully liberated from the ventilator and have his chest tubes removed.
CONCLUSION
EBV can safely be used in patients with alveolopleural fistula secondary to COVID-19 ARDS.
Declaration of patient consent
The 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.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | REMDESIVIR, TOCILIZUMAB | DrugsGivenReaction | CC BY-NC-SA | 33686984 | 20,932,243 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Central nervous system lesion'. | Miliary tuberculosis in a paediatric patient with psoriasis.
We present a 16-year-old girl with a history of well-controlled psoriasis, on immunosuppression, who sought evaluation in the emergency department for 4 months of fever, cough and unintentional weight loss. The patient had seen multiple providers who had diagnosed her with community-acquired pneumonia, but she was unimproved after oral antibiotic therapy. On presentation, she was noted to be febrile, tachycardic and chronically ill-appearing. Her chest X-ray showed diffuse opacities and a right upper lobe cavitary lesion concerning for tuberculosis. A subsequent chest CT revealed miliary pulmonary nodules in addition to the cavitary lesion. The patient underwent subsequent brain MRI, which revealed multifocal ring-enhancing nodules consistent with parenchymal involvement. The patient was diagnosed with miliary tuberculosis and improved on quadruple therapy. Though rates of tuberculosis are increasing, rates remain low in children, though special consideration should be given to children who are immunosuppressed.
Background
Tuberculosis remains relatively rare in children compared with adults but select paediatric patient-populations remain at an increased risk, one such population being immunosuppressed children. Given the growing availability and application of immunomodulatory medications for both autoimmune and transplant indications, there exists a growing population of children who are at an increased risk for the acquisition and deleterious effects of tuberculosis.
Case presentation
A 16-year-old girl with a history of psoriasis presented to the emergency department for fever, cough and unintentional weight loss. Her symptoms began 4 months prior to presentation with intermittent, non-productive daytime cough associated with pleuritic chest pain. She describes daily tactile fevers and chills. She has also had intermittent diffuse, ‘crampy’ abdominal pain with associated non-bloody, non-bilious emesis occurring approximately three times per week. Additionally, she described nausea and anorexia, resulting in a 15 kg weight loss over the past 4 months. She denied upper respiratory symptoms, sore throat, dysphagia, haematemesis, haemoptysis, cyanosis, diarrhoea, melena, haematochezia, dysuria, haematuria or rashes. She denied syncope, presyncope or seizures. She reported her last menstrual period as 3 months prior and denied any current vaginal symptoms. She denied recent travel, known sick contacts, sexual activity or illicit and recreational drug use. She was born in Ethiopia, moved to the USA relatively soon after birth and last travelled there 9 years ago. She had no contact with recent international travellers or prisoners.
She reported that during the past 4 months, she had been seen at an urgent care facility multiple times and treated with three different oral antibiotics for pneumonia; she cannot recall the names of these prescriptions. She has also been seen in an outpatient gastroenterology clinic and had an oesophagogastroduodenoscopy that demonstrated oesophageal candidiasis, for which she was treated with fluconazole. She was previously healthy with the exception of psoriasis. Regarding her psoriasis, she reported that she previously had diffuse skin involvement, but has never had arthritis. She was initially treated with adalimumab, a monoclonal antibody against tumour necrosis factor (TNF)-α, but was changed to methotrexate after being diagnosed with pneumonia. Her psoriatic symptoms are currently well controlled. She presented to the emergency department due to lack of improvement in systemic symptoms after the above management and a new sensation of a racing heartbeat.
In the emergency department, her initial vital signs were: temperature 39.2°C, heart rate of 140 beats/min, respiratory rate of 18 breaths/min, blood pressure of 115/61 mm Hg, oxygen saturation of 94% on room air and weight 54.6 kg. On examination, she was tired and chronically ill-appearing, but non-toxic. Her physical examination was remarkable for tachycardia without murmur, bounding radial pulses and mild respiratory distress with asymmetrically (right>left) diminished basilar aeration. She does not have lymphadenopathy, hepatosplenomegaly, ascites or peripheral oedema. The remainder of her examination was normal. Laboratory studies were remarkable for normocytic anaemia, lymphopenia, hypoalbuminemia, elevated prothrombin time and elevated inflammatory markers. Electrolytes, transaminases, thyroid profile and urine pregnancy test were normal. HIV antibody and viral load were negative. Review of records shows that her outside chest X-ray was remarkable for rounded opacities scattered throughout both lungs and a right upper lobe cavitary lesion. A chest CT was obtained, which reveals a cavitary right upper lobe mass (figure 1).
Figure 1 Contrast-enhanced CT of the chest shows a 3 cm round right upper cavitary lesion as well as prominent miliary nodules within the right upper lobe on axillary section (panel A). Further sections show multiple large necrotic mediastinal lymph nodes (panel B). coronal reformatting allows visualisation of the cavitary lesion (panel C) and miliary nodules (panel D) in plane with mediastinal lymphadenopathy.
Differential diagnosis
The patient’s chest CT revealed a cavitary right upper lobe mass, miliary pulmonary nodules and necrotic mediastinal lymphadenopathy. The radiographical differential of cavitary lesions and miliary nodules included congenital pulmonary airway malformations, lung abscesses, septic emboli, tuberculosis, histoplasmosis, blastomycosis, sarcoidosis and malignancies.1 2 However, the combination of findings in the setting of immunosuppression were highly suspicious for Mycobacterium tuberculosis.3
Investigations
Due to the strong suspicion for M. tuberculosis after her chest imaging, sputum PCR and cultures were obtained and were positive. She was diagnosed with miliary tuberculosis. Given her immunosuppression, she underwent evaluation for haematogenous seeding of M. tuberculosis. Brain MRI revealed multifocal ring-enhancing nodules consistent with parenchymal central nervous system (CNS) involvement (figure 2). MRI did not show meningeal enhancement, and a subsequent lumbar puncture revealed unremarkable cerebrospinal fluid parameters.
Figure 2 Contrast-enhanced MRI of the brain shows multifocal ring-enhancing lesions in the pons and cerebellum (panel A and D), and throughout the supratentorial brain (panel B, C and E), consistent with caseating tuberculous granulomas.
Treatment and clinical course
The patient was admitted to the hospital and maintained under negative pressure isolation. She was started on isoniazid, pyrazinamide, rifampin and moxifloxacin. Resistance testing revealed a pan-sensitive isolate. The local health department was notified, and her family members were tested for tuberculosis. She was discharged with a plan for extended direct observed therapy.
Outcome and follow-up
The patient remained on medication for 1 year following diagnosis and did not endorse any side effects for her antimycobacterial therapy. Throughout her time on therapy, as well as the subsequent 12 months, she has remained free of any flares of her psoriasis. Her psoriasis is now being managed with topical medications only. The patient was enrolling in college in the Autumn of 2020. Owing to her hospitalisation for tuberculosis and interest in her presentation, she was considering pursuing a course of study involving public health and/or medicine.
Discussion
Cases of disseminated or military tuberculosis, a disease caused by the acid-fast bacillus M. tuberculosis, secondary to TNF-α inhibitors are becoming more commonplace, though they remain rare in paediatric patients.4–8 However, the increasing use of immunomodulatory medications such as TNF-α inhibitors is increasing the risk of presentation. Testing for latent tuberculosis remains imperative prior to initiating immunomodulatory therapy, but it is unable to prevent all infections. Well-established treatment guidelines exist, but not all antituberculosis drugs have been well-studied in children.9 Furthermore, as was the case here, treatment regimens must be altered when there is CNS involvement.10
According to the Centers for Disease Control and Prevention, one-quarter of the world’s population is infected with M. tuberculosis.11 The incidence in the USA has fallen dramatically from 52.6/100 000 persons in 1953 to 2.9/100 000 persons in 2016.11 Children constitute approximately 14% of new cases.11 The falling rates of tuberculosis, and the low incidence in children, likely played a role in the patient’s delayed diagnosis. Risk factors for infection include Asian descent, recent immigration to the USA, diabetes, immunodeficiency, homelessness and incarceration.11 In the majority of infected persons, infection is followed by latent disease with no clinical symptoms.12 In children under 10 years, age of exposure is inversely correlated with the probability of developing clinical disease; nearly 50% of exposed infants under 1 year become symptomatic.12 13 There is a smaller peak of infection in adolescence, with the vast majority of these patients developing pulmonary disease.12 13
The spectrum of clinical disease caused by M. tuberculosis includes asymptomatic infection (latent tuberculosis), respiratory symptoms (pulmonary tuberculosis), and multisystem disease with or without pulmonary involvement (miliary tuberculosis).14 15 The age at acquisition strongly influences the form of disease that develops in the child, with one study looking at children ages 0–18 years showing that more than 60% present with disseminated disease.14–16 For children with pulmonary disease, the hallmark clinical symptoms in all age groups are chronic cough, fever and weight loss.15 17 Cough is rarely productive in infants or children, but may be in adolescents.15 Infants more typically present with examination features compatible with pneumonia, whereas adolescents typically lack physical findings.15 Chest X-ray may be diagnostic, though CT has higher sensitivity.3 Thick-walled cavitary lesions with ipsilateral hilar or paratracheal lymphadenopathy, miliary nodules and pleural effusions are all suggestive of pulmonary tuberculosis.3
Infants are much more likely than immunocompetent older children to develop extrapulmonary tuberculosis.12 15 18 Moreover, paediatric patients have an increased risk of CNS involvement.8 While no large studies have been conducted in children, retrospective reviews in adults have not been able to establish a clear link between CNS involvement and outcome.19 However, in two studies of adult patients maintained on antiTNF-α, such as adalimumab, more than half of those who contracted tuberculosis developed extrapulmonary manifestations.20 21 Extrapulmonary tuberculosis presents with variable symptoms depending on the affected organ system. The most common sites of extrapulmonary tuberculosis are lymph nodes, CNS, pleura, and the skeletal system.15 18 CNS tuberculosis is seen in approximately 50% of extrapulmonary cases and most often manifests as basilar meningitis; parenchymal tuberculomas are seen less frequently.15 22 23 CT or MRI can be used to screen for CNS tuberculosis.18 Obstructive hydrocephalus is the most common imaging finding, followed by basilar meningeal enhancement and infarction of the basal ganglia, thalami or anterior limbs of the internal capsules.18 Disseminated ring-enhancing caseating granulomas may be seen, and are often infratentorial in children.18 Abdominal tuberculosis is less common, but may include hepatic, splenic, renal, gastrointestinal, most commonly ileocecal or adrenal involvement.24
Diagnosis of tuberculosis is definitively established by the combination of a suspected exposure, clinical and imaging features consistent with disease, and isolation of M. tuberculosis in bacterial culture from sputum, bronchoscopy or biopsy specimen.12 14 25 Unfortunately, growth of M. tuberculosis in culture medium typically requires 1–2 weeks.25 Thus, when clinical suspicion of pulmonary tuberculosis is moderate or high, the Infectious Diseases Society of America (IDSA) recommends sending three sputum samples for acid-fast staining and nucleic acid amplification testing.25 The use of the two tests in combination on multiple samples increases sensitivity and specificity, and provides results in hours.25 However, false-negative results occur, and these tests should not be used to rule out the diagnosis.25
Treatment of tuberculosis depends on clinical manifestations. Patients with latent tuberculosis are usually treated with 9 months of isoniazid.26 For patients with pulmonary tuberculosis, the IDSA recommends 8 weeks of isoniazid, pyrazinamide, rifampin and ethambutol, followed by 18 weeks of isoniazid and rifampin.9 In children with CNS disease, the American Academy of Pediatrics recommends isoniazid, pyrazinamide, rifampin, and ethionamide or an aminoglycoside for 8 weeks followed by 28–40 weeks of isoniazid and rifampin.9 In adults, moxifloxacin may be used in place of ethionamide.27–29 Molecular testing for rifampin sensitivity is recommended in patients with risk factors for resistance.25 In tuberculous meningitis, the IDSA recommends the addition of corticosteroids tapered over 6–8 weeks.9 Corticosteroids should also be considered for evidence of immune reconstitution inflammatory syndrome.30 In the USA, tuberculosis is a reportable disease, and therapy is typically supervised by the community health department.31 Contacts of persons with infectious tuberculosis should be screened with tuberculosis skin testing or interferon gamma release assay at the time of discovery and 8–12 weeks later.32 Those with positive tests should be treated for latent tuberculosis.26 Young children are at increased risk of progression to active disease, and are often given prophylactic isoniazid in consultation with an infectious disease specialist.33
Learning points
Children account for approximately 14% of all diagnosis of tuberculosis.11
The spectrum of presentation of children with tuberculosis range from asymptomatic to multisystem involvement, and is strongly influenced by age.8 14–16
Central nervous system involvement occurs in 50% of patients with extrapulmonary involvement.8 15 22 23
The use of tumour necrosis factor-α inhibitors increase the risk of acquiring tuberculosis.4–6
Contributors: BB, JK, JP, SD, LP and SK: Conception and design, acquisition of data or analysis and interpretation of data. BB, JK, JP, SD, LP and SK: Drafting the article or revising it critically for important intellectual content. BB, JK, JP, SD, LP and SK: Final approval of the version published. BB, JK, JP, SD, LP and SK: Agreement to be accountable for the article and to ensure that all questions regarding the accuracy or integrity of the article are investigated and resolved. BB, JK, JP, SD, LP and SK: Agree with revisions and resubmission.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer-reviewed. | METHOTREXATE | DrugsGivenReaction | CC BY-NC | 33687934 | 19,840,401 | 2021-03-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disseminated tuberculosis'. | Miliary tuberculosis in a paediatric patient with psoriasis.
We present a 16-year-old girl with a history of well-controlled psoriasis, on immunosuppression, who sought evaluation in the emergency department for 4 months of fever, cough and unintentional weight loss. The patient had seen multiple providers who had diagnosed her with community-acquired pneumonia, but she was unimproved after oral antibiotic therapy. On presentation, she was noted to be febrile, tachycardic and chronically ill-appearing. Her chest X-ray showed diffuse opacities and a right upper lobe cavitary lesion concerning for tuberculosis. A subsequent chest CT revealed miliary pulmonary nodules in addition to the cavitary lesion. The patient underwent subsequent brain MRI, which revealed multifocal ring-enhancing nodules consistent with parenchymal involvement. The patient was diagnosed with miliary tuberculosis and improved on quadruple therapy. Though rates of tuberculosis are increasing, rates remain low in children, though special consideration should be given to children who are immunosuppressed.
Background
Tuberculosis remains relatively rare in children compared with adults but select paediatric patient-populations remain at an increased risk, one such population being immunosuppressed children. Given the growing availability and application of immunomodulatory medications for both autoimmune and transplant indications, there exists a growing population of children who are at an increased risk for the acquisition and deleterious effects of tuberculosis.
Case presentation
A 16-year-old girl with a history of psoriasis presented to the emergency department for fever, cough and unintentional weight loss. Her symptoms began 4 months prior to presentation with intermittent, non-productive daytime cough associated with pleuritic chest pain. She describes daily tactile fevers and chills. She has also had intermittent diffuse, ‘crampy’ abdominal pain with associated non-bloody, non-bilious emesis occurring approximately three times per week. Additionally, she described nausea and anorexia, resulting in a 15 kg weight loss over the past 4 months. She denied upper respiratory symptoms, sore throat, dysphagia, haematemesis, haemoptysis, cyanosis, diarrhoea, melena, haematochezia, dysuria, haematuria or rashes. She denied syncope, presyncope or seizures. She reported her last menstrual period as 3 months prior and denied any current vaginal symptoms. She denied recent travel, known sick contacts, sexual activity or illicit and recreational drug use. She was born in Ethiopia, moved to the USA relatively soon after birth and last travelled there 9 years ago. She had no contact with recent international travellers or prisoners.
She reported that during the past 4 months, she had been seen at an urgent care facility multiple times and treated with three different oral antibiotics for pneumonia; she cannot recall the names of these prescriptions. She has also been seen in an outpatient gastroenterology clinic and had an oesophagogastroduodenoscopy that demonstrated oesophageal candidiasis, for which she was treated with fluconazole. She was previously healthy with the exception of psoriasis. Regarding her psoriasis, she reported that she previously had diffuse skin involvement, but has never had arthritis. She was initially treated with adalimumab, a monoclonal antibody against tumour necrosis factor (TNF)-α, but was changed to methotrexate after being diagnosed with pneumonia. Her psoriatic symptoms are currently well controlled. She presented to the emergency department due to lack of improvement in systemic symptoms after the above management and a new sensation of a racing heartbeat.
In the emergency department, her initial vital signs were: temperature 39.2°C, heart rate of 140 beats/min, respiratory rate of 18 breaths/min, blood pressure of 115/61 mm Hg, oxygen saturation of 94% on room air and weight 54.6 kg. On examination, she was tired and chronically ill-appearing, but non-toxic. Her physical examination was remarkable for tachycardia without murmur, bounding radial pulses and mild respiratory distress with asymmetrically (right>left) diminished basilar aeration. She does not have lymphadenopathy, hepatosplenomegaly, ascites or peripheral oedema. The remainder of her examination was normal. Laboratory studies were remarkable for normocytic anaemia, lymphopenia, hypoalbuminemia, elevated prothrombin time and elevated inflammatory markers. Electrolytes, transaminases, thyroid profile and urine pregnancy test were normal. HIV antibody and viral load were negative. Review of records shows that her outside chest X-ray was remarkable for rounded opacities scattered throughout both lungs and a right upper lobe cavitary lesion. A chest CT was obtained, which reveals a cavitary right upper lobe mass (figure 1).
Figure 1 Contrast-enhanced CT of the chest shows a 3 cm round right upper cavitary lesion as well as prominent miliary nodules within the right upper lobe on axillary section (panel A). Further sections show multiple large necrotic mediastinal lymph nodes (panel B). coronal reformatting allows visualisation of the cavitary lesion (panel C) and miliary nodules (panel D) in plane with mediastinal lymphadenopathy.
Differential diagnosis
The patient’s chest CT revealed a cavitary right upper lobe mass, miliary pulmonary nodules and necrotic mediastinal lymphadenopathy. The radiographical differential of cavitary lesions and miliary nodules included congenital pulmonary airway malformations, lung abscesses, septic emboli, tuberculosis, histoplasmosis, blastomycosis, sarcoidosis and malignancies.1 2 However, the combination of findings in the setting of immunosuppression were highly suspicious for Mycobacterium tuberculosis.3
Investigations
Due to the strong suspicion for M. tuberculosis after her chest imaging, sputum PCR and cultures were obtained and were positive. She was diagnosed with miliary tuberculosis. Given her immunosuppression, she underwent evaluation for haematogenous seeding of M. tuberculosis. Brain MRI revealed multifocal ring-enhancing nodules consistent with parenchymal central nervous system (CNS) involvement (figure 2). MRI did not show meningeal enhancement, and a subsequent lumbar puncture revealed unremarkable cerebrospinal fluid parameters.
Figure 2 Contrast-enhanced MRI of the brain shows multifocal ring-enhancing lesions in the pons and cerebellum (panel A and D), and throughout the supratentorial brain (panel B, C and E), consistent with caseating tuberculous granulomas.
Treatment and clinical course
The patient was admitted to the hospital and maintained under negative pressure isolation. She was started on isoniazid, pyrazinamide, rifampin and moxifloxacin. Resistance testing revealed a pan-sensitive isolate. The local health department was notified, and her family members were tested for tuberculosis. She was discharged with a plan for extended direct observed therapy.
Outcome and follow-up
The patient remained on medication for 1 year following diagnosis and did not endorse any side effects for her antimycobacterial therapy. Throughout her time on therapy, as well as the subsequent 12 months, she has remained free of any flares of her psoriasis. Her psoriasis is now being managed with topical medications only. The patient was enrolling in college in the Autumn of 2020. Owing to her hospitalisation for tuberculosis and interest in her presentation, she was considering pursuing a course of study involving public health and/or medicine.
Discussion
Cases of disseminated or military tuberculosis, a disease caused by the acid-fast bacillus M. tuberculosis, secondary to TNF-α inhibitors are becoming more commonplace, though they remain rare in paediatric patients.4–8 However, the increasing use of immunomodulatory medications such as TNF-α inhibitors is increasing the risk of presentation. Testing for latent tuberculosis remains imperative prior to initiating immunomodulatory therapy, but it is unable to prevent all infections. Well-established treatment guidelines exist, but not all antituberculosis drugs have been well-studied in children.9 Furthermore, as was the case here, treatment regimens must be altered when there is CNS involvement.10
According to the Centers for Disease Control and Prevention, one-quarter of the world’s population is infected with M. tuberculosis.11 The incidence in the USA has fallen dramatically from 52.6/100 000 persons in 1953 to 2.9/100 000 persons in 2016.11 Children constitute approximately 14% of new cases.11 The falling rates of tuberculosis, and the low incidence in children, likely played a role in the patient’s delayed diagnosis. Risk factors for infection include Asian descent, recent immigration to the USA, diabetes, immunodeficiency, homelessness and incarceration.11 In the majority of infected persons, infection is followed by latent disease with no clinical symptoms.12 In children under 10 years, age of exposure is inversely correlated with the probability of developing clinical disease; nearly 50% of exposed infants under 1 year become symptomatic.12 13 There is a smaller peak of infection in adolescence, with the vast majority of these patients developing pulmonary disease.12 13
The spectrum of clinical disease caused by M. tuberculosis includes asymptomatic infection (latent tuberculosis), respiratory symptoms (pulmonary tuberculosis), and multisystem disease with or without pulmonary involvement (miliary tuberculosis).14 15 The age at acquisition strongly influences the form of disease that develops in the child, with one study looking at children ages 0–18 years showing that more than 60% present with disseminated disease.14–16 For children with pulmonary disease, the hallmark clinical symptoms in all age groups are chronic cough, fever and weight loss.15 17 Cough is rarely productive in infants or children, but may be in adolescents.15 Infants more typically present with examination features compatible with pneumonia, whereas adolescents typically lack physical findings.15 Chest X-ray may be diagnostic, though CT has higher sensitivity.3 Thick-walled cavitary lesions with ipsilateral hilar or paratracheal lymphadenopathy, miliary nodules and pleural effusions are all suggestive of pulmonary tuberculosis.3
Infants are much more likely than immunocompetent older children to develop extrapulmonary tuberculosis.12 15 18 Moreover, paediatric patients have an increased risk of CNS involvement.8 While no large studies have been conducted in children, retrospective reviews in adults have not been able to establish a clear link between CNS involvement and outcome.19 However, in two studies of adult patients maintained on antiTNF-α, such as adalimumab, more than half of those who contracted tuberculosis developed extrapulmonary manifestations.20 21 Extrapulmonary tuberculosis presents with variable symptoms depending on the affected organ system. The most common sites of extrapulmonary tuberculosis are lymph nodes, CNS, pleura, and the skeletal system.15 18 CNS tuberculosis is seen in approximately 50% of extrapulmonary cases and most often manifests as basilar meningitis; parenchymal tuberculomas are seen less frequently.15 22 23 CT or MRI can be used to screen for CNS tuberculosis.18 Obstructive hydrocephalus is the most common imaging finding, followed by basilar meningeal enhancement and infarction of the basal ganglia, thalami or anterior limbs of the internal capsules.18 Disseminated ring-enhancing caseating granulomas may be seen, and are often infratentorial in children.18 Abdominal tuberculosis is less common, but may include hepatic, splenic, renal, gastrointestinal, most commonly ileocecal or adrenal involvement.24
Diagnosis of tuberculosis is definitively established by the combination of a suspected exposure, clinical and imaging features consistent with disease, and isolation of M. tuberculosis in bacterial culture from sputum, bronchoscopy or biopsy specimen.12 14 25 Unfortunately, growth of M. tuberculosis in culture medium typically requires 1–2 weeks.25 Thus, when clinical suspicion of pulmonary tuberculosis is moderate or high, the Infectious Diseases Society of America (IDSA) recommends sending three sputum samples for acid-fast staining and nucleic acid amplification testing.25 The use of the two tests in combination on multiple samples increases sensitivity and specificity, and provides results in hours.25 However, false-negative results occur, and these tests should not be used to rule out the diagnosis.25
Treatment of tuberculosis depends on clinical manifestations. Patients with latent tuberculosis are usually treated with 9 months of isoniazid.26 For patients with pulmonary tuberculosis, the IDSA recommends 8 weeks of isoniazid, pyrazinamide, rifampin and ethambutol, followed by 18 weeks of isoniazid and rifampin.9 In children with CNS disease, the American Academy of Pediatrics recommends isoniazid, pyrazinamide, rifampin, and ethionamide or an aminoglycoside for 8 weeks followed by 28–40 weeks of isoniazid and rifampin.9 In adults, moxifloxacin may be used in place of ethionamide.27–29 Molecular testing for rifampin sensitivity is recommended in patients with risk factors for resistance.25 In tuberculous meningitis, the IDSA recommends the addition of corticosteroids tapered over 6–8 weeks.9 Corticosteroids should also be considered for evidence of immune reconstitution inflammatory syndrome.30 In the USA, tuberculosis is a reportable disease, and therapy is typically supervised by the community health department.31 Contacts of persons with infectious tuberculosis should be screened with tuberculosis skin testing or interferon gamma release assay at the time of discovery and 8–12 weeks later.32 Those with positive tests should be treated for latent tuberculosis.26 Young children are at increased risk of progression to active disease, and are often given prophylactic isoniazid in consultation with an infectious disease specialist.33
Learning points
Children account for approximately 14% of all diagnosis of tuberculosis.11
The spectrum of presentation of children with tuberculosis range from asymptomatic to multisystem involvement, and is strongly influenced by age.8 14–16
Central nervous system involvement occurs in 50% of patients with extrapulmonary involvement.8 15 22 23
The use of tumour necrosis factor-α inhibitors increase the risk of acquiring tuberculosis.4–6
Contributors: BB, JK, JP, SD, LP and SK: Conception and design, acquisition of data or analysis and interpretation of data. BB, JK, JP, SD, LP and SK: Drafting the article or revising it critically for important intellectual content. BB, JK, JP, SD, LP and SK: Final approval of the version published. BB, JK, JP, SD, LP and SK: Agreement to be accountable for the article and to ensure that all questions regarding the accuracy or integrity of the article are investigated and resolved. BB, JK, JP, SD, LP and SK: Agree with revisions and resubmission.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer-reviewed. | METHOTREXATE | DrugsGivenReaction | CC BY-NC | 33687934 | 19,840,401 | 2021-03-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Miliary tuberculosis in a paediatric patient with psoriasis.
We present a 16-year-old girl with a history of well-controlled psoriasis, on immunosuppression, who sought evaluation in the emergency department for 4 months of fever, cough and unintentional weight loss. The patient had seen multiple providers who had diagnosed her with community-acquired pneumonia, but she was unimproved after oral antibiotic therapy. On presentation, she was noted to be febrile, tachycardic and chronically ill-appearing. Her chest X-ray showed diffuse opacities and a right upper lobe cavitary lesion concerning for tuberculosis. A subsequent chest CT revealed miliary pulmonary nodules in addition to the cavitary lesion. The patient underwent subsequent brain MRI, which revealed multifocal ring-enhancing nodules consistent with parenchymal involvement. The patient was diagnosed with miliary tuberculosis and improved on quadruple therapy. Though rates of tuberculosis are increasing, rates remain low in children, though special consideration should be given to children who are immunosuppressed.
Background
Tuberculosis remains relatively rare in children compared with adults but select paediatric patient-populations remain at an increased risk, one such population being immunosuppressed children. Given the growing availability and application of immunomodulatory medications for both autoimmune and transplant indications, there exists a growing population of children who are at an increased risk for the acquisition and deleterious effects of tuberculosis.
Case presentation
A 16-year-old girl with a history of psoriasis presented to the emergency department for fever, cough and unintentional weight loss. Her symptoms began 4 months prior to presentation with intermittent, non-productive daytime cough associated with pleuritic chest pain. She describes daily tactile fevers and chills. She has also had intermittent diffuse, ‘crampy’ abdominal pain with associated non-bloody, non-bilious emesis occurring approximately three times per week. Additionally, she described nausea and anorexia, resulting in a 15 kg weight loss over the past 4 months. She denied upper respiratory symptoms, sore throat, dysphagia, haematemesis, haemoptysis, cyanosis, diarrhoea, melena, haematochezia, dysuria, haematuria or rashes. She denied syncope, presyncope or seizures. She reported her last menstrual period as 3 months prior and denied any current vaginal symptoms. She denied recent travel, known sick contacts, sexual activity or illicit and recreational drug use. She was born in Ethiopia, moved to the USA relatively soon after birth and last travelled there 9 years ago. She had no contact with recent international travellers or prisoners.
She reported that during the past 4 months, she had been seen at an urgent care facility multiple times and treated with three different oral antibiotics for pneumonia; she cannot recall the names of these prescriptions. She has also been seen in an outpatient gastroenterology clinic and had an oesophagogastroduodenoscopy that demonstrated oesophageal candidiasis, for which she was treated with fluconazole. She was previously healthy with the exception of psoriasis. Regarding her psoriasis, she reported that she previously had diffuse skin involvement, but has never had arthritis. She was initially treated with adalimumab, a monoclonal antibody against tumour necrosis factor (TNF)-α, but was changed to methotrexate after being diagnosed with pneumonia. Her psoriatic symptoms are currently well controlled. She presented to the emergency department due to lack of improvement in systemic symptoms after the above management and a new sensation of a racing heartbeat.
In the emergency department, her initial vital signs were: temperature 39.2°C, heart rate of 140 beats/min, respiratory rate of 18 breaths/min, blood pressure of 115/61 mm Hg, oxygen saturation of 94% on room air and weight 54.6 kg. On examination, she was tired and chronically ill-appearing, but non-toxic. Her physical examination was remarkable for tachycardia without murmur, bounding radial pulses and mild respiratory distress with asymmetrically (right>left) diminished basilar aeration. She does not have lymphadenopathy, hepatosplenomegaly, ascites or peripheral oedema. The remainder of her examination was normal. Laboratory studies were remarkable for normocytic anaemia, lymphopenia, hypoalbuminemia, elevated prothrombin time and elevated inflammatory markers. Electrolytes, transaminases, thyroid profile and urine pregnancy test were normal. HIV antibody and viral load were negative. Review of records shows that her outside chest X-ray was remarkable for rounded opacities scattered throughout both lungs and a right upper lobe cavitary lesion. A chest CT was obtained, which reveals a cavitary right upper lobe mass (figure 1).
Figure 1 Contrast-enhanced CT of the chest shows a 3 cm round right upper cavitary lesion as well as prominent miliary nodules within the right upper lobe on axillary section (panel A). Further sections show multiple large necrotic mediastinal lymph nodes (panel B). coronal reformatting allows visualisation of the cavitary lesion (panel C) and miliary nodules (panel D) in plane with mediastinal lymphadenopathy.
Differential diagnosis
The patient’s chest CT revealed a cavitary right upper lobe mass, miliary pulmonary nodules and necrotic mediastinal lymphadenopathy. The radiographical differential of cavitary lesions and miliary nodules included congenital pulmonary airway malformations, lung abscesses, septic emboli, tuberculosis, histoplasmosis, blastomycosis, sarcoidosis and malignancies.1 2 However, the combination of findings in the setting of immunosuppression were highly suspicious for Mycobacterium tuberculosis.3
Investigations
Due to the strong suspicion for M. tuberculosis after her chest imaging, sputum PCR and cultures were obtained and were positive. She was diagnosed with miliary tuberculosis. Given her immunosuppression, she underwent evaluation for haematogenous seeding of M. tuberculosis. Brain MRI revealed multifocal ring-enhancing nodules consistent with parenchymal central nervous system (CNS) involvement (figure 2). MRI did not show meningeal enhancement, and a subsequent lumbar puncture revealed unremarkable cerebrospinal fluid parameters.
Figure 2 Contrast-enhanced MRI of the brain shows multifocal ring-enhancing lesions in the pons and cerebellum (panel A and D), and throughout the supratentorial brain (panel B, C and E), consistent with caseating tuberculous granulomas.
Treatment and clinical course
The patient was admitted to the hospital and maintained under negative pressure isolation. She was started on isoniazid, pyrazinamide, rifampin and moxifloxacin. Resistance testing revealed a pan-sensitive isolate. The local health department was notified, and her family members were tested for tuberculosis. She was discharged with a plan for extended direct observed therapy.
Outcome and follow-up
The patient remained on medication for 1 year following diagnosis and did not endorse any side effects for her antimycobacterial therapy. Throughout her time on therapy, as well as the subsequent 12 months, she has remained free of any flares of her psoriasis. Her psoriasis is now being managed with topical medications only. The patient was enrolling in college in the Autumn of 2020. Owing to her hospitalisation for tuberculosis and interest in her presentation, she was considering pursuing a course of study involving public health and/or medicine.
Discussion
Cases of disseminated or military tuberculosis, a disease caused by the acid-fast bacillus M. tuberculosis, secondary to TNF-α inhibitors are becoming more commonplace, though they remain rare in paediatric patients.4–8 However, the increasing use of immunomodulatory medications such as TNF-α inhibitors is increasing the risk of presentation. Testing for latent tuberculosis remains imperative prior to initiating immunomodulatory therapy, but it is unable to prevent all infections. Well-established treatment guidelines exist, but not all antituberculosis drugs have been well-studied in children.9 Furthermore, as was the case here, treatment regimens must be altered when there is CNS involvement.10
According to the Centers for Disease Control and Prevention, one-quarter of the world’s population is infected with M. tuberculosis.11 The incidence in the USA has fallen dramatically from 52.6/100 000 persons in 1953 to 2.9/100 000 persons in 2016.11 Children constitute approximately 14% of new cases.11 The falling rates of tuberculosis, and the low incidence in children, likely played a role in the patient’s delayed diagnosis. Risk factors for infection include Asian descent, recent immigration to the USA, diabetes, immunodeficiency, homelessness and incarceration.11 In the majority of infected persons, infection is followed by latent disease with no clinical symptoms.12 In children under 10 years, age of exposure is inversely correlated with the probability of developing clinical disease; nearly 50% of exposed infants under 1 year become symptomatic.12 13 There is a smaller peak of infection in adolescence, with the vast majority of these patients developing pulmonary disease.12 13
The spectrum of clinical disease caused by M. tuberculosis includes asymptomatic infection (latent tuberculosis), respiratory symptoms (pulmonary tuberculosis), and multisystem disease with or without pulmonary involvement (miliary tuberculosis).14 15 The age at acquisition strongly influences the form of disease that develops in the child, with one study looking at children ages 0–18 years showing that more than 60% present with disseminated disease.14–16 For children with pulmonary disease, the hallmark clinical symptoms in all age groups are chronic cough, fever and weight loss.15 17 Cough is rarely productive in infants or children, but may be in adolescents.15 Infants more typically present with examination features compatible with pneumonia, whereas adolescents typically lack physical findings.15 Chest X-ray may be diagnostic, though CT has higher sensitivity.3 Thick-walled cavitary lesions with ipsilateral hilar or paratracheal lymphadenopathy, miliary nodules and pleural effusions are all suggestive of pulmonary tuberculosis.3
Infants are much more likely than immunocompetent older children to develop extrapulmonary tuberculosis.12 15 18 Moreover, paediatric patients have an increased risk of CNS involvement.8 While no large studies have been conducted in children, retrospective reviews in adults have not been able to establish a clear link between CNS involvement and outcome.19 However, in two studies of adult patients maintained on antiTNF-α, such as adalimumab, more than half of those who contracted tuberculosis developed extrapulmonary manifestations.20 21 Extrapulmonary tuberculosis presents with variable symptoms depending on the affected organ system. The most common sites of extrapulmonary tuberculosis are lymph nodes, CNS, pleura, and the skeletal system.15 18 CNS tuberculosis is seen in approximately 50% of extrapulmonary cases and most often manifests as basilar meningitis; parenchymal tuberculomas are seen less frequently.15 22 23 CT or MRI can be used to screen for CNS tuberculosis.18 Obstructive hydrocephalus is the most common imaging finding, followed by basilar meningeal enhancement and infarction of the basal ganglia, thalami or anterior limbs of the internal capsules.18 Disseminated ring-enhancing caseating granulomas may be seen, and are often infratentorial in children.18 Abdominal tuberculosis is less common, but may include hepatic, splenic, renal, gastrointestinal, most commonly ileocecal or adrenal involvement.24
Diagnosis of tuberculosis is definitively established by the combination of a suspected exposure, clinical and imaging features consistent with disease, and isolation of M. tuberculosis in bacterial culture from sputum, bronchoscopy or biopsy specimen.12 14 25 Unfortunately, growth of M. tuberculosis in culture medium typically requires 1–2 weeks.25 Thus, when clinical suspicion of pulmonary tuberculosis is moderate or high, the Infectious Diseases Society of America (IDSA) recommends sending three sputum samples for acid-fast staining and nucleic acid amplification testing.25 The use of the two tests in combination on multiple samples increases sensitivity and specificity, and provides results in hours.25 However, false-negative results occur, and these tests should not be used to rule out the diagnosis.25
Treatment of tuberculosis depends on clinical manifestations. Patients with latent tuberculosis are usually treated with 9 months of isoniazid.26 For patients with pulmonary tuberculosis, the IDSA recommends 8 weeks of isoniazid, pyrazinamide, rifampin and ethambutol, followed by 18 weeks of isoniazid and rifampin.9 In children with CNS disease, the American Academy of Pediatrics recommends isoniazid, pyrazinamide, rifampin, and ethionamide or an aminoglycoside for 8 weeks followed by 28–40 weeks of isoniazid and rifampin.9 In adults, moxifloxacin may be used in place of ethionamide.27–29 Molecular testing for rifampin sensitivity is recommended in patients with risk factors for resistance.25 In tuberculous meningitis, the IDSA recommends the addition of corticosteroids tapered over 6–8 weeks.9 Corticosteroids should also be considered for evidence of immune reconstitution inflammatory syndrome.30 In the USA, tuberculosis is a reportable disease, and therapy is typically supervised by the community health department.31 Contacts of persons with infectious tuberculosis should be screened with tuberculosis skin testing or interferon gamma release assay at the time of discovery and 8–12 weeks later.32 Those with positive tests should be treated for latent tuberculosis.26 Young children are at increased risk of progression to active disease, and are often given prophylactic isoniazid in consultation with an infectious disease specialist.33
Learning points
Children account for approximately 14% of all diagnosis of tuberculosis.11
The spectrum of presentation of children with tuberculosis range from asymptomatic to multisystem involvement, and is strongly influenced by age.8 14–16
Central nervous system involvement occurs in 50% of patients with extrapulmonary involvement.8 15 22 23
The use of tumour necrosis factor-α inhibitors increase the risk of acquiring tuberculosis.4–6
Contributors: BB, JK, JP, SD, LP and SK: Conception and design, acquisition of data or analysis and interpretation of data. BB, JK, JP, SD, LP and SK: Drafting the article or revising it critically for important intellectual content. BB, JK, JP, SD, LP and SK: Final approval of the version published. BB, JK, JP, SD, LP and SK: Agreement to be accountable for the article and to ensure that all questions regarding the accuracy or integrity of the article are investigated and resolved. BB, JK, JP, SD, LP and SK: Agree with revisions and resubmission.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer-reviewed. | METHOTREXATE | DrugsGivenReaction | CC BY-NC | 33687934 | 19,840,401 | 2021-03-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Palpitations'. | Miliary tuberculosis in a paediatric patient with psoriasis.
We present a 16-year-old girl with a history of well-controlled psoriasis, on immunosuppression, who sought evaluation in the emergency department for 4 months of fever, cough and unintentional weight loss. The patient had seen multiple providers who had diagnosed her with community-acquired pneumonia, but she was unimproved after oral antibiotic therapy. On presentation, she was noted to be febrile, tachycardic and chronically ill-appearing. Her chest X-ray showed diffuse opacities and a right upper lobe cavitary lesion concerning for tuberculosis. A subsequent chest CT revealed miliary pulmonary nodules in addition to the cavitary lesion. The patient underwent subsequent brain MRI, which revealed multifocal ring-enhancing nodules consistent with parenchymal involvement. The patient was diagnosed with miliary tuberculosis and improved on quadruple therapy. Though rates of tuberculosis are increasing, rates remain low in children, though special consideration should be given to children who are immunosuppressed.
Background
Tuberculosis remains relatively rare in children compared with adults but select paediatric patient-populations remain at an increased risk, one such population being immunosuppressed children. Given the growing availability and application of immunomodulatory medications for both autoimmune and transplant indications, there exists a growing population of children who are at an increased risk for the acquisition and deleterious effects of tuberculosis.
Case presentation
A 16-year-old girl with a history of psoriasis presented to the emergency department for fever, cough and unintentional weight loss. Her symptoms began 4 months prior to presentation with intermittent, non-productive daytime cough associated with pleuritic chest pain. She describes daily tactile fevers and chills. She has also had intermittent diffuse, ‘crampy’ abdominal pain with associated non-bloody, non-bilious emesis occurring approximately three times per week. Additionally, she described nausea and anorexia, resulting in a 15 kg weight loss over the past 4 months. She denied upper respiratory symptoms, sore throat, dysphagia, haematemesis, haemoptysis, cyanosis, diarrhoea, melena, haematochezia, dysuria, haematuria or rashes. She denied syncope, presyncope or seizures. She reported her last menstrual period as 3 months prior and denied any current vaginal symptoms. She denied recent travel, known sick contacts, sexual activity or illicit and recreational drug use. She was born in Ethiopia, moved to the USA relatively soon after birth and last travelled there 9 years ago. She had no contact with recent international travellers or prisoners.
She reported that during the past 4 months, she had been seen at an urgent care facility multiple times and treated with three different oral antibiotics for pneumonia; she cannot recall the names of these prescriptions. She has also been seen in an outpatient gastroenterology clinic and had an oesophagogastroduodenoscopy that demonstrated oesophageal candidiasis, for which she was treated with fluconazole. She was previously healthy with the exception of psoriasis. Regarding her psoriasis, she reported that she previously had diffuse skin involvement, but has never had arthritis. She was initially treated with adalimumab, a monoclonal antibody against tumour necrosis factor (TNF)-α, but was changed to methotrexate after being diagnosed with pneumonia. Her psoriatic symptoms are currently well controlled. She presented to the emergency department due to lack of improvement in systemic symptoms after the above management and a new sensation of a racing heartbeat.
In the emergency department, her initial vital signs were: temperature 39.2°C, heart rate of 140 beats/min, respiratory rate of 18 breaths/min, blood pressure of 115/61 mm Hg, oxygen saturation of 94% on room air and weight 54.6 kg. On examination, she was tired and chronically ill-appearing, but non-toxic. Her physical examination was remarkable for tachycardia without murmur, bounding radial pulses and mild respiratory distress with asymmetrically (right>left) diminished basilar aeration. She does not have lymphadenopathy, hepatosplenomegaly, ascites or peripheral oedema. The remainder of her examination was normal. Laboratory studies were remarkable for normocytic anaemia, lymphopenia, hypoalbuminemia, elevated prothrombin time and elevated inflammatory markers. Electrolytes, transaminases, thyroid profile and urine pregnancy test were normal. HIV antibody and viral load were negative. Review of records shows that her outside chest X-ray was remarkable for rounded opacities scattered throughout both lungs and a right upper lobe cavitary lesion. A chest CT was obtained, which reveals a cavitary right upper lobe mass (figure 1).
Figure 1 Contrast-enhanced CT of the chest shows a 3 cm round right upper cavitary lesion as well as prominent miliary nodules within the right upper lobe on axillary section (panel A). Further sections show multiple large necrotic mediastinal lymph nodes (panel B). coronal reformatting allows visualisation of the cavitary lesion (panel C) and miliary nodules (panel D) in plane with mediastinal lymphadenopathy.
Differential diagnosis
The patient’s chest CT revealed a cavitary right upper lobe mass, miliary pulmonary nodules and necrotic mediastinal lymphadenopathy. The radiographical differential of cavitary lesions and miliary nodules included congenital pulmonary airway malformations, lung abscesses, septic emboli, tuberculosis, histoplasmosis, blastomycosis, sarcoidosis and malignancies.1 2 However, the combination of findings in the setting of immunosuppression were highly suspicious for Mycobacterium tuberculosis.3
Investigations
Due to the strong suspicion for M. tuberculosis after her chest imaging, sputum PCR and cultures were obtained and were positive. She was diagnosed with miliary tuberculosis. Given her immunosuppression, she underwent evaluation for haematogenous seeding of M. tuberculosis. Brain MRI revealed multifocal ring-enhancing nodules consistent with parenchymal central nervous system (CNS) involvement (figure 2). MRI did not show meningeal enhancement, and a subsequent lumbar puncture revealed unremarkable cerebrospinal fluid parameters.
Figure 2 Contrast-enhanced MRI of the brain shows multifocal ring-enhancing lesions in the pons and cerebellum (panel A and D), and throughout the supratentorial brain (panel B, C and E), consistent with caseating tuberculous granulomas.
Treatment and clinical course
The patient was admitted to the hospital and maintained under negative pressure isolation. She was started on isoniazid, pyrazinamide, rifampin and moxifloxacin. Resistance testing revealed a pan-sensitive isolate. The local health department was notified, and her family members were tested for tuberculosis. She was discharged with a plan for extended direct observed therapy.
Outcome and follow-up
The patient remained on medication for 1 year following diagnosis and did not endorse any side effects for her antimycobacterial therapy. Throughout her time on therapy, as well as the subsequent 12 months, she has remained free of any flares of her psoriasis. Her psoriasis is now being managed with topical medications only. The patient was enrolling in college in the Autumn of 2020. Owing to her hospitalisation for tuberculosis and interest in her presentation, she was considering pursuing a course of study involving public health and/or medicine.
Discussion
Cases of disseminated or military tuberculosis, a disease caused by the acid-fast bacillus M. tuberculosis, secondary to TNF-α inhibitors are becoming more commonplace, though they remain rare in paediatric patients.4–8 However, the increasing use of immunomodulatory medications such as TNF-α inhibitors is increasing the risk of presentation. Testing for latent tuberculosis remains imperative prior to initiating immunomodulatory therapy, but it is unable to prevent all infections. Well-established treatment guidelines exist, but not all antituberculosis drugs have been well-studied in children.9 Furthermore, as was the case here, treatment regimens must be altered when there is CNS involvement.10
According to the Centers for Disease Control and Prevention, one-quarter of the world’s population is infected with M. tuberculosis.11 The incidence in the USA has fallen dramatically from 52.6/100 000 persons in 1953 to 2.9/100 000 persons in 2016.11 Children constitute approximately 14% of new cases.11 The falling rates of tuberculosis, and the low incidence in children, likely played a role in the patient’s delayed diagnosis. Risk factors for infection include Asian descent, recent immigration to the USA, diabetes, immunodeficiency, homelessness and incarceration.11 In the majority of infected persons, infection is followed by latent disease with no clinical symptoms.12 In children under 10 years, age of exposure is inversely correlated with the probability of developing clinical disease; nearly 50% of exposed infants under 1 year become symptomatic.12 13 There is a smaller peak of infection in adolescence, with the vast majority of these patients developing pulmonary disease.12 13
The spectrum of clinical disease caused by M. tuberculosis includes asymptomatic infection (latent tuberculosis), respiratory symptoms (pulmonary tuberculosis), and multisystem disease with or without pulmonary involvement (miliary tuberculosis).14 15 The age at acquisition strongly influences the form of disease that develops in the child, with one study looking at children ages 0–18 years showing that more than 60% present with disseminated disease.14–16 For children with pulmonary disease, the hallmark clinical symptoms in all age groups are chronic cough, fever and weight loss.15 17 Cough is rarely productive in infants or children, but may be in adolescents.15 Infants more typically present with examination features compatible with pneumonia, whereas adolescents typically lack physical findings.15 Chest X-ray may be diagnostic, though CT has higher sensitivity.3 Thick-walled cavitary lesions with ipsilateral hilar or paratracheal lymphadenopathy, miliary nodules and pleural effusions are all suggestive of pulmonary tuberculosis.3
Infants are much more likely than immunocompetent older children to develop extrapulmonary tuberculosis.12 15 18 Moreover, paediatric patients have an increased risk of CNS involvement.8 While no large studies have been conducted in children, retrospective reviews in adults have not been able to establish a clear link between CNS involvement and outcome.19 However, in two studies of adult patients maintained on antiTNF-α, such as adalimumab, more than half of those who contracted tuberculosis developed extrapulmonary manifestations.20 21 Extrapulmonary tuberculosis presents with variable symptoms depending on the affected organ system. The most common sites of extrapulmonary tuberculosis are lymph nodes, CNS, pleura, and the skeletal system.15 18 CNS tuberculosis is seen in approximately 50% of extrapulmonary cases and most often manifests as basilar meningitis; parenchymal tuberculomas are seen less frequently.15 22 23 CT or MRI can be used to screen for CNS tuberculosis.18 Obstructive hydrocephalus is the most common imaging finding, followed by basilar meningeal enhancement and infarction of the basal ganglia, thalami or anterior limbs of the internal capsules.18 Disseminated ring-enhancing caseating granulomas may be seen, and are often infratentorial in children.18 Abdominal tuberculosis is less common, but may include hepatic, splenic, renal, gastrointestinal, most commonly ileocecal or adrenal involvement.24
Diagnosis of tuberculosis is definitively established by the combination of a suspected exposure, clinical and imaging features consistent with disease, and isolation of M. tuberculosis in bacterial culture from sputum, bronchoscopy or biopsy specimen.12 14 25 Unfortunately, growth of M. tuberculosis in culture medium typically requires 1–2 weeks.25 Thus, when clinical suspicion of pulmonary tuberculosis is moderate or high, the Infectious Diseases Society of America (IDSA) recommends sending three sputum samples for acid-fast staining and nucleic acid amplification testing.25 The use of the two tests in combination on multiple samples increases sensitivity and specificity, and provides results in hours.25 However, false-negative results occur, and these tests should not be used to rule out the diagnosis.25
Treatment of tuberculosis depends on clinical manifestations. Patients with latent tuberculosis are usually treated with 9 months of isoniazid.26 For patients with pulmonary tuberculosis, the IDSA recommends 8 weeks of isoniazid, pyrazinamide, rifampin and ethambutol, followed by 18 weeks of isoniazid and rifampin.9 In children with CNS disease, the American Academy of Pediatrics recommends isoniazid, pyrazinamide, rifampin, and ethionamide or an aminoglycoside for 8 weeks followed by 28–40 weeks of isoniazid and rifampin.9 In adults, moxifloxacin may be used in place of ethionamide.27–29 Molecular testing for rifampin sensitivity is recommended in patients with risk factors for resistance.25 In tuberculous meningitis, the IDSA recommends the addition of corticosteroids tapered over 6–8 weeks.9 Corticosteroids should also be considered for evidence of immune reconstitution inflammatory syndrome.30 In the USA, tuberculosis is a reportable disease, and therapy is typically supervised by the community health department.31 Contacts of persons with infectious tuberculosis should be screened with tuberculosis skin testing or interferon gamma release assay at the time of discovery and 8–12 weeks later.32 Those with positive tests should be treated for latent tuberculosis.26 Young children are at increased risk of progression to active disease, and are often given prophylactic isoniazid in consultation with an infectious disease specialist.33
Learning points
Children account for approximately 14% of all diagnosis of tuberculosis.11
The spectrum of presentation of children with tuberculosis range from asymptomatic to multisystem involvement, and is strongly influenced by age.8 14–16
Central nervous system involvement occurs in 50% of patients with extrapulmonary involvement.8 15 22 23
The use of tumour necrosis factor-α inhibitors increase the risk of acquiring tuberculosis.4–6
Contributors: BB, JK, JP, SD, LP and SK: Conception and design, acquisition of data or analysis and interpretation of data. BB, JK, JP, SD, LP and SK: Drafting the article or revising it critically for important intellectual content. BB, JK, JP, SD, LP and SK: Final approval of the version published. BB, JK, JP, SD, LP and SK: Agreement to be accountable for the article and to ensure that all questions regarding the accuracy or integrity of the article are investigated and resolved. BB, JK, JP, SD, LP and SK: Agree with revisions and resubmission.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer-reviewed. | METHOTREXATE | DrugsGivenReaction | CC BY-NC | 33687934 | 19,840,401 | 2021-03-09 |
What was the dosage of drug 'METHOTREXATE'? | Miliary tuberculosis in a paediatric patient with psoriasis.
We present a 16-year-old girl with a history of well-controlled psoriasis, on immunosuppression, who sought evaluation in the emergency department for 4 months of fever, cough and unintentional weight loss. The patient had seen multiple providers who had diagnosed her with community-acquired pneumonia, but she was unimproved after oral antibiotic therapy. On presentation, she was noted to be febrile, tachycardic and chronically ill-appearing. Her chest X-ray showed diffuse opacities and a right upper lobe cavitary lesion concerning for tuberculosis. A subsequent chest CT revealed miliary pulmonary nodules in addition to the cavitary lesion. The patient underwent subsequent brain MRI, which revealed multifocal ring-enhancing nodules consistent with parenchymal involvement. The patient was diagnosed with miliary tuberculosis and improved on quadruple therapy. Though rates of tuberculosis are increasing, rates remain low in children, though special consideration should be given to children who are immunosuppressed.
Background
Tuberculosis remains relatively rare in children compared with adults but select paediatric patient-populations remain at an increased risk, one such population being immunosuppressed children. Given the growing availability and application of immunomodulatory medications for both autoimmune and transplant indications, there exists a growing population of children who are at an increased risk for the acquisition and deleterious effects of tuberculosis.
Case presentation
A 16-year-old girl with a history of psoriasis presented to the emergency department for fever, cough and unintentional weight loss. Her symptoms began 4 months prior to presentation with intermittent, non-productive daytime cough associated with pleuritic chest pain. She describes daily tactile fevers and chills. She has also had intermittent diffuse, ‘crampy’ abdominal pain with associated non-bloody, non-bilious emesis occurring approximately three times per week. Additionally, she described nausea and anorexia, resulting in a 15 kg weight loss over the past 4 months. She denied upper respiratory symptoms, sore throat, dysphagia, haematemesis, haemoptysis, cyanosis, diarrhoea, melena, haematochezia, dysuria, haematuria or rashes. She denied syncope, presyncope or seizures. She reported her last menstrual period as 3 months prior and denied any current vaginal symptoms. She denied recent travel, known sick contacts, sexual activity or illicit and recreational drug use. She was born in Ethiopia, moved to the USA relatively soon after birth and last travelled there 9 years ago. She had no contact with recent international travellers or prisoners.
She reported that during the past 4 months, she had been seen at an urgent care facility multiple times and treated with three different oral antibiotics for pneumonia; she cannot recall the names of these prescriptions. She has also been seen in an outpatient gastroenterology clinic and had an oesophagogastroduodenoscopy that demonstrated oesophageal candidiasis, for which she was treated with fluconazole. She was previously healthy with the exception of psoriasis. Regarding her psoriasis, she reported that she previously had diffuse skin involvement, but has never had arthritis. She was initially treated with adalimumab, a monoclonal antibody against tumour necrosis factor (TNF)-α, but was changed to methotrexate after being diagnosed with pneumonia. Her psoriatic symptoms are currently well controlled. She presented to the emergency department due to lack of improvement in systemic symptoms after the above management and a new sensation of a racing heartbeat.
In the emergency department, her initial vital signs were: temperature 39.2°C, heart rate of 140 beats/min, respiratory rate of 18 breaths/min, blood pressure of 115/61 mm Hg, oxygen saturation of 94% on room air and weight 54.6 kg. On examination, she was tired and chronically ill-appearing, but non-toxic. Her physical examination was remarkable for tachycardia without murmur, bounding radial pulses and mild respiratory distress with asymmetrically (right>left) diminished basilar aeration. She does not have lymphadenopathy, hepatosplenomegaly, ascites or peripheral oedema. The remainder of her examination was normal. Laboratory studies were remarkable for normocytic anaemia, lymphopenia, hypoalbuminemia, elevated prothrombin time and elevated inflammatory markers. Electrolytes, transaminases, thyroid profile and urine pregnancy test were normal. HIV antibody and viral load were negative. Review of records shows that her outside chest X-ray was remarkable for rounded opacities scattered throughout both lungs and a right upper lobe cavitary lesion. A chest CT was obtained, which reveals a cavitary right upper lobe mass (figure 1).
Figure 1 Contrast-enhanced CT of the chest shows a 3 cm round right upper cavitary lesion as well as prominent miliary nodules within the right upper lobe on axillary section (panel A). Further sections show multiple large necrotic mediastinal lymph nodes (panel B). coronal reformatting allows visualisation of the cavitary lesion (panel C) and miliary nodules (panel D) in plane with mediastinal lymphadenopathy.
Differential diagnosis
The patient’s chest CT revealed a cavitary right upper lobe mass, miliary pulmonary nodules and necrotic mediastinal lymphadenopathy. The radiographical differential of cavitary lesions and miliary nodules included congenital pulmonary airway malformations, lung abscesses, septic emboli, tuberculosis, histoplasmosis, blastomycosis, sarcoidosis and malignancies.1 2 However, the combination of findings in the setting of immunosuppression were highly suspicious for Mycobacterium tuberculosis.3
Investigations
Due to the strong suspicion for M. tuberculosis after her chest imaging, sputum PCR and cultures were obtained and were positive. She was diagnosed with miliary tuberculosis. Given her immunosuppression, she underwent evaluation for haematogenous seeding of M. tuberculosis. Brain MRI revealed multifocal ring-enhancing nodules consistent with parenchymal central nervous system (CNS) involvement (figure 2). MRI did not show meningeal enhancement, and a subsequent lumbar puncture revealed unremarkable cerebrospinal fluid parameters.
Figure 2 Contrast-enhanced MRI of the brain shows multifocal ring-enhancing lesions in the pons and cerebellum (panel A and D), and throughout the supratentorial brain (panel B, C and E), consistent with caseating tuberculous granulomas.
Treatment and clinical course
The patient was admitted to the hospital and maintained under negative pressure isolation. She was started on isoniazid, pyrazinamide, rifampin and moxifloxacin. Resistance testing revealed a pan-sensitive isolate. The local health department was notified, and her family members were tested for tuberculosis. She was discharged with a plan for extended direct observed therapy.
Outcome and follow-up
The patient remained on medication for 1 year following diagnosis and did not endorse any side effects for her antimycobacterial therapy. Throughout her time on therapy, as well as the subsequent 12 months, she has remained free of any flares of her psoriasis. Her psoriasis is now being managed with topical medications only. The patient was enrolling in college in the Autumn of 2020. Owing to her hospitalisation for tuberculosis and interest in her presentation, she was considering pursuing a course of study involving public health and/or medicine.
Discussion
Cases of disseminated or military tuberculosis, a disease caused by the acid-fast bacillus M. tuberculosis, secondary to TNF-α inhibitors are becoming more commonplace, though they remain rare in paediatric patients.4–8 However, the increasing use of immunomodulatory medications such as TNF-α inhibitors is increasing the risk of presentation. Testing for latent tuberculosis remains imperative prior to initiating immunomodulatory therapy, but it is unable to prevent all infections. Well-established treatment guidelines exist, but not all antituberculosis drugs have been well-studied in children.9 Furthermore, as was the case here, treatment regimens must be altered when there is CNS involvement.10
According to the Centers for Disease Control and Prevention, one-quarter of the world’s population is infected with M. tuberculosis.11 The incidence in the USA has fallen dramatically from 52.6/100 000 persons in 1953 to 2.9/100 000 persons in 2016.11 Children constitute approximately 14% of new cases.11 The falling rates of tuberculosis, and the low incidence in children, likely played a role in the patient’s delayed diagnosis. Risk factors for infection include Asian descent, recent immigration to the USA, diabetes, immunodeficiency, homelessness and incarceration.11 In the majority of infected persons, infection is followed by latent disease with no clinical symptoms.12 In children under 10 years, age of exposure is inversely correlated with the probability of developing clinical disease; nearly 50% of exposed infants under 1 year become symptomatic.12 13 There is a smaller peak of infection in adolescence, with the vast majority of these patients developing pulmonary disease.12 13
The spectrum of clinical disease caused by M. tuberculosis includes asymptomatic infection (latent tuberculosis), respiratory symptoms (pulmonary tuberculosis), and multisystem disease with or without pulmonary involvement (miliary tuberculosis).14 15 The age at acquisition strongly influences the form of disease that develops in the child, with one study looking at children ages 0–18 years showing that more than 60% present with disseminated disease.14–16 For children with pulmonary disease, the hallmark clinical symptoms in all age groups are chronic cough, fever and weight loss.15 17 Cough is rarely productive in infants or children, but may be in adolescents.15 Infants more typically present with examination features compatible with pneumonia, whereas adolescents typically lack physical findings.15 Chest X-ray may be diagnostic, though CT has higher sensitivity.3 Thick-walled cavitary lesions with ipsilateral hilar or paratracheal lymphadenopathy, miliary nodules and pleural effusions are all suggestive of pulmonary tuberculosis.3
Infants are much more likely than immunocompetent older children to develop extrapulmonary tuberculosis.12 15 18 Moreover, paediatric patients have an increased risk of CNS involvement.8 While no large studies have been conducted in children, retrospective reviews in adults have not been able to establish a clear link between CNS involvement and outcome.19 However, in two studies of adult patients maintained on antiTNF-α, such as adalimumab, more than half of those who contracted tuberculosis developed extrapulmonary manifestations.20 21 Extrapulmonary tuberculosis presents with variable symptoms depending on the affected organ system. The most common sites of extrapulmonary tuberculosis are lymph nodes, CNS, pleura, and the skeletal system.15 18 CNS tuberculosis is seen in approximately 50% of extrapulmonary cases and most often manifests as basilar meningitis; parenchymal tuberculomas are seen less frequently.15 22 23 CT or MRI can be used to screen for CNS tuberculosis.18 Obstructive hydrocephalus is the most common imaging finding, followed by basilar meningeal enhancement and infarction of the basal ganglia, thalami or anterior limbs of the internal capsules.18 Disseminated ring-enhancing caseating granulomas may be seen, and are often infratentorial in children.18 Abdominal tuberculosis is less common, but may include hepatic, splenic, renal, gastrointestinal, most commonly ileocecal or adrenal involvement.24
Diagnosis of tuberculosis is definitively established by the combination of a suspected exposure, clinical and imaging features consistent with disease, and isolation of M. tuberculosis in bacterial culture from sputum, bronchoscopy or biopsy specimen.12 14 25 Unfortunately, growth of M. tuberculosis in culture medium typically requires 1–2 weeks.25 Thus, when clinical suspicion of pulmonary tuberculosis is moderate or high, the Infectious Diseases Society of America (IDSA) recommends sending three sputum samples for acid-fast staining and nucleic acid amplification testing.25 The use of the two tests in combination on multiple samples increases sensitivity and specificity, and provides results in hours.25 However, false-negative results occur, and these tests should not be used to rule out the diagnosis.25
Treatment of tuberculosis depends on clinical manifestations. Patients with latent tuberculosis are usually treated with 9 months of isoniazid.26 For patients with pulmonary tuberculosis, the IDSA recommends 8 weeks of isoniazid, pyrazinamide, rifampin and ethambutol, followed by 18 weeks of isoniazid and rifampin.9 In children with CNS disease, the American Academy of Pediatrics recommends isoniazid, pyrazinamide, rifampin, and ethionamide or an aminoglycoside for 8 weeks followed by 28–40 weeks of isoniazid and rifampin.9 In adults, moxifloxacin may be used in place of ethionamide.27–29 Molecular testing for rifampin sensitivity is recommended in patients with risk factors for resistance.25 In tuberculous meningitis, the IDSA recommends the addition of corticosteroids tapered over 6–8 weeks.9 Corticosteroids should also be considered for evidence of immune reconstitution inflammatory syndrome.30 In the USA, tuberculosis is a reportable disease, and therapy is typically supervised by the community health department.31 Contacts of persons with infectious tuberculosis should be screened with tuberculosis skin testing or interferon gamma release assay at the time of discovery and 8–12 weeks later.32 Those with positive tests should be treated for latent tuberculosis.26 Young children are at increased risk of progression to active disease, and are often given prophylactic isoniazid in consultation with an infectious disease specialist.33
Learning points
Children account for approximately 14% of all diagnosis of tuberculosis.11
The spectrum of presentation of children with tuberculosis range from asymptomatic to multisystem involvement, and is strongly influenced by age.8 14–16
Central nervous system involvement occurs in 50% of patients with extrapulmonary involvement.8 15 22 23
The use of tumour necrosis factor-α inhibitors increase the risk of acquiring tuberculosis.4–6
Contributors: BB, JK, JP, SD, LP and SK: Conception and design, acquisition of data or analysis and interpretation of data. BB, JK, JP, SD, LP and SK: Drafting the article or revising it critically for important intellectual content. BB, JK, JP, SD, LP and SK: Final approval of the version published. BB, JK, JP, SD, LP and SK: Agreement to be accountable for the article and to ensure that all questions regarding the accuracy or integrity of the article are investigated and resolved. BB, JK, JP, SD, LP and SK: Agree with revisions and resubmission.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer-reviewed. | UNKNOWN | DrugDosageText | CC BY-NC | 33687934 | 19,840,401 | 2021-03-09 |
What was the outcome of reaction 'Disseminated tuberculosis'? | Miliary tuberculosis in a paediatric patient with psoriasis.
We present a 16-year-old girl with a history of well-controlled psoriasis, on immunosuppression, who sought evaluation in the emergency department for 4 months of fever, cough and unintentional weight loss. The patient had seen multiple providers who had diagnosed her with community-acquired pneumonia, but she was unimproved after oral antibiotic therapy. On presentation, she was noted to be febrile, tachycardic and chronically ill-appearing. Her chest X-ray showed diffuse opacities and a right upper lobe cavitary lesion concerning for tuberculosis. A subsequent chest CT revealed miliary pulmonary nodules in addition to the cavitary lesion. The patient underwent subsequent brain MRI, which revealed multifocal ring-enhancing nodules consistent with parenchymal involvement. The patient was diagnosed with miliary tuberculosis and improved on quadruple therapy. Though rates of tuberculosis are increasing, rates remain low in children, though special consideration should be given to children who are immunosuppressed.
Background
Tuberculosis remains relatively rare in children compared with adults but select paediatric patient-populations remain at an increased risk, one such population being immunosuppressed children. Given the growing availability and application of immunomodulatory medications for both autoimmune and transplant indications, there exists a growing population of children who are at an increased risk for the acquisition and deleterious effects of tuberculosis.
Case presentation
A 16-year-old girl with a history of psoriasis presented to the emergency department for fever, cough and unintentional weight loss. Her symptoms began 4 months prior to presentation with intermittent, non-productive daytime cough associated with pleuritic chest pain. She describes daily tactile fevers and chills. She has also had intermittent diffuse, ‘crampy’ abdominal pain with associated non-bloody, non-bilious emesis occurring approximately three times per week. Additionally, she described nausea and anorexia, resulting in a 15 kg weight loss over the past 4 months. She denied upper respiratory symptoms, sore throat, dysphagia, haematemesis, haemoptysis, cyanosis, diarrhoea, melena, haematochezia, dysuria, haematuria or rashes. She denied syncope, presyncope or seizures. She reported her last menstrual period as 3 months prior and denied any current vaginal symptoms. She denied recent travel, known sick contacts, sexual activity or illicit and recreational drug use. She was born in Ethiopia, moved to the USA relatively soon after birth and last travelled there 9 years ago. She had no contact with recent international travellers or prisoners.
She reported that during the past 4 months, she had been seen at an urgent care facility multiple times and treated with three different oral antibiotics for pneumonia; she cannot recall the names of these prescriptions. She has also been seen in an outpatient gastroenterology clinic and had an oesophagogastroduodenoscopy that demonstrated oesophageal candidiasis, for which she was treated with fluconazole. She was previously healthy with the exception of psoriasis. Regarding her psoriasis, she reported that she previously had diffuse skin involvement, but has never had arthritis. She was initially treated with adalimumab, a monoclonal antibody against tumour necrosis factor (TNF)-α, but was changed to methotrexate after being diagnosed with pneumonia. Her psoriatic symptoms are currently well controlled. She presented to the emergency department due to lack of improvement in systemic symptoms after the above management and a new sensation of a racing heartbeat.
In the emergency department, her initial vital signs were: temperature 39.2°C, heart rate of 140 beats/min, respiratory rate of 18 breaths/min, blood pressure of 115/61 mm Hg, oxygen saturation of 94% on room air and weight 54.6 kg. On examination, she was tired and chronically ill-appearing, but non-toxic. Her physical examination was remarkable for tachycardia without murmur, bounding radial pulses and mild respiratory distress with asymmetrically (right>left) diminished basilar aeration. She does not have lymphadenopathy, hepatosplenomegaly, ascites or peripheral oedema. The remainder of her examination was normal. Laboratory studies were remarkable for normocytic anaemia, lymphopenia, hypoalbuminemia, elevated prothrombin time and elevated inflammatory markers. Electrolytes, transaminases, thyroid profile and urine pregnancy test were normal. HIV antibody and viral load were negative. Review of records shows that her outside chest X-ray was remarkable for rounded opacities scattered throughout both lungs and a right upper lobe cavitary lesion. A chest CT was obtained, which reveals a cavitary right upper lobe mass (figure 1).
Figure 1 Contrast-enhanced CT of the chest shows a 3 cm round right upper cavitary lesion as well as prominent miliary nodules within the right upper lobe on axillary section (panel A). Further sections show multiple large necrotic mediastinal lymph nodes (panel B). coronal reformatting allows visualisation of the cavitary lesion (panel C) and miliary nodules (panel D) in plane with mediastinal lymphadenopathy.
Differential diagnosis
The patient’s chest CT revealed a cavitary right upper lobe mass, miliary pulmonary nodules and necrotic mediastinal lymphadenopathy. The radiographical differential of cavitary lesions and miliary nodules included congenital pulmonary airway malformations, lung abscesses, septic emboli, tuberculosis, histoplasmosis, blastomycosis, sarcoidosis and malignancies.1 2 However, the combination of findings in the setting of immunosuppression were highly suspicious for Mycobacterium tuberculosis.3
Investigations
Due to the strong suspicion for M. tuberculosis after her chest imaging, sputum PCR and cultures were obtained and were positive. She was diagnosed with miliary tuberculosis. Given her immunosuppression, she underwent evaluation for haematogenous seeding of M. tuberculosis. Brain MRI revealed multifocal ring-enhancing nodules consistent with parenchymal central nervous system (CNS) involvement (figure 2). MRI did not show meningeal enhancement, and a subsequent lumbar puncture revealed unremarkable cerebrospinal fluid parameters.
Figure 2 Contrast-enhanced MRI of the brain shows multifocal ring-enhancing lesions in the pons and cerebellum (panel A and D), and throughout the supratentorial brain (panel B, C and E), consistent with caseating tuberculous granulomas.
Treatment and clinical course
The patient was admitted to the hospital and maintained under negative pressure isolation. She was started on isoniazid, pyrazinamide, rifampin and moxifloxacin. Resistance testing revealed a pan-sensitive isolate. The local health department was notified, and her family members were tested for tuberculosis. She was discharged with a plan for extended direct observed therapy.
Outcome and follow-up
The patient remained on medication for 1 year following diagnosis and did not endorse any side effects for her antimycobacterial therapy. Throughout her time on therapy, as well as the subsequent 12 months, she has remained free of any flares of her psoriasis. Her psoriasis is now being managed with topical medications only. The patient was enrolling in college in the Autumn of 2020. Owing to her hospitalisation for tuberculosis and interest in her presentation, she was considering pursuing a course of study involving public health and/or medicine.
Discussion
Cases of disseminated or military tuberculosis, a disease caused by the acid-fast bacillus M. tuberculosis, secondary to TNF-α inhibitors are becoming more commonplace, though they remain rare in paediatric patients.4–8 However, the increasing use of immunomodulatory medications such as TNF-α inhibitors is increasing the risk of presentation. Testing for latent tuberculosis remains imperative prior to initiating immunomodulatory therapy, but it is unable to prevent all infections. Well-established treatment guidelines exist, but not all antituberculosis drugs have been well-studied in children.9 Furthermore, as was the case here, treatment regimens must be altered when there is CNS involvement.10
According to the Centers for Disease Control and Prevention, one-quarter of the world’s population is infected with M. tuberculosis.11 The incidence in the USA has fallen dramatically from 52.6/100 000 persons in 1953 to 2.9/100 000 persons in 2016.11 Children constitute approximately 14% of new cases.11 The falling rates of tuberculosis, and the low incidence in children, likely played a role in the patient’s delayed diagnosis. Risk factors for infection include Asian descent, recent immigration to the USA, diabetes, immunodeficiency, homelessness and incarceration.11 In the majority of infected persons, infection is followed by latent disease with no clinical symptoms.12 In children under 10 years, age of exposure is inversely correlated with the probability of developing clinical disease; nearly 50% of exposed infants under 1 year become symptomatic.12 13 There is a smaller peak of infection in adolescence, with the vast majority of these patients developing pulmonary disease.12 13
The spectrum of clinical disease caused by M. tuberculosis includes asymptomatic infection (latent tuberculosis), respiratory symptoms (pulmonary tuberculosis), and multisystem disease with or without pulmonary involvement (miliary tuberculosis).14 15 The age at acquisition strongly influences the form of disease that develops in the child, with one study looking at children ages 0–18 years showing that more than 60% present with disseminated disease.14–16 For children with pulmonary disease, the hallmark clinical symptoms in all age groups are chronic cough, fever and weight loss.15 17 Cough is rarely productive in infants or children, but may be in adolescents.15 Infants more typically present with examination features compatible with pneumonia, whereas adolescents typically lack physical findings.15 Chest X-ray may be diagnostic, though CT has higher sensitivity.3 Thick-walled cavitary lesions with ipsilateral hilar or paratracheal lymphadenopathy, miliary nodules and pleural effusions are all suggestive of pulmonary tuberculosis.3
Infants are much more likely than immunocompetent older children to develop extrapulmonary tuberculosis.12 15 18 Moreover, paediatric patients have an increased risk of CNS involvement.8 While no large studies have been conducted in children, retrospective reviews in adults have not been able to establish a clear link between CNS involvement and outcome.19 However, in two studies of adult patients maintained on antiTNF-α, such as adalimumab, more than half of those who contracted tuberculosis developed extrapulmonary manifestations.20 21 Extrapulmonary tuberculosis presents with variable symptoms depending on the affected organ system. The most common sites of extrapulmonary tuberculosis are lymph nodes, CNS, pleura, and the skeletal system.15 18 CNS tuberculosis is seen in approximately 50% of extrapulmonary cases and most often manifests as basilar meningitis; parenchymal tuberculomas are seen less frequently.15 22 23 CT or MRI can be used to screen for CNS tuberculosis.18 Obstructive hydrocephalus is the most common imaging finding, followed by basilar meningeal enhancement and infarction of the basal ganglia, thalami or anterior limbs of the internal capsules.18 Disseminated ring-enhancing caseating granulomas may be seen, and are often infratentorial in children.18 Abdominal tuberculosis is less common, but may include hepatic, splenic, renal, gastrointestinal, most commonly ileocecal or adrenal involvement.24
Diagnosis of tuberculosis is definitively established by the combination of a suspected exposure, clinical and imaging features consistent with disease, and isolation of M. tuberculosis in bacterial culture from sputum, bronchoscopy or biopsy specimen.12 14 25 Unfortunately, growth of M. tuberculosis in culture medium typically requires 1–2 weeks.25 Thus, when clinical suspicion of pulmonary tuberculosis is moderate or high, the Infectious Diseases Society of America (IDSA) recommends sending three sputum samples for acid-fast staining and nucleic acid amplification testing.25 The use of the two tests in combination on multiple samples increases sensitivity and specificity, and provides results in hours.25 However, false-negative results occur, and these tests should not be used to rule out the diagnosis.25
Treatment of tuberculosis depends on clinical manifestations. Patients with latent tuberculosis are usually treated with 9 months of isoniazid.26 For patients with pulmonary tuberculosis, the IDSA recommends 8 weeks of isoniazid, pyrazinamide, rifampin and ethambutol, followed by 18 weeks of isoniazid and rifampin.9 In children with CNS disease, the American Academy of Pediatrics recommends isoniazid, pyrazinamide, rifampin, and ethionamide or an aminoglycoside for 8 weeks followed by 28–40 weeks of isoniazid and rifampin.9 In adults, moxifloxacin may be used in place of ethionamide.27–29 Molecular testing for rifampin sensitivity is recommended in patients with risk factors for resistance.25 In tuberculous meningitis, the IDSA recommends the addition of corticosteroids tapered over 6–8 weeks.9 Corticosteroids should also be considered for evidence of immune reconstitution inflammatory syndrome.30 In the USA, tuberculosis is a reportable disease, and therapy is typically supervised by the community health department.31 Contacts of persons with infectious tuberculosis should be screened with tuberculosis skin testing or interferon gamma release assay at the time of discovery and 8–12 weeks later.32 Those with positive tests should be treated for latent tuberculosis.26 Young children are at increased risk of progression to active disease, and are often given prophylactic isoniazid in consultation with an infectious disease specialist.33
Learning points
Children account for approximately 14% of all diagnosis of tuberculosis.11
The spectrum of presentation of children with tuberculosis range from asymptomatic to multisystem involvement, and is strongly influenced by age.8 14–16
Central nervous system involvement occurs in 50% of patients with extrapulmonary involvement.8 15 22 23
The use of tumour necrosis factor-α inhibitors increase the risk of acquiring tuberculosis.4–6
Contributors: BB, JK, JP, SD, LP and SK: Conception and design, acquisition of data or analysis and interpretation of data. BB, JK, JP, SD, LP and SK: Drafting the article or revising it critically for important intellectual content. BB, JK, JP, SD, LP and SK: Final approval of the version published. BB, JK, JP, SD, LP and SK: Agreement to be accountable for the article and to ensure that all questions regarding the accuracy or integrity of the article are investigated and resolved. BB, JK, JP, SD, LP and SK: Agree with revisions and resubmission.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer-reviewed. | Recovering | ReactionOutcome | CC BY-NC | 33687934 | 19,840,401 | 2021-03-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatic function abnormal'. | Partial Response to Pyrotinib Plus Capecitabine in an Advanced Breast Cancer Patient with HER2 Amplification and R157W Mutation After Anti-HER2 Treatment: A Case Report and Literature Review.
Human epidermal growth factor receptor2 (HER2) overexpression/amplification is associated with high malignancy, rapid disease progression and poor overall survival in breast cancer. The application of anti-HER2 drugs has greatly improved the survival of patients with HER2-positive breast cancer, but drug resistance issues affect the long-term efficacy. The HER2 mutation is considered to be one of the reasons for resistance to anti-HER2 therapy, and there is currently no standard treatment. We report for the first time the detection of HER2 amplification with R157W mutation by second-generation sequencing (NGS) in a 57-year-old hormone receptor-negative, HER2-positive woman with advanced breast cancer who was resistant to multi-line anti-HER2 therapies. She subsequently received pyrotinib combined with capecitabine treatment and achieved partial response. The small-molecule pan-HER family irreversible inhibitor pyrotinib combined with capecitabine has shown a promising effect in the treatment of HER2 mutation-induced resistance, but the molecular mechanism and efficacy need to be further verified.
Introduction
Breast cancer is a malignant tumor with the highest morbidity and second highest mortality rate in women.1 HER2-positive (HER2 amplification) breast cancer accounts for about 15–20% of all breast cancers.2 Anti-HER2 drugs have greatly improved the survival of such patients. These drugs include humanized monoclonal antibodies like trastuzumab and pertuzumab, antibody-drug conjugates (ADC) like T-DM1, and novel oral small-molecule tyrosine kinase inhibitors like pyrotinib, neratinib, lapatinib and so on.
Acquired drug resistance is inevitable in patients with advanced HER2-positive breast cancer after first-line and second-line anti-HER2 treatments, and the mechanism is still under investigation. HER2 mutations are rare in breast cancer patients. A systematic review showed that the frequency of HER2 mutation in breast cancer patients was about 3%,3 while previous gene sequencing results suggested that patients with primary HER2-positive breast cancer had a lower frequency of HER2 mutation.4,5 Therefore, HER2 amplification and mutation are considered mutually exclusive in breast cancer patients. In recent years, studies have found that the HER2 gene mutation rate is higher in breast cancer patients treated with multi-line anti-HER2 therapies,6,7 and HER2 mutation is one of the causes of resistance to anti-HER2 treatment. There is no standard treatment for HER2 mutation patients yet. Of these, HER2 R157W mutation is a rare mutation and there are currently only two reports in the literature. One was somatic mutation found in micropapillary urothelial carcinoma (MPUC),8 which was not accompanied by HER2 overexpression and HER2 amplification. FATHMM prediction determined that it was a pathogenic mutation according to the COSMIC database. The other one was germline mutation found in breast cancer,9 of which the clinical significance is unknown. This is the first report of a patient with HER2-positive advanced breast cancer who developed HER2-amplification with R157W missense mutation after treatment of lapatinib plus trastuzumab and achieved partial response (PR) after using pyrotinib plus capecitabine.
Case Description
A 57-year-old Chinese female was initially presented to an outside hospital and underwent radical resection of left breast cancer diagnosed with stage IIIC (pTxN3M0) in Jan 2013. Pathology indicated invasive ductal carcinoma of breast estrogen receptor (ER) (-), progesterone receptor (PR) (-), and HER2(3+) by immunohistochemistry. Then, she received one cycle of adjuvant chemotherapy with docetaxel and three cycles of oncolytic virus therapy in other hospital, but the patient could not provide detailed information. In March 2013, PET/CT showed bilateral lung metastases. However, the patient refused chemotherapy and received traditional Chinese medicine (TCM) decoction treatment. In March 2014, follow-up PET/CT revealed multiple metastases in liver, both lungs and bones. A liver biopsy conducted in our department suggested hepatic metastasis of the breast cancer (ER(-), PR(-), HER2(3+)). The patient received eight cycles of first-line-targeted treatment with trastuzumab (8mg/kg IV day 1 followed by 6mg/kg IV day 1 every 21 days) plus paclitaxel (135mg/m2 IV day 1 every 21 days), followed by maintenance treatment with trastuzumab (6mg/kg IV day 1 every 21 days), achieving partial response and progression-free survival (PFS) for approximately 1 year. Subsequently, she was treated with docetaxel (75mg/m2 IV day 1 every 21 days), xeloda (1000mg/m2 PO bid days 1–14 every 21 days), and trastuzumab (6mg/kg IV day 1 every 21 days) as the second-line treatment for six cycles, with the best efficacy of partial response and PFS for 10 months. Upon disease progression, the third-line treatment was gemcitabine (1000mg/m2 IV day 1 every 21 days) plus S-1 (40mg PO bid days 1–14 every 21 days) based chemotherapy for 4 cycles, with the best efficacy of stable disease (SD) and PFS for nearly 4 months. In the fourth-line treatment, she received epirubicin (80mg/m2 IV day 1 every 21 days) plus lapatinib (0.25g PO qd). However, after one cycle, due to impaired liver function (with her alanine aminotransferase [ALT] level reaching 1122U/L), use of epirubicin was discontinued. Liver function improved following liver protection therapy, and the patient then continued lapatinib monotherapy (0.5g PO qd), maintaining an SD with PFS of 2 months.
In October 2017, enlarged lesions revealed in the chest and abdomen CT indicated progressive disease (PD). Next-generation sequencing (NGS) of plasma detected HER2 and CDK12 amplification, NSD1 gene fusion, and TP53 L257R mutation. The patient began to receive trastuzumab (6mg/kg IV day 1 every 21 days) combined with lapatinib (1g PO qd) as the fifth-line treatment from November 2017. The best efficacy was SD, and PFS was about 9 months. In August 2018, plasma NGS showed R157W missense mutation in HER2 exon 4, along with HER2 amplification and TP53 L257R mutation. That September, a chest and abdomen CT confirmed PD. The patient began to receive pyrotinib(400mg PO qd) plus xeloda (1000mg/m2 PO bid days 1–14 every 21 days) as the sixth-line treatment, with the best efficacy of PR and PFS for 13 months. Plasma NGS monitoring during the period (December 2018) suggested a decrease in HER2 copy number and abundance of R157W mutation. In November 2019, when her disease progressed again, the re-examination of the plasma NGS showed CDK12 and HER2 amplification, DNMT3A inactivation mutation and TP53 L257R mutation. There was no HER2 mutation.
From November 2019 to January 2020, the patient received the seventh-line treatment with Abraxane (200mg IV day 1 every 14 days), with the optimal efficacy of SD. In February 2020, she began to accept the eighth-line treatment with pertuzumab (840mg IV day 1 followed by 420mg IV day 1 every 21 days) combined with trastuzumab (8mg/kg IV da y1 followed by 6mg/kg IV day 1 every 21 days) and xeloda (1000mg/m2 PO bid days 1–14 every 21 days). The efficacy has not been evaluated at the time of writing this paper.
Discussion
HER2-amplified breast cancer accounts for about 15–20% of all breast cancers2 and is often characterized by rapid progression and poor prognosis.10,11 The precise treatment of HER2 has completely changed the survival rate for breast cancer with HER2-amplification. However, as time goes by, anti-HER2 treatment will inevitably produce acquired drug resistance, which will affect the survival of patients. Therefore, it is imperative to clarify the mechanism of drug resistance and make targeted treatments. The resistance mechanism of anti-HER2 drugs is complex, and the resistance caused by HER2 mutation has attracted more and more attention and may become a new potential therapeutic target.12 We report a 57-year-old woman with advanced HER2-positive breast cancer who received multiple lines of anti-HER2 therapy and was confirmed to have the HER2 R157W missense mutation in exon 4 by plasma NGS, and obtained PR after treatment with pyrotinib and capecitabine. This case provides a new potential treatment option for HER2 mutations following resistance to HER2 therapy.
Proto-oncogene HER2, also known as ErbB2, belongs to the ERB family with ErbB1(EGFR), ErbB3(HER3), and ErbB4(HER4). No high-affinity ligand has been found in HER2 so far, so it must form homologously or as a heterodimer with other members of the family, binding with ATP to activate intracellular tyrosine kinases, thereby initiating the downstream signaling pathway and regulating the proliferation and differentiation of cells.13–15 HER2 is the most important driver gene of breast cancer, and the most common positive form is gene amplification. Amplification of HER2 would lead to increased protein synthesis (ie, overexpression of HER2 protein) or increased protein function, which would lead to overactivation of downstream signaling pathways and overgrowth of cells, playing an important role in the proliferation, invasion, metastasis, and evolution of breast cancer cells.16–18
H0648g,19 M77001,20 EGF100151,21 EGF10490022 et al studies have shown that patients with HER2-positive breast cancer can benefit from anti-HER2 humanized trastuzumab and double HER2-EGFR tyrosine kinase inhibitor (TKI) lapatinib. However, approximately 50% of HER2-positive patients developed resistance to trastuzumab 1 year after treatment.23 Lapatinib has achieved certain clinical efficacy in metastatic HER2-positive breast cancer treated with trastuzumab, but a significant proportion of patients develop disease progression due to innate or acquired resistance to lapatinib.24,25 Studies on the molecular mechanisms of trastuzumab and lapatinib resistance26 found that overexpression of other HER family receptors and their ligands, loss of PTEN leading to activation of the PI3K/Akt/mTOR pathway, PI3KCA mutation, and Akt mutation or amplification were common causes of drug resistance. Drug resistance has become an urgent problem.
The patient developed resistance to lapatinib combined with trastuzumab. The HER2 gene mutation was not detected before the patient received lapatinib plus trastuzumab treatment, while the R157W mutation was found in the disease progression after treatment. Moreover, by comparing the two gene test results (Table 1), only the HER2 mutation was acquired, so it was believed that the HER2 mutation was the main mechanism of drug resistance in this case. In recent years, with the gradual deepening of the understanding of HER2, it is believed that HER2 mutation plays an important role in the incidence, development and resistance of breast cancer.27,28 The primary HER2 mutation mostly occurred in HER2 negative conditions, while in HER2 positive breast cancer the HER2 mutation mostly occurred after anti-HER2 treatment. Fang et al6 performed HER2 full-length gene sequencing on the tissues of 198 patients with metastatic breast cancer (MBC) after multiple cycles of treatment and found that the rate of HER2 mutations in patients treated with trastuzumab was as high as 17.7%. Park et al7 also carried out NGS tests on the tissues of 36 refractory MBC patients after multi-cycle and multi-drug treatment, and found that 5 out of 6 patients with HER2 mutation were HER2 positive and developed drug resistance after receiving anti-HER2 drugs (trastuzumab, lapatinib).Table 1 NGS Results Detected Before and After Treatment with Trastuzumab and Lapatinib
Genes 20171018
Before Trastuzumab with Lapatinib 20180820
After Resistance to Trastuzumab with Lapatinib Methodology
Variations Abundance CN Variations Abundance CN
HER2 CNG 2.1 CNG 7.7 NGS
p.R157W 2.0% NGS
TP53 p.L257R 6.4% p.L257R 49.9% NGS
CDK12 CNG 1.8 Negative NGS
NSD1 GF 0.2% Negative NGS
ESR1 Negative Negative NGS
BRCA1 Negative Negative NGS
BRCA2 Negative Negative NGS
Abbreviations: HER2, human epidermal growth factor receptor-2; TP53, tumor protein p53; CDK12, cyclin-dependent kinase 12; NSD1, nuclear receptor binding SET domain protein 1; ESR1, estrogen receptor 1; BRCA1, breast cancer susceptibility gene 1; BRCA2, breast cancer susceptibility gene 2; CNG, copy number gain; CN, copy number; GF, gene fusion; NGS, next-generation sequencing.
In the literature, the most common HER2 mutation sites in breast cancer were L755S, V777L, D769H, D769Y, G778_P780dup, Y772_A775dup in the kinase domain, and S310F and S310Y in the extracellular domain.3,29 There are no studies to prove the difference between HER2-negative combined mutation and HER2 positive-combined mutation, and most of the mutations can occur in both. The causes of resistance to HER2 therapy due to HER2 mutations are not fully understood. A cell-induced drug resistance test suggested that drug resistance of lapatinib might be related to the change of kinase structure caused by L755S and P780L mutations, which would activate the kinase activity and interfere with the inactive structure required for lapatinib binding.30,31 It may also be related to the production of larger amino acids after L726F, L785F, and other mutations, which interfered with the binding of lapatinib spatially.30 In addition, T789 mutation can stabilize the active conformation and directly compete with lapatinib for ATP binding sites, which may also be one of the causes of lapatinib resistance.30,31 Other studies have found that increased levels of EGFR-HER3 dimerization and expression of HER4 can also lead to lapatinib resistance. The extracellular resistance test of trastuzumab suggested that mutations in the HER2 kinase domain might alter the PI3K/AKT cascade signaling, thereby weakening the inhibition of trastuzumab to the PI3K/AKT pathway.32 It has also been observed in cell experiments that L755S mutation can lead to overactivation of PI3K/AKT/mTOR and MAPK pathways, leading to resistance to lapatinib and neratinib.33 Hanker B et al34 reported that a breast cancer patient with HER2 L869R mutation got new T798I mutation when neratinib resistance happened. Cell models confirmed that the presence of isoleucine at the 798 site leads to steric hindrance, reducing the binding affinity of neratinib. Smyth et al29 believed that HER2 mutation accompanied with other changes in HER family signaling pathways, such as HER3 mutation, might lead to drug resistance to neratinib.
This case reported that R157W missense mutation happened in the extracellular domain belonging to exon4 of HER2 which could be found in the cBioPortal database35,36 within the TCGA data set (Figure 1). Prior to this, only two cases of HER2 R157W mutation have been reported in the literature, and that which was found in breast cancer harbored germline mutations. As this residue is presented in the extracellular domain, we think the drug-resistant mechanism may be related to the change of the extracellular domain receptor structure, which interfered with the binding of trastuzumab. It may also strengthen dimerization with other family receptors, such as HER2/HER3, and HER2/HER4 polymerization, thereby weakening the inhibition of lapatinib, which activated downstream pathways and caused a cascade reaction, eventually leading to tumor progression.Figure 1 Mutation site map of R157W gene in TCGA dataset from cBioPortal database.35,36
There is no standard treatment for HER2 mutation, but many studies have begun to explore treatment strategies. A number of studies have demonstrated that the pan-HER2 irreversible inhibitor neratinib has a good inhibitory effect on certain mutations. Zuo et al28 found that neratinib had a strong inhibitory effect on drug-resistant mutant cell lines bearing K753E or L755S mutations. Cocco et al37 demonstrated that neratinib could not only effectively overcome the acquired resistance to HER2 therapy in breast cancer cells carrying both HER2 amplification and L755S somatic mutation but also significantly inhibit tumor growth in mice which are resistant to trastuzumab and lapatinib as well as carrying both D769Y mutation and HER2 amplification. At the same time, it was observed that neratinib had clinical activity in breast cancer patients with both HER2 gene amplification and mutation. SUMMIT is a Phase II basket clinical trial involving patients with cancers featuring HER2 mutations, and the result shows that neratinib has a good clinical effect on patients with breast cancer accompanied by HER2 mutations but without amplification, with an ORR of 32% at 8 weeks,4 but resistance to T798-related mutations.33 Overall, neratinib has a certain clinical efficacy against common HER2 mutations, but has not yet been marketed in China.
Pyrotinib is a new generation of small-molecule irreversible pan-ErbB receptor TKI, covalently binding with the ATP binding site in the intracellular kinase regions of HER1, HER2, and HER4, which prevents the formation of homodimers/heterodimers in the HER family, inhibits phosphorylation itself, blocks the activation of downstream signaling pathways, and inhibits tumor cell growth.38 Its structure and mechanism of action are similar to neratinib, but it has stronger inhibitory activity in vitro. In 2019, Jiang et al, reported a phenix study orally at the ASCO conference, confirming that to HER2 positive MBC females who previously received paclitaxel and trastuzumab, pyrotinib plus capecitabine, compared to placebo plus capecitabine, can effectively improve the median PFS. In this case, the patient developed disease progression in September 2018 after receiving trastuzumab combined with lapatinib, and received pyrotinib plus capecitabine. Three months later, she got partial response, (Figure 2) and symptoms were relieved. Plasma NGS indicated that both the copy number of HER2 amplification and the abundance of R157W mutations were decreased compared with previous results (Table 2). The relationship between gene dynamics and efficacy is shown in Figure 3.Table 2 NGS Results Detected Before and After Treatment with Pyrotinib and Capecitabine
Genes 20180820
Before Pyrotinib with Capecitabine 20181212
After Pyrotinib with Capecitabine Methodology
Variations Abundance CN Variations Abundance CN
HER2 p.R157W 2.0% p.R157W 1.3% NGS
CNG 7.7 CNG 2.1 NGS
TP53 p.L257R 49.9% p.L257R 5.7% NGS
ESR1 Negative Negative NGS
BRCA1 Negative Negative NGS
BRCA2 Negative Negative NGS
Abbreviations: HER2, human epidermal growth factor receptor-2; TP53, tumor protein p53; ESR1, estrogen receptor 1; BRCA1, breast cancer susceptibility gene 1; BRCA2, breast cancer susceptibility gene 2; CNG, copy number gain; CN, copy number; NGS, next-generation sequencing.
Figure 2 Changes of images before and after treatment. The red arrows indicate the metastatic tumor.
Figure 3 The relationship between gene dynamics and efficacy. The red arrows indicate the metastatic tumor.
Conclusion
Drug resistance has affected the efficacy of anti-HER2 therapy in breast cancer, and HER2 mutation is one of the causes. However, there is no standard treatment yet. We report for the first time the occurrence of HER2 amplification accompanied by R157W mutation after anti-HER2 treatment. This case is the first clinical report of pyrotinib plus capecitabine effective for HER2 mutation, which shows a good clinical efficacy against HER2 resistance accompanied with mutation in MBC patients, and provides a possible new management strategy of anti-HER2 treatment for patients with HER2-positive breast cancer.
Acknowledgments
The authors thank the patient and her family. This study did not receive any funding support from external sources. Yanchun Qu and Yufeng Liu are co-first authors for this study.
Ethical Approval
Institutional approval was not required to publish the case details.
Patient Informed Consent
Written informed consent was obtained from the patient for the publication of her case details and images.
Disclosure
Xiaoyu Hong is the employee of Nanjing Geneseeq Technology Inc. The other authors have no conflicts of interest that are directly relevant to the content of this article. | EPIRUBICIN HYDROCHLORIDE, LAPATINIB | DrugsGivenReaction | CC BY-NC | 33688205 | 19,110,981 | 2021 |
What was the administration route of drug 'EPIRUBICIN HYDROCHLORIDE'? | Partial Response to Pyrotinib Plus Capecitabine in an Advanced Breast Cancer Patient with HER2 Amplification and R157W Mutation After Anti-HER2 Treatment: A Case Report and Literature Review.
Human epidermal growth factor receptor2 (HER2) overexpression/amplification is associated with high malignancy, rapid disease progression and poor overall survival in breast cancer. The application of anti-HER2 drugs has greatly improved the survival of patients with HER2-positive breast cancer, but drug resistance issues affect the long-term efficacy. The HER2 mutation is considered to be one of the reasons for resistance to anti-HER2 therapy, and there is currently no standard treatment. We report for the first time the detection of HER2 amplification with R157W mutation by second-generation sequencing (NGS) in a 57-year-old hormone receptor-negative, HER2-positive woman with advanced breast cancer who was resistant to multi-line anti-HER2 therapies. She subsequently received pyrotinib combined with capecitabine treatment and achieved partial response. The small-molecule pan-HER family irreversible inhibitor pyrotinib combined with capecitabine has shown a promising effect in the treatment of HER2 mutation-induced resistance, but the molecular mechanism and efficacy need to be further verified.
Introduction
Breast cancer is a malignant tumor with the highest morbidity and second highest mortality rate in women.1 HER2-positive (HER2 amplification) breast cancer accounts for about 15–20% of all breast cancers.2 Anti-HER2 drugs have greatly improved the survival of such patients. These drugs include humanized monoclonal antibodies like trastuzumab and pertuzumab, antibody-drug conjugates (ADC) like T-DM1, and novel oral small-molecule tyrosine kinase inhibitors like pyrotinib, neratinib, lapatinib and so on.
Acquired drug resistance is inevitable in patients with advanced HER2-positive breast cancer after first-line and second-line anti-HER2 treatments, and the mechanism is still under investigation. HER2 mutations are rare in breast cancer patients. A systematic review showed that the frequency of HER2 mutation in breast cancer patients was about 3%,3 while previous gene sequencing results suggested that patients with primary HER2-positive breast cancer had a lower frequency of HER2 mutation.4,5 Therefore, HER2 amplification and mutation are considered mutually exclusive in breast cancer patients. In recent years, studies have found that the HER2 gene mutation rate is higher in breast cancer patients treated with multi-line anti-HER2 therapies,6,7 and HER2 mutation is one of the causes of resistance to anti-HER2 treatment. There is no standard treatment for HER2 mutation patients yet. Of these, HER2 R157W mutation is a rare mutation and there are currently only two reports in the literature. One was somatic mutation found in micropapillary urothelial carcinoma (MPUC),8 which was not accompanied by HER2 overexpression and HER2 amplification. FATHMM prediction determined that it was a pathogenic mutation according to the COSMIC database. The other one was germline mutation found in breast cancer,9 of which the clinical significance is unknown. This is the first report of a patient with HER2-positive advanced breast cancer who developed HER2-amplification with R157W missense mutation after treatment of lapatinib plus trastuzumab and achieved partial response (PR) after using pyrotinib plus capecitabine.
Case Description
A 57-year-old Chinese female was initially presented to an outside hospital and underwent radical resection of left breast cancer diagnosed with stage IIIC (pTxN3M0) in Jan 2013. Pathology indicated invasive ductal carcinoma of breast estrogen receptor (ER) (-), progesterone receptor (PR) (-), and HER2(3+) by immunohistochemistry. Then, she received one cycle of adjuvant chemotherapy with docetaxel and three cycles of oncolytic virus therapy in other hospital, but the patient could not provide detailed information. In March 2013, PET/CT showed bilateral lung metastases. However, the patient refused chemotherapy and received traditional Chinese medicine (TCM) decoction treatment. In March 2014, follow-up PET/CT revealed multiple metastases in liver, both lungs and bones. A liver biopsy conducted in our department suggested hepatic metastasis of the breast cancer (ER(-), PR(-), HER2(3+)). The patient received eight cycles of first-line-targeted treatment with trastuzumab (8mg/kg IV day 1 followed by 6mg/kg IV day 1 every 21 days) plus paclitaxel (135mg/m2 IV day 1 every 21 days), followed by maintenance treatment with trastuzumab (6mg/kg IV day 1 every 21 days), achieving partial response and progression-free survival (PFS) for approximately 1 year. Subsequently, she was treated with docetaxel (75mg/m2 IV day 1 every 21 days), xeloda (1000mg/m2 PO bid days 1–14 every 21 days), and trastuzumab (6mg/kg IV day 1 every 21 days) as the second-line treatment for six cycles, with the best efficacy of partial response and PFS for 10 months. Upon disease progression, the third-line treatment was gemcitabine (1000mg/m2 IV day 1 every 21 days) plus S-1 (40mg PO bid days 1–14 every 21 days) based chemotherapy for 4 cycles, with the best efficacy of stable disease (SD) and PFS for nearly 4 months. In the fourth-line treatment, she received epirubicin (80mg/m2 IV day 1 every 21 days) plus lapatinib (0.25g PO qd). However, after one cycle, due to impaired liver function (with her alanine aminotransferase [ALT] level reaching 1122U/L), use of epirubicin was discontinued. Liver function improved following liver protection therapy, and the patient then continued lapatinib monotherapy (0.5g PO qd), maintaining an SD with PFS of 2 months.
In October 2017, enlarged lesions revealed in the chest and abdomen CT indicated progressive disease (PD). Next-generation sequencing (NGS) of plasma detected HER2 and CDK12 amplification, NSD1 gene fusion, and TP53 L257R mutation. The patient began to receive trastuzumab (6mg/kg IV day 1 every 21 days) combined with lapatinib (1g PO qd) as the fifth-line treatment from November 2017. The best efficacy was SD, and PFS was about 9 months. In August 2018, plasma NGS showed R157W missense mutation in HER2 exon 4, along with HER2 amplification and TP53 L257R mutation. That September, a chest and abdomen CT confirmed PD. The patient began to receive pyrotinib(400mg PO qd) plus xeloda (1000mg/m2 PO bid days 1–14 every 21 days) as the sixth-line treatment, with the best efficacy of PR and PFS for 13 months. Plasma NGS monitoring during the period (December 2018) suggested a decrease in HER2 copy number and abundance of R157W mutation. In November 2019, when her disease progressed again, the re-examination of the plasma NGS showed CDK12 and HER2 amplification, DNMT3A inactivation mutation and TP53 L257R mutation. There was no HER2 mutation.
From November 2019 to January 2020, the patient received the seventh-line treatment with Abraxane (200mg IV day 1 every 14 days), with the optimal efficacy of SD. In February 2020, she began to accept the eighth-line treatment with pertuzumab (840mg IV day 1 followed by 420mg IV day 1 every 21 days) combined with trastuzumab (8mg/kg IV da y1 followed by 6mg/kg IV day 1 every 21 days) and xeloda (1000mg/m2 PO bid days 1–14 every 21 days). The efficacy has not been evaluated at the time of writing this paper.
Discussion
HER2-amplified breast cancer accounts for about 15–20% of all breast cancers2 and is often characterized by rapid progression and poor prognosis.10,11 The precise treatment of HER2 has completely changed the survival rate for breast cancer with HER2-amplification. However, as time goes by, anti-HER2 treatment will inevitably produce acquired drug resistance, which will affect the survival of patients. Therefore, it is imperative to clarify the mechanism of drug resistance and make targeted treatments. The resistance mechanism of anti-HER2 drugs is complex, and the resistance caused by HER2 mutation has attracted more and more attention and may become a new potential therapeutic target.12 We report a 57-year-old woman with advanced HER2-positive breast cancer who received multiple lines of anti-HER2 therapy and was confirmed to have the HER2 R157W missense mutation in exon 4 by plasma NGS, and obtained PR after treatment with pyrotinib and capecitabine. This case provides a new potential treatment option for HER2 mutations following resistance to HER2 therapy.
Proto-oncogene HER2, also known as ErbB2, belongs to the ERB family with ErbB1(EGFR), ErbB3(HER3), and ErbB4(HER4). No high-affinity ligand has been found in HER2 so far, so it must form homologously or as a heterodimer with other members of the family, binding with ATP to activate intracellular tyrosine kinases, thereby initiating the downstream signaling pathway and regulating the proliferation and differentiation of cells.13–15 HER2 is the most important driver gene of breast cancer, and the most common positive form is gene amplification. Amplification of HER2 would lead to increased protein synthesis (ie, overexpression of HER2 protein) or increased protein function, which would lead to overactivation of downstream signaling pathways and overgrowth of cells, playing an important role in the proliferation, invasion, metastasis, and evolution of breast cancer cells.16–18
H0648g,19 M77001,20 EGF100151,21 EGF10490022 et al studies have shown that patients with HER2-positive breast cancer can benefit from anti-HER2 humanized trastuzumab and double HER2-EGFR tyrosine kinase inhibitor (TKI) lapatinib. However, approximately 50% of HER2-positive patients developed resistance to trastuzumab 1 year after treatment.23 Lapatinib has achieved certain clinical efficacy in metastatic HER2-positive breast cancer treated with trastuzumab, but a significant proportion of patients develop disease progression due to innate or acquired resistance to lapatinib.24,25 Studies on the molecular mechanisms of trastuzumab and lapatinib resistance26 found that overexpression of other HER family receptors and their ligands, loss of PTEN leading to activation of the PI3K/Akt/mTOR pathway, PI3KCA mutation, and Akt mutation or amplification were common causes of drug resistance. Drug resistance has become an urgent problem.
The patient developed resistance to lapatinib combined with trastuzumab. The HER2 gene mutation was not detected before the patient received lapatinib plus trastuzumab treatment, while the R157W mutation was found in the disease progression after treatment. Moreover, by comparing the two gene test results (Table 1), only the HER2 mutation was acquired, so it was believed that the HER2 mutation was the main mechanism of drug resistance in this case. In recent years, with the gradual deepening of the understanding of HER2, it is believed that HER2 mutation plays an important role in the incidence, development and resistance of breast cancer.27,28 The primary HER2 mutation mostly occurred in HER2 negative conditions, while in HER2 positive breast cancer the HER2 mutation mostly occurred after anti-HER2 treatment. Fang et al6 performed HER2 full-length gene sequencing on the tissues of 198 patients with metastatic breast cancer (MBC) after multiple cycles of treatment and found that the rate of HER2 mutations in patients treated with trastuzumab was as high as 17.7%. Park et al7 also carried out NGS tests on the tissues of 36 refractory MBC patients after multi-cycle and multi-drug treatment, and found that 5 out of 6 patients with HER2 mutation were HER2 positive and developed drug resistance after receiving anti-HER2 drugs (trastuzumab, lapatinib).Table 1 NGS Results Detected Before and After Treatment with Trastuzumab and Lapatinib
Genes 20171018
Before Trastuzumab with Lapatinib 20180820
After Resistance to Trastuzumab with Lapatinib Methodology
Variations Abundance CN Variations Abundance CN
HER2 CNG 2.1 CNG 7.7 NGS
p.R157W 2.0% NGS
TP53 p.L257R 6.4% p.L257R 49.9% NGS
CDK12 CNG 1.8 Negative NGS
NSD1 GF 0.2% Negative NGS
ESR1 Negative Negative NGS
BRCA1 Negative Negative NGS
BRCA2 Negative Negative NGS
Abbreviations: HER2, human epidermal growth factor receptor-2; TP53, tumor protein p53; CDK12, cyclin-dependent kinase 12; NSD1, nuclear receptor binding SET domain protein 1; ESR1, estrogen receptor 1; BRCA1, breast cancer susceptibility gene 1; BRCA2, breast cancer susceptibility gene 2; CNG, copy number gain; CN, copy number; GF, gene fusion; NGS, next-generation sequencing.
In the literature, the most common HER2 mutation sites in breast cancer were L755S, V777L, D769H, D769Y, G778_P780dup, Y772_A775dup in the kinase domain, and S310F and S310Y in the extracellular domain.3,29 There are no studies to prove the difference between HER2-negative combined mutation and HER2 positive-combined mutation, and most of the mutations can occur in both. The causes of resistance to HER2 therapy due to HER2 mutations are not fully understood. A cell-induced drug resistance test suggested that drug resistance of lapatinib might be related to the change of kinase structure caused by L755S and P780L mutations, which would activate the kinase activity and interfere with the inactive structure required for lapatinib binding.30,31 It may also be related to the production of larger amino acids after L726F, L785F, and other mutations, which interfered with the binding of lapatinib spatially.30 In addition, T789 mutation can stabilize the active conformation and directly compete with lapatinib for ATP binding sites, which may also be one of the causes of lapatinib resistance.30,31 Other studies have found that increased levels of EGFR-HER3 dimerization and expression of HER4 can also lead to lapatinib resistance. The extracellular resistance test of trastuzumab suggested that mutations in the HER2 kinase domain might alter the PI3K/AKT cascade signaling, thereby weakening the inhibition of trastuzumab to the PI3K/AKT pathway.32 It has also been observed in cell experiments that L755S mutation can lead to overactivation of PI3K/AKT/mTOR and MAPK pathways, leading to resistance to lapatinib and neratinib.33 Hanker B et al34 reported that a breast cancer patient with HER2 L869R mutation got new T798I mutation when neratinib resistance happened. Cell models confirmed that the presence of isoleucine at the 798 site leads to steric hindrance, reducing the binding affinity of neratinib. Smyth et al29 believed that HER2 mutation accompanied with other changes in HER family signaling pathways, such as HER3 mutation, might lead to drug resistance to neratinib.
This case reported that R157W missense mutation happened in the extracellular domain belonging to exon4 of HER2 which could be found in the cBioPortal database35,36 within the TCGA data set (Figure 1). Prior to this, only two cases of HER2 R157W mutation have been reported in the literature, and that which was found in breast cancer harbored germline mutations. As this residue is presented in the extracellular domain, we think the drug-resistant mechanism may be related to the change of the extracellular domain receptor structure, which interfered with the binding of trastuzumab. It may also strengthen dimerization with other family receptors, such as HER2/HER3, and HER2/HER4 polymerization, thereby weakening the inhibition of lapatinib, which activated downstream pathways and caused a cascade reaction, eventually leading to tumor progression.Figure 1 Mutation site map of R157W gene in TCGA dataset from cBioPortal database.35,36
There is no standard treatment for HER2 mutation, but many studies have begun to explore treatment strategies. A number of studies have demonstrated that the pan-HER2 irreversible inhibitor neratinib has a good inhibitory effect on certain mutations. Zuo et al28 found that neratinib had a strong inhibitory effect on drug-resistant mutant cell lines bearing K753E or L755S mutations. Cocco et al37 demonstrated that neratinib could not only effectively overcome the acquired resistance to HER2 therapy in breast cancer cells carrying both HER2 amplification and L755S somatic mutation but also significantly inhibit tumor growth in mice which are resistant to trastuzumab and lapatinib as well as carrying both D769Y mutation and HER2 amplification. At the same time, it was observed that neratinib had clinical activity in breast cancer patients with both HER2 gene amplification and mutation. SUMMIT is a Phase II basket clinical trial involving patients with cancers featuring HER2 mutations, and the result shows that neratinib has a good clinical effect on patients with breast cancer accompanied by HER2 mutations but without amplification, with an ORR of 32% at 8 weeks,4 but resistance to T798-related mutations.33 Overall, neratinib has a certain clinical efficacy against common HER2 mutations, but has not yet been marketed in China.
Pyrotinib is a new generation of small-molecule irreversible pan-ErbB receptor TKI, covalently binding with the ATP binding site in the intracellular kinase regions of HER1, HER2, and HER4, which prevents the formation of homodimers/heterodimers in the HER family, inhibits phosphorylation itself, blocks the activation of downstream signaling pathways, and inhibits tumor cell growth.38 Its structure and mechanism of action are similar to neratinib, but it has stronger inhibitory activity in vitro. In 2019, Jiang et al, reported a phenix study orally at the ASCO conference, confirming that to HER2 positive MBC females who previously received paclitaxel and trastuzumab, pyrotinib plus capecitabine, compared to placebo plus capecitabine, can effectively improve the median PFS. In this case, the patient developed disease progression in September 2018 after receiving trastuzumab combined with lapatinib, and received pyrotinib plus capecitabine. Three months later, she got partial response, (Figure 2) and symptoms were relieved. Plasma NGS indicated that both the copy number of HER2 amplification and the abundance of R157W mutations were decreased compared with previous results (Table 2). The relationship between gene dynamics and efficacy is shown in Figure 3.Table 2 NGS Results Detected Before and After Treatment with Pyrotinib and Capecitabine
Genes 20180820
Before Pyrotinib with Capecitabine 20181212
After Pyrotinib with Capecitabine Methodology
Variations Abundance CN Variations Abundance CN
HER2 p.R157W 2.0% p.R157W 1.3% NGS
CNG 7.7 CNG 2.1 NGS
TP53 p.L257R 49.9% p.L257R 5.7% NGS
ESR1 Negative Negative NGS
BRCA1 Negative Negative NGS
BRCA2 Negative Negative NGS
Abbreviations: HER2, human epidermal growth factor receptor-2; TP53, tumor protein p53; ESR1, estrogen receptor 1; BRCA1, breast cancer susceptibility gene 1; BRCA2, breast cancer susceptibility gene 2; CNG, copy number gain; CN, copy number; NGS, next-generation sequencing.
Figure 2 Changes of images before and after treatment. The red arrows indicate the metastatic tumor.
Figure 3 The relationship between gene dynamics and efficacy. The red arrows indicate the metastatic tumor.
Conclusion
Drug resistance has affected the efficacy of anti-HER2 therapy in breast cancer, and HER2 mutation is one of the causes. However, there is no standard treatment yet. We report for the first time the occurrence of HER2 amplification accompanied by R157W mutation after anti-HER2 treatment. This case is the first clinical report of pyrotinib plus capecitabine effective for HER2 mutation, which shows a good clinical efficacy against HER2 resistance accompanied with mutation in MBC patients, and provides a possible new management strategy of anti-HER2 treatment for patients with HER2-positive breast cancer.
Acknowledgments
The authors thank the patient and her family. This study did not receive any funding support from external sources. Yanchun Qu and Yufeng Liu are co-first authors for this study.
Ethical Approval
Institutional approval was not required to publish the case details.
Patient Informed Consent
Written informed consent was obtained from the patient for the publication of her case details and images.
Disclosure
Xiaoyu Hong is the employee of Nanjing Geneseeq Technology Inc. The other authors have no conflicts of interest that are directly relevant to the content of this article. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33688205 | 19,110,981 | 2021 |
What was the administration route of drug 'LAPATINIB'? | Partial Response to Pyrotinib Plus Capecitabine in an Advanced Breast Cancer Patient with HER2 Amplification and R157W Mutation After Anti-HER2 Treatment: A Case Report and Literature Review.
Human epidermal growth factor receptor2 (HER2) overexpression/amplification is associated with high malignancy, rapid disease progression and poor overall survival in breast cancer. The application of anti-HER2 drugs has greatly improved the survival of patients with HER2-positive breast cancer, but drug resistance issues affect the long-term efficacy. The HER2 mutation is considered to be one of the reasons for resistance to anti-HER2 therapy, and there is currently no standard treatment. We report for the first time the detection of HER2 amplification with R157W mutation by second-generation sequencing (NGS) in a 57-year-old hormone receptor-negative, HER2-positive woman with advanced breast cancer who was resistant to multi-line anti-HER2 therapies. She subsequently received pyrotinib combined with capecitabine treatment and achieved partial response. The small-molecule pan-HER family irreversible inhibitor pyrotinib combined with capecitabine has shown a promising effect in the treatment of HER2 mutation-induced resistance, but the molecular mechanism and efficacy need to be further verified.
Introduction
Breast cancer is a malignant tumor with the highest morbidity and second highest mortality rate in women.1 HER2-positive (HER2 amplification) breast cancer accounts for about 15–20% of all breast cancers.2 Anti-HER2 drugs have greatly improved the survival of such patients. These drugs include humanized monoclonal antibodies like trastuzumab and pertuzumab, antibody-drug conjugates (ADC) like T-DM1, and novel oral small-molecule tyrosine kinase inhibitors like pyrotinib, neratinib, lapatinib and so on.
Acquired drug resistance is inevitable in patients with advanced HER2-positive breast cancer after first-line and second-line anti-HER2 treatments, and the mechanism is still under investigation. HER2 mutations are rare in breast cancer patients. A systematic review showed that the frequency of HER2 mutation in breast cancer patients was about 3%,3 while previous gene sequencing results suggested that patients with primary HER2-positive breast cancer had a lower frequency of HER2 mutation.4,5 Therefore, HER2 amplification and mutation are considered mutually exclusive in breast cancer patients. In recent years, studies have found that the HER2 gene mutation rate is higher in breast cancer patients treated with multi-line anti-HER2 therapies,6,7 and HER2 mutation is one of the causes of resistance to anti-HER2 treatment. There is no standard treatment for HER2 mutation patients yet. Of these, HER2 R157W mutation is a rare mutation and there are currently only two reports in the literature. One was somatic mutation found in micropapillary urothelial carcinoma (MPUC),8 which was not accompanied by HER2 overexpression and HER2 amplification. FATHMM prediction determined that it was a pathogenic mutation according to the COSMIC database. The other one was germline mutation found in breast cancer,9 of which the clinical significance is unknown. This is the first report of a patient with HER2-positive advanced breast cancer who developed HER2-amplification with R157W missense mutation after treatment of lapatinib plus trastuzumab and achieved partial response (PR) after using pyrotinib plus capecitabine.
Case Description
A 57-year-old Chinese female was initially presented to an outside hospital and underwent radical resection of left breast cancer diagnosed with stage IIIC (pTxN3M0) in Jan 2013. Pathology indicated invasive ductal carcinoma of breast estrogen receptor (ER) (-), progesterone receptor (PR) (-), and HER2(3+) by immunohistochemistry. Then, she received one cycle of adjuvant chemotherapy with docetaxel and three cycles of oncolytic virus therapy in other hospital, but the patient could not provide detailed information. In March 2013, PET/CT showed bilateral lung metastases. However, the patient refused chemotherapy and received traditional Chinese medicine (TCM) decoction treatment. In March 2014, follow-up PET/CT revealed multiple metastases in liver, both lungs and bones. A liver biopsy conducted in our department suggested hepatic metastasis of the breast cancer (ER(-), PR(-), HER2(3+)). The patient received eight cycles of first-line-targeted treatment with trastuzumab (8mg/kg IV day 1 followed by 6mg/kg IV day 1 every 21 days) plus paclitaxel (135mg/m2 IV day 1 every 21 days), followed by maintenance treatment with trastuzumab (6mg/kg IV day 1 every 21 days), achieving partial response and progression-free survival (PFS) for approximately 1 year. Subsequently, she was treated with docetaxel (75mg/m2 IV day 1 every 21 days), xeloda (1000mg/m2 PO bid days 1–14 every 21 days), and trastuzumab (6mg/kg IV day 1 every 21 days) as the second-line treatment for six cycles, with the best efficacy of partial response and PFS for 10 months. Upon disease progression, the third-line treatment was gemcitabine (1000mg/m2 IV day 1 every 21 days) plus S-1 (40mg PO bid days 1–14 every 21 days) based chemotherapy for 4 cycles, with the best efficacy of stable disease (SD) and PFS for nearly 4 months. In the fourth-line treatment, she received epirubicin (80mg/m2 IV day 1 every 21 days) plus lapatinib (0.25g PO qd). However, after one cycle, due to impaired liver function (with her alanine aminotransferase [ALT] level reaching 1122U/L), use of epirubicin was discontinued. Liver function improved following liver protection therapy, and the patient then continued lapatinib monotherapy (0.5g PO qd), maintaining an SD with PFS of 2 months.
In October 2017, enlarged lesions revealed in the chest and abdomen CT indicated progressive disease (PD). Next-generation sequencing (NGS) of plasma detected HER2 and CDK12 amplification, NSD1 gene fusion, and TP53 L257R mutation. The patient began to receive trastuzumab (6mg/kg IV day 1 every 21 days) combined with lapatinib (1g PO qd) as the fifth-line treatment from November 2017. The best efficacy was SD, and PFS was about 9 months. In August 2018, plasma NGS showed R157W missense mutation in HER2 exon 4, along with HER2 amplification and TP53 L257R mutation. That September, a chest and abdomen CT confirmed PD. The patient began to receive pyrotinib(400mg PO qd) plus xeloda (1000mg/m2 PO bid days 1–14 every 21 days) as the sixth-line treatment, with the best efficacy of PR and PFS for 13 months. Plasma NGS monitoring during the period (December 2018) suggested a decrease in HER2 copy number and abundance of R157W mutation. In November 2019, when her disease progressed again, the re-examination of the plasma NGS showed CDK12 and HER2 amplification, DNMT3A inactivation mutation and TP53 L257R mutation. There was no HER2 mutation.
From November 2019 to January 2020, the patient received the seventh-line treatment with Abraxane (200mg IV day 1 every 14 days), with the optimal efficacy of SD. In February 2020, she began to accept the eighth-line treatment with pertuzumab (840mg IV day 1 followed by 420mg IV day 1 every 21 days) combined with trastuzumab (8mg/kg IV da y1 followed by 6mg/kg IV day 1 every 21 days) and xeloda (1000mg/m2 PO bid days 1–14 every 21 days). The efficacy has not been evaluated at the time of writing this paper.
Discussion
HER2-amplified breast cancer accounts for about 15–20% of all breast cancers2 and is often characterized by rapid progression and poor prognosis.10,11 The precise treatment of HER2 has completely changed the survival rate for breast cancer with HER2-amplification. However, as time goes by, anti-HER2 treatment will inevitably produce acquired drug resistance, which will affect the survival of patients. Therefore, it is imperative to clarify the mechanism of drug resistance and make targeted treatments. The resistance mechanism of anti-HER2 drugs is complex, and the resistance caused by HER2 mutation has attracted more and more attention and may become a new potential therapeutic target.12 We report a 57-year-old woman with advanced HER2-positive breast cancer who received multiple lines of anti-HER2 therapy and was confirmed to have the HER2 R157W missense mutation in exon 4 by plasma NGS, and obtained PR after treatment with pyrotinib and capecitabine. This case provides a new potential treatment option for HER2 mutations following resistance to HER2 therapy.
Proto-oncogene HER2, also known as ErbB2, belongs to the ERB family with ErbB1(EGFR), ErbB3(HER3), and ErbB4(HER4). No high-affinity ligand has been found in HER2 so far, so it must form homologously or as a heterodimer with other members of the family, binding with ATP to activate intracellular tyrosine kinases, thereby initiating the downstream signaling pathway and regulating the proliferation and differentiation of cells.13–15 HER2 is the most important driver gene of breast cancer, and the most common positive form is gene amplification. Amplification of HER2 would lead to increased protein synthesis (ie, overexpression of HER2 protein) or increased protein function, which would lead to overactivation of downstream signaling pathways and overgrowth of cells, playing an important role in the proliferation, invasion, metastasis, and evolution of breast cancer cells.16–18
H0648g,19 M77001,20 EGF100151,21 EGF10490022 et al studies have shown that patients with HER2-positive breast cancer can benefit from anti-HER2 humanized trastuzumab and double HER2-EGFR tyrosine kinase inhibitor (TKI) lapatinib. However, approximately 50% of HER2-positive patients developed resistance to trastuzumab 1 year after treatment.23 Lapatinib has achieved certain clinical efficacy in metastatic HER2-positive breast cancer treated with trastuzumab, but a significant proportion of patients develop disease progression due to innate or acquired resistance to lapatinib.24,25 Studies on the molecular mechanisms of trastuzumab and lapatinib resistance26 found that overexpression of other HER family receptors and their ligands, loss of PTEN leading to activation of the PI3K/Akt/mTOR pathway, PI3KCA mutation, and Akt mutation or amplification were common causes of drug resistance. Drug resistance has become an urgent problem.
The patient developed resistance to lapatinib combined with trastuzumab. The HER2 gene mutation was not detected before the patient received lapatinib plus trastuzumab treatment, while the R157W mutation was found in the disease progression after treatment. Moreover, by comparing the two gene test results (Table 1), only the HER2 mutation was acquired, so it was believed that the HER2 mutation was the main mechanism of drug resistance in this case. In recent years, with the gradual deepening of the understanding of HER2, it is believed that HER2 mutation plays an important role in the incidence, development and resistance of breast cancer.27,28 The primary HER2 mutation mostly occurred in HER2 negative conditions, while in HER2 positive breast cancer the HER2 mutation mostly occurred after anti-HER2 treatment. Fang et al6 performed HER2 full-length gene sequencing on the tissues of 198 patients with metastatic breast cancer (MBC) after multiple cycles of treatment and found that the rate of HER2 mutations in patients treated with trastuzumab was as high as 17.7%. Park et al7 also carried out NGS tests on the tissues of 36 refractory MBC patients after multi-cycle and multi-drug treatment, and found that 5 out of 6 patients with HER2 mutation were HER2 positive and developed drug resistance after receiving anti-HER2 drugs (trastuzumab, lapatinib).Table 1 NGS Results Detected Before and After Treatment with Trastuzumab and Lapatinib
Genes 20171018
Before Trastuzumab with Lapatinib 20180820
After Resistance to Trastuzumab with Lapatinib Methodology
Variations Abundance CN Variations Abundance CN
HER2 CNG 2.1 CNG 7.7 NGS
p.R157W 2.0% NGS
TP53 p.L257R 6.4% p.L257R 49.9% NGS
CDK12 CNG 1.8 Negative NGS
NSD1 GF 0.2% Negative NGS
ESR1 Negative Negative NGS
BRCA1 Negative Negative NGS
BRCA2 Negative Negative NGS
Abbreviations: HER2, human epidermal growth factor receptor-2; TP53, tumor protein p53; CDK12, cyclin-dependent kinase 12; NSD1, nuclear receptor binding SET domain protein 1; ESR1, estrogen receptor 1; BRCA1, breast cancer susceptibility gene 1; BRCA2, breast cancer susceptibility gene 2; CNG, copy number gain; CN, copy number; GF, gene fusion; NGS, next-generation sequencing.
In the literature, the most common HER2 mutation sites in breast cancer were L755S, V777L, D769H, D769Y, G778_P780dup, Y772_A775dup in the kinase domain, and S310F and S310Y in the extracellular domain.3,29 There are no studies to prove the difference between HER2-negative combined mutation and HER2 positive-combined mutation, and most of the mutations can occur in both. The causes of resistance to HER2 therapy due to HER2 mutations are not fully understood. A cell-induced drug resistance test suggested that drug resistance of lapatinib might be related to the change of kinase structure caused by L755S and P780L mutations, which would activate the kinase activity and interfere with the inactive structure required for lapatinib binding.30,31 It may also be related to the production of larger amino acids after L726F, L785F, and other mutations, which interfered with the binding of lapatinib spatially.30 In addition, T789 mutation can stabilize the active conformation and directly compete with lapatinib for ATP binding sites, which may also be one of the causes of lapatinib resistance.30,31 Other studies have found that increased levels of EGFR-HER3 dimerization and expression of HER4 can also lead to lapatinib resistance. The extracellular resistance test of trastuzumab suggested that mutations in the HER2 kinase domain might alter the PI3K/AKT cascade signaling, thereby weakening the inhibition of trastuzumab to the PI3K/AKT pathway.32 It has also been observed in cell experiments that L755S mutation can lead to overactivation of PI3K/AKT/mTOR and MAPK pathways, leading to resistance to lapatinib and neratinib.33 Hanker B et al34 reported that a breast cancer patient with HER2 L869R mutation got new T798I mutation when neratinib resistance happened. Cell models confirmed that the presence of isoleucine at the 798 site leads to steric hindrance, reducing the binding affinity of neratinib. Smyth et al29 believed that HER2 mutation accompanied with other changes in HER family signaling pathways, such as HER3 mutation, might lead to drug resistance to neratinib.
This case reported that R157W missense mutation happened in the extracellular domain belonging to exon4 of HER2 which could be found in the cBioPortal database35,36 within the TCGA data set (Figure 1). Prior to this, only two cases of HER2 R157W mutation have been reported in the literature, and that which was found in breast cancer harbored germline mutations. As this residue is presented in the extracellular domain, we think the drug-resistant mechanism may be related to the change of the extracellular domain receptor structure, which interfered with the binding of trastuzumab. It may also strengthen dimerization with other family receptors, such as HER2/HER3, and HER2/HER4 polymerization, thereby weakening the inhibition of lapatinib, which activated downstream pathways and caused a cascade reaction, eventually leading to tumor progression.Figure 1 Mutation site map of R157W gene in TCGA dataset from cBioPortal database.35,36
There is no standard treatment for HER2 mutation, but many studies have begun to explore treatment strategies. A number of studies have demonstrated that the pan-HER2 irreversible inhibitor neratinib has a good inhibitory effect on certain mutations. Zuo et al28 found that neratinib had a strong inhibitory effect on drug-resistant mutant cell lines bearing K753E or L755S mutations. Cocco et al37 demonstrated that neratinib could not only effectively overcome the acquired resistance to HER2 therapy in breast cancer cells carrying both HER2 amplification and L755S somatic mutation but also significantly inhibit tumor growth in mice which are resistant to trastuzumab and lapatinib as well as carrying both D769Y mutation and HER2 amplification. At the same time, it was observed that neratinib had clinical activity in breast cancer patients with both HER2 gene amplification and mutation. SUMMIT is a Phase II basket clinical trial involving patients with cancers featuring HER2 mutations, and the result shows that neratinib has a good clinical effect on patients with breast cancer accompanied by HER2 mutations but without amplification, with an ORR of 32% at 8 weeks,4 but resistance to T798-related mutations.33 Overall, neratinib has a certain clinical efficacy against common HER2 mutations, but has not yet been marketed in China.
Pyrotinib is a new generation of small-molecule irreversible pan-ErbB receptor TKI, covalently binding with the ATP binding site in the intracellular kinase regions of HER1, HER2, and HER4, which prevents the formation of homodimers/heterodimers in the HER family, inhibits phosphorylation itself, blocks the activation of downstream signaling pathways, and inhibits tumor cell growth.38 Its structure and mechanism of action are similar to neratinib, but it has stronger inhibitory activity in vitro. In 2019, Jiang et al, reported a phenix study orally at the ASCO conference, confirming that to HER2 positive MBC females who previously received paclitaxel and trastuzumab, pyrotinib plus capecitabine, compared to placebo plus capecitabine, can effectively improve the median PFS. In this case, the patient developed disease progression in September 2018 after receiving trastuzumab combined with lapatinib, and received pyrotinib plus capecitabine. Three months later, she got partial response, (Figure 2) and symptoms were relieved. Plasma NGS indicated that both the copy number of HER2 amplification and the abundance of R157W mutations were decreased compared with previous results (Table 2). The relationship between gene dynamics and efficacy is shown in Figure 3.Table 2 NGS Results Detected Before and After Treatment with Pyrotinib and Capecitabine
Genes 20180820
Before Pyrotinib with Capecitabine 20181212
After Pyrotinib with Capecitabine Methodology
Variations Abundance CN Variations Abundance CN
HER2 p.R157W 2.0% p.R157W 1.3% NGS
CNG 7.7 CNG 2.1 NGS
TP53 p.L257R 49.9% p.L257R 5.7% NGS
ESR1 Negative Negative NGS
BRCA1 Negative Negative NGS
BRCA2 Negative Negative NGS
Abbreviations: HER2, human epidermal growth factor receptor-2; TP53, tumor protein p53; ESR1, estrogen receptor 1; BRCA1, breast cancer susceptibility gene 1; BRCA2, breast cancer susceptibility gene 2; CNG, copy number gain; CN, copy number; NGS, next-generation sequencing.
Figure 2 Changes of images before and after treatment. The red arrows indicate the metastatic tumor.
Figure 3 The relationship between gene dynamics and efficacy. The red arrows indicate the metastatic tumor.
Conclusion
Drug resistance has affected the efficacy of anti-HER2 therapy in breast cancer, and HER2 mutation is one of the causes. However, there is no standard treatment yet. We report for the first time the occurrence of HER2 amplification accompanied by R157W mutation after anti-HER2 treatment. This case is the first clinical report of pyrotinib plus capecitabine effective for HER2 mutation, which shows a good clinical efficacy against HER2 resistance accompanied with mutation in MBC patients, and provides a possible new management strategy of anti-HER2 treatment for patients with HER2-positive breast cancer.
Acknowledgments
The authors thank the patient and her family. This study did not receive any funding support from external sources. Yanchun Qu and Yufeng Liu are co-first authors for this study.
Ethical Approval
Institutional approval was not required to publish the case details.
Patient Informed Consent
Written informed consent was obtained from the patient for the publication of her case details and images.
Disclosure
Xiaoyu Hong is the employee of Nanjing Geneseeq Technology Inc. The other authors have no conflicts of interest that are directly relevant to the content of this article. | Oral | DrugAdministrationRoute | CC BY-NC | 33688205 | 19,110,981 | 2021 |
What was the dosage of drug 'EPIRUBICIN HYDROCHLORIDE'? | Partial Response to Pyrotinib Plus Capecitabine in an Advanced Breast Cancer Patient with HER2 Amplification and R157W Mutation After Anti-HER2 Treatment: A Case Report and Literature Review.
Human epidermal growth factor receptor2 (HER2) overexpression/amplification is associated with high malignancy, rapid disease progression and poor overall survival in breast cancer. The application of anti-HER2 drugs has greatly improved the survival of patients with HER2-positive breast cancer, but drug resistance issues affect the long-term efficacy. The HER2 mutation is considered to be one of the reasons for resistance to anti-HER2 therapy, and there is currently no standard treatment. We report for the first time the detection of HER2 amplification with R157W mutation by second-generation sequencing (NGS) in a 57-year-old hormone receptor-negative, HER2-positive woman with advanced breast cancer who was resistant to multi-line anti-HER2 therapies. She subsequently received pyrotinib combined with capecitabine treatment and achieved partial response. The small-molecule pan-HER family irreversible inhibitor pyrotinib combined with capecitabine has shown a promising effect in the treatment of HER2 mutation-induced resistance, but the molecular mechanism and efficacy need to be further verified.
Introduction
Breast cancer is a malignant tumor with the highest morbidity and second highest mortality rate in women.1 HER2-positive (HER2 amplification) breast cancer accounts for about 15–20% of all breast cancers.2 Anti-HER2 drugs have greatly improved the survival of such patients. These drugs include humanized monoclonal antibodies like trastuzumab and pertuzumab, antibody-drug conjugates (ADC) like T-DM1, and novel oral small-molecule tyrosine kinase inhibitors like pyrotinib, neratinib, lapatinib and so on.
Acquired drug resistance is inevitable in patients with advanced HER2-positive breast cancer after first-line and second-line anti-HER2 treatments, and the mechanism is still under investigation. HER2 mutations are rare in breast cancer patients. A systematic review showed that the frequency of HER2 mutation in breast cancer patients was about 3%,3 while previous gene sequencing results suggested that patients with primary HER2-positive breast cancer had a lower frequency of HER2 mutation.4,5 Therefore, HER2 amplification and mutation are considered mutually exclusive in breast cancer patients. In recent years, studies have found that the HER2 gene mutation rate is higher in breast cancer patients treated with multi-line anti-HER2 therapies,6,7 and HER2 mutation is one of the causes of resistance to anti-HER2 treatment. There is no standard treatment for HER2 mutation patients yet. Of these, HER2 R157W mutation is a rare mutation and there are currently only two reports in the literature. One was somatic mutation found in micropapillary urothelial carcinoma (MPUC),8 which was not accompanied by HER2 overexpression and HER2 amplification. FATHMM prediction determined that it was a pathogenic mutation according to the COSMIC database. The other one was germline mutation found in breast cancer,9 of which the clinical significance is unknown. This is the first report of a patient with HER2-positive advanced breast cancer who developed HER2-amplification with R157W missense mutation after treatment of lapatinib plus trastuzumab and achieved partial response (PR) after using pyrotinib plus capecitabine.
Case Description
A 57-year-old Chinese female was initially presented to an outside hospital and underwent radical resection of left breast cancer diagnosed with stage IIIC (pTxN3M0) in Jan 2013. Pathology indicated invasive ductal carcinoma of breast estrogen receptor (ER) (-), progesterone receptor (PR) (-), and HER2(3+) by immunohistochemistry. Then, she received one cycle of adjuvant chemotherapy with docetaxel and three cycles of oncolytic virus therapy in other hospital, but the patient could not provide detailed information. In March 2013, PET/CT showed bilateral lung metastases. However, the patient refused chemotherapy and received traditional Chinese medicine (TCM) decoction treatment. In March 2014, follow-up PET/CT revealed multiple metastases in liver, both lungs and bones. A liver biopsy conducted in our department suggested hepatic metastasis of the breast cancer (ER(-), PR(-), HER2(3+)). The patient received eight cycles of first-line-targeted treatment with trastuzumab (8mg/kg IV day 1 followed by 6mg/kg IV day 1 every 21 days) plus paclitaxel (135mg/m2 IV day 1 every 21 days), followed by maintenance treatment with trastuzumab (6mg/kg IV day 1 every 21 days), achieving partial response and progression-free survival (PFS) for approximately 1 year. Subsequently, she was treated with docetaxel (75mg/m2 IV day 1 every 21 days), xeloda (1000mg/m2 PO bid days 1–14 every 21 days), and trastuzumab (6mg/kg IV day 1 every 21 days) as the second-line treatment for six cycles, with the best efficacy of partial response and PFS for 10 months. Upon disease progression, the third-line treatment was gemcitabine (1000mg/m2 IV day 1 every 21 days) plus S-1 (40mg PO bid days 1–14 every 21 days) based chemotherapy for 4 cycles, with the best efficacy of stable disease (SD) and PFS for nearly 4 months. In the fourth-line treatment, she received epirubicin (80mg/m2 IV day 1 every 21 days) plus lapatinib (0.25g PO qd). However, after one cycle, due to impaired liver function (with her alanine aminotransferase [ALT] level reaching 1122U/L), use of epirubicin was discontinued. Liver function improved following liver protection therapy, and the patient then continued lapatinib monotherapy (0.5g PO qd), maintaining an SD with PFS of 2 months.
In October 2017, enlarged lesions revealed in the chest and abdomen CT indicated progressive disease (PD). Next-generation sequencing (NGS) of plasma detected HER2 and CDK12 amplification, NSD1 gene fusion, and TP53 L257R mutation. The patient began to receive trastuzumab (6mg/kg IV day 1 every 21 days) combined with lapatinib (1g PO qd) as the fifth-line treatment from November 2017. The best efficacy was SD, and PFS was about 9 months. In August 2018, plasma NGS showed R157W missense mutation in HER2 exon 4, along with HER2 amplification and TP53 L257R mutation. That September, a chest and abdomen CT confirmed PD. The patient began to receive pyrotinib(400mg PO qd) plus xeloda (1000mg/m2 PO bid days 1–14 every 21 days) as the sixth-line treatment, with the best efficacy of PR and PFS for 13 months. Plasma NGS monitoring during the period (December 2018) suggested a decrease in HER2 copy number and abundance of R157W mutation. In November 2019, when her disease progressed again, the re-examination of the plasma NGS showed CDK12 and HER2 amplification, DNMT3A inactivation mutation and TP53 L257R mutation. There was no HER2 mutation.
From November 2019 to January 2020, the patient received the seventh-line treatment with Abraxane (200mg IV day 1 every 14 days), with the optimal efficacy of SD. In February 2020, she began to accept the eighth-line treatment with pertuzumab (840mg IV day 1 followed by 420mg IV day 1 every 21 days) combined with trastuzumab (8mg/kg IV da y1 followed by 6mg/kg IV day 1 every 21 days) and xeloda (1000mg/m2 PO bid days 1–14 every 21 days). The efficacy has not been evaluated at the time of writing this paper.
Discussion
HER2-amplified breast cancer accounts for about 15–20% of all breast cancers2 and is often characterized by rapid progression and poor prognosis.10,11 The precise treatment of HER2 has completely changed the survival rate for breast cancer with HER2-amplification. However, as time goes by, anti-HER2 treatment will inevitably produce acquired drug resistance, which will affect the survival of patients. Therefore, it is imperative to clarify the mechanism of drug resistance and make targeted treatments. The resistance mechanism of anti-HER2 drugs is complex, and the resistance caused by HER2 mutation has attracted more and more attention and may become a new potential therapeutic target.12 We report a 57-year-old woman with advanced HER2-positive breast cancer who received multiple lines of anti-HER2 therapy and was confirmed to have the HER2 R157W missense mutation in exon 4 by plasma NGS, and obtained PR after treatment with pyrotinib and capecitabine. This case provides a new potential treatment option for HER2 mutations following resistance to HER2 therapy.
Proto-oncogene HER2, also known as ErbB2, belongs to the ERB family with ErbB1(EGFR), ErbB3(HER3), and ErbB4(HER4). No high-affinity ligand has been found in HER2 so far, so it must form homologously or as a heterodimer with other members of the family, binding with ATP to activate intracellular tyrosine kinases, thereby initiating the downstream signaling pathway and regulating the proliferation and differentiation of cells.13–15 HER2 is the most important driver gene of breast cancer, and the most common positive form is gene amplification. Amplification of HER2 would lead to increased protein synthesis (ie, overexpression of HER2 protein) or increased protein function, which would lead to overactivation of downstream signaling pathways and overgrowth of cells, playing an important role in the proliferation, invasion, metastasis, and evolution of breast cancer cells.16–18
H0648g,19 M77001,20 EGF100151,21 EGF10490022 et al studies have shown that patients with HER2-positive breast cancer can benefit from anti-HER2 humanized trastuzumab and double HER2-EGFR tyrosine kinase inhibitor (TKI) lapatinib. However, approximately 50% of HER2-positive patients developed resistance to trastuzumab 1 year after treatment.23 Lapatinib has achieved certain clinical efficacy in metastatic HER2-positive breast cancer treated with trastuzumab, but a significant proportion of patients develop disease progression due to innate or acquired resistance to lapatinib.24,25 Studies on the molecular mechanisms of trastuzumab and lapatinib resistance26 found that overexpression of other HER family receptors and their ligands, loss of PTEN leading to activation of the PI3K/Akt/mTOR pathway, PI3KCA mutation, and Akt mutation or amplification were common causes of drug resistance. Drug resistance has become an urgent problem.
The patient developed resistance to lapatinib combined with trastuzumab. The HER2 gene mutation was not detected before the patient received lapatinib plus trastuzumab treatment, while the R157W mutation was found in the disease progression after treatment. Moreover, by comparing the two gene test results (Table 1), only the HER2 mutation was acquired, so it was believed that the HER2 mutation was the main mechanism of drug resistance in this case. In recent years, with the gradual deepening of the understanding of HER2, it is believed that HER2 mutation plays an important role in the incidence, development and resistance of breast cancer.27,28 The primary HER2 mutation mostly occurred in HER2 negative conditions, while in HER2 positive breast cancer the HER2 mutation mostly occurred after anti-HER2 treatment. Fang et al6 performed HER2 full-length gene sequencing on the tissues of 198 patients with metastatic breast cancer (MBC) after multiple cycles of treatment and found that the rate of HER2 mutations in patients treated with trastuzumab was as high as 17.7%. Park et al7 also carried out NGS tests on the tissues of 36 refractory MBC patients after multi-cycle and multi-drug treatment, and found that 5 out of 6 patients with HER2 mutation were HER2 positive and developed drug resistance after receiving anti-HER2 drugs (trastuzumab, lapatinib).Table 1 NGS Results Detected Before and After Treatment with Trastuzumab and Lapatinib
Genes 20171018
Before Trastuzumab with Lapatinib 20180820
After Resistance to Trastuzumab with Lapatinib Methodology
Variations Abundance CN Variations Abundance CN
HER2 CNG 2.1 CNG 7.7 NGS
p.R157W 2.0% NGS
TP53 p.L257R 6.4% p.L257R 49.9% NGS
CDK12 CNG 1.8 Negative NGS
NSD1 GF 0.2% Negative NGS
ESR1 Negative Negative NGS
BRCA1 Negative Negative NGS
BRCA2 Negative Negative NGS
Abbreviations: HER2, human epidermal growth factor receptor-2; TP53, tumor protein p53; CDK12, cyclin-dependent kinase 12; NSD1, nuclear receptor binding SET domain protein 1; ESR1, estrogen receptor 1; BRCA1, breast cancer susceptibility gene 1; BRCA2, breast cancer susceptibility gene 2; CNG, copy number gain; CN, copy number; GF, gene fusion; NGS, next-generation sequencing.
In the literature, the most common HER2 mutation sites in breast cancer were L755S, V777L, D769H, D769Y, G778_P780dup, Y772_A775dup in the kinase domain, and S310F and S310Y in the extracellular domain.3,29 There are no studies to prove the difference between HER2-negative combined mutation and HER2 positive-combined mutation, and most of the mutations can occur in both. The causes of resistance to HER2 therapy due to HER2 mutations are not fully understood. A cell-induced drug resistance test suggested that drug resistance of lapatinib might be related to the change of kinase structure caused by L755S and P780L mutations, which would activate the kinase activity and interfere with the inactive structure required for lapatinib binding.30,31 It may also be related to the production of larger amino acids after L726F, L785F, and other mutations, which interfered with the binding of lapatinib spatially.30 In addition, T789 mutation can stabilize the active conformation and directly compete with lapatinib for ATP binding sites, which may also be one of the causes of lapatinib resistance.30,31 Other studies have found that increased levels of EGFR-HER3 dimerization and expression of HER4 can also lead to lapatinib resistance. The extracellular resistance test of trastuzumab suggested that mutations in the HER2 kinase domain might alter the PI3K/AKT cascade signaling, thereby weakening the inhibition of trastuzumab to the PI3K/AKT pathway.32 It has also been observed in cell experiments that L755S mutation can lead to overactivation of PI3K/AKT/mTOR and MAPK pathways, leading to resistance to lapatinib and neratinib.33 Hanker B et al34 reported that a breast cancer patient with HER2 L869R mutation got new T798I mutation when neratinib resistance happened. Cell models confirmed that the presence of isoleucine at the 798 site leads to steric hindrance, reducing the binding affinity of neratinib. Smyth et al29 believed that HER2 mutation accompanied with other changes in HER family signaling pathways, such as HER3 mutation, might lead to drug resistance to neratinib.
This case reported that R157W missense mutation happened in the extracellular domain belonging to exon4 of HER2 which could be found in the cBioPortal database35,36 within the TCGA data set (Figure 1). Prior to this, only two cases of HER2 R157W mutation have been reported in the literature, and that which was found in breast cancer harbored germline mutations. As this residue is presented in the extracellular domain, we think the drug-resistant mechanism may be related to the change of the extracellular domain receptor structure, which interfered with the binding of trastuzumab. It may also strengthen dimerization with other family receptors, such as HER2/HER3, and HER2/HER4 polymerization, thereby weakening the inhibition of lapatinib, which activated downstream pathways and caused a cascade reaction, eventually leading to tumor progression.Figure 1 Mutation site map of R157W gene in TCGA dataset from cBioPortal database.35,36
There is no standard treatment for HER2 mutation, but many studies have begun to explore treatment strategies. A number of studies have demonstrated that the pan-HER2 irreversible inhibitor neratinib has a good inhibitory effect on certain mutations. Zuo et al28 found that neratinib had a strong inhibitory effect on drug-resistant mutant cell lines bearing K753E or L755S mutations. Cocco et al37 demonstrated that neratinib could not only effectively overcome the acquired resistance to HER2 therapy in breast cancer cells carrying both HER2 amplification and L755S somatic mutation but also significantly inhibit tumor growth in mice which are resistant to trastuzumab and lapatinib as well as carrying both D769Y mutation and HER2 amplification. At the same time, it was observed that neratinib had clinical activity in breast cancer patients with both HER2 gene amplification and mutation. SUMMIT is a Phase II basket clinical trial involving patients with cancers featuring HER2 mutations, and the result shows that neratinib has a good clinical effect on patients with breast cancer accompanied by HER2 mutations but without amplification, with an ORR of 32% at 8 weeks,4 but resistance to T798-related mutations.33 Overall, neratinib has a certain clinical efficacy against common HER2 mutations, but has not yet been marketed in China.
Pyrotinib is a new generation of small-molecule irreversible pan-ErbB receptor TKI, covalently binding with the ATP binding site in the intracellular kinase regions of HER1, HER2, and HER4, which prevents the formation of homodimers/heterodimers in the HER family, inhibits phosphorylation itself, blocks the activation of downstream signaling pathways, and inhibits tumor cell growth.38 Its structure and mechanism of action are similar to neratinib, but it has stronger inhibitory activity in vitro. In 2019, Jiang et al, reported a phenix study orally at the ASCO conference, confirming that to HER2 positive MBC females who previously received paclitaxel and trastuzumab, pyrotinib plus capecitabine, compared to placebo plus capecitabine, can effectively improve the median PFS. In this case, the patient developed disease progression in September 2018 after receiving trastuzumab combined with lapatinib, and received pyrotinib plus capecitabine. Three months later, she got partial response, (Figure 2) and symptoms were relieved. Plasma NGS indicated that both the copy number of HER2 amplification and the abundance of R157W mutations were decreased compared with previous results (Table 2). The relationship between gene dynamics and efficacy is shown in Figure 3.Table 2 NGS Results Detected Before and After Treatment with Pyrotinib and Capecitabine
Genes 20180820
Before Pyrotinib with Capecitabine 20181212
After Pyrotinib with Capecitabine Methodology
Variations Abundance CN Variations Abundance CN
HER2 p.R157W 2.0% p.R157W 1.3% NGS
CNG 7.7 CNG 2.1 NGS
TP53 p.L257R 49.9% p.L257R 5.7% NGS
ESR1 Negative Negative NGS
BRCA1 Negative Negative NGS
BRCA2 Negative Negative NGS
Abbreviations: HER2, human epidermal growth factor receptor-2; TP53, tumor protein p53; ESR1, estrogen receptor 1; BRCA1, breast cancer susceptibility gene 1; BRCA2, breast cancer susceptibility gene 2; CNG, copy number gain; CN, copy number; NGS, next-generation sequencing.
Figure 2 Changes of images before and after treatment. The red arrows indicate the metastatic tumor.
Figure 3 The relationship between gene dynamics and efficacy. The red arrows indicate the metastatic tumor.
Conclusion
Drug resistance has affected the efficacy of anti-HER2 therapy in breast cancer, and HER2 mutation is one of the causes. However, there is no standard treatment yet. We report for the first time the occurrence of HER2 amplification accompanied by R157W mutation after anti-HER2 treatment. This case is the first clinical report of pyrotinib plus capecitabine effective for HER2 mutation, which shows a good clinical efficacy against HER2 resistance accompanied with mutation in MBC patients, and provides a possible new management strategy of anti-HER2 treatment for patients with HER2-positive breast cancer.
Acknowledgments
The authors thank the patient and her family. This study did not receive any funding support from external sources. Yanchun Qu and Yufeng Liu are co-first authors for this study.
Ethical Approval
Institutional approval was not required to publish the case details.
Patient Informed Consent
Written informed consent was obtained from the patient for the publication of her case details and images.
Disclosure
Xiaoyu Hong is the employee of Nanjing Geneseeq Technology Inc. The other authors have no conflicts of interest that are directly relevant to the content of this article. | 80 MG/M2, CYCLIC (DAY 1 EVERY 21 DAYS) | DrugDosageText | CC BY-NC | 33688205 | 19,110,981 | 2021 |
What was the dosage of drug 'LAPATINIB'? | Partial Response to Pyrotinib Plus Capecitabine in an Advanced Breast Cancer Patient with HER2 Amplification and R157W Mutation After Anti-HER2 Treatment: A Case Report and Literature Review.
Human epidermal growth factor receptor2 (HER2) overexpression/amplification is associated with high malignancy, rapid disease progression and poor overall survival in breast cancer. The application of anti-HER2 drugs has greatly improved the survival of patients with HER2-positive breast cancer, but drug resistance issues affect the long-term efficacy. The HER2 mutation is considered to be one of the reasons for resistance to anti-HER2 therapy, and there is currently no standard treatment. We report for the first time the detection of HER2 amplification with R157W mutation by second-generation sequencing (NGS) in a 57-year-old hormone receptor-negative, HER2-positive woman with advanced breast cancer who was resistant to multi-line anti-HER2 therapies. She subsequently received pyrotinib combined with capecitabine treatment and achieved partial response. The small-molecule pan-HER family irreversible inhibitor pyrotinib combined with capecitabine has shown a promising effect in the treatment of HER2 mutation-induced resistance, but the molecular mechanism and efficacy need to be further verified.
Introduction
Breast cancer is a malignant tumor with the highest morbidity and second highest mortality rate in women.1 HER2-positive (HER2 amplification) breast cancer accounts for about 15–20% of all breast cancers.2 Anti-HER2 drugs have greatly improved the survival of such patients. These drugs include humanized monoclonal antibodies like trastuzumab and pertuzumab, antibody-drug conjugates (ADC) like T-DM1, and novel oral small-molecule tyrosine kinase inhibitors like pyrotinib, neratinib, lapatinib and so on.
Acquired drug resistance is inevitable in patients with advanced HER2-positive breast cancer after first-line and second-line anti-HER2 treatments, and the mechanism is still under investigation. HER2 mutations are rare in breast cancer patients. A systematic review showed that the frequency of HER2 mutation in breast cancer patients was about 3%,3 while previous gene sequencing results suggested that patients with primary HER2-positive breast cancer had a lower frequency of HER2 mutation.4,5 Therefore, HER2 amplification and mutation are considered mutually exclusive in breast cancer patients. In recent years, studies have found that the HER2 gene mutation rate is higher in breast cancer patients treated with multi-line anti-HER2 therapies,6,7 and HER2 mutation is one of the causes of resistance to anti-HER2 treatment. There is no standard treatment for HER2 mutation patients yet. Of these, HER2 R157W mutation is a rare mutation and there are currently only two reports in the literature. One was somatic mutation found in micropapillary urothelial carcinoma (MPUC),8 which was not accompanied by HER2 overexpression and HER2 amplification. FATHMM prediction determined that it was a pathogenic mutation according to the COSMIC database. The other one was germline mutation found in breast cancer,9 of which the clinical significance is unknown. This is the first report of a patient with HER2-positive advanced breast cancer who developed HER2-amplification with R157W missense mutation after treatment of lapatinib plus trastuzumab and achieved partial response (PR) after using pyrotinib plus capecitabine.
Case Description
A 57-year-old Chinese female was initially presented to an outside hospital and underwent radical resection of left breast cancer diagnosed with stage IIIC (pTxN3M0) in Jan 2013. Pathology indicated invasive ductal carcinoma of breast estrogen receptor (ER) (-), progesterone receptor (PR) (-), and HER2(3+) by immunohistochemistry. Then, she received one cycle of adjuvant chemotherapy with docetaxel and three cycles of oncolytic virus therapy in other hospital, but the patient could not provide detailed information. In March 2013, PET/CT showed bilateral lung metastases. However, the patient refused chemotherapy and received traditional Chinese medicine (TCM) decoction treatment. In March 2014, follow-up PET/CT revealed multiple metastases in liver, both lungs and bones. A liver biopsy conducted in our department suggested hepatic metastasis of the breast cancer (ER(-), PR(-), HER2(3+)). The patient received eight cycles of first-line-targeted treatment with trastuzumab (8mg/kg IV day 1 followed by 6mg/kg IV day 1 every 21 days) plus paclitaxel (135mg/m2 IV day 1 every 21 days), followed by maintenance treatment with trastuzumab (6mg/kg IV day 1 every 21 days), achieving partial response and progression-free survival (PFS) for approximately 1 year. Subsequently, she was treated with docetaxel (75mg/m2 IV day 1 every 21 days), xeloda (1000mg/m2 PO bid days 1–14 every 21 days), and trastuzumab (6mg/kg IV day 1 every 21 days) as the second-line treatment for six cycles, with the best efficacy of partial response and PFS for 10 months. Upon disease progression, the third-line treatment was gemcitabine (1000mg/m2 IV day 1 every 21 days) plus S-1 (40mg PO bid days 1–14 every 21 days) based chemotherapy for 4 cycles, with the best efficacy of stable disease (SD) and PFS for nearly 4 months. In the fourth-line treatment, she received epirubicin (80mg/m2 IV day 1 every 21 days) plus lapatinib (0.25g PO qd). However, after one cycle, due to impaired liver function (with her alanine aminotransferase [ALT] level reaching 1122U/L), use of epirubicin was discontinued. Liver function improved following liver protection therapy, and the patient then continued lapatinib monotherapy (0.5g PO qd), maintaining an SD with PFS of 2 months.
In October 2017, enlarged lesions revealed in the chest and abdomen CT indicated progressive disease (PD). Next-generation sequencing (NGS) of plasma detected HER2 and CDK12 amplification, NSD1 gene fusion, and TP53 L257R mutation. The patient began to receive trastuzumab (6mg/kg IV day 1 every 21 days) combined with lapatinib (1g PO qd) as the fifth-line treatment from November 2017. The best efficacy was SD, and PFS was about 9 months. In August 2018, plasma NGS showed R157W missense mutation in HER2 exon 4, along with HER2 amplification and TP53 L257R mutation. That September, a chest and abdomen CT confirmed PD. The patient began to receive pyrotinib(400mg PO qd) plus xeloda (1000mg/m2 PO bid days 1–14 every 21 days) as the sixth-line treatment, with the best efficacy of PR and PFS for 13 months. Plasma NGS monitoring during the period (December 2018) suggested a decrease in HER2 copy number and abundance of R157W mutation. In November 2019, when her disease progressed again, the re-examination of the plasma NGS showed CDK12 and HER2 amplification, DNMT3A inactivation mutation and TP53 L257R mutation. There was no HER2 mutation.
From November 2019 to January 2020, the patient received the seventh-line treatment with Abraxane (200mg IV day 1 every 14 days), with the optimal efficacy of SD. In February 2020, she began to accept the eighth-line treatment with pertuzumab (840mg IV day 1 followed by 420mg IV day 1 every 21 days) combined with trastuzumab (8mg/kg IV da y1 followed by 6mg/kg IV day 1 every 21 days) and xeloda (1000mg/m2 PO bid days 1–14 every 21 days). The efficacy has not been evaluated at the time of writing this paper.
Discussion
HER2-amplified breast cancer accounts for about 15–20% of all breast cancers2 and is often characterized by rapid progression and poor prognosis.10,11 The precise treatment of HER2 has completely changed the survival rate for breast cancer with HER2-amplification. However, as time goes by, anti-HER2 treatment will inevitably produce acquired drug resistance, which will affect the survival of patients. Therefore, it is imperative to clarify the mechanism of drug resistance and make targeted treatments. The resistance mechanism of anti-HER2 drugs is complex, and the resistance caused by HER2 mutation has attracted more and more attention and may become a new potential therapeutic target.12 We report a 57-year-old woman with advanced HER2-positive breast cancer who received multiple lines of anti-HER2 therapy and was confirmed to have the HER2 R157W missense mutation in exon 4 by plasma NGS, and obtained PR after treatment with pyrotinib and capecitabine. This case provides a new potential treatment option for HER2 mutations following resistance to HER2 therapy.
Proto-oncogene HER2, also known as ErbB2, belongs to the ERB family with ErbB1(EGFR), ErbB3(HER3), and ErbB4(HER4). No high-affinity ligand has been found in HER2 so far, so it must form homologously or as a heterodimer with other members of the family, binding with ATP to activate intracellular tyrosine kinases, thereby initiating the downstream signaling pathway and regulating the proliferation and differentiation of cells.13–15 HER2 is the most important driver gene of breast cancer, and the most common positive form is gene amplification. Amplification of HER2 would lead to increased protein synthesis (ie, overexpression of HER2 protein) or increased protein function, which would lead to overactivation of downstream signaling pathways and overgrowth of cells, playing an important role in the proliferation, invasion, metastasis, and evolution of breast cancer cells.16–18
H0648g,19 M77001,20 EGF100151,21 EGF10490022 et al studies have shown that patients with HER2-positive breast cancer can benefit from anti-HER2 humanized trastuzumab and double HER2-EGFR tyrosine kinase inhibitor (TKI) lapatinib. However, approximately 50% of HER2-positive patients developed resistance to trastuzumab 1 year after treatment.23 Lapatinib has achieved certain clinical efficacy in metastatic HER2-positive breast cancer treated with trastuzumab, but a significant proportion of patients develop disease progression due to innate or acquired resistance to lapatinib.24,25 Studies on the molecular mechanisms of trastuzumab and lapatinib resistance26 found that overexpression of other HER family receptors and their ligands, loss of PTEN leading to activation of the PI3K/Akt/mTOR pathway, PI3KCA mutation, and Akt mutation or amplification were common causes of drug resistance. Drug resistance has become an urgent problem.
The patient developed resistance to lapatinib combined with trastuzumab. The HER2 gene mutation was not detected before the patient received lapatinib plus trastuzumab treatment, while the R157W mutation was found in the disease progression after treatment. Moreover, by comparing the two gene test results (Table 1), only the HER2 mutation was acquired, so it was believed that the HER2 mutation was the main mechanism of drug resistance in this case. In recent years, with the gradual deepening of the understanding of HER2, it is believed that HER2 mutation plays an important role in the incidence, development and resistance of breast cancer.27,28 The primary HER2 mutation mostly occurred in HER2 negative conditions, while in HER2 positive breast cancer the HER2 mutation mostly occurred after anti-HER2 treatment. Fang et al6 performed HER2 full-length gene sequencing on the tissues of 198 patients with metastatic breast cancer (MBC) after multiple cycles of treatment and found that the rate of HER2 mutations in patients treated with trastuzumab was as high as 17.7%. Park et al7 also carried out NGS tests on the tissues of 36 refractory MBC patients after multi-cycle and multi-drug treatment, and found that 5 out of 6 patients with HER2 mutation were HER2 positive and developed drug resistance after receiving anti-HER2 drugs (trastuzumab, lapatinib).Table 1 NGS Results Detected Before and After Treatment with Trastuzumab and Lapatinib
Genes 20171018
Before Trastuzumab with Lapatinib 20180820
After Resistance to Trastuzumab with Lapatinib Methodology
Variations Abundance CN Variations Abundance CN
HER2 CNG 2.1 CNG 7.7 NGS
p.R157W 2.0% NGS
TP53 p.L257R 6.4% p.L257R 49.9% NGS
CDK12 CNG 1.8 Negative NGS
NSD1 GF 0.2% Negative NGS
ESR1 Negative Negative NGS
BRCA1 Negative Negative NGS
BRCA2 Negative Negative NGS
Abbreviations: HER2, human epidermal growth factor receptor-2; TP53, tumor protein p53; CDK12, cyclin-dependent kinase 12; NSD1, nuclear receptor binding SET domain protein 1; ESR1, estrogen receptor 1; BRCA1, breast cancer susceptibility gene 1; BRCA2, breast cancer susceptibility gene 2; CNG, copy number gain; CN, copy number; GF, gene fusion; NGS, next-generation sequencing.
In the literature, the most common HER2 mutation sites in breast cancer were L755S, V777L, D769H, D769Y, G778_P780dup, Y772_A775dup in the kinase domain, and S310F and S310Y in the extracellular domain.3,29 There are no studies to prove the difference between HER2-negative combined mutation and HER2 positive-combined mutation, and most of the mutations can occur in both. The causes of resistance to HER2 therapy due to HER2 mutations are not fully understood. A cell-induced drug resistance test suggested that drug resistance of lapatinib might be related to the change of kinase structure caused by L755S and P780L mutations, which would activate the kinase activity and interfere with the inactive structure required for lapatinib binding.30,31 It may also be related to the production of larger amino acids after L726F, L785F, and other mutations, which interfered with the binding of lapatinib spatially.30 In addition, T789 mutation can stabilize the active conformation and directly compete with lapatinib for ATP binding sites, which may also be one of the causes of lapatinib resistance.30,31 Other studies have found that increased levels of EGFR-HER3 dimerization and expression of HER4 can also lead to lapatinib resistance. The extracellular resistance test of trastuzumab suggested that mutations in the HER2 kinase domain might alter the PI3K/AKT cascade signaling, thereby weakening the inhibition of trastuzumab to the PI3K/AKT pathway.32 It has also been observed in cell experiments that L755S mutation can lead to overactivation of PI3K/AKT/mTOR and MAPK pathways, leading to resistance to lapatinib and neratinib.33 Hanker B et al34 reported that a breast cancer patient with HER2 L869R mutation got new T798I mutation when neratinib resistance happened. Cell models confirmed that the presence of isoleucine at the 798 site leads to steric hindrance, reducing the binding affinity of neratinib. Smyth et al29 believed that HER2 mutation accompanied with other changes in HER family signaling pathways, such as HER3 mutation, might lead to drug resistance to neratinib.
This case reported that R157W missense mutation happened in the extracellular domain belonging to exon4 of HER2 which could be found in the cBioPortal database35,36 within the TCGA data set (Figure 1). Prior to this, only two cases of HER2 R157W mutation have been reported in the literature, and that which was found in breast cancer harbored germline mutations. As this residue is presented in the extracellular domain, we think the drug-resistant mechanism may be related to the change of the extracellular domain receptor structure, which interfered with the binding of trastuzumab. It may also strengthen dimerization with other family receptors, such as HER2/HER3, and HER2/HER4 polymerization, thereby weakening the inhibition of lapatinib, which activated downstream pathways and caused a cascade reaction, eventually leading to tumor progression.Figure 1 Mutation site map of R157W gene in TCGA dataset from cBioPortal database.35,36
There is no standard treatment for HER2 mutation, but many studies have begun to explore treatment strategies. A number of studies have demonstrated that the pan-HER2 irreversible inhibitor neratinib has a good inhibitory effect on certain mutations. Zuo et al28 found that neratinib had a strong inhibitory effect on drug-resistant mutant cell lines bearing K753E or L755S mutations. Cocco et al37 demonstrated that neratinib could not only effectively overcome the acquired resistance to HER2 therapy in breast cancer cells carrying both HER2 amplification and L755S somatic mutation but also significantly inhibit tumor growth in mice which are resistant to trastuzumab and lapatinib as well as carrying both D769Y mutation and HER2 amplification. At the same time, it was observed that neratinib had clinical activity in breast cancer patients with both HER2 gene amplification and mutation. SUMMIT is a Phase II basket clinical trial involving patients with cancers featuring HER2 mutations, and the result shows that neratinib has a good clinical effect on patients with breast cancer accompanied by HER2 mutations but without amplification, with an ORR of 32% at 8 weeks,4 but resistance to T798-related mutations.33 Overall, neratinib has a certain clinical efficacy against common HER2 mutations, but has not yet been marketed in China.
Pyrotinib is a new generation of small-molecule irreversible pan-ErbB receptor TKI, covalently binding with the ATP binding site in the intracellular kinase regions of HER1, HER2, and HER4, which prevents the formation of homodimers/heterodimers in the HER family, inhibits phosphorylation itself, blocks the activation of downstream signaling pathways, and inhibits tumor cell growth.38 Its structure and mechanism of action are similar to neratinib, but it has stronger inhibitory activity in vitro. In 2019, Jiang et al, reported a phenix study orally at the ASCO conference, confirming that to HER2 positive MBC females who previously received paclitaxel and trastuzumab, pyrotinib plus capecitabine, compared to placebo plus capecitabine, can effectively improve the median PFS. In this case, the patient developed disease progression in September 2018 after receiving trastuzumab combined with lapatinib, and received pyrotinib plus capecitabine. Three months later, she got partial response, (Figure 2) and symptoms were relieved. Plasma NGS indicated that both the copy number of HER2 amplification and the abundance of R157W mutations were decreased compared with previous results (Table 2). The relationship between gene dynamics and efficacy is shown in Figure 3.Table 2 NGS Results Detected Before and After Treatment with Pyrotinib and Capecitabine
Genes 20180820
Before Pyrotinib with Capecitabine 20181212
After Pyrotinib with Capecitabine Methodology
Variations Abundance CN Variations Abundance CN
HER2 p.R157W 2.0% p.R157W 1.3% NGS
CNG 7.7 CNG 2.1 NGS
TP53 p.L257R 49.9% p.L257R 5.7% NGS
ESR1 Negative Negative NGS
BRCA1 Negative Negative NGS
BRCA2 Negative Negative NGS
Abbreviations: HER2, human epidermal growth factor receptor-2; TP53, tumor protein p53; ESR1, estrogen receptor 1; BRCA1, breast cancer susceptibility gene 1; BRCA2, breast cancer susceptibility gene 2; CNG, copy number gain; CN, copy number; NGS, next-generation sequencing.
Figure 2 Changes of images before and after treatment. The red arrows indicate the metastatic tumor.
Figure 3 The relationship between gene dynamics and efficacy. The red arrows indicate the metastatic tumor.
Conclusion
Drug resistance has affected the efficacy of anti-HER2 therapy in breast cancer, and HER2 mutation is one of the causes. However, there is no standard treatment yet. We report for the first time the occurrence of HER2 amplification accompanied by R157W mutation after anti-HER2 treatment. This case is the first clinical report of pyrotinib plus capecitabine effective for HER2 mutation, which shows a good clinical efficacy against HER2 resistance accompanied with mutation in MBC patients, and provides a possible new management strategy of anti-HER2 treatment for patients with HER2-positive breast cancer.
Acknowledgments
The authors thank the patient and her family. This study did not receive any funding support from external sources. Yanchun Qu and Yufeng Liu are co-first authors for this study.
Ethical Approval
Institutional approval was not required to publish the case details.
Patient Informed Consent
Written informed consent was obtained from the patient for the publication of her case details and images.
Disclosure
Xiaoyu Hong is the employee of Nanjing Geneseeq Technology Inc. The other authors have no conflicts of interest that are directly relevant to the content of this article. | 0.25 G, 1X/DAY | DrugDosageText | CC BY-NC | 33688205 | 19,110,981 | 2021 |
What was the outcome of reaction 'Hepatic function abnormal'? | Partial Response to Pyrotinib Plus Capecitabine in an Advanced Breast Cancer Patient with HER2 Amplification and R157W Mutation After Anti-HER2 Treatment: A Case Report and Literature Review.
Human epidermal growth factor receptor2 (HER2) overexpression/amplification is associated with high malignancy, rapid disease progression and poor overall survival in breast cancer. The application of anti-HER2 drugs has greatly improved the survival of patients with HER2-positive breast cancer, but drug resistance issues affect the long-term efficacy. The HER2 mutation is considered to be one of the reasons for resistance to anti-HER2 therapy, and there is currently no standard treatment. We report for the first time the detection of HER2 amplification with R157W mutation by second-generation sequencing (NGS) in a 57-year-old hormone receptor-negative, HER2-positive woman with advanced breast cancer who was resistant to multi-line anti-HER2 therapies. She subsequently received pyrotinib combined with capecitabine treatment and achieved partial response. The small-molecule pan-HER family irreversible inhibitor pyrotinib combined with capecitabine has shown a promising effect in the treatment of HER2 mutation-induced resistance, but the molecular mechanism and efficacy need to be further verified.
Introduction
Breast cancer is a malignant tumor with the highest morbidity and second highest mortality rate in women.1 HER2-positive (HER2 amplification) breast cancer accounts for about 15–20% of all breast cancers.2 Anti-HER2 drugs have greatly improved the survival of such patients. These drugs include humanized monoclonal antibodies like trastuzumab and pertuzumab, antibody-drug conjugates (ADC) like T-DM1, and novel oral small-molecule tyrosine kinase inhibitors like pyrotinib, neratinib, lapatinib and so on.
Acquired drug resistance is inevitable in patients with advanced HER2-positive breast cancer after first-line and second-line anti-HER2 treatments, and the mechanism is still under investigation. HER2 mutations are rare in breast cancer patients. A systematic review showed that the frequency of HER2 mutation in breast cancer patients was about 3%,3 while previous gene sequencing results suggested that patients with primary HER2-positive breast cancer had a lower frequency of HER2 mutation.4,5 Therefore, HER2 amplification and mutation are considered mutually exclusive in breast cancer patients. In recent years, studies have found that the HER2 gene mutation rate is higher in breast cancer patients treated with multi-line anti-HER2 therapies,6,7 and HER2 mutation is one of the causes of resistance to anti-HER2 treatment. There is no standard treatment for HER2 mutation patients yet. Of these, HER2 R157W mutation is a rare mutation and there are currently only two reports in the literature. One was somatic mutation found in micropapillary urothelial carcinoma (MPUC),8 which was not accompanied by HER2 overexpression and HER2 amplification. FATHMM prediction determined that it was a pathogenic mutation according to the COSMIC database. The other one was germline mutation found in breast cancer,9 of which the clinical significance is unknown. This is the first report of a patient with HER2-positive advanced breast cancer who developed HER2-amplification with R157W missense mutation after treatment of lapatinib plus trastuzumab and achieved partial response (PR) after using pyrotinib plus capecitabine.
Case Description
A 57-year-old Chinese female was initially presented to an outside hospital and underwent radical resection of left breast cancer diagnosed with stage IIIC (pTxN3M0) in Jan 2013. Pathology indicated invasive ductal carcinoma of breast estrogen receptor (ER) (-), progesterone receptor (PR) (-), and HER2(3+) by immunohistochemistry. Then, she received one cycle of adjuvant chemotherapy with docetaxel and three cycles of oncolytic virus therapy in other hospital, but the patient could not provide detailed information. In March 2013, PET/CT showed bilateral lung metastases. However, the patient refused chemotherapy and received traditional Chinese medicine (TCM) decoction treatment. In March 2014, follow-up PET/CT revealed multiple metastases in liver, both lungs and bones. A liver biopsy conducted in our department suggested hepatic metastasis of the breast cancer (ER(-), PR(-), HER2(3+)). The patient received eight cycles of first-line-targeted treatment with trastuzumab (8mg/kg IV day 1 followed by 6mg/kg IV day 1 every 21 days) plus paclitaxel (135mg/m2 IV day 1 every 21 days), followed by maintenance treatment with trastuzumab (6mg/kg IV day 1 every 21 days), achieving partial response and progression-free survival (PFS) for approximately 1 year. Subsequently, she was treated with docetaxel (75mg/m2 IV day 1 every 21 days), xeloda (1000mg/m2 PO bid days 1–14 every 21 days), and trastuzumab (6mg/kg IV day 1 every 21 days) as the second-line treatment for six cycles, with the best efficacy of partial response and PFS for 10 months. Upon disease progression, the third-line treatment was gemcitabine (1000mg/m2 IV day 1 every 21 days) plus S-1 (40mg PO bid days 1–14 every 21 days) based chemotherapy for 4 cycles, with the best efficacy of stable disease (SD) and PFS for nearly 4 months. In the fourth-line treatment, she received epirubicin (80mg/m2 IV day 1 every 21 days) plus lapatinib (0.25g PO qd). However, after one cycle, due to impaired liver function (with her alanine aminotransferase [ALT] level reaching 1122U/L), use of epirubicin was discontinued. Liver function improved following liver protection therapy, and the patient then continued lapatinib monotherapy (0.5g PO qd), maintaining an SD with PFS of 2 months.
In October 2017, enlarged lesions revealed in the chest and abdomen CT indicated progressive disease (PD). Next-generation sequencing (NGS) of plasma detected HER2 and CDK12 amplification, NSD1 gene fusion, and TP53 L257R mutation. The patient began to receive trastuzumab (6mg/kg IV day 1 every 21 days) combined with lapatinib (1g PO qd) as the fifth-line treatment from November 2017. The best efficacy was SD, and PFS was about 9 months. In August 2018, plasma NGS showed R157W missense mutation in HER2 exon 4, along with HER2 amplification and TP53 L257R mutation. That September, a chest and abdomen CT confirmed PD. The patient began to receive pyrotinib(400mg PO qd) plus xeloda (1000mg/m2 PO bid days 1–14 every 21 days) as the sixth-line treatment, with the best efficacy of PR and PFS for 13 months. Plasma NGS monitoring during the period (December 2018) suggested a decrease in HER2 copy number and abundance of R157W mutation. In November 2019, when her disease progressed again, the re-examination of the plasma NGS showed CDK12 and HER2 amplification, DNMT3A inactivation mutation and TP53 L257R mutation. There was no HER2 mutation.
From November 2019 to January 2020, the patient received the seventh-line treatment with Abraxane (200mg IV day 1 every 14 days), with the optimal efficacy of SD. In February 2020, she began to accept the eighth-line treatment with pertuzumab (840mg IV day 1 followed by 420mg IV day 1 every 21 days) combined with trastuzumab (8mg/kg IV da y1 followed by 6mg/kg IV day 1 every 21 days) and xeloda (1000mg/m2 PO bid days 1–14 every 21 days). The efficacy has not been evaluated at the time of writing this paper.
Discussion
HER2-amplified breast cancer accounts for about 15–20% of all breast cancers2 and is often characterized by rapid progression and poor prognosis.10,11 The precise treatment of HER2 has completely changed the survival rate for breast cancer with HER2-amplification. However, as time goes by, anti-HER2 treatment will inevitably produce acquired drug resistance, which will affect the survival of patients. Therefore, it is imperative to clarify the mechanism of drug resistance and make targeted treatments. The resistance mechanism of anti-HER2 drugs is complex, and the resistance caused by HER2 mutation has attracted more and more attention and may become a new potential therapeutic target.12 We report a 57-year-old woman with advanced HER2-positive breast cancer who received multiple lines of anti-HER2 therapy and was confirmed to have the HER2 R157W missense mutation in exon 4 by plasma NGS, and obtained PR after treatment with pyrotinib and capecitabine. This case provides a new potential treatment option for HER2 mutations following resistance to HER2 therapy.
Proto-oncogene HER2, also known as ErbB2, belongs to the ERB family with ErbB1(EGFR), ErbB3(HER3), and ErbB4(HER4). No high-affinity ligand has been found in HER2 so far, so it must form homologously or as a heterodimer with other members of the family, binding with ATP to activate intracellular tyrosine kinases, thereby initiating the downstream signaling pathway and regulating the proliferation and differentiation of cells.13–15 HER2 is the most important driver gene of breast cancer, and the most common positive form is gene amplification. Amplification of HER2 would lead to increased protein synthesis (ie, overexpression of HER2 protein) or increased protein function, which would lead to overactivation of downstream signaling pathways and overgrowth of cells, playing an important role in the proliferation, invasion, metastasis, and evolution of breast cancer cells.16–18
H0648g,19 M77001,20 EGF100151,21 EGF10490022 et al studies have shown that patients with HER2-positive breast cancer can benefit from anti-HER2 humanized trastuzumab and double HER2-EGFR tyrosine kinase inhibitor (TKI) lapatinib. However, approximately 50% of HER2-positive patients developed resistance to trastuzumab 1 year after treatment.23 Lapatinib has achieved certain clinical efficacy in metastatic HER2-positive breast cancer treated with trastuzumab, but a significant proportion of patients develop disease progression due to innate or acquired resistance to lapatinib.24,25 Studies on the molecular mechanisms of trastuzumab and lapatinib resistance26 found that overexpression of other HER family receptors and their ligands, loss of PTEN leading to activation of the PI3K/Akt/mTOR pathway, PI3KCA mutation, and Akt mutation or amplification were common causes of drug resistance. Drug resistance has become an urgent problem.
The patient developed resistance to lapatinib combined with trastuzumab. The HER2 gene mutation was not detected before the patient received lapatinib plus trastuzumab treatment, while the R157W mutation was found in the disease progression after treatment. Moreover, by comparing the two gene test results (Table 1), only the HER2 mutation was acquired, so it was believed that the HER2 mutation was the main mechanism of drug resistance in this case. In recent years, with the gradual deepening of the understanding of HER2, it is believed that HER2 mutation plays an important role in the incidence, development and resistance of breast cancer.27,28 The primary HER2 mutation mostly occurred in HER2 negative conditions, while in HER2 positive breast cancer the HER2 mutation mostly occurred after anti-HER2 treatment. Fang et al6 performed HER2 full-length gene sequencing on the tissues of 198 patients with metastatic breast cancer (MBC) after multiple cycles of treatment and found that the rate of HER2 mutations in patients treated with trastuzumab was as high as 17.7%. Park et al7 also carried out NGS tests on the tissues of 36 refractory MBC patients after multi-cycle and multi-drug treatment, and found that 5 out of 6 patients with HER2 mutation were HER2 positive and developed drug resistance after receiving anti-HER2 drugs (trastuzumab, lapatinib).Table 1 NGS Results Detected Before and After Treatment with Trastuzumab and Lapatinib
Genes 20171018
Before Trastuzumab with Lapatinib 20180820
After Resistance to Trastuzumab with Lapatinib Methodology
Variations Abundance CN Variations Abundance CN
HER2 CNG 2.1 CNG 7.7 NGS
p.R157W 2.0% NGS
TP53 p.L257R 6.4% p.L257R 49.9% NGS
CDK12 CNG 1.8 Negative NGS
NSD1 GF 0.2% Negative NGS
ESR1 Negative Negative NGS
BRCA1 Negative Negative NGS
BRCA2 Negative Negative NGS
Abbreviations: HER2, human epidermal growth factor receptor-2; TP53, tumor protein p53; CDK12, cyclin-dependent kinase 12; NSD1, nuclear receptor binding SET domain protein 1; ESR1, estrogen receptor 1; BRCA1, breast cancer susceptibility gene 1; BRCA2, breast cancer susceptibility gene 2; CNG, copy number gain; CN, copy number; GF, gene fusion; NGS, next-generation sequencing.
In the literature, the most common HER2 mutation sites in breast cancer were L755S, V777L, D769H, D769Y, G778_P780dup, Y772_A775dup in the kinase domain, and S310F and S310Y in the extracellular domain.3,29 There are no studies to prove the difference between HER2-negative combined mutation and HER2 positive-combined mutation, and most of the mutations can occur in both. The causes of resistance to HER2 therapy due to HER2 mutations are not fully understood. A cell-induced drug resistance test suggested that drug resistance of lapatinib might be related to the change of kinase structure caused by L755S and P780L mutations, which would activate the kinase activity and interfere with the inactive structure required for lapatinib binding.30,31 It may also be related to the production of larger amino acids after L726F, L785F, and other mutations, which interfered with the binding of lapatinib spatially.30 In addition, T789 mutation can stabilize the active conformation and directly compete with lapatinib for ATP binding sites, which may also be one of the causes of lapatinib resistance.30,31 Other studies have found that increased levels of EGFR-HER3 dimerization and expression of HER4 can also lead to lapatinib resistance. The extracellular resistance test of trastuzumab suggested that mutations in the HER2 kinase domain might alter the PI3K/AKT cascade signaling, thereby weakening the inhibition of trastuzumab to the PI3K/AKT pathway.32 It has also been observed in cell experiments that L755S mutation can lead to overactivation of PI3K/AKT/mTOR and MAPK pathways, leading to resistance to lapatinib and neratinib.33 Hanker B et al34 reported that a breast cancer patient with HER2 L869R mutation got new T798I mutation when neratinib resistance happened. Cell models confirmed that the presence of isoleucine at the 798 site leads to steric hindrance, reducing the binding affinity of neratinib. Smyth et al29 believed that HER2 mutation accompanied with other changes in HER family signaling pathways, such as HER3 mutation, might lead to drug resistance to neratinib.
This case reported that R157W missense mutation happened in the extracellular domain belonging to exon4 of HER2 which could be found in the cBioPortal database35,36 within the TCGA data set (Figure 1). Prior to this, only two cases of HER2 R157W mutation have been reported in the literature, and that which was found in breast cancer harbored germline mutations. As this residue is presented in the extracellular domain, we think the drug-resistant mechanism may be related to the change of the extracellular domain receptor structure, which interfered with the binding of trastuzumab. It may also strengthen dimerization with other family receptors, such as HER2/HER3, and HER2/HER4 polymerization, thereby weakening the inhibition of lapatinib, which activated downstream pathways and caused a cascade reaction, eventually leading to tumor progression.Figure 1 Mutation site map of R157W gene in TCGA dataset from cBioPortal database.35,36
There is no standard treatment for HER2 mutation, but many studies have begun to explore treatment strategies. A number of studies have demonstrated that the pan-HER2 irreversible inhibitor neratinib has a good inhibitory effect on certain mutations. Zuo et al28 found that neratinib had a strong inhibitory effect on drug-resistant mutant cell lines bearing K753E or L755S mutations. Cocco et al37 demonstrated that neratinib could not only effectively overcome the acquired resistance to HER2 therapy in breast cancer cells carrying both HER2 amplification and L755S somatic mutation but also significantly inhibit tumor growth in mice which are resistant to trastuzumab and lapatinib as well as carrying both D769Y mutation and HER2 amplification. At the same time, it was observed that neratinib had clinical activity in breast cancer patients with both HER2 gene amplification and mutation. SUMMIT is a Phase II basket clinical trial involving patients with cancers featuring HER2 mutations, and the result shows that neratinib has a good clinical effect on patients with breast cancer accompanied by HER2 mutations but without amplification, with an ORR of 32% at 8 weeks,4 but resistance to T798-related mutations.33 Overall, neratinib has a certain clinical efficacy against common HER2 mutations, but has not yet been marketed in China.
Pyrotinib is a new generation of small-molecule irreversible pan-ErbB receptor TKI, covalently binding with the ATP binding site in the intracellular kinase regions of HER1, HER2, and HER4, which prevents the formation of homodimers/heterodimers in the HER family, inhibits phosphorylation itself, blocks the activation of downstream signaling pathways, and inhibits tumor cell growth.38 Its structure and mechanism of action are similar to neratinib, but it has stronger inhibitory activity in vitro. In 2019, Jiang et al, reported a phenix study orally at the ASCO conference, confirming that to HER2 positive MBC females who previously received paclitaxel and trastuzumab, pyrotinib plus capecitabine, compared to placebo plus capecitabine, can effectively improve the median PFS. In this case, the patient developed disease progression in September 2018 after receiving trastuzumab combined with lapatinib, and received pyrotinib plus capecitabine. Three months later, she got partial response, (Figure 2) and symptoms were relieved. Plasma NGS indicated that both the copy number of HER2 amplification and the abundance of R157W mutations were decreased compared with previous results (Table 2). The relationship between gene dynamics and efficacy is shown in Figure 3.Table 2 NGS Results Detected Before and After Treatment with Pyrotinib and Capecitabine
Genes 20180820
Before Pyrotinib with Capecitabine 20181212
After Pyrotinib with Capecitabine Methodology
Variations Abundance CN Variations Abundance CN
HER2 p.R157W 2.0% p.R157W 1.3% NGS
CNG 7.7 CNG 2.1 NGS
TP53 p.L257R 49.9% p.L257R 5.7% NGS
ESR1 Negative Negative NGS
BRCA1 Negative Negative NGS
BRCA2 Negative Negative NGS
Abbreviations: HER2, human epidermal growth factor receptor-2; TP53, tumor protein p53; ESR1, estrogen receptor 1; BRCA1, breast cancer susceptibility gene 1; BRCA2, breast cancer susceptibility gene 2; CNG, copy number gain; CN, copy number; NGS, next-generation sequencing.
Figure 2 Changes of images before and after treatment. The red arrows indicate the metastatic tumor.
Figure 3 The relationship between gene dynamics and efficacy. The red arrows indicate the metastatic tumor.
Conclusion
Drug resistance has affected the efficacy of anti-HER2 therapy in breast cancer, and HER2 mutation is one of the causes. However, there is no standard treatment yet. We report for the first time the occurrence of HER2 amplification accompanied by R157W mutation after anti-HER2 treatment. This case is the first clinical report of pyrotinib plus capecitabine effective for HER2 mutation, which shows a good clinical efficacy against HER2 resistance accompanied with mutation in MBC patients, and provides a possible new management strategy of anti-HER2 treatment for patients with HER2-positive breast cancer.
Acknowledgments
The authors thank the patient and her family. This study did not receive any funding support from external sources. Yanchun Qu and Yufeng Liu are co-first authors for this study.
Ethical Approval
Institutional approval was not required to publish the case details.
Patient Informed Consent
Written informed consent was obtained from the patient for the publication of her case details and images.
Disclosure
Xiaoyu Hong is the employee of Nanjing Geneseeq Technology Inc. The other authors have no conflicts of interest that are directly relevant to the content of this article. | Recovering | ReactionOutcome | CC BY-NC | 33688205 | 19,110,981 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Palmar-plantar erythrodysaesthesia syndrome'. | Encouraging Pathological Complete Response Rate from Neoadjuvant Chemotherapy with Albumin-Bound Paclitaxel Plus Cisplatin and Capecitabine for Locally Advanced Esophageal Squamous Carcinoma: Preliminary Outcome of a Retrospective Study.
To evaluate the efficacy and safety of neoadjuvant chemotherapy with albumin-bound paclitaxel plus cisplatin and capecitabine for locally advanced esophageal squamous cell carcinoma (ESCC).
The data of thirty-one patients with locally advanced ESCC (cT1-2N+M0, cT3-4aNanyM0) received preoperative chemotherapy with albumin-bound paclitaxel plus cisplatin and capecitabine (referred as APCC regimen) were retrospectively analysed. The primary endpoint was pathological complete response (pCR) rate.
The median number of chemotherapy cycles with APCC regimen every 3 weeks were 4 (range: 1-6), which was completed by 23 patients. The clinical efficacy of 30 patients was evaluated and all showed reduction of tumours in varying degrees. Five patients received radiotherapy following chemotherapy. Four patients could not receive surgery due to COVID-19 pandemic. Of the 24 patients who underwent surgery, 3 received radiotherapy following chemotherapy, the resection rate of R0 was 95.8%, 9 cases (37.5%) showed pCR and 16 cases (66.7%) showed major pathological response (MPR). Postoperative pathology of 15 cases (62.5%) were stage I (ypT0-2N0M0). Of the 21 patients who underwent surgery after neoadjuvant chemotherapy alone, 8 (38.1%) had pCR and 15 (71.4%) had MPR. The most common grade 3/4 adverse events of chemotherapy included neutropenia (35.5%) and leukopenia (9.7%). Grade 2 postoperative complications occurred in 3 (12.5%) patients.
The preliminary results of this study suggest that preoperative chemotherapy with the triplet regimen of albumin-bound paclitaxel, cisplatin and capecitabine for patients with locally advanced ESCC revealed significant tumour downstage and encouraging pCR rate, with well-tolerable toxicities. The role of this regimen warrants further investigation.
Introduction
Esophageal cancer (EC) ranks seventh (572,000 new cases) in incidence and sixth (509,000 deaths) in mortality among all the malignant tumour globally in 2018.1 Adenocarcinoma is the most common subtype of EC in Western population,2 however, squamous cell carcinoma accounts for over 90% of the Chinese population.3 Esophageal squamous cell carcinoma (ESCC) remains a major concern in China, where the number of new and death cases reached 307,000 and 283,000 respectively, accounting for 53.7% and 55.7% of the total global new and death cases respectively in 2018.1 After surgery alone, the prognosis for patients with locally advanced EC remains poor, with a 5-year survival rate of only 25%.4 Combined modality therapy has been shown to significantly increase survival in esophageal cancer patients with locally advanced disease compared to resection alone.5
Neoadjuvant chemoradiotherapy (nCRT) has been considered as the standard care for locally advanced EC. Various studies have reported that nCRT along with surgery can significantly reduce tumour size and the recurrence rate while improving the R0 resection rate and overall survival.5–8 The pathological complete response (pCR) rate of nCRT was 13% to 22% for esophageal adenocarcinoma, and reached approximately 40% for squamous cell carcinoma.9–12 However, in some studies, concurrent chemoradiotherapy not only achieved good results, but also increased adverse reactions. As reported by Yang et al, the incidences of postoperative complications such as arrhythmia (13% vs 4.0%; P =0.001) as well as pretreatment mortality (2.2% vs 0.4%; P =0.212) were higher in the nCRT group over surgery alone.12 Similar findings were observed in the FFCD9901 study, where nCRT did not improve R0 resection rate or 3-year survival, but enhanced the postoperative mortality (11.1% vs 3.4%, P = 0.049) in patients with stage I or II EC compared with surgery alone.13
Recently, neoadjuvant chemotherapy (nCT) alone has also been shown to be effective in terms of improving resection rate of R0 and overall survival for locally advanced EC. For example, administration of 2 cycles of cisplatin with 5-FU, a previously most commonly used regimen, prior to surgery improved resection rate of R0 (60% vs 54%, P<0.0001) and 5-year survival rate (23% vs 17%, P = 0.03) compared with surgery alone in OEO2 study.14 However, in most studies, nCT with cisplatin and 5-FU, revealed an unsatisfactory pCR rate of only 1.7% to 9% in both esophageal adenocarcinoma and ESCC, which limits the application of nCT alone.11,14,15 So far, the best nCT regimen has not been well established. Thus, investigation of potent nCT regimen is of major clinical concern for locally advanced EC. In advanced ESCC, cisplatin plus paclitaxel seemed to increase objective response rate (42.5% vs 38.4%, P =0. 948) and improve progression-free survival (PFS) (7.85 months vs 6.53 months, P=0.02).16 Furthermore, a recent study demonstrated that preoperative regimen of cisplatin, 5-FU and paclitaxel improved the pCR rate by 24.1%, R0 resection rate was 82.5%, and the perioperative mortality rate was only 1.9%.17 As a solvent-free form of paclitaxel, albumin-bound paclitaxel is widely used in the treatment of advanced gastric cancer and pancreatic cancer due to advantages such as enhanced solubility, high affinity of binding to tumour tissue and low incidence of allergic reaction. Since 2018, we adopted a triplet regimen with albumin-bound paclitaxel, cisplatin and capecitabine (referred as APCC regimen) as neoadjuvant chemotherapy for locally advanced ESCC. Here, we reported the preliminary results.
Patients and Methods
Study Design
This was a retrospective study, in which the data of all eligible patients with locally advanced ESCC from April 2018 to October 2020 were collected retrospectively. The patients were included based on the following criteria: (1) histologically confirmed locally advanced ESCC; (2) clinical TNM staging of cT1-2N+M0, cT3-4aNanyM0 according to American Joint Committee on Cancer (AJCC 8th Edition); (3) an Eastern Cooperative Oncology Group (ECOG) score of 0–1; (4) those who received at least 1 cycle of neoadjuvant chemotherapy. The patients were excluded if they showed the presence of any one of the following: (1) non-squamous cell carcinoma on pathological examination; (2) cervical esophageal cancer; (3) previous chemotherapy or radiotherapy for esophageal lesions; (4) distant metastatic (M1) diseases; (5) other malignant tumours in the past 5 years, except for cervical carcinoma in situ, cutaneous squamous or basal cell carcinoma treated for radical purposes.
The study protocol was reviewed and approved by the Ethics Committee of Cancer Hospital Chinese Academy of Medical Sciences (approval No: 20/381-2577). The study met the requirements of the Declaration of Helsinki formulated by the World Medical Association. Personal data during the study will be protected in accordance with the law.
Chemotherapeutic Regimen
All the patients were treated with APCC regimen as neoadjuvant chemotherapy. The choice of APCC regimen was determined by the clinical experience of physicians. APCC regimen consisted of albumin-bound paclitaxel administered at dose of 125 mg/m2, day 1 and day 8; cisplatin at 60 mg/m2 dose at day 1, or divided into 2 days; and capecitabine 1750 mg/m2, oral twice a day, from day 1 to day14; every 21 days. During the period of chemotherapy, the efficacy was evaluated by enhanced computed tomography (CT) of the neck, chest and abdomen every 2 cycles. A maximum of 4 cycles of chemotherapy was planned in patients with clinical tumor remission. Radical esophagectomy was performed within 4 to 6 weeks after cessation of last dose of chemotherapy.
Efficacy and Toxicity Evaluation
The primary endpoint of the study was pCR rate. The secondary endpoints were major pathological response (MPR) rate, radical resection rate (R0 resection rate) and safety. Here, pCR was defined as no residual tumour cells found in the surgical specimens of primary esophageal lesions and drainage lymph nodes. Cases with residual high-grade dysplasia/carcinoma in situ without invasive carcinoma is also included in pCR. MPR was defined as tumour regression induced by neoadjuvant chemotherapy, when ≤10% of residual tumour tissue in resected primary tissue. The clinical and pathologic stages are expressed according to the American Joint Committee on Cancer (AJCC 8th Edition) TNM staging.18 In addition, the toxicities were graded according to US Department of Health and Human Services Common Terminology Criteria for Adverse Events (CTCAE) version 5.0,19 while Clavien-Dindo classification system was used to assess postoperative complications.20
Results
Baseline Characteristics
A total of 31 patients with locally advanced ESCC were included in the study. The baseline characteristics of the patients are summarized in Table 1. The median age of patients was 57 years (range: 25–75 years) and included 25 males and 6 females. Twenty-nine patients (93.5%) belonged to T3 and T4a, and further 21 patients (67.7%) were lymph node positive.Table 1 Patient Baseline Demographics and Clinic Pathological Characteristics (N = 31)
Baseline Characteristics N (%)
Age, years
Median (range) 57 (25–75)
Gender
Male 25 (80.6)
Female 6 (19.4)
ECOG PS
0 15 (48.4)
1 16 (51.6)
Clinical T stage
T2 2 (6.5)
T3 17 (54.8)
T4a 12 (38.7)
Clinical N stage
N0 10 (32.3)
N1 12 (38.7)
N2 8 (25.8)
N3 1 (3.2)
cTNM staging
II 8 (25.8)
III 11 (35.5)
IVa 12 (38.7)
Position
Upper 3 (9.7)
Middle 12 (38.7)
Lower 16 (51.6)
Abbreviations: cTNM, tumor, nodes, metastasis classification of staging; ECOG PS, Eastern Cooperative Oncology Group Performance Status.
Treatment Compliance
Among the 31 patients, 29 patients (93.5%) were treated with APCC regimen every 3 weeks, while the other 2 patients (aged over 70 years, determined by the physician) were adjusted to bi-weekly APCC regimen (albumin-bound paclitaxel 125 mg/m2, d1; cisplatin 40 mg/m2, d1 and capecitabine 1750 mg/m2, d1-10; 14 days as a cycle) (Figure 1). Most patients completed four cycles of neoadjuvant chemotherapy as planned, but some patients did not receive four cycles of chemotherapy as planned due to personal or epidemic reasons. The median number of preoperative treatment cycles was 4 (ranging from 1 to 6 cycles) in patients who received APCC regimen, every 3 weeks. Twenty-three (79.3%) of the 29 patients with APCC regimen, every 3 weeks, completed 4 cycles of chemotherapy, whereas 3 patients (10.3%) completed 2 cycles of chemotherapy, 2 patients (6.8%) completed 6 cycles of chemotherapy, and 1 patient (3.6%) completed one cycle of chemotherapy (discontinued treatment due to personal reasons) who was considered unevaluable for efficacy. Two patients with bi-weekly APCC regimen completed 3 and 6 cycles of chemotherapy, respectively. Five patients received local radiotherapy post completion of neoadjuvant chemotherapy, 3 of whom underwent surgical resection after radiotherapy. The causes of combined radiotherapy were as follows: in order to preserve the larynx in 1 case with upper thoracic esophageal carcinoma near neck, surgical intolerance in 1 case (73 years old), advanced baseline tumour staging in 1 case (cT4aN2), and close relationship between tumour and large vessels in 2 cases. Four patients failed to receive the expected surgery after 4 cycles of chemotherapy due to the COVID-19 outbreak. Ultimately, 24 patients underwent surgical resection. Of the 24 patients, 3 patients received additional preoperative radiotherapy, while 21 patients received preoperative chemotherapy alone.Figure 1 Patient flow diagram of this study.
Efficacy Outcomes
The clinical efficacy outcomes were evaluated among 30 patients. The size of the tumour was reduced to varying degrees in all the patients post-treatment with APCC regimen. The R0 resection rate among 24 patients was 95.8% (23/24). One patient was detected with primary esophageal lesion invading the descending aorta during the surgery; hence, the tumour was not resected and the patient refused to receive radiation and continued chemotherapy post-surgery. Of the 24 patients who underwent surgery, 9 (37.5%) achieved pCR and 16 (66.7%) achieved MPR. Further, 15 (62.5%) patients were reduced to stage I (ypT0-2N0M0), 18 (75%) were N0, and 5 patients had positive lymph nodes, 4 were N1 stage and only 1 was N2 stage after surgery. Of the 21 patients who underwent surgery with neoadjuvant chemotherapy alone, 8 (38.1%) had pCR and 15 (71.4%) had achieved MPR (Table 2).Table 2 Efficacy Outcomes Post-Surgery with Neoadjuvant Chemotherapy Regimen
Variables N (%)
Patients who received surgery after neoadjuvant chemotherapy alone (n = 21)
pCR 8/21 (38.1)
MPR 15/21 (71.4)
Patients who received surgery (n = 24)
pCR 9/24 (37.5)
MPR 16/24 (66.7)
R0 resection 23/24 (95.8)
Stage I (ypT1-2N0) 15 (62.5)
Stage II (ypT3N0) 3 (12.5)
Stage IIIA (ypT0-2N1) 4 (16.7)
Stage IIIB (ypT3N1/T0-3N2/T4a N0) 1 (8.3)
ypN0 18 (75)
ypN1 4 (16.7)
ypN2 1 (8.3)
Post-surgical morbidities 3 (12.5)
Pleural cavity infection 1 (4.2)
Pneumonia 1 (4.2)
Mediastinitis 1 (4.2)
Abbreviations: MPR, major pathological response; pCR, partial complete response.
Safety Outcomes
The commonly observed adverse events related to chemotherapy were leukopenia and neutropenia, as well as gastrointestinal adverse reactions, mostly of grade 1 and 2. The most common grade 3 or more adverse events were neutropenia (35.5%) and leukopenia (9.7%). A total of 3 patients (9.7%) were adjusted for drug dose due to adverse reactions, including 2 patients with grade 4 neutropenia and 1 patient with grade 2 hand foot syndrome. Significant complications occurred in 3 patients within 1 month after surgery, including thoracic infection (pleural effusion), pneumonia and mediastinal infection after drainage tube removal in each one patient, all of which were grade 2. The above postoperative complications were improved after symptomatic treatment, and the postoperative hospital stay was 15, 17, and 24 days, respectively. No treatment-related deaths occurred during neoadjuvant chemotherapy and within 30 days after surgery (Table 3). Of the 23 patients who underwent radical surgical resection, 4 patients continued the original regimen of chemotherapy until a total of 6 cycles after surgery and 1 patient was given postoperative radiotherapy considering the postoperative stage as ypT3N2.Table 3 Adverse Events Due to Neoadjuvant Chemotherapy (N = 31)
Events Any Grade N (%) Grade 3 N (%) Grade 4 N (%)
Neutropenia 23 (74.2%) 9 (29%) 2 (6.5%)
Leukopenia 21 (67.7%) 3 (9.7%) 0
Anaemia 17 (54.8%) 0 0
Thrombocytopenia 9 (29%) 0 1 (3.2%)
Elevated ALT 3 (9.7%) 1 (3.2%) 0
Nausea 22 (70.9%) 0 0
Vomiting 11 (35.5%) 0 0
Loss of appetite 12 (38.7%) 0 0
Fatigue 7 (22.6%) 0 0
Peripheral neurotoxicity 12 (38.7%) 0 0
Alopecia 15 (48.3%) 0 0
Foot-hand syndrome 6 (19.4%) 0 0
Abbreviation: ALT, alanine transaminase.
As of November 15, 2020, with a median follow-up time of 12.4 months (range: 10.1–31.2), 3 patients died (2 patients did not receive surgery, 1 patient received surgery). Among the 23 patients who underwent R0 resection, the median follow-up time after surgery was 8.3 months (range: 1.1–26.1). One patient developed lung metastasis 7.9 months after surgery, and his overall survival time was 24 months. Due to the breakdown of COVID 19, one patient received surgery 6 months after the end of 4 cycles of preoperative chemotherapy. The postoperative pathological stage of this patient was ypTisN1. However here, the follow-up time was only 1.1 months.
Discussion
In this study, neoadjuvant chemotherapy with the triplet regimen of albumin-bound paclitaxel with cisplatin and capecitabine (APCC regimen) for locally advanced resectable ESCC showed high anti-tumor activities and significant effect on tumour downstaging. None of the evaluable patients (n=30) had disease progression after chemotherapy. Though six patients did not receive surgery after chemotherapy for various reasons and this might have confounded our findings of the actual results, a pCR rate of 38.1% and a MPR rate of 71.4% in the 21 patients who received neoadjuvant chemotherapy alone were quite encouraging. This pCR rate seemed to be higher than that of previous neoadjuvant chemotherapy with cisplatin and fluorouracil.11,14,15 Further, in all 24 patients received surgery, the R0 resection rate was 95.8%, the pCR rate was 37.5%, the MPR rate was 66.7%, and 62.5% of the patients’ postoperative pathological stage was stage I (ypT0-2N0). As with the pCR rate in the previously reported studies nCRT were believed to often has a significant advantage over nCT alone, especially for squamous cell carcinoma. The randomized-controlled CROSS study reported a pCR rate of 49% in the squamous cell carcinoma subgroup.9 NEOCRTEC5010 study use of vinorelbine and cisplatin with concurrent radiotherapy (DT 40Gy) resulted in a pCR rate of 43.2% in patients with locally advanced ESCC.12 However, whether the higher pCR rate of nCRT over nCT could transfer to the survival benefit need further investigation. In the Phase 2 randomized trial NeoRes I, a higher pCR rate of 28% from cisplatin and fluorouracil based nCRT did not produce significant OS improvement over cisplatin and fluorouracil neoadjuvant chemotherapy alone.21 There are two ongoing randomized Phase III trials to compare the efficacy of platinum and paclitaxel concurrent radiotherapy and neochemotherapy alone for locally advanced ESCC.22,23 Our study findings suggest that APCC regimen seems to be able to further narrow the gap in pCR rate between nCT and nCRT. Recently, immune checkpoint combined with chemotherapy has been tried for neoadjuvant treatment of locally advanced esophageal cancer, but the results are still preliminary. Two prospective small sample studies showed that 2 cycles of anti-PD-1 monoclonal antibody combined with nab-paclitaxel plus S-1 or paclitaxel plus carboplatin regimen as nCT achieved pathological complete response rates of 16.67% and 45.4%, respectively.24,25
79.3% of patients in this study completed 4 cycles of preoperative chemotherapy with APCC regimen, which was longer than the duration of chemotherapy reported in other relevant studies with EC.14,15 At present, there is no clear information with regards to the optimal number of cycles of perioperative chemotherapy for locally advanced EC. In the previous studies of nCRT and nCT, usually 2 to 3 cycles of chemotherapy were used. Findings by Zhao et al17 suggested that prolonging the number of chemotherapy cycles during perioperative period could further reduce the recurrence rate and improve the overall survival. The study compared the efficacy of 4 and 2 cycles of paclitaxel, cisplatin and 5-FU during the perioperative period. It was observed that treatment with 4 cycles of chemotherapy resulted in better 5-year disease-free survival (DFS) (31% vs. 17%, HR 0.62; 95% CI, 0.49–0.73; P<0.001) and OS (38% vs 22%, HR 0.79; 95% CI 0.59–0.95; P<0.001).
In this study, 2 to 4 cycles of preoperative neoadjuvant triplet chemotherapy with APCC regimen were well tolerated. Most of the common adverse reactions were grade 1 or 2 neutropenia and gastrointestinal adverse events with the most common grade 3 or 4 adverse reactions being neutropenia (35.5%). However, 3 (12.5%) patients had chest, lung or mediastinal infection after surgery, which need more attention to in future research.
There are some limitations on this study that warrant mention. Since this was a retrospective study with a limited sample size and short follow-up time, the tumour recurrence rate and overall survival was not reached yet. In addition, as mentioned earlier, the inability of 6 (20%) patients to undergo surgery due to the age, personal will and COVID-19 epidemic might affect the accurate interpretation of pCR rate resulted from this regimen.
Conclusion
The preliminary results of this study suggest that the triplet regimen of albumin-bound paclitaxel, cisplatin and capecitabine as preoperative neoadjuvant chemotherapy for patients with locally advanced ESCC revealed significant tumour downstaging and encouraging pCR rate, with favourable safety profile. The role of this triplet regimen warrants further investigation in the neoadjuvant treatment for ESCC and a prospective Phase II study (NCT04390958) has already been in progress.
Ethics Approval
The study protocol was reviewed and approved by the Ethics Committee of Cancer Hospital Chinese Academy of Medical Sciences (approval No: 20/381-2577). This study is a retrospective non-intervention study, which does not interfere with the routine diagnosis and treatment, does not affect any medical rights and interests of patients, and does not increase the risk of patients. The results of the study will be published in the form of statistical analysis without any identifiable patient information. Most of the patients in this study have completed the treatment and cannot obtain their informed consent objectively. Based on the above reasons. We have applied to the Ethics Committee for exemption from the informed consent of all patients in this study and have been approved.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors declare no conflict of interest. | CAPECITABINE, CISPLATIN, PACLITAXEL | DrugsGivenReaction | CC BY-NC | 33688259 | 19,063,857 | 2021 |
What was the administration route of drug 'PACLITAXEL'? | Encouraging Pathological Complete Response Rate from Neoadjuvant Chemotherapy with Albumin-Bound Paclitaxel Plus Cisplatin and Capecitabine for Locally Advanced Esophageal Squamous Carcinoma: Preliminary Outcome of a Retrospective Study.
To evaluate the efficacy and safety of neoadjuvant chemotherapy with albumin-bound paclitaxel plus cisplatin and capecitabine for locally advanced esophageal squamous cell carcinoma (ESCC).
The data of thirty-one patients with locally advanced ESCC (cT1-2N+M0, cT3-4aNanyM0) received preoperative chemotherapy with albumin-bound paclitaxel plus cisplatin and capecitabine (referred as APCC regimen) were retrospectively analysed. The primary endpoint was pathological complete response (pCR) rate.
The median number of chemotherapy cycles with APCC regimen every 3 weeks were 4 (range: 1-6), which was completed by 23 patients. The clinical efficacy of 30 patients was evaluated and all showed reduction of tumours in varying degrees. Five patients received radiotherapy following chemotherapy. Four patients could not receive surgery due to COVID-19 pandemic. Of the 24 patients who underwent surgery, 3 received radiotherapy following chemotherapy, the resection rate of R0 was 95.8%, 9 cases (37.5%) showed pCR and 16 cases (66.7%) showed major pathological response (MPR). Postoperative pathology of 15 cases (62.5%) were stage I (ypT0-2N0M0). Of the 21 patients who underwent surgery after neoadjuvant chemotherapy alone, 8 (38.1%) had pCR and 15 (71.4%) had MPR. The most common grade 3/4 adverse events of chemotherapy included neutropenia (35.5%) and leukopenia (9.7%). Grade 2 postoperative complications occurred in 3 (12.5%) patients.
The preliminary results of this study suggest that preoperative chemotherapy with the triplet regimen of albumin-bound paclitaxel, cisplatin and capecitabine for patients with locally advanced ESCC revealed significant tumour downstage and encouraging pCR rate, with well-tolerable toxicities. The role of this regimen warrants further investigation.
Introduction
Esophageal cancer (EC) ranks seventh (572,000 new cases) in incidence and sixth (509,000 deaths) in mortality among all the malignant tumour globally in 2018.1 Adenocarcinoma is the most common subtype of EC in Western population,2 however, squamous cell carcinoma accounts for over 90% of the Chinese population.3 Esophageal squamous cell carcinoma (ESCC) remains a major concern in China, where the number of new and death cases reached 307,000 and 283,000 respectively, accounting for 53.7% and 55.7% of the total global new and death cases respectively in 2018.1 After surgery alone, the prognosis for patients with locally advanced EC remains poor, with a 5-year survival rate of only 25%.4 Combined modality therapy has been shown to significantly increase survival in esophageal cancer patients with locally advanced disease compared to resection alone.5
Neoadjuvant chemoradiotherapy (nCRT) has been considered as the standard care for locally advanced EC. Various studies have reported that nCRT along with surgery can significantly reduce tumour size and the recurrence rate while improving the R0 resection rate and overall survival.5–8 The pathological complete response (pCR) rate of nCRT was 13% to 22% for esophageal adenocarcinoma, and reached approximately 40% for squamous cell carcinoma.9–12 However, in some studies, concurrent chemoradiotherapy not only achieved good results, but also increased adverse reactions. As reported by Yang et al, the incidences of postoperative complications such as arrhythmia (13% vs 4.0%; P =0.001) as well as pretreatment mortality (2.2% vs 0.4%; P =0.212) were higher in the nCRT group over surgery alone.12 Similar findings were observed in the FFCD9901 study, where nCRT did not improve R0 resection rate or 3-year survival, but enhanced the postoperative mortality (11.1% vs 3.4%, P = 0.049) in patients with stage I or II EC compared with surgery alone.13
Recently, neoadjuvant chemotherapy (nCT) alone has also been shown to be effective in terms of improving resection rate of R0 and overall survival for locally advanced EC. For example, administration of 2 cycles of cisplatin with 5-FU, a previously most commonly used regimen, prior to surgery improved resection rate of R0 (60% vs 54%, P<0.0001) and 5-year survival rate (23% vs 17%, P = 0.03) compared with surgery alone in OEO2 study.14 However, in most studies, nCT with cisplatin and 5-FU, revealed an unsatisfactory pCR rate of only 1.7% to 9% in both esophageal adenocarcinoma and ESCC, which limits the application of nCT alone.11,14,15 So far, the best nCT regimen has not been well established. Thus, investigation of potent nCT regimen is of major clinical concern for locally advanced EC. In advanced ESCC, cisplatin plus paclitaxel seemed to increase objective response rate (42.5% vs 38.4%, P =0. 948) and improve progression-free survival (PFS) (7.85 months vs 6.53 months, P=0.02).16 Furthermore, a recent study demonstrated that preoperative regimen of cisplatin, 5-FU and paclitaxel improved the pCR rate by 24.1%, R0 resection rate was 82.5%, and the perioperative mortality rate was only 1.9%.17 As a solvent-free form of paclitaxel, albumin-bound paclitaxel is widely used in the treatment of advanced gastric cancer and pancreatic cancer due to advantages such as enhanced solubility, high affinity of binding to tumour tissue and low incidence of allergic reaction. Since 2018, we adopted a triplet regimen with albumin-bound paclitaxel, cisplatin and capecitabine (referred as APCC regimen) as neoadjuvant chemotherapy for locally advanced ESCC. Here, we reported the preliminary results.
Patients and Methods
Study Design
This was a retrospective study, in which the data of all eligible patients with locally advanced ESCC from April 2018 to October 2020 were collected retrospectively. The patients were included based on the following criteria: (1) histologically confirmed locally advanced ESCC; (2) clinical TNM staging of cT1-2N+M0, cT3-4aNanyM0 according to American Joint Committee on Cancer (AJCC 8th Edition); (3) an Eastern Cooperative Oncology Group (ECOG) score of 0–1; (4) those who received at least 1 cycle of neoadjuvant chemotherapy. The patients were excluded if they showed the presence of any one of the following: (1) non-squamous cell carcinoma on pathological examination; (2) cervical esophageal cancer; (3) previous chemotherapy or radiotherapy for esophageal lesions; (4) distant metastatic (M1) diseases; (5) other malignant tumours in the past 5 years, except for cervical carcinoma in situ, cutaneous squamous or basal cell carcinoma treated for radical purposes.
The study protocol was reviewed and approved by the Ethics Committee of Cancer Hospital Chinese Academy of Medical Sciences (approval No: 20/381-2577). The study met the requirements of the Declaration of Helsinki formulated by the World Medical Association. Personal data during the study will be protected in accordance with the law.
Chemotherapeutic Regimen
All the patients were treated with APCC regimen as neoadjuvant chemotherapy. The choice of APCC regimen was determined by the clinical experience of physicians. APCC regimen consisted of albumin-bound paclitaxel administered at dose of 125 mg/m2, day 1 and day 8; cisplatin at 60 mg/m2 dose at day 1, or divided into 2 days; and capecitabine 1750 mg/m2, oral twice a day, from day 1 to day14; every 21 days. During the period of chemotherapy, the efficacy was evaluated by enhanced computed tomography (CT) of the neck, chest and abdomen every 2 cycles. A maximum of 4 cycles of chemotherapy was planned in patients with clinical tumor remission. Radical esophagectomy was performed within 4 to 6 weeks after cessation of last dose of chemotherapy.
Efficacy and Toxicity Evaluation
The primary endpoint of the study was pCR rate. The secondary endpoints were major pathological response (MPR) rate, radical resection rate (R0 resection rate) and safety. Here, pCR was defined as no residual tumour cells found in the surgical specimens of primary esophageal lesions and drainage lymph nodes. Cases with residual high-grade dysplasia/carcinoma in situ without invasive carcinoma is also included in pCR. MPR was defined as tumour regression induced by neoadjuvant chemotherapy, when ≤10% of residual tumour tissue in resected primary tissue. The clinical and pathologic stages are expressed according to the American Joint Committee on Cancer (AJCC 8th Edition) TNM staging.18 In addition, the toxicities were graded according to US Department of Health and Human Services Common Terminology Criteria for Adverse Events (CTCAE) version 5.0,19 while Clavien-Dindo classification system was used to assess postoperative complications.20
Results
Baseline Characteristics
A total of 31 patients with locally advanced ESCC were included in the study. The baseline characteristics of the patients are summarized in Table 1. The median age of patients was 57 years (range: 25–75 years) and included 25 males and 6 females. Twenty-nine patients (93.5%) belonged to T3 and T4a, and further 21 patients (67.7%) were lymph node positive.Table 1 Patient Baseline Demographics and Clinic Pathological Characteristics (N = 31)
Baseline Characteristics N (%)
Age, years
Median (range) 57 (25–75)
Gender
Male 25 (80.6)
Female 6 (19.4)
ECOG PS
0 15 (48.4)
1 16 (51.6)
Clinical T stage
T2 2 (6.5)
T3 17 (54.8)
T4a 12 (38.7)
Clinical N stage
N0 10 (32.3)
N1 12 (38.7)
N2 8 (25.8)
N3 1 (3.2)
cTNM staging
II 8 (25.8)
III 11 (35.5)
IVa 12 (38.7)
Position
Upper 3 (9.7)
Middle 12 (38.7)
Lower 16 (51.6)
Abbreviations: cTNM, tumor, nodes, metastasis classification of staging; ECOG PS, Eastern Cooperative Oncology Group Performance Status.
Treatment Compliance
Among the 31 patients, 29 patients (93.5%) were treated with APCC regimen every 3 weeks, while the other 2 patients (aged over 70 years, determined by the physician) were adjusted to bi-weekly APCC regimen (albumin-bound paclitaxel 125 mg/m2, d1; cisplatin 40 mg/m2, d1 and capecitabine 1750 mg/m2, d1-10; 14 days as a cycle) (Figure 1). Most patients completed four cycles of neoadjuvant chemotherapy as planned, but some patients did not receive four cycles of chemotherapy as planned due to personal or epidemic reasons. The median number of preoperative treatment cycles was 4 (ranging from 1 to 6 cycles) in patients who received APCC regimen, every 3 weeks. Twenty-three (79.3%) of the 29 patients with APCC regimen, every 3 weeks, completed 4 cycles of chemotherapy, whereas 3 patients (10.3%) completed 2 cycles of chemotherapy, 2 patients (6.8%) completed 6 cycles of chemotherapy, and 1 patient (3.6%) completed one cycle of chemotherapy (discontinued treatment due to personal reasons) who was considered unevaluable for efficacy. Two patients with bi-weekly APCC regimen completed 3 and 6 cycles of chemotherapy, respectively. Five patients received local radiotherapy post completion of neoadjuvant chemotherapy, 3 of whom underwent surgical resection after radiotherapy. The causes of combined radiotherapy were as follows: in order to preserve the larynx in 1 case with upper thoracic esophageal carcinoma near neck, surgical intolerance in 1 case (73 years old), advanced baseline tumour staging in 1 case (cT4aN2), and close relationship between tumour and large vessels in 2 cases. Four patients failed to receive the expected surgery after 4 cycles of chemotherapy due to the COVID-19 outbreak. Ultimately, 24 patients underwent surgical resection. Of the 24 patients, 3 patients received additional preoperative radiotherapy, while 21 patients received preoperative chemotherapy alone.Figure 1 Patient flow diagram of this study.
Efficacy Outcomes
The clinical efficacy outcomes were evaluated among 30 patients. The size of the tumour was reduced to varying degrees in all the patients post-treatment with APCC regimen. The R0 resection rate among 24 patients was 95.8% (23/24). One patient was detected with primary esophageal lesion invading the descending aorta during the surgery; hence, the tumour was not resected and the patient refused to receive radiation and continued chemotherapy post-surgery. Of the 24 patients who underwent surgery, 9 (37.5%) achieved pCR and 16 (66.7%) achieved MPR. Further, 15 (62.5%) patients were reduced to stage I (ypT0-2N0M0), 18 (75%) were N0, and 5 patients had positive lymph nodes, 4 were N1 stage and only 1 was N2 stage after surgery. Of the 21 patients who underwent surgery with neoadjuvant chemotherapy alone, 8 (38.1%) had pCR and 15 (71.4%) had achieved MPR (Table 2).Table 2 Efficacy Outcomes Post-Surgery with Neoadjuvant Chemotherapy Regimen
Variables N (%)
Patients who received surgery after neoadjuvant chemotherapy alone (n = 21)
pCR 8/21 (38.1)
MPR 15/21 (71.4)
Patients who received surgery (n = 24)
pCR 9/24 (37.5)
MPR 16/24 (66.7)
R0 resection 23/24 (95.8)
Stage I (ypT1-2N0) 15 (62.5)
Stage II (ypT3N0) 3 (12.5)
Stage IIIA (ypT0-2N1) 4 (16.7)
Stage IIIB (ypT3N1/T0-3N2/T4a N0) 1 (8.3)
ypN0 18 (75)
ypN1 4 (16.7)
ypN2 1 (8.3)
Post-surgical morbidities 3 (12.5)
Pleural cavity infection 1 (4.2)
Pneumonia 1 (4.2)
Mediastinitis 1 (4.2)
Abbreviations: MPR, major pathological response; pCR, partial complete response.
Safety Outcomes
The commonly observed adverse events related to chemotherapy were leukopenia and neutropenia, as well as gastrointestinal adverse reactions, mostly of grade 1 and 2. The most common grade 3 or more adverse events were neutropenia (35.5%) and leukopenia (9.7%). A total of 3 patients (9.7%) were adjusted for drug dose due to adverse reactions, including 2 patients with grade 4 neutropenia and 1 patient with grade 2 hand foot syndrome. Significant complications occurred in 3 patients within 1 month after surgery, including thoracic infection (pleural effusion), pneumonia and mediastinal infection after drainage tube removal in each one patient, all of which were grade 2. The above postoperative complications were improved after symptomatic treatment, and the postoperative hospital stay was 15, 17, and 24 days, respectively. No treatment-related deaths occurred during neoadjuvant chemotherapy and within 30 days after surgery (Table 3). Of the 23 patients who underwent radical surgical resection, 4 patients continued the original regimen of chemotherapy until a total of 6 cycles after surgery and 1 patient was given postoperative radiotherapy considering the postoperative stage as ypT3N2.Table 3 Adverse Events Due to Neoadjuvant Chemotherapy (N = 31)
Events Any Grade N (%) Grade 3 N (%) Grade 4 N (%)
Neutropenia 23 (74.2%) 9 (29%) 2 (6.5%)
Leukopenia 21 (67.7%) 3 (9.7%) 0
Anaemia 17 (54.8%) 0 0
Thrombocytopenia 9 (29%) 0 1 (3.2%)
Elevated ALT 3 (9.7%) 1 (3.2%) 0
Nausea 22 (70.9%) 0 0
Vomiting 11 (35.5%) 0 0
Loss of appetite 12 (38.7%) 0 0
Fatigue 7 (22.6%) 0 0
Peripheral neurotoxicity 12 (38.7%) 0 0
Alopecia 15 (48.3%) 0 0
Foot-hand syndrome 6 (19.4%) 0 0
Abbreviation: ALT, alanine transaminase.
As of November 15, 2020, with a median follow-up time of 12.4 months (range: 10.1–31.2), 3 patients died (2 patients did not receive surgery, 1 patient received surgery). Among the 23 patients who underwent R0 resection, the median follow-up time after surgery was 8.3 months (range: 1.1–26.1). One patient developed lung metastasis 7.9 months after surgery, and his overall survival time was 24 months. Due to the breakdown of COVID 19, one patient received surgery 6 months after the end of 4 cycles of preoperative chemotherapy. The postoperative pathological stage of this patient was ypTisN1. However here, the follow-up time was only 1.1 months.
Discussion
In this study, neoadjuvant chemotherapy with the triplet regimen of albumin-bound paclitaxel with cisplatin and capecitabine (APCC regimen) for locally advanced resectable ESCC showed high anti-tumor activities and significant effect on tumour downstaging. None of the evaluable patients (n=30) had disease progression after chemotherapy. Though six patients did not receive surgery after chemotherapy for various reasons and this might have confounded our findings of the actual results, a pCR rate of 38.1% and a MPR rate of 71.4% in the 21 patients who received neoadjuvant chemotherapy alone were quite encouraging. This pCR rate seemed to be higher than that of previous neoadjuvant chemotherapy with cisplatin and fluorouracil.11,14,15 Further, in all 24 patients received surgery, the R0 resection rate was 95.8%, the pCR rate was 37.5%, the MPR rate was 66.7%, and 62.5% of the patients’ postoperative pathological stage was stage I (ypT0-2N0). As with the pCR rate in the previously reported studies nCRT were believed to often has a significant advantage over nCT alone, especially for squamous cell carcinoma. The randomized-controlled CROSS study reported a pCR rate of 49% in the squamous cell carcinoma subgroup.9 NEOCRTEC5010 study use of vinorelbine and cisplatin with concurrent radiotherapy (DT 40Gy) resulted in a pCR rate of 43.2% in patients with locally advanced ESCC.12 However, whether the higher pCR rate of nCRT over nCT could transfer to the survival benefit need further investigation. In the Phase 2 randomized trial NeoRes I, a higher pCR rate of 28% from cisplatin and fluorouracil based nCRT did not produce significant OS improvement over cisplatin and fluorouracil neoadjuvant chemotherapy alone.21 There are two ongoing randomized Phase III trials to compare the efficacy of platinum and paclitaxel concurrent radiotherapy and neochemotherapy alone for locally advanced ESCC.22,23 Our study findings suggest that APCC regimen seems to be able to further narrow the gap in pCR rate between nCT and nCRT. Recently, immune checkpoint combined with chemotherapy has been tried for neoadjuvant treatment of locally advanced esophageal cancer, but the results are still preliminary. Two prospective small sample studies showed that 2 cycles of anti-PD-1 monoclonal antibody combined with nab-paclitaxel plus S-1 or paclitaxel plus carboplatin regimen as nCT achieved pathological complete response rates of 16.67% and 45.4%, respectively.24,25
79.3% of patients in this study completed 4 cycles of preoperative chemotherapy with APCC regimen, which was longer than the duration of chemotherapy reported in other relevant studies with EC.14,15 At present, there is no clear information with regards to the optimal number of cycles of perioperative chemotherapy for locally advanced EC. In the previous studies of nCRT and nCT, usually 2 to 3 cycles of chemotherapy were used. Findings by Zhao et al17 suggested that prolonging the number of chemotherapy cycles during perioperative period could further reduce the recurrence rate and improve the overall survival. The study compared the efficacy of 4 and 2 cycles of paclitaxel, cisplatin and 5-FU during the perioperative period. It was observed that treatment with 4 cycles of chemotherapy resulted in better 5-year disease-free survival (DFS) (31% vs. 17%, HR 0.62; 95% CI, 0.49–0.73; P<0.001) and OS (38% vs 22%, HR 0.79; 95% CI 0.59–0.95; P<0.001).
In this study, 2 to 4 cycles of preoperative neoadjuvant triplet chemotherapy with APCC regimen were well tolerated. Most of the common adverse reactions were grade 1 or 2 neutropenia and gastrointestinal adverse events with the most common grade 3 or 4 adverse reactions being neutropenia (35.5%). However, 3 (12.5%) patients had chest, lung or mediastinal infection after surgery, which need more attention to in future research.
There are some limitations on this study that warrant mention. Since this was a retrospective study with a limited sample size and short follow-up time, the tumour recurrence rate and overall survival was not reached yet. In addition, as mentioned earlier, the inability of 6 (20%) patients to undergo surgery due to the age, personal will and COVID-19 epidemic might affect the accurate interpretation of pCR rate resulted from this regimen.
Conclusion
The preliminary results of this study suggest that the triplet regimen of albumin-bound paclitaxel, cisplatin and capecitabine as preoperative neoadjuvant chemotherapy for patients with locally advanced ESCC revealed significant tumour downstaging and encouraging pCR rate, with favourable safety profile. The role of this triplet regimen warrants further investigation in the neoadjuvant treatment for ESCC and a prospective Phase II study (NCT04390958) has already been in progress.
Ethics Approval
The study protocol was reviewed and approved by the Ethics Committee of Cancer Hospital Chinese Academy of Medical Sciences (approval No: 20/381-2577). This study is a retrospective non-intervention study, which does not interfere with the routine diagnosis and treatment, does not affect any medical rights and interests of patients, and does not increase the risk of patients. The results of the study will be published in the form of statistical analysis without any identifiable patient information. Most of the patients in this study have completed the treatment and cannot obtain their informed consent objectively. Based on the above reasons. We have applied to the Ethics Committee for exemption from the informed consent of all patients in this study and have been approved.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors declare no conflict of interest. | Intravenous drip | DrugAdministrationRoute | CC BY-NC | 33688259 | 19,063,857 | 2021 |
What was the dosage of drug 'CAPECITABINE'? | Encouraging Pathological Complete Response Rate from Neoadjuvant Chemotherapy with Albumin-Bound Paclitaxel Plus Cisplatin and Capecitabine for Locally Advanced Esophageal Squamous Carcinoma: Preliminary Outcome of a Retrospective Study.
To evaluate the efficacy and safety of neoadjuvant chemotherapy with albumin-bound paclitaxel plus cisplatin and capecitabine for locally advanced esophageal squamous cell carcinoma (ESCC).
The data of thirty-one patients with locally advanced ESCC (cT1-2N+M0, cT3-4aNanyM0) received preoperative chemotherapy with albumin-bound paclitaxel plus cisplatin and capecitabine (referred as APCC regimen) were retrospectively analysed. The primary endpoint was pathological complete response (pCR) rate.
The median number of chemotherapy cycles with APCC regimen every 3 weeks were 4 (range: 1-6), which was completed by 23 patients. The clinical efficacy of 30 patients was evaluated and all showed reduction of tumours in varying degrees. Five patients received radiotherapy following chemotherapy. Four patients could not receive surgery due to COVID-19 pandemic. Of the 24 patients who underwent surgery, 3 received radiotherapy following chemotherapy, the resection rate of R0 was 95.8%, 9 cases (37.5%) showed pCR and 16 cases (66.7%) showed major pathological response (MPR). Postoperative pathology of 15 cases (62.5%) were stage I (ypT0-2N0M0). Of the 21 patients who underwent surgery after neoadjuvant chemotherapy alone, 8 (38.1%) had pCR and 15 (71.4%) had MPR. The most common grade 3/4 adverse events of chemotherapy included neutropenia (35.5%) and leukopenia (9.7%). Grade 2 postoperative complications occurred in 3 (12.5%) patients.
The preliminary results of this study suggest that preoperative chemotherapy with the triplet regimen of albumin-bound paclitaxel, cisplatin and capecitabine for patients with locally advanced ESCC revealed significant tumour downstage and encouraging pCR rate, with well-tolerable toxicities. The role of this regimen warrants further investigation.
Introduction
Esophageal cancer (EC) ranks seventh (572,000 new cases) in incidence and sixth (509,000 deaths) in mortality among all the malignant tumour globally in 2018.1 Adenocarcinoma is the most common subtype of EC in Western population,2 however, squamous cell carcinoma accounts for over 90% of the Chinese population.3 Esophageal squamous cell carcinoma (ESCC) remains a major concern in China, where the number of new and death cases reached 307,000 and 283,000 respectively, accounting for 53.7% and 55.7% of the total global new and death cases respectively in 2018.1 After surgery alone, the prognosis for patients with locally advanced EC remains poor, with a 5-year survival rate of only 25%.4 Combined modality therapy has been shown to significantly increase survival in esophageal cancer patients with locally advanced disease compared to resection alone.5
Neoadjuvant chemoradiotherapy (nCRT) has been considered as the standard care for locally advanced EC. Various studies have reported that nCRT along with surgery can significantly reduce tumour size and the recurrence rate while improving the R0 resection rate and overall survival.5–8 The pathological complete response (pCR) rate of nCRT was 13% to 22% for esophageal adenocarcinoma, and reached approximately 40% for squamous cell carcinoma.9–12 However, in some studies, concurrent chemoradiotherapy not only achieved good results, but also increased adverse reactions. As reported by Yang et al, the incidences of postoperative complications such as arrhythmia (13% vs 4.0%; P =0.001) as well as pretreatment mortality (2.2% vs 0.4%; P =0.212) were higher in the nCRT group over surgery alone.12 Similar findings were observed in the FFCD9901 study, where nCRT did not improve R0 resection rate or 3-year survival, but enhanced the postoperative mortality (11.1% vs 3.4%, P = 0.049) in patients with stage I or II EC compared with surgery alone.13
Recently, neoadjuvant chemotherapy (nCT) alone has also been shown to be effective in terms of improving resection rate of R0 and overall survival for locally advanced EC. For example, administration of 2 cycles of cisplatin with 5-FU, a previously most commonly used regimen, prior to surgery improved resection rate of R0 (60% vs 54%, P<0.0001) and 5-year survival rate (23% vs 17%, P = 0.03) compared with surgery alone in OEO2 study.14 However, in most studies, nCT with cisplatin and 5-FU, revealed an unsatisfactory pCR rate of only 1.7% to 9% in both esophageal adenocarcinoma and ESCC, which limits the application of nCT alone.11,14,15 So far, the best nCT regimen has not been well established. Thus, investigation of potent nCT regimen is of major clinical concern for locally advanced EC. In advanced ESCC, cisplatin plus paclitaxel seemed to increase objective response rate (42.5% vs 38.4%, P =0. 948) and improve progression-free survival (PFS) (7.85 months vs 6.53 months, P=0.02).16 Furthermore, a recent study demonstrated that preoperative regimen of cisplatin, 5-FU and paclitaxel improved the pCR rate by 24.1%, R0 resection rate was 82.5%, and the perioperative mortality rate was only 1.9%.17 As a solvent-free form of paclitaxel, albumin-bound paclitaxel is widely used in the treatment of advanced gastric cancer and pancreatic cancer due to advantages such as enhanced solubility, high affinity of binding to tumour tissue and low incidence of allergic reaction. Since 2018, we adopted a triplet regimen with albumin-bound paclitaxel, cisplatin and capecitabine (referred as APCC regimen) as neoadjuvant chemotherapy for locally advanced ESCC. Here, we reported the preliminary results.
Patients and Methods
Study Design
This was a retrospective study, in which the data of all eligible patients with locally advanced ESCC from April 2018 to October 2020 were collected retrospectively. The patients were included based on the following criteria: (1) histologically confirmed locally advanced ESCC; (2) clinical TNM staging of cT1-2N+M0, cT3-4aNanyM0 according to American Joint Committee on Cancer (AJCC 8th Edition); (3) an Eastern Cooperative Oncology Group (ECOG) score of 0–1; (4) those who received at least 1 cycle of neoadjuvant chemotherapy. The patients were excluded if they showed the presence of any one of the following: (1) non-squamous cell carcinoma on pathological examination; (2) cervical esophageal cancer; (3) previous chemotherapy or radiotherapy for esophageal lesions; (4) distant metastatic (M1) diseases; (5) other malignant tumours in the past 5 years, except for cervical carcinoma in situ, cutaneous squamous or basal cell carcinoma treated for radical purposes.
The study protocol was reviewed and approved by the Ethics Committee of Cancer Hospital Chinese Academy of Medical Sciences (approval No: 20/381-2577). The study met the requirements of the Declaration of Helsinki formulated by the World Medical Association. Personal data during the study will be protected in accordance with the law.
Chemotherapeutic Regimen
All the patients were treated with APCC regimen as neoadjuvant chemotherapy. The choice of APCC regimen was determined by the clinical experience of physicians. APCC regimen consisted of albumin-bound paclitaxel administered at dose of 125 mg/m2, day 1 and day 8; cisplatin at 60 mg/m2 dose at day 1, or divided into 2 days; and capecitabine 1750 mg/m2, oral twice a day, from day 1 to day14; every 21 days. During the period of chemotherapy, the efficacy was evaluated by enhanced computed tomography (CT) of the neck, chest and abdomen every 2 cycles. A maximum of 4 cycles of chemotherapy was planned in patients with clinical tumor remission. Radical esophagectomy was performed within 4 to 6 weeks after cessation of last dose of chemotherapy.
Efficacy and Toxicity Evaluation
The primary endpoint of the study was pCR rate. The secondary endpoints were major pathological response (MPR) rate, radical resection rate (R0 resection rate) and safety. Here, pCR was defined as no residual tumour cells found in the surgical specimens of primary esophageal lesions and drainage lymph nodes. Cases with residual high-grade dysplasia/carcinoma in situ without invasive carcinoma is also included in pCR. MPR was defined as tumour regression induced by neoadjuvant chemotherapy, when ≤10% of residual tumour tissue in resected primary tissue. The clinical and pathologic stages are expressed according to the American Joint Committee on Cancer (AJCC 8th Edition) TNM staging.18 In addition, the toxicities were graded according to US Department of Health and Human Services Common Terminology Criteria for Adverse Events (CTCAE) version 5.0,19 while Clavien-Dindo classification system was used to assess postoperative complications.20
Results
Baseline Characteristics
A total of 31 patients with locally advanced ESCC were included in the study. The baseline characteristics of the patients are summarized in Table 1. The median age of patients was 57 years (range: 25–75 years) and included 25 males and 6 females. Twenty-nine patients (93.5%) belonged to T3 and T4a, and further 21 patients (67.7%) were lymph node positive.Table 1 Patient Baseline Demographics and Clinic Pathological Characteristics (N = 31)
Baseline Characteristics N (%)
Age, years
Median (range) 57 (25–75)
Gender
Male 25 (80.6)
Female 6 (19.4)
ECOG PS
0 15 (48.4)
1 16 (51.6)
Clinical T stage
T2 2 (6.5)
T3 17 (54.8)
T4a 12 (38.7)
Clinical N stage
N0 10 (32.3)
N1 12 (38.7)
N2 8 (25.8)
N3 1 (3.2)
cTNM staging
II 8 (25.8)
III 11 (35.5)
IVa 12 (38.7)
Position
Upper 3 (9.7)
Middle 12 (38.7)
Lower 16 (51.6)
Abbreviations: cTNM, tumor, nodes, metastasis classification of staging; ECOG PS, Eastern Cooperative Oncology Group Performance Status.
Treatment Compliance
Among the 31 patients, 29 patients (93.5%) were treated with APCC regimen every 3 weeks, while the other 2 patients (aged over 70 years, determined by the physician) were adjusted to bi-weekly APCC regimen (albumin-bound paclitaxel 125 mg/m2, d1; cisplatin 40 mg/m2, d1 and capecitabine 1750 mg/m2, d1-10; 14 days as a cycle) (Figure 1). Most patients completed four cycles of neoadjuvant chemotherapy as planned, but some patients did not receive four cycles of chemotherapy as planned due to personal or epidemic reasons. The median number of preoperative treatment cycles was 4 (ranging from 1 to 6 cycles) in patients who received APCC regimen, every 3 weeks. Twenty-three (79.3%) of the 29 patients with APCC regimen, every 3 weeks, completed 4 cycles of chemotherapy, whereas 3 patients (10.3%) completed 2 cycles of chemotherapy, 2 patients (6.8%) completed 6 cycles of chemotherapy, and 1 patient (3.6%) completed one cycle of chemotherapy (discontinued treatment due to personal reasons) who was considered unevaluable for efficacy. Two patients with bi-weekly APCC regimen completed 3 and 6 cycles of chemotherapy, respectively. Five patients received local radiotherapy post completion of neoadjuvant chemotherapy, 3 of whom underwent surgical resection after radiotherapy. The causes of combined radiotherapy were as follows: in order to preserve the larynx in 1 case with upper thoracic esophageal carcinoma near neck, surgical intolerance in 1 case (73 years old), advanced baseline tumour staging in 1 case (cT4aN2), and close relationship between tumour and large vessels in 2 cases. Four patients failed to receive the expected surgery after 4 cycles of chemotherapy due to the COVID-19 outbreak. Ultimately, 24 patients underwent surgical resection. Of the 24 patients, 3 patients received additional preoperative radiotherapy, while 21 patients received preoperative chemotherapy alone.Figure 1 Patient flow diagram of this study.
Efficacy Outcomes
The clinical efficacy outcomes were evaluated among 30 patients. The size of the tumour was reduced to varying degrees in all the patients post-treatment with APCC regimen. The R0 resection rate among 24 patients was 95.8% (23/24). One patient was detected with primary esophageal lesion invading the descending aorta during the surgery; hence, the tumour was not resected and the patient refused to receive radiation and continued chemotherapy post-surgery. Of the 24 patients who underwent surgery, 9 (37.5%) achieved pCR and 16 (66.7%) achieved MPR. Further, 15 (62.5%) patients were reduced to stage I (ypT0-2N0M0), 18 (75%) were N0, and 5 patients had positive lymph nodes, 4 were N1 stage and only 1 was N2 stage after surgery. Of the 21 patients who underwent surgery with neoadjuvant chemotherapy alone, 8 (38.1%) had pCR and 15 (71.4%) had achieved MPR (Table 2).Table 2 Efficacy Outcomes Post-Surgery with Neoadjuvant Chemotherapy Regimen
Variables N (%)
Patients who received surgery after neoadjuvant chemotherapy alone (n = 21)
pCR 8/21 (38.1)
MPR 15/21 (71.4)
Patients who received surgery (n = 24)
pCR 9/24 (37.5)
MPR 16/24 (66.7)
R0 resection 23/24 (95.8)
Stage I (ypT1-2N0) 15 (62.5)
Stage II (ypT3N0) 3 (12.5)
Stage IIIA (ypT0-2N1) 4 (16.7)
Stage IIIB (ypT3N1/T0-3N2/T4a N0) 1 (8.3)
ypN0 18 (75)
ypN1 4 (16.7)
ypN2 1 (8.3)
Post-surgical morbidities 3 (12.5)
Pleural cavity infection 1 (4.2)
Pneumonia 1 (4.2)
Mediastinitis 1 (4.2)
Abbreviations: MPR, major pathological response; pCR, partial complete response.
Safety Outcomes
The commonly observed adverse events related to chemotherapy were leukopenia and neutropenia, as well as gastrointestinal adverse reactions, mostly of grade 1 and 2. The most common grade 3 or more adverse events were neutropenia (35.5%) and leukopenia (9.7%). A total of 3 patients (9.7%) were adjusted for drug dose due to adverse reactions, including 2 patients with grade 4 neutropenia and 1 patient with grade 2 hand foot syndrome. Significant complications occurred in 3 patients within 1 month after surgery, including thoracic infection (pleural effusion), pneumonia and mediastinal infection after drainage tube removal in each one patient, all of which were grade 2. The above postoperative complications were improved after symptomatic treatment, and the postoperative hospital stay was 15, 17, and 24 days, respectively. No treatment-related deaths occurred during neoadjuvant chemotherapy and within 30 days after surgery (Table 3). Of the 23 patients who underwent radical surgical resection, 4 patients continued the original regimen of chemotherapy until a total of 6 cycles after surgery and 1 patient was given postoperative radiotherapy considering the postoperative stage as ypT3N2.Table 3 Adverse Events Due to Neoadjuvant Chemotherapy (N = 31)
Events Any Grade N (%) Grade 3 N (%) Grade 4 N (%)
Neutropenia 23 (74.2%) 9 (29%) 2 (6.5%)
Leukopenia 21 (67.7%) 3 (9.7%) 0
Anaemia 17 (54.8%) 0 0
Thrombocytopenia 9 (29%) 0 1 (3.2%)
Elevated ALT 3 (9.7%) 1 (3.2%) 0
Nausea 22 (70.9%) 0 0
Vomiting 11 (35.5%) 0 0
Loss of appetite 12 (38.7%) 0 0
Fatigue 7 (22.6%) 0 0
Peripheral neurotoxicity 12 (38.7%) 0 0
Alopecia 15 (48.3%) 0 0
Foot-hand syndrome 6 (19.4%) 0 0
Abbreviation: ALT, alanine transaminase.
As of November 15, 2020, with a median follow-up time of 12.4 months (range: 10.1–31.2), 3 patients died (2 patients did not receive surgery, 1 patient received surgery). Among the 23 patients who underwent R0 resection, the median follow-up time after surgery was 8.3 months (range: 1.1–26.1). One patient developed lung metastasis 7.9 months after surgery, and his overall survival time was 24 months. Due to the breakdown of COVID 19, one patient received surgery 6 months after the end of 4 cycles of preoperative chemotherapy. The postoperative pathological stage of this patient was ypTisN1. However here, the follow-up time was only 1.1 months.
Discussion
In this study, neoadjuvant chemotherapy with the triplet regimen of albumin-bound paclitaxel with cisplatin and capecitabine (APCC regimen) for locally advanced resectable ESCC showed high anti-tumor activities and significant effect on tumour downstaging. None of the evaluable patients (n=30) had disease progression after chemotherapy. Though six patients did not receive surgery after chemotherapy for various reasons and this might have confounded our findings of the actual results, a pCR rate of 38.1% and a MPR rate of 71.4% in the 21 patients who received neoadjuvant chemotherapy alone were quite encouraging. This pCR rate seemed to be higher than that of previous neoadjuvant chemotherapy with cisplatin and fluorouracil.11,14,15 Further, in all 24 patients received surgery, the R0 resection rate was 95.8%, the pCR rate was 37.5%, the MPR rate was 66.7%, and 62.5% of the patients’ postoperative pathological stage was stage I (ypT0-2N0). As with the pCR rate in the previously reported studies nCRT were believed to often has a significant advantage over nCT alone, especially for squamous cell carcinoma. The randomized-controlled CROSS study reported a pCR rate of 49% in the squamous cell carcinoma subgroup.9 NEOCRTEC5010 study use of vinorelbine and cisplatin with concurrent radiotherapy (DT 40Gy) resulted in a pCR rate of 43.2% in patients with locally advanced ESCC.12 However, whether the higher pCR rate of nCRT over nCT could transfer to the survival benefit need further investigation. In the Phase 2 randomized trial NeoRes I, a higher pCR rate of 28% from cisplatin and fluorouracil based nCRT did not produce significant OS improvement over cisplatin and fluorouracil neoadjuvant chemotherapy alone.21 There are two ongoing randomized Phase III trials to compare the efficacy of platinum and paclitaxel concurrent radiotherapy and neochemotherapy alone for locally advanced ESCC.22,23 Our study findings suggest that APCC regimen seems to be able to further narrow the gap in pCR rate between nCT and nCRT. Recently, immune checkpoint combined with chemotherapy has been tried for neoadjuvant treatment of locally advanced esophageal cancer, but the results are still preliminary. Two prospective small sample studies showed that 2 cycles of anti-PD-1 monoclonal antibody combined with nab-paclitaxel plus S-1 or paclitaxel plus carboplatin regimen as nCT achieved pathological complete response rates of 16.67% and 45.4%, respectively.24,25
79.3% of patients in this study completed 4 cycles of preoperative chemotherapy with APCC regimen, which was longer than the duration of chemotherapy reported in other relevant studies with EC.14,15 At present, there is no clear information with regards to the optimal number of cycles of perioperative chemotherapy for locally advanced EC. In the previous studies of nCRT and nCT, usually 2 to 3 cycles of chemotherapy were used. Findings by Zhao et al17 suggested that prolonging the number of chemotherapy cycles during perioperative period could further reduce the recurrence rate and improve the overall survival. The study compared the efficacy of 4 and 2 cycles of paclitaxel, cisplatin and 5-FU during the perioperative period. It was observed that treatment with 4 cycles of chemotherapy resulted in better 5-year disease-free survival (DFS) (31% vs. 17%, HR 0.62; 95% CI, 0.49–0.73; P<0.001) and OS (38% vs 22%, HR 0.79; 95% CI 0.59–0.95; P<0.001).
In this study, 2 to 4 cycles of preoperative neoadjuvant triplet chemotherapy with APCC regimen were well tolerated. Most of the common adverse reactions were grade 1 or 2 neutropenia and gastrointestinal adverse events with the most common grade 3 or 4 adverse reactions being neutropenia (35.5%). However, 3 (12.5%) patients had chest, lung or mediastinal infection after surgery, which need more attention to in future research.
There are some limitations on this study that warrant mention. Since this was a retrospective study with a limited sample size and short follow-up time, the tumour recurrence rate and overall survival was not reached yet. In addition, as mentioned earlier, the inability of 6 (20%) patients to undergo surgery due to the age, personal will and COVID-19 epidemic might affect the accurate interpretation of pCR rate resulted from this regimen.
Conclusion
The preliminary results of this study suggest that the triplet regimen of albumin-bound paclitaxel, cisplatin and capecitabine as preoperative neoadjuvant chemotherapy for patients with locally advanced ESCC revealed significant tumour downstaging and encouraging pCR rate, with favourable safety profile. The role of this triplet regimen warrants further investigation in the neoadjuvant treatment for ESCC and a prospective Phase II study (NCT04390958) has already been in progress.
Ethics Approval
The study protocol was reviewed and approved by the Ethics Committee of Cancer Hospital Chinese Academy of Medical Sciences (approval No: 20/381-2577). This study is a retrospective non-intervention study, which does not interfere with the routine diagnosis and treatment, does not affect any medical rights and interests of patients, and does not increase the risk of patients. The results of the study will be published in the form of statistical analysis without any identifiable patient information. Most of the patients in this study have completed the treatment and cannot obtain their informed consent objectively. Based on the above reasons. We have applied to the Ethics Committee for exemption from the informed consent of all patients in this study and have been approved.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors declare no conflict of interest. | 3500 MILLIGRAM/SQ. METER | DrugDosageText | CC BY-NC | 33688259 | 19,063,857 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bradycardia'. | CMV Pancreatitis in an Immunocompromised Patient.
Cytomegalovirus (CMV) is a common double-stranded DNA (dsDNA) virus affecting a large majority of the world's population. In immunocompetent patients, CMV infection can range anywhere from an asymptomatic course to mononucleosis. However, in the immunocompromised patient, prognosis can be deadly as CMV can disseminate to the retina, liver, lungs, heart, and GI tract. We present a case of CMV pancreatitis afflicting an immunocompromised patient. Case Summary. A 45-year-old Hispanic female with no past medical history presented to the emergency department (ED) for three days of abdominal pain associated with nausea, vomiting, and diarrhea. ED vitals showed a sepsis picture with fever, tachycardia, low white blood cell (WBC) count with bandemia, and CT scan showing acute pancreatitis, cholelithiasis, gastritis, and colitis. The patient denied alcohol use and MRCP showed no stone impaction. Sepsis protocolled was initiated for biliary pancreatitis, and the patient was admitted to the medicine floors with appropriate consulting services. Over the course of admission, the patient responded poorly to treatment and had a steady decline in respiratory status. She tested positive for HIV with a severely depressed CD4 count (42 cells/McL) and high viral load (1,492,761 copies/ml) and started on appropriate prophylactic antibiotics and HAART therapy. The patient was moved to the Medical Intensive Care Unit (MICU) after acute respiratory failure secondary to ARDS requiring mechanical ventilation with initiation of ARDS protocol. The patient was hemodynamically unstable and required vasopressor support. Hospital course was complicated by melena which prompted an esophagogastroduodenostomy (EGD) with biopsy yielding CMV gastritis. Serum CMV viral load was also found to be positive along with an elevated lipase level, indicative of pancreatitis. Despite initiation of ganciclovir, the patient continued to have refractory hypoxia despite full ventilatory support and proning. Unfortunately, the patient was deemed too unstable for transfer to an ECMO facility. She eventually succumbed to respiratory failure. Discussion. CMV is a Herpesviridae virus that is prevalent among more than half of the world's population. Its effects range from no presenting symptoms to respiratory failure depending on immune status. CMV more commonly affects the retina, lungs, liver, and GI tract; however, in rare cases, it is known to affect the pancreas as well. Other more common causes of pancreatitis were ruled out during the progression of this patient, and an elevated lipase with high CMV viral load points towards CMV pancreatitis.
This is one of only a few reported cases of CMV pancreatitis and warrants further study due to the massive prevalence of CMV in the entire world's population. Our case demonstrates the extent of dissemination of CMV in a severely immunocompromised patient by showing clear cut pancreatitis secondary to said viral infection with exclusion of other possible causes. Our hope is that clinicians will change their practice to include a more scrutinized study into causes of pancreatitis especially in their immunocompromised patients.
1. Introduction
Cytomegalovirus (CMV) is a common double-stranded DNA (dsDNA) virus found in approximately 59% of the population [1]. In the immunocompetent patient, it has a self-limiting course; however, in the immunocompromised patient, CMV infection can often have a grave prognosis [2]. CMV in immunocompromised patients is aggressive and can disseminate to multiple organs causing disease including but not limited to retinitis, hepatitis, esophagitis, colitis, and pneumonitis. The retina is the most common site for disseminated CMV to proliferate and cause inflammatory responses; however, CMV has the potential to spread to any organ [3, 4]. We present a rare case of CMV pancreatitis in a 45-year-old immunocompromised woman from El Salvador.
2. Case Presentation
A 45-year-old Hispanic female with no significant past medical history presented to the emergency department with three-day history of abdominal pain, nausea, vomiting, and diarrhea. Abdominal pain was described as a severe, burning sensation in the epigastrium radiating to her back, exacerbated by po intake and associated with fevers, nonbloody, nonbilious emesis, and enumerable episodes of nonbloody diarrhea. Vitals on admission were as follows: Temp 101.1F BP 104/67 mmHg P 101 RR 17 SpO2 98% on ambient air. On physical exam, the patient had tenderness to palpation over her right upper quadrant. Laboratory results revealed a WBC 5.32, low lymphocyte count (11%), bandemia (10%), ALT of 26 U/L, AST of 39 U/L, Alkaline Phosphatase of 90 U/L, and a lipase count 3 times the level of normal (153 U/L). A CT abdomen/Pelvis revealed acute pancreatitis, cholecystolithiasis, gastritis, colitis, and moderate ascites (Figure 1).
On the medicine floors, the patient was initially started on ciprofloxacin, metronidazole, and cefepime for acute biliary pancreatitis and colitis, and coverage was broadened to meropenem and amikacin for persistent fevers (101-102F), worsening leukocytosis and worsening clinical symptomatology of epigastric pain, diarrhea, nonbloody, nonbilious emesis, and dyspnea with exertion. Despite approximately 6 L fluid resuscitation with normal saline, the patient remained hypotensive. An MRCP revealed a single 0.8 cm stone in the fundus of the gallbladder yet no bile duct impaction, making biliary pancreatitis less likely. A week into her admission, a screening HIV test was found to be positive with a CD4 of 42 cells/McL.
With her hemodynamics steadily deteriorating likely secondary to respiratory distress secondary to Pneumocystis jiroveci, the pneumonia patient was started on TMP/SMX and systemic steroids, and MAC prophylaxis and Descovy were also initiated. However, despite these measures, the patient had a declining respiratory status. A chest X-ray showed diffuse pulmonary haziness, and a CT thorax revealed diffuse ground-glass opacities consistent with ARDS. The patient was hypoxemic on a nonrebreather mask, and her saturation continued to fall on high flow oxygen. A bronchoscopy was performed due to high suspicion of pneumocystis pneumonia (PCP). Bronchoalveolar lavage (BAL) cytology was negative for malignant cells as was PCP; however, aspergillus was cultured. During the hospital course, the patient began to desaturate to 70% on 70% FiO2 via Hi-Flow nasal cannula. Her PaO2/FiO2 ratio was <100 indicating severe ARDS, requiring intubation, and was subsequently transferred to MICU service. Chest X-ray obtained postintubation compared with earlier X-rays correlated with ARDS. MICU admission was complicated by melena prompting endoscopic workup. Esophagogastroduodenoscopy (EGD) revealed nodular ulcers in the esophagus, extensive gastric ulcers with exudates, and hemorrhage throughout the stomach with EGD biopsies revealing severe active chronic inflammation with epithelial cells with eosinophilic inclusions consistent with cytomegalovirus infection (Figures 2 and 3). Furthermore, serum CMV viral load was more than 2 million and Ganciclovir was initiated. Ophthalmology was consulted for possible CMV retinitis which was ruled out. Abdominal ultrasound revealed moderate ascites and cholecystitis.
Despite ARDS protocol initiation including paralytic initiation and prone positioning, the patient had refractory hypoxia. The patient was deemed too unstable for Extracorporeal Membrane Oxygenation (ECMO). Despite initiation of Continuous Renal Replacement Therapies (CRRT), her renal function and severe metabolic acidosis failed to improve. Despite the exhausted efforts of the MICU team, the patient became severely hypoxemic, bradycardic, and eventually passed away. Autopsy was declined by the family.
3. Discussion
CMV, a member of the Herpesviridae family, is a double-stranded DNA virus and replicates itself inside the host cell nucleus. It uses its host to package more infectious products and dense bodies which enumerate in quantity and eventually lyse the cell and spread throughout the host. CMV-infected cells have a textbook histological footprint, often presenting with “Owl-eyes” inclusions within the nucleus of the cell [3].
In immunocompetent patients, CMV is usually asymptomatic or can present with flu-like symptoms and possibly enlarged lymph nodes and/or spleen. For such patients, it is usually self-limiting and does not progress any further. Immunocompromised patients, however, are afflicted with a more severe and disseminating infection. The two biggest populations of immunosuppressed patients infected with CMV are transplant recipients and HIV/AIDs infected patients. It is known that CMV in HIV patients typically affects part or all of the GI tract, the most prominent being colitis, esophagitis, and gastritis. Our patient presented similarly with multiple imaging modalities confirming each of these. The EGD performed revealed multiple irregular ulcers in the esophagus and a vast blanket of exudative ulcers in the stomach that made the tissue friable and prone to bleeding [4, 5].
Pancreatitis is an atypical finding in CMV infection. However, reports reveal that it is known to afflict these groups of immunocompromised patients, including those on chronic steroid or immunosuppressive therapy and patients with systemic lupus erythematosus [5]. Our patient presented with diagnostic findings consistent with acute pancreatitis including abdominal pain, lipase three times the upper limit of normal within 3 days of symptom onset, and imaging (both CT abd/pelvis and abdominal ultrasound) findings consistent with acute pancreatitis. Further lab work during the patient's admission showed an elevated Anti-1-Antitrypsin level and an elevated amylase, also consistent with acute pancreatitis.
There are numerous causes of pancreatitis, the most common of which are alcohol (variable consumption period of 4-7 drinks per day) and gallstones. The patient denied any alcohol use and though the MRCP showed a single 0.8 cm gallstone in the fundus of the gallbladder; it also showed no stone impaction within the common bile duct, making the diagnosis of biliary pancreatitis less likely. Furthermore, certain medications have been known to cause pancreatitis including but not limited to amiodarone, enalapril, losartan, isoniazid, and sulfonylureas. Our patient endorsed no known medical history or regular medication [6].
Certain factors are identified that could have aided towards a stronger case of pancreatitis. Although the evidence strongly suggests CMV pancreatitis, a positive biopsy or autopsy would have provided a definitive diagnosis. Biopsy of the pancreas could not be performed due to the patient's critical status and the family of the patient declined autopsy, so confirmation could not be confirmed. The immune status of the patient was not discovered until later into the development and decline of the patient. Late into her admission, she revealed her history of rape by multiple different men (5 years ago) while attempting to cross into US border; she never revealed her rapists' identity or sought medical attention afterwards as she feared her undocumented status would be revealed. CMV was tested for much later on, and although valganciclovir therapy only slows down the progression of the disease, it was started only after CMV infection was confirmed. The monitoring of pancreatic enzyme levels regularly could have mapped out the status of the patient's pancreatitis and given a better picture of just what phase she was in based on the levels. The patient's family refusal for autopsy hindered the possibility of pancreatic biopsy to confirm infection of the pancreas with CMV.
4. Conclusion
Due to the prominence and its effect on more than half of the world's population, we encourage clinicians to further the study of CMV and the reach of its dissemination. Our case accurately portrayed the effect of CMV in an immunocompromised patient and revealed how devastating a common Herpesviridae virus can be to a host with a suppressed immune system. By encouraging this study, we hope to help clinicians recognize the commonalities within the pattern of symptoms and signs for both CMV infection and pancreatitis. This is one of only a few cases of CMV pancreatitis found in a literature review, and it is our goal that we can use this study to aid in the early diagnosis and treatment of disseminated CMV.
Acknowledgments
We thank the pulmonary critical care staff including the critical care nurses and respiratory therapy team who worked tirelessly to treat this patient until her last days. Thank you to the family of the patient for giving us this opportunity to learn from her disease.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 CT abdomen image obtained in Emergency Department indicating findings consistent with pancreatitis.
Figure 2 EGD image of body of stomach showing ulceration secondary to CMV.
Figure 3 EGD image of antrum of stomach showing ulceration secondary to CMV. | AMIKACIN, CEFEPIME HYDROCHLORIDE, CIPROFLOXACIN, GANCICLOVIR, MEROPENEM, METRONIDAZOLE, VALGANCICLOVIR | DrugsGivenReaction | CC BY | 33688440 | 19,030,299 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metabolic acidosis'. | CMV Pancreatitis in an Immunocompromised Patient.
Cytomegalovirus (CMV) is a common double-stranded DNA (dsDNA) virus affecting a large majority of the world's population. In immunocompetent patients, CMV infection can range anywhere from an asymptomatic course to mononucleosis. However, in the immunocompromised patient, prognosis can be deadly as CMV can disseminate to the retina, liver, lungs, heart, and GI tract. We present a case of CMV pancreatitis afflicting an immunocompromised patient. Case Summary. A 45-year-old Hispanic female with no past medical history presented to the emergency department (ED) for three days of abdominal pain associated with nausea, vomiting, and diarrhea. ED vitals showed a sepsis picture with fever, tachycardia, low white blood cell (WBC) count with bandemia, and CT scan showing acute pancreatitis, cholelithiasis, gastritis, and colitis. The patient denied alcohol use and MRCP showed no stone impaction. Sepsis protocolled was initiated for biliary pancreatitis, and the patient was admitted to the medicine floors with appropriate consulting services. Over the course of admission, the patient responded poorly to treatment and had a steady decline in respiratory status. She tested positive for HIV with a severely depressed CD4 count (42 cells/McL) and high viral load (1,492,761 copies/ml) and started on appropriate prophylactic antibiotics and HAART therapy. The patient was moved to the Medical Intensive Care Unit (MICU) after acute respiratory failure secondary to ARDS requiring mechanical ventilation with initiation of ARDS protocol. The patient was hemodynamically unstable and required vasopressor support. Hospital course was complicated by melena which prompted an esophagogastroduodenostomy (EGD) with biopsy yielding CMV gastritis. Serum CMV viral load was also found to be positive along with an elevated lipase level, indicative of pancreatitis. Despite initiation of ganciclovir, the patient continued to have refractory hypoxia despite full ventilatory support and proning. Unfortunately, the patient was deemed too unstable for transfer to an ECMO facility. She eventually succumbed to respiratory failure. Discussion. CMV is a Herpesviridae virus that is prevalent among more than half of the world's population. Its effects range from no presenting symptoms to respiratory failure depending on immune status. CMV more commonly affects the retina, lungs, liver, and GI tract; however, in rare cases, it is known to affect the pancreas as well. Other more common causes of pancreatitis were ruled out during the progression of this patient, and an elevated lipase with high CMV viral load points towards CMV pancreatitis.
This is one of only a few reported cases of CMV pancreatitis and warrants further study due to the massive prevalence of CMV in the entire world's population. Our case demonstrates the extent of dissemination of CMV in a severely immunocompromised patient by showing clear cut pancreatitis secondary to said viral infection with exclusion of other possible causes. Our hope is that clinicians will change their practice to include a more scrutinized study into causes of pancreatitis especially in their immunocompromised patients.
1. Introduction
Cytomegalovirus (CMV) is a common double-stranded DNA (dsDNA) virus found in approximately 59% of the population [1]. In the immunocompetent patient, it has a self-limiting course; however, in the immunocompromised patient, CMV infection can often have a grave prognosis [2]. CMV in immunocompromised patients is aggressive and can disseminate to multiple organs causing disease including but not limited to retinitis, hepatitis, esophagitis, colitis, and pneumonitis. The retina is the most common site for disseminated CMV to proliferate and cause inflammatory responses; however, CMV has the potential to spread to any organ [3, 4]. We present a rare case of CMV pancreatitis in a 45-year-old immunocompromised woman from El Salvador.
2. Case Presentation
A 45-year-old Hispanic female with no significant past medical history presented to the emergency department with three-day history of abdominal pain, nausea, vomiting, and diarrhea. Abdominal pain was described as a severe, burning sensation in the epigastrium radiating to her back, exacerbated by po intake and associated with fevers, nonbloody, nonbilious emesis, and enumerable episodes of nonbloody diarrhea. Vitals on admission were as follows: Temp 101.1F BP 104/67 mmHg P 101 RR 17 SpO2 98% on ambient air. On physical exam, the patient had tenderness to palpation over her right upper quadrant. Laboratory results revealed a WBC 5.32, low lymphocyte count (11%), bandemia (10%), ALT of 26 U/L, AST of 39 U/L, Alkaline Phosphatase of 90 U/L, and a lipase count 3 times the level of normal (153 U/L). A CT abdomen/Pelvis revealed acute pancreatitis, cholecystolithiasis, gastritis, colitis, and moderate ascites (Figure 1).
On the medicine floors, the patient was initially started on ciprofloxacin, metronidazole, and cefepime for acute biliary pancreatitis and colitis, and coverage was broadened to meropenem and amikacin for persistent fevers (101-102F), worsening leukocytosis and worsening clinical symptomatology of epigastric pain, diarrhea, nonbloody, nonbilious emesis, and dyspnea with exertion. Despite approximately 6 L fluid resuscitation with normal saline, the patient remained hypotensive. An MRCP revealed a single 0.8 cm stone in the fundus of the gallbladder yet no bile duct impaction, making biliary pancreatitis less likely. A week into her admission, a screening HIV test was found to be positive with a CD4 of 42 cells/McL.
With her hemodynamics steadily deteriorating likely secondary to respiratory distress secondary to Pneumocystis jiroveci, the pneumonia patient was started on TMP/SMX and systemic steroids, and MAC prophylaxis and Descovy were also initiated. However, despite these measures, the patient had a declining respiratory status. A chest X-ray showed diffuse pulmonary haziness, and a CT thorax revealed diffuse ground-glass opacities consistent with ARDS. The patient was hypoxemic on a nonrebreather mask, and her saturation continued to fall on high flow oxygen. A bronchoscopy was performed due to high suspicion of pneumocystis pneumonia (PCP). Bronchoalveolar lavage (BAL) cytology was negative for malignant cells as was PCP; however, aspergillus was cultured. During the hospital course, the patient began to desaturate to 70% on 70% FiO2 via Hi-Flow nasal cannula. Her PaO2/FiO2 ratio was <100 indicating severe ARDS, requiring intubation, and was subsequently transferred to MICU service. Chest X-ray obtained postintubation compared with earlier X-rays correlated with ARDS. MICU admission was complicated by melena prompting endoscopic workup. Esophagogastroduodenoscopy (EGD) revealed nodular ulcers in the esophagus, extensive gastric ulcers with exudates, and hemorrhage throughout the stomach with EGD biopsies revealing severe active chronic inflammation with epithelial cells with eosinophilic inclusions consistent with cytomegalovirus infection (Figures 2 and 3). Furthermore, serum CMV viral load was more than 2 million and Ganciclovir was initiated. Ophthalmology was consulted for possible CMV retinitis which was ruled out. Abdominal ultrasound revealed moderate ascites and cholecystitis.
Despite ARDS protocol initiation including paralytic initiation and prone positioning, the patient had refractory hypoxia. The patient was deemed too unstable for Extracorporeal Membrane Oxygenation (ECMO). Despite initiation of Continuous Renal Replacement Therapies (CRRT), her renal function and severe metabolic acidosis failed to improve. Despite the exhausted efforts of the MICU team, the patient became severely hypoxemic, bradycardic, and eventually passed away. Autopsy was declined by the family.
3. Discussion
CMV, a member of the Herpesviridae family, is a double-stranded DNA virus and replicates itself inside the host cell nucleus. It uses its host to package more infectious products and dense bodies which enumerate in quantity and eventually lyse the cell and spread throughout the host. CMV-infected cells have a textbook histological footprint, often presenting with “Owl-eyes” inclusions within the nucleus of the cell [3].
In immunocompetent patients, CMV is usually asymptomatic or can present with flu-like symptoms and possibly enlarged lymph nodes and/or spleen. For such patients, it is usually self-limiting and does not progress any further. Immunocompromised patients, however, are afflicted with a more severe and disseminating infection. The two biggest populations of immunosuppressed patients infected with CMV are transplant recipients and HIV/AIDs infected patients. It is known that CMV in HIV patients typically affects part or all of the GI tract, the most prominent being colitis, esophagitis, and gastritis. Our patient presented similarly with multiple imaging modalities confirming each of these. The EGD performed revealed multiple irregular ulcers in the esophagus and a vast blanket of exudative ulcers in the stomach that made the tissue friable and prone to bleeding [4, 5].
Pancreatitis is an atypical finding in CMV infection. However, reports reveal that it is known to afflict these groups of immunocompromised patients, including those on chronic steroid or immunosuppressive therapy and patients with systemic lupus erythematosus [5]. Our patient presented with diagnostic findings consistent with acute pancreatitis including abdominal pain, lipase three times the upper limit of normal within 3 days of symptom onset, and imaging (both CT abd/pelvis and abdominal ultrasound) findings consistent with acute pancreatitis. Further lab work during the patient's admission showed an elevated Anti-1-Antitrypsin level and an elevated amylase, also consistent with acute pancreatitis.
There are numerous causes of pancreatitis, the most common of which are alcohol (variable consumption period of 4-7 drinks per day) and gallstones. The patient denied any alcohol use and though the MRCP showed a single 0.8 cm gallstone in the fundus of the gallbladder; it also showed no stone impaction within the common bile duct, making the diagnosis of biliary pancreatitis less likely. Furthermore, certain medications have been known to cause pancreatitis including but not limited to amiodarone, enalapril, losartan, isoniazid, and sulfonylureas. Our patient endorsed no known medical history or regular medication [6].
Certain factors are identified that could have aided towards a stronger case of pancreatitis. Although the evidence strongly suggests CMV pancreatitis, a positive biopsy or autopsy would have provided a definitive diagnosis. Biopsy of the pancreas could not be performed due to the patient's critical status and the family of the patient declined autopsy, so confirmation could not be confirmed. The immune status of the patient was not discovered until later into the development and decline of the patient. Late into her admission, she revealed her history of rape by multiple different men (5 years ago) while attempting to cross into US border; she never revealed her rapists' identity or sought medical attention afterwards as she feared her undocumented status would be revealed. CMV was tested for much later on, and although valganciclovir therapy only slows down the progression of the disease, it was started only after CMV infection was confirmed. The monitoring of pancreatic enzyme levels regularly could have mapped out the status of the patient's pancreatitis and given a better picture of just what phase she was in based on the levels. The patient's family refusal for autopsy hindered the possibility of pancreatic biopsy to confirm infection of the pancreas with CMV.
4. Conclusion
Due to the prominence and its effect on more than half of the world's population, we encourage clinicians to further the study of CMV and the reach of its dissemination. Our case accurately portrayed the effect of CMV in an immunocompromised patient and revealed how devastating a common Herpesviridae virus can be to a host with a suppressed immune system. By encouraging this study, we hope to help clinicians recognize the commonalities within the pattern of symptoms and signs for both CMV infection and pancreatitis. This is one of only a few cases of CMV pancreatitis found in a literature review, and it is our goal that we can use this study to aid in the early diagnosis and treatment of disseminated CMV.
Acknowledgments
We thank the pulmonary critical care staff including the critical care nurses and respiratory therapy team who worked tirelessly to treat this patient until her last days. Thank you to the family of the patient for giving us this opportunity to learn from her disease.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 CT abdomen image obtained in Emergency Department indicating findings consistent with pancreatitis.
Figure 2 EGD image of body of stomach showing ulceration secondary to CMV.
Figure 3 EGD image of antrum of stomach showing ulceration secondary to CMV. | AMIKACIN, CEFEPIME HYDROCHLORIDE, CIPROFLOXACIN, GANCICLOVIR, MEROPENEM, METRONIDAZOLE, VALGANCICLOVIR | DrugsGivenReaction | CC BY | 33688440 | 19,030,299 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal impairment'. | CMV Pancreatitis in an Immunocompromised Patient.
Cytomegalovirus (CMV) is a common double-stranded DNA (dsDNA) virus affecting a large majority of the world's population. In immunocompetent patients, CMV infection can range anywhere from an asymptomatic course to mononucleosis. However, in the immunocompromised patient, prognosis can be deadly as CMV can disseminate to the retina, liver, lungs, heart, and GI tract. We present a case of CMV pancreatitis afflicting an immunocompromised patient. Case Summary. A 45-year-old Hispanic female with no past medical history presented to the emergency department (ED) for three days of abdominal pain associated with nausea, vomiting, and diarrhea. ED vitals showed a sepsis picture with fever, tachycardia, low white blood cell (WBC) count with bandemia, and CT scan showing acute pancreatitis, cholelithiasis, gastritis, and colitis. The patient denied alcohol use and MRCP showed no stone impaction. Sepsis protocolled was initiated for biliary pancreatitis, and the patient was admitted to the medicine floors with appropriate consulting services. Over the course of admission, the patient responded poorly to treatment and had a steady decline in respiratory status. She tested positive for HIV with a severely depressed CD4 count (42 cells/McL) and high viral load (1,492,761 copies/ml) and started on appropriate prophylactic antibiotics and HAART therapy. The patient was moved to the Medical Intensive Care Unit (MICU) after acute respiratory failure secondary to ARDS requiring mechanical ventilation with initiation of ARDS protocol. The patient was hemodynamically unstable and required vasopressor support. Hospital course was complicated by melena which prompted an esophagogastroduodenostomy (EGD) with biopsy yielding CMV gastritis. Serum CMV viral load was also found to be positive along with an elevated lipase level, indicative of pancreatitis. Despite initiation of ganciclovir, the patient continued to have refractory hypoxia despite full ventilatory support and proning. Unfortunately, the patient was deemed too unstable for transfer to an ECMO facility. She eventually succumbed to respiratory failure. Discussion. CMV is a Herpesviridae virus that is prevalent among more than half of the world's population. Its effects range from no presenting symptoms to respiratory failure depending on immune status. CMV more commonly affects the retina, lungs, liver, and GI tract; however, in rare cases, it is known to affect the pancreas as well. Other more common causes of pancreatitis were ruled out during the progression of this patient, and an elevated lipase with high CMV viral load points towards CMV pancreatitis.
This is one of only a few reported cases of CMV pancreatitis and warrants further study due to the massive prevalence of CMV in the entire world's population. Our case demonstrates the extent of dissemination of CMV in a severely immunocompromised patient by showing clear cut pancreatitis secondary to said viral infection with exclusion of other possible causes. Our hope is that clinicians will change their practice to include a more scrutinized study into causes of pancreatitis especially in their immunocompromised patients.
1. Introduction
Cytomegalovirus (CMV) is a common double-stranded DNA (dsDNA) virus found in approximately 59% of the population [1]. In the immunocompetent patient, it has a self-limiting course; however, in the immunocompromised patient, CMV infection can often have a grave prognosis [2]. CMV in immunocompromised patients is aggressive and can disseminate to multiple organs causing disease including but not limited to retinitis, hepatitis, esophagitis, colitis, and pneumonitis. The retina is the most common site for disseminated CMV to proliferate and cause inflammatory responses; however, CMV has the potential to spread to any organ [3, 4]. We present a rare case of CMV pancreatitis in a 45-year-old immunocompromised woman from El Salvador.
2. Case Presentation
A 45-year-old Hispanic female with no significant past medical history presented to the emergency department with three-day history of abdominal pain, nausea, vomiting, and diarrhea. Abdominal pain was described as a severe, burning sensation in the epigastrium radiating to her back, exacerbated by po intake and associated with fevers, nonbloody, nonbilious emesis, and enumerable episodes of nonbloody diarrhea. Vitals on admission were as follows: Temp 101.1F BP 104/67 mmHg P 101 RR 17 SpO2 98% on ambient air. On physical exam, the patient had tenderness to palpation over her right upper quadrant. Laboratory results revealed a WBC 5.32, low lymphocyte count (11%), bandemia (10%), ALT of 26 U/L, AST of 39 U/L, Alkaline Phosphatase of 90 U/L, and a lipase count 3 times the level of normal (153 U/L). A CT abdomen/Pelvis revealed acute pancreatitis, cholecystolithiasis, gastritis, colitis, and moderate ascites (Figure 1).
On the medicine floors, the patient was initially started on ciprofloxacin, metronidazole, and cefepime for acute biliary pancreatitis and colitis, and coverage was broadened to meropenem and amikacin for persistent fevers (101-102F), worsening leukocytosis and worsening clinical symptomatology of epigastric pain, diarrhea, nonbloody, nonbilious emesis, and dyspnea with exertion. Despite approximately 6 L fluid resuscitation with normal saline, the patient remained hypotensive. An MRCP revealed a single 0.8 cm stone in the fundus of the gallbladder yet no bile duct impaction, making biliary pancreatitis less likely. A week into her admission, a screening HIV test was found to be positive with a CD4 of 42 cells/McL.
With her hemodynamics steadily deteriorating likely secondary to respiratory distress secondary to Pneumocystis jiroveci, the pneumonia patient was started on TMP/SMX and systemic steroids, and MAC prophylaxis and Descovy were also initiated. However, despite these measures, the patient had a declining respiratory status. A chest X-ray showed diffuse pulmonary haziness, and a CT thorax revealed diffuse ground-glass opacities consistent with ARDS. The patient was hypoxemic on a nonrebreather mask, and her saturation continued to fall on high flow oxygen. A bronchoscopy was performed due to high suspicion of pneumocystis pneumonia (PCP). Bronchoalveolar lavage (BAL) cytology was negative for malignant cells as was PCP; however, aspergillus was cultured. During the hospital course, the patient began to desaturate to 70% on 70% FiO2 via Hi-Flow nasal cannula. Her PaO2/FiO2 ratio was <100 indicating severe ARDS, requiring intubation, and was subsequently transferred to MICU service. Chest X-ray obtained postintubation compared with earlier X-rays correlated with ARDS. MICU admission was complicated by melena prompting endoscopic workup. Esophagogastroduodenoscopy (EGD) revealed nodular ulcers in the esophagus, extensive gastric ulcers with exudates, and hemorrhage throughout the stomach with EGD biopsies revealing severe active chronic inflammation with epithelial cells with eosinophilic inclusions consistent with cytomegalovirus infection (Figures 2 and 3). Furthermore, serum CMV viral load was more than 2 million and Ganciclovir was initiated. Ophthalmology was consulted for possible CMV retinitis which was ruled out. Abdominal ultrasound revealed moderate ascites and cholecystitis.
Despite ARDS protocol initiation including paralytic initiation and prone positioning, the patient had refractory hypoxia. The patient was deemed too unstable for Extracorporeal Membrane Oxygenation (ECMO). Despite initiation of Continuous Renal Replacement Therapies (CRRT), her renal function and severe metabolic acidosis failed to improve. Despite the exhausted efforts of the MICU team, the patient became severely hypoxemic, bradycardic, and eventually passed away. Autopsy was declined by the family.
3. Discussion
CMV, a member of the Herpesviridae family, is a double-stranded DNA virus and replicates itself inside the host cell nucleus. It uses its host to package more infectious products and dense bodies which enumerate in quantity and eventually lyse the cell and spread throughout the host. CMV-infected cells have a textbook histological footprint, often presenting with “Owl-eyes” inclusions within the nucleus of the cell [3].
In immunocompetent patients, CMV is usually asymptomatic or can present with flu-like symptoms and possibly enlarged lymph nodes and/or spleen. For such patients, it is usually self-limiting and does not progress any further. Immunocompromised patients, however, are afflicted with a more severe and disseminating infection. The two biggest populations of immunosuppressed patients infected with CMV are transplant recipients and HIV/AIDs infected patients. It is known that CMV in HIV patients typically affects part or all of the GI tract, the most prominent being colitis, esophagitis, and gastritis. Our patient presented similarly with multiple imaging modalities confirming each of these. The EGD performed revealed multiple irregular ulcers in the esophagus and a vast blanket of exudative ulcers in the stomach that made the tissue friable and prone to bleeding [4, 5].
Pancreatitis is an atypical finding in CMV infection. However, reports reveal that it is known to afflict these groups of immunocompromised patients, including those on chronic steroid or immunosuppressive therapy and patients with systemic lupus erythematosus [5]. Our patient presented with diagnostic findings consistent with acute pancreatitis including abdominal pain, lipase three times the upper limit of normal within 3 days of symptom onset, and imaging (both CT abd/pelvis and abdominal ultrasound) findings consistent with acute pancreatitis. Further lab work during the patient's admission showed an elevated Anti-1-Antitrypsin level and an elevated amylase, also consistent with acute pancreatitis.
There are numerous causes of pancreatitis, the most common of which are alcohol (variable consumption period of 4-7 drinks per day) and gallstones. The patient denied any alcohol use and though the MRCP showed a single 0.8 cm gallstone in the fundus of the gallbladder; it also showed no stone impaction within the common bile duct, making the diagnosis of biliary pancreatitis less likely. Furthermore, certain medications have been known to cause pancreatitis including but not limited to amiodarone, enalapril, losartan, isoniazid, and sulfonylureas. Our patient endorsed no known medical history or regular medication [6].
Certain factors are identified that could have aided towards a stronger case of pancreatitis. Although the evidence strongly suggests CMV pancreatitis, a positive biopsy or autopsy would have provided a definitive diagnosis. Biopsy of the pancreas could not be performed due to the patient's critical status and the family of the patient declined autopsy, so confirmation could not be confirmed. The immune status of the patient was not discovered until later into the development and decline of the patient. Late into her admission, she revealed her history of rape by multiple different men (5 years ago) while attempting to cross into US border; she never revealed her rapists' identity or sought medical attention afterwards as she feared her undocumented status would be revealed. CMV was tested for much later on, and although valganciclovir therapy only slows down the progression of the disease, it was started only after CMV infection was confirmed. The monitoring of pancreatic enzyme levels regularly could have mapped out the status of the patient's pancreatitis and given a better picture of just what phase she was in based on the levels. The patient's family refusal for autopsy hindered the possibility of pancreatic biopsy to confirm infection of the pancreas with CMV.
4. Conclusion
Due to the prominence and its effect on more than half of the world's population, we encourage clinicians to further the study of CMV and the reach of its dissemination. Our case accurately portrayed the effect of CMV in an immunocompromised patient and revealed how devastating a common Herpesviridae virus can be to a host with a suppressed immune system. By encouraging this study, we hope to help clinicians recognize the commonalities within the pattern of symptoms and signs for both CMV infection and pancreatitis. This is one of only a few cases of CMV pancreatitis found in a literature review, and it is our goal that we can use this study to aid in the early diagnosis and treatment of disseminated CMV.
Acknowledgments
We thank the pulmonary critical care staff including the critical care nurses and respiratory therapy team who worked tirelessly to treat this patient until her last days. Thank you to the family of the patient for giving us this opportunity to learn from her disease.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 CT abdomen image obtained in Emergency Department indicating findings consistent with pancreatitis.
Figure 2 EGD image of body of stomach showing ulceration secondary to CMV.
Figure 3 EGD image of antrum of stomach showing ulceration secondary to CMV. | AMIKACIN, CEFEPIME HYDROCHLORIDE, CIPROFLOXACIN, GANCICLOVIR, MEROPENEM, METRONIDAZOLE, VALGANCICLOVIR | DrugsGivenReaction | CC BY | 33688440 | 19,030,299 | 2021 |
What was the outcome of reaction 'Metabolic acidosis'? | CMV Pancreatitis in an Immunocompromised Patient.
Cytomegalovirus (CMV) is a common double-stranded DNA (dsDNA) virus affecting a large majority of the world's population. In immunocompetent patients, CMV infection can range anywhere from an asymptomatic course to mononucleosis. However, in the immunocompromised patient, prognosis can be deadly as CMV can disseminate to the retina, liver, lungs, heart, and GI tract. We present a case of CMV pancreatitis afflicting an immunocompromised patient. Case Summary. A 45-year-old Hispanic female with no past medical history presented to the emergency department (ED) for three days of abdominal pain associated with nausea, vomiting, and diarrhea. ED vitals showed a sepsis picture with fever, tachycardia, low white blood cell (WBC) count with bandemia, and CT scan showing acute pancreatitis, cholelithiasis, gastritis, and colitis. The patient denied alcohol use and MRCP showed no stone impaction. Sepsis protocolled was initiated for biliary pancreatitis, and the patient was admitted to the medicine floors with appropriate consulting services. Over the course of admission, the patient responded poorly to treatment and had a steady decline in respiratory status. She tested positive for HIV with a severely depressed CD4 count (42 cells/McL) and high viral load (1,492,761 copies/ml) and started on appropriate prophylactic antibiotics and HAART therapy. The patient was moved to the Medical Intensive Care Unit (MICU) after acute respiratory failure secondary to ARDS requiring mechanical ventilation with initiation of ARDS protocol. The patient was hemodynamically unstable and required vasopressor support. Hospital course was complicated by melena which prompted an esophagogastroduodenostomy (EGD) with biopsy yielding CMV gastritis. Serum CMV viral load was also found to be positive along with an elevated lipase level, indicative of pancreatitis. Despite initiation of ganciclovir, the patient continued to have refractory hypoxia despite full ventilatory support and proning. Unfortunately, the patient was deemed too unstable for transfer to an ECMO facility. She eventually succumbed to respiratory failure. Discussion. CMV is a Herpesviridae virus that is prevalent among more than half of the world's population. Its effects range from no presenting symptoms to respiratory failure depending on immune status. CMV more commonly affects the retina, lungs, liver, and GI tract; however, in rare cases, it is known to affect the pancreas as well. Other more common causes of pancreatitis were ruled out during the progression of this patient, and an elevated lipase with high CMV viral load points towards CMV pancreatitis.
This is one of only a few reported cases of CMV pancreatitis and warrants further study due to the massive prevalence of CMV in the entire world's population. Our case demonstrates the extent of dissemination of CMV in a severely immunocompromised patient by showing clear cut pancreatitis secondary to said viral infection with exclusion of other possible causes. Our hope is that clinicians will change their practice to include a more scrutinized study into causes of pancreatitis especially in their immunocompromised patients.
1. Introduction
Cytomegalovirus (CMV) is a common double-stranded DNA (dsDNA) virus found in approximately 59% of the population [1]. In the immunocompetent patient, it has a self-limiting course; however, in the immunocompromised patient, CMV infection can often have a grave prognosis [2]. CMV in immunocompromised patients is aggressive and can disseminate to multiple organs causing disease including but not limited to retinitis, hepatitis, esophagitis, colitis, and pneumonitis. The retina is the most common site for disseminated CMV to proliferate and cause inflammatory responses; however, CMV has the potential to spread to any organ [3, 4]. We present a rare case of CMV pancreatitis in a 45-year-old immunocompromised woman from El Salvador.
2. Case Presentation
A 45-year-old Hispanic female with no significant past medical history presented to the emergency department with three-day history of abdominal pain, nausea, vomiting, and diarrhea. Abdominal pain was described as a severe, burning sensation in the epigastrium radiating to her back, exacerbated by po intake and associated with fevers, nonbloody, nonbilious emesis, and enumerable episodes of nonbloody diarrhea. Vitals on admission were as follows: Temp 101.1F BP 104/67 mmHg P 101 RR 17 SpO2 98% on ambient air. On physical exam, the patient had tenderness to palpation over her right upper quadrant. Laboratory results revealed a WBC 5.32, low lymphocyte count (11%), bandemia (10%), ALT of 26 U/L, AST of 39 U/L, Alkaline Phosphatase of 90 U/L, and a lipase count 3 times the level of normal (153 U/L). A CT abdomen/Pelvis revealed acute pancreatitis, cholecystolithiasis, gastritis, colitis, and moderate ascites (Figure 1).
On the medicine floors, the patient was initially started on ciprofloxacin, metronidazole, and cefepime for acute biliary pancreatitis and colitis, and coverage was broadened to meropenem and amikacin for persistent fevers (101-102F), worsening leukocytosis and worsening clinical symptomatology of epigastric pain, diarrhea, nonbloody, nonbilious emesis, and dyspnea with exertion. Despite approximately 6 L fluid resuscitation with normal saline, the patient remained hypotensive. An MRCP revealed a single 0.8 cm stone in the fundus of the gallbladder yet no bile duct impaction, making biliary pancreatitis less likely. A week into her admission, a screening HIV test was found to be positive with a CD4 of 42 cells/McL.
With her hemodynamics steadily deteriorating likely secondary to respiratory distress secondary to Pneumocystis jiroveci, the pneumonia patient was started on TMP/SMX and systemic steroids, and MAC prophylaxis and Descovy were also initiated. However, despite these measures, the patient had a declining respiratory status. A chest X-ray showed diffuse pulmonary haziness, and a CT thorax revealed diffuse ground-glass opacities consistent with ARDS. The patient was hypoxemic on a nonrebreather mask, and her saturation continued to fall on high flow oxygen. A bronchoscopy was performed due to high suspicion of pneumocystis pneumonia (PCP). Bronchoalveolar lavage (BAL) cytology was negative for malignant cells as was PCP; however, aspergillus was cultured. During the hospital course, the patient began to desaturate to 70% on 70% FiO2 via Hi-Flow nasal cannula. Her PaO2/FiO2 ratio was <100 indicating severe ARDS, requiring intubation, and was subsequently transferred to MICU service. Chest X-ray obtained postintubation compared with earlier X-rays correlated with ARDS. MICU admission was complicated by melena prompting endoscopic workup. Esophagogastroduodenoscopy (EGD) revealed nodular ulcers in the esophagus, extensive gastric ulcers with exudates, and hemorrhage throughout the stomach with EGD biopsies revealing severe active chronic inflammation with epithelial cells with eosinophilic inclusions consistent with cytomegalovirus infection (Figures 2 and 3). Furthermore, serum CMV viral load was more than 2 million and Ganciclovir was initiated. Ophthalmology was consulted for possible CMV retinitis which was ruled out. Abdominal ultrasound revealed moderate ascites and cholecystitis.
Despite ARDS protocol initiation including paralytic initiation and prone positioning, the patient had refractory hypoxia. The patient was deemed too unstable for Extracorporeal Membrane Oxygenation (ECMO). Despite initiation of Continuous Renal Replacement Therapies (CRRT), her renal function and severe metabolic acidosis failed to improve. Despite the exhausted efforts of the MICU team, the patient became severely hypoxemic, bradycardic, and eventually passed away. Autopsy was declined by the family.
3. Discussion
CMV, a member of the Herpesviridae family, is a double-stranded DNA virus and replicates itself inside the host cell nucleus. It uses its host to package more infectious products and dense bodies which enumerate in quantity and eventually lyse the cell and spread throughout the host. CMV-infected cells have a textbook histological footprint, often presenting with “Owl-eyes” inclusions within the nucleus of the cell [3].
In immunocompetent patients, CMV is usually asymptomatic or can present with flu-like symptoms and possibly enlarged lymph nodes and/or spleen. For such patients, it is usually self-limiting and does not progress any further. Immunocompromised patients, however, are afflicted with a more severe and disseminating infection. The two biggest populations of immunosuppressed patients infected with CMV are transplant recipients and HIV/AIDs infected patients. It is known that CMV in HIV patients typically affects part or all of the GI tract, the most prominent being colitis, esophagitis, and gastritis. Our patient presented similarly with multiple imaging modalities confirming each of these. The EGD performed revealed multiple irregular ulcers in the esophagus and a vast blanket of exudative ulcers in the stomach that made the tissue friable and prone to bleeding [4, 5].
Pancreatitis is an atypical finding in CMV infection. However, reports reveal that it is known to afflict these groups of immunocompromised patients, including those on chronic steroid or immunosuppressive therapy and patients with systemic lupus erythematosus [5]. Our patient presented with diagnostic findings consistent with acute pancreatitis including abdominal pain, lipase three times the upper limit of normal within 3 days of symptom onset, and imaging (both CT abd/pelvis and abdominal ultrasound) findings consistent with acute pancreatitis. Further lab work during the patient's admission showed an elevated Anti-1-Antitrypsin level and an elevated amylase, also consistent with acute pancreatitis.
There are numerous causes of pancreatitis, the most common of which are alcohol (variable consumption period of 4-7 drinks per day) and gallstones. The patient denied any alcohol use and though the MRCP showed a single 0.8 cm gallstone in the fundus of the gallbladder; it also showed no stone impaction within the common bile duct, making the diagnosis of biliary pancreatitis less likely. Furthermore, certain medications have been known to cause pancreatitis including but not limited to amiodarone, enalapril, losartan, isoniazid, and sulfonylureas. Our patient endorsed no known medical history or regular medication [6].
Certain factors are identified that could have aided towards a stronger case of pancreatitis. Although the evidence strongly suggests CMV pancreatitis, a positive biopsy or autopsy would have provided a definitive diagnosis. Biopsy of the pancreas could not be performed due to the patient's critical status and the family of the patient declined autopsy, so confirmation could not be confirmed. The immune status of the patient was not discovered until later into the development and decline of the patient. Late into her admission, she revealed her history of rape by multiple different men (5 years ago) while attempting to cross into US border; she never revealed her rapists' identity or sought medical attention afterwards as she feared her undocumented status would be revealed. CMV was tested for much later on, and although valganciclovir therapy only slows down the progression of the disease, it was started only after CMV infection was confirmed. The monitoring of pancreatic enzyme levels regularly could have mapped out the status of the patient's pancreatitis and given a better picture of just what phase she was in based on the levels. The patient's family refusal for autopsy hindered the possibility of pancreatic biopsy to confirm infection of the pancreas with CMV.
4. Conclusion
Due to the prominence and its effect on more than half of the world's population, we encourage clinicians to further the study of CMV and the reach of its dissemination. Our case accurately portrayed the effect of CMV in an immunocompromised patient and revealed how devastating a common Herpesviridae virus can be to a host with a suppressed immune system. By encouraging this study, we hope to help clinicians recognize the commonalities within the pattern of symptoms and signs for both CMV infection and pancreatitis. This is one of only a few cases of CMV pancreatitis found in a literature review, and it is our goal that we can use this study to aid in the early diagnosis and treatment of disseminated CMV.
Acknowledgments
We thank the pulmonary critical care staff including the critical care nurses and respiratory therapy team who worked tirelessly to treat this patient until her last days. Thank you to the family of the patient for giving us this opportunity to learn from her disease.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 CT abdomen image obtained in Emergency Department indicating findings consistent with pancreatitis.
Figure 2 EGD image of body of stomach showing ulceration secondary to CMV.
Figure 3 EGD image of antrum of stomach showing ulceration secondary to CMV. | Not recovered | ReactionOutcome | CC BY | 33688440 | 19,030,299 | 2021 |
What was the outcome of reaction 'Renal impairment'? | CMV Pancreatitis in an Immunocompromised Patient.
Cytomegalovirus (CMV) is a common double-stranded DNA (dsDNA) virus affecting a large majority of the world's population. In immunocompetent patients, CMV infection can range anywhere from an asymptomatic course to mononucleosis. However, in the immunocompromised patient, prognosis can be deadly as CMV can disseminate to the retina, liver, lungs, heart, and GI tract. We present a case of CMV pancreatitis afflicting an immunocompromised patient. Case Summary. A 45-year-old Hispanic female with no past medical history presented to the emergency department (ED) for three days of abdominal pain associated with nausea, vomiting, and diarrhea. ED vitals showed a sepsis picture with fever, tachycardia, low white blood cell (WBC) count with bandemia, and CT scan showing acute pancreatitis, cholelithiasis, gastritis, and colitis. The patient denied alcohol use and MRCP showed no stone impaction. Sepsis protocolled was initiated for biliary pancreatitis, and the patient was admitted to the medicine floors with appropriate consulting services. Over the course of admission, the patient responded poorly to treatment and had a steady decline in respiratory status. She tested positive for HIV with a severely depressed CD4 count (42 cells/McL) and high viral load (1,492,761 copies/ml) and started on appropriate prophylactic antibiotics and HAART therapy. The patient was moved to the Medical Intensive Care Unit (MICU) after acute respiratory failure secondary to ARDS requiring mechanical ventilation with initiation of ARDS protocol. The patient was hemodynamically unstable and required vasopressor support. Hospital course was complicated by melena which prompted an esophagogastroduodenostomy (EGD) with biopsy yielding CMV gastritis. Serum CMV viral load was also found to be positive along with an elevated lipase level, indicative of pancreatitis. Despite initiation of ganciclovir, the patient continued to have refractory hypoxia despite full ventilatory support and proning. Unfortunately, the patient was deemed too unstable for transfer to an ECMO facility. She eventually succumbed to respiratory failure. Discussion. CMV is a Herpesviridae virus that is prevalent among more than half of the world's population. Its effects range from no presenting symptoms to respiratory failure depending on immune status. CMV more commonly affects the retina, lungs, liver, and GI tract; however, in rare cases, it is known to affect the pancreas as well. Other more common causes of pancreatitis were ruled out during the progression of this patient, and an elevated lipase with high CMV viral load points towards CMV pancreatitis.
This is one of only a few reported cases of CMV pancreatitis and warrants further study due to the massive prevalence of CMV in the entire world's population. Our case demonstrates the extent of dissemination of CMV in a severely immunocompromised patient by showing clear cut pancreatitis secondary to said viral infection with exclusion of other possible causes. Our hope is that clinicians will change their practice to include a more scrutinized study into causes of pancreatitis especially in their immunocompromised patients.
1. Introduction
Cytomegalovirus (CMV) is a common double-stranded DNA (dsDNA) virus found in approximately 59% of the population [1]. In the immunocompetent patient, it has a self-limiting course; however, in the immunocompromised patient, CMV infection can often have a grave prognosis [2]. CMV in immunocompromised patients is aggressive and can disseminate to multiple organs causing disease including but not limited to retinitis, hepatitis, esophagitis, colitis, and pneumonitis. The retina is the most common site for disseminated CMV to proliferate and cause inflammatory responses; however, CMV has the potential to spread to any organ [3, 4]. We present a rare case of CMV pancreatitis in a 45-year-old immunocompromised woman from El Salvador.
2. Case Presentation
A 45-year-old Hispanic female with no significant past medical history presented to the emergency department with three-day history of abdominal pain, nausea, vomiting, and diarrhea. Abdominal pain was described as a severe, burning sensation in the epigastrium radiating to her back, exacerbated by po intake and associated with fevers, nonbloody, nonbilious emesis, and enumerable episodes of nonbloody diarrhea. Vitals on admission were as follows: Temp 101.1F BP 104/67 mmHg P 101 RR 17 SpO2 98% on ambient air. On physical exam, the patient had tenderness to palpation over her right upper quadrant. Laboratory results revealed a WBC 5.32, low lymphocyte count (11%), bandemia (10%), ALT of 26 U/L, AST of 39 U/L, Alkaline Phosphatase of 90 U/L, and a lipase count 3 times the level of normal (153 U/L). A CT abdomen/Pelvis revealed acute pancreatitis, cholecystolithiasis, gastritis, colitis, and moderate ascites (Figure 1).
On the medicine floors, the patient was initially started on ciprofloxacin, metronidazole, and cefepime for acute biliary pancreatitis and colitis, and coverage was broadened to meropenem and amikacin for persistent fevers (101-102F), worsening leukocytosis and worsening clinical symptomatology of epigastric pain, diarrhea, nonbloody, nonbilious emesis, and dyspnea with exertion. Despite approximately 6 L fluid resuscitation with normal saline, the patient remained hypotensive. An MRCP revealed a single 0.8 cm stone in the fundus of the gallbladder yet no bile duct impaction, making biliary pancreatitis less likely. A week into her admission, a screening HIV test was found to be positive with a CD4 of 42 cells/McL.
With her hemodynamics steadily deteriorating likely secondary to respiratory distress secondary to Pneumocystis jiroveci, the pneumonia patient was started on TMP/SMX and systemic steroids, and MAC prophylaxis and Descovy were also initiated. However, despite these measures, the patient had a declining respiratory status. A chest X-ray showed diffuse pulmonary haziness, and a CT thorax revealed diffuse ground-glass opacities consistent with ARDS. The patient was hypoxemic on a nonrebreather mask, and her saturation continued to fall on high flow oxygen. A bronchoscopy was performed due to high suspicion of pneumocystis pneumonia (PCP). Bronchoalveolar lavage (BAL) cytology was negative for malignant cells as was PCP; however, aspergillus was cultured. During the hospital course, the patient began to desaturate to 70% on 70% FiO2 via Hi-Flow nasal cannula. Her PaO2/FiO2 ratio was <100 indicating severe ARDS, requiring intubation, and was subsequently transferred to MICU service. Chest X-ray obtained postintubation compared with earlier X-rays correlated with ARDS. MICU admission was complicated by melena prompting endoscopic workup. Esophagogastroduodenoscopy (EGD) revealed nodular ulcers in the esophagus, extensive gastric ulcers with exudates, and hemorrhage throughout the stomach with EGD biopsies revealing severe active chronic inflammation with epithelial cells with eosinophilic inclusions consistent with cytomegalovirus infection (Figures 2 and 3). Furthermore, serum CMV viral load was more than 2 million and Ganciclovir was initiated. Ophthalmology was consulted for possible CMV retinitis which was ruled out. Abdominal ultrasound revealed moderate ascites and cholecystitis.
Despite ARDS protocol initiation including paralytic initiation and prone positioning, the patient had refractory hypoxia. The patient was deemed too unstable for Extracorporeal Membrane Oxygenation (ECMO). Despite initiation of Continuous Renal Replacement Therapies (CRRT), her renal function and severe metabolic acidosis failed to improve. Despite the exhausted efforts of the MICU team, the patient became severely hypoxemic, bradycardic, and eventually passed away. Autopsy was declined by the family.
3. Discussion
CMV, a member of the Herpesviridae family, is a double-stranded DNA virus and replicates itself inside the host cell nucleus. It uses its host to package more infectious products and dense bodies which enumerate in quantity and eventually lyse the cell and spread throughout the host. CMV-infected cells have a textbook histological footprint, often presenting with “Owl-eyes” inclusions within the nucleus of the cell [3].
In immunocompetent patients, CMV is usually asymptomatic or can present with flu-like symptoms and possibly enlarged lymph nodes and/or spleen. For such patients, it is usually self-limiting and does not progress any further. Immunocompromised patients, however, are afflicted with a more severe and disseminating infection. The two biggest populations of immunosuppressed patients infected with CMV are transplant recipients and HIV/AIDs infected patients. It is known that CMV in HIV patients typically affects part or all of the GI tract, the most prominent being colitis, esophagitis, and gastritis. Our patient presented similarly with multiple imaging modalities confirming each of these. The EGD performed revealed multiple irregular ulcers in the esophagus and a vast blanket of exudative ulcers in the stomach that made the tissue friable and prone to bleeding [4, 5].
Pancreatitis is an atypical finding in CMV infection. However, reports reveal that it is known to afflict these groups of immunocompromised patients, including those on chronic steroid or immunosuppressive therapy and patients with systemic lupus erythematosus [5]. Our patient presented with diagnostic findings consistent with acute pancreatitis including abdominal pain, lipase three times the upper limit of normal within 3 days of symptom onset, and imaging (both CT abd/pelvis and abdominal ultrasound) findings consistent with acute pancreatitis. Further lab work during the patient's admission showed an elevated Anti-1-Antitrypsin level and an elevated amylase, also consistent with acute pancreatitis.
There are numerous causes of pancreatitis, the most common of which are alcohol (variable consumption period of 4-7 drinks per day) and gallstones. The patient denied any alcohol use and though the MRCP showed a single 0.8 cm gallstone in the fundus of the gallbladder; it also showed no stone impaction within the common bile duct, making the diagnosis of biliary pancreatitis less likely. Furthermore, certain medications have been known to cause pancreatitis including but not limited to amiodarone, enalapril, losartan, isoniazid, and sulfonylureas. Our patient endorsed no known medical history or regular medication [6].
Certain factors are identified that could have aided towards a stronger case of pancreatitis. Although the evidence strongly suggests CMV pancreatitis, a positive biopsy or autopsy would have provided a definitive diagnosis. Biopsy of the pancreas could not be performed due to the patient's critical status and the family of the patient declined autopsy, so confirmation could not be confirmed. The immune status of the patient was not discovered until later into the development and decline of the patient. Late into her admission, she revealed her history of rape by multiple different men (5 years ago) while attempting to cross into US border; she never revealed her rapists' identity or sought medical attention afterwards as she feared her undocumented status would be revealed. CMV was tested for much later on, and although valganciclovir therapy only slows down the progression of the disease, it was started only after CMV infection was confirmed. The monitoring of pancreatic enzyme levels regularly could have mapped out the status of the patient's pancreatitis and given a better picture of just what phase she was in based on the levels. The patient's family refusal for autopsy hindered the possibility of pancreatic biopsy to confirm infection of the pancreas with CMV.
4. Conclusion
Due to the prominence and its effect on more than half of the world's population, we encourage clinicians to further the study of CMV and the reach of its dissemination. Our case accurately portrayed the effect of CMV in an immunocompromised patient and revealed how devastating a common Herpesviridae virus can be to a host with a suppressed immune system. By encouraging this study, we hope to help clinicians recognize the commonalities within the pattern of symptoms and signs for both CMV infection and pancreatitis. This is one of only a few cases of CMV pancreatitis found in a literature review, and it is our goal that we can use this study to aid in the early diagnosis and treatment of disseminated CMV.
Acknowledgments
We thank the pulmonary critical care staff including the critical care nurses and respiratory therapy team who worked tirelessly to treat this patient until her last days. Thank you to the family of the patient for giving us this opportunity to learn from her disease.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 CT abdomen image obtained in Emergency Department indicating findings consistent with pancreatitis.
Figure 2 EGD image of body of stomach showing ulceration secondary to CMV.
Figure 3 EGD image of antrum of stomach showing ulceration secondary to CMV. | Not recovered | ReactionOutcome | CC BY | 33688440 | 19,030,299 | 2021 |
What was the administration route of drug 'DEXMEDETOMIDINE HYDROCHLORIDE'? | Dexmedetomidine Induced Polyuria in the Intensive Care Unit.
Dexmedetomidine is an α2-adrenergic used as an adjunct therapy for sedation in the intensive care unit. While it is known to cause polyuria exclusively in perioperative conditions, not many cases are known in the intensive care unit, thus making the diagnosis challenging. We present the case of a 61-year-old male who had developed polyuria secondary to central diabetes insipidus after receiving dexmedetomidine intravenous infusion in the medical ICU. Increased awareness of this uncommon side effect of dexmedetomidine will help clinicians recognize and address it early.
1. Introduction
The use of dexmedetomidine is a common practice in the medical intensive care units (ICU) to minimize delirium and to serve as an adjunctive sedative therapy in intubated patients. Morelli et al. demonstrated that dexmedetomidine is associated with decreased norepinephrine requirements in septic shock patients as compared with propofol [1]. While hypotension and bradycardia [2] are known side effects, the occurrence of central diabetes insipidus (DI) due to dexmedetomidine is a rare phenomenon and not well documented in literature [3, 4]. Rapid onset of dehydration due to fluid loss and electrolyte imbalance may further worsen hypotension and cause complications in already critically ill patients. There is a need for widespread awareness of this rare but potentially serious side effect of dexmedetomidine among critical care physicians, so that this is included in the differential diagnosis early on in cases of polyuria among critically ill patients. We report a case of polyuria in a complex critically ill patient where dexmedetomidine was not initially suspected as a causative agent.
2. Case Report
A 61-year-old male with a past medical history of advanced stage COPD, heart failure with reduced ejection fraction, was admitted to the medical ICU with acute on chronic hypercapnic respiratory failure secondary to exacerbation of his chronic obstructive pulmonary disease requiring ventilatory support. He was treated with steroids and azithromycin. His kidney function stayed stable with average urine output of around 2 liters per 24 hours for the first 7 days of hospitalization. On the eighth day of hospitalization, he developed abrupt onset polyuria with an increase in urine output from 70-80 cc/hr. to 200-225 cc/hr., totaling approximately 5.4 L over the next 24 hr. Urine osmolality was 193 mOsm/kg H2O, while his random urine sodium also increased from 23 to 179 mmol per liter urine.
The cause was not immediately apparent. His medications included aspirin, albuterol, isosorbide mononitrate, amiodarone, lisinopril, and metoprolol. CT scan of the head was negative for any intracranial processes ruling out a pituitary lesion as the cause of central DI. The patient was not on any medication known to cause nephrogenic DI and serum electrolytes were within normal limits. The patient was euvolemic and had normal serum glucose, BUN, and other organic acid levels ruling out osmotic diuresis as the cause of polyuria. Renal ultrasound was negative for any obstruction. Pertinent labs included BUN 16 mg/dL, creatinine 0.65 mg/dL, glucose 130 mg/dL, sodium 134 mmol/L, potassium 3.6 mmol/L, and calcium 8.8 mg/dL. Urine electrolytes were sodium 179 mmol/L, potassium 14 mmol/L, chloride 25 mmol/L, creatinine 37 mg/dL, and lithium level <0.1 mmol/L.
A thorough chart review identified that the patient had received dexmedetomidine due to worsening delirium at a rate of 0.2 mcg/kg/hr for a brief period, immediately before the abrupt onset of polyuria. No other instigating cause was identified; we suspected central DI secondary to dexmedetomidine. A DDAVP stimulation test was planned as a therapeutic challenge for central DI, but 48 hours after the cessation of dexmedetomidine, the urine output spontaneously decreased to 50-100 cc/hr and urine osmolality increased to 306 mOsm/kgH2O so the test was not done. His serum osmolality also normalized after that. The patient was not rechallenged with dexmedetomidine. At no time did the patient develop hypernatremia due to strict replacement of carefully calculated water losses.
In the light of extensive negative workup and temporal relationship of polyuria with dexmedetomidine infusion and resolution of the polyuria with drug abstinence, we concluded that the polyuria was secondary to transient central Diabetes Insipidus secondary to dexmedetomidine infusion. The Naranjo Score for dexmedetomidine induced polyuria for this patient was 8, thereby putting the medication in the probable likelihood of causing the adverse reaction of polyuria [5].
3. Discussion
Polyuria is defined as a urinary output of greater than 3 L/day, the causes of which can be divided into solute (osmotic) and water diuresis. Solute diuresis most commonly occurs secondary to glycosuria, whereas water diuresis occurs either due to a defect in antidiuretic hormone (ADH) production or due to decreased renal responsiveness to ADH.
In this case, a thorough review was negative for osmotic diuresis secondary to hyperglycemia, azotemia, or intravenous volume expansion. There was no evidence of neuroendocrine disorders such as head trauma as evidenced by the CT scan, acute renal pathologies such as obstruction, or recovery from acute kidney injury or the use of diuretics that could trigger polyuria. The low urine osmolality could not be attributed to hypokalemia, hypercalcemia, or lithium use that is associated with nephrogenic diabetes insipidus.
To our knowledge, only one other case in a medical intensive care unit has been published in abstract form [3]. Polyuria associated with dexmedetomidine, a highly selective α2-adrenoceptor agonist that works on the locus coeruleus, has been reported in case report form, almost exclusively in perioperative conditions [6–8]. Lesions of the locus coeruleus have been associated with decreased secretion of ADH [8, 9] thereby resulting in transient central diabetes insipidus. Early work by Sawchenko and Swanson [10] and others [11] demonstrated noradrenergic pathways from the locus coeruleus to the paraventricular and supraoptic nuclei (Figure 1). These pathways have been shown to modulate ADH release from the posterior pituitary into the peripheral circulation particularly under conditions of physiologic stress [12].
Previously reported cases occurred primarily in the operative setting under anesthesia. They also showed a rapid resolution of polyuria once dexmedetomidine was withheld [6, 7]. Our case is unique in that it occurred within the medical ICU setting and that the effect persisted for 48 hr after stopping dexmedetomidine. The half-life of dexmedetomidine is only 3.7 hr; however, its metabolite has a half-life of 9.7 hr [2]. At least two possibilities present themselves. Either the concurrent administration of drugs metabolized via several CYP450 enzymes prolonged the half-life or the H-3 metabolite or another breakdown product may have an impact on ADH secretion manifesting as polyuria. Our case is distinct in that it highlights that even without a loading dose and a relatively low dose infusion (0.2 mcg/kg/hr) of dexmedetomidine with short duration had induced polyuria that persisted well beyond the time limit in the previously reported cases, suggesting that the side effects are likely to be dose independent.
4. Conclusion
Increased awareness of this uncommon but significant side effect of dexmedetomidine will promote providers to include it in the differential diagnoses when assessing for polyuria in the intensive care unit while, at the same time, promoting careful monitoring of concurrent medications, underlying liver disease, and urine output, particularly in susceptible patients.
Data Availability
None.
Conflicts of Interest
There are no conflicts of interest.
Figure 1 Neural pathways involved in dexmedetomidine-induced central diabetes insipidus. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33688441 | 19,190,517 | 2021 |
What was the administration route of drug 'DEXMEDETOMIDINE'? | Dexmedetomidine Induced Polyuria in the Intensive Care Unit.
Dexmedetomidine is an α2-adrenergic used as an adjunct therapy for sedation in the intensive care unit. While it is known to cause polyuria exclusively in perioperative conditions, not many cases are known in the intensive care unit, thus making the diagnosis challenging. We present the case of a 61-year-old male who had developed polyuria secondary to central diabetes insipidus after receiving dexmedetomidine intravenous infusion in the medical ICU. Increased awareness of this uncommon side effect of dexmedetomidine will help clinicians recognize and address it early.
1. Introduction
The use of dexmedetomidine is a common practice in the medical intensive care units (ICU) to minimize delirium and to serve as an adjunctive sedative therapy in intubated patients. Morelli et al. demonstrated that dexmedetomidine is associated with decreased norepinephrine requirements in septic shock patients as compared with propofol [1]. While hypotension and bradycardia [2] are known side effects, the occurrence of central diabetes insipidus (DI) due to dexmedetomidine is a rare phenomenon and not well documented in literature [3, 4]. Rapid onset of dehydration due to fluid loss and electrolyte imbalance may further worsen hypotension and cause complications in already critically ill patients. There is a need for widespread awareness of this rare but potentially serious side effect of dexmedetomidine among critical care physicians, so that this is included in the differential diagnosis early on in cases of polyuria among critically ill patients. We report a case of polyuria in a complex critically ill patient where dexmedetomidine was not initially suspected as a causative agent.
2. Case Report
A 61-year-old male with a past medical history of advanced stage COPD, heart failure with reduced ejection fraction, was admitted to the medical ICU with acute on chronic hypercapnic respiratory failure secondary to exacerbation of his chronic obstructive pulmonary disease requiring ventilatory support. He was treated with steroids and azithromycin. His kidney function stayed stable with average urine output of around 2 liters per 24 hours for the first 7 days of hospitalization. On the eighth day of hospitalization, he developed abrupt onset polyuria with an increase in urine output from 70-80 cc/hr. to 200-225 cc/hr., totaling approximately 5.4 L over the next 24 hr. Urine osmolality was 193 mOsm/kg H2O, while his random urine sodium also increased from 23 to 179 mmol per liter urine.
The cause was not immediately apparent. His medications included aspirin, albuterol, isosorbide mononitrate, amiodarone, lisinopril, and metoprolol. CT scan of the head was negative for any intracranial processes ruling out a pituitary lesion as the cause of central DI. The patient was not on any medication known to cause nephrogenic DI and serum electrolytes were within normal limits. The patient was euvolemic and had normal serum glucose, BUN, and other organic acid levels ruling out osmotic diuresis as the cause of polyuria. Renal ultrasound was negative for any obstruction. Pertinent labs included BUN 16 mg/dL, creatinine 0.65 mg/dL, glucose 130 mg/dL, sodium 134 mmol/L, potassium 3.6 mmol/L, and calcium 8.8 mg/dL. Urine electrolytes were sodium 179 mmol/L, potassium 14 mmol/L, chloride 25 mmol/L, creatinine 37 mg/dL, and lithium level <0.1 mmol/L.
A thorough chart review identified that the patient had received dexmedetomidine due to worsening delirium at a rate of 0.2 mcg/kg/hr for a brief period, immediately before the abrupt onset of polyuria. No other instigating cause was identified; we suspected central DI secondary to dexmedetomidine. A DDAVP stimulation test was planned as a therapeutic challenge for central DI, but 48 hours after the cessation of dexmedetomidine, the urine output spontaneously decreased to 50-100 cc/hr and urine osmolality increased to 306 mOsm/kgH2O so the test was not done. His serum osmolality also normalized after that. The patient was not rechallenged with dexmedetomidine. At no time did the patient develop hypernatremia due to strict replacement of carefully calculated water losses.
In the light of extensive negative workup and temporal relationship of polyuria with dexmedetomidine infusion and resolution of the polyuria with drug abstinence, we concluded that the polyuria was secondary to transient central Diabetes Insipidus secondary to dexmedetomidine infusion. The Naranjo Score for dexmedetomidine induced polyuria for this patient was 8, thereby putting the medication in the probable likelihood of causing the adverse reaction of polyuria [5].
3. Discussion
Polyuria is defined as a urinary output of greater than 3 L/day, the causes of which can be divided into solute (osmotic) and water diuresis. Solute diuresis most commonly occurs secondary to glycosuria, whereas water diuresis occurs either due to a defect in antidiuretic hormone (ADH) production or due to decreased renal responsiveness to ADH.
In this case, a thorough review was negative for osmotic diuresis secondary to hyperglycemia, azotemia, or intravenous volume expansion. There was no evidence of neuroendocrine disorders such as head trauma as evidenced by the CT scan, acute renal pathologies such as obstruction, or recovery from acute kidney injury or the use of diuretics that could trigger polyuria. The low urine osmolality could not be attributed to hypokalemia, hypercalcemia, or lithium use that is associated with nephrogenic diabetes insipidus.
To our knowledge, only one other case in a medical intensive care unit has been published in abstract form [3]. Polyuria associated with dexmedetomidine, a highly selective α2-adrenoceptor agonist that works on the locus coeruleus, has been reported in case report form, almost exclusively in perioperative conditions [6–8]. Lesions of the locus coeruleus have been associated with decreased secretion of ADH [8, 9] thereby resulting in transient central diabetes insipidus. Early work by Sawchenko and Swanson [10] and others [11] demonstrated noradrenergic pathways from the locus coeruleus to the paraventricular and supraoptic nuclei (Figure 1). These pathways have been shown to modulate ADH release from the posterior pituitary into the peripheral circulation particularly under conditions of physiologic stress [12].
Previously reported cases occurred primarily in the operative setting under anesthesia. They also showed a rapid resolution of polyuria once dexmedetomidine was withheld [6, 7]. Our case is unique in that it occurred within the medical ICU setting and that the effect persisted for 48 hr after stopping dexmedetomidine. The half-life of dexmedetomidine is only 3.7 hr; however, its metabolite has a half-life of 9.7 hr [2]. At least two possibilities present themselves. Either the concurrent administration of drugs metabolized via several CYP450 enzymes prolonged the half-life or the H-3 metabolite or another breakdown product may have an impact on ADH secretion manifesting as polyuria. Our case is distinct in that it highlights that even without a loading dose and a relatively low dose infusion (0.2 mcg/kg/hr) of dexmedetomidine with short duration had induced polyuria that persisted well beyond the time limit in the previously reported cases, suggesting that the side effects are likely to be dose independent.
4. Conclusion
Increased awareness of this uncommon but significant side effect of dexmedetomidine will promote providers to include it in the differential diagnoses when assessing for polyuria in the intensive care unit while, at the same time, promoting careful monitoring of concurrent medications, underlying liver disease, and urine output, particularly in susceptible patients.
Data Availability
None.
Conflicts of Interest
There are no conflicts of interest.
Figure 1 Neural pathways involved in dexmedetomidine-induced central diabetes insipidus. | Intravenous drip | DrugAdministrationRoute | CC BY | 33688441 | 19,218,312 | 2021 |
What was the outcome of reaction 'Off label use'? | Dexmedetomidine Induced Polyuria in the Intensive Care Unit.
Dexmedetomidine is an α2-adrenergic used as an adjunct therapy for sedation in the intensive care unit. While it is known to cause polyuria exclusively in perioperative conditions, not many cases are known in the intensive care unit, thus making the diagnosis challenging. We present the case of a 61-year-old male who had developed polyuria secondary to central diabetes insipidus after receiving dexmedetomidine intravenous infusion in the medical ICU. Increased awareness of this uncommon side effect of dexmedetomidine will help clinicians recognize and address it early.
1. Introduction
The use of dexmedetomidine is a common practice in the medical intensive care units (ICU) to minimize delirium and to serve as an adjunctive sedative therapy in intubated patients. Morelli et al. demonstrated that dexmedetomidine is associated with decreased norepinephrine requirements in septic shock patients as compared with propofol [1]. While hypotension and bradycardia [2] are known side effects, the occurrence of central diabetes insipidus (DI) due to dexmedetomidine is a rare phenomenon and not well documented in literature [3, 4]. Rapid onset of dehydration due to fluid loss and electrolyte imbalance may further worsen hypotension and cause complications in already critically ill patients. There is a need for widespread awareness of this rare but potentially serious side effect of dexmedetomidine among critical care physicians, so that this is included in the differential diagnosis early on in cases of polyuria among critically ill patients. We report a case of polyuria in a complex critically ill patient where dexmedetomidine was not initially suspected as a causative agent.
2. Case Report
A 61-year-old male with a past medical history of advanced stage COPD, heart failure with reduced ejection fraction, was admitted to the medical ICU with acute on chronic hypercapnic respiratory failure secondary to exacerbation of his chronic obstructive pulmonary disease requiring ventilatory support. He was treated with steroids and azithromycin. His kidney function stayed stable with average urine output of around 2 liters per 24 hours for the first 7 days of hospitalization. On the eighth day of hospitalization, he developed abrupt onset polyuria with an increase in urine output from 70-80 cc/hr. to 200-225 cc/hr., totaling approximately 5.4 L over the next 24 hr. Urine osmolality was 193 mOsm/kg H2O, while his random urine sodium also increased from 23 to 179 mmol per liter urine.
The cause was not immediately apparent. His medications included aspirin, albuterol, isosorbide mononitrate, amiodarone, lisinopril, and metoprolol. CT scan of the head was negative for any intracranial processes ruling out a pituitary lesion as the cause of central DI. The patient was not on any medication known to cause nephrogenic DI and serum electrolytes were within normal limits. The patient was euvolemic and had normal serum glucose, BUN, and other organic acid levels ruling out osmotic diuresis as the cause of polyuria. Renal ultrasound was negative for any obstruction. Pertinent labs included BUN 16 mg/dL, creatinine 0.65 mg/dL, glucose 130 mg/dL, sodium 134 mmol/L, potassium 3.6 mmol/L, and calcium 8.8 mg/dL. Urine electrolytes were sodium 179 mmol/L, potassium 14 mmol/L, chloride 25 mmol/L, creatinine 37 mg/dL, and lithium level <0.1 mmol/L.
A thorough chart review identified that the patient had received dexmedetomidine due to worsening delirium at a rate of 0.2 mcg/kg/hr for a brief period, immediately before the abrupt onset of polyuria. No other instigating cause was identified; we suspected central DI secondary to dexmedetomidine. A DDAVP stimulation test was planned as a therapeutic challenge for central DI, but 48 hours after the cessation of dexmedetomidine, the urine output spontaneously decreased to 50-100 cc/hr and urine osmolality increased to 306 mOsm/kgH2O so the test was not done. His serum osmolality also normalized after that. The patient was not rechallenged with dexmedetomidine. At no time did the patient develop hypernatremia due to strict replacement of carefully calculated water losses.
In the light of extensive negative workup and temporal relationship of polyuria with dexmedetomidine infusion and resolution of the polyuria with drug abstinence, we concluded that the polyuria was secondary to transient central Diabetes Insipidus secondary to dexmedetomidine infusion. The Naranjo Score for dexmedetomidine induced polyuria for this patient was 8, thereby putting the medication in the probable likelihood of causing the adverse reaction of polyuria [5].
3. Discussion
Polyuria is defined as a urinary output of greater than 3 L/day, the causes of which can be divided into solute (osmotic) and water diuresis. Solute diuresis most commonly occurs secondary to glycosuria, whereas water diuresis occurs either due to a defect in antidiuretic hormone (ADH) production or due to decreased renal responsiveness to ADH.
In this case, a thorough review was negative for osmotic diuresis secondary to hyperglycemia, azotemia, or intravenous volume expansion. There was no evidence of neuroendocrine disorders such as head trauma as evidenced by the CT scan, acute renal pathologies such as obstruction, or recovery from acute kidney injury or the use of diuretics that could trigger polyuria. The low urine osmolality could not be attributed to hypokalemia, hypercalcemia, or lithium use that is associated with nephrogenic diabetes insipidus.
To our knowledge, only one other case in a medical intensive care unit has been published in abstract form [3]. Polyuria associated with dexmedetomidine, a highly selective α2-adrenoceptor agonist that works on the locus coeruleus, has been reported in case report form, almost exclusively in perioperative conditions [6–8]. Lesions of the locus coeruleus have been associated with decreased secretion of ADH [8, 9] thereby resulting in transient central diabetes insipidus. Early work by Sawchenko and Swanson [10] and others [11] demonstrated noradrenergic pathways from the locus coeruleus to the paraventricular and supraoptic nuclei (Figure 1). These pathways have been shown to modulate ADH release from the posterior pituitary into the peripheral circulation particularly under conditions of physiologic stress [12].
Previously reported cases occurred primarily in the operative setting under anesthesia. They also showed a rapid resolution of polyuria once dexmedetomidine was withheld [6, 7]. Our case is unique in that it occurred within the medical ICU setting and that the effect persisted for 48 hr after stopping dexmedetomidine. The half-life of dexmedetomidine is only 3.7 hr; however, its metabolite has a half-life of 9.7 hr [2]. At least two possibilities present themselves. Either the concurrent administration of drugs metabolized via several CYP450 enzymes prolonged the half-life or the H-3 metabolite or another breakdown product may have an impact on ADH secretion manifesting as polyuria. Our case is distinct in that it highlights that even without a loading dose and a relatively low dose infusion (0.2 mcg/kg/hr) of dexmedetomidine with short duration had induced polyuria that persisted well beyond the time limit in the previously reported cases, suggesting that the side effects are likely to be dose independent.
4. Conclusion
Increased awareness of this uncommon but significant side effect of dexmedetomidine will promote providers to include it in the differential diagnoses when assessing for polyuria in the intensive care unit while, at the same time, promoting careful monitoring of concurrent medications, underlying liver disease, and urine output, particularly in susceptible patients.
Data Availability
None.
Conflicts of Interest
There are no conflicts of interest.
Figure 1 Neural pathways involved in dexmedetomidine-induced central diabetes insipidus. | Recovered | ReactionOutcome | CC BY | 33688441 | 19,190,517 | 2021 |
What was the outcome of reaction 'Polyuria'? | Dexmedetomidine Induced Polyuria in the Intensive Care Unit.
Dexmedetomidine is an α2-adrenergic used as an adjunct therapy for sedation in the intensive care unit. While it is known to cause polyuria exclusively in perioperative conditions, not many cases are known in the intensive care unit, thus making the diagnosis challenging. We present the case of a 61-year-old male who had developed polyuria secondary to central diabetes insipidus after receiving dexmedetomidine intravenous infusion in the medical ICU. Increased awareness of this uncommon side effect of dexmedetomidine will help clinicians recognize and address it early.
1. Introduction
The use of dexmedetomidine is a common practice in the medical intensive care units (ICU) to minimize delirium and to serve as an adjunctive sedative therapy in intubated patients. Morelli et al. demonstrated that dexmedetomidine is associated with decreased norepinephrine requirements in septic shock patients as compared with propofol [1]. While hypotension and bradycardia [2] are known side effects, the occurrence of central diabetes insipidus (DI) due to dexmedetomidine is a rare phenomenon and not well documented in literature [3, 4]. Rapid onset of dehydration due to fluid loss and electrolyte imbalance may further worsen hypotension and cause complications in already critically ill patients. There is a need for widespread awareness of this rare but potentially serious side effect of dexmedetomidine among critical care physicians, so that this is included in the differential diagnosis early on in cases of polyuria among critically ill patients. We report a case of polyuria in a complex critically ill patient where dexmedetomidine was not initially suspected as a causative agent.
2. Case Report
A 61-year-old male with a past medical history of advanced stage COPD, heart failure with reduced ejection fraction, was admitted to the medical ICU with acute on chronic hypercapnic respiratory failure secondary to exacerbation of his chronic obstructive pulmonary disease requiring ventilatory support. He was treated with steroids and azithromycin. His kidney function stayed stable with average urine output of around 2 liters per 24 hours for the first 7 days of hospitalization. On the eighth day of hospitalization, he developed abrupt onset polyuria with an increase in urine output from 70-80 cc/hr. to 200-225 cc/hr., totaling approximately 5.4 L over the next 24 hr. Urine osmolality was 193 mOsm/kg H2O, while his random urine sodium also increased from 23 to 179 mmol per liter urine.
The cause was not immediately apparent. His medications included aspirin, albuterol, isosorbide mononitrate, amiodarone, lisinopril, and metoprolol. CT scan of the head was negative for any intracranial processes ruling out a pituitary lesion as the cause of central DI. The patient was not on any medication known to cause nephrogenic DI and serum electrolytes were within normal limits. The patient was euvolemic and had normal serum glucose, BUN, and other organic acid levels ruling out osmotic diuresis as the cause of polyuria. Renal ultrasound was negative for any obstruction. Pertinent labs included BUN 16 mg/dL, creatinine 0.65 mg/dL, glucose 130 mg/dL, sodium 134 mmol/L, potassium 3.6 mmol/L, and calcium 8.8 mg/dL. Urine electrolytes were sodium 179 mmol/L, potassium 14 mmol/L, chloride 25 mmol/L, creatinine 37 mg/dL, and lithium level <0.1 mmol/L.
A thorough chart review identified that the patient had received dexmedetomidine due to worsening delirium at a rate of 0.2 mcg/kg/hr for a brief period, immediately before the abrupt onset of polyuria. No other instigating cause was identified; we suspected central DI secondary to dexmedetomidine. A DDAVP stimulation test was planned as a therapeutic challenge for central DI, but 48 hours after the cessation of dexmedetomidine, the urine output spontaneously decreased to 50-100 cc/hr and urine osmolality increased to 306 mOsm/kgH2O so the test was not done. His serum osmolality also normalized after that. The patient was not rechallenged with dexmedetomidine. At no time did the patient develop hypernatremia due to strict replacement of carefully calculated water losses.
In the light of extensive negative workup and temporal relationship of polyuria with dexmedetomidine infusion and resolution of the polyuria with drug abstinence, we concluded that the polyuria was secondary to transient central Diabetes Insipidus secondary to dexmedetomidine infusion. The Naranjo Score for dexmedetomidine induced polyuria for this patient was 8, thereby putting the medication in the probable likelihood of causing the adverse reaction of polyuria [5].
3. Discussion
Polyuria is defined as a urinary output of greater than 3 L/day, the causes of which can be divided into solute (osmotic) and water diuresis. Solute diuresis most commonly occurs secondary to glycosuria, whereas water diuresis occurs either due to a defect in antidiuretic hormone (ADH) production or due to decreased renal responsiveness to ADH.
In this case, a thorough review was negative for osmotic diuresis secondary to hyperglycemia, azotemia, or intravenous volume expansion. There was no evidence of neuroendocrine disorders such as head trauma as evidenced by the CT scan, acute renal pathologies such as obstruction, or recovery from acute kidney injury or the use of diuretics that could trigger polyuria. The low urine osmolality could not be attributed to hypokalemia, hypercalcemia, or lithium use that is associated with nephrogenic diabetes insipidus.
To our knowledge, only one other case in a medical intensive care unit has been published in abstract form [3]. Polyuria associated with dexmedetomidine, a highly selective α2-adrenoceptor agonist that works on the locus coeruleus, has been reported in case report form, almost exclusively in perioperative conditions [6–8]. Lesions of the locus coeruleus have been associated with decreased secretion of ADH [8, 9] thereby resulting in transient central diabetes insipidus. Early work by Sawchenko and Swanson [10] and others [11] demonstrated noradrenergic pathways from the locus coeruleus to the paraventricular and supraoptic nuclei (Figure 1). These pathways have been shown to modulate ADH release from the posterior pituitary into the peripheral circulation particularly under conditions of physiologic stress [12].
Previously reported cases occurred primarily in the operative setting under anesthesia. They also showed a rapid resolution of polyuria once dexmedetomidine was withheld [6, 7]. Our case is unique in that it occurred within the medical ICU setting and that the effect persisted for 48 hr after stopping dexmedetomidine. The half-life of dexmedetomidine is only 3.7 hr; however, its metabolite has a half-life of 9.7 hr [2]. At least two possibilities present themselves. Either the concurrent administration of drugs metabolized via several CYP450 enzymes prolonged the half-life or the H-3 metabolite or another breakdown product may have an impact on ADH secretion manifesting as polyuria. Our case is distinct in that it highlights that even without a loading dose and a relatively low dose infusion (0.2 mcg/kg/hr) of dexmedetomidine with short duration had induced polyuria that persisted well beyond the time limit in the previously reported cases, suggesting that the side effects are likely to be dose independent.
4. Conclusion
Increased awareness of this uncommon but significant side effect of dexmedetomidine will promote providers to include it in the differential diagnoses when assessing for polyuria in the intensive care unit while, at the same time, promoting careful monitoring of concurrent medications, underlying liver disease, and urine output, particularly in susceptible patients.
Data Availability
None.
Conflicts of Interest
There are no conflicts of interest.
Figure 1 Neural pathways involved in dexmedetomidine-induced central diabetes insipidus. | Recovered | ReactionOutcome | CC BY | 33688441 | 19,168,544 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute kidney injury'. | Considerations of HLA, Renal Failure, Valproic Acid Use, and Current Treatment Guidelines in Clozapine-Induced Agranulocytosis.
Clozapine, the choice atypical antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder, has been shown to reduce positive and negative symptoms of schizophrenia. Clozapine, though beneficial in reducing the need for hospitalization, rehabilitation, and health care costs, is known as a drug of last resort due to its potential adverse event of clozapine-induced agranulocytosis, which holds a case fatality rate between 4.2 and 16%. Herein, we describe a female patient with longstanding schizoaffective disorder and chronic kidney disease who suffered from clozapine-induced agranulocytosis after failing two other atypical antipsychotics. Retrospective considerations of this case and management highlight risk factors such as HLA status, renal failure, and concurrent valproic acid use which presently do not have official screening, guidelines, or restrictions in place when prescribing clozapine. Additionally, there are no specific clozapine-induced agranulocytosis management recommendations such as G-CSF/filgrastim dose, timing of bone marrow aspirate and biopsy, and use of concomitant valproate. We propose that further comprehensive official screening, monitoring, and guidelines in the prescribing of clozapine, and further guidelines in the treatment of clozapine induced agranulocytosis, could increase the cost-effectiveness of clozapine treatment, and decrease the incidence, and morbidity of this feared adverse event.
1. Introduction
Clozapine, a dibenzodiazepine antipsychotic exhibiting weak dopaminergic activity and atypical pharmacological properties, is the choice antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder [1–4]. Advantages of clozapine include decreased positive symptoms of schizophrenia such as voices and hallucinations and decreased negative symptoms such as blunted affect and suicidal behavior [5]. The decreased positive and negative symptoms result in reduced need for hospitalization, rehabilitation, and subsequent health care costs [6]. However, known and feared disadvantages include neutropenia and life-threatening agranulocytosis [7, 8].
A benign form of neutropenia with an absolute neutrophil count (ANC) < 1500 cells/μL [9] is known to occur more frequently than clinically significant, agranulocytosis, where ANC < 500 cells/μL [10]. A high risk of severe and/or opportunistic infections is noted to be associated with ANC <200 [9]. In 2008, clozapine-induced agranulocytosis (CIA) had a known rate of seven cases per one million [11]. In 2006, the case fatality caused by CIA was estimated to be 4.2% to 16% [12]. In 2016, the observed mortality rate ranged from 0.1 and 0.3 per thousand, and the case fatality rate was estimated to be between 2.2 and 4.2 [13]. Standard established protocol includes immediate discontinuation of clozapine should white blood cell count reach <500 ANC [10, 14]. Patients' WBC and ANC must be monitored daily until WBC > 3000/mm3 and ANC > 1500/mm3 [7].
As more cases of CIA are occurring, more information concerning prescribing this efficacious antipsychotic as well as the treatment of CIA has become available. Here, we describe a patient with longstanding schizoaffective disorder who suffered from CIA after being transitioned to clozapine due to failed trials of risperidone and olanzapine. Retrospective considerations of her placement on clozapine and subsequent management of her CIA brought into question many factors which do not have clear guidelines, including official screening of risk factors which increase likelihood of CIA, as well as clear clinical management for this feared adverse event. This case report provides a spotlight on many factors such as screening for chronic kidney disease (CKD), human leukocyte antigen(HLA) typing, concurrent valproate administration due to potential CYP interactions, and management considerations such as dosing for filgrastim/G-CSF and timing of bone marrow biopsy. This analysis aims for further study and ultimately future implementation of screening and management guidelines for better informed management of refractory schizophrenia treatment, reduced cases of CIA, and improved management of CIA should it occur.
2. Case Presentation
A 60-year-old Caucasian female nursing home resident was brought in by EMS to the ED due to disorganized behavior, auditory hallucinations, and disorganized speech with loosening associations and was admitted to the inpatient psychiatric unit. Past psychiatric history included longstanding schizoaffective disorder. As a psychiatric inpatient, after having failed treatment with risperidone and olanzapine, the patient was started on clozapine 25 mg PO daily and was titrated to 150 mg PO BID over the course of 28 days. Recorded WBC on day 28 of treatment was 4.5 × 109/L (4.5 to 11.0 × 109/L). On the 35th day of clozapine treatment, the patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. WBC was found to be 0.2 × 109/L (4.5 to 11.0 × 109/L), and ANC was 0.05 [1.5 to 8.0 (1,500 to 8,000/mm3)]. The valproate level was 36.5 (50-100). Subsequently, the patient was transferred to the inpatient medicine floor this same day due to clozapine-induced leukocytopenia (day of transfer to medicine/Treatment day 0).
Past medical history included arthritis, deep vein thrombosis, chronic kidney disease (CKD) (stage 3), right bundle branch block, left anterior fascicular block, syncope, and epilepsy. On admission, patient was alert and oriented ×2 to self and place. The patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. The patient denied headache, shortness of breath, abdominal pain, dysuria, or urinary frequency. The patient's allergies included penicillamine, penicillin, and shellfish. Active medications included sodium valproate, amlodipine, docusate, and polyethylene glycol. Physical exam was unremarkable, and vitals were within normal limits (See Table 1).
2.1. Treatment Course
On the day of transfer to medicine (Treatment day 0-Table 1), clozapine was immediately discontinued, the patient was placed in reverse isolation, and a throat culture was taken. On Treatment day 1, upon recommendation from hematology, the patient received filgrastim/G-CSF 300 mcg subcutaneously. The patient continued this dosage of filgrastim for two days along with home dose of valproate.
On Treatment day 3, the patient spiked a fever of 103.1°F. A fever source was investigated, and an uncomplicated cellulitis on the abdominal wall was found. Filgrastim was adjusted to a dose of 800 mcg subcutaneous daily (see Table 1), and the patient was administered acetaminophen, aztreonam, clindamycin, and gentamicin while monitoring the kidney function.
Gentamicin was discontinued on Treatment day 5 (two days after initiation) when eGFR was 17.24 indicative of AKI stage 4 (see Table 1). Aztreonam and clindamycin were continued till Treatment day 6, and micafungin and meropenem administration began on Treatment day 7.
Patient status stabilized on Treatment day 10 when her ANC count rose to 1.8, up from 0.4 on Treatment day 9 (See Table 1). The patient remained hospitalized an additional two days to correct electrolyte abnormalities.
3. Discussion
As CIA has become more prevalent, it has been noted that risk factors and poor prognostic indicators include female sex, increasing age, ANC < 100, preexisting renal, cardiac or inflammatory disease comorbidities, and sepsis. [14]. Considering these factors, the 60 years of age in our female patient, her CKD, the acquisition of cellulitis during her treatment, and ANC of 5, we were satisfied with the treatment course and outcome. However, other factors have been noted in literature to potentially increase susceptibility of CIA. Specific human leukocyte antigen (HLA) has been identified for increased susceptibility to CIA. Potential CYP reactions in valproate, which remain unclear in literature, could also potentially increase risk of CIA. And certain treatment guidelines of CIA remain vague in literature. Clinical screening either separately or combined for many of these risk factors should be established. Additionally, consideration for a standardized protocol for timeline and dosing of treatment for CIA should be established.
3.1. Screening: Renal Failure and HLA
Though CIA is an adverse event which occurs in less than 1% of adults with psychiatric conditions [15], more research is being conducted to determine risk factors which may increase the likelihood of patients developing this condition. By screening for risk factors, we may mitigate the occurrence of these events. It is noted that our patient who had a past medical history of CKD was dosed with gentamicin upon initial fever of 103.1°F on Treatment day 3. Though gentamicin has known nephrotoxic effects and was thus discontinued to prevent further kidney toxicity, many case reports have suggested that clozapine may induce and/or exacerbate renal failure and nephritis [16–19]. While further research is necessary to quantify the precise risk of clozapine on the kidney function, prior to initiating a trial dose of clozapine, including a thorough history, measuring a patient's kidney function, or eGFR, and BUN/creatinine panel in addition to weekly monitoring of clozapine and ANC levels may reduce exacerbation of CKD.
Associations between susceptibility of CIA and human leukocyte antigen (HLA) were initially reported in the 1990s [20]. In 2014, HLA-DQB1 and HLA-B alleles were specifically implicated in amino acid changes responsible for patient's susceptibility to CIA [21]. Currently, there is no guidance on mandatory panels or screening for HLA alleles prior to administration of clozapine though such screening has been shown to be health and cost-effective [15]. While the past medical history indicated that our subject had been diagnosed with arthritis, we did not investigate which type of arthritis. We performed HLA screening towards the end of her CIA treatment and discovered that our patient was, indeed, HLA-DQB1 and HLA-DQ2 positive. Had we implemented HLA screening prior to initiating clozapine, we could have potentially avoided her CIA.
3.2. Management Protocol for Clozapine-Induced Agranulocytosis
While standard procedures for the management of CIA have been established, many of the details remain either up to physician determination or unestablished guidelines. Filgrastim/G-CSF has been shown to decrease the recovery time associated with agranulocytosis [7]. However, there is not an established dose for filgrastim for the treatment of CIA. There are established guidelines for filgrastim/G-CSF use in patients suffering from a number of immunocompromising diseases and cancers [22]. However, there is no direct guidance for administering filgrastim for patients suffering from CIA. Filgrastim/G-CSF is available in 300 mcg or 480 mcg vials or single dose syringes with recommended starting dose 5mcg/kg/day [22]. It is recommended to be administered up to 2 weeks or until ANC has reached 10,000/mm3 and is to be discontinued if ANC surpasses 10,000/mm3 after expected nadir [22].
In our patient, treatment of CIA took a total of 10 days of which Neupogen was dosed a total of 6 days with dosages of 300 mcg and 800 mcg (see Table 1) for patient recovery to a normal range of WBC 7 L and ANC 3.97 μL. Further study may provide more efficient dosing and thus more expedient and cost-effective care.
There also continues to be nebulous guidelines in management of CIA through the utilization of bone marrow aspirate and biopsy. Current protocol in the initial studies for the diagnosis of CIA includes CBC, white cell differential, examination of the peripheral smear, observation of recovery after cessation of the drug in a healthy patient, bacterial and/or viral studies if the patient is febrile, and a bone marrow aspiration and biopsy [12, 14]. As the utilization of the bone marrow biopsy is to ascertain patient granulopoiesis status, physicians may choose to begin filgrastim/G-CSF treatment prior to performing a bone marrow aspirate. For our case, hematology recommended bone marrow biopsy on Treatment day 3 to rule out WBC aplasia; however, they suggested performing the biopsy only if the increased filgrastim dose to 800 mcg did not prove effective in improving neutrophils levels. When peripheral blood screening revealed cellular morphology categorized as normal, a bone marrow biopsy was not performed on our subject. Importantly, upon literature review, there are no stated guidelines on when to perform the bone biopsy [10, 14].
3.3. Valproic Acid and CYP Effects
Finally, while clozapine was immediately discontinued upon admission, valproate was continued throughout the duration of treatment for the patient's schizoaffective disorder (see Table 1). There has been suggestion that valproate may be a clozapine metabolism inducer [23], the serum valproate level was subtherapeutic 36.5 (50-100) on treatment day 0/admission to the medicine floor, and the clozapine level was not taken at admission; so, no definitive conclusion can be made. Other studies suggest that valproate is a weak inhibitor of CYP 3A4 [24, 25] and potent CYP 2C9 inhibitor [26, 27]. Additionally, in 2018, the Malik et al. case control study of 136 cases found an association of increased risk of CIA in those with concurrent use of sodium valproate and clozapine [28]. These findings might suggest that our subjects' concomitant dosing of valproate with her clozapine could have exacerbated the clozapine effect causing CIA. Should these theories prove true on larger study, the decision to continue the patient's prescription of valproate during treatment for CIA could have elongated the recovery process due to the CYP inhibitor effects of valproate on clozapine levels. Future investigation for drug interaction of valproate with clozapine together should be studied. Should valproate prove to be a CYP inhibitor, or exacerbate CIA, standardized guidelines should indicate valproate be discontinued in future findings of CIA, and alternative therapeutics should be explored. Additionally, adjunctive use of lithium with clozapine has been initially investigated to mitigate the level of neutropenia for those experiencing CIA [29]. Additional study into adjunct dosing of lithium should be investigated. Concurrent use of valproate with clozapine, adjunct dosing of lithium, and other patient risk factors may need to be considered while determining proper individualized treatment.
4. Conclusion
Through this case of CIA in a patient with longstanding schizoaffective disorder, CKD, and HLA-DQB1 and HLA-DQ2 positivity, the importance of implementing a standardized screen which accounts for the renal function and HLA status is imperative for safe practices in prescribing clozapine for psychiatric disorders and mitigating the risk for CIA. Additionally, proper standardized monitoring of renal status through the treatment process may also mitigate risk of potential kidney failure. Further study is necessary to distinguish valproate's role in agranulocytosis singularly or in concert with clozapine. More detailed standardized guidelines would be beneficial for treatment of CIA, should it occur. As clozapine is known as a drug of last resort to be administered when there is failure of more traditional, and risk averse therapeutics, it is difficult to deny this treatment option, as it ultimately implies that all other treatment options have been exhausted. Proper screening and established protocol and guidelines could increase the level of monitoring in patients with known risk factors as revealed by the official screen. This risk factor screen and subsequent monitoring could increase the cost-effectiveness of clozapine treatment and decrease the incidence and morbidity of this feared adverse event.
Acknowledgments
The authors would like to thank the nursing staff and social workers for their day-to-day involvement in the care of the patient. We would also like to thank the following residents for the day-to-day involvement in managing the care of our patient: Chris Alfred, Ainsley Backman, Vito D'Angelo, Randy Lai, and Jai Patel. We would also like to thank Jonathan Eckstein, Steven Rubel, and Albert Strojan for the feedback given during the development of this paper. The authors also would like to thank Alvin Holcomb for the role he plays in resident medical education on a daily basis.
Abbreviations
CIA: Clozapine-induced agranulocytosis
ANC: Absolute neutrophil count
DVT: Deep vein thrombosis
CKD: Chronic kidney disease
AKI: Acute kidney injury
CYP: Cytochrome P450
EMS: Emergency medical services
ED: Emergency department
HLA: Human leukocyte antigen
G-CSF: Granulocyte-colony stimulating factor.
Data Availability
The subject data used to support the findings of this study are included in the Table within the article. Prior studies used to support the findings of this study are cited at relevant places within the text as references [1–29].
Consent
Written informed consent was obtained and is on the file.
Conflicts of Interest
The authors declare that there that there is no conflict of interest regarding the publication of this article.
Table 1 Treatment course lab table.
Treatment day Treatment day 0 Treatment day 1 Treatment day 2 Treatment day 3 Treatment day 4 Treatment day 5 Treatment day 6 Treatment day 7 Treatment day 8 Treatment day 9 Treatment day 10 Treatment day 11 Treatment day 12
Lab value
ANC level (μL) 0.05 0 0.01 0.01 0.01 0.01 0 0.02 0.04 0.57 3.97 11.51 10.38
WBC (L) N/A 0.4 0.4 0.3 0.2 0.3 0.2 0.3 0.4 1.8 7 18.7 N/A
Temperature max 98.8 98.6 100.7 103.1 101 98.5 99.3 97.3 98.1 98.6 97.8 97.7 98.1
BP 127/79 144/77 110/59 113/48 131/59 101/53 129/61 127/65 119/64 130/75 117/65 130/70
Hgb (G/DL) 10.4 9.9 11 10.5 9.8 8.9 8.5 8 8 8.6 9.6 9.3 8.4
Hematocrit (%) 33.8 31.8 36.4 33.6 31.6 29.3 27.2 26.3 26.1 28.1 32.2 30.6 28.6
H&H 10.4/33.8 9.9/31.8 11.0/36.4 10.5/33.6 9.8/31.6 8.9/29.3 8.5/27.2 8.0/26.3 8.0/26.1 8.6/28.1 9.6/32.2 9.3/30.6 8.4/28.6
BUN N/A N/A 38 36 46 55 77 70 57 43 33 29 25
CR N/A N/A 1.57 1.93 2.3 2.8 3.2 2.45 1.98 1.69 1.75 1.55 1.59
eGFR N/A N/A 33.61 26.48 21.63 17.24 14.78 20.11 25.71 30.87 29.65 34.11 33.12
Valproate level 36.5 L 50.9 L
Amlodipine dose 10 mg 10 mg 10 mg Not given Not given 10 mg 10 mg 10 mg Refused 10 mg 10 mg 10 mg 10 mg
Docusate dose Refused 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg
PEG dose 17 grams 17 grams
Valproate dose 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d
Filgrastim dose N/A 300 mcg 300 mcg 800 mcg 800 mcg 800 mcg N/A N/A 800 mcg N/A N/A N/A N/A | ACETAMINOPHEN, AMLODIPINE BESYLATE, AZTREONAM, CLINDAMYCIN, CLOZAPINE, DOCUSATE, GENTAMICIN, OLANZAPINE, POLYETHYLENE GLYCOLS, RISPERIDONE, VALPROATE SODIUM | DrugsGivenReaction | CC BY | 33688445 | 19,142,002 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Considerations of HLA, Renal Failure, Valproic Acid Use, and Current Treatment Guidelines in Clozapine-Induced Agranulocytosis.
Clozapine, the choice atypical antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder, has been shown to reduce positive and negative symptoms of schizophrenia. Clozapine, though beneficial in reducing the need for hospitalization, rehabilitation, and health care costs, is known as a drug of last resort due to its potential adverse event of clozapine-induced agranulocytosis, which holds a case fatality rate between 4.2 and 16%. Herein, we describe a female patient with longstanding schizoaffective disorder and chronic kidney disease who suffered from clozapine-induced agranulocytosis after failing two other atypical antipsychotics. Retrospective considerations of this case and management highlight risk factors such as HLA status, renal failure, and concurrent valproic acid use which presently do not have official screening, guidelines, or restrictions in place when prescribing clozapine. Additionally, there are no specific clozapine-induced agranulocytosis management recommendations such as G-CSF/filgrastim dose, timing of bone marrow aspirate and biopsy, and use of concomitant valproate. We propose that further comprehensive official screening, monitoring, and guidelines in the prescribing of clozapine, and further guidelines in the treatment of clozapine induced agranulocytosis, could increase the cost-effectiveness of clozapine treatment, and decrease the incidence, and morbidity of this feared adverse event.
1. Introduction
Clozapine, a dibenzodiazepine antipsychotic exhibiting weak dopaminergic activity and atypical pharmacological properties, is the choice antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder [1–4]. Advantages of clozapine include decreased positive symptoms of schizophrenia such as voices and hallucinations and decreased negative symptoms such as blunted affect and suicidal behavior [5]. The decreased positive and negative symptoms result in reduced need for hospitalization, rehabilitation, and subsequent health care costs [6]. However, known and feared disadvantages include neutropenia and life-threatening agranulocytosis [7, 8].
A benign form of neutropenia with an absolute neutrophil count (ANC) < 1500 cells/μL [9] is known to occur more frequently than clinically significant, agranulocytosis, where ANC < 500 cells/μL [10]. A high risk of severe and/or opportunistic infections is noted to be associated with ANC <200 [9]. In 2008, clozapine-induced agranulocytosis (CIA) had a known rate of seven cases per one million [11]. In 2006, the case fatality caused by CIA was estimated to be 4.2% to 16% [12]. In 2016, the observed mortality rate ranged from 0.1 and 0.3 per thousand, and the case fatality rate was estimated to be between 2.2 and 4.2 [13]. Standard established protocol includes immediate discontinuation of clozapine should white blood cell count reach <500 ANC [10, 14]. Patients' WBC and ANC must be monitored daily until WBC > 3000/mm3 and ANC > 1500/mm3 [7].
As more cases of CIA are occurring, more information concerning prescribing this efficacious antipsychotic as well as the treatment of CIA has become available. Here, we describe a patient with longstanding schizoaffective disorder who suffered from CIA after being transitioned to clozapine due to failed trials of risperidone and olanzapine. Retrospective considerations of her placement on clozapine and subsequent management of her CIA brought into question many factors which do not have clear guidelines, including official screening of risk factors which increase likelihood of CIA, as well as clear clinical management for this feared adverse event. This case report provides a spotlight on many factors such as screening for chronic kidney disease (CKD), human leukocyte antigen(HLA) typing, concurrent valproate administration due to potential CYP interactions, and management considerations such as dosing for filgrastim/G-CSF and timing of bone marrow biopsy. This analysis aims for further study and ultimately future implementation of screening and management guidelines for better informed management of refractory schizophrenia treatment, reduced cases of CIA, and improved management of CIA should it occur.
2. Case Presentation
A 60-year-old Caucasian female nursing home resident was brought in by EMS to the ED due to disorganized behavior, auditory hallucinations, and disorganized speech with loosening associations and was admitted to the inpatient psychiatric unit. Past psychiatric history included longstanding schizoaffective disorder. As a psychiatric inpatient, after having failed treatment with risperidone and olanzapine, the patient was started on clozapine 25 mg PO daily and was titrated to 150 mg PO BID over the course of 28 days. Recorded WBC on day 28 of treatment was 4.5 × 109/L (4.5 to 11.0 × 109/L). On the 35th day of clozapine treatment, the patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. WBC was found to be 0.2 × 109/L (4.5 to 11.0 × 109/L), and ANC was 0.05 [1.5 to 8.0 (1,500 to 8,000/mm3)]. The valproate level was 36.5 (50-100). Subsequently, the patient was transferred to the inpatient medicine floor this same day due to clozapine-induced leukocytopenia (day of transfer to medicine/Treatment day 0).
Past medical history included arthritis, deep vein thrombosis, chronic kidney disease (CKD) (stage 3), right bundle branch block, left anterior fascicular block, syncope, and epilepsy. On admission, patient was alert and oriented ×2 to self and place. The patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. The patient denied headache, shortness of breath, abdominal pain, dysuria, or urinary frequency. The patient's allergies included penicillamine, penicillin, and shellfish. Active medications included sodium valproate, amlodipine, docusate, and polyethylene glycol. Physical exam was unremarkable, and vitals were within normal limits (See Table 1).
2.1. Treatment Course
On the day of transfer to medicine (Treatment day 0-Table 1), clozapine was immediately discontinued, the patient was placed in reverse isolation, and a throat culture was taken. On Treatment day 1, upon recommendation from hematology, the patient received filgrastim/G-CSF 300 mcg subcutaneously. The patient continued this dosage of filgrastim for two days along with home dose of valproate.
On Treatment day 3, the patient spiked a fever of 103.1°F. A fever source was investigated, and an uncomplicated cellulitis on the abdominal wall was found. Filgrastim was adjusted to a dose of 800 mcg subcutaneous daily (see Table 1), and the patient was administered acetaminophen, aztreonam, clindamycin, and gentamicin while monitoring the kidney function.
Gentamicin was discontinued on Treatment day 5 (two days after initiation) when eGFR was 17.24 indicative of AKI stage 4 (see Table 1). Aztreonam and clindamycin were continued till Treatment day 6, and micafungin and meropenem administration began on Treatment day 7.
Patient status stabilized on Treatment day 10 when her ANC count rose to 1.8, up from 0.4 on Treatment day 9 (See Table 1). The patient remained hospitalized an additional two days to correct electrolyte abnormalities.
3. Discussion
As CIA has become more prevalent, it has been noted that risk factors and poor prognostic indicators include female sex, increasing age, ANC < 100, preexisting renal, cardiac or inflammatory disease comorbidities, and sepsis. [14]. Considering these factors, the 60 years of age in our female patient, her CKD, the acquisition of cellulitis during her treatment, and ANC of 5, we were satisfied with the treatment course and outcome. However, other factors have been noted in literature to potentially increase susceptibility of CIA. Specific human leukocyte antigen (HLA) has been identified for increased susceptibility to CIA. Potential CYP reactions in valproate, which remain unclear in literature, could also potentially increase risk of CIA. And certain treatment guidelines of CIA remain vague in literature. Clinical screening either separately or combined for many of these risk factors should be established. Additionally, consideration for a standardized protocol for timeline and dosing of treatment for CIA should be established.
3.1. Screening: Renal Failure and HLA
Though CIA is an adverse event which occurs in less than 1% of adults with psychiatric conditions [15], more research is being conducted to determine risk factors which may increase the likelihood of patients developing this condition. By screening for risk factors, we may mitigate the occurrence of these events. It is noted that our patient who had a past medical history of CKD was dosed with gentamicin upon initial fever of 103.1°F on Treatment day 3. Though gentamicin has known nephrotoxic effects and was thus discontinued to prevent further kidney toxicity, many case reports have suggested that clozapine may induce and/or exacerbate renal failure and nephritis [16–19]. While further research is necessary to quantify the precise risk of clozapine on the kidney function, prior to initiating a trial dose of clozapine, including a thorough history, measuring a patient's kidney function, or eGFR, and BUN/creatinine panel in addition to weekly monitoring of clozapine and ANC levels may reduce exacerbation of CKD.
Associations between susceptibility of CIA and human leukocyte antigen (HLA) were initially reported in the 1990s [20]. In 2014, HLA-DQB1 and HLA-B alleles were specifically implicated in amino acid changes responsible for patient's susceptibility to CIA [21]. Currently, there is no guidance on mandatory panels or screening for HLA alleles prior to administration of clozapine though such screening has been shown to be health and cost-effective [15]. While the past medical history indicated that our subject had been diagnosed with arthritis, we did not investigate which type of arthritis. We performed HLA screening towards the end of her CIA treatment and discovered that our patient was, indeed, HLA-DQB1 and HLA-DQ2 positive. Had we implemented HLA screening prior to initiating clozapine, we could have potentially avoided her CIA.
3.2. Management Protocol for Clozapine-Induced Agranulocytosis
While standard procedures for the management of CIA have been established, many of the details remain either up to physician determination or unestablished guidelines. Filgrastim/G-CSF has been shown to decrease the recovery time associated with agranulocytosis [7]. However, there is not an established dose for filgrastim for the treatment of CIA. There are established guidelines for filgrastim/G-CSF use in patients suffering from a number of immunocompromising diseases and cancers [22]. However, there is no direct guidance for administering filgrastim for patients suffering from CIA. Filgrastim/G-CSF is available in 300 mcg or 480 mcg vials or single dose syringes with recommended starting dose 5mcg/kg/day [22]. It is recommended to be administered up to 2 weeks or until ANC has reached 10,000/mm3 and is to be discontinued if ANC surpasses 10,000/mm3 after expected nadir [22].
In our patient, treatment of CIA took a total of 10 days of which Neupogen was dosed a total of 6 days with dosages of 300 mcg and 800 mcg (see Table 1) for patient recovery to a normal range of WBC 7 L and ANC 3.97 μL. Further study may provide more efficient dosing and thus more expedient and cost-effective care.
There also continues to be nebulous guidelines in management of CIA through the utilization of bone marrow aspirate and biopsy. Current protocol in the initial studies for the diagnosis of CIA includes CBC, white cell differential, examination of the peripheral smear, observation of recovery after cessation of the drug in a healthy patient, bacterial and/or viral studies if the patient is febrile, and a bone marrow aspiration and biopsy [12, 14]. As the utilization of the bone marrow biopsy is to ascertain patient granulopoiesis status, physicians may choose to begin filgrastim/G-CSF treatment prior to performing a bone marrow aspirate. For our case, hematology recommended bone marrow biopsy on Treatment day 3 to rule out WBC aplasia; however, they suggested performing the biopsy only if the increased filgrastim dose to 800 mcg did not prove effective in improving neutrophils levels. When peripheral blood screening revealed cellular morphology categorized as normal, a bone marrow biopsy was not performed on our subject. Importantly, upon literature review, there are no stated guidelines on when to perform the bone biopsy [10, 14].
3.3. Valproic Acid and CYP Effects
Finally, while clozapine was immediately discontinued upon admission, valproate was continued throughout the duration of treatment for the patient's schizoaffective disorder (see Table 1). There has been suggestion that valproate may be a clozapine metabolism inducer [23], the serum valproate level was subtherapeutic 36.5 (50-100) on treatment day 0/admission to the medicine floor, and the clozapine level was not taken at admission; so, no definitive conclusion can be made. Other studies suggest that valproate is a weak inhibitor of CYP 3A4 [24, 25] and potent CYP 2C9 inhibitor [26, 27]. Additionally, in 2018, the Malik et al. case control study of 136 cases found an association of increased risk of CIA in those with concurrent use of sodium valproate and clozapine [28]. These findings might suggest that our subjects' concomitant dosing of valproate with her clozapine could have exacerbated the clozapine effect causing CIA. Should these theories prove true on larger study, the decision to continue the patient's prescription of valproate during treatment for CIA could have elongated the recovery process due to the CYP inhibitor effects of valproate on clozapine levels. Future investigation for drug interaction of valproate with clozapine together should be studied. Should valproate prove to be a CYP inhibitor, or exacerbate CIA, standardized guidelines should indicate valproate be discontinued in future findings of CIA, and alternative therapeutics should be explored. Additionally, adjunctive use of lithium with clozapine has been initially investigated to mitigate the level of neutropenia for those experiencing CIA [29]. Additional study into adjunct dosing of lithium should be investigated. Concurrent use of valproate with clozapine, adjunct dosing of lithium, and other patient risk factors may need to be considered while determining proper individualized treatment.
4. Conclusion
Through this case of CIA in a patient with longstanding schizoaffective disorder, CKD, and HLA-DQB1 and HLA-DQ2 positivity, the importance of implementing a standardized screen which accounts for the renal function and HLA status is imperative for safe practices in prescribing clozapine for psychiatric disorders and mitigating the risk for CIA. Additionally, proper standardized monitoring of renal status through the treatment process may also mitigate risk of potential kidney failure. Further study is necessary to distinguish valproate's role in agranulocytosis singularly or in concert with clozapine. More detailed standardized guidelines would be beneficial for treatment of CIA, should it occur. As clozapine is known as a drug of last resort to be administered when there is failure of more traditional, and risk averse therapeutics, it is difficult to deny this treatment option, as it ultimately implies that all other treatment options have been exhausted. Proper screening and established protocol and guidelines could increase the level of monitoring in patients with known risk factors as revealed by the official screen. This risk factor screen and subsequent monitoring could increase the cost-effectiveness of clozapine treatment and decrease the incidence and morbidity of this feared adverse event.
Acknowledgments
The authors would like to thank the nursing staff and social workers for their day-to-day involvement in the care of the patient. We would also like to thank the following residents for the day-to-day involvement in managing the care of our patient: Chris Alfred, Ainsley Backman, Vito D'Angelo, Randy Lai, and Jai Patel. We would also like to thank Jonathan Eckstein, Steven Rubel, and Albert Strojan for the feedback given during the development of this paper. The authors also would like to thank Alvin Holcomb for the role he plays in resident medical education on a daily basis.
Abbreviations
CIA: Clozapine-induced agranulocytosis
ANC: Absolute neutrophil count
DVT: Deep vein thrombosis
CKD: Chronic kidney disease
AKI: Acute kidney injury
CYP: Cytochrome P450
EMS: Emergency medical services
ED: Emergency department
HLA: Human leukocyte antigen
G-CSF: Granulocyte-colony stimulating factor.
Data Availability
The subject data used to support the findings of this study are included in the Table within the article. Prior studies used to support the findings of this study are cited at relevant places within the text as references [1–29].
Consent
Written informed consent was obtained and is on the file.
Conflicts of Interest
The authors declare that there that there is no conflict of interest regarding the publication of this article.
Table 1 Treatment course lab table.
Treatment day Treatment day 0 Treatment day 1 Treatment day 2 Treatment day 3 Treatment day 4 Treatment day 5 Treatment day 6 Treatment day 7 Treatment day 8 Treatment day 9 Treatment day 10 Treatment day 11 Treatment day 12
Lab value
ANC level (μL) 0.05 0 0.01 0.01 0.01 0.01 0 0.02 0.04 0.57 3.97 11.51 10.38
WBC (L) N/A 0.4 0.4 0.3 0.2 0.3 0.2 0.3 0.4 1.8 7 18.7 N/A
Temperature max 98.8 98.6 100.7 103.1 101 98.5 99.3 97.3 98.1 98.6 97.8 97.7 98.1
BP 127/79 144/77 110/59 113/48 131/59 101/53 129/61 127/65 119/64 130/75 117/65 130/70
Hgb (G/DL) 10.4 9.9 11 10.5 9.8 8.9 8.5 8 8 8.6 9.6 9.3 8.4
Hematocrit (%) 33.8 31.8 36.4 33.6 31.6 29.3 27.2 26.3 26.1 28.1 32.2 30.6 28.6
H&H 10.4/33.8 9.9/31.8 11.0/36.4 10.5/33.6 9.8/31.6 8.9/29.3 8.5/27.2 8.0/26.3 8.0/26.1 8.6/28.1 9.6/32.2 9.3/30.6 8.4/28.6
BUN N/A N/A 38 36 46 55 77 70 57 43 33 29 25
CR N/A N/A 1.57 1.93 2.3 2.8 3.2 2.45 1.98 1.69 1.75 1.55 1.59
eGFR N/A N/A 33.61 26.48 21.63 17.24 14.78 20.11 25.71 30.87 29.65 34.11 33.12
Valproate level 36.5 L 50.9 L
Amlodipine dose 10 mg 10 mg 10 mg Not given Not given 10 mg 10 mg 10 mg Refused 10 mg 10 mg 10 mg 10 mg
Docusate dose Refused 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg
PEG dose 17 grams 17 grams
Valproate dose 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d
Filgrastim dose N/A 300 mcg 300 mcg 800 mcg 800 mcg 800 mcg N/A N/A 800 mcg N/A N/A N/A N/A | ACETAMINOPHEN, AMLODIPINE BESYLATE, AZTREONAM, CLINDAMYCIN, CLOZAPINE, DOCUSATE, FILGRASTIM, GENTAMICIN, OLANZAPINE, POLYETHYLENE GLYCOLS, RISPERIDONE, VALPROIC ACID | DrugsGivenReaction | CC BY | 33688445 | 19,084,247 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug level below therapeutic'. | Considerations of HLA, Renal Failure, Valproic Acid Use, and Current Treatment Guidelines in Clozapine-Induced Agranulocytosis.
Clozapine, the choice atypical antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder, has been shown to reduce positive and negative symptoms of schizophrenia. Clozapine, though beneficial in reducing the need for hospitalization, rehabilitation, and health care costs, is known as a drug of last resort due to its potential adverse event of clozapine-induced agranulocytosis, which holds a case fatality rate between 4.2 and 16%. Herein, we describe a female patient with longstanding schizoaffective disorder and chronic kidney disease who suffered from clozapine-induced agranulocytosis after failing two other atypical antipsychotics. Retrospective considerations of this case and management highlight risk factors such as HLA status, renal failure, and concurrent valproic acid use which presently do not have official screening, guidelines, or restrictions in place when prescribing clozapine. Additionally, there are no specific clozapine-induced agranulocytosis management recommendations such as G-CSF/filgrastim dose, timing of bone marrow aspirate and biopsy, and use of concomitant valproate. We propose that further comprehensive official screening, monitoring, and guidelines in the prescribing of clozapine, and further guidelines in the treatment of clozapine induced agranulocytosis, could increase the cost-effectiveness of clozapine treatment, and decrease the incidence, and morbidity of this feared adverse event.
1. Introduction
Clozapine, a dibenzodiazepine antipsychotic exhibiting weak dopaminergic activity and atypical pharmacological properties, is the choice antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder [1–4]. Advantages of clozapine include decreased positive symptoms of schizophrenia such as voices and hallucinations and decreased negative symptoms such as blunted affect and suicidal behavior [5]. The decreased positive and negative symptoms result in reduced need for hospitalization, rehabilitation, and subsequent health care costs [6]. However, known and feared disadvantages include neutropenia and life-threatening agranulocytosis [7, 8].
A benign form of neutropenia with an absolute neutrophil count (ANC) < 1500 cells/μL [9] is known to occur more frequently than clinically significant, agranulocytosis, where ANC < 500 cells/μL [10]. A high risk of severe and/or opportunistic infections is noted to be associated with ANC <200 [9]. In 2008, clozapine-induced agranulocytosis (CIA) had a known rate of seven cases per one million [11]. In 2006, the case fatality caused by CIA was estimated to be 4.2% to 16% [12]. In 2016, the observed mortality rate ranged from 0.1 and 0.3 per thousand, and the case fatality rate was estimated to be between 2.2 and 4.2 [13]. Standard established protocol includes immediate discontinuation of clozapine should white blood cell count reach <500 ANC [10, 14]. Patients' WBC and ANC must be monitored daily until WBC > 3000/mm3 and ANC > 1500/mm3 [7].
As more cases of CIA are occurring, more information concerning prescribing this efficacious antipsychotic as well as the treatment of CIA has become available. Here, we describe a patient with longstanding schizoaffective disorder who suffered from CIA after being transitioned to clozapine due to failed trials of risperidone and olanzapine. Retrospective considerations of her placement on clozapine and subsequent management of her CIA brought into question many factors which do not have clear guidelines, including official screening of risk factors which increase likelihood of CIA, as well as clear clinical management for this feared adverse event. This case report provides a spotlight on many factors such as screening for chronic kidney disease (CKD), human leukocyte antigen(HLA) typing, concurrent valproate administration due to potential CYP interactions, and management considerations such as dosing for filgrastim/G-CSF and timing of bone marrow biopsy. This analysis aims for further study and ultimately future implementation of screening and management guidelines for better informed management of refractory schizophrenia treatment, reduced cases of CIA, and improved management of CIA should it occur.
2. Case Presentation
A 60-year-old Caucasian female nursing home resident was brought in by EMS to the ED due to disorganized behavior, auditory hallucinations, and disorganized speech with loosening associations and was admitted to the inpatient psychiatric unit. Past psychiatric history included longstanding schizoaffective disorder. As a psychiatric inpatient, after having failed treatment with risperidone and olanzapine, the patient was started on clozapine 25 mg PO daily and was titrated to 150 mg PO BID over the course of 28 days. Recorded WBC on day 28 of treatment was 4.5 × 109/L (4.5 to 11.0 × 109/L). On the 35th day of clozapine treatment, the patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. WBC was found to be 0.2 × 109/L (4.5 to 11.0 × 109/L), and ANC was 0.05 [1.5 to 8.0 (1,500 to 8,000/mm3)]. The valproate level was 36.5 (50-100). Subsequently, the patient was transferred to the inpatient medicine floor this same day due to clozapine-induced leukocytopenia (day of transfer to medicine/Treatment day 0).
Past medical history included arthritis, deep vein thrombosis, chronic kidney disease (CKD) (stage 3), right bundle branch block, left anterior fascicular block, syncope, and epilepsy. On admission, patient was alert and oriented ×2 to self and place. The patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. The patient denied headache, shortness of breath, abdominal pain, dysuria, or urinary frequency. The patient's allergies included penicillamine, penicillin, and shellfish. Active medications included sodium valproate, amlodipine, docusate, and polyethylene glycol. Physical exam was unremarkable, and vitals were within normal limits (See Table 1).
2.1. Treatment Course
On the day of transfer to medicine (Treatment day 0-Table 1), clozapine was immediately discontinued, the patient was placed in reverse isolation, and a throat culture was taken. On Treatment day 1, upon recommendation from hematology, the patient received filgrastim/G-CSF 300 mcg subcutaneously. The patient continued this dosage of filgrastim for two days along with home dose of valproate.
On Treatment day 3, the patient spiked a fever of 103.1°F. A fever source was investigated, and an uncomplicated cellulitis on the abdominal wall was found. Filgrastim was adjusted to a dose of 800 mcg subcutaneous daily (see Table 1), and the patient was administered acetaminophen, aztreonam, clindamycin, and gentamicin while monitoring the kidney function.
Gentamicin was discontinued on Treatment day 5 (two days after initiation) when eGFR was 17.24 indicative of AKI stage 4 (see Table 1). Aztreonam and clindamycin were continued till Treatment day 6, and micafungin and meropenem administration began on Treatment day 7.
Patient status stabilized on Treatment day 10 when her ANC count rose to 1.8, up from 0.4 on Treatment day 9 (See Table 1). The patient remained hospitalized an additional two days to correct electrolyte abnormalities.
3. Discussion
As CIA has become more prevalent, it has been noted that risk factors and poor prognostic indicators include female sex, increasing age, ANC < 100, preexisting renal, cardiac or inflammatory disease comorbidities, and sepsis. [14]. Considering these factors, the 60 years of age in our female patient, her CKD, the acquisition of cellulitis during her treatment, and ANC of 5, we were satisfied with the treatment course and outcome. However, other factors have been noted in literature to potentially increase susceptibility of CIA. Specific human leukocyte antigen (HLA) has been identified for increased susceptibility to CIA. Potential CYP reactions in valproate, which remain unclear in literature, could also potentially increase risk of CIA. And certain treatment guidelines of CIA remain vague in literature. Clinical screening either separately or combined for many of these risk factors should be established. Additionally, consideration for a standardized protocol for timeline and dosing of treatment for CIA should be established.
3.1. Screening: Renal Failure and HLA
Though CIA is an adverse event which occurs in less than 1% of adults with psychiatric conditions [15], more research is being conducted to determine risk factors which may increase the likelihood of patients developing this condition. By screening for risk factors, we may mitigate the occurrence of these events. It is noted that our patient who had a past medical history of CKD was dosed with gentamicin upon initial fever of 103.1°F on Treatment day 3. Though gentamicin has known nephrotoxic effects and was thus discontinued to prevent further kidney toxicity, many case reports have suggested that clozapine may induce and/or exacerbate renal failure and nephritis [16–19]. While further research is necessary to quantify the precise risk of clozapine on the kidney function, prior to initiating a trial dose of clozapine, including a thorough history, measuring a patient's kidney function, or eGFR, and BUN/creatinine panel in addition to weekly monitoring of clozapine and ANC levels may reduce exacerbation of CKD.
Associations between susceptibility of CIA and human leukocyte antigen (HLA) were initially reported in the 1990s [20]. In 2014, HLA-DQB1 and HLA-B alleles were specifically implicated in amino acid changes responsible for patient's susceptibility to CIA [21]. Currently, there is no guidance on mandatory panels or screening for HLA alleles prior to administration of clozapine though such screening has been shown to be health and cost-effective [15]. While the past medical history indicated that our subject had been diagnosed with arthritis, we did not investigate which type of arthritis. We performed HLA screening towards the end of her CIA treatment and discovered that our patient was, indeed, HLA-DQB1 and HLA-DQ2 positive. Had we implemented HLA screening prior to initiating clozapine, we could have potentially avoided her CIA.
3.2. Management Protocol for Clozapine-Induced Agranulocytosis
While standard procedures for the management of CIA have been established, many of the details remain either up to physician determination or unestablished guidelines. Filgrastim/G-CSF has been shown to decrease the recovery time associated with agranulocytosis [7]. However, there is not an established dose for filgrastim for the treatment of CIA. There are established guidelines for filgrastim/G-CSF use in patients suffering from a number of immunocompromising diseases and cancers [22]. However, there is no direct guidance for administering filgrastim for patients suffering from CIA. Filgrastim/G-CSF is available in 300 mcg or 480 mcg vials or single dose syringes with recommended starting dose 5mcg/kg/day [22]. It is recommended to be administered up to 2 weeks or until ANC has reached 10,000/mm3 and is to be discontinued if ANC surpasses 10,000/mm3 after expected nadir [22].
In our patient, treatment of CIA took a total of 10 days of which Neupogen was dosed a total of 6 days with dosages of 300 mcg and 800 mcg (see Table 1) for patient recovery to a normal range of WBC 7 L and ANC 3.97 μL. Further study may provide more efficient dosing and thus more expedient and cost-effective care.
There also continues to be nebulous guidelines in management of CIA through the utilization of bone marrow aspirate and biopsy. Current protocol in the initial studies for the diagnosis of CIA includes CBC, white cell differential, examination of the peripheral smear, observation of recovery after cessation of the drug in a healthy patient, bacterial and/or viral studies if the patient is febrile, and a bone marrow aspiration and biopsy [12, 14]. As the utilization of the bone marrow biopsy is to ascertain patient granulopoiesis status, physicians may choose to begin filgrastim/G-CSF treatment prior to performing a bone marrow aspirate. For our case, hematology recommended bone marrow biopsy on Treatment day 3 to rule out WBC aplasia; however, they suggested performing the biopsy only if the increased filgrastim dose to 800 mcg did not prove effective in improving neutrophils levels. When peripheral blood screening revealed cellular morphology categorized as normal, a bone marrow biopsy was not performed on our subject. Importantly, upon literature review, there are no stated guidelines on when to perform the bone biopsy [10, 14].
3.3. Valproic Acid and CYP Effects
Finally, while clozapine was immediately discontinued upon admission, valproate was continued throughout the duration of treatment for the patient's schizoaffective disorder (see Table 1). There has been suggestion that valproate may be a clozapine metabolism inducer [23], the serum valproate level was subtherapeutic 36.5 (50-100) on treatment day 0/admission to the medicine floor, and the clozapine level was not taken at admission; so, no definitive conclusion can be made. Other studies suggest that valproate is a weak inhibitor of CYP 3A4 [24, 25] and potent CYP 2C9 inhibitor [26, 27]. Additionally, in 2018, the Malik et al. case control study of 136 cases found an association of increased risk of CIA in those with concurrent use of sodium valproate and clozapine [28]. These findings might suggest that our subjects' concomitant dosing of valproate with her clozapine could have exacerbated the clozapine effect causing CIA. Should these theories prove true on larger study, the decision to continue the patient's prescription of valproate during treatment for CIA could have elongated the recovery process due to the CYP inhibitor effects of valproate on clozapine levels. Future investigation for drug interaction of valproate with clozapine together should be studied. Should valproate prove to be a CYP inhibitor, or exacerbate CIA, standardized guidelines should indicate valproate be discontinued in future findings of CIA, and alternative therapeutics should be explored. Additionally, adjunctive use of lithium with clozapine has been initially investigated to mitigate the level of neutropenia for those experiencing CIA [29]. Additional study into adjunct dosing of lithium should be investigated. Concurrent use of valproate with clozapine, adjunct dosing of lithium, and other patient risk factors may need to be considered while determining proper individualized treatment.
4. Conclusion
Through this case of CIA in a patient with longstanding schizoaffective disorder, CKD, and HLA-DQB1 and HLA-DQ2 positivity, the importance of implementing a standardized screen which accounts for the renal function and HLA status is imperative for safe practices in prescribing clozapine for psychiatric disorders and mitigating the risk for CIA. Additionally, proper standardized monitoring of renal status through the treatment process may also mitigate risk of potential kidney failure. Further study is necessary to distinguish valproate's role in agranulocytosis singularly or in concert with clozapine. More detailed standardized guidelines would be beneficial for treatment of CIA, should it occur. As clozapine is known as a drug of last resort to be administered when there is failure of more traditional, and risk averse therapeutics, it is difficult to deny this treatment option, as it ultimately implies that all other treatment options have been exhausted. Proper screening and established protocol and guidelines could increase the level of monitoring in patients with known risk factors as revealed by the official screen. This risk factor screen and subsequent monitoring could increase the cost-effectiveness of clozapine treatment and decrease the incidence and morbidity of this feared adverse event.
Acknowledgments
The authors would like to thank the nursing staff and social workers for their day-to-day involvement in the care of the patient. We would also like to thank the following residents for the day-to-day involvement in managing the care of our patient: Chris Alfred, Ainsley Backman, Vito D'Angelo, Randy Lai, and Jai Patel. We would also like to thank Jonathan Eckstein, Steven Rubel, and Albert Strojan for the feedback given during the development of this paper. The authors also would like to thank Alvin Holcomb for the role he plays in resident medical education on a daily basis.
Abbreviations
CIA: Clozapine-induced agranulocytosis
ANC: Absolute neutrophil count
DVT: Deep vein thrombosis
CKD: Chronic kidney disease
AKI: Acute kidney injury
CYP: Cytochrome P450
EMS: Emergency medical services
ED: Emergency department
HLA: Human leukocyte antigen
G-CSF: Granulocyte-colony stimulating factor.
Data Availability
The subject data used to support the findings of this study are included in the Table within the article. Prior studies used to support the findings of this study are cited at relevant places within the text as references [1–29].
Consent
Written informed consent was obtained and is on the file.
Conflicts of Interest
The authors declare that there that there is no conflict of interest regarding the publication of this article.
Table 1 Treatment course lab table.
Treatment day Treatment day 0 Treatment day 1 Treatment day 2 Treatment day 3 Treatment day 4 Treatment day 5 Treatment day 6 Treatment day 7 Treatment day 8 Treatment day 9 Treatment day 10 Treatment day 11 Treatment day 12
Lab value
ANC level (μL) 0.05 0 0.01 0.01 0.01 0.01 0 0.02 0.04 0.57 3.97 11.51 10.38
WBC (L) N/A 0.4 0.4 0.3 0.2 0.3 0.2 0.3 0.4 1.8 7 18.7 N/A
Temperature max 98.8 98.6 100.7 103.1 101 98.5 99.3 97.3 98.1 98.6 97.8 97.7 98.1
BP 127/79 144/77 110/59 113/48 131/59 101/53 129/61 127/65 119/64 130/75 117/65 130/70
Hgb (G/DL) 10.4 9.9 11 10.5 9.8 8.9 8.5 8 8 8.6 9.6 9.3 8.4
Hematocrit (%) 33.8 31.8 36.4 33.6 31.6 29.3 27.2 26.3 26.1 28.1 32.2 30.6 28.6
H&H 10.4/33.8 9.9/31.8 11.0/36.4 10.5/33.6 9.8/31.6 8.9/29.3 8.5/27.2 8.0/26.3 8.0/26.1 8.6/28.1 9.6/32.2 9.3/30.6 8.4/28.6
BUN N/A N/A 38 36 46 55 77 70 57 43 33 29 25
CR N/A N/A 1.57 1.93 2.3 2.8 3.2 2.45 1.98 1.69 1.75 1.55 1.59
eGFR N/A N/A 33.61 26.48 21.63 17.24 14.78 20.11 25.71 30.87 29.65 34.11 33.12
Valproate level 36.5 L 50.9 L
Amlodipine dose 10 mg 10 mg 10 mg Not given Not given 10 mg 10 mg 10 mg Refused 10 mg 10 mg 10 mg 10 mg
Docusate dose Refused 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg
PEG dose 17 grams 17 grams
Valproate dose 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d
Filgrastim dose N/A 300 mcg 300 mcg 800 mcg 800 mcg 800 mcg N/A N/A 800 mcg N/A N/A N/A N/A | AMLODIPINE BESYLATE, CLOZAPINE, DOCUSATE, OLANZAPINE, POLYETHYLENE GLYCOLS, RISPERIDONE, VALPROIC ACID | DrugsGivenReaction | CC BY | 33688445 | 19,037,229 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Potentiating drug interaction'. | Considerations of HLA, Renal Failure, Valproic Acid Use, and Current Treatment Guidelines in Clozapine-Induced Agranulocytosis.
Clozapine, the choice atypical antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder, has been shown to reduce positive and negative symptoms of schizophrenia. Clozapine, though beneficial in reducing the need for hospitalization, rehabilitation, and health care costs, is known as a drug of last resort due to its potential adverse event of clozapine-induced agranulocytosis, which holds a case fatality rate between 4.2 and 16%. Herein, we describe a female patient with longstanding schizoaffective disorder and chronic kidney disease who suffered from clozapine-induced agranulocytosis after failing two other atypical antipsychotics. Retrospective considerations of this case and management highlight risk factors such as HLA status, renal failure, and concurrent valproic acid use which presently do not have official screening, guidelines, or restrictions in place when prescribing clozapine. Additionally, there are no specific clozapine-induced agranulocytosis management recommendations such as G-CSF/filgrastim dose, timing of bone marrow aspirate and biopsy, and use of concomitant valproate. We propose that further comprehensive official screening, monitoring, and guidelines in the prescribing of clozapine, and further guidelines in the treatment of clozapine induced agranulocytosis, could increase the cost-effectiveness of clozapine treatment, and decrease the incidence, and morbidity of this feared adverse event.
1. Introduction
Clozapine, a dibenzodiazepine antipsychotic exhibiting weak dopaminergic activity and atypical pharmacological properties, is the choice antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder [1–4]. Advantages of clozapine include decreased positive symptoms of schizophrenia such as voices and hallucinations and decreased negative symptoms such as blunted affect and suicidal behavior [5]. The decreased positive and negative symptoms result in reduced need for hospitalization, rehabilitation, and subsequent health care costs [6]. However, known and feared disadvantages include neutropenia and life-threatening agranulocytosis [7, 8].
A benign form of neutropenia with an absolute neutrophil count (ANC) < 1500 cells/μL [9] is known to occur more frequently than clinically significant, agranulocytosis, where ANC < 500 cells/μL [10]. A high risk of severe and/or opportunistic infections is noted to be associated with ANC <200 [9]. In 2008, clozapine-induced agranulocytosis (CIA) had a known rate of seven cases per one million [11]. In 2006, the case fatality caused by CIA was estimated to be 4.2% to 16% [12]. In 2016, the observed mortality rate ranged from 0.1 and 0.3 per thousand, and the case fatality rate was estimated to be between 2.2 and 4.2 [13]. Standard established protocol includes immediate discontinuation of clozapine should white blood cell count reach <500 ANC [10, 14]. Patients' WBC and ANC must be monitored daily until WBC > 3000/mm3 and ANC > 1500/mm3 [7].
As more cases of CIA are occurring, more information concerning prescribing this efficacious antipsychotic as well as the treatment of CIA has become available. Here, we describe a patient with longstanding schizoaffective disorder who suffered from CIA after being transitioned to clozapine due to failed trials of risperidone and olanzapine. Retrospective considerations of her placement on clozapine and subsequent management of her CIA brought into question many factors which do not have clear guidelines, including official screening of risk factors which increase likelihood of CIA, as well as clear clinical management for this feared adverse event. This case report provides a spotlight on many factors such as screening for chronic kidney disease (CKD), human leukocyte antigen(HLA) typing, concurrent valproate administration due to potential CYP interactions, and management considerations such as dosing for filgrastim/G-CSF and timing of bone marrow biopsy. This analysis aims for further study and ultimately future implementation of screening and management guidelines for better informed management of refractory schizophrenia treatment, reduced cases of CIA, and improved management of CIA should it occur.
2. Case Presentation
A 60-year-old Caucasian female nursing home resident was brought in by EMS to the ED due to disorganized behavior, auditory hallucinations, and disorganized speech with loosening associations and was admitted to the inpatient psychiatric unit. Past psychiatric history included longstanding schizoaffective disorder. As a psychiatric inpatient, after having failed treatment with risperidone and olanzapine, the patient was started on clozapine 25 mg PO daily and was titrated to 150 mg PO BID over the course of 28 days. Recorded WBC on day 28 of treatment was 4.5 × 109/L (4.5 to 11.0 × 109/L). On the 35th day of clozapine treatment, the patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. WBC was found to be 0.2 × 109/L (4.5 to 11.0 × 109/L), and ANC was 0.05 [1.5 to 8.0 (1,500 to 8,000/mm3)]. The valproate level was 36.5 (50-100). Subsequently, the patient was transferred to the inpatient medicine floor this same day due to clozapine-induced leukocytopenia (day of transfer to medicine/Treatment day 0).
Past medical history included arthritis, deep vein thrombosis, chronic kidney disease (CKD) (stage 3), right bundle branch block, left anterior fascicular block, syncope, and epilepsy. On admission, patient was alert and oriented ×2 to self and place. The patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. The patient denied headache, shortness of breath, abdominal pain, dysuria, or urinary frequency. The patient's allergies included penicillamine, penicillin, and shellfish. Active medications included sodium valproate, amlodipine, docusate, and polyethylene glycol. Physical exam was unremarkable, and vitals were within normal limits (See Table 1).
2.1. Treatment Course
On the day of transfer to medicine (Treatment day 0-Table 1), clozapine was immediately discontinued, the patient was placed in reverse isolation, and a throat culture was taken. On Treatment day 1, upon recommendation from hematology, the patient received filgrastim/G-CSF 300 mcg subcutaneously. The patient continued this dosage of filgrastim for two days along with home dose of valproate.
On Treatment day 3, the patient spiked a fever of 103.1°F. A fever source was investigated, and an uncomplicated cellulitis on the abdominal wall was found. Filgrastim was adjusted to a dose of 800 mcg subcutaneous daily (see Table 1), and the patient was administered acetaminophen, aztreonam, clindamycin, and gentamicin while monitoring the kidney function.
Gentamicin was discontinued on Treatment day 5 (two days after initiation) when eGFR was 17.24 indicative of AKI stage 4 (see Table 1). Aztreonam and clindamycin were continued till Treatment day 6, and micafungin and meropenem administration began on Treatment day 7.
Patient status stabilized on Treatment day 10 when her ANC count rose to 1.8, up from 0.4 on Treatment day 9 (See Table 1). The patient remained hospitalized an additional two days to correct electrolyte abnormalities.
3. Discussion
As CIA has become more prevalent, it has been noted that risk factors and poor prognostic indicators include female sex, increasing age, ANC < 100, preexisting renal, cardiac or inflammatory disease comorbidities, and sepsis. [14]. Considering these factors, the 60 years of age in our female patient, her CKD, the acquisition of cellulitis during her treatment, and ANC of 5, we were satisfied with the treatment course and outcome. However, other factors have been noted in literature to potentially increase susceptibility of CIA. Specific human leukocyte antigen (HLA) has been identified for increased susceptibility to CIA. Potential CYP reactions in valproate, which remain unclear in literature, could also potentially increase risk of CIA. And certain treatment guidelines of CIA remain vague in literature. Clinical screening either separately or combined for many of these risk factors should be established. Additionally, consideration for a standardized protocol for timeline and dosing of treatment for CIA should be established.
3.1. Screening: Renal Failure and HLA
Though CIA is an adverse event which occurs in less than 1% of adults with psychiatric conditions [15], more research is being conducted to determine risk factors which may increase the likelihood of patients developing this condition. By screening for risk factors, we may mitigate the occurrence of these events. It is noted that our patient who had a past medical history of CKD was dosed with gentamicin upon initial fever of 103.1°F on Treatment day 3. Though gentamicin has known nephrotoxic effects and was thus discontinued to prevent further kidney toxicity, many case reports have suggested that clozapine may induce and/or exacerbate renal failure and nephritis [16–19]. While further research is necessary to quantify the precise risk of clozapine on the kidney function, prior to initiating a trial dose of clozapine, including a thorough history, measuring a patient's kidney function, or eGFR, and BUN/creatinine panel in addition to weekly monitoring of clozapine and ANC levels may reduce exacerbation of CKD.
Associations between susceptibility of CIA and human leukocyte antigen (HLA) were initially reported in the 1990s [20]. In 2014, HLA-DQB1 and HLA-B alleles were specifically implicated in amino acid changes responsible for patient's susceptibility to CIA [21]. Currently, there is no guidance on mandatory panels or screening for HLA alleles prior to administration of clozapine though such screening has been shown to be health and cost-effective [15]. While the past medical history indicated that our subject had been diagnosed with arthritis, we did not investigate which type of arthritis. We performed HLA screening towards the end of her CIA treatment and discovered that our patient was, indeed, HLA-DQB1 and HLA-DQ2 positive. Had we implemented HLA screening prior to initiating clozapine, we could have potentially avoided her CIA.
3.2. Management Protocol for Clozapine-Induced Agranulocytosis
While standard procedures for the management of CIA have been established, many of the details remain either up to physician determination or unestablished guidelines. Filgrastim/G-CSF has been shown to decrease the recovery time associated with agranulocytosis [7]. However, there is not an established dose for filgrastim for the treatment of CIA. There are established guidelines for filgrastim/G-CSF use in patients suffering from a number of immunocompromising diseases and cancers [22]. However, there is no direct guidance for administering filgrastim for patients suffering from CIA. Filgrastim/G-CSF is available in 300 mcg or 480 mcg vials or single dose syringes with recommended starting dose 5mcg/kg/day [22]. It is recommended to be administered up to 2 weeks or until ANC has reached 10,000/mm3 and is to be discontinued if ANC surpasses 10,000/mm3 after expected nadir [22].
In our patient, treatment of CIA took a total of 10 days of which Neupogen was dosed a total of 6 days with dosages of 300 mcg and 800 mcg (see Table 1) for patient recovery to a normal range of WBC 7 L and ANC 3.97 μL. Further study may provide more efficient dosing and thus more expedient and cost-effective care.
There also continues to be nebulous guidelines in management of CIA through the utilization of bone marrow aspirate and biopsy. Current protocol in the initial studies for the diagnosis of CIA includes CBC, white cell differential, examination of the peripheral smear, observation of recovery after cessation of the drug in a healthy patient, bacterial and/or viral studies if the patient is febrile, and a bone marrow aspiration and biopsy [12, 14]. As the utilization of the bone marrow biopsy is to ascertain patient granulopoiesis status, physicians may choose to begin filgrastim/G-CSF treatment prior to performing a bone marrow aspirate. For our case, hematology recommended bone marrow biopsy on Treatment day 3 to rule out WBC aplasia; however, they suggested performing the biopsy only if the increased filgrastim dose to 800 mcg did not prove effective in improving neutrophils levels. When peripheral blood screening revealed cellular morphology categorized as normal, a bone marrow biopsy was not performed on our subject. Importantly, upon literature review, there are no stated guidelines on when to perform the bone biopsy [10, 14].
3.3. Valproic Acid and CYP Effects
Finally, while clozapine was immediately discontinued upon admission, valproate was continued throughout the duration of treatment for the patient's schizoaffective disorder (see Table 1). There has been suggestion that valproate may be a clozapine metabolism inducer [23], the serum valproate level was subtherapeutic 36.5 (50-100) on treatment day 0/admission to the medicine floor, and the clozapine level was not taken at admission; so, no definitive conclusion can be made. Other studies suggest that valproate is a weak inhibitor of CYP 3A4 [24, 25] and potent CYP 2C9 inhibitor [26, 27]. Additionally, in 2018, the Malik et al. case control study of 136 cases found an association of increased risk of CIA in those with concurrent use of sodium valproate and clozapine [28]. These findings might suggest that our subjects' concomitant dosing of valproate with her clozapine could have exacerbated the clozapine effect causing CIA. Should these theories prove true on larger study, the decision to continue the patient's prescription of valproate during treatment for CIA could have elongated the recovery process due to the CYP inhibitor effects of valproate on clozapine levels. Future investigation for drug interaction of valproate with clozapine together should be studied. Should valproate prove to be a CYP inhibitor, or exacerbate CIA, standardized guidelines should indicate valproate be discontinued in future findings of CIA, and alternative therapeutics should be explored. Additionally, adjunctive use of lithium with clozapine has been initially investigated to mitigate the level of neutropenia for those experiencing CIA [29]. Additional study into adjunct dosing of lithium should be investigated. Concurrent use of valproate with clozapine, adjunct dosing of lithium, and other patient risk factors may need to be considered while determining proper individualized treatment.
4. Conclusion
Through this case of CIA in a patient with longstanding schizoaffective disorder, CKD, and HLA-DQB1 and HLA-DQ2 positivity, the importance of implementing a standardized screen which accounts for the renal function and HLA status is imperative for safe practices in prescribing clozapine for psychiatric disorders and mitigating the risk for CIA. Additionally, proper standardized monitoring of renal status through the treatment process may also mitigate risk of potential kidney failure. Further study is necessary to distinguish valproate's role in agranulocytosis singularly or in concert with clozapine. More detailed standardized guidelines would be beneficial for treatment of CIA, should it occur. As clozapine is known as a drug of last resort to be administered when there is failure of more traditional, and risk averse therapeutics, it is difficult to deny this treatment option, as it ultimately implies that all other treatment options have been exhausted. Proper screening and established protocol and guidelines could increase the level of monitoring in patients with known risk factors as revealed by the official screen. This risk factor screen and subsequent monitoring could increase the cost-effectiveness of clozapine treatment and decrease the incidence and morbidity of this feared adverse event.
Acknowledgments
The authors would like to thank the nursing staff and social workers for their day-to-day involvement in the care of the patient. We would also like to thank the following residents for the day-to-day involvement in managing the care of our patient: Chris Alfred, Ainsley Backman, Vito D'Angelo, Randy Lai, and Jai Patel. We would also like to thank Jonathan Eckstein, Steven Rubel, and Albert Strojan for the feedback given during the development of this paper. The authors also would like to thank Alvin Holcomb for the role he plays in resident medical education on a daily basis.
Abbreviations
CIA: Clozapine-induced agranulocytosis
ANC: Absolute neutrophil count
DVT: Deep vein thrombosis
CKD: Chronic kidney disease
AKI: Acute kidney injury
CYP: Cytochrome P450
EMS: Emergency medical services
ED: Emergency department
HLA: Human leukocyte antigen
G-CSF: Granulocyte-colony stimulating factor.
Data Availability
The subject data used to support the findings of this study are included in the Table within the article. Prior studies used to support the findings of this study are cited at relevant places within the text as references [1–29].
Consent
Written informed consent was obtained and is on the file.
Conflicts of Interest
The authors declare that there that there is no conflict of interest regarding the publication of this article.
Table 1 Treatment course lab table.
Treatment day Treatment day 0 Treatment day 1 Treatment day 2 Treatment day 3 Treatment day 4 Treatment day 5 Treatment day 6 Treatment day 7 Treatment day 8 Treatment day 9 Treatment day 10 Treatment day 11 Treatment day 12
Lab value
ANC level (μL) 0.05 0 0.01 0.01 0.01 0.01 0 0.02 0.04 0.57 3.97 11.51 10.38
WBC (L) N/A 0.4 0.4 0.3 0.2 0.3 0.2 0.3 0.4 1.8 7 18.7 N/A
Temperature max 98.8 98.6 100.7 103.1 101 98.5 99.3 97.3 98.1 98.6 97.8 97.7 98.1
BP 127/79 144/77 110/59 113/48 131/59 101/53 129/61 127/65 119/64 130/75 117/65 130/70
Hgb (G/DL) 10.4 9.9 11 10.5 9.8 8.9 8.5 8 8 8.6 9.6 9.3 8.4
Hematocrit (%) 33.8 31.8 36.4 33.6 31.6 29.3 27.2 26.3 26.1 28.1 32.2 30.6 28.6
H&H 10.4/33.8 9.9/31.8 11.0/36.4 10.5/33.6 9.8/31.6 8.9/29.3 8.5/27.2 8.0/26.3 8.0/26.1 8.6/28.1 9.6/32.2 9.3/30.6 8.4/28.6
BUN N/A N/A 38 36 46 55 77 70 57 43 33 29 25
CR N/A N/A 1.57 1.93 2.3 2.8 3.2 2.45 1.98 1.69 1.75 1.55 1.59
eGFR N/A N/A 33.61 26.48 21.63 17.24 14.78 20.11 25.71 30.87 29.65 34.11 33.12
Valproate level 36.5 L 50.9 L
Amlodipine dose 10 mg 10 mg 10 mg Not given Not given 10 mg 10 mg 10 mg Refused 10 mg 10 mg 10 mg 10 mg
Docusate dose Refused 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg
PEG dose 17 grams 17 grams
Valproate dose 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d
Filgrastim dose N/A 300 mcg 300 mcg 800 mcg 800 mcg 800 mcg N/A N/A 800 mcg N/A N/A N/A N/A | AMLODIPINE BESYLATE, CLOZAPINE, DOCUSATE, OLANZAPINE, POLYETHYLENE GLYCOLS, RISPERIDONE, VALPROIC ACID | DrugsGivenReaction | CC BY | 33688445 | 19,037,229 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal failure'. | Considerations of HLA, Renal Failure, Valproic Acid Use, and Current Treatment Guidelines in Clozapine-Induced Agranulocytosis.
Clozapine, the choice atypical antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder, has been shown to reduce positive and negative symptoms of schizophrenia. Clozapine, though beneficial in reducing the need for hospitalization, rehabilitation, and health care costs, is known as a drug of last resort due to its potential adverse event of clozapine-induced agranulocytosis, which holds a case fatality rate between 4.2 and 16%. Herein, we describe a female patient with longstanding schizoaffective disorder and chronic kidney disease who suffered from clozapine-induced agranulocytosis after failing two other atypical antipsychotics. Retrospective considerations of this case and management highlight risk factors such as HLA status, renal failure, and concurrent valproic acid use which presently do not have official screening, guidelines, or restrictions in place when prescribing clozapine. Additionally, there are no specific clozapine-induced agranulocytosis management recommendations such as G-CSF/filgrastim dose, timing of bone marrow aspirate and biopsy, and use of concomitant valproate. We propose that further comprehensive official screening, monitoring, and guidelines in the prescribing of clozapine, and further guidelines in the treatment of clozapine induced agranulocytosis, could increase the cost-effectiveness of clozapine treatment, and decrease the incidence, and morbidity of this feared adverse event.
1. Introduction
Clozapine, a dibenzodiazepine antipsychotic exhibiting weak dopaminergic activity and atypical pharmacological properties, is the choice antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder [1–4]. Advantages of clozapine include decreased positive symptoms of schizophrenia such as voices and hallucinations and decreased negative symptoms such as blunted affect and suicidal behavior [5]. The decreased positive and negative symptoms result in reduced need for hospitalization, rehabilitation, and subsequent health care costs [6]. However, known and feared disadvantages include neutropenia and life-threatening agranulocytosis [7, 8].
A benign form of neutropenia with an absolute neutrophil count (ANC) < 1500 cells/μL [9] is known to occur more frequently than clinically significant, agranulocytosis, where ANC < 500 cells/μL [10]. A high risk of severe and/or opportunistic infections is noted to be associated with ANC <200 [9]. In 2008, clozapine-induced agranulocytosis (CIA) had a known rate of seven cases per one million [11]. In 2006, the case fatality caused by CIA was estimated to be 4.2% to 16% [12]. In 2016, the observed mortality rate ranged from 0.1 and 0.3 per thousand, and the case fatality rate was estimated to be between 2.2 and 4.2 [13]. Standard established protocol includes immediate discontinuation of clozapine should white blood cell count reach <500 ANC [10, 14]. Patients' WBC and ANC must be monitored daily until WBC > 3000/mm3 and ANC > 1500/mm3 [7].
As more cases of CIA are occurring, more information concerning prescribing this efficacious antipsychotic as well as the treatment of CIA has become available. Here, we describe a patient with longstanding schizoaffective disorder who suffered from CIA after being transitioned to clozapine due to failed trials of risperidone and olanzapine. Retrospective considerations of her placement on clozapine and subsequent management of her CIA brought into question many factors which do not have clear guidelines, including official screening of risk factors which increase likelihood of CIA, as well as clear clinical management for this feared adverse event. This case report provides a spotlight on many factors such as screening for chronic kidney disease (CKD), human leukocyte antigen(HLA) typing, concurrent valproate administration due to potential CYP interactions, and management considerations such as dosing for filgrastim/G-CSF and timing of bone marrow biopsy. This analysis aims for further study and ultimately future implementation of screening and management guidelines for better informed management of refractory schizophrenia treatment, reduced cases of CIA, and improved management of CIA should it occur.
2. Case Presentation
A 60-year-old Caucasian female nursing home resident was brought in by EMS to the ED due to disorganized behavior, auditory hallucinations, and disorganized speech with loosening associations and was admitted to the inpatient psychiatric unit. Past psychiatric history included longstanding schizoaffective disorder. As a psychiatric inpatient, after having failed treatment with risperidone and olanzapine, the patient was started on clozapine 25 mg PO daily and was titrated to 150 mg PO BID over the course of 28 days. Recorded WBC on day 28 of treatment was 4.5 × 109/L (4.5 to 11.0 × 109/L). On the 35th day of clozapine treatment, the patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. WBC was found to be 0.2 × 109/L (4.5 to 11.0 × 109/L), and ANC was 0.05 [1.5 to 8.0 (1,500 to 8,000/mm3)]. The valproate level was 36.5 (50-100). Subsequently, the patient was transferred to the inpatient medicine floor this same day due to clozapine-induced leukocytopenia (day of transfer to medicine/Treatment day 0).
Past medical history included arthritis, deep vein thrombosis, chronic kidney disease (CKD) (stage 3), right bundle branch block, left anterior fascicular block, syncope, and epilepsy. On admission, patient was alert and oriented ×2 to self and place. The patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. The patient denied headache, shortness of breath, abdominal pain, dysuria, or urinary frequency. The patient's allergies included penicillamine, penicillin, and shellfish. Active medications included sodium valproate, amlodipine, docusate, and polyethylene glycol. Physical exam was unremarkable, and vitals were within normal limits (See Table 1).
2.1. Treatment Course
On the day of transfer to medicine (Treatment day 0-Table 1), clozapine was immediately discontinued, the patient was placed in reverse isolation, and a throat culture was taken. On Treatment day 1, upon recommendation from hematology, the patient received filgrastim/G-CSF 300 mcg subcutaneously. The patient continued this dosage of filgrastim for two days along with home dose of valproate.
On Treatment day 3, the patient spiked a fever of 103.1°F. A fever source was investigated, and an uncomplicated cellulitis on the abdominal wall was found. Filgrastim was adjusted to a dose of 800 mcg subcutaneous daily (see Table 1), and the patient was administered acetaminophen, aztreonam, clindamycin, and gentamicin while monitoring the kidney function.
Gentamicin was discontinued on Treatment day 5 (two days after initiation) when eGFR was 17.24 indicative of AKI stage 4 (see Table 1). Aztreonam and clindamycin were continued till Treatment day 6, and micafungin and meropenem administration began on Treatment day 7.
Patient status stabilized on Treatment day 10 when her ANC count rose to 1.8, up from 0.4 on Treatment day 9 (See Table 1). The patient remained hospitalized an additional two days to correct electrolyte abnormalities.
3. Discussion
As CIA has become more prevalent, it has been noted that risk factors and poor prognostic indicators include female sex, increasing age, ANC < 100, preexisting renal, cardiac or inflammatory disease comorbidities, and sepsis. [14]. Considering these factors, the 60 years of age in our female patient, her CKD, the acquisition of cellulitis during her treatment, and ANC of 5, we were satisfied with the treatment course and outcome. However, other factors have been noted in literature to potentially increase susceptibility of CIA. Specific human leukocyte antigen (HLA) has been identified for increased susceptibility to CIA. Potential CYP reactions in valproate, which remain unclear in literature, could also potentially increase risk of CIA. And certain treatment guidelines of CIA remain vague in literature. Clinical screening either separately or combined for many of these risk factors should be established. Additionally, consideration for a standardized protocol for timeline and dosing of treatment for CIA should be established.
3.1. Screening: Renal Failure and HLA
Though CIA is an adverse event which occurs in less than 1% of adults with psychiatric conditions [15], more research is being conducted to determine risk factors which may increase the likelihood of patients developing this condition. By screening for risk factors, we may mitigate the occurrence of these events. It is noted that our patient who had a past medical history of CKD was dosed with gentamicin upon initial fever of 103.1°F on Treatment day 3. Though gentamicin has known nephrotoxic effects and was thus discontinued to prevent further kidney toxicity, many case reports have suggested that clozapine may induce and/or exacerbate renal failure and nephritis [16–19]. While further research is necessary to quantify the precise risk of clozapine on the kidney function, prior to initiating a trial dose of clozapine, including a thorough history, measuring a patient's kidney function, or eGFR, and BUN/creatinine panel in addition to weekly monitoring of clozapine and ANC levels may reduce exacerbation of CKD.
Associations between susceptibility of CIA and human leukocyte antigen (HLA) were initially reported in the 1990s [20]. In 2014, HLA-DQB1 and HLA-B alleles were specifically implicated in amino acid changes responsible for patient's susceptibility to CIA [21]. Currently, there is no guidance on mandatory panels or screening for HLA alleles prior to administration of clozapine though such screening has been shown to be health and cost-effective [15]. While the past medical history indicated that our subject had been diagnosed with arthritis, we did not investigate which type of arthritis. We performed HLA screening towards the end of her CIA treatment and discovered that our patient was, indeed, HLA-DQB1 and HLA-DQ2 positive. Had we implemented HLA screening prior to initiating clozapine, we could have potentially avoided her CIA.
3.2. Management Protocol for Clozapine-Induced Agranulocytosis
While standard procedures for the management of CIA have been established, many of the details remain either up to physician determination or unestablished guidelines. Filgrastim/G-CSF has been shown to decrease the recovery time associated with agranulocytosis [7]. However, there is not an established dose for filgrastim for the treatment of CIA. There are established guidelines for filgrastim/G-CSF use in patients suffering from a number of immunocompromising diseases and cancers [22]. However, there is no direct guidance for administering filgrastim for patients suffering from CIA. Filgrastim/G-CSF is available in 300 mcg or 480 mcg vials or single dose syringes with recommended starting dose 5mcg/kg/day [22]. It is recommended to be administered up to 2 weeks or until ANC has reached 10,000/mm3 and is to be discontinued if ANC surpasses 10,000/mm3 after expected nadir [22].
In our patient, treatment of CIA took a total of 10 days of which Neupogen was dosed a total of 6 days with dosages of 300 mcg and 800 mcg (see Table 1) for patient recovery to a normal range of WBC 7 L and ANC 3.97 μL. Further study may provide more efficient dosing and thus more expedient and cost-effective care.
There also continues to be nebulous guidelines in management of CIA through the utilization of bone marrow aspirate and biopsy. Current protocol in the initial studies for the diagnosis of CIA includes CBC, white cell differential, examination of the peripheral smear, observation of recovery after cessation of the drug in a healthy patient, bacterial and/or viral studies if the patient is febrile, and a bone marrow aspiration and biopsy [12, 14]. As the utilization of the bone marrow biopsy is to ascertain patient granulopoiesis status, physicians may choose to begin filgrastim/G-CSF treatment prior to performing a bone marrow aspirate. For our case, hematology recommended bone marrow biopsy on Treatment day 3 to rule out WBC aplasia; however, they suggested performing the biopsy only if the increased filgrastim dose to 800 mcg did not prove effective in improving neutrophils levels. When peripheral blood screening revealed cellular morphology categorized as normal, a bone marrow biopsy was not performed on our subject. Importantly, upon literature review, there are no stated guidelines on when to perform the bone biopsy [10, 14].
3.3. Valproic Acid and CYP Effects
Finally, while clozapine was immediately discontinued upon admission, valproate was continued throughout the duration of treatment for the patient's schizoaffective disorder (see Table 1). There has been suggestion that valproate may be a clozapine metabolism inducer [23], the serum valproate level was subtherapeutic 36.5 (50-100) on treatment day 0/admission to the medicine floor, and the clozapine level was not taken at admission; so, no definitive conclusion can be made. Other studies suggest that valproate is a weak inhibitor of CYP 3A4 [24, 25] and potent CYP 2C9 inhibitor [26, 27]. Additionally, in 2018, the Malik et al. case control study of 136 cases found an association of increased risk of CIA in those with concurrent use of sodium valproate and clozapine [28]. These findings might suggest that our subjects' concomitant dosing of valproate with her clozapine could have exacerbated the clozapine effect causing CIA. Should these theories prove true on larger study, the decision to continue the patient's prescription of valproate during treatment for CIA could have elongated the recovery process due to the CYP inhibitor effects of valproate on clozapine levels. Future investigation for drug interaction of valproate with clozapine together should be studied. Should valproate prove to be a CYP inhibitor, or exacerbate CIA, standardized guidelines should indicate valproate be discontinued in future findings of CIA, and alternative therapeutics should be explored. Additionally, adjunctive use of lithium with clozapine has been initially investigated to mitigate the level of neutropenia for those experiencing CIA [29]. Additional study into adjunct dosing of lithium should be investigated. Concurrent use of valproate with clozapine, adjunct dosing of lithium, and other patient risk factors may need to be considered while determining proper individualized treatment.
4. Conclusion
Through this case of CIA in a patient with longstanding schizoaffective disorder, CKD, and HLA-DQB1 and HLA-DQ2 positivity, the importance of implementing a standardized screen which accounts for the renal function and HLA status is imperative for safe practices in prescribing clozapine for psychiatric disorders and mitigating the risk for CIA. Additionally, proper standardized monitoring of renal status through the treatment process may also mitigate risk of potential kidney failure. Further study is necessary to distinguish valproate's role in agranulocytosis singularly or in concert with clozapine. More detailed standardized guidelines would be beneficial for treatment of CIA, should it occur. As clozapine is known as a drug of last resort to be administered when there is failure of more traditional, and risk averse therapeutics, it is difficult to deny this treatment option, as it ultimately implies that all other treatment options have been exhausted. Proper screening and established protocol and guidelines could increase the level of monitoring in patients with known risk factors as revealed by the official screen. This risk factor screen and subsequent monitoring could increase the cost-effectiveness of clozapine treatment and decrease the incidence and morbidity of this feared adverse event.
Acknowledgments
The authors would like to thank the nursing staff and social workers for their day-to-day involvement in the care of the patient. We would also like to thank the following residents for the day-to-day involvement in managing the care of our patient: Chris Alfred, Ainsley Backman, Vito D'Angelo, Randy Lai, and Jai Patel. We would also like to thank Jonathan Eckstein, Steven Rubel, and Albert Strojan for the feedback given during the development of this paper. The authors also would like to thank Alvin Holcomb for the role he plays in resident medical education on a daily basis.
Abbreviations
CIA: Clozapine-induced agranulocytosis
ANC: Absolute neutrophil count
DVT: Deep vein thrombosis
CKD: Chronic kidney disease
AKI: Acute kidney injury
CYP: Cytochrome P450
EMS: Emergency medical services
ED: Emergency department
HLA: Human leukocyte antigen
G-CSF: Granulocyte-colony stimulating factor.
Data Availability
The subject data used to support the findings of this study are included in the Table within the article. Prior studies used to support the findings of this study are cited at relevant places within the text as references [1–29].
Consent
Written informed consent was obtained and is on the file.
Conflicts of Interest
The authors declare that there that there is no conflict of interest regarding the publication of this article.
Table 1 Treatment course lab table.
Treatment day Treatment day 0 Treatment day 1 Treatment day 2 Treatment day 3 Treatment day 4 Treatment day 5 Treatment day 6 Treatment day 7 Treatment day 8 Treatment day 9 Treatment day 10 Treatment day 11 Treatment day 12
Lab value
ANC level (μL) 0.05 0 0.01 0.01 0.01 0.01 0 0.02 0.04 0.57 3.97 11.51 10.38
WBC (L) N/A 0.4 0.4 0.3 0.2 0.3 0.2 0.3 0.4 1.8 7 18.7 N/A
Temperature max 98.8 98.6 100.7 103.1 101 98.5 99.3 97.3 98.1 98.6 97.8 97.7 98.1
BP 127/79 144/77 110/59 113/48 131/59 101/53 129/61 127/65 119/64 130/75 117/65 130/70
Hgb (G/DL) 10.4 9.9 11 10.5 9.8 8.9 8.5 8 8 8.6 9.6 9.3 8.4
Hematocrit (%) 33.8 31.8 36.4 33.6 31.6 29.3 27.2 26.3 26.1 28.1 32.2 30.6 28.6
H&H 10.4/33.8 9.9/31.8 11.0/36.4 10.5/33.6 9.8/31.6 8.9/29.3 8.5/27.2 8.0/26.3 8.0/26.1 8.6/28.1 9.6/32.2 9.3/30.6 8.4/28.6
BUN N/A N/A 38 36 46 55 77 70 57 43 33 29 25
CR N/A N/A 1.57 1.93 2.3 2.8 3.2 2.45 1.98 1.69 1.75 1.55 1.59
eGFR N/A N/A 33.61 26.48 21.63 17.24 14.78 20.11 25.71 30.87 29.65 34.11 33.12
Valproate level 36.5 L 50.9 L
Amlodipine dose 10 mg 10 mg 10 mg Not given Not given 10 mg 10 mg 10 mg Refused 10 mg 10 mg 10 mg 10 mg
Docusate dose Refused 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg
PEG dose 17 grams 17 grams
Valproate dose 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d
Filgrastim dose N/A 300 mcg 300 mcg 800 mcg 800 mcg 800 mcg N/A N/A 800 mcg N/A N/A N/A N/A | ACETAMINOPHEN, AMLODIPINE BESYLATE, AZTREONAM, CLINDAMYCIN, CLOZAPINE, DOCUSATE, GENTAMICIN, OLANZAPINE, POLYETHYLENE GLYCOLS, RISPERIDONE, VALPROATE SODIUM | DrugsGivenReaction | CC BY | 33688445 | 19,142,002 | 2021 |
What was the administration route of drug 'CLOZAPINE'? | Considerations of HLA, Renal Failure, Valproic Acid Use, and Current Treatment Guidelines in Clozapine-Induced Agranulocytosis.
Clozapine, the choice atypical antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder, has been shown to reduce positive and negative symptoms of schizophrenia. Clozapine, though beneficial in reducing the need for hospitalization, rehabilitation, and health care costs, is known as a drug of last resort due to its potential adverse event of clozapine-induced agranulocytosis, which holds a case fatality rate between 4.2 and 16%. Herein, we describe a female patient with longstanding schizoaffective disorder and chronic kidney disease who suffered from clozapine-induced agranulocytosis after failing two other atypical antipsychotics. Retrospective considerations of this case and management highlight risk factors such as HLA status, renal failure, and concurrent valproic acid use which presently do not have official screening, guidelines, or restrictions in place when prescribing clozapine. Additionally, there are no specific clozapine-induced agranulocytosis management recommendations such as G-CSF/filgrastim dose, timing of bone marrow aspirate and biopsy, and use of concomitant valproate. We propose that further comprehensive official screening, monitoring, and guidelines in the prescribing of clozapine, and further guidelines in the treatment of clozapine induced agranulocytosis, could increase the cost-effectiveness of clozapine treatment, and decrease the incidence, and morbidity of this feared adverse event.
1. Introduction
Clozapine, a dibenzodiazepine antipsychotic exhibiting weak dopaminergic activity and atypical pharmacological properties, is the choice antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder [1–4]. Advantages of clozapine include decreased positive symptoms of schizophrenia such as voices and hallucinations and decreased negative symptoms such as blunted affect and suicidal behavior [5]. The decreased positive and negative symptoms result in reduced need for hospitalization, rehabilitation, and subsequent health care costs [6]. However, known and feared disadvantages include neutropenia and life-threatening agranulocytosis [7, 8].
A benign form of neutropenia with an absolute neutrophil count (ANC) < 1500 cells/μL [9] is known to occur more frequently than clinically significant, agranulocytosis, where ANC < 500 cells/μL [10]. A high risk of severe and/or opportunistic infections is noted to be associated with ANC <200 [9]. In 2008, clozapine-induced agranulocytosis (CIA) had a known rate of seven cases per one million [11]. In 2006, the case fatality caused by CIA was estimated to be 4.2% to 16% [12]. In 2016, the observed mortality rate ranged from 0.1 and 0.3 per thousand, and the case fatality rate was estimated to be between 2.2 and 4.2 [13]. Standard established protocol includes immediate discontinuation of clozapine should white blood cell count reach <500 ANC [10, 14]. Patients' WBC and ANC must be monitored daily until WBC > 3000/mm3 and ANC > 1500/mm3 [7].
As more cases of CIA are occurring, more information concerning prescribing this efficacious antipsychotic as well as the treatment of CIA has become available. Here, we describe a patient with longstanding schizoaffective disorder who suffered from CIA after being transitioned to clozapine due to failed trials of risperidone and olanzapine. Retrospective considerations of her placement on clozapine and subsequent management of her CIA brought into question many factors which do not have clear guidelines, including official screening of risk factors which increase likelihood of CIA, as well as clear clinical management for this feared adverse event. This case report provides a spotlight on many factors such as screening for chronic kidney disease (CKD), human leukocyte antigen(HLA) typing, concurrent valproate administration due to potential CYP interactions, and management considerations such as dosing for filgrastim/G-CSF and timing of bone marrow biopsy. This analysis aims for further study and ultimately future implementation of screening and management guidelines for better informed management of refractory schizophrenia treatment, reduced cases of CIA, and improved management of CIA should it occur.
2. Case Presentation
A 60-year-old Caucasian female nursing home resident was brought in by EMS to the ED due to disorganized behavior, auditory hallucinations, and disorganized speech with loosening associations and was admitted to the inpatient psychiatric unit. Past psychiatric history included longstanding schizoaffective disorder. As a psychiatric inpatient, after having failed treatment with risperidone and olanzapine, the patient was started on clozapine 25 mg PO daily and was titrated to 150 mg PO BID over the course of 28 days. Recorded WBC on day 28 of treatment was 4.5 × 109/L (4.5 to 11.0 × 109/L). On the 35th day of clozapine treatment, the patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. WBC was found to be 0.2 × 109/L (4.5 to 11.0 × 109/L), and ANC was 0.05 [1.5 to 8.0 (1,500 to 8,000/mm3)]. The valproate level was 36.5 (50-100). Subsequently, the patient was transferred to the inpatient medicine floor this same day due to clozapine-induced leukocytopenia (day of transfer to medicine/Treatment day 0).
Past medical history included arthritis, deep vein thrombosis, chronic kidney disease (CKD) (stage 3), right bundle branch block, left anterior fascicular block, syncope, and epilepsy. On admission, patient was alert and oriented ×2 to self and place. The patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. The patient denied headache, shortness of breath, abdominal pain, dysuria, or urinary frequency. The patient's allergies included penicillamine, penicillin, and shellfish. Active medications included sodium valproate, amlodipine, docusate, and polyethylene glycol. Physical exam was unremarkable, and vitals were within normal limits (See Table 1).
2.1. Treatment Course
On the day of transfer to medicine (Treatment day 0-Table 1), clozapine was immediately discontinued, the patient was placed in reverse isolation, and a throat culture was taken. On Treatment day 1, upon recommendation from hematology, the patient received filgrastim/G-CSF 300 mcg subcutaneously. The patient continued this dosage of filgrastim for two days along with home dose of valproate.
On Treatment day 3, the patient spiked a fever of 103.1°F. A fever source was investigated, and an uncomplicated cellulitis on the abdominal wall was found. Filgrastim was adjusted to a dose of 800 mcg subcutaneous daily (see Table 1), and the patient was administered acetaminophen, aztreonam, clindamycin, and gentamicin while monitoring the kidney function.
Gentamicin was discontinued on Treatment day 5 (two days after initiation) when eGFR was 17.24 indicative of AKI stage 4 (see Table 1). Aztreonam and clindamycin were continued till Treatment day 6, and micafungin and meropenem administration began on Treatment day 7.
Patient status stabilized on Treatment day 10 when her ANC count rose to 1.8, up from 0.4 on Treatment day 9 (See Table 1). The patient remained hospitalized an additional two days to correct electrolyte abnormalities.
3. Discussion
As CIA has become more prevalent, it has been noted that risk factors and poor prognostic indicators include female sex, increasing age, ANC < 100, preexisting renal, cardiac or inflammatory disease comorbidities, and sepsis. [14]. Considering these factors, the 60 years of age in our female patient, her CKD, the acquisition of cellulitis during her treatment, and ANC of 5, we were satisfied with the treatment course and outcome. However, other factors have been noted in literature to potentially increase susceptibility of CIA. Specific human leukocyte antigen (HLA) has been identified for increased susceptibility to CIA. Potential CYP reactions in valproate, which remain unclear in literature, could also potentially increase risk of CIA. And certain treatment guidelines of CIA remain vague in literature. Clinical screening either separately or combined for many of these risk factors should be established. Additionally, consideration for a standardized protocol for timeline and dosing of treatment for CIA should be established.
3.1. Screening: Renal Failure and HLA
Though CIA is an adverse event which occurs in less than 1% of adults with psychiatric conditions [15], more research is being conducted to determine risk factors which may increase the likelihood of patients developing this condition. By screening for risk factors, we may mitigate the occurrence of these events. It is noted that our patient who had a past medical history of CKD was dosed with gentamicin upon initial fever of 103.1°F on Treatment day 3. Though gentamicin has known nephrotoxic effects and was thus discontinued to prevent further kidney toxicity, many case reports have suggested that clozapine may induce and/or exacerbate renal failure and nephritis [16–19]. While further research is necessary to quantify the precise risk of clozapine on the kidney function, prior to initiating a trial dose of clozapine, including a thorough history, measuring a patient's kidney function, or eGFR, and BUN/creatinine panel in addition to weekly monitoring of clozapine and ANC levels may reduce exacerbation of CKD.
Associations between susceptibility of CIA and human leukocyte antigen (HLA) were initially reported in the 1990s [20]. In 2014, HLA-DQB1 and HLA-B alleles were specifically implicated in amino acid changes responsible for patient's susceptibility to CIA [21]. Currently, there is no guidance on mandatory panels or screening for HLA alleles prior to administration of clozapine though such screening has been shown to be health and cost-effective [15]. While the past medical history indicated that our subject had been diagnosed with arthritis, we did not investigate which type of arthritis. We performed HLA screening towards the end of her CIA treatment and discovered that our patient was, indeed, HLA-DQB1 and HLA-DQ2 positive. Had we implemented HLA screening prior to initiating clozapine, we could have potentially avoided her CIA.
3.2. Management Protocol for Clozapine-Induced Agranulocytosis
While standard procedures for the management of CIA have been established, many of the details remain either up to physician determination or unestablished guidelines. Filgrastim/G-CSF has been shown to decrease the recovery time associated with agranulocytosis [7]. However, there is not an established dose for filgrastim for the treatment of CIA. There are established guidelines for filgrastim/G-CSF use in patients suffering from a number of immunocompromising diseases and cancers [22]. However, there is no direct guidance for administering filgrastim for patients suffering from CIA. Filgrastim/G-CSF is available in 300 mcg or 480 mcg vials or single dose syringes with recommended starting dose 5mcg/kg/day [22]. It is recommended to be administered up to 2 weeks or until ANC has reached 10,000/mm3 and is to be discontinued if ANC surpasses 10,000/mm3 after expected nadir [22].
In our patient, treatment of CIA took a total of 10 days of which Neupogen was dosed a total of 6 days with dosages of 300 mcg and 800 mcg (see Table 1) for patient recovery to a normal range of WBC 7 L and ANC 3.97 μL. Further study may provide more efficient dosing and thus more expedient and cost-effective care.
There also continues to be nebulous guidelines in management of CIA through the utilization of bone marrow aspirate and biopsy. Current protocol in the initial studies for the diagnosis of CIA includes CBC, white cell differential, examination of the peripheral smear, observation of recovery after cessation of the drug in a healthy patient, bacterial and/or viral studies if the patient is febrile, and a bone marrow aspiration and biopsy [12, 14]. As the utilization of the bone marrow biopsy is to ascertain patient granulopoiesis status, physicians may choose to begin filgrastim/G-CSF treatment prior to performing a bone marrow aspirate. For our case, hematology recommended bone marrow biopsy on Treatment day 3 to rule out WBC aplasia; however, they suggested performing the biopsy only if the increased filgrastim dose to 800 mcg did not prove effective in improving neutrophils levels. When peripheral blood screening revealed cellular morphology categorized as normal, a bone marrow biopsy was not performed on our subject. Importantly, upon literature review, there are no stated guidelines on when to perform the bone biopsy [10, 14].
3.3. Valproic Acid and CYP Effects
Finally, while clozapine was immediately discontinued upon admission, valproate was continued throughout the duration of treatment for the patient's schizoaffective disorder (see Table 1). There has been suggestion that valproate may be a clozapine metabolism inducer [23], the serum valproate level was subtherapeutic 36.5 (50-100) on treatment day 0/admission to the medicine floor, and the clozapine level was not taken at admission; so, no definitive conclusion can be made. Other studies suggest that valproate is a weak inhibitor of CYP 3A4 [24, 25] and potent CYP 2C9 inhibitor [26, 27]. Additionally, in 2018, the Malik et al. case control study of 136 cases found an association of increased risk of CIA in those with concurrent use of sodium valproate and clozapine [28]. These findings might suggest that our subjects' concomitant dosing of valproate with her clozapine could have exacerbated the clozapine effect causing CIA. Should these theories prove true on larger study, the decision to continue the patient's prescription of valproate during treatment for CIA could have elongated the recovery process due to the CYP inhibitor effects of valproate on clozapine levels. Future investigation for drug interaction of valproate with clozapine together should be studied. Should valproate prove to be a CYP inhibitor, or exacerbate CIA, standardized guidelines should indicate valproate be discontinued in future findings of CIA, and alternative therapeutics should be explored. Additionally, adjunctive use of lithium with clozapine has been initially investigated to mitigate the level of neutropenia for those experiencing CIA [29]. Additional study into adjunct dosing of lithium should be investigated. Concurrent use of valproate with clozapine, adjunct dosing of lithium, and other patient risk factors may need to be considered while determining proper individualized treatment.
4. Conclusion
Through this case of CIA in a patient with longstanding schizoaffective disorder, CKD, and HLA-DQB1 and HLA-DQ2 positivity, the importance of implementing a standardized screen which accounts for the renal function and HLA status is imperative for safe practices in prescribing clozapine for psychiatric disorders and mitigating the risk for CIA. Additionally, proper standardized monitoring of renal status through the treatment process may also mitigate risk of potential kidney failure. Further study is necessary to distinguish valproate's role in agranulocytosis singularly or in concert with clozapine. More detailed standardized guidelines would be beneficial for treatment of CIA, should it occur. As clozapine is known as a drug of last resort to be administered when there is failure of more traditional, and risk averse therapeutics, it is difficult to deny this treatment option, as it ultimately implies that all other treatment options have been exhausted. Proper screening and established protocol and guidelines could increase the level of monitoring in patients with known risk factors as revealed by the official screen. This risk factor screen and subsequent monitoring could increase the cost-effectiveness of clozapine treatment and decrease the incidence and morbidity of this feared adverse event.
Acknowledgments
The authors would like to thank the nursing staff and social workers for their day-to-day involvement in the care of the patient. We would also like to thank the following residents for the day-to-day involvement in managing the care of our patient: Chris Alfred, Ainsley Backman, Vito D'Angelo, Randy Lai, and Jai Patel. We would also like to thank Jonathan Eckstein, Steven Rubel, and Albert Strojan for the feedback given during the development of this paper. The authors also would like to thank Alvin Holcomb for the role he plays in resident medical education on a daily basis.
Abbreviations
CIA: Clozapine-induced agranulocytosis
ANC: Absolute neutrophil count
DVT: Deep vein thrombosis
CKD: Chronic kidney disease
AKI: Acute kidney injury
CYP: Cytochrome P450
EMS: Emergency medical services
ED: Emergency department
HLA: Human leukocyte antigen
G-CSF: Granulocyte-colony stimulating factor.
Data Availability
The subject data used to support the findings of this study are included in the Table within the article. Prior studies used to support the findings of this study are cited at relevant places within the text as references [1–29].
Consent
Written informed consent was obtained and is on the file.
Conflicts of Interest
The authors declare that there that there is no conflict of interest regarding the publication of this article.
Table 1 Treatment course lab table.
Treatment day Treatment day 0 Treatment day 1 Treatment day 2 Treatment day 3 Treatment day 4 Treatment day 5 Treatment day 6 Treatment day 7 Treatment day 8 Treatment day 9 Treatment day 10 Treatment day 11 Treatment day 12
Lab value
ANC level (μL) 0.05 0 0.01 0.01 0.01 0.01 0 0.02 0.04 0.57 3.97 11.51 10.38
WBC (L) N/A 0.4 0.4 0.3 0.2 0.3 0.2 0.3 0.4 1.8 7 18.7 N/A
Temperature max 98.8 98.6 100.7 103.1 101 98.5 99.3 97.3 98.1 98.6 97.8 97.7 98.1
BP 127/79 144/77 110/59 113/48 131/59 101/53 129/61 127/65 119/64 130/75 117/65 130/70
Hgb (G/DL) 10.4 9.9 11 10.5 9.8 8.9 8.5 8 8 8.6 9.6 9.3 8.4
Hematocrit (%) 33.8 31.8 36.4 33.6 31.6 29.3 27.2 26.3 26.1 28.1 32.2 30.6 28.6
H&H 10.4/33.8 9.9/31.8 11.0/36.4 10.5/33.6 9.8/31.6 8.9/29.3 8.5/27.2 8.0/26.3 8.0/26.1 8.6/28.1 9.6/32.2 9.3/30.6 8.4/28.6
BUN N/A N/A 38 36 46 55 77 70 57 43 33 29 25
CR N/A N/A 1.57 1.93 2.3 2.8 3.2 2.45 1.98 1.69 1.75 1.55 1.59
eGFR N/A N/A 33.61 26.48 21.63 17.24 14.78 20.11 25.71 30.87 29.65 34.11 33.12
Valproate level 36.5 L 50.9 L
Amlodipine dose 10 mg 10 mg 10 mg Not given Not given 10 mg 10 mg 10 mg Refused 10 mg 10 mg 10 mg 10 mg
Docusate dose Refused 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg
PEG dose 17 grams 17 grams
Valproate dose 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d
Filgrastim dose N/A 300 mcg 300 mcg 800 mcg 800 mcg 800 mcg N/A N/A 800 mcg N/A N/A N/A N/A | Oral | DrugAdministrationRoute | CC BY | 33688445 | 19,084,247 | 2021 |
What was the administration route of drug 'FILGRASTIM'? | Considerations of HLA, Renal Failure, Valproic Acid Use, and Current Treatment Guidelines in Clozapine-Induced Agranulocytosis.
Clozapine, the choice atypical antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder, has been shown to reduce positive and negative symptoms of schizophrenia. Clozapine, though beneficial in reducing the need for hospitalization, rehabilitation, and health care costs, is known as a drug of last resort due to its potential adverse event of clozapine-induced agranulocytosis, which holds a case fatality rate between 4.2 and 16%. Herein, we describe a female patient with longstanding schizoaffective disorder and chronic kidney disease who suffered from clozapine-induced agranulocytosis after failing two other atypical antipsychotics. Retrospective considerations of this case and management highlight risk factors such as HLA status, renal failure, and concurrent valproic acid use which presently do not have official screening, guidelines, or restrictions in place when prescribing clozapine. Additionally, there are no specific clozapine-induced agranulocytosis management recommendations such as G-CSF/filgrastim dose, timing of bone marrow aspirate and biopsy, and use of concomitant valproate. We propose that further comprehensive official screening, monitoring, and guidelines in the prescribing of clozapine, and further guidelines in the treatment of clozapine induced agranulocytosis, could increase the cost-effectiveness of clozapine treatment, and decrease the incidence, and morbidity of this feared adverse event.
1. Introduction
Clozapine, a dibenzodiazepine antipsychotic exhibiting weak dopaminergic activity and atypical pharmacological properties, is the choice antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder [1–4]. Advantages of clozapine include decreased positive symptoms of schizophrenia such as voices and hallucinations and decreased negative symptoms such as blunted affect and suicidal behavior [5]. The decreased positive and negative symptoms result in reduced need for hospitalization, rehabilitation, and subsequent health care costs [6]. However, known and feared disadvantages include neutropenia and life-threatening agranulocytosis [7, 8].
A benign form of neutropenia with an absolute neutrophil count (ANC) < 1500 cells/μL [9] is known to occur more frequently than clinically significant, agranulocytosis, where ANC < 500 cells/μL [10]. A high risk of severe and/or opportunistic infections is noted to be associated with ANC <200 [9]. In 2008, clozapine-induced agranulocytosis (CIA) had a known rate of seven cases per one million [11]. In 2006, the case fatality caused by CIA was estimated to be 4.2% to 16% [12]. In 2016, the observed mortality rate ranged from 0.1 and 0.3 per thousand, and the case fatality rate was estimated to be between 2.2 and 4.2 [13]. Standard established protocol includes immediate discontinuation of clozapine should white blood cell count reach <500 ANC [10, 14]. Patients' WBC and ANC must be monitored daily until WBC > 3000/mm3 and ANC > 1500/mm3 [7].
As more cases of CIA are occurring, more information concerning prescribing this efficacious antipsychotic as well as the treatment of CIA has become available. Here, we describe a patient with longstanding schizoaffective disorder who suffered from CIA after being transitioned to clozapine due to failed trials of risperidone and olanzapine. Retrospective considerations of her placement on clozapine and subsequent management of her CIA brought into question many factors which do not have clear guidelines, including official screening of risk factors which increase likelihood of CIA, as well as clear clinical management for this feared adverse event. This case report provides a spotlight on many factors such as screening for chronic kidney disease (CKD), human leukocyte antigen(HLA) typing, concurrent valproate administration due to potential CYP interactions, and management considerations such as dosing for filgrastim/G-CSF and timing of bone marrow biopsy. This analysis aims for further study and ultimately future implementation of screening and management guidelines for better informed management of refractory schizophrenia treatment, reduced cases of CIA, and improved management of CIA should it occur.
2. Case Presentation
A 60-year-old Caucasian female nursing home resident was brought in by EMS to the ED due to disorganized behavior, auditory hallucinations, and disorganized speech with loosening associations and was admitted to the inpatient psychiatric unit. Past psychiatric history included longstanding schizoaffective disorder. As a psychiatric inpatient, after having failed treatment with risperidone and olanzapine, the patient was started on clozapine 25 mg PO daily and was titrated to 150 mg PO BID over the course of 28 days. Recorded WBC on day 28 of treatment was 4.5 × 109/L (4.5 to 11.0 × 109/L). On the 35th day of clozapine treatment, the patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. WBC was found to be 0.2 × 109/L (4.5 to 11.0 × 109/L), and ANC was 0.05 [1.5 to 8.0 (1,500 to 8,000/mm3)]. The valproate level was 36.5 (50-100). Subsequently, the patient was transferred to the inpatient medicine floor this same day due to clozapine-induced leukocytopenia (day of transfer to medicine/Treatment day 0).
Past medical history included arthritis, deep vein thrombosis, chronic kidney disease (CKD) (stage 3), right bundle branch block, left anterior fascicular block, syncope, and epilepsy. On admission, patient was alert and oriented ×2 to self and place. The patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. The patient denied headache, shortness of breath, abdominal pain, dysuria, or urinary frequency. The patient's allergies included penicillamine, penicillin, and shellfish. Active medications included sodium valproate, amlodipine, docusate, and polyethylene glycol. Physical exam was unremarkable, and vitals were within normal limits (See Table 1).
2.1. Treatment Course
On the day of transfer to medicine (Treatment day 0-Table 1), clozapine was immediately discontinued, the patient was placed in reverse isolation, and a throat culture was taken. On Treatment day 1, upon recommendation from hematology, the patient received filgrastim/G-CSF 300 mcg subcutaneously. The patient continued this dosage of filgrastim for two days along with home dose of valproate.
On Treatment day 3, the patient spiked a fever of 103.1°F. A fever source was investigated, and an uncomplicated cellulitis on the abdominal wall was found. Filgrastim was adjusted to a dose of 800 mcg subcutaneous daily (see Table 1), and the patient was administered acetaminophen, aztreonam, clindamycin, and gentamicin while monitoring the kidney function.
Gentamicin was discontinued on Treatment day 5 (two days after initiation) when eGFR was 17.24 indicative of AKI stage 4 (see Table 1). Aztreonam and clindamycin were continued till Treatment day 6, and micafungin and meropenem administration began on Treatment day 7.
Patient status stabilized on Treatment day 10 when her ANC count rose to 1.8, up from 0.4 on Treatment day 9 (See Table 1). The patient remained hospitalized an additional two days to correct electrolyte abnormalities.
3. Discussion
As CIA has become more prevalent, it has been noted that risk factors and poor prognostic indicators include female sex, increasing age, ANC < 100, preexisting renal, cardiac or inflammatory disease comorbidities, and sepsis. [14]. Considering these factors, the 60 years of age in our female patient, her CKD, the acquisition of cellulitis during her treatment, and ANC of 5, we were satisfied with the treatment course and outcome. However, other factors have been noted in literature to potentially increase susceptibility of CIA. Specific human leukocyte antigen (HLA) has been identified for increased susceptibility to CIA. Potential CYP reactions in valproate, which remain unclear in literature, could also potentially increase risk of CIA. And certain treatment guidelines of CIA remain vague in literature. Clinical screening either separately or combined for many of these risk factors should be established. Additionally, consideration for a standardized protocol for timeline and dosing of treatment for CIA should be established.
3.1. Screening: Renal Failure and HLA
Though CIA is an adverse event which occurs in less than 1% of adults with psychiatric conditions [15], more research is being conducted to determine risk factors which may increase the likelihood of patients developing this condition. By screening for risk factors, we may mitigate the occurrence of these events. It is noted that our patient who had a past medical history of CKD was dosed with gentamicin upon initial fever of 103.1°F on Treatment day 3. Though gentamicin has known nephrotoxic effects and was thus discontinued to prevent further kidney toxicity, many case reports have suggested that clozapine may induce and/or exacerbate renal failure and nephritis [16–19]. While further research is necessary to quantify the precise risk of clozapine on the kidney function, prior to initiating a trial dose of clozapine, including a thorough history, measuring a patient's kidney function, or eGFR, and BUN/creatinine panel in addition to weekly monitoring of clozapine and ANC levels may reduce exacerbation of CKD.
Associations between susceptibility of CIA and human leukocyte antigen (HLA) were initially reported in the 1990s [20]. In 2014, HLA-DQB1 and HLA-B alleles were specifically implicated in amino acid changes responsible for patient's susceptibility to CIA [21]. Currently, there is no guidance on mandatory panels or screening for HLA alleles prior to administration of clozapine though such screening has been shown to be health and cost-effective [15]. While the past medical history indicated that our subject had been diagnosed with arthritis, we did not investigate which type of arthritis. We performed HLA screening towards the end of her CIA treatment and discovered that our patient was, indeed, HLA-DQB1 and HLA-DQ2 positive. Had we implemented HLA screening prior to initiating clozapine, we could have potentially avoided her CIA.
3.2. Management Protocol for Clozapine-Induced Agranulocytosis
While standard procedures for the management of CIA have been established, many of the details remain either up to physician determination or unestablished guidelines. Filgrastim/G-CSF has been shown to decrease the recovery time associated with agranulocytosis [7]. However, there is not an established dose for filgrastim for the treatment of CIA. There are established guidelines for filgrastim/G-CSF use in patients suffering from a number of immunocompromising diseases and cancers [22]. However, there is no direct guidance for administering filgrastim for patients suffering from CIA. Filgrastim/G-CSF is available in 300 mcg or 480 mcg vials or single dose syringes with recommended starting dose 5mcg/kg/day [22]. It is recommended to be administered up to 2 weeks or until ANC has reached 10,000/mm3 and is to be discontinued if ANC surpasses 10,000/mm3 after expected nadir [22].
In our patient, treatment of CIA took a total of 10 days of which Neupogen was dosed a total of 6 days with dosages of 300 mcg and 800 mcg (see Table 1) for patient recovery to a normal range of WBC 7 L and ANC 3.97 μL. Further study may provide more efficient dosing and thus more expedient and cost-effective care.
There also continues to be nebulous guidelines in management of CIA through the utilization of bone marrow aspirate and biopsy. Current protocol in the initial studies for the diagnosis of CIA includes CBC, white cell differential, examination of the peripheral smear, observation of recovery after cessation of the drug in a healthy patient, bacterial and/or viral studies if the patient is febrile, and a bone marrow aspiration and biopsy [12, 14]. As the utilization of the bone marrow biopsy is to ascertain patient granulopoiesis status, physicians may choose to begin filgrastim/G-CSF treatment prior to performing a bone marrow aspirate. For our case, hematology recommended bone marrow biopsy on Treatment day 3 to rule out WBC aplasia; however, they suggested performing the biopsy only if the increased filgrastim dose to 800 mcg did not prove effective in improving neutrophils levels. When peripheral blood screening revealed cellular morphology categorized as normal, a bone marrow biopsy was not performed on our subject. Importantly, upon literature review, there are no stated guidelines on when to perform the bone biopsy [10, 14].
3.3. Valproic Acid and CYP Effects
Finally, while clozapine was immediately discontinued upon admission, valproate was continued throughout the duration of treatment for the patient's schizoaffective disorder (see Table 1). There has been suggestion that valproate may be a clozapine metabolism inducer [23], the serum valproate level was subtherapeutic 36.5 (50-100) on treatment day 0/admission to the medicine floor, and the clozapine level was not taken at admission; so, no definitive conclusion can be made. Other studies suggest that valproate is a weak inhibitor of CYP 3A4 [24, 25] and potent CYP 2C9 inhibitor [26, 27]. Additionally, in 2018, the Malik et al. case control study of 136 cases found an association of increased risk of CIA in those with concurrent use of sodium valproate and clozapine [28]. These findings might suggest that our subjects' concomitant dosing of valproate with her clozapine could have exacerbated the clozapine effect causing CIA. Should these theories prove true on larger study, the decision to continue the patient's prescription of valproate during treatment for CIA could have elongated the recovery process due to the CYP inhibitor effects of valproate on clozapine levels. Future investigation for drug interaction of valproate with clozapine together should be studied. Should valproate prove to be a CYP inhibitor, or exacerbate CIA, standardized guidelines should indicate valproate be discontinued in future findings of CIA, and alternative therapeutics should be explored. Additionally, adjunctive use of lithium with clozapine has been initially investigated to mitigate the level of neutropenia for those experiencing CIA [29]. Additional study into adjunct dosing of lithium should be investigated. Concurrent use of valproate with clozapine, adjunct dosing of lithium, and other patient risk factors may need to be considered while determining proper individualized treatment.
4. Conclusion
Through this case of CIA in a patient with longstanding schizoaffective disorder, CKD, and HLA-DQB1 and HLA-DQ2 positivity, the importance of implementing a standardized screen which accounts for the renal function and HLA status is imperative for safe practices in prescribing clozapine for psychiatric disorders and mitigating the risk for CIA. Additionally, proper standardized monitoring of renal status through the treatment process may also mitigate risk of potential kidney failure. Further study is necessary to distinguish valproate's role in agranulocytosis singularly or in concert with clozapine. More detailed standardized guidelines would be beneficial for treatment of CIA, should it occur. As clozapine is known as a drug of last resort to be administered when there is failure of more traditional, and risk averse therapeutics, it is difficult to deny this treatment option, as it ultimately implies that all other treatment options have been exhausted. Proper screening and established protocol and guidelines could increase the level of monitoring in patients with known risk factors as revealed by the official screen. This risk factor screen and subsequent monitoring could increase the cost-effectiveness of clozapine treatment and decrease the incidence and morbidity of this feared adverse event.
Acknowledgments
The authors would like to thank the nursing staff and social workers for their day-to-day involvement in the care of the patient. We would also like to thank the following residents for the day-to-day involvement in managing the care of our patient: Chris Alfred, Ainsley Backman, Vito D'Angelo, Randy Lai, and Jai Patel. We would also like to thank Jonathan Eckstein, Steven Rubel, and Albert Strojan for the feedback given during the development of this paper. The authors also would like to thank Alvin Holcomb for the role he plays in resident medical education on a daily basis.
Abbreviations
CIA: Clozapine-induced agranulocytosis
ANC: Absolute neutrophil count
DVT: Deep vein thrombosis
CKD: Chronic kidney disease
AKI: Acute kidney injury
CYP: Cytochrome P450
EMS: Emergency medical services
ED: Emergency department
HLA: Human leukocyte antigen
G-CSF: Granulocyte-colony stimulating factor.
Data Availability
The subject data used to support the findings of this study are included in the Table within the article. Prior studies used to support the findings of this study are cited at relevant places within the text as references [1–29].
Consent
Written informed consent was obtained and is on the file.
Conflicts of Interest
The authors declare that there that there is no conflict of interest regarding the publication of this article.
Table 1 Treatment course lab table.
Treatment day Treatment day 0 Treatment day 1 Treatment day 2 Treatment day 3 Treatment day 4 Treatment day 5 Treatment day 6 Treatment day 7 Treatment day 8 Treatment day 9 Treatment day 10 Treatment day 11 Treatment day 12
Lab value
ANC level (μL) 0.05 0 0.01 0.01 0.01 0.01 0 0.02 0.04 0.57 3.97 11.51 10.38
WBC (L) N/A 0.4 0.4 0.3 0.2 0.3 0.2 0.3 0.4 1.8 7 18.7 N/A
Temperature max 98.8 98.6 100.7 103.1 101 98.5 99.3 97.3 98.1 98.6 97.8 97.7 98.1
BP 127/79 144/77 110/59 113/48 131/59 101/53 129/61 127/65 119/64 130/75 117/65 130/70
Hgb (G/DL) 10.4 9.9 11 10.5 9.8 8.9 8.5 8 8 8.6 9.6 9.3 8.4
Hematocrit (%) 33.8 31.8 36.4 33.6 31.6 29.3 27.2 26.3 26.1 28.1 32.2 30.6 28.6
H&H 10.4/33.8 9.9/31.8 11.0/36.4 10.5/33.6 9.8/31.6 8.9/29.3 8.5/27.2 8.0/26.3 8.0/26.1 8.6/28.1 9.6/32.2 9.3/30.6 8.4/28.6
BUN N/A N/A 38 36 46 55 77 70 57 43 33 29 25
CR N/A N/A 1.57 1.93 2.3 2.8 3.2 2.45 1.98 1.69 1.75 1.55 1.59
eGFR N/A N/A 33.61 26.48 21.63 17.24 14.78 20.11 25.71 30.87 29.65 34.11 33.12
Valproate level 36.5 L 50.9 L
Amlodipine dose 10 mg 10 mg 10 mg Not given Not given 10 mg 10 mg 10 mg Refused 10 mg 10 mg 10 mg 10 mg
Docusate dose Refused 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg
PEG dose 17 grams 17 grams
Valproate dose 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d
Filgrastim dose N/A 300 mcg 300 mcg 800 mcg 800 mcg 800 mcg N/A N/A 800 mcg N/A N/A N/A N/A | Subcutaneous | DrugAdministrationRoute | CC BY | 33688445 | 19,084,247 | 2021 |
What was the dosage of drug 'AZTREONAM'? | Considerations of HLA, Renal Failure, Valproic Acid Use, and Current Treatment Guidelines in Clozapine-Induced Agranulocytosis.
Clozapine, the choice atypical antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder, has been shown to reduce positive and negative symptoms of schizophrenia. Clozapine, though beneficial in reducing the need for hospitalization, rehabilitation, and health care costs, is known as a drug of last resort due to its potential adverse event of clozapine-induced agranulocytosis, which holds a case fatality rate between 4.2 and 16%. Herein, we describe a female patient with longstanding schizoaffective disorder and chronic kidney disease who suffered from clozapine-induced agranulocytosis after failing two other atypical antipsychotics. Retrospective considerations of this case and management highlight risk factors such as HLA status, renal failure, and concurrent valproic acid use which presently do not have official screening, guidelines, or restrictions in place when prescribing clozapine. Additionally, there are no specific clozapine-induced agranulocytosis management recommendations such as G-CSF/filgrastim dose, timing of bone marrow aspirate and biopsy, and use of concomitant valproate. We propose that further comprehensive official screening, monitoring, and guidelines in the prescribing of clozapine, and further guidelines in the treatment of clozapine induced agranulocytosis, could increase the cost-effectiveness of clozapine treatment, and decrease the incidence, and morbidity of this feared adverse event.
1. Introduction
Clozapine, a dibenzodiazepine antipsychotic exhibiting weak dopaminergic activity and atypical pharmacological properties, is the choice antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder [1–4]. Advantages of clozapine include decreased positive symptoms of schizophrenia such as voices and hallucinations and decreased negative symptoms such as blunted affect and suicidal behavior [5]. The decreased positive and negative symptoms result in reduced need for hospitalization, rehabilitation, and subsequent health care costs [6]. However, known and feared disadvantages include neutropenia and life-threatening agranulocytosis [7, 8].
A benign form of neutropenia with an absolute neutrophil count (ANC) < 1500 cells/μL [9] is known to occur more frequently than clinically significant, agranulocytosis, where ANC < 500 cells/μL [10]. A high risk of severe and/or opportunistic infections is noted to be associated with ANC <200 [9]. In 2008, clozapine-induced agranulocytosis (CIA) had a known rate of seven cases per one million [11]. In 2006, the case fatality caused by CIA was estimated to be 4.2% to 16% [12]. In 2016, the observed mortality rate ranged from 0.1 and 0.3 per thousand, and the case fatality rate was estimated to be between 2.2 and 4.2 [13]. Standard established protocol includes immediate discontinuation of clozapine should white blood cell count reach <500 ANC [10, 14]. Patients' WBC and ANC must be monitored daily until WBC > 3000/mm3 and ANC > 1500/mm3 [7].
As more cases of CIA are occurring, more information concerning prescribing this efficacious antipsychotic as well as the treatment of CIA has become available. Here, we describe a patient with longstanding schizoaffective disorder who suffered from CIA after being transitioned to clozapine due to failed trials of risperidone and olanzapine. Retrospective considerations of her placement on clozapine and subsequent management of her CIA brought into question many factors which do not have clear guidelines, including official screening of risk factors which increase likelihood of CIA, as well as clear clinical management for this feared adverse event. This case report provides a spotlight on many factors such as screening for chronic kidney disease (CKD), human leukocyte antigen(HLA) typing, concurrent valproate administration due to potential CYP interactions, and management considerations such as dosing for filgrastim/G-CSF and timing of bone marrow biopsy. This analysis aims for further study and ultimately future implementation of screening and management guidelines for better informed management of refractory schizophrenia treatment, reduced cases of CIA, and improved management of CIA should it occur.
2. Case Presentation
A 60-year-old Caucasian female nursing home resident was brought in by EMS to the ED due to disorganized behavior, auditory hallucinations, and disorganized speech with loosening associations and was admitted to the inpatient psychiatric unit. Past psychiatric history included longstanding schizoaffective disorder. As a psychiatric inpatient, after having failed treatment with risperidone and olanzapine, the patient was started on clozapine 25 mg PO daily and was titrated to 150 mg PO BID over the course of 28 days. Recorded WBC on day 28 of treatment was 4.5 × 109/L (4.5 to 11.0 × 109/L). On the 35th day of clozapine treatment, the patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. WBC was found to be 0.2 × 109/L (4.5 to 11.0 × 109/L), and ANC was 0.05 [1.5 to 8.0 (1,500 to 8,000/mm3)]. The valproate level was 36.5 (50-100). Subsequently, the patient was transferred to the inpatient medicine floor this same day due to clozapine-induced leukocytopenia (day of transfer to medicine/Treatment day 0).
Past medical history included arthritis, deep vein thrombosis, chronic kidney disease (CKD) (stage 3), right bundle branch block, left anterior fascicular block, syncope, and epilepsy. On admission, patient was alert and oriented ×2 to self and place. The patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. The patient denied headache, shortness of breath, abdominal pain, dysuria, or urinary frequency. The patient's allergies included penicillamine, penicillin, and shellfish. Active medications included sodium valproate, amlodipine, docusate, and polyethylene glycol. Physical exam was unremarkable, and vitals were within normal limits (See Table 1).
2.1. Treatment Course
On the day of transfer to medicine (Treatment day 0-Table 1), clozapine was immediately discontinued, the patient was placed in reverse isolation, and a throat culture was taken. On Treatment day 1, upon recommendation from hematology, the patient received filgrastim/G-CSF 300 mcg subcutaneously. The patient continued this dosage of filgrastim for two days along with home dose of valproate.
On Treatment day 3, the patient spiked a fever of 103.1°F. A fever source was investigated, and an uncomplicated cellulitis on the abdominal wall was found. Filgrastim was adjusted to a dose of 800 mcg subcutaneous daily (see Table 1), and the patient was administered acetaminophen, aztreonam, clindamycin, and gentamicin while monitoring the kidney function.
Gentamicin was discontinued on Treatment day 5 (two days after initiation) when eGFR was 17.24 indicative of AKI stage 4 (see Table 1). Aztreonam and clindamycin were continued till Treatment day 6, and micafungin and meropenem administration began on Treatment day 7.
Patient status stabilized on Treatment day 10 when her ANC count rose to 1.8, up from 0.4 on Treatment day 9 (See Table 1). The patient remained hospitalized an additional two days to correct electrolyte abnormalities.
3. Discussion
As CIA has become more prevalent, it has been noted that risk factors and poor prognostic indicators include female sex, increasing age, ANC < 100, preexisting renal, cardiac or inflammatory disease comorbidities, and sepsis. [14]. Considering these factors, the 60 years of age in our female patient, her CKD, the acquisition of cellulitis during her treatment, and ANC of 5, we were satisfied with the treatment course and outcome. However, other factors have been noted in literature to potentially increase susceptibility of CIA. Specific human leukocyte antigen (HLA) has been identified for increased susceptibility to CIA. Potential CYP reactions in valproate, which remain unclear in literature, could also potentially increase risk of CIA. And certain treatment guidelines of CIA remain vague in literature. Clinical screening either separately or combined for many of these risk factors should be established. Additionally, consideration for a standardized protocol for timeline and dosing of treatment for CIA should be established.
3.1. Screening: Renal Failure and HLA
Though CIA is an adverse event which occurs in less than 1% of adults with psychiatric conditions [15], more research is being conducted to determine risk factors which may increase the likelihood of patients developing this condition. By screening for risk factors, we may mitigate the occurrence of these events. It is noted that our patient who had a past medical history of CKD was dosed with gentamicin upon initial fever of 103.1°F on Treatment day 3. Though gentamicin has known nephrotoxic effects and was thus discontinued to prevent further kidney toxicity, many case reports have suggested that clozapine may induce and/or exacerbate renal failure and nephritis [16–19]. While further research is necessary to quantify the precise risk of clozapine on the kidney function, prior to initiating a trial dose of clozapine, including a thorough history, measuring a patient's kidney function, or eGFR, and BUN/creatinine panel in addition to weekly monitoring of clozapine and ANC levels may reduce exacerbation of CKD.
Associations between susceptibility of CIA and human leukocyte antigen (HLA) were initially reported in the 1990s [20]. In 2014, HLA-DQB1 and HLA-B alleles were specifically implicated in amino acid changes responsible for patient's susceptibility to CIA [21]. Currently, there is no guidance on mandatory panels or screening for HLA alleles prior to administration of clozapine though such screening has been shown to be health and cost-effective [15]. While the past medical history indicated that our subject had been diagnosed with arthritis, we did not investigate which type of arthritis. We performed HLA screening towards the end of her CIA treatment and discovered that our patient was, indeed, HLA-DQB1 and HLA-DQ2 positive. Had we implemented HLA screening prior to initiating clozapine, we could have potentially avoided her CIA.
3.2. Management Protocol for Clozapine-Induced Agranulocytosis
While standard procedures for the management of CIA have been established, many of the details remain either up to physician determination or unestablished guidelines. Filgrastim/G-CSF has been shown to decrease the recovery time associated with agranulocytosis [7]. However, there is not an established dose for filgrastim for the treatment of CIA. There are established guidelines for filgrastim/G-CSF use in patients suffering from a number of immunocompromising diseases and cancers [22]. However, there is no direct guidance for administering filgrastim for patients suffering from CIA. Filgrastim/G-CSF is available in 300 mcg or 480 mcg vials or single dose syringes with recommended starting dose 5mcg/kg/day [22]. It is recommended to be administered up to 2 weeks or until ANC has reached 10,000/mm3 and is to be discontinued if ANC surpasses 10,000/mm3 after expected nadir [22].
In our patient, treatment of CIA took a total of 10 days of which Neupogen was dosed a total of 6 days with dosages of 300 mcg and 800 mcg (see Table 1) for patient recovery to a normal range of WBC 7 L and ANC 3.97 μL. Further study may provide more efficient dosing and thus more expedient and cost-effective care.
There also continues to be nebulous guidelines in management of CIA through the utilization of bone marrow aspirate and biopsy. Current protocol in the initial studies for the diagnosis of CIA includes CBC, white cell differential, examination of the peripheral smear, observation of recovery after cessation of the drug in a healthy patient, bacterial and/or viral studies if the patient is febrile, and a bone marrow aspiration and biopsy [12, 14]. As the utilization of the bone marrow biopsy is to ascertain patient granulopoiesis status, physicians may choose to begin filgrastim/G-CSF treatment prior to performing a bone marrow aspirate. For our case, hematology recommended bone marrow biopsy on Treatment day 3 to rule out WBC aplasia; however, they suggested performing the biopsy only if the increased filgrastim dose to 800 mcg did not prove effective in improving neutrophils levels. When peripheral blood screening revealed cellular morphology categorized as normal, a bone marrow biopsy was not performed on our subject. Importantly, upon literature review, there are no stated guidelines on when to perform the bone biopsy [10, 14].
3.3. Valproic Acid and CYP Effects
Finally, while clozapine was immediately discontinued upon admission, valproate was continued throughout the duration of treatment for the patient's schizoaffective disorder (see Table 1). There has been suggestion that valproate may be a clozapine metabolism inducer [23], the serum valproate level was subtherapeutic 36.5 (50-100) on treatment day 0/admission to the medicine floor, and the clozapine level was not taken at admission; so, no definitive conclusion can be made. Other studies suggest that valproate is a weak inhibitor of CYP 3A4 [24, 25] and potent CYP 2C9 inhibitor [26, 27]. Additionally, in 2018, the Malik et al. case control study of 136 cases found an association of increased risk of CIA in those with concurrent use of sodium valproate and clozapine [28]. These findings might suggest that our subjects' concomitant dosing of valproate with her clozapine could have exacerbated the clozapine effect causing CIA. Should these theories prove true on larger study, the decision to continue the patient's prescription of valproate during treatment for CIA could have elongated the recovery process due to the CYP inhibitor effects of valproate on clozapine levels. Future investigation for drug interaction of valproate with clozapine together should be studied. Should valproate prove to be a CYP inhibitor, or exacerbate CIA, standardized guidelines should indicate valproate be discontinued in future findings of CIA, and alternative therapeutics should be explored. Additionally, adjunctive use of lithium with clozapine has been initially investigated to mitigate the level of neutropenia for those experiencing CIA [29]. Additional study into adjunct dosing of lithium should be investigated. Concurrent use of valproate with clozapine, adjunct dosing of lithium, and other patient risk factors may need to be considered while determining proper individualized treatment.
4. Conclusion
Through this case of CIA in a patient with longstanding schizoaffective disorder, CKD, and HLA-DQB1 and HLA-DQ2 positivity, the importance of implementing a standardized screen which accounts for the renal function and HLA status is imperative for safe practices in prescribing clozapine for psychiatric disorders and mitigating the risk for CIA. Additionally, proper standardized monitoring of renal status through the treatment process may also mitigate risk of potential kidney failure. Further study is necessary to distinguish valproate's role in agranulocytosis singularly or in concert with clozapine. More detailed standardized guidelines would be beneficial for treatment of CIA, should it occur. As clozapine is known as a drug of last resort to be administered when there is failure of more traditional, and risk averse therapeutics, it is difficult to deny this treatment option, as it ultimately implies that all other treatment options have been exhausted. Proper screening and established protocol and guidelines could increase the level of monitoring in patients with known risk factors as revealed by the official screen. This risk factor screen and subsequent monitoring could increase the cost-effectiveness of clozapine treatment and decrease the incidence and morbidity of this feared adverse event.
Acknowledgments
The authors would like to thank the nursing staff and social workers for their day-to-day involvement in the care of the patient. We would also like to thank the following residents for the day-to-day involvement in managing the care of our patient: Chris Alfred, Ainsley Backman, Vito D'Angelo, Randy Lai, and Jai Patel. We would also like to thank Jonathan Eckstein, Steven Rubel, and Albert Strojan for the feedback given during the development of this paper. The authors also would like to thank Alvin Holcomb for the role he plays in resident medical education on a daily basis.
Abbreviations
CIA: Clozapine-induced agranulocytosis
ANC: Absolute neutrophil count
DVT: Deep vein thrombosis
CKD: Chronic kidney disease
AKI: Acute kidney injury
CYP: Cytochrome P450
EMS: Emergency medical services
ED: Emergency department
HLA: Human leukocyte antigen
G-CSF: Granulocyte-colony stimulating factor.
Data Availability
The subject data used to support the findings of this study are included in the Table within the article. Prior studies used to support the findings of this study are cited at relevant places within the text as references [1–29].
Consent
Written informed consent was obtained and is on the file.
Conflicts of Interest
The authors declare that there that there is no conflict of interest regarding the publication of this article.
Table 1 Treatment course lab table.
Treatment day Treatment day 0 Treatment day 1 Treatment day 2 Treatment day 3 Treatment day 4 Treatment day 5 Treatment day 6 Treatment day 7 Treatment day 8 Treatment day 9 Treatment day 10 Treatment day 11 Treatment day 12
Lab value
ANC level (μL) 0.05 0 0.01 0.01 0.01 0.01 0 0.02 0.04 0.57 3.97 11.51 10.38
WBC (L) N/A 0.4 0.4 0.3 0.2 0.3 0.2 0.3 0.4 1.8 7 18.7 N/A
Temperature max 98.8 98.6 100.7 103.1 101 98.5 99.3 97.3 98.1 98.6 97.8 97.7 98.1
BP 127/79 144/77 110/59 113/48 131/59 101/53 129/61 127/65 119/64 130/75 117/65 130/70
Hgb (G/DL) 10.4 9.9 11 10.5 9.8 8.9 8.5 8 8 8.6 9.6 9.3 8.4
Hematocrit (%) 33.8 31.8 36.4 33.6 31.6 29.3 27.2 26.3 26.1 28.1 32.2 30.6 28.6
H&H 10.4/33.8 9.9/31.8 11.0/36.4 10.5/33.6 9.8/31.6 8.9/29.3 8.5/27.2 8.0/26.3 8.0/26.1 8.6/28.1 9.6/32.2 9.3/30.6 8.4/28.6
BUN N/A N/A 38 36 46 55 77 70 57 43 33 29 25
CR N/A N/A 1.57 1.93 2.3 2.8 3.2 2.45 1.98 1.69 1.75 1.55 1.59
eGFR N/A N/A 33.61 26.48 21.63 17.24 14.78 20.11 25.71 30.87 29.65 34.11 33.12
Valproate level 36.5 L 50.9 L
Amlodipine dose 10 mg 10 mg 10 mg Not given Not given 10 mg 10 mg 10 mg Refused 10 mg 10 mg 10 mg 10 mg
Docusate dose Refused 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg
PEG dose 17 grams 17 grams
Valproate dose 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d
Filgrastim dose N/A 300 mcg 300 mcg 800 mcg 800 mcg 800 mcg N/A N/A 800 mcg N/A N/A N/A N/A | CONTINUED TILL TREATMENT DAY 6 | DrugDosageText | CC BY | 33688445 | 19,084,247 | 2021 |
What was the dosage of drug 'CLINDAMYCIN'? | Considerations of HLA, Renal Failure, Valproic Acid Use, and Current Treatment Guidelines in Clozapine-Induced Agranulocytosis.
Clozapine, the choice atypical antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder, has been shown to reduce positive and negative symptoms of schizophrenia. Clozapine, though beneficial in reducing the need for hospitalization, rehabilitation, and health care costs, is known as a drug of last resort due to its potential adverse event of clozapine-induced agranulocytosis, which holds a case fatality rate between 4.2 and 16%. Herein, we describe a female patient with longstanding schizoaffective disorder and chronic kidney disease who suffered from clozapine-induced agranulocytosis after failing two other atypical antipsychotics. Retrospective considerations of this case and management highlight risk factors such as HLA status, renal failure, and concurrent valproic acid use which presently do not have official screening, guidelines, or restrictions in place when prescribing clozapine. Additionally, there are no specific clozapine-induced agranulocytosis management recommendations such as G-CSF/filgrastim dose, timing of bone marrow aspirate and biopsy, and use of concomitant valproate. We propose that further comprehensive official screening, monitoring, and guidelines in the prescribing of clozapine, and further guidelines in the treatment of clozapine induced agranulocytosis, could increase the cost-effectiveness of clozapine treatment, and decrease the incidence, and morbidity of this feared adverse event.
1. Introduction
Clozapine, a dibenzodiazepine antipsychotic exhibiting weak dopaminergic activity and atypical pharmacological properties, is the choice antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder [1–4]. Advantages of clozapine include decreased positive symptoms of schizophrenia such as voices and hallucinations and decreased negative symptoms such as blunted affect and suicidal behavior [5]. The decreased positive and negative symptoms result in reduced need for hospitalization, rehabilitation, and subsequent health care costs [6]. However, known and feared disadvantages include neutropenia and life-threatening agranulocytosis [7, 8].
A benign form of neutropenia with an absolute neutrophil count (ANC) < 1500 cells/μL [9] is known to occur more frequently than clinically significant, agranulocytosis, where ANC < 500 cells/μL [10]. A high risk of severe and/or opportunistic infections is noted to be associated with ANC <200 [9]. In 2008, clozapine-induced agranulocytosis (CIA) had a known rate of seven cases per one million [11]. In 2006, the case fatality caused by CIA was estimated to be 4.2% to 16% [12]. In 2016, the observed mortality rate ranged from 0.1 and 0.3 per thousand, and the case fatality rate was estimated to be between 2.2 and 4.2 [13]. Standard established protocol includes immediate discontinuation of clozapine should white blood cell count reach <500 ANC [10, 14]. Patients' WBC and ANC must be monitored daily until WBC > 3000/mm3 and ANC > 1500/mm3 [7].
As more cases of CIA are occurring, more information concerning prescribing this efficacious antipsychotic as well as the treatment of CIA has become available. Here, we describe a patient with longstanding schizoaffective disorder who suffered from CIA after being transitioned to clozapine due to failed trials of risperidone and olanzapine. Retrospective considerations of her placement on clozapine and subsequent management of her CIA brought into question many factors which do not have clear guidelines, including official screening of risk factors which increase likelihood of CIA, as well as clear clinical management for this feared adverse event. This case report provides a spotlight on many factors such as screening for chronic kidney disease (CKD), human leukocyte antigen(HLA) typing, concurrent valproate administration due to potential CYP interactions, and management considerations such as dosing for filgrastim/G-CSF and timing of bone marrow biopsy. This analysis aims for further study and ultimately future implementation of screening and management guidelines for better informed management of refractory schizophrenia treatment, reduced cases of CIA, and improved management of CIA should it occur.
2. Case Presentation
A 60-year-old Caucasian female nursing home resident was brought in by EMS to the ED due to disorganized behavior, auditory hallucinations, and disorganized speech with loosening associations and was admitted to the inpatient psychiatric unit. Past psychiatric history included longstanding schizoaffective disorder. As a psychiatric inpatient, after having failed treatment with risperidone and olanzapine, the patient was started on clozapine 25 mg PO daily and was titrated to 150 mg PO BID over the course of 28 days. Recorded WBC on day 28 of treatment was 4.5 × 109/L (4.5 to 11.0 × 109/L). On the 35th day of clozapine treatment, the patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. WBC was found to be 0.2 × 109/L (4.5 to 11.0 × 109/L), and ANC was 0.05 [1.5 to 8.0 (1,500 to 8,000/mm3)]. The valproate level was 36.5 (50-100). Subsequently, the patient was transferred to the inpatient medicine floor this same day due to clozapine-induced leukocytopenia (day of transfer to medicine/Treatment day 0).
Past medical history included arthritis, deep vein thrombosis, chronic kidney disease (CKD) (stage 3), right bundle branch block, left anterior fascicular block, syncope, and epilepsy. On admission, patient was alert and oriented ×2 to self and place. The patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. The patient denied headache, shortness of breath, abdominal pain, dysuria, or urinary frequency. The patient's allergies included penicillamine, penicillin, and shellfish. Active medications included sodium valproate, amlodipine, docusate, and polyethylene glycol. Physical exam was unremarkable, and vitals were within normal limits (See Table 1).
2.1. Treatment Course
On the day of transfer to medicine (Treatment day 0-Table 1), clozapine was immediately discontinued, the patient was placed in reverse isolation, and a throat culture was taken. On Treatment day 1, upon recommendation from hematology, the patient received filgrastim/G-CSF 300 mcg subcutaneously. The patient continued this dosage of filgrastim for two days along with home dose of valproate.
On Treatment day 3, the patient spiked a fever of 103.1°F. A fever source was investigated, and an uncomplicated cellulitis on the abdominal wall was found. Filgrastim was adjusted to a dose of 800 mcg subcutaneous daily (see Table 1), and the patient was administered acetaminophen, aztreonam, clindamycin, and gentamicin while monitoring the kidney function.
Gentamicin was discontinued on Treatment day 5 (two days after initiation) when eGFR was 17.24 indicative of AKI stage 4 (see Table 1). Aztreonam and clindamycin were continued till Treatment day 6, and micafungin and meropenem administration began on Treatment day 7.
Patient status stabilized on Treatment day 10 when her ANC count rose to 1.8, up from 0.4 on Treatment day 9 (See Table 1). The patient remained hospitalized an additional two days to correct electrolyte abnormalities.
3. Discussion
As CIA has become more prevalent, it has been noted that risk factors and poor prognostic indicators include female sex, increasing age, ANC < 100, preexisting renal, cardiac or inflammatory disease comorbidities, and sepsis. [14]. Considering these factors, the 60 years of age in our female patient, her CKD, the acquisition of cellulitis during her treatment, and ANC of 5, we were satisfied with the treatment course and outcome. However, other factors have been noted in literature to potentially increase susceptibility of CIA. Specific human leukocyte antigen (HLA) has been identified for increased susceptibility to CIA. Potential CYP reactions in valproate, which remain unclear in literature, could also potentially increase risk of CIA. And certain treatment guidelines of CIA remain vague in literature. Clinical screening either separately or combined for many of these risk factors should be established. Additionally, consideration for a standardized protocol for timeline and dosing of treatment for CIA should be established.
3.1. Screening: Renal Failure and HLA
Though CIA is an adverse event which occurs in less than 1% of adults with psychiatric conditions [15], more research is being conducted to determine risk factors which may increase the likelihood of patients developing this condition. By screening for risk factors, we may mitigate the occurrence of these events. It is noted that our patient who had a past medical history of CKD was dosed with gentamicin upon initial fever of 103.1°F on Treatment day 3. Though gentamicin has known nephrotoxic effects and was thus discontinued to prevent further kidney toxicity, many case reports have suggested that clozapine may induce and/or exacerbate renal failure and nephritis [16–19]. While further research is necessary to quantify the precise risk of clozapine on the kidney function, prior to initiating a trial dose of clozapine, including a thorough history, measuring a patient's kidney function, or eGFR, and BUN/creatinine panel in addition to weekly monitoring of clozapine and ANC levels may reduce exacerbation of CKD.
Associations between susceptibility of CIA and human leukocyte antigen (HLA) were initially reported in the 1990s [20]. In 2014, HLA-DQB1 and HLA-B alleles were specifically implicated in amino acid changes responsible for patient's susceptibility to CIA [21]. Currently, there is no guidance on mandatory panels or screening for HLA alleles prior to administration of clozapine though such screening has been shown to be health and cost-effective [15]. While the past medical history indicated that our subject had been diagnosed with arthritis, we did not investigate which type of arthritis. We performed HLA screening towards the end of her CIA treatment and discovered that our patient was, indeed, HLA-DQB1 and HLA-DQ2 positive. Had we implemented HLA screening prior to initiating clozapine, we could have potentially avoided her CIA.
3.2. Management Protocol for Clozapine-Induced Agranulocytosis
While standard procedures for the management of CIA have been established, many of the details remain either up to physician determination or unestablished guidelines. Filgrastim/G-CSF has been shown to decrease the recovery time associated with agranulocytosis [7]. However, there is not an established dose for filgrastim for the treatment of CIA. There are established guidelines for filgrastim/G-CSF use in patients suffering from a number of immunocompromising diseases and cancers [22]. However, there is no direct guidance for administering filgrastim for patients suffering from CIA. Filgrastim/G-CSF is available in 300 mcg or 480 mcg vials or single dose syringes with recommended starting dose 5mcg/kg/day [22]. It is recommended to be administered up to 2 weeks or until ANC has reached 10,000/mm3 and is to be discontinued if ANC surpasses 10,000/mm3 after expected nadir [22].
In our patient, treatment of CIA took a total of 10 days of which Neupogen was dosed a total of 6 days with dosages of 300 mcg and 800 mcg (see Table 1) for patient recovery to a normal range of WBC 7 L and ANC 3.97 μL. Further study may provide more efficient dosing and thus more expedient and cost-effective care.
There also continues to be nebulous guidelines in management of CIA through the utilization of bone marrow aspirate and biopsy. Current protocol in the initial studies for the diagnosis of CIA includes CBC, white cell differential, examination of the peripheral smear, observation of recovery after cessation of the drug in a healthy patient, bacterial and/or viral studies if the patient is febrile, and a bone marrow aspiration and biopsy [12, 14]. As the utilization of the bone marrow biopsy is to ascertain patient granulopoiesis status, physicians may choose to begin filgrastim/G-CSF treatment prior to performing a bone marrow aspirate. For our case, hematology recommended bone marrow biopsy on Treatment day 3 to rule out WBC aplasia; however, they suggested performing the biopsy only if the increased filgrastim dose to 800 mcg did not prove effective in improving neutrophils levels. When peripheral blood screening revealed cellular morphology categorized as normal, a bone marrow biopsy was not performed on our subject. Importantly, upon literature review, there are no stated guidelines on when to perform the bone biopsy [10, 14].
3.3. Valproic Acid and CYP Effects
Finally, while clozapine was immediately discontinued upon admission, valproate was continued throughout the duration of treatment for the patient's schizoaffective disorder (see Table 1). There has been suggestion that valproate may be a clozapine metabolism inducer [23], the serum valproate level was subtherapeutic 36.5 (50-100) on treatment day 0/admission to the medicine floor, and the clozapine level was not taken at admission; so, no definitive conclusion can be made. Other studies suggest that valproate is a weak inhibitor of CYP 3A4 [24, 25] and potent CYP 2C9 inhibitor [26, 27]. Additionally, in 2018, the Malik et al. case control study of 136 cases found an association of increased risk of CIA in those with concurrent use of sodium valproate and clozapine [28]. These findings might suggest that our subjects' concomitant dosing of valproate with her clozapine could have exacerbated the clozapine effect causing CIA. Should these theories prove true on larger study, the decision to continue the patient's prescription of valproate during treatment for CIA could have elongated the recovery process due to the CYP inhibitor effects of valproate on clozapine levels. Future investigation for drug interaction of valproate with clozapine together should be studied. Should valproate prove to be a CYP inhibitor, or exacerbate CIA, standardized guidelines should indicate valproate be discontinued in future findings of CIA, and alternative therapeutics should be explored. Additionally, adjunctive use of lithium with clozapine has been initially investigated to mitigate the level of neutropenia for those experiencing CIA [29]. Additional study into adjunct dosing of lithium should be investigated. Concurrent use of valproate with clozapine, adjunct dosing of lithium, and other patient risk factors may need to be considered while determining proper individualized treatment.
4. Conclusion
Through this case of CIA in a patient with longstanding schizoaffective disorder, CKD, and HLA-DQB1 and HLA-DQ2 positivity, the importance of implementing a standardized screen which accounts for the renal function and HLA status is imperative for safe practices in prescribing clozapine for psychiatric disorders and mitigating the risk for CIA. Additionally, proper standardized monitoring of renal status through the treatment process may also mitigate risk of potential kidney failure. Further study is necessary to distinguish valproate's role in agranulocytosis singularly or in concert with clozapine. More detailed standardized guidelines would be beneficial for treatment of CIA, should it occur. As clozapine is known as a drug of last resort to be administered when there is failure of more traditional, and risk averse therapeutics, it is difficult to deny this treatment option, as it ultimately implies that all other treatment options have been exhausted. Proper screening and established protocol and guidelines could increase the level of monitoring in patients with known risk factors as revealed by the official screen. This risk factor screen and subsequent monitoring could increase the cost-effectiveness of clozapine treatment and decrease the incidence and morbidity of this feared adverse event.
Acknowledgments
The authors would like to thank the nursing staff and social workers for their day-to-day involvement in the care of the patient. We would also like to thank the following residents for the day-to-day involvement in managing the care of our patient: Chris Alfred, Ainsley Backman, Vito D'Angelo, Randy Lai, and Jai Patel. We would also like to thank Jonathan Eckstein, Steven Rubel, and Albert Strojan for the feedback given during the development of this paper. The authors also would like to thank Alvin Holcomb for the role he plays in resident medical education on a daily basis.
Abbreviations
CIA: Clozapine-induced agranulocytosis
ANC: Absolute neutrophil count
DVT: Deep vein thrombosis
CKD: Chronic kidney disease
AKI: Acute kidney injury
CYP: Cytochrome P450
EMS: Emergency medical services
ED: Emergency department
HLA: Human leukocyte antigen
G-CSF: Granulocyte-colony stimulating factor.
Data Availability
The subject data used to support the findings of this study are included in the Table within the article. Prior studies used to support the findings of this study are cited at relevant places within the text as references [1–29].
Consent
Written informed consent was obtained and is on the file.
Conflicts of Interest
The authors declare that there that there is no conflict of interest regarding the publication of this article.
Table 1 Treatment course lab table.
Treatment day Treatment day 0 Treatment day 1 Treatment day 2 Treatment day 3 Treatment day 4 Treatment day 5 Treatment day 6 Treatment day 7 Treatment day 8 Treatment day 9 Treatment day 10 Treatment day 11 Treatment day 12
Lab value
ANC level (μL) 0.05 0 0.01 0.01 0.01 0.01 0 0.02 0.04 0.57 3.97 11.51 10.38
WBC (L) N/A 0.4 0.4 0.3 0.2 0.3 0.2 0.3 0.4 1.8 7 18.7 N/A
Temperature max 98.8 98.6 100.7 103.1 101 98.5 99.3 97.3 98.1 98.6 97.8 97.7 98.1
BP 127/79 144/77 110/59 113/48 131/59 101/53 129/61 127/65 119/64 130/75 117/65 130/70
Hgb (G/DL) 10.4 9.9 11 10.5 9.8 8.9 8.5 8 8 8.6 9.6 9.3 8.4
Hematocrit (%) 33.8 31.8 36.4 33.6 31.6 29.3 27.2 26.3 26.1 28.1 32.2 30.6 28.6
H&H 10.4/33.8 9.9/31.8 11.0/36.4 10.5/33.6 9.8/31.6 8.9/29.3 8.5/27.2 8.0/26.3 8.0/26.1 8.6/28.1 9.6/32.2 9.3/30.6 8.4/28.6
BUN N/A N/A 38 36 46 55 77 70 57 43 33 29 25
CR N/A N/A 1.57 1.93 2.3 2.8 3.2 2.45 1.98 1.69 1.75 1.55 1.59
eGFR N/A N/A 33.61 26.48 21.63 17.24 14.78 20.11 25.71 30.87 29.65 34.11 33.12
Valproate level 36.5 L 50.9 L
Amlodipine dose 10 mg 10 mg 10 mg Not given Not given 10 mg 10 mg 10 mg Refused 10 mg 10 mg 10 mg 10 mg
Docusate dose Refused 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg
PEG dose 17 grams 17 grams
Valproate dose 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d
Filgrastim dose N/A 300 mcg 300 mcg 800 mcg 800 mcg 800 mcg N/A N/A 800 mcg N/A N/A N/A N/A | CONTINUED TILL TREATMENT DAY 6 | DrugDosageText | CC BY | 33688445 | 19,084,247 | 2021 |
What was the outcome of reaction 'Acute kidney injury'? | Considerations of HLA, Renal Failure, Valproic Acid Use, and Current Treatment Guidelines in Clozapine-Induced Agranulocytosis.
Clozapine, the choice atypical antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder, has been shown to reduce positive and negative symptoms of schizophrenia. Clozapine, though beneficial in reducing the need for hospitalization, rehabilitation, and health care costs, is known as a drug of last resort due to its potential adverse event of clozapine-induced agranulocytosis, which holds a case fatality rate between 4.2 and 16%. Herein, we describe a female patient with longstanding schizoaffective disorder and chronic kidney disease who suffered from clozapine-induced agranulocytosis after failing two other atypical antipsychotics. Retrospective considerations of this case and management highlight risk factors such as HLA status, renal failure, and concurrent valproic acid use which presently do not have official screening, guidelines, or restrictions in place when prescribing clozapine. Additionally, there are no specific clozapine-induced agranulocytosis management recommendations such as G-CSF/filgrastim dose, timing of bone marrow aspirate and biopsy, and use of concomitant valproate. We propose that further comprehensive official screening, monitoring, and guidelines in the prescribing of clozapine, and further guidelines in the treatment of clozapine induced agranulocytosis, could increase the cost-effectiveness of clozapine treatment, and decrease the incidence, and morbidity of this feared adverse event.
1. Introduction
Clozapine, a dibenzodiazepine antipsychotic exhibiting weak dopaminergic activity and atypical pharmacological properties, is the choice antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder [1–4]. Advantages of clozapine include decreased positive symptoms of schizophrenia such as voices and hallucinations and decreased negative symptoms such as blunted affect and suicidal behavior [5]. The decreased positive and negative symptoms result in reduced need for hospitalization, rehabilitation, and subsequent health care costs [6]. However, known and feared disadvantages include neutropenia and life-threatening agranulocytosis [7, 8].
A benign form of neutropenia with an absolute neutrophil count (ANC) < 1500 cells/μL [9] is known to occur more frequently than clinically significant, agranulocytosis, where ANC < 500 cells/μL [10]. A high risk of severe and/or opportunistic infections is noted to be associated with ANC <200 [9]. In 2008, clozapine-induced agranulocytosis (CIA) had a known rate of seven cases per one million [11]. In 2006, the case fatality caused by CIA was estimated to be 4.2% to 16% [12]. In 2016, the observed mortality rate ranged from 0.1 and 0.3 per thousand, and the case fatality rate was estimated to be between 2.2 and 4.2 [13]. Standard established protocol includes immediate discontinuation of clozapine should white blood cell count reach <500 ANC [10, 14]. Patients' WBC and ANC must be monitored daily until WBC > 3000/mm3 and ANC > 1500/mm3 [7].
As more cases of CIA are occurring, more information concerning prescribing this efficacious antipsychotic as well as the treatment of CIA has become available. Here, we describe a patient with longstanding schizoaffective disorder who suffered from CIA after being transitioned to clozapine due to failed trials of risperidone and olanzapine. Retrospective considerations of her placement on clozapine and subsequent management of her CIA brought into question many factors which do not have clear guidelines, including official screening of risk factors which increase likelihood of CIA, as well as clear clinical management for this feared adverse event. This case report provides a spotlight on many factors such as screening for chronic kidney disease (CKD), human leukocyte antigen(HLA) typing, concurrent valproate administration due to potential CYP interactions, and management considerations such as dosing for filgrastim/G-CSF and timing of bone marrow biopsy. This analysis aims for further study and ultimately future implementation of screening and management guidelines for better informed management of refractory schizophrenia treatment, reduced cases of CIA, and improved management of CIA should it occur.
2. Case Presentation
A 60-year-old Caucasian female nursing home resident was brought in by EMS to the ED due to disorganized behavior, auditory hallucinations, and disorganized speech with loosening associations and was admitted to the inpatient psychiatric unit. Past psychiatric history included longstanding schizoaffective disorder. As a psychiatric inpatient, after having failed treatment with risperidone and olanzapine, the patient was started on clozapine 25 mg PO daily and was titrated to 150 mg PO BID over the course of 28 days. Recorded WBC on day 28 of treatment was 4.5 × 109/L (4.5 to 11.0 × 109/L). On the 35th day of clozapine treatment, the patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. WBC was found to be 0.2 × 109/L (4.5 to 11.0 × 109/L), and ANC was 0.05 [1.5 to 8.0 (1,500 to 8,000/mm3)]. The valproate level was 36.5 (50-100). Subsequently, the patient was transferred to the inpatient medicine floor this same day due to clozapine-induced leukocytopenia (day of transfer to medicine/Treatment day 0).
Past medical history included arthritis, deep vein thrombosis, chronic kidney disease (CKD) (stage 3), right bundle branch block, left anterior fascicular block, syncope, and epilepsy. On admission, patient was alert and oriented ×2 to self and place. The patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. The patient denied headache, shortness of breath, abdominal pain, dysuria, or urinary frequency. The patient's allergies included penicillamine, penicillin, and shellfish. Active medications included sodium valproate, amlodipine, docusate, and polyethylene glycol. Physical exam was unremarkable, and vitals were within normal limits (See Table 1).
2.1. Treatment Course
On the day of transfer to medicine (Treatment day 0-Table 1), clozapine was immediately discontinued, the patient was placed in reverse isolation, and a throat culture was taken. On Treatment day 1, upon recommendation from hematology, the patient received filgrastim/G-CSF 300 mcg subcutaneously. The patient continued this dosage of filgrastim for two days along with home dose of valproate.
On Treatment day 3, the patient spiked a fever of 103.1°F. A fever source was investigated, and an uncomplicated cellulitis on the abdominal wall was found. Filgrastim was adjusted to a dose of 800 mcg subcutaneous daily (see Table 1), and the patient was administered acetaminophen, aztreonam, clindamycin, and gentamicin while monitoring the kidney function.
Gentamicin was discontinued on Treatment day 5 (two days after initiation) when eGFR was 17.24 indicative of AKI stage 4 (see Table 1). Aztreonam and clindamycin were continued till Treatment day 6, and micafungin and meropenem administration began on Treatment day 7.
Patient status stabilized on Treatment day 10 when her ANC count rose to 1.8, up from 0.4 on Treatment day 9 (See Table 1). The patient remained hospitalized an additional two days to correct electrolyte abnormalities.
3. Discussion
As CIA has become more prevalent, it has been noted that risk factors and poor prognostic indicators include female sex, increasing age, ANC < 100, preexisting renal, cardiac or inflammatory disease comorbidities, and sepsis. [14]. Considering these factors, the 60 years of age in our female patient, her CKD, the acquisition of cellulitis during her treatment, and ANC of 5, we were satisfied with the treatment course and outcome. However, other factors have been noted in literature to potentially increase susceptibility of CIA. Specific human leukocyte antigen (HLA) has been identified for increased susceptibility to CIA. Potential CYP reactions in valproate, which remain unclear in literature, could also potentially increase risk of CIA. And certain treatment guidelines of CIA remain vague in literature. Clinical screening either separately or combined for many of these risk factors should be established. Additionally, consideration for a standardized protocol for timeline and dosing of treatment for CIA should be established.
3.1. Screening: Renal Failure and HLA
Though CIA is an adverse event which occurs in less than 1% of adults with psychiatric conditions [15], more research is being conducted to determine risk factors which may increase the likelihood of patients developing this condition. By screening for risk factors, we may mitigate the occurrence of these events. It is noted that our patient who had a past medical history of CKD was dosed with gentamicin upon initial fever of 103.1°F on Treatment day 3. Though gentamicin has known nephrotoxic effects and was thus discontinued to prevent further kidney toxicity, many case reports have suggested that clozapine may induce and/or exacerbate renal failure and nephritis [16–19]. While further research is necessary to quantify the precise risk of clozapine on the kidney function, prior to initiating a trial dose of clozapine, including a thorough history, measuring a patient's kidney function, or eGFR, and BUN/creatinine panel in addition to weekly monitoring of clozapine and ANC levels may reduce exacerbation of CKD.
Associations between susceptibility of CIA and human leukocyte antigen (HLA) were initially reported in the 1990s [20]. In 2014, HLA-DQB1 and HLA-B alleles were specifically implicated in amino acid changes responsible for patient's susceptibility to CIA [21]. Currently, there is no guidance on mandatory panels or screening for HLA alleles prior to administration of clozapine though such screening has been shown to be health and cost-effective [15]. While the past medical history indicated that our subject had been diagnosed with arthritis, we did not investigate which type of arthritis. We performed HLA screening towards the end of her CIA treatment and discovered that our patient was, indeed, HLA-DQB1 and HLA-DQ2 positive. Had we implemented HLA screening prior to initiating clozapine, we could have potentially avoided her CIA.
3.2. Management Protocol for Clozapine-Induced Agranulocytosis
While standard procedures for the management of CIA have been established, many of the details remain either up to physician determination or unestablished guidelines. Filgrastim/G-CSF has been shown to decrease the recovery time associated with agranulocytosis [7]. However, there is not an established dose for filgrastim for the treatment of CIA. There are established guidelines for filgrastim/G-CSF use in patients suffering from a number of immunocompromising diseases and cancers [22]. However, there is no direct guidance for administering filgrastim for patients suffering from CIA. Filgrastim/G-CSF is available in 300 mcg or 480 mcg vials or single dose syringes with recommended starting dose 5mcg/kg/day [22]. It is recommended to be administered up to 2 weeks or until ANC has reached 10,000/mm3 and is to be discontinued if ANC surpasses 10,000/mm3 after expected nadir [22].
In our patient, treatment of CIA took a total of 10 days of which Neupogen was dosed a total of 6 days with dosages of 300 mcg and 800 mcg (see Table 1) for patient recovery to a normal range of WBC 7 L and ANC 3.97 μL. Further study may provide more efficient dosing and thus more expedient and cost-effective care.
There also continues to be nebulous guidelines in management of CIA through the utilization of bone marrow aspirate and biopsy. Current protocol in the initial studies for the diagnosis of CIA includes CBC, white cell differential, examination of the peripheral smear, observation of recovery after cessation of the drug in a healthy patient, bacterial and/or viral studies if the patient is febrile, and a bone marrow aspiration and biopsy [12, 14]. As the utilization of the bone marrow biopsy is to ascertain patient granulopoiesis status, physicians may choose to begin filgrastim/G-CSF treatment prior to performing a bone marrow aspirate. For our case, hematology recommended bone marrow biopsy on Treatment day 3 to rule out WBC aplasia; however, they suggested performing the biopsy only if the increased filgrastim dose to 800 mcg did not prove effective in improving neutrophils levels. When peripheral blood screening revealed cellular morphology categorized as normal, a bone marrow biopsy was not performed on our subject. Importantly, upon literature review, there are no stated guidelines on when to perform the bone biopsy [10, 14].
3.3. Valproic Acid and CYP Effects
Finally, while clozapine was immediately discontinued upon admission, valproate was continued throughout the duration of treatment for the patient's schizoaffective disorder (see Table 1). There has been suggestion that valproate may be a clozapine metabolism inducer [23], the serum valproate level was subtherapeutic 36.5 (50-100) on treatment day 0/admission to the medicine floor, and the clozapine level was not taken at admission; so, no definitive conclusion can be made. Other studies suggest that valproate is a weak inhibitor of CYP 3A4 [24, 25] and potent CYP 2C9 inhibitor [26, 27]. Additionally, in 2018, the Malik et al. case control study of 136 cases found an association of increased risk of CIA in those with concurrent use of sodium valproate and clozapine [28]. These findings might suggest that our subjects' concomitant dosing of valproate with her clozapine could have exacerbated the clozapine effect causing CIA. Should these theories prove true on larger study, the decision to continue the patient's prescription of valproate during treatment for CIA could have elongated the recovery process due to the CYP inhibitor effects of valproate on clozapine levels. Future investigation for drug interaction of valproate with clozapine together should be studied. Should valproate prove to be a CYP inhibitor, or exacerbate CIA, standardized guidelines should indicate valproate be discontinued in future findings of CIA, and alternative therapeutics should be explored. Additionally, adjunctive use of lithium with clozapine has been initially investigated to mitigate the level of neutropenia for those experiencing CIA [29]. Additional study into adjunct dosing of lithium should be investigated. Concurrent use of valproate with clozapine, adjunct dosing of lithium, and other patient risk factors may need to be considered while determining proper individualized treatment.
4. Conclusion
Through this case of CIA in a patient with longstanding schizoaffective disorder, CKD, and HLA-DQB1 and HLA-DQ2 positivity, the importance of implementing a standardized screen which accounts for the renal function and HLA status is imperative for safe practices in prescribing clozapine for psychiatric disorders and mitigating the risk for CIA. Additionally, proper standardized monitoring of renal status through the treatment process may also mitigate risk of potential kidney failure. Further study is necessary to distinguish valproate's role in agranulocytosis singularly or in concert with clozapine. More detailed standardized guidelines would be beneficial for treatment of CIA, should it occur. As clozapine is known as a drug of last resort to be administered when there is failure of more traditional, and risk averse therapeutics, it is difficult to deny this treatment option, as it ultimately implies that all other treatment options have been exhausted. Proper screening and established protocol and guidelines could increase the level of monitoring in patients with known risk factors as revealed by the official screen. This risk factor screen and subsequent monitoring could increase the cost-effectiveness of clozapine treatment and decrease the incidence and morbidity of this feared adverse event.
Acknowledgments
The authors would like to thank the nursing staff and social workers for their day-to-day involvement in the care of the patient. We would also like to thank the following residents for the day-to-day involvement in managing the care of our patient: Chris Alfred, Ainsley Backman, Vito D'Angelo, Randy Lai, and Jai Patel. We would also like to thank Jonathan Eckstein, Steven Rubel, and Albert Strojan for the feedback given during the development of this paper. The authors also would like to thank Alvin Holcomb for the role he plays in resident medical education on a daily basis.
Abbreviations
CIA: Clozapine-induced agranulocytosis
ANC: Absolute neutrophil count
DVT: Deep vein thrombosis
CKD: Chronic kidney disease
AKI: Acute kidney injury
CYP: Cytochrome P450
EMS: Emergency medical services
ED: Emergency department
HLA: Human leukocyte antigen
G-CSF: Granulocyte-colony stimulating factor.
Data Availability
The subject data used to support the findings of this study are included in the Table within the article. Prior studies used to support the findings of this study are cited at relevant places within the text as references [1–29].
Consent
Written informed consent was obtained and is on the file.
Conflicts of Interest
The authors declare that there that there is no conflict of interest regarding the publication of this article.
Table 1 Treatment course lab table.
Treatment day Treatment day 0 Treatment day 1 Treatment day 2 Treatment day 3 Treatment day 4 Treatment day 5 Treatment day 6 Treatment day 7 Treatment day 8 Treatment day 9 Treatment day 10 Treatment day 11 Treatment day 12
Lab value
ANC level (μL) 0.05 0 0.01 0.01 0.01 0.01 0 0.02 0.04 0.57 3.97 11.51 10.38
WBC (L) N/A 0.4 0.4 0.3 0.2 0.3 0.2 0.3 0.4 1.8 7 18.7 N/A
Temperature max 98.8 98.6 100.7 103.1 101 98.5 99.3 97.3 98.1 98.6 97.8 97.7 98.1
BP 127/79 144/77 110/59 113/48 131/59 101/53 129/61 127/65 119/64 130/75 117/65 130/70
Hgb (G/DL) 10.4 9.9 11 10.5 9.8 8.9 8.5 8 8 8.6 9.6 9.3 8.4
Hematocrit (%) 33.8 31.8 36.4 33.6 31.6 29.3 27.2 26.3 26.1 28.1 32.2 30.6 28.6
H&H 10.4/33.8 9.9/31.8 11.0/36.4 10.5/33.6 9.8/31.6 8.9/29.3 8.5/27.2 8.0/26.3 8.0/26.1 8.6/28.1 9.6/32.2 9.3/30.6 8.4/28.6
BUN N/A N/A 38 36 46 55 77 70 57 43 33 29 25
CR N/A N/A 1.57 1.93 2.3 2.8 3.2 2.45 1.98 1.69 1.75 1.55 1.59
eGFR N/A N/A 33.61 26.48 21.63 17.24 14.78 20.11 25.71 30.87 29.65 34.11 33.12
Valproate level 36.5 L 50.9 L
Amlodipine dose 10 mg 10 mg 10 mg Not given Not given 10 mg 10 mg 10 mg Refused 10 mg 10 mg 10 mg 10 mg
Docusate dose Refused 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg
PEG dose 17 grams 17 grams
Valproate dose 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d
Filgrastim dose N/A 300 mcg 300 mcg 800 mcg 800 mcg 800 mcg N/A N/A 800 mcg N/A N/A N/A N/A | Recovering | ReactionOutcome | CC BY | 33688445 | 19,142,002 | 2021 |
What was the outcome of reaction 'Condition aggravated'? | Considerations of HLA, Renal Failure, Valproic Acid Use, and Current Treatment Guidelines in Clozapine-Induced Agranulocytosis.
Clozapine, the choice atypical antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder, has been shown to reduce positive and negative symptoms of schizophrenia. Clozapine, though beneficial in reducing the need for hospitalization, rehabilitation, and health care costs, is known as a drug of last resort due to its potential adverse event of clozapine-induced agranulocytosis, which holds a case fatality rate between 4.2 and 16%. Herein, we describe a female patient with longstanding schizoaffective disorder and chronic kidney disease who suffered from clozapine-induced agranulocytosis after failing two other atypical antipsychotics. Retrospective considerations of this case and management highlight risk factors such as HLA status, renal failure, and concurrent valproic acid use which presently do not have official screening, guidelines, or restrictions in place when prescribing clozapine. Additionally, there are no specific clozapine-induced agranulocytosis management recommendations such as G-CSF/filgrastim dose, timing of bone marrow aspirate and biopsy, and use of concomitant valproate. We propose that further comprehensive official screening, monitoring, and guidelines in the prescribing of clozapine, and further guidelines in the treatment of clozapine induced agranulocytosis, could increase the cost-effectiveness of clozapine treatment, and decrease the incidence, and morbidity of this feared adverse event.
1. Introduction
Clozapine, a dibenzodiazepine antipsychotic exhibiting weak dopaminergic activity and atypical pharmacological properties, is the choice antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder [1–4]. Advantages of clozapine include decreased positive symptoms of schizophrenia such as voices and hallucinations and decreased negative symptoms such as blunted affect and suicidal behavior [5]. The decreased positive and negative symptoms result in reduced need for hospitalization, rehabilitation, and subsequent health care costs [6]. However, known and feared disadvantages include neutropenia and life-threatening agranulocytosis [7, 8].
A benign form of neutropenia with an absolute neutrophil count (ANC) < 1500 cells/μL [9] is known to occur more frequently than clinically significant, agranulocytosis, where ANC < 500 cells/μL [10]. A high risk of severe and/or opportunistic infections is noted to be associated with ANC <200 [9]. In 2008, clozapine-induced agranulocytosis (CIA) had a known rate of seven cases per one million [11]. In 2006, the case fatality caused by CIA was estimated to be 4.2% to 16% [12]. In 2016, the observed mortality rate ranged from 0.1 and 0.3 per thousand, and the case fatality rate was estimated to be between 2.2 and 4.2 [13]. Standard established protocol includes immediate discontinuation of clozapine should white blood cell count reach <500 ANC [10, 14]. Patients' WBC and ANC must be monitored daily until WBC > 3000/mm3 and ANC > 1500/mm3 [7].
As more cases of CIA are occurring, more information concerning prescribing this efficacious antipsychotic as well as the treatment of CIA has become available. Here, we describe a patient with longstanding schizoaffective disorder who suffered from CIA after being transitioned to clozapine due to failed trials of risperidone and olanzapine. Retrospective considerations of her placement on clozapine and subsequent management of her CIA brought into question many factors which do not have clear guidelines, including official screening of risk factors which increase likelihood of CIA, as well as clear clinical management for this feared adverse event. This case report provides a spotlight on many factors such as screening for chronic kidney disease (CKD), human leukocyte antigen(HLA) typing, concurrent valproate administration due to potential CYP interactions, and management considerations such as dosing for filgrastim/G-CSF and timing of bone marrow biopsy. This analysis aims for further study and ultimately future implementation of screening and management guidelines for better informed management of refractory schizophrenia treatment, reduced cases of CIA, and improved management of CIA should it occur.
2. Case Presentation
A 60-year-old Caucasian female nursing home resident was brought in by EMS to the ED due to disorganized behavior, auditory hallucinations, and disorganized speech with loosening associations and was admitted to the inpatient psychiatric unit. Past psychiatric history included longstanding schizoaffective disorder. As a psychiatric inpatient, after having failed treatment with risperidone and olanzapine, the patient was started on clozapine 25 mg PO daily and was titrated to 150 mg PO BID over the course of 28 days. Recorded WBC on day 28 of treatment was 4.5 × 109/L (4.5 to 11.0 × 109/L). On the 35th day of clozapine treatment, the patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. WBC was found to be 0.2 × 109/L (4.5 to 11.0 × 109/L), and ANC was 0.05 [1.5 to 8.0 (1,500 to 8,000/mm3)]. The valproate level was 36.5 (50-100). Subsequently, the patient was transferred to the inpatient medicine floor this same day due to clozapine-induced leukocytopenia (day of transfer to medicine/Treatment day 0).
Past medical history included arthritis, deep vein thrombosis, chronic kidney disease (CKD) (stage 3), right bundle branch block, left anterior fascicular block, syncope, and epilepsy. On admission, patient was alert and oriented ×2 to self and place. The patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. The patient denied headache, shortness of breath, abdominal pain, dysuria, or urinary frequency. The patient's allergies included penicillamine, penicillin, and shellfish. Active medications included sodium valproate, amlodipine, docusate, and polyethylene glycol. Physical exam was unremarkable, and vitals were within normal limits (See Table 1).
2.1. Treatment Course
On the day of transfer to medicine (Treatment day 0-Table 1), clozapine was immediately discontinued, the patient was placed in reverse isolation, and a throat culture was taken. On Treatment day 1, upon recommendation from hematology, the patient received filgrastim/G-CSF 300 mcg subcutaneously. The patient continued this dosage of filgrastim for two days along with home dose of valproate.
On Treatment day 3, the patient spiked a fever of 103.1°F. A fever source was investigated, and an uncomplicated cellulitis on the abdominal wall was found. Filgrastim was adjusted to a dose of 800 mcg subcutaneous daily (see Table 1), and the patient was administered acetaminophen, aztreonam, clindamycin, and gentamicin while monitoring the kidney function.
Gentamicin was discontinued on Treatment day 5 (two days after initiation) when eGFR was 17.24 indicative of AKI stage 4 (see Table 1). Aztreonam and clindamycin were continued till Treatment day 6, and micafungin and meropenem administration began on Treatment day 7.
Patient status stabilized on Treatment day 10 when her ANC count rose to 1.8, up from 0.4 on Treatment day 9 (See Table 1). The patient remained hospitalized an additional two days to correct electrolyte abnormalities.
3. Discussion
As CIA has become more prevalent, it has been noted that risk factors and poor prognostic indicators include female sex, increasing age, ANC < 100, preexisting renal, cardiac or inflammatory disease comorbidities, and sepsis. [14]. Considering these factors, the 60 years of age in our female patient, her CKD, the acquisition of cellulitis during her treatment, and ANC of 5, we were satisfied with the treatment course and outcome. However, other factors have been noted in literature to potentially increase susceptibility of CIA. Specific human leukocyte antigen (HLA) has been identified for increased susceptibility to CIA. Potential CYP reactions in valproate, which remain unclear in literature, could also potentially increase risk of CIA. And certain treatment guidelines of CIA remain vague in literature. Clinical screening either separately or combined for many of these risk factors should be established. Additionally, consideration for a standardized protocol for timeline and dosing of treatment for CIA should be established.
3.1. Screening: Renal Failure and HLA
Though CIA is an adverse event which occurs in less than 1% of adults with psychiatric conditions [15], more research is being conducted to determine risk factors which may increase the likelihood of patients developing this condition. By screening for risk factors, we may mitigate the occurrence of these events. It is noted that our patient who had a past medical history of CKD was dosed with gentamicin upon initial fever of 103.1°F on Treatment day 3. Though gentamicin has known nephrotoxic effects and was thus discontinued to prevent further kidney toxicity, many case reports have suggested that clozapine may induce and/or exacerbate renal failure and nephritis [16–19]. While further research is necessary to quantify the precise risk of clozapine on the kidney function, prior to initiating a trial dose of clozapine, including a thorough history, measuring a patient's kidney function, or eGFR, and BUN/creatinine panel in addition to weekly monitoring of clozapine and ANC levels may reduce exacerbation of CKD.
Associations between susceptibility of CIA and human leukocyte antigen (HLA) were initially reported in the 1990s [20]. In 2014, HLA-DQB1 and HLA-B alleles were specifically implicated in amino acid changes responsible for patient's susceptibility to CIA [21]. Currently, there is no guidance on mandatory panels or screening for HLA alleles prior to administration of clozapine though such screening has been shown to be health and cost-effective [15]. While the past medical history indicated that our subject had been diagnosed with arthritis, we did not investigate which type of arthritis. We performed HLA screening towards the end of her CIA treatment and discovered that our patient was, indeed, HLA-DQB1 and HLA-DQ2 positive. Had we implemented HLA screening prior to initiating clozapine, we could have potentially avoided her CIA.
3.2. Management Protocol for Clozapine-Induced Agranulocytosis
While standard procedures for the management of CIA have been established, many of the details remain either up to physician determination or unestablished guidelines. Filgrastim/G-CSF has been shown to decrease the recovery time associated with agranulocytosis [7]. However, there is not an established dose for filgrastim for the treatment of CIA. There are established guidelines for filgrastim/G-CSF use in patients suffering from a number of immunocompromising diseases and cancers [22]. However, there is no direct guidance for administering filgrastim for patients suffering from CIA. Filgrastim/G-CSF is available in 300 mcg or 480 mcg vials or single dose syringes with recommended starting dose 5mcg/kg/day [22]. It is recommended to be administered up to 2 weeks or until ANC has reached 10,000/mm3 and is to be discontinued if ANC surpasses 10,000/mm3 after expected nadir [22].
In our patient, treatment of CIA took a total of 10 days of which Neupogen was dosed a total of 6 days with dosages of 300 mcg and 800 mcg (see Table 1) for patient recovery to a normal range of WBC 7 L and ANC 3.97 μL. Further study may provide more efficient dosing and thus more expedient and cost-effective care.
There also continues to be nebulous guidelines in management of CIA through the utilization of bone marrow aspirate and biopsy. Current protocol in the initial studies for the diagnosis of CIA includes CBC, white cell differential, examination of the peripheral smear, observation of recovery after cessation of the drug in a healthy patient, bacterial and/or viral studies if the patient is febrile, and a bone marrow aspiration and biopsy [12, 14]. As the utilization of the bone marrow biopsy is to ascertain patient granulopoiesis status, physicians may choose to begin filgrastim/G-CSF treatment prior to performing a bone marrow aspirate. For our case, hematology recommended bone marrow biopsy on Treatment day 3 to rule out WBC aplasia; however, they suggested performing the biopsy only if the increased filgrastim dose to 800 mcg did not prove effective in improving neutrophils levels. When peripheral blood screening revealed cellular morphology categorized as normal, a bone marrow biopsy was not performed on our subject. Importantly, upon literature review, there are no stated guidelines on when to perform the bone biopsy [10, 14].
3.3. Valproic Acid and CYP Effects
Finally, while clozapine was immediately discontinued upon admission, valproate was continued throughout the duration of treatment for the patient's schizoaffective disorder (see Table 1). There has been suggestion that valproate may be a clozapine metabolism inducer [23], the serum valproate level was subtherapeutic 36.5 (50-100) on treatment day 0/admission to the medicine floor, and the clozapine level was not taken at admission; so, no definitive conclusion can be made. Other studies suggest that valproate is a weak inhibitor of CYP 3A4 [24, 25] and potent CYP 2C9 inhibitor [26, 27]. Additionally, in 2018, the Malik et al. case control study of 136 cases found an association of increased risk of CIA in those with concurrent use of sodium valproate and clozapine [28]. These findings might suggest that our subjects' concomitant dosing of valproate with her clozapine could have exacerbated the clozapine effect causing CIA. Should these theories prove true on larger study, the decision to continue the patient's prescription of valproate during treatment for CIA could have elongated the recovery process due to the CYP inhibitor effects of valproate on clozapine levels. Future investigation for drug interaction of valproate with clozapine together should be studied. Should valproate prove to be a CYP inhibitor, or exacerbate CIA, standardized guidelines should indicate valproate be discontinued in future findings of CIA, and alternative therapeutics should be explored. Additionally, adjunctive use of lithium with clozapine has been initially investigated to mitigate the level of neutropenia for those experiencing CIA [29]. Additional study into adjunct dosing of lithium should be investigated. Concurrent use of valproate with clozapine, adjunct dosing of lithium, and other patient risk factors may need to be considered while determining proper individualized treatment.
4. Conclusion
Through this case of CIA in a patient with longstanding schizoaffective disorder, CKD, and HLA-DQB1 and HLA-DQ2 positivity, the importance of implementing a standardized screen which accounts for the renal function and HLA status is imperative for safe practices in prescribing clozapine for psychiatric disorders and mitigating the risk for CIA. Additionally, proper standardized monitoring of renal status through the treatment process may also mitigate risk of potential kidney failure. Further study is necessary to distinguish valproate's role in agranulocytosis singularly or in concert with clozapine. More detailed standardized guidelines would be beneficial for treatment of CIA, should it occur. As clozapine is known as a drug of last resort to be administered when there is failure of more traditional, and risk averse therapeutics, it is difficult to deny this treatment option, as it ultimately implies that all other treatment options have been exhausted. Proper screening and established protocol and guidelines could increase the level of monitoring in patients with known risk factors as revealed by the official screen. This risk factor screen and subsequent monitoring could increase the cost-effectiveness of clozapine treatment and decrease the incidence and morbidity of this feared adverse event.
Acknowledgments
The authors would like to thank the nursing staff and social workers for their day-to-day involvement in the care of the patient. We would also like to thank the following residents for the day-to-day involvement in managing the care of our patient: Chris Alfred, Ainsley Backman, Vito D'Angelo, Randy Lai, and Jai Patel. We would also like to thank Jonathan Eckstein, Steven Rubel, and Albert Strojan for the feedback given during the development of this paper. The authors also would like to thank Alvin Holcomb for the role he plays in resident medical education on a daily basis.
Abbreviations
CIA: Clozapine-induced agranulocytosis
ANC: Absolute neutrophil count
DVT: Deep vein thrombosis
CKD: Chronic kidney disease
AKI: Acute kidney injury
CYP: Cytochrome P450
EMS: Emergency medical services
ED: Emergency department
HLA: Human leukocyte antigen
G-CSF: Granulocyte-colony stimulating factor.
Data Availability
The subject data used to support the findings of this study are included in the Table within the article. Prior studies used to support the findings of this study are cited at relevant places within the text as references [1–29].
Consent
Written informed consent was obtained and is on the file.
Conflicts of Interest
The authors declare that there that there is no conflict of interest regarding the publication of this article.
Table 1 Treatment course lab table.
Treatment day Treatment day 0 Treatment day 1 Treatment day 2 Treatment day 3 Treatment day 4 Treatment day 5 Treatment day 6 Treatment day 7 Treatment day 8 Treatment day 9 Treatment day 10 Treatment day 11 Treatment day 12
Lab value
ANC level (μL) 0.05 0 0.01 0.01 0.01 0.01 0 0.02 0.04 0.57 3.97 11.51 10.38
WBC (L) N/A 0.4 0.4 0.3 0.2 0.3 0.2 0.3 0.4 1.8 7 18.7 N/A
Temperature max 98.8 98.6 100.7 103.1 101 98.5 99.3 97.3 98.1 98.6 97.8 97.7 98.1
BP 127/79 144/77 110/59 113/48 131/59 101/53 129/61 127/65 119/64 130/75 117/65 130/70
Hgb (G/DL) 10.4 9.9 11 10.5 9.8 8.9 8.5 8 8 8.6 9.6 9.3 8.4
Hematocrit (%) 33.8 31.8 36.4 33.6 31.6 29.3 27.2 26.3 26.1 28.1 32.2 30.6 28.6
H&H 10.4/33.8 9.9/31.8 11.0/36.4 10.5/33.6 9.8/31.6 8.9/29.3 8.5/27.2 8.0/26.3 8.0/26.1 8.6/28.1 9.6/32.2 9.3/30.6 8.4/28.6
BUN N/A N/A 38 36 46 55 77 70 57 43 33 29 25
CR N/A N/A 1.57 1.93 2.3 2.8 3.2 2.45 1.98 1.69 1.75 1.55 1.59
eGFR N/A N/A 33.61 26.48 21.63 17.24 14.78 20.11 25.71 30.87 29.65 34.11 33.12
Valproate level 36.5 L 50.9 L
Amlodipine dose 10 mg 10 mg 10 mg Not given Not given 10 mg 10 mg 10 mg Refused 10 mg 10 mg 10 mg 10 mg
Docusate dose Refused 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg
PEG dose 17 grams 17 grams
Valproate dose 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d
Filgrastim dose N/A 300 mcg 300 mcg 800 mcg 800 mcg 800 mcg N/A N/A 800 mcg N/A N/A N/A N/A | Recovering | ReactionOutcome | CC BY | 33688445 | 19,084,247 | 2021 |
What was the outcome of reaction 'Drug interaction'? | Considerations of HLA, Renal Failure, Valproic Acid Use, and Current Treatment Guidelines in Clozapine-Induced Agranulocytosis.
Clozapine, the choice atypical antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder, has been shown to reduce positive and negative symptoms of schizophrenia. Clozapine, though beneficial in reducing the need for hospitalization, rehabilitation, and health care costs, is known as a drug of last resort due to its potential adverse event of clozapine-induced agranulocytosis, which holds a case fatality rate between 4.2 and 16%. Herein, we describe a female patient with longstanding schizoaffective disorder and chronic kidney disease who suffered from clozapine-induced agranulocytosis after failing two other atypical antipsychotics. Retrospective considerations of this case and management highlight risk factors such as HLA status, renal failure, and concurrent valproic acid use which presently do not have official screening, guidelines, or restrictions in place when prescribing clozapine. Additionally, there are no specific clozapine-induced agranulocytosis management recommendations such as G-CSF/filgrastim dose, timing of bone marrow aspirate and biopsy, and use of concomitant valproate. We propose that further comprehensive official screening, monitoring, and guidelines in the prescribing of clozapine, and further guidelines in the treatment of clozapine induced agranulocytosis, could increase the cost-effectiveness of clozapine treatment, and decrease the incidence, and morbidity of this feared adverse event.
1. Introduction
Clozapine, a dibenzodiazepine antipsychotic exhibiting weak dopaminergic activity and atypical pharmacological properties, is the choice antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder [1–4]. Advantages of clozapine include decreased positive symptoms of schizophrenia such as voices and hallucinations and decreased negative symptoms such as blunted affect and suicidal behavior [5]. The decreased positive and negative symptoms result in reduced need for hospitalization, rehabilitation, and subsequent health care costs [6]. However, known and feared disadvantages include neutropenia and life-threatening agranulocytosis [7, 8].
A benign form of neutropenia with an absolute neutrophil count (ANC) < 1500 cells/μL [9] is known to occur more frequently than clinically significant, agranulocytosis, where ANC < 500 cells/μL [10]. A high risk of severe and/or opportunistic infections is noted to be associated with ANC <200 [9]. In 2008, clozapine-induced agranulocytosis (CIA) had a known rate of seven cases per one million [11]. In 2006, the case fatality caused by CIA was estimated to be 4.2% to 16% [12]. In 2016, the observed mortality rate ranged from 0.1 and 0.3 per thousand, and the case fatality rate was estimated to be between 2.2 and 4.2 [13]. Standard established protocol includes immediate discontinuation of clozapine should white blood cell count reach <500 ANC [10, 14]. Patients' WBC and ANC must be monitored daily until WBC > 3000/mm3 and ANC > 1500/mm3 [7].
As more cases of CIA are occurring, more information concerning prescribing this efficacious antipsychotic as well as the treatment of CIA has become available. Here, we describe a patient with longstanding schizoaffective disorder who suffered from CIA after being transitioned to clozapine due to failed trials of risperidone and olanzapine. Retrospective considerations of her placement on clozapine and subsequent management of her CIA brought into question many factors which do not have clear guidelines, including official screening of risk factors which increase likelihood of CIA, as well as clear clinical management for this feared adverse event. This case report provides a spotlight on many factors such as screening for chronic kidney disease (CKD), human leukocyte antigen(HLA) typing, concurrent valproate administration due to potential CYP interactions, and management considerations such as dosing for filgrastim/G-CSF and timing of bone marrow biopsy. This analysis aims for further study and ultimately future implementation of screening and management guidelines for better informed management of refractory schizophrenia treatment, reduced cases of CIA, and improved management of CIA should it occur.
2. Case Presentation
A 60-year-old Caucasian female nursing home resident was brought in by EMS to the ED due to disorganized behavior, auditory hallucinations, and disorganized speech with loosening associations and was admitted to the inpatient psychiatric unit. Past psychiatric history included longstanding schizoaffective disorder. As a psychiatric inpatient, after having failed treatment with risperidone and olanzapine, the patient was started on clozapine 25 mg PO daily and was titrated to 150 mg PO BID over the course of 28 days. Recorded WBC on day 28 of treatment was 4.5 × 109/L (4.5 to 11.0 × 109/L). On the 35th day of clozapine treatment, the patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. WBC was found to be 0.2 × 109/L (4.5 to 11.0 × 109/L), and ANC was 0.05 [1.5 to 8.0 (1,500 to 8,000/mm3)]. The valproate level was 36.5 (50-100). Subsequently, the patient was transferred to the inpatient medicine floor this same day due to clozapine-induced leukocytopenia (day of transfer to medicine/Treatment day 0).
Past medical history included arthritis, deep vein thrombosis, chronic kidney disease (CKD) (stage 3), right bundle branch block, left anterior fascicular block, syncope, and epilepsy. On admission, patient was alert and oriented ×2 to self and place. The patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. The patient denied headache, shortness of breath, abdominal pain, dysuria, or urinary frequency. The patient's allergies included penicillamine, penicillin, and shellfish. Active medications included sodium valproate, amlodipine, docusate, and polyethylene glycol. Physical exam was unremarkable, and vitals were within normal limits (See Table 1).
2.1. Treatment Course
On the day of transfer to medicine (Treatment day 0-Table 1), clozapine was immediately discontinued, the patient was placed in reverse isolation, and a throat culture was taken. On Treatment day 1, upon recommendation from hematology, the patient received filgrastim/G-CSF 300 mcg subcutaneously. The patient continued this dosage of filgrastim for two days along with home dose of valproate.
On Treatment day 3, the patient spiked a fever of 103.1°F. A fever source was investigated, and an uncomplicated cellulitis on the abdominal wall was found. Filgrastim was adjusted to a dose of 800 mcg subcutaneous daily (see Table 1), and the patient was administered acetaminophen, aztreonam, clindamycin, and gentamicin while monitoring the kidney function.
Gentamicin was discontinued on Treatment day 5 (two days after initiation) when eGFR was 17.24 indicative of AKI stage 4 (see Table 1). Aztreonam and clindamycin were continued till Treatment day 6, and micafungin and meropenem administration began on Treatment day 7.
Patient status stabilized on Treatment day 10 when her ANC count rose to 1.8, up from 0.4 on Treatment day 9 (See Table 1). The patient remained hospitalized an additional two days to correct electrolyte abnormalities.
3. Discussion
As CIA has become more prevalent, it has been noted that risk factors and poor prognostic indicators include female sex, increasing age, ANC < 100, preexisting renal, cardiac or inflammatory disease comorbidities, and sepsis. [14]. Considering these factors, the 60 years of age in our female patient, her CKD, the acquisition of cellulitis during her treatment, and ANC of 5, we were satisfied with the treatment course and outcome. However, other factors have been noted in literature to potentially increase susceptibility of CIA. Specific human leukocyte antigen (HLA) has been identified for increased susceptibility to CIA. Potential CYP reactions in valproate, which remain unclear in literature, could also potentially increase risk of CIA. And certain treatment guidelines of CIA remain vague in literature. Clinical screening either separately or combined for many of these risk factors should be established. Additionally, consideration for a standardized protocol for timeline and dosing of treatment for CIA should be established.
3.1. Screening: Renal Failure and HLA
Though CIA is an adverse event which occurs in less than 1% of adults with psychiatric conditions [15], more research is being conducted to determine risk factors which may increase the likelihood of patients developing this condition. By screening for risk factors, we may mitigate the occurrence of these events. It is noted that our patient who had a past medical history of CKD was dosed with gentamicin upon initial fever of 103.1°F on Treatment day 3. Though gentamicin has known nephrotoxic effects and was thus discontinued to prevent further kidney toxicity, many case reports have suggested that clozapine may induce and/or exacerbate renal failure and nephritis [16–19]. While further research is necessary to quantify the precise risk of clozapine on the kidney function, prior to initiating a trial dose of clozapine, including a thorough history, measuring a patient's kidney function, or eGFR, and BUN/creatinine panel in addition to weekly monitoring of clozapine and ANC levels may reduce exacerbation of CKD.
Associations between susceptibility of CIA and human leukocyte antigen (HLA) were initially reported in the 1990s [20]. In 2014, HLA-DQB1 and HLA-B alleles were specifically implicated in amino acid changes responsible for patient's susceptibility to CIA [21]. Currently, there is no guidance on mandatory panels or screening for HLA alleles prior to administration of clozapine though such screening has been shown to be health and cost-effective [15]. While the past medical history indicated that our subject had been diagnosed with arthritis, we did not investigate which type of arthritis. We performed HLA screening towards the end of her CIA treatment and discovered that our patient was, indeed, HLA-DQB1 and HLA-DQ2 positive. Had we implemented HLA screening prior to initiating clozapine, we could have potentially avoided her CIA.
3.2. Management Protocol for Clozapine-Induced Agranulocytosis
While standard procedures for the management of CIA have been established, many of the details remain either up to physician determination or unestablished guidelines. Filgrastim/G-CSF has been shown to decrease the recovery time associated with agranulocytosis [7]. However, there is not an established dose for filgrastim for the treatment of CIA. There are established guidelines for filgrastim/G-CSF use in patients suffering from a number of immunocompromising diseases and cancers [22]. However, there is no direct guidance for administering filgrastim for patients suffering from CIA. Filgrastim/G-CSF is available in 300 mcg or 480 mcg vials or single dose syringes with recommended starting dose 5mcg/kg/day [22]. It is recommended to be administered up to 2 weeks or until ANC has reached 10,000/mm3 and is to be discontinued if ANC surpasses 10,000/mm3 after expected nadir [22].
In our patient, treatment of CIA took a total of 10 days of which Neupogen was dosed a total of 6 days with dosages of 300 mcg and 800 mcg (see Table 1) for patient recovery to a normal range of WBC 7 L and ANC 3.97 μL. Further study may provide more efficient dosing and thus more expedient and cost-effective care.
There also continues to be nebulous guidelines in management of CIA through the utilization of bone marrow aspirate and biopsy. Current protocol in the initial studies for the diagnosis of CIA includes CBC, white cell differential, examination of the peripheral smear, observation of recovery after cessation of the drug in a healthy patient, bacterial and/or viral studies if the patient is febrile, and a bone marrow aspiration and biopsy [12, 14]. As the utilization of the bone marrow biopsy is to ascertain patient granulopoiesis status, physicians may choose to begin filgrastim/G-CSF treatment prior to performing a bone marrow aspirate. For our case, hematology recommended bone marrow biopsy on Treatment day 3 to rule out WBC aplasia; however, they suggested performing the biopsy only if the increased filgrastim dose to 800 mcg did not prove effective in improving neutrophils levels. When peripheral blood screening revealed cellular morphology categorized as normal, a bone marrow biopsy was not performed on our subject. Importantly, upon literature review, there are no stated guidelines on when to perform the bone biopsy [10, 14].
3.3. Valproic Acid and CYP Effects
Finally, while clozapine was immediately discontinued upon admission, valproate was continued throughout the duration of treatment for the patient's schizoaffective disorder (see Table 1). There has been suggestion that valproate may be a clozapine metabolism inducer [23], the serum valproate level was subtherapeutic 36.5 (50-100) on treatment day 0/admission to the medicine floor, and the clozapine level was not taken at admission; so, no definitive conclusion can be made. Other studies suggest that valproate is a weak inhibitor of CYP 3A4 [24, 25] and potent CYP 2C9 inhibitor [26, 27]. Additionally, in 2018, the Malik et al. case control study of 136 cases found an association of increased risk of CIA in those with concurrent use of sodium valproate and clozapine [28]. These findings might suggest that our subjects' concomitant dosing of valproate with her clozapine could have exacerbated the clozapine effect causing CIA. Should these theories prove true on larger study, the decision to continue the patient's prescription of valproate during treatment for CIA could have elongated the recovery process due to the CYP inhibitor effects of valproate on clozapine levels. Future investigation for drug interaction of valproate with clozapine together should be studied. Should valproate prove to be a CYP inhibitor, or exacerbate CIA, standardized guidelines should indicate valproate be discontinued in future findings of CIA, and alternative therapeutics should be explored. Additionally, adjunctive use of lithium with clozapine has been initially investigated to mitigate the level of neutropenia for those experiencing CIA [29]. Additional study into adjunct dosing of lithium should be investigated. Concurrent use of valproate with clozapine, adjunct dosing of lithium, and other patient risk factors may need to be considered while determining proper individualized treatment.
4. Conclusion
Through this case of CIA in a patient with longstanding schizoaffective disorder, CKD, and HLA-DQB1 and HLA-DQ2 positivity, the importance of implementing a standardized screen which accounts for the renal function and HLA status is imperative for safe practices in prescribing clozapine for psychiatric disorders and mitigating the risk for CIA. Additionally, proper standardized monitoring of renal status through the treatment process may also mitigate risk of potential kidney failure. Further study is necessary to distinguish valproate's role in agranulocytosis singularly or in concert with clozapine. More detailed standardized guidelines would be beneficial for treatment of CIA, should it occur. As clozapine is known as a drug of last resort to be administered when there is failure of more traditional, and risk averse therapeutics, it is difficult to deny this treatment option, as it ultimately implies that all other treatment options have been exhausted. Proper screening and established protocol and guidelines could increase the level of monitoring in patients with known risk factors as revealed by the official screen. This risk factor screen and subsequent monitoring could increase the cost-effectiveness of clozapine treatment and decrease the incidence and morbidity of this feared adverse event.
Acknowledgments
The authors would like to thank the nursing staff and social workers for their day-to-day involvement in the care of the patient. We would also like to thank the following residents for the day-to-day involvement in managing the care of our patient: Chris Alfred, Ainsley Backman, Vito D'Angelo, Randy Lai, and Jai Patel. We would also like to thank Jonathan Eckstein, Steven Rubel, and Albert Strojan for the feedback given during the development of this paper. The authors also would like to thank Alvin Holcomb for the role he plays in resident medical education on a daily basis.
Abbreviations
CIA: Clozapine-induced agranulocytosis
ANC: Absolute neutrophil count
DVT: Deep vein thrombosis
CKD: Chronic kidney disease
AKI: Acute kidney injury
CYP: Cytochrome P450
EMS: Emergency medical services
ED: Emergency department
HLA: Human leukocyte antigen
G-CSF: Granulocyte-colony stimulating factor.
Data Availability
The subject data used to support the findings of this study are included in the Table within the article. Prior studies used to support the findings of this study are cited at relevant places within the text as references [1–29].
Consent
Written informed consent was obtained and is on the file.
Conflicts of Interest
The authors declare that there that there is no conflict of interest regarding the publication of this article.
Table 1 Treatment course lab table.
Treatment day Treatment day 0 Treatment day 1 Treatment day 2 Treatment day 3 Treatment day 4 Treatment day 5 Treatment day 6 Treatment day 7 Treatment day 8 Treatment day 9 Treatment day 10 Treatment day 11 Treatment day 12
Lab value
ANC level (μL) 0.05 0 0.01 0.01 0.01 0.01 0 0.02 0.04 0.57 3.97 11.51 10.38
WBC (L) N/A 0.4 0.4 0.3 0.2 0.3 0.2 0.3 0.4 1.8 7 18.7 N/A
Temperature max 98.8 98.6 100.7 103.1 101 98.5 99.3 97.3 98.1 98.6 97.8 97.7 98.1
BP 127/79 144/77 110/59 113/48 131/59 101/53 129/61 127/65 119/64 130/75 117/65 130/70
Hgb (G/DL) 10.4 9.9 11 10.5 9.8 8.9 8.5 8 8 8.6 9.6 9.3 8.4
Hematocrit (%) 33.8 31.8 36.4 33.6 31.6 29.3 27.2 26.3 26.1 28.1 32.2 30.6 28.6
H&H 10.4/33.8 9.9/31.8 11.0/36.4 10.5/33.6 9.8/31.6 8.9/29.3 8.5/27.2 8.0/26.3 8.0/26.1 8.6/28.1 9.6/32.2 9.3/30.6 8.4/28.6
BUN N/A N/A 38 36 46 55 77 70 57 43 33 29 25
CR N/A N/A 1.57 1.93 2.3 2.8 3.2 2.45 1.98 1.69 1.75 1.55 1.59
eGFR N/A N/A 33.61 26.48 21.63 17.24 14.78 20.11 25.71 30.87 29.65 34.11 33.12
Valproate level 36.5 L 50.9 L
Amlodipine dose 10 mg 10 mg 10 mg Not given Not given 10 mg 10 mg 10 mg Refused 10 mg 10 mg 10 mg 10 mg
Docusate dose Refused 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg
PEG dose 17 grams 17 grams
Valproate dose 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d
Filgrastim dose N/A 300 mcg 300 mcg 800 mcg 800 mcg 800 mcg N/A N/A 800 mcg N/A N/A N/A N/A | Recovering | ReactionOutcome | CC BY | 33688445 | 19,084,247 | 2021 |
What was the outcome of reaction 'Potentiating drug interaction'? | Considerations of HLA, Renal Failure, Valproic Acid Use, and Current Treatment Guidelines in Clozapine-Induced Agranulocytosis.
Clozapine, the choice atypical antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder, has been shown to reduce positive and negative symptoms of schizophrenia. Clozapine, though beneficial in reducing the need for hospitalization, rehabilitation, and health care costs, is known as a drug of last resort due to its potential adverse event of clozapine-induced agranulocytosis, which holds a case fatality rate between 4.2 and 16%. Herein, we describe a female patient with longstanding schizoaffective disorder and chronic kidney disease who suffered from clozapine-induced agranulocytosis after failing two other atypical antipsychotics. Retrospective considerations of this case and management highlight risk factors such as HLA status, renal failure, and concurrent valproic acid use which presently do not have official screening, guidelines, or restrictions in place when prescribing clozapine. Additionally, there are no specific clozapine-induced agranulocytosis management recommendations such as G-CSF/filgrastim dose, timing of bone marrow aspirate and biopsy, and use of concomitant valproate. We propose that further comprehensive official screening, monitoring, and guidelines in the prescribing of clozapine, and further guidelines in the treatment of clozapine induced agranulocytosis, could increase the cost-effectiveness of clozapine treatment, and decrease the incidence, and morbidity of this feared adverse event.
1. Introduction
Clozapine, a dibenzodiazepine antipsychotic exhibiting weak dopaminergic activity and atypical pharmacological properties, is the choice antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder [1–4]. Advantages of clozapine include decreased positive symptoms of schizophrenia such as voices and hallucinations and decreased negative symptoms such as blunted affect and suicidal behavior [5]. The decreased positive and negative symptoms result in reduced need for hospitalization, rehabilitation, and subsequent health care costs [6]. However, known and feared disadvantages include neutropenia and life-threatening agranulocytosis [7, 8].
A benign form of neutropenia with an absolute neutrophil count (ANC) < 1500 cells/μL [9] is known to occur more frequently than clinically significant, agranulocytosis, where ANC < 500 cells/μL [10]. A high risk of severe and/or opportunistic infections is noted to be associated with ANC <200 [9]. In 2008, clozapine-induced agranulocytosis (CIA) had a known rate of seven cases per one million [11]. In 2006, the case fatality caused by CIA was estimated to be 4.2% to 16% [12]. In 2016, the observed mortality rate ranged from 0.1 and 0.3 per thousand, and the case fatality rate was estimated to be between 2.2 and 4.2 [13]. Standard established protocol includes immediate discontinuation of clozapine should white blood cell count reach <500 ANC [10, 14]. Patients' WBC and ANC must be monitored daily until WBC > 3000/mm3 and ANC > 1500/mm3 [7].
As more cases of CIA are occurring, more information concerning prescribing this efficacious antipsychotic as well as the treatment of CIA has become available. Here, we describe a patient with longstanding schizoaffective disorder who suffered from CIA after being transitioned to clozapine due to failed trials of risperidone and olanzapine. Retrospective considerations of her placement on clozapine and subsequent management of her CIA brought into question many factors which do not have clear guidelines, including official screening of risk factors which increase likelihood of CIA, as well as clear clinical management for this feared adverse event. This case report provides a spotlight on many factors such as screening for chronic kidney disease (CKD), human leukocyte antigen(HLA) typing, concurrent valproate administration due to potential CYP interactions, and management considerations such as dosing for filgrastim/G-CSF and timing of bone marrow biopsy. This analysis aims for further study and ultimately future implementation of screening and management guidelines for better informed management of refractory schizophrenia treatment, reduced cases of CIA, and improved management of CIA should it occur.
2. Case Presentation
A 60-year-old Caucasian female nursing home resident was brought in by EMS to the ED due to disorganized behavior, auditory hallucinations, and disorganized speech with loosening associations and was admitted to the inpatient psychiatric unit. Past psychiatric history included longstanding schizoaffective disorder. As a psychiatric inpatient, after having failed treatment with risperidone and olanzapine, the patient was started on clozapine 25 mg PO daily and was titrated to 150 mg PO BID over the course of 28 days. Recorded WBC on day 28 of treatment was 4.5 × 109/L (4.5 to 11.0 × 109/L). On the 35th day of clozapine treatment, the patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. WBC was found to be 0.2 × 109/L (4.5 to 11.0 × 109/L), and ANC was 0.05 [1.5 to 8.0 (1,500 to 8,000/mm3)]. The valproate level was 36.5 (50-100). Subsequently, the patient was transferred to the inpatient medicine floor this same day due to clozapine-induced leukocytopenia (day of transfer to medicine/Treatment day 0).
Past medical history included arthritis, deep vein thrombosis, chronic kidney disease (CKD) (stage 3), right bundle branch block, left anterior fascicular block, syncope, and epilepsy. On admission, patient was alert and oriented ×2 to self and place. The patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. The patient denied headache, shortness of breath, abdominal pain, dysuria, or urinary frequency. The patient's allergies included penicillamine, penicillin, and shellfish. Active medications included sodium valproate, amlodipine, docusate, and polyethylene glycol. Physical exam was unremarkable, and vitals were within normal limits (See Table 1).
2.1. Treatment Course
On the day of transfer to medicine (Treatment day 0-Table 1), clozapine was immediately discontinued, the patient was placed in reverse isolation, and a throat culture was taken. On Treatment day 1, upon recommendation from hematology, the patient received filgrastim/G-CSF 300 mcg subcutaneously. The patient continued this dosage of filgrastim for two days along with home dose of valproate.
On Treatment day 3, the patient spiked a fever of 103.1°F. A fever source was investigated, and an uncomplicated cellulitis on the abdominal wall was found. Filgrastim was adjusted to a dose of 800 mcg subcutaneous daily (see Table 1), and the patient was administered acetaminophen, aztreonam, clindamycin, and gentamicin while monitoring the kidney function.
Gentamicin was discontinued on Treatment day 5 (two days after initiation) when eGFR was 17.24 indicative of AKI stage 4 (see Table 1). Aztreonam and clindamycin were continued till Treatment day 6, and micafungin and meropenem administration began on Treatment day 7.
Patient status stabilized on Treatment day 10 when her ANC count rose to 1.8, up from 0.4 on Treatment day 9 (See Table 1). The patient remained hospitalized an additional two days to correct electrolyte abnormalities.
3. Discussion
As CIA has become more prevalent, it has been noted that risk factors and poor prognostic indicators include female sex, increasing age, ANC < 100, preexisting renal, cardiac or inflammatory disease comorbidities, and sepsis. [14]. Considering these factors, the 60 years of age in our female patient, her CKD, the acquisition of cellulitis during her treatment, and ANC of 5, we were satisfied with the treatment course and outcome. However, other factors have been noted in literature to potentially increase susceptibility of CIA. Specific human leukocyte antigen (HLA) has been identified for increased susceptibility to CIA. Potential CYP reactions in valproate, which remain unclear in literature, could also potentially increase risk of CIA. And certain treatment guidelines of CIA remain vague in literature. Clinical screening either separately or combined for many of these risk factors should be established. Additionally, consideration for a standardized protocol for timeline and dosing of treatment for CIA should be established.
3.1. Screening: Renal Failure and HLA
Though CIA is an adverse event which occurs in less than 1% of adults with psychiatric conditions [15], more research is being conducted to determine risk factors which may increase the likelihood of patients developing this condition. By screening for risk factors, we may mitigate the occurrence of these events. It is noted that our patient who had a past medical history of CKD was dosed with gentamicin upon initial fever of 103.1°F on Treatment day 3. Though gentamicin has known nephrotoxic effects and was thus discontinued to prevent further kidney toxicity, many case reports have suggested that clozapine may induce and/or exacerbate renal failure and nephritis [16–19]. While further research is necessary to quantify the precise risk of clozapine on the kidney function, prior to initiating a trial dose of clozapine, including a thorough history, measuring a patient's kidney function, or eGFR, and BUN/creatinine panel in addition to weekly monitoring of clozapine and ANC levels may reduce exacerbation of CKD.
Associations between susceptibility of CIA and human leukocyte antigen (HLA) were initially reported in the 1990s [20]. In 2014, HLA-DQB1 and HLA-B alleles were specifically implicated in amino acid changes responsible for patient's susceptibility to CIA [21]. Currently, there is no guidance on mandatory panels or screening for HLA alleles prior to administration of clozapine though such screening has been shown to be health and cost-effective [15]. While the past medical history indicated that our subject had been diagnosed with arthritis, we did not investigate which type of arthritis. We performed HLA screening towards the end of her CIA treatment and discovered that our patient was, indeed, HLA-DQB1 and HLA-DQ2 positive. Had we implemented HLA screening prior to initiating clozapine, we could have potentially avoided her CIA.
3.2. Management Protocol for Clozapine-Induced Agranulocytosis
While standard procedures for the management of CIA have been established, many of the details remain either up to physician determination or unestablished guidelines. Filgrastim/G-CSF has been shown to decrease the recovery time associated with agranulocytosis [7]. However, there is not an established dose for filgrastim for the treatment of CIA. There are established guidelines for filgrastim/G-CSF use in patients suffering from a number of immunocompromising diseases and cancers [22]. However, there is no direct guidance for administering filgrastim for patients suffering from CIA. Filgrastim/G-CSF is available in 300 mcg or 480 mcg vials or single dose syringes with recommended starting dose 5mcg/kg/day [22]. It is recommended to be administered up to 2 weeks or until ANC has reached 10,000/mm3 and is to be discontinued if ANC surpasses 10,000/mm3 after expected nadir [22].
In our patient, treatment of CIA took a total of 10 days of which Neupogen was dosed a total of 6 days with dosages of 300 mcg and 800 mcg (see Table 1) for patient recovery to a normal range of WBC 7 L and ANC 3.97 μL. Further study may provide more efficient dosing and thus more expedient and cost-effective care.
There also continues to be nebulous guidelines in management of CIA through the utilization of bone marrow aspirate and biopsy. Current protocol in the initial studies for the diagnosis of CIA includes CBC, white cell differential, examination of the peripheral smear, observation of recovery after cessation of the drug in a healthy patient, bacterial and/or viral studies if the patient is febrile, and a bone marrow aspiration and biopsy [12, 14]. As the utilization of the bone marrow biopsy is to ascertain patient granulopoiesis status, physicians may choose to begin filgrastim/G-CSF treatment prior to performing a bone marrow aspirate. For our case, hematology recommended bone marrow biopsy on Treatment day 3 to rule out WBC aplasia; however, they suggested performing the biopsy only if the increased filgrastim dose to 800 mcg did not prove effective in improving neutrophils levels. When peripheral blood screening revealed cellular morphology categorized as normal, a bone marrow biopsy was not performed on our subject. Importantly, upon literature review, there are no stated guidelines on when to perform the bone biopsy [10, 14].
3.3. Valproic Acid and CYP Effects
Finally, while clozapine was immediately discontinued upon admission, valproate was continued throughout the duration of treatment for the patient's schizoaffective disorder (see Table 1). There has been suggestion that valproate may be a clozapine metabolism inducer [23], the serum valproate level was subtherapeutic 36.5 (50-100) on treatment day 0/admission to the medicine floor, and the clozapine level was not taken at admission; so, no definitive conclusion can be made. Other studies suggest that valproate is a weak inhibitor of CYP 3A4 [24, 25] and potent CYP 2C9 inhibitor [26, 27]. Additionally, in 2018, the Malik et al. case control study of 136 cases found an association of increased risk of CIA in those with concurrent use of sodium valproate and clozapine [28]. These findings might suggest that our subjects' concomitant dosing of valproate with her clozapine could have exacerbated the clozapine effect causing CIA. Should these theories prove true on larger study, the decision to continue the patient's prescription of valproate during treatment for CIA could have elongated the recovery process due to the CYP inhibitor effects of valproate on clozapine levels. Future investigation for drug interaction of valproate with clozapine together should be studied. Should valproate prove to be a CYP inhibitor, or exacerbate CIA, standardized guidelines should indicate valproate be discontinued in future findings of CIA, and alternative therapeutics should be explored. Additionally, adjunctive use of lithium with clozapine has been initially investigated to mitigate the level of neutropenia for those experiencing CIA [29]. Additional study into adjunct dosing of lithium should be investigated. Concurrent use of valproate with clozapine, adjunct dosing of lithium, and other patient risk factors may need to be considered while determining proper individualized treatment.
4. Conclusion
Through this case of CIA in a patient with longstanding schizoaffective disorder, CKD, and HLA-DQB1 and HLA-DQ2 positivity, the importance of implementing a standardized screen which accounts for the renal function and HLA status is imperative for safe practices in prescribing clozapine for psychiatric disorders and mitigating the risk for CIA. Additionally, proper standardized monitoring of renal status through the treatment process may also mitigate risk of potential kidney failure. Further study is necessary to distinguish valproate's role in agranulocytosis singularly or in concert with clozapine. More detailed standardized guidelines would be beneficial for treatment of CIA, should it occur. As clozapine is known as a drug of last resort to be administered when there is failure of more traditional, and risk averse therapeutics, it is difficult to deny this treatment option, as it ultimately implies that all other treatment options have been exhausted. Proper screening and established protocol and guidelines could increase the level of monitoring in patients with known risk factors as revealed by the official screen. This risk factor screen and subsequent monitoring could increase the cost-effectiveness of clozapine treatment and decrease the incidence and morbidity of this feared adverse event.
Acknowledgments
The authors would like to thank the nursing staff and social workers for their day-to-day involvement in the care of the patient. We would also like to thank the following residents for the day-to-day involvement in managing the care of our patient: Chris Alfred, Ainsley Backman, Vito D'Angelo, Randy Lai, and Jai Patel. We would also like to thank Jonathan Eckstein, Steven Rubel, and Albert Strojan for the feedback given during the development of this paper. The authors also would like to thank Alvin Holcomb for the role he plays in resident medical education on a daily basis.
Abbreviations
CIA: Clozapine-induced agranulocytosis
ANC: Absolute neutrophil count
DVT: Deep vein thrombosis
CKD: Chronic kidney disease
AKI: Acute kidney injury
CYP: Cytochrome P450
EMS: Emergency medical services
ED: Emergency department
HLA: Human leukocyte antigen
G-CSF: Granulocyte-colony stimulating factor.
Data Availability
The subject data used to support the findings of this study are included in the Table within the article. Prior studies used to support the findings of this study are cited at relevant places within the text as references [1–29].
Consent
Written informed consent was obtained and is on the file.
Conflicts of Interest
The authors declare that there that there is no conflict of interest regarding the publication of this article.
Table 1 Treatment course lab table.
Treatment day Treatment day 0 Treatment day 1 Treatment day 2 Treatment day 3 Treatment day 4 Treatment day 5 Treatment day 6 Treatment day 7 Treatment day 8 Treatment day 9 Treatment day 10 Treatment day 11 Treatment day 12
Lab value
ANC level (μL) 0.05 0 0.01 0.01 0.01 0.01 0 0.02 0.04 0.57 3.97 11.51 10.38
WBC (L) N/A 0.4 0.4 0.3 0.2 0.3 0.2 0.3 0.4 1.8 7 18.7 N/A
Temperature max 98.8 98.6 100.7 103.1 101 98.5 99.3 97.3 98.1 98.6 97.8 97.7 98.1
BP 127/79 144/77 110/59 113/48 131/59 101/53 129/61 127/65 119/64 130/75 117/65 130/70
Hgb (G/DL) 10.4 9.9 11 10.5 9.8 8.9 8.5 8 8 8.6 9.6 9.3 8.4
Hematocrit (%) 33.8 31.8 36.4 33.6 31.6 29.3 27.2 26.3 26.1 28.1 32.2 30.6 28.6
H&H 10.4/33.8 9.9/31.8 11.0/36.4 10.5/33.6 9.8/31.6 8.9/29.3 8.5/27.2 8.0/26.3 8.0/26.1 8.6/28.1 9.6/32.2 9.3/30.6 8.4/28.6
BUN N/A N/A 38 36 46 55 77 70 57 43 33 29 25
CR N/A N/A 1.57 1.93 2.3 2.8 3.2 2.45 1.98 1.69 1.75 1.55 1.59
eGFR N/A N/A 33.61 26.48 21.63 17.24 14.78 20.11 25.71 30.87 29.65 34.11 33.12
Valproate level 36.5 L 50.9 L
Amlodipine dose 10 mg 10 mg 10 mg Not given Not given 10 mg 10 mg 10 mg Refused 10 mg 10 mg 10 mg 10 mg
Docusate dose Refused 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg
PEG dose 17 grams 17 grams
Valproate dose 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d
Filgrastim dose N/A 300 mcg 300 mcg 800 mcg 800 mcg 800 mcg N/A N/A 800 mcg N/A N/A N/A N/A | Recovered | ReactionOutcome | CC BY | 33688445 | 19,037,229 | 2021 |
What was the outcome of reaction 'Renal failure'? | Considerations of HLA, Renal Failure, Valproic Acid Use, and Current Treatment Guidelines in Clozapine-Induced Agranulocytosis.
Clozapine, the choice atypical antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder, has been shown to reduce positive and negative symptoms of schizophrenia. Clozapine, though beneficial in reducing the need for hospitalization, rehabilitation, and health care costs, is known as a drug of last resort due to its potential adverse event of clozapine-induced agranulocytosis, which holds a case fatality rate between 4.2 and 16%. Herein, we describe a female patient with longstanding schizoaffective disorder and chronic kidney disease who suffered from clozapine-induced agranulocytosis after failing two other atypical antipsychotics. Retrospective considerations of this case and management highlight risk factors such as HLA status, renal failure, and concurrent valproic acid use which presently do not have official screening, guidelines, or restrictions in place when prescribing clozapine. Additionally, there are no specific clozapine-induced agranulocytosis management recommendations such as G-CSF/filgrastim dose, timing of bone marrow aspirate and biopsy, and use of concomitant valproate. We propose that further comprehensive official screening, monitoring, and guidelines in the prescribing of clozapine, and further guidelines in the treatment of clozapine induced agranulocytosis, could increase the cost-effectiveness of clozapine treatment, and decrease the incidence, and morbidity of this feared adverse event.
1. Introduction
Clozapine, a dibenzodiazepine antipsychotic exhibiting weak dopaminergic activity and atypical pharmacological properties, is the choice antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder [1–4]. Advantages of clozapine include decreased positive symptoms of schizophrenia such as voices and hallucinations and decreased negative symptoms such as blunted affect and suicidal behavior [5]. The decreased positive and negative symptoms result in reduced need for hospitalization, rehabilitation, and subsequent health care costs [6]. However, known and feared disadvantages include neutropenia and life-threatening agranulocytosis [7, 8].
A benign form of neutropenia with an absolute neutrophil count (ANC) < 1500 cells/μL [9] is known to occur more frequently than clinically significant, agranulocytosis, where ANC < 500 cells/μL [10]. A high risk of severe and/or opportunistic infections is noted to be associated with ANC <200 [9]. In 2008, clozapine-induced agranulocytosis (CIA) had a known rate of seven cases per one million [11]. In 2006, the case fatality caused by CIA was estimated to be 4.2% to 16% [12]. In 2016, the observed mortality rate ranged from 0.1 and 0.3 per thousand, and the case fatality rate was estimated to be between 2.2 and 4.2 [13]. Standard established protocol includes immediate discontinuation of clozapine should white blood cell count reach <500 ANC [10, 14]. Patients' WBC and ANC must be monitored daily until WBC > 3000/mm3 and ANC > 1500/mm3 [7].
As more cases of CIA are occurring, more information concerning prescribing this efficacious antipsychotic as well as the treatment of CIA has become available. Here, we describe a patient with longstanding schizoaffective disorder who suffered from CIA after being transitioned to clozapine due to failed trials of risperidone and olanzapine. Retrospective considerations of her placement on clozapine and subsequent management of her CIA brought into question many factors which do not have clear guidelines, including official screening of risk factors which increase likelihood of CIA, as well as clear clinical management for this feared adverse event. This case report provides a spotlight on many factors such as screening for chronic kidney disease (CKD), human leukocyte antigen(HLA) typing, concurrent valproate administration due to potential CYP interactions, and management considerations such as dosing for filgrastim/G-CSF and timing of bone marrow biopsy. This analysis aims for further study and ultimately future implementation of screening and management guidelines for better informed management of refractory schizophrenia treatment, reduced cases of CIA, and improved management of CIA should it occur.
2. Case Presentation
A 60-year-old Caucasian female nursing home resident was brought in by EMS to the ED due to disorganized behavior, auditory hallucinations, and disorganized speech with loosening associations and was admitted to the inpatient psychiatric unit. Past psychiatric history included longstanding schizoaffective disorder. As a psychiatric inpatient, after having failed treatment with risperidone and olanzapine, the patient was started on clozapine 25 mg PO daily and was titrated to 150 mg PO BID over the course of 28 days. Recorded WBC on day 28 of treatment was 4.5 × 109/L (4.5 to 11.0 × 109/L). On the 35th day of clozapine treatment, the patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. WBC was found to be 0.2 × 109/L (4.5 to 11.0 × 109/L), and ANC was 0.05 [1.5 to 8.0 (1,500 to 8,000/mm3)]. The valproate level was 36.5 (50-100). Subsequently, the patient was transferred to the inpatient medicine floor this same day due to clozapine-induced leukocytopenia (day of transfer to medicine/Treatment day 0).
Past medical history included arthritis, deep vein thrombosis, chronic kidney disease (CKD) (stage 3), right bundle branch block, left anterior fascicular block, syncope, and epilepsy. On admission, patient was alert and oriented ×2 to self and place. The patient reported sore throat, nausea, diarrhea, and difficulty falling asleep. The patient denied headache, shortness of breath, abdominal pain, dysuria, or urinary frequency. The patient's allergies included penicillamine, penicillin, and shellfish. Active medications included sodium valproate, amlodipine, docusate, and polyethylene glycol. Physical exam was unremarkable, and vitals were within normal limits (See Table 1).
2.1. Treatment Course
On the day of transfer to medicine (Treatment day 0-Table 1), clozapine was immediately discontinued, the patient was placed in reverse isolation, and a throat culture was taken. On Treatment day 1, upon recommendation from hematology, the patient received filgrastim/G-CSF 300 mcg subcutaneously. The patient continued this dosage of filgrastim for two days along with home dose of valproate.
On Treatment day 3, the patient spiked a fever of 103.1°F. A fever source was investigated, and an uncomplicated cellulitis on the abdominal wall was found. Filgrastim was adjusted to a dose of 800 mcg subcutaneous daily (see Table 1), and the patient was administered acetaminophen, aztreonam, clindamycin, and gentamicin while monitoring the kidney function.
Gentamicin was discontinued on Treatment day 5 (two days after initiation) when eGFR was 17.24 indicative of AKI stage 4 (see Table 1). Aztreonam and clindamycin were continued till Treatment day 6, and micafungin and meropenem administration began on Treatment day 7.
Patient status stabilized on Treatment day 10 when her ANC count rose to 1.8, up from 0.4 on Treatment day 9 (See Table 1). The patient remained hospitalized an additional two days to correct electrolyte abnormalities.
3. Discussion
As CIA has become more prevalent, it has been noted that risk factors and poor prognostic indicators include female sex, increasing age, ANC < 100, preexisting renal, cardiac or inflammatory disease comorbidities, and sepsis. [14]. Considering these factors, the 60 years of age in our female patient, her CKD, the acquisition of cellulitis during her treatment, and ANC of 5, we were satisfied with the treatment course and outcome. However, other factors have been noted in literature to potentially increase susceptibility of CIA. Specific human leukocyte antigen (HLA) has been identified for increased susceptibility to CIA. Potential CYP reactions in valproate, which remain unclear in literature, could also potentially increase risk of CIA. And certain treatment guidelines of CIA remain vague in literature. Clinical screening either separately or combined for many of these risk factors should be established. Additionally, consideration for a standardized protocol for timeline and dosing of treatment for CIA should be established.
3.1. Screening: Renal Failure and HLA
Though CIA is an adverse event which occurs in less than 1% of adults with psychiatric conditions [15], more research is being conducted to determine risk factors which may increase the likelihood of patients developing this condition. By screening for risk factors, we may mitigate the occurrence of these events. It is noted that our patient who had a past medical history of CKD was dosed with gentamicin upon initial fever of 103.1°F on Treatment day 3. Though gentamicin has known nephrotoxic effects and was thus discontinued to prevent further kidney toxicity, many case reports have suggested that clozapine may induce and/or exacerbate renal failure and nephritis [16–19]. While further research is necessary to quantify the precise risk of clozapine on the kidney function, prior to initiating a trial dose of clozapine, including a thorough history, measuring a patient's kidney function, or eGFR, and BUN/creatinine panel in addition to weekly monitoring of clozapine and ANC levels may reduce exacerbation of CKD.
Associations between susceptibility of CIA and human leukocyte antigen (HLA) were initially reported in the 1990s [20]. In 2014, HLA-DQB1 and HLA-B alleles were specifically implicated in amino acid changes responsible for patient's susceptibility to CIA [21]. Currently, there is no guidance on mandatory panels or screening for HLA alleles prior to administration of clozapine though such screening has been shown to be health and cost-effective [15]. While the past medical history indicated that our subject had been diagnosed with arthritis, we did not investigate which type of arthritis. We performed HLA screening towards the end of her CIA treatment and discovered that our patient was, indeed, HLA-DQB1 and HLA-DQ2 positive. Had we implemented HLA screening prior to initiating clozapine, we could have potentially avoided her CIA.
3.2. Management Protocol for Clozapine-Induced Agranulocytosis
While standard procedures for the management of CIA have been established, many of the details remain either up to physician determination or unestablished guidelines. Filgrastim/G-CSF has been shown to decrease the recovery time associated with agranulocytosis [7]. However, there is not an established dose for filgrastim for the treatment of CIA. There are established guidelines for filgrastim/G-CSF use in patients suffering from a number of immunocompromising diseases and cancers [22]. However, there is no direct guidance for administering filgrastim for patients suffering from CIA. Filgrastim/G-CSF is available in 300 mcg or 480 mcg vials or single dose syringes with recommended starting dose 5mcg/kg/day [22]. It is recommended to be administered up to 2 weeks or until ANC has reached 10,000/mm3 and is to be discontinued if ANC surpasses 10,000/mm3 after expected nadir [22].
In our patient, treatment of CIA took a total of 10 days of which Neupogen was dosed a total of 6 days with dosages of 300 mcg and 800 mcg (see Table 1) for patient recovery to a normal range of WBC 7 L and ANC 3.97 μL. Further study may provide more efficient dosing and thus more expedient and cost-effective care.
There also continues to be nebulous guidelines in management of CIA through the utilization of bone marrow aspirate and biopsy. Current protocol in the initial studies for the diagnosis of CIA includes CBC, white cell differential, examination of the peripheral smear, observation of recovery after cessation of the drug in a healthy patient, bacterial and/or viral studies if the patient is febrile, and a bone marrow aspiration and biopsy [12, 14]. As the utilization of the bone marrow biopsy is to ascertain patient granulopoiesis status, physicians may choose to begin filgrastim/G-CSF treatment prior to performing a bone marrow aspirate. For our case, hematology recommended bone marrow biopsy on Treatment day 3 to rule out WBC aplasia; however, they suggested performing the biopsy only if the increased filgrastim dose to 800 mcg did not prove effective in improving neutrophils levels. When peripheral blood screening revealed cellular morphology categorized as normal, a bone marrow biopsy was not performed on our subject. Importantly, upon literature review, there are no stated guidelines on when to perform the bone biopsy [10, 14].
3.3. Valproic Acid and CYP Effects
Finally, while clozapine was immediately discontinued upon admission, valproate was continued throughout the duration of treatment for the patient's schizoaffective disorder (see Table 1). There has been suggestion that valproate may be a clozapine metabolism inducer [23], the serum valproate level was subtherapeutic 36.5 (50-100) on treatment day 0/admission to the medicine floor, and the clozapine level was not taken at admission; so, no definitive conclusion can be made. Other studies suggest that valproate is a weak inhibitor of CYP 3A4 [24, 25] and potent CYP 2C9 inhibitor [26, 27]. Additionally, in 2018, the Malik et al. case control study of 136 cases found an association of increased risk of CIA in those with concurrent use of sodium valproate and clozapine [28]. These findings might suggest that our subjects' concomitant dosing of valproate with her clozapine could have exacerbated the clozapine effect causing CIA. Should these theories prove true on larger study, the decision to continue the patient's prescription of valproate during treatment for CIA could have elongated the recovery process due to the CYP inhibitor effects of valproate on clozapine levels. Future investigation for drug interaction of valproate with clozapine together should be studied. Should valproate prove to be a CYP inhibitor, or exacerbate CIA, standardized guidelines should indicate valproate be discontinued in future findings of CIA, and alternative therapeutics should be explored. Additionally, adjunctive use of lithium with clozapine has been initially investigated to mitigate the level of neutropenia for those experiencing CIA [29]. Additional study into adjunct dosing of lithium should be investigated. Concurrent use of valproate with clozapine, adjunct dosing of lithium, and other patient risk factors may need to be considered while determining proper individualized treatment.
4. Conclusion
Through this case of CIA in a patient with longstanding schizoaffective disorder, CKD, and HLA-DQB1 and HLA-DQ2 positivity, the importance of implementing a standardized screen which accounts for the renal function and HLA status is imperative for safe practices in prescribing clozapine for psychiatric disorders and mitigating the risk for CIA. Additionally, proper standardized monitoring of renal status through the treatment process may also mitigate risk of potential kidney failure. Further study is necessary to distinguish valproate's role in agranulocytosis singularly or in concert with clozapine. More detailed standardized guidelines would be beneficial for treatment of CIA, should it occur. As clozapine is known as a drug of last resort to be administered when there is failure of more traditional, and risk averse therapeutics, it is difficult to deny this treatment option, as it ultimately implies that all other treatment options have been exhausted. Proper screening and established protocol and guidelines could increase the level of monitoring in patients with known risk factors as revealed by the official screen. This risk factor screen and subsequent monitoring could increase the cost-effectiveness of clozapine treatment and decrease the incidence and morbidity of this feared adverse event.
Acknowledgments
The authors would like to thank the nursing staff and social workers for their day-to-day involvement in the care of the patient. We would also like to thank the following residents for the day-to-day involvement in managing the care of our patient: Chris Alfred, Ainsley Backman, Vito D'Angelo, Randy Lai, and Jai Patel. We would also like to thank Jonathan Eckstein, Steven Rubel, and Albert Strojan for the feedback given during the development of this paper. The authors also would like to thank Alvin Holcomb for the role he plays in resident medical education on a daily basis.
Abbreviations
CIA: Clozapine-induced agranulocytosis
ANC: Absolute neutrophil count
DVT: Deep vein thrombosis
CKD: Chronic kidney disease
AKI: Acute kidney injury
CYP: Cytochrome P450
EMS: Emergency medical services
ED: Emergency department
HLA: Human leukocyte antigen
G-CSF: Granulocyte-colony stimulating factor.
Data Availability
The subject data used to support the findings of this study are included in the Table within the article. Prior studies used to support the findings of this study are cited at relevant places within the text as references [1–29].
Consent
Written informed consent was obtained and is on the file.
Conflicts of Interest
The authors declare that there that there is no conflict of interest regarding the publication of this article.
Table 1 Treatment course lab table.
Treatment day Treatment day 0 Treatment day 1 Treatment day 2 Treatment day 3 Treatment day 4 Treatment day 5 Treatment day 6 Treatment day 7 Treatment day 8 Treatment day 9 Treatment day 10 Treatment day 11 Treatment day 12
Lab value
ANC level (μL) 0.05 0 0.01 0.01 0.01 0.01 0 0.02 0.04 0.57 3.97 11.51 10.38
WBC (L) N/A 0.4 0.4 0.3 0.2 0.3 0.2 0.3 0.4 1.8 7 18.7 N/A
Temperature max 98.8 98.6 100.7 103.1 101 98.5 99.3 97.3 98.1 98.6 97.8 97.7 98.1
BP 127/79 144/77 110/59 113/48 131/59 101/53 129/61 127/65 119/64 130/75 117/65 130/70
Hgb (G/DL) 10.4 9.9 11 10.5 9.8 8.9 8.5 8 8 8.6 9.6 9.3 8.4
Hematocrit (%) 33.8 31.8 36.4 33.6 31.6 29.3 27.2 26.3 26.1 28.1 32.2 30.6 28.6
H&H 10.4/33.8 9.9/31.8 11.0/36.4 10.5/33.6 9.8/31.6 8.9/29.3 8.5/27.2 8.0/26.3 8.0/26.1 8.6/28.1 9.6/32.2 9.3/30.6 8.4/28.6
BUN N/A N/A 38 36 46 55 77 70 57 43 33 29 25
CR N/A N/A 1.57 1.93 2.3 2.8 3.2 2.45 1.98 1.69 1.75 1.55 1.59
eGFR N/A N/A 33.61 26.48 21.63 17.24 14.78 20.11 25.71 30.87 29.65 34.11 33.12
Valproate level 36.5 L 50.9 L
Amlodipine dose 10 mg 10 mg 10 mg Not given Not given 10 mg 10 mg 10 mg Refused 10 mg 10 mg 10 mg 10 mg
Docusate dose Refused 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg
PEG dose 17 grams 17 grams
Valproate dose 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d 500 mg t.i.d
Filgrastim dose N/A 300 mcg 300 mcg 800 mcg 800 mcg 800 mcg N/A N/A 800 mcg N/A N/A N/A N/A | Recovering | ReactionOutcome | CC BY | 33688445 | 19,142,002 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective for unapproved indication'. | Pedal gangrene in a patient with COVID-19 treated with prone positioning and extracorporeal membrane oxygenation.
Many patients hospitalized with coronavirus disease 2019 are treated with venovenous extracorporeal membrane oxygenation and prone positioning to optimize oxygenation. However, this combination can result in lower extremity tissue necrosis, especially without adequate offloading. We report the case of a 31-year-old man who required mechanical ventilation and venovenous extracorporeal membrane oxygenation secondary to complications from coronavirus disease 2019, and subsequently developed pedal dry gangrene. The patient was discharged and healed without requiring an amputation. Our institution has since revised the prone positioning protocol to address offloading the lower extremities and feet.
Although most patients with coronavirus disease 2019 (COVID-19) experience mild symptoms, some progress to develop severe acute respiratory distress syndrome, requiring mechanical ventilation and prolonged stays in the intensive care unit.1 Those with hypoxemia refractory to mechanical ventilation and prone positioning might be considered for venovenous extracorporeal membrane oxygenation (VV-ECMO), which provides temporary pulmonary support via gas exchange.2,3 The combination of prone positioning, VV-ECMO, and vasopressors can result in lower extremity tissue necrosis, especially without adequate offloading. In this report, we present the case of a 31-year-old man who required mechanical ventilation and VV-ECMO secondary to complications from COVID-19, and subsequently developed pedal dry gangrene. The patient provided verbal consent to the publication of the case details and clinical images.
Case report
A 31-year-old man presented to the emergency department with a 5-day history of fevers and a 2-day history of dry cough. Past medical history included hypertension and obesity. On presentation, he was found to be febrile, hypoxic, and tachycardic. Physical examination revealed bilateral pulmonary crackles and a computed tomography scan of the chest showed peripheral bilateral diffuse ground glass opacities. He was admitted to the general medicine floor and started on empiric ceftriaxone and azithromycin. A nasal swab was positive for COVID-19, and therapy with chloroquine, thiamine, vitamin C, and anakinra was started. He continued to have persistent fevers (maximum temperature 104.5°F), and developed acute hypoxemia, for which he was intubated and transferred to the intensive care unit. The patient was hypotensive, requiring vasopressor support. For deep venous thrombosis prophylaxis, he was placed on continuous heparin infusion, with goal activated partial thromboplastin time of 50 to 70 seconds, as per hospital COVID-19 treatment guidelines.
Despite high ventilator settings, medical therapy, and prone positioning for an average of 15-hour intervals over 6 days, he remained with severe acute respiratory distress syndrome and respiratory acidosis, so he was placed on extracorporeal carbon dioxide removal. He was subsequently transitioned to VV-ECMO for refractory hypoxemia and was started on methylprednisone. The ECMO cannulas were placed in the right internal jugular vein and the right femoral vein. Once ECMO was initiated, anticoagulation therapy was transitioned to argatroban continuous infusion, as per hospital protocol. Dosing was therapeutic with a goal activated partial thromboplastin time of 50 to 90 seconds. The patient's intensive care unit course was complicated by new-onset atrial fibrillation, with emergent successful cardioversion. He was treated with amiodarone. ECMO was successfully decannulated on day 24, and the patient was extubated on day 34.
Podiatry was consulted on day 35 for concern of new-onset pedal gangrene. Vascular examination revealed palpable femoral, popliteal, dorsalis, pedis and posterior tibial artery pulses bilaterally. Epicritic sensation was intact to the toes bilaterally. There was partial thickness dry gangrene on the plantar aspect of the right hallux, plantar distal aspect of the right second digit, plantar distal aspect of the left fifth digit, and the plantar aspect of metatarsal heads 3 to 5 of the left foot. The left plantar forefoot skin was slightly dusky and mottled in appearance (Fig 1). No signs of infection were present. It was noted that the patient's feet were firmly pressed against the footboard of the hospital bed and not properly offloaded. Z-flow boots for offloading of the feet were placed on at this time, and local wound care with betadine paint every other day was started. The plan was to await demarcation of the gangrene to determine if the skin would become viable or ultimately require an amputation.Fig 1 Partial thickness gangrene in bilateral feet on hospital day 35. All necrotic areas were dry and stable in appearance with no associated fluctuance or crepitus, no malodor, no surrounding edema or erythema, and no signs of infection.
Throughout the hospital course, increased necrosis was noted to the left plantar forefoot (Fig 2). Based on the stable nature and partial-thickness depth of the gangrene, the prognosis for healing and prevention of limb and toe loss was favorable. The patient was discharged to acute rehabilitation after a 55-day duration of stay. The plan was to continue wearing offloading boots, wound care with betadine paint every other day, and regular follow-up with podiatry to monitor demarcation. Unfortunately, the patient was lost to follow-up. The patient was called for follow-up, and family revealed that he had moved to the Dominican Republic and that his foot wounds healed without requiring amputation.Fig 2 Partial thickness gangrene in bilateral feet on hospital day 45. Increased necrosis of the left plantar forefoot gangrene, which was dry and stable in appearance.
Discussion
The cause of pedal gangrene in this patient was likely multifactorial, including the use of ECMO and vasopressors, prone positioning without proper offloading, and the hypercoagulable nature of COVID-19. Here, we delve further into the role of prone positioning and ECMO in the development of pedal tissue necrosis and discuss the other contributing factors.
Prone positioning can optimize oxygenation in patients with worsening hypoxemia.4 However, necrosis can develop at pressure points without proper offloading. Intubated patients typically remain prone for 12 to 16 hours per day, increasing the probability of developing pressure wounds.4 Risk factors for the development of prone-related pressure injuries include high body mass index, male sex, and age greater than 60 years, two of which pertain to this patient.5,6 Although the dorsal feet and toes are main pressure points in the prone position, no studies have detailed lower extremity wounds secondary to prolonged prone positioning.
Patients who remain hypoxic despite prone positioning may require ECMO support. The use of ECMO throughout the pandemic has steadily increased with promising results.7,8 However, patient selection is stringent and is reserved for those younger than 65 years, with a body mass index of less than 40, who are not immunocompromised, and who have been on mechanical ventilation for fewer than 10 days.7,9 Therefore, this patient was an ideal candidate. Limb ischemia can result from ECMO owing to vessel damage during cannulation, preexisting atherosclerotic disease, and prolonged vasopressor use.10 Prior case series on pedal complications after ECMO show gangrene occurring more readily in younger patients, possibly secondary to smaller caliber vessels and fewer collaterals.10, 11, 12 Patients are typically on ECMO for 1 to 3 weeks, and the risk of ischemia increases with prolonged duration (13 days in this patient).3,13
Coagulopathy and limb ischemia in the setting of COVID-19 is widely recognized.14, 15, 16 Studies have reported on the hypercoagulable effects of COVID-19 resulting in the development of acute limb ischemia and digital gangrene despite anticoagulation.15, 16, 17 Low-intensity heparin infusion is recommended in critically ill patients with COVID-19 and has been associated with survival benefit.16,18,19 This finding is reflected in our hospital's anticoagulation protocol.
Vasopressors are associated with the development of digital gangrene, because they create peripheral vasoconstriction to perfuse organs during hemodynamic instability.20 This patient was on vasopressors (epinephrine injection, phenylephrine, and norepinephrine infusions) for 30 days. Vasopressor-induced digital necrosis is a known side effect reported in the literature, often reported as being bilateral and symmetrical in the toes.21, 22, 23 Atrial fibrillation has also been associated with toe necrosis owing to showering of microemboli, although less likely in this patient owing to the short duration of arrhythmia.24
The lack of adequate offloading perhaps played the largest role in the development of pedal gangrene in this patient. Constant pressure to an area creates capillary occlusion, ultimately leading to tissue ischemia owing to inadequate oxygenation.25 Therefore, proper offloading in the bed is of great importance. Heel offloading boots have been found to decrease heel contact forces and can alleviate pressure from the footboard.25 Placing a pillow underneath the shins or positioning the feet off the end of the bed can alleviate pressure on the dorsal feet and toes when the patient is prone. Pressure redistribution support surfaces and prophylactic silicone dressings over bony prominences as well as frequent repositioning can also prevent these injuries.4 At our institution, the podiatry, vascular, and wound care teams have since revised the prone positioning protocol to address offloading of the lower extremities and feet.
Conclusions
We have presented this case to highlight the importance of proper offloading to decrease pressure necrosis injuries from occurring in patients with COVID-19. In patients who are prone positioned and on ECMO and vasopressor support, the risk of developing these wounds is only exacerbated. Efforts to decrease lower extremity pressure wounds are paramount in decreasing the rates of partial and total limb loss.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | ANAKINRA, ASCORBIC ACID, CHLOROQUINE, THIAMINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33688601 | 19,910,563 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gangrene'. | Pedal gangrene in a patient with COVID-19 treated with prone positioning and extracorporeal membrane oxygenation.
Many patients hospitalized with coronavirus disease 2019 are treated with venovenous extracorporeal membrane oxygenation and prone positioning to optimize oxygenation. However, this combination can result in lower extremity tissue necrosis, especially without adequate offloading. We report the case of a 31-year-old man who required mechanical ventilation and venovenous extracorporeal membrane oxygenation secondary to complications from coronavirus disease 2019, and subsequently developed pedal dry gangrene. The patient was discharged and healed without requiring an amputation. Our institution has since revised the prone positioning protocol to address offloading the lower extremities and feet.
Although most patients with coronavirus disease 2019 (COVID-19) experience mild symptoms, some progress to develop severe acute respiratory distress syndrome, requiring mechanical ventilation and prolonged stays in the intensive care unit.1 Those with hypoxemia refractory to mechanical ventilation and prone positioning might be considered for venovenous extracorporeal membrane oxygenation (VV-ECMO), which provides temporary pulmonary support via gas exchange.2,3 The combination of prone positioning, VV-ECMO, and vasopressors can result in lower extremity tissue necrosis, especially without adequate offloading. In this report, we present the case of a 31-year-old man who required mechanical ventilation and VV-ECMO secondary to complications from COVID-19, and subsequently developed pedal dry gangrene. The patient provided verbal consent to the publication of the case details and clinical images.
Case report
A 31-year-old man presented to the emergency department with a 5-day history of fevers and a 2-day history of dry cough. Past medical history included hypertension and obesity. On presentation, he was found to be febrile, hypoxic, and tachycardic. Physical examination revealed bilateral pulmonary crackles and a computed tomography scan of the chest showed peripheral bilateral diffuse ground glass opacities. He was admitted to the general medicine floor and started on empiric ceftriaxone and azithromycin. A nasal swab was positive for COVID-19, and therapy with chloroquine, thiamine, vitamin C, and anakinra was started. He continued to have persistent fevers (maximum temperature 104.5°F), and developed acute hypoxemia, for which he was intubated and transferred to the intensive care unit. The patient was hypotensive, requiring vasopressor support. For deep venous thrombosis prophylaxis, he was placed on continuous heparin infusion, with goal activated partial thromboplastin time of 50 to 70 seconds, as per hospital COVID-19 treatment guidelines.
Despite high ventilator settings, medical therapy, and prone positioning for an average of 15-hour intervals over 6 days, he remained with severe acute respiratory distress syndrome and respiratory acidosis, so he was placed on extracorporeal carbon dioxide removal. He was subsequently transitioned to VV-ECMO for refractory hypoxemia and was started on methylprednisone. The ECMO cannulas were placed in the right internal jugular vein and the right femoral vein. Once ECMO was initiated, anticoagulation therapy was transitioned to argatroban continuous infusion, as per hospital protocol. Dosing was therapeutic with a goal activated partial thromboplastin time of 50 to 90 seconds. The patient's intensive care unit course was complicated by new-onset atrial fibrillation, with emergent successful cardioversion. He was treated with amiodarone. ECMO was successfully decannulated on day 24, and the patient was extubated on day 34.
Podiatry was consulted on day 35 for concern of new-onset pedal gangrene. Vascular examination revealed palpable femoral, popliteal, dorsalis, pedis and posterior tibial artery pulses bilaterally. Epicritic sensation was intact to the toes bilaterally. There was partial thickness dry gangrene on the plantar aspect of the right hallux, plantar distal aspect of the right second digit, plantar distal aspect of the left fifth digit, and the plantar aspect of metatarsal heads 3 to 5 of the left foot. The left plantar forefoot skin was slightly dusky and mottled in appearance (Fig 1). No signs of infection were present. It was noted that the patient's feet were firmly pressed against the footboard of the hospital bed and not properly offloaded. Z-flow boots for offloading of the feet were placed on at this time, and local wound care with betadine paint every other day was started. The plan was to await demarcation of the gangrene to determine if the skin would become viable or ultimately require an amputation.Fig 1 Partial thickness gangrene in bilateral feet on hospital day 35. All necrotic areas were dry and stable in appearance with no associated fluctuance or crepitus, no malodor, no surrounding edema or erythema, and no signs of infection.
Throughout the hospital course, increased necrosis was noted to the left plantar forefoot (Fig 2). Based on the stable nature and partial-thickness depth of the gangrene, the prognosis for healing and prevention of limb and toe loss was favorable. The patient was discharged to acute rehabilitation after a 55-day duration of stay. The plan was to continue wearing offloading boots, wound care with betadine paint every other day, and regular follow-up with podiatry to monitor demarcation. Unfortunately, the patient was lost to follow-up. The patient was called for follow-up, and family revealed that he had moved to the Dominican Republic and that his foot wounds healed without requiring amputation.Fig 2 Partial thickness gangrene in bilateral feet on hospital day 45. Increased necrosis of the left plantar forefoot gangrene, which was dry and stable in appearance.
Discussion
The cause of pedal gangrene in this patient was likely multifactorial, including the use of ECMO and vasopressors, prone positioning without proper offloading, and the hypercoagulable nature of COVID-19. Here, we delve further into the role of prone positioning and ECMO in the development of pedal tissue necrosis and discuss the other contributing factors.
Prone positioning can optimize oxygenation in patients with worsening hypoxemia.4 However, necrosis can develop at pressure points without proper offloading. Intubated patients typically remain prone for 12 to 16 hours per day, increasing the probability of developing pressure wounds.4 Risk factors for the development of prone-related pressure injuries include high body mass index, male sex, and age greater than 60 years, two of which pertain to this patient.5,6 Although the dorsal feet and toes are main pressure points in the prone position, no studies have detailed lower extremity wounds secondary to prolonged prone positioning.
Patients who remain hypoxic despite prone positioning may require ECMO support. The use of ECMO throughout the pandemic has steadily increased with promising results.7,8 However, patient selection is stringent and is reserved for those younger than 65 years, with a body mass index of less than 40, who are not immunocompromised, and who have been on mechanical ventilation for fewer than 10 days.7,9 Therefore, this patient was an ideal candidate. Limb ischemia can result from ECMO owing to vessel damage during cannulation, preexisting atherosclerotic disease, and prolonged vasopressor use.10 Prior case series on pedal complications after ECMO show gangrene occurring more readily in younger patients, possibly secondary to smaller caliber vessels and fewer collaterals.10, 11, 12 Patients are typically on ECMO for 1 to 3 weeks, and the risk of ischemia increases with prolonged duration (13 days in this patient).3,13
Coagulopathy and limb ischemia in the setting of COVID-19 is widely recognized.14, 15, 16 Studies have reported on the hypercoagulable effects of COVID-19 resulting in the development of acute limb ischemia and digital gangrene despite anticoagulation.15, 16, 17 Low-intensity heparin infusion is recommended in critically ill patients with COVID-19 and has been associated with survival benefit.16,18,19 This finding is reflected in our hospital's anticoagulation protocol.
Vasopressors are associated with the development of digital gangrene, because they create peripheral vasoconstriction to perfuse organs during hemodynamic instability.20 This patient was on vasopressors (epinephrine injection, phenylephrine, and norepinephrine infusions) for 30 days. Vasopressor-induced digital necrosis is a known side effect reported in the literature, often reported as being bilateral and symmetrical in the toes.21, 22, 23 Atrial fibrillation has also been associated with toe necrosis owing to showering of microemboli, although less likely in this patient owing to the short duration of arrhythmia.24
The lack of adequate offloading perhaps played the largest role in the development of pedal gangrene in this patient. Constant pressure to an area creates capillary occlusion, ultimately leading to tissue ischemia owing to inadequate oxygenation.25 Therefore, proper offloading in the bed is of great importance. Heel offloading boots have been found to decrease heel contact forces and can alleviate pressure from the footboard.25 Placing a pillow underneath the shins or positioning the feet off the end of the bed can alleviate pressure on the dorsal feet and toes when the patient is prone. Pressure redistribution support surfaces and prophylactic silicone dressings over bony prominences as well as frequent repositioning can also prevent these injuries.4 At our institution, the podiatry, vascular, and wound care teams have since revised the prone positioning protocol to address offloading of the lower extremities and feet.
Conclusions
We have presented this case to highlight the importance of proper offloading to decrease pressure necrosis injuries from occurring in patients with COVID-19. In patients who are prone positioned and on ECMO and vasopressor support, the risk of developing these wounds is only exacerbated. Efforts to decrease lower extremity pressure wounds are paramount in decreasing the rates of partial and total limb loss.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | AMIODARONE, ANAKINRA, ARGATROBAN, ASCORBIC ACID, AZITHROMYCIN ANHYDROUS, CEFTRIAXONE, CHLOROQUINE, EPINEPHRINE, HEPARIN SODIUM, METHYLPREDNISOLONE, NOREPINEPHRINE, PHENYLEPHRINE HYDROCHLORIDE, POVIDONE-IODINE, THIAMINE | DrugsGivenReaction | CC BY-NC-ND | 33688601 | 19,951,856 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypoxia'. | Pedal gangrene in a patient with COVID-19 treated with prone positioning and extracorporeal membrane oxygenation.
Many patients hospitalized with coronavirus disease 2019 are treated with venovenous extracorporeal membrane oxygenation and prone positioning to optimize oxygenation. However, this combination can result in lower extremity tissue necrosis, especially without adequate offloading. We report the case of a 31-year-old man who required mechanical ventilation and venovenous extracorporeal membrane oxygenation secondary to complications from coronavirus disease 2019, and subsequently developed pedal dry gangrene. The patient was discharged and healed without requiring an amputation. Our institution has since revised the prone positioning protocol to address offloading the lower extremities and feet.
Although most patients with coronavirus disease 2019 (COVID-19) experience mild symptoms, some progress to develop severe acute respiratory distress syndrome, requiring mechanical ventilation and prolonged stays in the intensive care unit.1 Those with hypoxemia refractory to mechanical ventilation and prone positioning might be considered for venovenous extracorporeal membrane oxygenation (VV-ECMO), which provides temporary pulmonary support via gas exchange.2,3 The combination of prone positioning, VV-ECMO, and vasopressors can result in lower extremity tissue necrosis, especially without adequate offloading. In this report, we present the case of a 31-year-old man who required mechanical ventilation and VV-ECMO secondary to complications from COVID-19, and subsequently developed pedal dry gangrene. The patient provided verbal consent to the publication of the case details and clinical images.
Case report
A 31-year-old man presented to the emergency department with a 5-day history of fevers and a 2-day history of dry cough. Past medical history included hypertension and obesity. On presentation, he was found to be febrile, hypoxic, and tachycardic. Physical examination revealed bilateral pulmonary crackles and a computed tomography scan of the chest showed peripheral bilateral diffuse ground glass opacities. He was admitted to the general medicine floor and started on empiric ceftriaxone and azithromycin. A nasal swab was positive for COVID-19, and therapy with chloroquine, thiamine, vitamin C, and anakinra was started. He continued to have persistent fevers (maximum temperature 104.5°F), and developed acute hypoxemia, for which he was intubated and transferred to the intensive care unit. The patient was hypotensive, requiring vasopressor support. For deep venous thrombosis prophylaxis, he was placed on continuous heparin infusion, with goal activated partial thromboplastin time of 50 to 70 seconds, as per hospital COVID-19 treatment guidelines.
Despite high ventilator settings, medical therapy, and prone positioning for an average of 15-hour intervals over 6 days, he remained with severe acute respiratory distress syndrome and respiratory acidosis, so he was placed on extracorporeal carbon dioxide removal. He was subsequently transitioned to VV-ECMO for refractory hypoxemia and was started on methylprednisone. The ECMO cannulas were placed in the right internal jugular vein and the right femoral vein. Once ECMO was initiated, anticoagulation therapy was transitioned to argatroban continuous infusion, as per hospital protocol. Dosing was therapeutic with a goal activated partial thromboplastin time of 50 to 90 seconds. The patient's intensive care unit course was complicated by new-onset atrial fibrillation, with emergent successful cardioversion. He was treated with amiodarone. ECMO was successfully decannulated on day 24, and the patient was extubated on day 34.
Podiatry was consulted on day 35 for concern of new-onset pedal gangrene. Vascular examination revealed palpable femoral, popliteal, dorsalis, pedis and posterior tibial artery pulses bilaterally. Epicritic sensation was intact to the toes bilaterally. There was partial thickness dry gangrene on the plantar aspect of the right hallux, plantar distal aspect of the right second digit, plantar distal aspect of the left fifth digit, and the plantar aspect of metatarsal heads 3 to 5 of the left foot. The left plantar forefoot skin was slightly dusky and mottled in appearance (Fig 1). No signs of infection were present. It was noted that the patient's feet were firmly pressed against the footboard of the hospital bed and not properly offloaded. Z-flow boots for offloading of the feet were placed on at this time, and local wound care with betadine paint every other day was started. The plan was to await demarcation of the gangrene to determine if the skin would become viable or ultimately require an amputation.Fig 1 Partial thickness gangrene in bilateral feet on hospital day 35. All necrotic areas were dry and stable in appearance with no associated fluctuance or crepitus, no malodor, no surrounding edema or erythema, and no signs of infection.
Throughout the hospital course, increased necrosis was noted to the left plantar forefoot (Fig 2). Based on the stable nature and partial-thickness depth of the gangrene, the prognosis for healing and prevention of limb and toe loss was favorable. The patient was discharged to acute rehabilitation after a 55-day duration of stay. The plan was to continue wearing offloading boots, wound care with betadine paint every other day, and regular follow-up with podiatry to monitor demarcation. Unfortunately, the patient was lost to follow-up. The patient was called for follow-up, and family revealed that he had moved to the Dominican Republic and that his foot wounds healed without requiring amputation.Fig 2 Partial thickness gangrene in bilateral feet on hospital day 45. Increased necrosis of the left plantar forefoot gangrene, which was dry and stable in appearance.
Discussion
The cause of pedal gangrene in this patient was likely multifactorial, including the use of ECMO and vasopressors, prone positioning without proper offloading, and the hypercoagulable nature of COVID-19. Here, we delve further into the role of prone positioning and ECMO in the development of pedal tissue necrosis and discuss the other contributing factors.
Prone positioning can optimize oxygenation in patients with worsening hypoxemia.4 However, necrosis can develop at pressure points without proper offloading. Intubated patients typically remain prone for 12 to 16 hours per day, increasing the probability of developing pressure wounds.4 Risk factors for the development of prone-related pressure injuries include high body mass index, male sex, and age greater than 60 years, two of which pertain to this patient.5,6 Although the dorsal feet and toes are main pressure points in the prone position, no studies have detailed lower extremity wounds secondary to prolonged prone positioning.
Patients who remain hypoxic despite prone positioning may require ECMO support. The use of ECMO throughout the pandemic has steadily increased with promising results.7,8 However, patient selection is stringent and is reserved for those younger than 65 years, with a body mass index of less than 40, who are not immunocompromised, and who have been on mechanical ventilation for fewer than 10 days.7,9 Therefore, this patient was an ideal candidate. Limb ischemia can result from ECMO owing to vessel damage during cannulation, preexisting atherosclerotic disease, and prolonged vasopressor use.10 Prior case series on pedal complications after ECMO show gangrene occurring more readily in younger patients, possibly secondary to smaller caliber vessels and fewer collaterals.10, 11, 12 Patients are typically on ECMO for 1 to 3 weeks, and the risk of ischemia increases with prolonged duration (13 days in this patient).3,13
Coagulopathy and limb ischemia in the setting of COVID-19 is widely recognized.14, 15, 16 Studies have reported on the hypercoagulable effects of COVID-19 resulting in the development of acute limb ischemia and digital gangrene despite anticoagulation.15, 16, 17 Low-intensity heparin infusion is recommended in critically ill patients with COVID-19 and has been associated with survival benefit.16,18,19 This finding is reflected in our hospital's anticoagulation protocol.
Vasopressors are associated with the development of digital gangrene, because they create peripheral vasoconstriction to perfuse organs during hemodynamic instability.20 This patient was on vasopressors (epinephrine injection, phenylephrine, and norepinephrine infusions) for 30 days. Vasopressor-induced digital necrosis is a known side effect reported in the literature, often reported as being bilateral and symmetrical in the toes.21, 22, 23 Atrial fibrillation has also been associated with toe necrosis owing to showering of microemboli, although less likely in this patient owing to the short duration of arrhythmia.24
The lack of adequate offloading perhaps played the largest role in the development of pedal gangrene in this patient. Constant pressure to an area creates capillary occlusion, ultimately leading to tissue ischemia owing to inadequate oxygenation.25 Therefore, proper offloading in the bed is of great importance. Heel offloading boots have been found to decrease heel contact forces and can alleviate pressure from the footboard.25 Placing a pillow underneath the shins or positioning the feet off the end of the bed can alleviate pressure on the dorsal feet and toes when the patient is prone. Pressure redistribution support surfaces and prophylactic silicone dressings over bony prominences as well as frequent repositioning can also prevent these injuries.4 At our institution, the podiatry, vascular, and wound care teams have since revised the prone positioning protocol to address offloading of the lower extremities and feet.
Conclusions
We have presented this case to highlight the importance of proper offloading to decrease pressure necrosis injuries from occurring in patients with COVID-19. In patients who are prone positioned and on ECMO and vasopressor support, the risk of developing these wounds is only exacerbated. Efforts to decrease lower extremity pressure wounds are paramount in decreasing the rates of partial and total limb loss.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | ANAKINRA, ASCORBIC ACID, AZITHROMYCIN ANHYDROUS, CEFTRIAXONE, CHLOROQUINE, THIAMINE | DrugsGivenReaction | CC BY-NC-ND | 33688601 | 19,911,071 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Pedal gangrene in a patient with COVID-19 treated with prone positioning and extracorporeal membrane oxygenation.
Many patients hospitalized with coronavirus disease 2019 are treated with venovenous extracorporeal membrane oxygenation and prone positioning to optimize oxygenation. However, this combination can result in lower extremity tissue necrosis, especially without adequate offloading. We report the case of a 31-year-old man who required mechanical ventilation and venovenous extracorporeal membrane oxygenation secondary to complications from coronavirus disease 2019, and subsequently developed pedal dry gangrene. The patient was discharged and healed without requiring an amputation. Our institution has since revised the prone positioning protocol to address offloading the lower extremities and feet.
Although most patients with coronavirus disease 2019 (COVID-19) experience mild symptoms, some progress to develop severe acute respiratory distress syndrome, requiring mechanical ventilation and prolonged stays in the intensive care unit.1 Those with hypoxemia refractory to mechanical ventilation and prone positioning might be considered for venovenous extracorporeal membrane oxygenation (VV-ECMO), which provides temporary pulmonary support via gas exchange.2,3 The combination of prone positioning, VV-ECMO, and vasopressors can result in lower extremity tissue necrosis, especially without adequate offloading. In this report, we present the case of a 31-year-old man who required mechanical ventilation and VV-ECMO secondary to complications from COVID-19, and subsequently developed pedal dry gangrene. The patient provided verbal consent to the publication of the case details and clinical images.
Case report
A 31-year-old man presented to the emergency department with a 5-day history of fevers and a 2-day history of dry cough. Past medical history included hypertension and obesity. On presentation, he was found to be febrile, hypoxic, and tachycardic. Physical examination revealed bilateral pulmonary crackles and a computed tomography scan of the chest showed peripheral bilateral diffuse ground glass opacities. He was admitted to the general medicine floor and started on empiric ceftriaxone and azithromycin. A nasal swab was positive for COVID-19, and therapy with chloroquine, thiamine, vitamin C, and anakinra was started. He continued to have persistent fevers (maximum temperature 104.5°F), and developed acute hypoxemia, for which he was intubated and transferred to the intensive care unit. The patient was hypotensive, requiring vasopressor support. For deep venous thrombosis prophylaxis, he was placed on continuous heparin infusion, with goal activated partial thromboplastin time of 50 to 70 seconds, as per hospital COVID-19 treatment guidelines.
Despite high ventilator settings, medical therapy, and prone positioning for an average of 15-hour intervals over 6 days, he remained with severe acute respiratory distress syndrome and respiratory acidosis, so he was placed on extracorporeal carbon dioxide removal. He was subsequently transitioned to VV-ECMO for refractory hypoxemia and was started on methylprednisone. The ECMO cannulas were placed in the right internal jugular vein and the right femoral vein. Once ECMO was initiated, anticoagulation therapy was transitioned to argatroban continuous infusion, as per hospital protocol. Dosing was therapeutic with a goal activated partial thromboplastin time of 50 to 90 seconds. The patient's intensive care unit course was complicated by new-onset atrial fibrillation, with emergent successful cardioversion. He was treated with amiodarone. ECMO was successfully decannulated on day 24, and the patient was extubated on day 34.
Podiatry was consulted on day 35 for concern of new-onset pedal gangrene. Vascular examination revealed palpable femoral, popliteal, dorsalis, pedis and posterior tibial artery pulses bilaterally. Epicritic sensation was intact to the toes bilaterally. There was partial thickness dry gangrene on the plantar aspect of the right hallux, plantar distal aspect of the right second digit, plantar distal aspect of the left fifth digit, and the plantar aspect of metatarsal heads 3 to 5 of the left foot. The left plantar forefoot skin was slightly dusky and mottled in appearance (Fig 1). No signs of infection were present. It was noted that the patient's feet were firmly pressed against the footboard of the hospital bed and not properly offloaded. Z-flow boots for offloading of the feet were placed on at this time, and local wound care with betadine paint every other day was started. The plan was to await demarcation of the gangrene to determine if the skin would become viable or ultimately require an amputation.Fig 1 Partial thickness gangrene in bilateral feet on hospital day 35. All necrotic areas were dry and stable in appearance with no associated fluctuance or crepitus, no malodor, no surrounding edema or erythema, and no signs of infection.
Throughout the hospital course, increased necrosis was noted to the left plantar forefoot (Fig 2). Based on the stable nature and partial-thickness depth of the gangrene, the prognosis for healing and prevention of limb and toe loss was favorable. The patient was discharged to acute rehabilitation after a 55-day duration of stay. The plan was to continue wearing offloading boots, wound care with betadine paint every other day, and regular follow-up with podiatry to monitor demarcation. Unfortunately, the patient was lost to follow-up. The patient was called for follow-up, and family revealed that he had moved to the Dominican Republic and that his foot wounds healed without requiring amputation.Fig 2 Partial thickness gangrene in bilateral feet on hospital day 45. Increased necrosis of the left plantar forefoot gangrene, which was dry and stable in appearance.
Discussion
The cause of pedal gangrene in this patient was likely multifactorial, including the use of ECMO and vasopressors, prone positioning without proper offloading, and the hypercoagulable nature of COVID-19. Here, we delve further into the role of prone positioning and ECMO in the development of pedal tissue necrosis and discuss the other contributing factors.
Prone positioning can optimize oxygenation in patients with worsening hypoxemia.4 However, necrosis can develop at pressure points without proper offloading. Intubated patients typically remain prone for 12 to 16 hours per day, increasing the probability of developing pressure wounds.4 Risk factors for the development of prone-related pressure injuries include high body mass index, male sex, and age greater than 60 years, two of which pertain to this patient.5,6 Although the dorsal feet and toes are main pressure points in the prone position, no studies have detailed lower extremity wounds secondary to prolonged prone positioning.
Patients who remain hypoxic despite prone positioning may require ECMO support. The use of ECMO throughout the pandemic has steadily increased with promising results.7,8 However, patient selection is stringent and is reserved for those younger than 65 years, with a body mass index of less than 40, who are not immunocompromised, and who have been on mechanical ventilation for fewer than 10 days.7,9 Therefore, this patient was an ideal candidate. Limb ischemia can result from ECMO owing to vessel damage during cannulation, preexisting atherosclerotic disease, and prolonged vasopressor use.10 Prior case series on pedal complications after ECMO show gangrene occurring more readily in younger patients, possibly secondary to smaller caliber vessels and fewer collaterals.10, 11, 12 Patients are typically on ECMO for 1 to 3 weeks, and the risk of ischemia increases with prolonged duration (13 days in this patient).3,13
Coagulopathy and limb ischemia in the setting of COVID-19 is widely recognized.14, 15, 16 Studies have reported on the hypercoagulable effects of COVID-19 resulting in the development of acute limb ischemia and digital gangrene despite anticoagulation.15, 16, 17 Low-intensity heparin infusion is recommended in critically ill patients with COVID-19 and has been associated with survival benefit.16,18,19 This finding is reflected in our hospital's anticoagulation protocol.
Vasopressors are associated with the development of digital gangrene, because they create peripheral vasoconstriction to perfuse organs during hemodynamic instability.20 This patient was on vasopressors (epinephrine injection, phenylephrine, and norepinephrine infusions) for 30 days. Vasopressor-induced digital necrosis is a known side effect reported in the literature, often reported as being bilateral and symmetrical in the toes.21, 22, 23 Atrial fibrillation has also been associated with toe necrosis owing to showering of microemboli, although less likely in this patient owing to the short duration of arrhythmia.24
The lack of adequate offloading perhaps played the largest role in the development of pedal gangrene in this patient. Constant pressure to an area creates capillary occlusion, ultimately leading to tissue ischemia owing to inadequate oxygenation.25 Therefore, proper offloading in the bed is of great importance. Heel offloading boots have been found to decrease heel contact forces and can alleviate pressure from the footboard.25 Placing a pillow underneath the shins or positioning the feet off the end of the bed can alleviate pressure on the dorsal feet and toes when the patient is prone. Pressure redistribution support surfaces and prophylactic silicone dressings over bony prominences as well as frequent repositioning can also prevent these injuries.4 At our institution, the podiatry, vascular, and wound care teams have since revised the prone positioning protocol to address offloading of the lower extremities and feet.
Conclusions
We have presented this case to highlight the importance of proper offloading to decrease pressure necrosis injuries from occurring in patients with COVID-19. In patients who are prone positioned and on ECMO and vasopressor support, the risk of developing these wounds is only exacerbated. Efforts to decrease lower extremity pressure wounds are paramount in decreasing the rates of partial and total limb loss.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | AMIODARONE, ANAKINRA, ARGATROBAN, ASCORBIC ACID, AZITHROMYCIN ANHYDROUS, CEFTRIAXONE, CHLOROQUINE, EPINEPHRINE, HEPARIN SODIUM, METHYLPREDNISOLONE, NOREPINEPHRINE, PHENYLEPHRINE HYDROCHLORIDE, POVIDONE-IODINE, THIAMINE | DrugsGivenReaction | CC BY-NC-ND | 33688601 | 19,951,856 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Pedal gangrene in a patient with COVID-19 treated with prone positioning and extracorporeal membrane oxygenation.
Many patients hospitalized with coronavirus disease 2019 are treated with venovenous extracorporeal membrane oxygenation and prone positioning to optimize oxygenation. However, this combination can result in lower extremity tissue necrosis, especially without adequate offloading. We report the case of a 31-year-old man who required mechanical ventilation and venovenous extracorporeal membrane oxygenation secondary to complications from coronavirus disease 2019, and subsequently developed pedal dry gangrene. The patient was discharged and healed without requiring an amputation. Our institution has since revised the prone positioning protocol to address offloading the lower extremities and feet.
Although most patients with coronavirus disease 2019 (COVID-19) experience mild symptoms, some progress to develop severe acute respiratory distress syndrome, requiring mechanical ventilation and prolonged stays in the intensive care unit.1 Those with hypoxemia refractory to mechanical ventilation and prone positioning might be considered for venovenous extracorporeal membrane oxygenation (VV-ECMO), which provides temporary pulmonary support via gas exchange.2,3 The combination of prone positioning, VV-ECMO, and vasopressors can result in lower extremity tissue necrosis, especially without adequate offloading. In this report, we present the case of a 31-year-old man who required mechanical ventilation and VV-ECMO secondary to complications from COVID-19, and subsequently developed pedal dry gangrene. The patient provided verbal consent to the publication of the case details and clinical images.
Case report
A 31-year-old man presented to the emergency department with a 5-day history of fevers and a 2-day history of dry cough. Past medical history included hypertension and obesity. On presentation, he was found to be febrile, hypoxic, and tachycardic. Physical examination revealed bilateral pulmonary crackles and a computed tomography scan of the chest showed peripheral bilateral diffuse ground glass opacities. He was admitted to the general medicine floor and started on empiric ceftriaxone and azithromycin. A nasal swab was positive for COVID-19, and therapy with chloroquine, thiamine, vitamin C, and anakinra was started. He continued to have persistent fevers (maximum temperature 104.5°F), and developed acute hypoxemia, for which he was intubated and transferred to the intensive care unit. The patient was hypotensive, requiring vasopressor support. For deep venous thrombosis prophylaxis, he was placed on continuous heparin infusion, with goal activated partial thromboplastin time of 50 to 70 seconds, as per hospital COVID-19 treatment guidelines.
Despite high ventilator settings, medical therapy, and prone positioning for an average of 15-hour intervals over 6 days, he remained with severe acute respiratory distress syndrome and respiratory acidosis, so he was placed on extracorporeal carbon dioxide removal. He was subsequently transitioned to VV-ECMO for refractory hypoxemia and was started on methylprednisone. The ECMO cannulas were placed in the right internal jugular vein and the right femoral vein. Once ECMO was initiated, anticoagulation therapy was transitioned to argatroban continuous infusion, as per hospital protocol. Dosing was therapeutic with a goal activated partial thromboplastin time of 50 to 90 seconds. The patient's intensive care unit course was complicated by new-onset atrial fibrillation, with emergent successful cardioversion. He was treated with amiodarone. ECMO was successfully decannulated on day 24, and the patient was extubated on day 34.
Podiatry was consulted on day 35 for concern of new-onset pedal gangrene. Vascular examination revealed palpable femoral, popliteal, dorsalis, pedis and posterior tibial artery pulses bilaterally. Epicritic sensation was intact to the toes bilaterally. There was partial thickness dry gangrene on the plantar aspect of the right hallux, plantar distal aspect of the right second digit, plantar distal aspect of the left fifth digit, and the plantar aspect of metatarsal heads 3 to 5 of the left foot. The left plantar forefoot skin was slightly dusky and mottled in appearance (Fig 1). No signs of infection were present. It was noted that the patient's feet were firmly pressed against the footboard of the hospital bed and not properly offloaded. Z-flow boots for offloading of the feet were placed on at this time, and local wound care with betadine paint every other day was started. The plan was to await demarcation of the gangrene to determine if the skin would become viable or ultimately require an amputation.Fig 1 Partial thickness gangrene in bilateral feet on hospital day 35. All necrotic areas were dry and stable in appearance with no associated fluctuance or crepitus, no malodor, no surrounding edema or erythema, and no signs of infection.
Throughout the hospital course, increased necrosis was noted to the left plantar forefoot (Fig 2). Based on the stable nature and partial-thickness depth of the gangrene, the prognosis for healing and prevention of limb and toe loss was favorable. The patient was discharged to acute rehabilitation after a 55-day duration of stay. The plan was to continue wearing offloading boots, wound care with betadine paint every other day, and regular follow-up with podiatry to monitor demarcation. Unfortunately, the patient was lost to follow-up. The patient was called for follow-up, and family revealed that he had moved to the Dominican Republic and that his foot wounds healed without requiring amputation.Fig 2 Partial thickness gangrene in bilateral feet on hospital day 45. Increased necrosis of the left plantar forefoot gangrene, which was dry and stable in appearance.
Discussion
The cause of pedal gangrene in this patient was likely multifactorial, including the use of ECMO and vasopressors, prone positioning without proper offloading, and the hypercoagulable nature of COVID-19. Here, we delve further into the role of prone positioning and ECMO in the development of pedal tissue necrosis and discuss the other contributing factors.
Prone positioning can optimize oxygenation in patients with worsening hypoxemia.4 However, necrosis can develop at pressure points without proper offloading. Intubated patients typically remain prone for 12 to 16 hours per day, increasing the probability of developing pressure wounds.4 Risk factors for the development of prone-related pressure injuries include high body mass index, male sex, and age greater than 60 years, two of which pertain to this patient.5,6 Although the dorsal feet and toes are main pressure points in the prone position, no studies have detailed lower extremity wounds secondary to prolonged prone positioning.
Patients who remain hypoxic despite prone positioning may require ECMO support. The use of ECMO throughout the pandemic has steadily increased with promising results.7,8 However, patient selection is stringent and is reserved for those younger than 65 years, with a body mass index of less than 40, who are not immunocompromised, and who have been on mechanical ventilation for fewer than 10 days.7,9 Therefore, this patient was an ideal candidate. Limb ischemia can result from ECMO owing to vessel damage during cannulation, preexisting atherosclerotic disease, and prolonged vasopressor use.10 Prior case series on pedal complications after ECMO show gangrene occurring more readily in younger patients, possibly secondary to smaller caliber vessels and fewer collaterals.10, 11, 12 Patients are typically on ECMO for 1 to 3 weeks, and the risk of ischemia increases with prolonged duration (13 days in this patient).3,13
Coagulopathy and limb ischemia in the setting of COVID-19 is widely recognized.14, 15, 16 Studies have reported on the hypercoagulable effects of COVID-19 resulting in the development of acute limb ischemia and digital gangrene despite anticoagulation.15, 16, 17 Low-intensity heparin infusion is recommended in critically ill patients with COVID-19 and has been associated with survival benefit.16,18,19 This finding is reflected in our hospital's anticoagulation protocol.
Vasopressors are associated with the development of digital gangrene, because they create peripheral vasoconstriction to perfuse organs during hemodynamic instability.20 This patient was on vasopressors (epinephrine injection, phenylephrine, and norepinephrine infusions) for 30 days. Vasopressor-induced digital necrosis is a known side effect reported in the literature, often reported as being bilateral and symmetrical in the toes.21, 22, 23 Atrial fibrillation has also been associated with toe necrosis owing to showering of microemboli, although less likely in this patient owing to the short duration of arrhythmia.24
The lack of adequate offloading perhaps played the largest role in the development of pedal gangrene in this patient. Constant pressure to an area creates capillary occlusion, ultimately leading to tissue ischemia owing to inadequate oxygenation.25 Therefore, proper offloading in the bed is of great importance. Heel offloading boots have been found to decrease heel contact forces and can alleviate pressure from the footboard.25 Placing a pillow underneath the shins or positioning the feet off the end of the bed can alleviate pressure on the dorsal feet and toes when the patient is prone. Pressure redistribution support surfaces and prophylactic silicone dressings over bony prominences as well as frequent repositioning can also prevent these injuries.4 At our institution, the podiatry, vascular, and wound care teams have since revised the prone positioning protocol to address offloading of the lower extremities and feet.
Conclusions
We have presented this case to highlight the importance of proper offloading to decrease pressure necrosis injuries from occurring in patients with COVID-19. In patients who are prone positioned and on ECMO and vasopressor support, the risk of developing these wounds is only exacerbated. Efforts to decrease lower extremity pressure wounds are paramount in decreasing the rates of partial and total limb loss.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | ANAKINRA, ARGATROBAN, ASCORBIC ACID, AZITHROMYCIN ANHYDROUS, CEFTRIAXONE, CHLOROQUINE, EPINEPHRINE, HEPARIN SODIUM, METHYLPREDNISOLONE, NOREPINEPHRINE, PHENYLEPHRINE HYDROCHLORIDE, THIAMINE | DrugsGivenReaction | CC BY-NC-ND | 33688601 | 19,933,808 | 2021-06 |
What was the administration route of drug 'AMIODARONE'? | Pedal gangrene in a patient with COVID-19 treated with prone positioning and extracorporeal membrane oxygenation.
Many patients hospitalized with coronavirus disease 2019 are treated with venovenous extracorporeal membrane oxygenation and prone positioning to optimize oxygenation. However, this combination can result in lower extremity tissue necrosis, especially without adequate offloading. We report the case of a 31-year-old man who required mechanical ventilation and venovenous extracorporeal membrane oxygenation secondary to complications from coronavirus disease 2019, and subsequently developed pedal dry gangrene. The patient was discharged and healed without requiring an amputation. Our institution has since revised the prone positioning protocol to address offloading the lower extremities and feet.
Although most patients with coronavirus disease 2019 (COVID-19) experience mild symptoms, some progress to develop severe acute respiratory distress syndrome, requiring mechanical ventilation and prolonged stays in the intensive care unit.1 Those with hypoxemia refractory to mechanical ventilation and prone positioning might be considered for venovenous extracorporeal membrane oxygenation (VV-ECMO), which provides temporary pulmonary support via gas exchange.2,3 The combination of prone positioning, VV-ECMO, and vasopressors can result in lower extremity tissue necrosis, especially without adequate offloading. In this report, we present the case of a 31-year-old man who required mechanical ventilation and VV-ECMO secondary to complications from COVID-19, and subsequently developed pedal dry gangrene. The patient provided verbal consent to the publication of the case details and clinical images.
Case report
A 31-year-old man presented to the emergency department with a 5-day history of fevers and a 2-day history of dry cough. Past medical history included hypertension and obesity. On presentation, he was found to be febrile, hypoxic, and tachycardic. Physical examination revealed bilateral pulmonary crackles and a computed tomography scan of the chest showed peripheral bilateral diffuse ground glass opacities. He was admitted to the general medicine floor and started on empiric ceftriaxone and azithromycin. A nasal swab was positive for COVID-19, and therapy with chloroquine, thiamine, vitamin C, and anakinra was started. He continued to have persistent fevers (maximum temperature 104.5°F), and developed acute hypoxemia, for which he was intubated and transferred to the intensive care unit. The patient was hypotensive, requiring vasopressor support. For deep venous thrombosis prophylaxis, he was placed on continuous heparin infusion, with goal activated partial thromboplastin time of 50 to 70 seconds, as per hospital COVID-19 treatment guidelines.
Despite high ventilator settings, medical therapy, and prone positioning for an average of 15-hour intervals over 6 days, he remained with severe acute respiratory distress syndrome and respiratory acidosis, so he was placed on extracorporeal carbon dioxide removal. He was subsequently transitioned to VV-ECMO for refractory hypoxemia and was started on methylprednisone. The ECMO cannulas were placed in the right internal jugular vein and the right femoral vein. Once ECMO was initiated, anticoagulation therapy was transitioned to argatroban continuous infusion, as per hospital protocol. Dosing was therapeutic with a goal activated partial thromboplastin time of 50 to 90 seconds. The patient's intensive care unit course was complicated by new-onset atrial fibrillation, with emergent successful cardioversion. He was treated with amiodarone. ECMO was successfully decannulated on day 24, and the patient was extubated on day 34.
Podiatry was consulted on day 35 for concern of new-onset pedal gangrene. Vascular examination revealed palpable femoral, popliteal, dorsalis, pedis and posterior tibial artery pulses bilaterally. Epicritic sensation was intact to the toes bilaterally. There was partial thickness dry gangrene on the plantar aspect of the right hallux, plantar distal aspect of the right second digit, plantar distal aspect of the left fifth digit, and the plantar aspect of metatarsal heads 3 to 5 of the left foot. The left plantar forefoot skin was slightly dusky and mottled in appearance (Fig 1). No signs of infection were present. It was noted that the patient's feet were firmly pressed against the footboard of the hospital bed and not properly offloaded. Z-flow boots for offloading of the feet were placed on at this time, and local wound care with betadine paint every other day was started. The plan was to await demarcation of the gangrene to determine if the skin would become viable or ultimately require an amputation.Fig 1 Partial thickness gangrene in bilateral feet on hospital day 35. All necrotic areas were dry and stable in appearance with no associated fluctuance or crepitus, no malodor, no surrounding edema or erythema, and no signs of infection.
Throughout the hospital course, increased necrosis was noted to the left plantar forefoot (Fig 2). Based on the stable nature and partial-thickness depth of the gangrene, the prognosis for healing and prevention of limb and toe loss was favorable. The patient was discharged to acute rehabilitation after a 55-day duration of stay. The plan was to continue wearing offloading boots, wound care with betadine paint every other day, and regular follow-up with podiatry to monitor demarcation. Unfortunately, the patient was lost to follow-up. The patient was called for follow-up, and family revealed that he had moved to the Dominican Republic and that his foot wounds healed without requiring amputation.Fig 2 Partial thickness gangrene in bilateral feet on hospital day 45. Increased necrosis of the left plantar forefoot gangrene, which was dry and stable in appearance.
Discussion
The cause of pedal gangrene in this patient was likely multifactorial, including the use of ECMO and vasopressors, prone positioning without proper offloading, and the hypercoagulable nature of COVID-19. Here, we delve further into the role of prone positioning and ECMO in the development of pedal tissue necrosis and discuss the other contributing factors.
Prone positioning can optimize oxygenation in patients with worsening hypoxemia.4 However, necrosis can develop at pressure points without proper offloading. Intubated patients typically remain prone for 12 to 16 hours per day, increasing the probability of developing pressure wounds.4 Risk factors for the development of prone-related pressure injuries include high body mass index, male sex, and age greater than 60 years, two of which pertain to this patient.5,6 Although the dorsal feet and toes are main pressure points in the prone position, no studies have detailed lower extremity wounds secondary to prolonged prone positioning.
Patients who remain hypoxic despite prone positioning may require ECMO support. The use of ECMO throughout the pandemic has steadily increased with promising results.7,8 However, patient selection is stringent and is reserved for those younger than 65 years, with a body mass index of less than 40, who are not immunocompromised, and who have been on mechanical ventilation for fewer than 10 days.7,9 Therefore, this patient was an ideal candidate. Limb ischemia can result from ECMO owing to vessel damage during cannulation, preexisting atherosclerotic disease, and prolonged vasopressor use.10 Prior case series on pedal complications after ECMO show gangrene occurring more readily in younger patients, possibly secondary to smaller caliber vessels and fewer collaterals.10, 11, 12 Patients are typically on ECMO for 1 to 3 weeks, and the risk of ischemia increases with prolonged duration (13 days in this patient).3,13
Coagulopathy and limb ischemia in the setting of COVID-19 is widely recognized.14, 15, 16 Studies have reported on the hypercoagulable effects of COVID-19 resulting in the development of acute limb ischemia and digital gangrene despite anticoagulation.15, 16, 17 Low-intensity heparin infusion is recommended in critically ill patients with COVID-19 and has been associated with survival benefit.16,18,19 This finding is reflected in our hospital's anticoagulation protocol.
Vasopressors are associated with the development of digital gangrene, because they create peripheral vasoconstriction to perfuse organs during hemodynamic instability.20 This patient was on vasopressors (epinephrine injection, phenylephrine, and norepinephrine infusions) for 30 days. Vasopressor-induced digital necrosis is a known side effect reported in the literature, often reported as being bilateral and symmetrical in the toes.21, 22, 23 Atrial fibrillation has also been associated with toe necrosis owing to showering of microemboli, although less likely in this patient owing to the short duration of arrhythmia.24
The lack of adequate offloading perhaps played the largest role in the development of pedal gangrene in this patient. Constant pressure to an area creates capillary occlusion, ultimately leading to tissue ischemia owing to inadequate oxygenation.25 Therefore, proper offloading in the bed is of great importance. Heel offloading boots have been found to decrease heel contact forces and can alleviate pressure from the footboard.25 Placing a pillow underneath the shins or positioning the feet off the end of the bed can alleviate pressure on the dorsal feet and toes when the patient is prone. Pressure redistribution support surfaces and prophylactic silicone dressings over bony prominences as well as frequent repositioning can also prevent these injuries.4 At our institution, the podiatry, vascular, and wound care teams have since revised the prone positioning protocol to address offloading of the lower extremities and feet.
Conclusions
We have presented this case to highlight the importance of proper offloading to decrease pressure necrosis injuries from occurring in patients with COVID-19. In patients who are prone positioned and on ECMO and vasopressor support, the risk of developing these wounds is only exacerbated. Efforts to decrease lower extremity pressure wounds are paramount in decreasing the rates of partial and total limb loss.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | Other | DrugAdministrationRoute | CC BY-NC-ND | 33688601 | 19,951,856 | 2021-06 |
What was the administration route of drug 'EPINEPHRINE'? | Pedal gangrene in a patient with COVID-19 treated with prone positioning and extracorporeal membrane oxygenation.
Many patients hospitalized with coronavirus disease 2019 are treated with venovenous extracorporeal membrane oxygenation and prone positioning to optimize oxygenation. However, this combination can result in lower extremity tissue necrosis, especially without adequate offloading. We report the case of a 31-year-old man who required mechanical ventilation and venovenous extracorporeal membrane oxygenation secondary to complications from coronavirus disease 2019, and subsequently developed pedal dry gangrene. The patient was discharged and healed without requiring an amputation. Our institution has since revised the prone positioning protocol to address offloading the lower extremities and feet.
Although most patients with coronavirus disease 2019 (COVID-19) experience mild symptoms, some progress to develop severe acute respiratory distress syndrome, requiring mechanical ventilation and prolonged stays in the intensive care unit.1 Those with hypoxemia refractory to mechanical ventilation and prone positioning might be considered for venovenous extracorporeal membrane oxygenation (VV-ECMO), which provides temporary pulmonary support via gas exchange.2,3 The combination of prone positioning, VV-ECMO, and vasopressors can result in lower extremity tissue necrosis, especially without adequate offloading. In this report, we present the case of a 31-year-old man who required mechanical ventilation and VV-ECMO secondary to complications from COVID-19, and subsequently developed pedal dry gangrene. The patient provided verbal consent to the publication of the case details and clinical images.
Case report
A 31-year-old man presented to the emergency department with a 5-day history of fevers and a 2-day history of dry cough. Past medical history included hypertension and obesity. On presentation, he was found to be febrile, hypoxic, and tachycardic. Physical examination revealed bilateral pulmonary crackles and a computed tomography scan of the chest showed peripheral bilateral diffuse ground glass opacities. He was admitted to the general medicine floor and started on empiric ceftriaxone and azithromycin. A nasal swab was positive for COVID-19, and therapy with chloroquine, thiamine, vitamin C, and anakinra was started. He continued to have persistent fevers (maximum temperature 104.5°F), and developed acute hypoxemia, for which he was intubated and transferred to the intensive care unit. The patient was hypotensive, requiring vasopressor support. For deep venous thrombosis prophylaxis, he was placed on continuous heparin infusion, with goal activated partial thromboplastin time of 50 to 70 seconds, as per hospital COVID-19 treatment guidelines.
Despite high ventilator settings, medical therapy, and prone positioning for an average of 15-hour intervals over 6 days, he remained with severe acute respiratory distress syndrome and respiratory acidosis, so he was placed on extracorporeal carbon dioxide removal. He was subsequently transitioned to VV-ECMO for refractory hypoxemia and was started on methylprednisone. The ECMO cannulas were placed in the right internal jugular vein and the right femoral vein. Once ECMO was initiated, anticoagulation therapy was transitioned to argatroban continuous infusion, as per hospital protocol. Dosing was therapeutic with a goal activated partial thromboplastin time of 50 to 90 seconds. The patient's intensive care unit course was complicated by new-onset atrial fibrillation, with emergent successful cardioversion. He was treated with amiodarone. ECMO was successfully decannulated on day 24, and the patient was extubated on day 34.
Podiatry was consulted on day 35 for concern of new-onset pedal gangrene. Vascular examination revealed palpable femoral, popliteal, dorsalis, pedis and posterior tibial artery pulses bilaterally. Epicritic sensation was intact to the toes bilaterally. There was partial thickness dry gangrene on the plantar aspect of the right hallux, plantar distal aspect of the right second digit, plantar distal aspect of the left fifth digit, and the plantar aspect of metatarsal heads 3 to 5 of the left foot. The left plantar forefoot skin was slightly dusky and mottled in appearance (Fig 1). No signs of infection were present. It was noted that the patient's feet were firmly pressed against the footboard of the hospital bed and not properly offloaded. Z-flow boots for offloading of the feet were placed on at this time, and local wound care with betadine paint every other day was started. The plan was to await demarcation of the gangrene to determine if the skin would become viable or ultimately require an amputation.Fig 1 Partial thickness gangrene in bilateral feet on hospital day 35. All necrotic areas were dry and stable in appearance with no associated fluctuance or crepitus, no malodor, no surrounding edema or erythema, and no signs of infection.
Throughout the hospital course, increased necrosis was noted to the left plantar forefoot (Fig 2). Based on the stable nature and partial-thickness depth of the gangrene, the prognosis for healing and prevention of limb and toe loss was favorable. The patient was discharged to acute rehabilitation after a 55-day duration of stay. The plan was to continue wearing offloading boots, wound care with betadine paint every other day, and regular follow-up with podiatry to monitor demarcation. Unfortunately, the patient was lost to follow-up. The patient was called for follow-up, and family revealed that he had moved to the Dominican Republic and that his foot wounds healed without requiring amputation.Fig 2 Partial thickness gangrene in bilateral feet on hospital day 45. Increased necrosis of the left plantar forefoot gangrene, which was dry and stable in appearance.
Discussion
The cause of pedal gangrene in this patient was likely multifactorial, including the use of ECMO and vasopressors, prone positioning without proper offloading, and the hypercoagulable nature of COVID-19. Here, we delve further into the role of prone positioning and ECMO in the development of pedal tissue necrosis and discuss the other contributing factors.
Prone positioning can optimize oxygenation in patients with worsening hypoxemia.4 However, necrosis can develop at pressure points without proper offloading. Intubated patients typically remain prone for 12 to 16 hours per day, increasing the probability of developing pressure wounds.4 Risk factors for the development of prone-related pressure injuries include high body mass index, male sex, and age greater than 60 years, two of which pertain to this patient.5,6 Although the dorsal feet and toes are main pressure points in the prone position, no studies have detailed lower extremity wounds secondary to prolonged prone positioning.
Patients who remain hypoxic despite prone positioning may require ECMO support. The use of ECMO throughout the pandemic has steadily increased with promising results.7,8 However, patient selection is stringent and is reserved for those younger than 65 years, with a body mass index of less than 40, who are not immunocompromised, and who have been on mechanical ventilation for fewer than 10 days.7,9 Therefore, this patient was an ideal candidate. Limb ischemia can result from ECMO owing to vessel damage during cannulation, preexisting atherosclerotic disease, and prolonged vasopressor use.10 Prior case series on pedal complications after ECMO show gangrene occurring more readily in younger patients, possibly secondary to smaller caliber vessels and fewer collaterals.10, 11, 12 Patients are typically on ECMO for 1 to 3 weeks, and the risk of ischemia increases with prolonged duration (13 days in this patient).3,13
Coagulopathy and limb ischemia in the setting of COVID-19 is widely recognized.14, 15, 16 Studies have reported on the hypercoagulable effects of COVID-19 resulting in the development of acute limb ischemia and digital gangrene despite anticoagulation.15, 16, 17 Low-intensity heparin infusion is recommended in critically ill patients with COVID-19 and has been associated with survival benefit.16,18,19 This finding is reflected in our hospital's anticoagulation protocol.
Vasopressors are associated with the development of digital gangrene, because they create peripheral vasoconstriction to perfuse organs during hemodynamic instability.20 This patient was on vasopressors (epinephrine injection, phenylephrine, and norepinephrine infusions) for 30 days. Vasopressor-induced digital necrosis is a known side effect reported in the literature, often reported as being bilateral and symmetrical in the toes.21, 22, 23 Atrial fibrillation has also been associated with toe necrosis owing to showering of microemboli, although less likely in this patient owing to the short duration of arrhythmia.24
The lack of adequate offloading perhaps played the largest role in the development of pedal gangrene in this patient. Constant pressure to an area creates capillary occlusion, ultimately leading to tissue ischemia owing to inadequate oxygenation.25 Therefore, proper offloading in the bed is of great importance. Heel offloading boots have been found to decrease heel contact forces and can alleviate pressure from the footboard.25 Placing a pillow underneath the shins or positioning the feet off the end of the bed can alleviate pressure on the dorsal feet and toes when the patient is prone. Pressure redistribution support surfaces and prophylactic silicone dressings over bony prominences as well as frequent repositioning can also prevent these injuries.4 At our institution, the podiatry, vascular, and wound care teams have since revised the prone positioning protocol to address offloading of the lower extremities and feet.
Conclusions
We have presented this case to highlight the importance of proper offloading to decrease pressure necrosis injuries from occurring in patients with COVID-19. In patients who are prone positioned and on ECMO and vasopressor support, the risk of developing these wounds is only exacerbated. Efforts to decrease lower extremity pressure wounds are paramount in decreasing the rates of partial and total limb loss.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | Other | DrugAdministrationRoute | CC BY-NC-ND | 33688601 | 19,951,856 | 2021-06 |
What was the dosage of drug 'EPINEPHRINE'? | Pedal gangrene in a patient with COVID-19 treated with prone positioning and extracorporeal membrane oxygenation.
Many patients hospitalized with coronavirus disease 2019 are treated with venovenous extracorporeal membrane oxygenation and prone positioning to optimize oxygenation. However, this combination can result in lower extremity tissue necrosis, especially without adequate offloading. We report the case of a 31-year-old man who required mechanical ventilation and venovenous extracorporeal membrane oxygenation secondary to complications from coronavirus disease 2019, and subsequently developed pedal dry gangrene. The patient was discharged and healed without requiring an amputation. Our institution has since revised the prone positioning protocol to address offloading the lower extremities and feet.
Although most patients with coronavirus disease 2019 (COVID-19) experience mild symptoms, some progress to develop severe acute respiratory distress syndrome, requiring mechanical ventilation and prolonged stays in the intensive care unit.1 Those with hypoxemia refractory to mechanical ventilation and prone positioning might be considered for venovenous extracorporeal membrane oxygenation (VV-ECMO), which provides temporary pulmonary support via gas exchange.2,3 The combination of prone positioning, VV-ECMO, and vasopressors can result in lower extremity tissue necrosis, especially without adequate offloading. In this report, we present the case of a 31-year-old man who required mechanical ventilation and VV-ECMO secondary to complications from COVID-19, and subsequently developed pedal dry gangrene. The patient provided verbal consent to the publication of the case details and clinical images.
Case report
A 31-year-old man presented to the emergency department with a 5-day history of fevers and a 2-day history of dry cough. Past medical history included hypertension and obesity. On presentation, he was found to be febrile, hypoxic, and tachycardic. Physical examination revealed bilateral pulmonary crackles and a computed tomography scan of the chest showed peripheral bilateral diffuse ground glass opacities. He was admitted to the general medicine floor and started on empiric ceftriaxone and azithromycin. A nasal swab was positive for COVID-19, and therapy with chloroquine, thiamine, vitamin C, and anakinra was started. He continued to have persistent fevers (maximum temperature 104.5°F), and developed acute hypoxemia, for which he was intubated and transferred to the intensive care unit. The patient was hypotensive, requiring vasopressor support. For deep venous thrombosis prophylaxis, he was placed on continuous heparin infusion, with goal activated partial thromboplastin time of 50 to 70 seconds, as per hospital COVID-19 treatment guidelines.
Despite high ventilator settings, medical therapy, and prone positioning for an average of 15-hour intervals over 6 days, he remained with severe acute respiratory distress syndrome and respiratory acidosis, so he was placed on extracorporeal carbon dioxide removal. He was subsequently transitioned to VV-ECMO for refractory hypoxemia and was started on methylprednisone. The ECMO cannulas were placed in the right internal jugular vein and the right femoral vein. Once ECMO was initiated, anticoagulation therapy was transitioned to argatroban continuous infusion, as per hospital protocol. Dosing was therapeutic with a goal activated partial thromboplastin time of 50 to 90 seconds. The patient's intensive care unit course was complicated by new-onset atrial fibrillation, with emergent successful cardioversion. He was treated with amiodarone. ECMO was successfully decannulated on day 24, and the patient was extubated on day 34.
Podiatry was consulted on day 35 for concern of new-onset pedal gangrene. Vascular examination revealed palpable femoral, popliteal, dorsalis, pedis and posterior tibial artery pulses bilaterally. Epicritic sensation was intact to the toes bilaterally. There was partial thickness dry gangrene on the plantar aspect of the right hallux, plantar distal aspect of the right second digit, plantar distal aspect of the left fifth digit, and the plantar aspect of metatarsal heads 3 to 5 of the left foot. The left plantar forefoot skin was slightly dusky and mottled in appearance (Fig 1). No signs of infection were present. It was noted that the patient's feet were firmly pressed against the footboard of the hospital bed and not properly offloaded. Z-flow boots for offloading of the feet were placed on at this time, and local wound care with betadine paint every other day was started. The plan was to await demarcation of the gangrene to determine if the skin would become viable or ultimately require an amputation.Fig 1 Partial thickness gangrene in bilateral feet on hospital day 35. All necrotic areas were dry and stable in appearance with no associated fluctuance or crepitus, no malodor, no surrounding edema or erythema, and no signs of infection.
Throughout the hospital course, increased necrosis was noted to the left plantar forefoot (Fig 2). Based on the stable nature and partial-thickness depth of the gangrene, the prognosis for healing and prevention of limb and toe loss was favorable. The patient was discharged to acute rehabilitation after a 55-day duration of stay. The plan was to continue wearing offloading boots, wound care with betadine paint every other day, and regular follow-up with podiatry to monitor demarcation. Unfortunately, the patient was lost to follow-up. The patient was called for follow-up, and family revealed that he had moved to the Dominican Republic and that his foot wounds healed without requiring amputation.Fig 2 Partial thickness gangrene in bilateral feet on hospital day 45. Increased necrosis of the left plantar forefoot gangrene, which was dry and stable in appearance.
Discussion
The cause of pedal gangrene in this patient was likely multifactorial, including the use of ECMO and vasopressors, prone positioning without proper offloading, and the hypercoagulable nature of COVID-19. Here, we delve further into the role of prone positioning and ECMO in the development of pedal tissue necrosis and discuss the other contributing factors.
Prone positioning can optimize oxygenation in patients with worsening hypoxemia.4 However, necrosis can develop at pressure points without proper offloading. Intubated patients typically remain prone for 12 to 16 hours per day, increasing the probability of developing pressure wounds.4 Risk factors for the development of prone-related pressure injuries include high body mass index, male sex, and age greater than 60 years, two of which pertain to this patient.5,6 Although the dorsal feet and toes are main pressure points in the prone position, no studies have detailed lower extremity wounds secondary to prolonged prone positioning.
Patients who remain hypoxic despite prone positioning may require ECMO support. The use of ECMO throughout the pandemic has steadily increased with promising results.7,8 However, patient selection is stringent and is reserved for those younger than 65 years, with a body mass index of less than 40, who are not immunocompromised, and who have been on mechanical ventilation for fewer than 10 days.7,9 Therefore, this patient was an ideal candidate. Limb ischemia can result from ECMO owing to vessel damage during cannulation, preexisting atherosclerotic disease, and prolonged vasopressor use.10 Prior case series on pedal complications after ECMO show gangrene occurring more readily in younger patients, possibly secondary to smaller caliber vessels and fewer collaterals.10, 11, 12 Patients are typically on ECMO for 1 to 3 weeks, and the risk of ischemia increases with prolonged duration (13 days in this patient).3,13
Coagulopathy and limb ischemia in the setting of COVID-19 is widely recognized.14, 15, 16 Studies have reported on the hypercoagulable effects of COVID-19 resulting in the development of acute limb ischemia and digital gangrene despite anticoagulation.15, 16, 17 Low-intensity heparin infusion is recommended in critically ill patients with COVID-19 and has been associated with survival benefit.16,18,19 This finding is reflected in our hospital's anticoagulation protocol.
Vasopressors are associated with the development of digital gangrene, because they create peripheral vasoconstriction to perfuse organs during hemodynamic instability.20 This patient was on vasopressors (epinephrine injection, phenylephrine, and norepinephrine infusions) for 30 days. Vasopressor-induced digital necrosis is a known side effect reported in the literature, often reported as being bilateral and symmetrical in the toes.21, 22, 23 Atrial fibrillation has also been associated with toe necrosis owing to showering of microemboli, although less likely in this patient owing to the short duration of arrhythmia.24
The lack of adequate offloading perhaps played the largest role in the development of pedal gangrene in this patient. Constant pressure to an area creates capillary occlusion, ultimately leading to tissue ischemia owing to inadequate oxygenation.25 Therefore, proper offloading in the bed is of great importance. Heel offloading boots have been found to decrease heel contact forces and can alleviate pressure from the footboard.25 Placing a pillow underneath the shins or positioning the feet off the end of the bed can alleviate pressure on the dorsal feet and toes when the patient is prone. Pressure redistribution support surfaces and prophylactic silicone dressings over bony prominences as well as frequent repositioning can also prevent these injuries.4 At our institution, the podiatry, vascular, and wound care teams have since revised the prone positioning protocol to address offloading of the lower extremities and feet.
Conclusions
We have presented this case to highlight the importance of proper offloading to decrease pressure necrosis injuries from occurring in patients with COVID-19. In patients who are prone positioned and on ECMO and vasopressor support, the risk of developing these wounds is only exacerbated. Efforts to decrease lower extremity pressure wounds are paramount in decreasing the rates of partial and total limb loss.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | INFUSION FOR 30 DAYS | DrugDosageText | CC BY-NC-ND | 33688601 | 19,951,856 | 2021-06 |
What was the dosage of drug 'HEPARIN SODIUM'? | Pedal gangrene in a patient with COVID-19 treated with prone positioning and extracorporeal membrane oxygenation.
Many patients hospitalized with coronavirus disease 2019 are treated with venovenous extracorporeal membrane oxygenation and prone positioning to optimize oxygenation. However, this combination can result in lower extremity tissue necrosis, especially without adequate offloading. We report the case of a 31-year-old man who required mechanical ventilation and venovenous extracorporeal membrane oxygenation secondary to complications from coronavirus disease 2019, and subsequently developed pedal dry gangrene. The patient was discharged and healed without requiring an amputation. Our institution has since revised the prone positioning protocol to address offloading the lower extremities and feet.
Although most patients with coronavirus disease 2019 (COVID-19) experience mild symptoms, some progress to develop severe acute respiratory distress syndrome, requiring mechanical ventilation and prolonged stays in the intensive care unit.1 Those with hypoxemia refractory to mechanical ventilation and prone positioning might be considered for venovenous extracorporeal membrane oxygenation (VV-ECMO), which provides temporary pulmonary support via gas exchange.2,3 The combination of prone positioning, VV-ECMO, and vasopressors can result in lower extremity tissue necrosis, especially without adequate offloading. In this report, we present the case of a 31-year-old man who required mechanical ventilation and VV-ECMO secondary to complications from COVID-19, and subsequently developed pedal dry gangrene. The patient provided verbal consent to the publication of the case details and clinical images.
Case report
A 31-year-old man presented to the emergency department with a 5-day history of fevers and a 2-day history of dry cough. Past medical history included hypertension and obesity. On presentation, he was found to be febrile, hypoxic, and tachycardic. Physical examination revealed bilateral pulmonary crackles and a computed tomography scan of the chest showed peripheral bilateral diffuse ground glass opacities. He was admitted to the general medicine floor and started on empiric ceftriaxone and azithromycin. A nasal swab was positive for COVID-19, and therapy with chloroquine, thiamine, vitamin C, and anakinra was started. He continued to have persistent fevers (maximum temperature 104.5°F), and developed acute hypoxemia, for which he was intubated and transferred to the intensive care unit. The patient was hypotensive, requiring vasopressor support. For deep venous thrombosis prophylaxis, he was placed on continuous heparin infusion, with goal activated partial thromboplastin time of 50 to 70 seconds, as per hospital COVID-19 treatment guidelines.
Despite high ventilator settings, medical therapy, and prone positioning for an average of 15-hour intervals over 6 days, he remained with severe acute respiratory distress syndrome and respiratory acidosis, so he was placed on extracorporeal carbon dioxide removal. He was subsequently transitioned to VV-ECMO for refractory hypoxemia and was started on methylprednisone. The ECMO cannulas were placed in the right internal jugular vein and the right femoral vein. Once ECMO was initiated, anticoagulation therapy was transitioned to argatroban continuous infusion, as per hospital protocol. Dosing was therapeutic with a goal activated partial thromboplastin time of 50 to 90 seconds. The patient's intensive care unit course was complicated by new-onset atrial fibrillation, with emergent successful cardioversion. He was treated with amiodarone. ECMO was successfully decannulated on day 24, and the patient was extubated on day 34.
Podiatry was consulted on day 35 for concern of new-onset pedal gangrene. Vascular examination revealed palpable femoral, popliteal, dorsalis, pedis and posterior tibial artery pulses bilaterally. Epicritic sensation was intact to the toes bilaterally. There was partial thickness dry gangrene on the plantar aspect of the right hallux, plantar distal aspect of the right second digit, plantar distal aspect of the left fifth digit, and the plantar aspect of metatarsal heads 3 to 5 of the left foot. The left plantar forefoot skin was slightly dusky and mottled in appearance (Fig 1). No signs of infection were present. It was noted that the patient's feet were firmly pressed against the footboard of the hospital bed and not properly offloaded. Z-flow boots for offloading of the feet were placed on at this time, and local wound care with betadine paint every other day was started. The plan was to await demarcation of the gangrene to determine if the skin would become viable or ultimately require an amputation.Fig 1 Partial thickness gangrene in bilateral feet on hospital day 35. All necrotic areas were dry and stable in appearance with no associated fluctuance or crepitus, no malodor, no surrounding edema or erythema, and no signs of infection.
Throughout the hospital course, increased necrosis was noted to the left plantar forefoot (Fig 2). Based on the stable nature and partial-thickness depth of the gangrene, the prognosis for healing and prevention of limb and toe loss was favorable. The patient was discharged to acute rehabilitation after a 55-day duration of stay. The plan was to continue wearing offloading boots, wound care with betadine paint every other day, and regular follow-up with podiatry to monitor demarcation. Unfortunately, the patient was lost to follow-up. The patient was called for follow-up, and family revealed that he had moved to the Dominican Republic and that his foot wounds healed without requiring amputation.Fig 2 Partial thickness gangrene in bilateral feet on hospital day 45. Increased necrosis of the left plantar forefoot gangrene, which was dry and stable in appearance.
Discussion
The cause of pedal gangrene in this patient was likely multifactorial, including the use of ECMO and vasopressors, prone positioning without proper offloading, and the hypercoagulable nature of COVID-19. Here, we delve further into the role of prone positioning and ECMO in the development of pedal tissue necrosis and discuss the other contributing factors.
Prone positioning can optimize oxygenation in patients with worsening hypoxemia.4 However, necrosis can develop at pressure points without proper offloading. Intubated patients typically remain prone for 12 to 16 hours per day, increasing the probability of developing pressure wounds.4 Risk factors for the development of prone-related pressure injuries include high body mass index, male sex, and age greater than 60 years, two of which pertain to this patient.5,6 Although the dorsal feet and toes are main pressure points in the prone position, no studies have detailed lower extremity wounds secondary to prolonged prone positioning.
Patients who remain hypoxic despite prone positioning may require ECMO support. The use of ECMO throughout the pandemic has steadily increased with promising results.7,8 However, patient selection is stringent and is reserved for those younger than 65 years, with a body mass index of less than 40, who are not immunocompromised, and who have been on mechanical ventilation for fewer than 10 days.7,9 Therefore, this patient was an ideal candidate. Limb ischemia can result from ECMO owing to vessel damage during cannulation, preexisting atherosclerotic disease, and prolonged vasopressor use.10 Prior case series on pedal complications after ECMO show gangrene occurring more readily in younger patients, possibly secondary to smaller caliber vessels and fewer collaterals.10, 11, 12 Patients are typically on ECMO for 1 to 3 weeks, and the risk of ischemia increases with prolonged duration (13 days in this patient).3,13
Coagulopathy and limb ischemia in the setting of COVID-19 is widely recognized.14, 15, 16 Studies have reported on the hypercoagulable effects of COVID-19 resulting in the development of acute limb ischemia and digital gangrene despite anticoagulation.15, 16, 17 Low-intensity heparin infusion is recommended in critically ill patients with COVID-19 and has been associated with survival benefit.16,18,19 This finding is reflected in our hospital's anticoagulation protocol.
Vasopressors are associated with the development of digital gangrene, because they create peripheral vasoconstriction to perfuse organs during hemodynamic instability.20 This patient was on vasopressors (epinephrine injection, phenylephrine, and norepinephrine infusions) for 30 days. Vasopressor-induced digital necrosis is a known side effect reported in the literature, often reported as being bilateral and symmetrical in the toes.21, 22, 23 Atrial fibrillation has also been associated with toe necrosis owing to showering of microemboli, although less likely in this patient owing to the short duration of arrhythmia.24
The lack of adequate offloading perhaps played the largest role in the development of pedal gangrene in this patient. Constant pressure to an area creates capillary occlusion, ultimately leading to tissue ischemia owing to inadequate oxygenation.25 Therefore, proper offloading in the bed is of great importance. Heel offloading boots have been found to decrease heel contact forces and can alleviate pressure from the footboard.25 Placing a pillow underneath the shins or positioning the feet off the end of the bed can alleviate pressure on the dorsal feet and toes when the patient is prone. Pressure redistribution support surfaces and prophylactic silicone dressings over bony prominences as well as frequent repositioning can also prevent these injuries.4 At our institution, the podiatry, vascular, and wound care teams have since revised the prone positioning protocol to address offloading of the lower extremities and feet.
Conclusions
We have presented this case to highlight the importance of proper offloading to decrease pressure necrosis injuries from occurring in patients with COVID-19. In patients who are prone positioned and on ECMO and vasopressor support, the risk of developing these wounds is only exacerbated. Efforts to decrease lower extremity pressure wounds are paramount in decreasing the rates of partial and total limb loss.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | UNK, CONTINUOUS INFUSION | DrugDosageText | CC BY-NC-ND | 33688601 | 19,933,808 | 2021-06 |
What was the dosage of drug 'NOREPINEPHRINE'? | Pedal gangrene in a patient with COVID-19 treated with prone positioning and extracorporeal membrane oxygenation.
Many patients hospitalized with coronavirus disease 2019 are treated with venovenous extracorporeal membrane oxygenation and prone positioning to optimize oxygenation. However, this combination can result in lower extremity tissue necrosis, especially without adequate offloading. We report the case of a 31-year-old man who required mechanical ventilation and venovenous extracorporeal membrane oxygenation secondary to complications from coronavirus disease 2019, and subsequently developed pedal dry gangrene. The patient was discharged and healed without requiring an amputation. Our institution has since revised the prone positioning protocol to address offloading the lower extremities and feet.
Although most patients with coronavirus disease 2019 (COVID-19) experience mild symptoms, some progress to develop severe acute respiratory distress syndrome, requiring mechanical ventilation and prolonged stays in the intensive care unit.1 Those with hypoxemia refractory to mechanical ventilation and prone positioning might be considered for venovenous extracorporeal membrane oxygenation (VV-ECMO), which provides temporary pulmonary support via gas exchange.2,3 The combination of prone positioning, VV-ECMO, and vasopressors can result in lower extremity tissue necrosis, especially without adequate offloading. In this report, we present the case of a 31-year-old man who required mechanical ventilation and VV-ECMO secondary to complications from COVID-19, and subsequently developed pedal dry gangrene. The patient provided verbal consent to the publication of the case details and clinical images.
Case report
A 31-year-old man presented to the emergency department with a 5-day history of fevers and a 2-day history of dry cough. Past medical history included hypertension and obesity. On presentation, he was found to be febrile, hypoxic, and tachycardic. Physical examination revealed bilateral pulmonary crackles and a computed tomography scan of the chest showed peripheral bilateral diffuse ground glass opacities. He was admitted to the general medicine floor and started on empiric ceftriaxone and azithromycin. A nasal swab was positive for COVID-19, and therapy with chloroquine, thiamine, vitamin C, and anakinra was started. He continued to have persistent fevers (maximum temperature 104.5°F), and developed acute hypoxemia, for which he was intubated and transferred to the intensive care unit. The patient was hypotensive, requiring vasopressor support. For deep venous thrombosis prophylaxis, he was placed on continuous heparin infusion, with goal activated partial thromboplastin time of 50 to 70 seconds, as per hospital COVID-19 treatment guidelines.
Despite high ventilator settings, medical therapy, and prone positioning for an average of 15-hour intervals over 6 days, he remained with severe acute respiratory distress syndrome and respiratory acidosis, so he was placed on extracorporeal carbon dioxide removal. He was subsequently transitioned to VV-ECMO for refractory hypoxemia and was started on methylprednisone. The ECMO cannulas were placed in the right internal jugular vein and the right femoral vein. Once ECMO was initiated, anticoagulation therapy was transitioned to argatroban continuous infusion, as per hospital protocol. Dosing was therapeutic with a goal activated partial thromboplastin time of 50 to 90 seconds. The patient's intensive care unit course was complicated by new-onset atrial fibrillation, with emergent successful cardioversion. He was treated with amiodarone. ECMO was successfully decannulated on day 24, and the patient was extubated on day 34.
Podiatry was consulted on day 35 for concern of new-onset pedal gangrene. Vascular examination revealed palpable femoral, popliteal, dorsalis, pedis and posterior tibial artery pulses bilaterally. Epicritic sensation was intact to the toes bilaterally. There was partial thickness dry gangrene on the plantar aspect of the right hallux, plantar distal aspect of the right second digit, plantar distal aspect of the left fifth digit, and the plantar aspect of metatarsal heads 3 to 5 of the left foot. The left plantar forefoot skin was slightly dusky and mottled in appearance (Fig 1). No signs of infection were present. It was noted that the patient's feet were firmly pressed against the footboard of the hospital bed and not properly offloaded. Z-flow boots for offloading of the feet were placed on at this time, and local wound care with betadine paint every other day was started. The plan was to await demarcation of the gangrene to determine if the skin would become viable or ultimately require an amputation.Fig 1 Partial thickness gangrene in bilateral feet on hospital day 35. All necrotic areas were dry and stable in appearance with no associated fluctuance or crepitus, no malodor, no surrounding edema or erythema, and no signs of infection.
Throughout the hospital course, increased necrosis was noted to the left plantar forefoot (Fig 2). Based on the stable nature and partial-thickness depth of the gangrene, the prognosis for healing and prevention of limb and toe loss was favorable. The patient was discharged to acute rehabilitation after a 55-day duration of stay. The plan was to continue wearing offloading boots, wound care with betadine paint every other day, and regular follow-up with podiatry to monitor demarcation. Unfortunately, the patient was lost to follow-up. The patient was called for follow-up, and family revealed that he had moved to the Dominican Republic and that his foot wounds healed without requiring amputation.Fig 2 Partial thickness gangrene in bilateral feet on hospital day 45. Increased necrosis of the left plantar forefoot gangrene, which was dry and stable in appearance.
Discussion
The cause of pedal gangrene in this patient was likely multifactorial, including the use of ECMO and vasopressors, prone positioning without proper offloading, and the hypercoagulable nature of COVID-19. Here, we delve further into the role of prone positioning and ECMO in the development of pedal tissue necrosis and discuss the other contributing factors.
Prone positioning can optimize oxygenation in patients with worsening hypoxemia.4 However, necrosis can develop at pressure points without proper offloading. Intubated patients typically remain prone for 12 to 16 hours per day, increasing the probability of developing pressure wounds.4 Risk factors for the development of prone-related pressure injuries include high body mass index, male sex, and age greater than 60 years, two of which pertain to this patient.5,6 Although the dorsal feet and toes are main pressure points in the prone position, no studies have detailed lower extremity wounds secondary to prolonged prone positioning.
Patients who remain hypoxic despite prone positioning may require ECMO support. The use of ECMO throughout the pandemic has steadily increased with promising results.7,8 However, patient selection is stringent and is reserved for those younger than 65 years, with a body mass index of less than 40, who are not immunocompromised, and who have been on mechanical ventilation for fewer than 10 days.7,9 Therefore, this patient was an ideal candidate. Limb ischemia can result from ECMO owing to vessel damage during cannulation, preexisting atherosclerotic disease, and prolonged vasopressor use.10 Prior case series on pedal complications after ECMO show gangrene occurring more readily in younger patients, possibly secondary to smaller caliber vessels and fewer collaterals.10, 11, 12 Patients are typically on ECMO for 1 to 3 weeks, and the risk of ischemia increases with prolonged duration (13 days in this patient).3,13
Coagulopathy and limb ischemia in the setting of COVID-19 is widely recognized.14, 15, 16 Studies have reported on the hypercoagulable effects of COVID-19 resulting in the development of acute limb ischemia and digital gangrene despite anticoagulation.15, 16, 17 Low-intensity heparin infusion is recommended in critically ill patients with COVID-19 and has been associated with survival benefit.16,18,19 This finding is reflected in our hospital's anticoagulation protocol.
Vasopressors are associated with the development of digital gangrene, because they create peripheral vasoconstriction to perfuse organs during hemodynamic instability.20 This patient was on vasopressors (epinephrine injection, phenylephrine, and norepinephrine infusions) for 30 days. Vasopressor-induced digital necrosis is a known side effect reported in the literature, often reported as being bilateral and symmetrical in the toes.21, 22, 23 Atrial fibrillation has also been associated with toe necrosis owing to showering of microemboli, although less likely in this patient owing to the short duration of arrhythmia.24
The lack of adequate offloading perhaps played the largest role in the development of pedal gangrene in this patient. Constant pressure to an area creates capillary occlusion, ultimately leading to tissue ischemia owing to inadequate oxygenation.25 Therefore, proper offloading in the bed is of great importance. Heel offloading boots have been found to decrease heel contact forces and can alleviate pressure from the footboard.25 Placing a pillow underneath the shins or positioning the feet off the end of the bed can alleviate pressure on the dorsal feet and toes when the patient is prone. Pressure redistribution support surfaces and prophylactic silicone dressings over bony prominences as well as frequent repositioning can also prevent these injuries.4 At our institution, the podiatry, vascular, and wound care teams have since revised the prone positioning protocol to address offloading of the lower extremities and feet.
Conclusions
We have presented this case to highlight the importance of proper offloading to decrease pressure necrosis injuries from occurring in patients with COVID-19. In patients who are prone positioned and on ECMO and vasopressor support, the risk of developing these wounds is only exacerbated. Efforts to decrease lower extremity pressure wounds are paramount in decreasing the rates of partial and total limb loss.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | FOR 30 DAYS | DrugDosageText | CC BY-NC-ND | 33688601 | 19,951,856 | 2021-06 |
What was the dosage of drug 'PHENYLEPHRINE HYDROCHLORIDE'? | Pedal gangrene in a patient with COVID-19 treated with prone positioning and extracorporeal membrane oxygenation.
Many patients hospitalized with coronavirus disease 2019 are treated with venovenous extracorporeal membrane oxygenation and prone positioning to optimize oxygenation. However, this combination can result in lower extremity tissue necrosis, especially without adequate offloading. We report the case of a 31-year-old man who required mechanical ventilation and venovenous extracorporeal membrane oxygenation secondary to complications from coronavirus disease 2019, and subsequently developed pedal dry gangrene. The patient was discharged and healed without requiring an amputation. Our institution has since revised the prone positioning protocol to address offloading the lower extremities and feet.
Although most patients with coronavirus disease 2019 (COVID-19) experience mild symptoms, some progress to develop severe acute respiratory distress syndrome, requiring mechanical ventilation and prolonged stays in the intensive care unit.1 Those with hypoxemia refractory to mechanical ventilation and prone positioning might be considered for venovenous extracorporeal membrane oxygenation (VV-ECMO), which provides temporary pulmonary support via gas exchange.2,3 The combination of prone positioning, VV-ECMO, and vasopressors can result in lower extremity tissue necrosis, especially without adequate offloading. In this report, we present the case of a 31-year-old man who required mechanical ventilation and VV-ECMO secondary to complications from COVID-19, and subsequently developed pedal dry gangrene. The patient provided verbal consent to the publication of the case details and clinical images.
Case report
A 31-year-old man presented to the emergency department with a 5-day history of fevers and a 2-day history of dry cough. Past medical history included hypertension and obesity. On presentation, he was found to be febrile, hypoxic, and tachycardic. Physical examination revealed bilateral pulmonary crackles and a computed tomography scan of the chest showed peripheral bilateral diffuse ground glass opacities. He was admitted to the general medicine floor and started on empiric ceftriaxone and azithromycin. A nasal swab was positive for COVID-19, and therapy with chloroquine, thiamine, vitamin C, and anakinra was started. He continued to have persistent fevers (maximum temperature 104.5°F), and developed acute hypoxemia, for which he was intubated and transferred to the intensive care unit. The patient was hypotensive, requiring vasopressor support. For deep venous thrombosis prophylaxis, he was placed on continuous heparin infusion, with goal activated partial thromboplastin time of 50 to 70 seconds, as per hospital COVID-19 treatment guidelines.
Despite high ventilator settings, medical therapy, and prone positioning for an average of 15-hour intervals over 6 days, he remained with severe acute respiratory distress syndrome and respiratory acidosis, so he was placed on extracorporeal carbon dioxide removal. He was subsequently transitioned to VV-ECMO for refractory hypoxemia and was started on methylprednisone. The ECMO cannulas were placed in the right internal jugular vein and the right femoral vein. Once ECMO was initiated, anticoagulation therapy was transitioned to argatroban continuous infusion, as per hospital protocol. Dosing was therapeutic with a goal activated partial thromboplastin time of 50 to 90 seconds. The patient's intensive care unit course was complicated by new-onset atrial fibrillation, with emergent successful cardioversion. He was treated with amiodarone. ECMO was successfully decannulated on day 24, and the patient was extubated on day 34.
Podiatry was consulted on day 35 for concern of new-onset pedal gangrene. Vascular examination revealed palpable femoral, popliteal, dorsalis, pedis and posterior tibial artery pulses bilaterally. Epicritic sensation was intact to the toes bilaterally. There was partial thickness dry gangrene on the plantar aspect of the right hallux, plantar distal aspect of the right second digit, plantar distal aspect of the left fifth digit, and the plantar aspect of metatarsal heads 3 to 5 of the left foot. The left plantar forefoot skin was slightly dusky and mottled in appearance (Fig 1). No signs of infection were present. It was noted that the patient's feet were firmly pressed against the footboard of the hospital bed and not properly offloaded. Z-flow boots for offloading of the feet were placed on at this time, and local wound care with betadine paint every other day was started. The plan was to await demarcation of the gangrene to determine if the skin would become viable or ultimately require an amputation.Fig 1 Partial thickness gangrene in bilateral feet on hospital day 35. All necrotic areas were dry and stable in appearance with no associated fluctuance or crepitus, no malodor, no surrounding edema or erythema, and no signs of infection.
Throughout the hospital course, increased necrosis was noted to the left plantar forefoot (Fig 2). Based on the stable nature and partial-thickness depth of the gangrene, the prognosis for healing and prevention of limb and toe loss was favorable. The patient was discharged to acute rehabilitation after a 55-day duration of stay. The plan was to continue wearing offloading boots, wound care with betadine paint every other day, and regular follow-up with podiatry to monitor demarcation. Unfortunately, the patient was lost to follow-up. The patient was called for follow-up, and family revealed that he had moved to the Dominican Republic and that his foot wounds healed without requiring amputation.Fig 2 Partial thickness gangrene in bilateral feet on hospital day 45. Increased necrosis of the left plantar forefoot gangrene, which was dry and stable in appearance.
Discussion
The cause of pedal gangrene in this patient was likely multifactorial, including the use of ECMO and vasopressors, prone positioning without proper offloading, and the hypercoagulable nature of COVID-19. Here, we delve further into the role of prone positioning and ECMO in the development of pedal tissue necrosis and discuss the other contributing factors.
Prone positioning can optimize oxygenation in patients with worsening hypoxemia.4 However, necrosis can develop at pressure points without proper offloading. Intubated patients typically remain prone for 12 to 16 hours per day, increasing the probability of developing pressure wounds.4 Risk factors for the development of prone-related pressure injuries include high body mass index, male sex, and age greater than 60 years, two of which pertain to this patient.5,6 Although the dorsal feet and toes are main pressure points in the prone position, no studies have detailed lower extremity wounds secondary to prolonged prone positioning.
Patients who remain hypoxic despite prone positioning may require ECMO support. The use of ECMO throughout the pandemic has steadily increased with promising results.7,8 However, patient selection is stringent and is reserved for those younger than 65 years, with a body mass index of less than 40, who are not immunocompromised, and who have been on mechanical ventilation for fewer than 10 days.7,9 Therefore, this patient was an ideal candidate. Limb ischemia can result from ECMO owing to vessel damage during cannulation, preexisting atherosclerotic disease, and prolonged vasopressor use.10 Prior case series on pedal complications after ECMO show gangrene occurring more readily in younger patients, possibly secondary to smaller caliber vessels and fewer collaterals.10, 11, 12 Patients are typically on ECMO for 1 to 3 weeks, and the risk of ischemia increases with prolonged duration (13 days in this patient).3,13
Coagulopathy and limb ischemia in the setting of COVID-19 is widely recognized.14, 15, 16 Studies have reported on the hypercoagulable effects of COVID-19 resulting in the development of acute limb ischemia and digital gangrene despite anticoagulation.15, 16, 17 Low-intensity heparin infusion is recommended in critically ill patients with COVID-19 and has been associated with survival benefit.16,18,19 This finding is reflected in our hospital's anticoagulation protocol.
Vasopressors are associated with the development of digital gangrene, because they create peripheral vasoconstriction to perfuse organs during hemodynamic instability.20 This patient was on vasopressors (epinephrine injection, phenylephrine, and norepinephrine infusions) for 30 days. Vasopressor-induced digital necrosis is a known side effect reported in the literature, often reported as being bilateral and symmetrical in the toes.21, 22, 23 Atrial fibrillation has also been associated with toe necrosis owing to showering of microemboli, although less likely in this patient owing to the short duration of arrhythmia.24
The lack of adequate offloading perhaps played the largest role in the development of pedal gangrene in this patient. Constant pressure to an area creates capillary occlusion, ultimately leading to tissue ischemia owing to inadequate oxygenation.25 Therefore, proper offloading in the bed is of great importance. Heel offloading boots have been found to decrease heel contact forces and can alleviate pressure from the footboard.25 Placing a pillow underneath the shins or positioning the feet off the end of the bed can alleviate pressure on the dorsal feet and toes when the patient is prone. Pressure redistribution support surfaces and prophylactic silicone dressings over bony prominences as well as frequent repositioning can also prevent these injuries.4 At our institution, the podiatry, vascular, and wound care teams have since revised the prone positioning protocol to address offloading of the lower extremities and feet.
Conclusions
We have presented this case to highlight the importance of proper offloading to decrease pressure necrosis injuries from occurring in patients with COVID-19. In patients who are prone positioned and on ECMO and vasopressor support, the risk of developing these wounds is only exacerbated. Efforts to decrease lower extremity pressure wounds are paramount in decreasing the rates of partial and total limb loss.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | FOR 30 DAYS | DrugDosageText | CC BY-NC-ND | 33688601 | 19,951,856 | 2021-06 |
What was the outcome of reaction 'Dry gangrene'? | Pedal gangrene in a patient with COVID-19 treated with prone positioning and extracorporeal membrane oxygenation.
Many patients hospitalized with coronavirus disease 2019 are treated with venovenous extracorporeal membrane oxygenation and prone positioning to optimize oxygenation. However, this combination can result in lower extremity tissue necrosis, especially without adequate offloading. We report the case of a 31-year-old man who required mechanical ventilation and venovenous extracorporeal membrane oxygenation secondary to complications from coronavirus disease 2019, and subsequently developed pedal dry gangrene. The patient was discharged and healed without requiring an amputation. Our institution has since revised the prone positioning protocol to address offloading the lower extremities and feet.
Although most patients with coronavirus disease 2019 (COVID-19) experience mild symptoms, some progress to develop severe acute respiratory distress syndrome, requiring mechanical ventilation and prolonged stays in the intensive care unit.1 Those with hypoxemia refractory to mechanical ventilation and prone positioning might be considered for venovenous extracorporeal membrane oxygenation (VV-ECMO), which provides temporary pulmonary support via gas exchange.2,3 The combination of prone positioning, VV-ECMO, and vasopressors can result in lower extremity tissue necrosis, especially without adequate offloading. In this report, we present the case of a 31-year-old man who required mechanical ventilation and VV-ECMO secondary to complications from COVID-19, and subsequently developed pedal dry gangrene. The patient provided verbal consent to the publication of the case details and clinical images.
Case report
A 31-year-old man presented to the emergency department with a 5-day history of fevers and a 2-day history of dry cough. Past medical history included hypertension and obesity. On presentation, he was found to be febrile, hypoxic, and tachycardic. Physical examination revealed bilateral pulmonary crackles and a computed tomography scan of the chest showed peripheral bilateral diffuse ground glass opacities. He was admitted to the general medicine floor and started on empiric ceftriaxone and azithromycin. A nasal swab was positive for COVID-19, and therapy with chloroquine, thiamine, vitamin C, and anakinra was started. He continued to have persistent fevers (maximum temperature 104.5°F), and developed acute hypoxemia, for which he was intubated and transferred to the intensive care unit. The patient was hypotensive, requiring vasopressor support. For deep venous thrombosis prophylaxis, he was placed on continuous heparin infusion, with goal activated partial thromboplastin time of 50 to 70 seconds, as per hospital COVID-19 treatment guidelines.
Despite high ventilator settings, medical therapy, and prone positioning for an average of 15-hour intervals over 6 days, he remained with severe acute respiratory distress syndrome and respiratory acidosis, so he was placed on extracorporeal carbon dioxide removal. He was subsequently transitioned to VV-ECMO for refractory hypoxemia and was started on methylprednisone. The ECMO cannulas were placed in the right internal jugular vein and the right femoral vein. Once ECMO was initiated, anticoagulation therapy was transitioned to argatroban continuous infusion, as per hospital protocol. Dosing was therapeutic with a goal activated partial thromboplastin time of 50 to 90 seconds. The patient's intensive care unit course was complicated by new-onset atrial fibrillation, with emergent successful cardioversion. He was treated with amiodarone. ECMO was successfully decannulated on day 24, and the patient was extubated on day 34.
Podiatry was consulted on day 35 for concern of new-onset pedal gangrene. Vascular examination revealed palpable femoral, popliteal, dorsalis, pedis and posterior tibial artery pulses bilaterally. Epicritic sensation was intact to the toes bilaterally. There was partial thickness dry gangrene on the plantar aspect of the right hallux, plantar distal aspect of the right second digit, plantar distal aspect of the left fifth digit, and the plantar aspect of metatarsal heads 3 to 5 of the left foot. The left plantar forefoot skin was slightly dusky and mottled in appearance (Fig 1). No signs of infection were present. It was noted that the patient's feet were firmly pressed against the footboard of the hospital bed and not properly offloaded. Z-flow boots for offloading of the feet were placed on at this time, and local wound care with betadine paint every other day was started. The plan was to await demarcation of the gangrene to determine if the skin would become viable or ultimately require an amputation.Fig 1 Partial thickness gangrene in bilateral feet on hospital day 35. All necrotic areas were dry and stable in appearance with no associated fluctuance or crepitus, no malodor, no surrounding edema or erythema, and no signs of infection.
Throughout the hospital course, increased necrosis was noted to the left plantar forefoot (Fig 2). Based on the stable nature and partial-thickness depth of the gangrene, the prognosis for healing and prevention of limb and toe loss was favorable. The patient was discharged to acute rehabilitation after a 55-day duration of stay. The plan was to continue wearing offloading boots, wound care with betadine paint every other day, and regular follow-up with podiatry to monitor demarcation. Unfortunately, the patient was lost to follow-up. The patient was called for follow-up, and family revealed that he had moved to the Dominican Republic and that his foot wounds healed without requiring amputation.Fig 2 Partial thickness gangrene in bilateral feet on hospital day 45. Increased necrosis of the left plantar forefoot gangrene, which was dry and stable in appearance.
Discussion
The cause of pedal gangrene in this patient was likely multifactorial, including the use of ECMO and vasopressors, prone positioning without proper offloading, and the hypercoagulable nature of COVID-19. Here, we delve further into the role of prone positioning and ECMO in the development of pedal tissue necrosis and discuss the other contributing factors.
Prone positioning can optimize oxygenation in patients with worsening hypoxemia.4 However, necrosis can develop at pressure points without proper offloading. Intubated patients typically remain prone for 12 to 16 hours per day, increasing the probability of developing pressure wounds.4 Risk factors for the development of prone-related pressure injuries include high body mass index, male sex, and age greater than 60 years, two of which pertain to this patient.5,6 Although the dorsal feet and toes are main pressure points in the prone position, no studies have detailed lower extremity wounds secondary to prolonged prone positioning.
Patients who remain hypoxic despite prone positioning may require ECMO support. The use of ECMO throughout the pandemic has steadily increased with promising results.7,8 However, patient selection is stringent and is reserved for those younger than 65 years, with a body mass index of less than 40, who are not immunocompromised, and who have been on mechanical ventilation for fewer than 10 days.7,9 Therefore, this patient was an ideal candidate. Limb ischemia can result from ECMO owing to vessel damage during cannulation, preexisting atherosclerotic disease, and prolonged vasopressor use.10 Prior case series on pedal complications after ECMO show gangrene occurring more readily in younger patients, possibly secondary to smaller caliber vessels and fewer collaterals.10, 11, 12 Patients are typically on ECMO for 1 to 3 weeks, and the risk of ischemia increases with prolonged duration (13 days in this patient).3,13
Coagulopathy and limb ischemia in the setting of COVID-19 is widely recognized.14, 15, 16 Studies have reported on the hypercoagulable effects of COVID-19 resulting in the development of acute limb ischemia and digital gangrene despite anticoagulation.15, 16, 17 Low-intensity heparin infusion is recommended in critically ill patients with COVID-19 and has been associated with survival benefit.16,18,19 This finding is reflected in our hospital's anticoagulation protocol.
Vasopressors are associated with the development of digital gangrene, because they create peripheral vasoconstriction to perfuse organs during hemodynamic instability.20 This patient was on vasopressors (epinephrine injection, phenylephrine, and norepinephrine infusions) for 30 days. Vasopressor-induced digital necrosis is a known side effect reported in the literature, often reported as being bilateral and symmetrical in the toes.21, 22, 23 Atrial fibrillation has also been associated with toe necrosis owing to showering of microemboli, although less likely in this patient owing to the short duration of arrhythmia.24
The lack of adequate offloading perhaps played the largest role in the development of pedal gangrene in this patient. Constant pressure to an area creates capillary occlusion, ultimately leading to tissue ischemia owing to inadequate oxygenation.25 Therefore, proper offloading in the bed is of great importance. Heel offloading boots have been found to decrease heel contact forces and can alleviate pressure from the footboard.25 Placing a pillow underneath the shins or positioning the feet off the end of the bed can alleviate pressure on the dorsal feet and toes when the patient is prone. Pressure redistribution support surfaces and prophylactic silicone dressings over bony prominences as well as frequent repositioning can also prevent these injuries.4 At our institution, the podiatry, vascular, and wound care teams have since revised the prone positioning protocol to address offloading of the lower extremities and feet.
Conclusions
We have presented this case to highlight the importance of proper offloading to decrease pressure necrosis injuries from occurring in patients with COVID-19. In patients who are prone positioned and on ECMO and vasopressor support, the risk of developing these wounds is only exacerbated. Efforts to decrease lower extremity pressure wounds are paramount in decreasing the rates of partial and total limb loss.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | Recovered | ReactionOutcome | CC BY-NC-ND | 33688601 | 19,933,808 | 2021-06 |
What was the outcome of reaction 'Gangrene'? | Pedal gangrene in a patient with COVID-19 treated with prone positioning and extracorporeal membrane oxygenation.
Many patients hospitalized with coronavirus disease 2019 are treated with venovenous extracorporeal membrane oxygenation and prone positioning to optimize oxygenation. However, this combination can result in lower extremity tissue necrosis, especially without adequate offloading. We report the case of a 31-year-old man who required mechanical ventilation and venovenous extracorporeal membrane oxygenation secondary to complications from coronavirus disease 2019, and subsequently developed pedal dry gangrene. The patient was discharged and healed without requiring an amputation. Our institution has since revised the prone positioning protocol to address offloading the lower extremities and feet.
Although most patients with coronavirus disease 2019 (COVID-19) experience mild symptoms, some progress to develop severe acute respiratory distress syndrome, requiring mechanical ventilation and prolonged stays in the intensive care unit.1 Those with hypoxemia refractory to mechanical ventilation and prone positioning might be considered for venovenous extracorporeal membrane oxygenation (VV-ECMO), which provides temporary pulmonary support via gas exchange.2,3 The combination of prone positioning, VV-ECMO, and vasopressors can result in lower extremity tissue necrosis, especially without adequate offloading. In this report, we present the case of a 31-year-old man who required mechanical ventilation and VV-ECMO secondary to complications from COVID-19, and subsequently developed pedal dry gangrene. The patient provided verbal consent to the publication of the case details and clinical images.
Case report
A 31-year-old man presented to the emergency department with a 5-day history of fevers and a 2-day history of dry cough. Past medical history included hypertension and obesity. On presentation, he was found to be febrile, hypoxic, and tachycardic. Physical examination revealed bilateral pulmonary crackles and a computed tomography scan of the chest showed peripheral bilateral diffuse ground glass opacities. He was admitted to the general medicine floor and started on empiric ceftriaxone and azithromycin. A nasal swab was positive for COVID-19, and therapy with chloroquine, thiamine, vitamin C, and anakinra was started. He continued to have persistent fevers (maximum temperature 104.5°F), and developed acute hypoxemia, for which he was intubated and transferred to the intensive care unit. The patient was hypotensive, requiring vasopressor support. For deep venous thrombosis prophylaxis, he was placed on continuous heparin infusion, with goal activated partial thromboplastin time of 50 to 70 seconds, as per hospital COVID-19 treatment guidelines.
Despite high ventilator settings, medical therapy, and prone positioning for an average of 15-hour intervals over 6 days, he remained with severe acute respiratory distress syndrome and respiratory acidosis, so he was placed on extracorporeal carbon dioxide removal. He was subsequently transitioned to VV-ECMO for refractory hypoxemia and was started on methylprednisone. The ECMO cannulas were placed in the right internal jugular vein and the right femoral vein. Once ECMO was initiated, anticoagulation therapy was transitioned to argatroban continuous infusion, as per hospital protocol. Dosing was therapeutic with a goal activated partial thromboplastin time of 50 to 90 seconds. The patient's intensive care unit course was complicated by new-onset atrial fibrillation, with emergent successful cardioversion. He was treated with amiodarone. ECMO was successfully decannulated on day 24, and the patient was extubated on day 34.
Podiatry was consulted on day 35 for concern of new-onset pedal gangrene. Vascular examination revealed palpable femoral, popliteal, dorsalis, pedis and posterior tibial artery pulses bilaterally. Epicritic sensation was intact to the toes bilaterally. There was partial thickness dry gangrene on the plantar aspect of the right hallux, plantar distal aspect of the right second digit, plantar distal aspect of the left fifth digit, and the plantar aspect of metatarsal heads 3 to 5 of the left foot. The left plantar forefoot skin was slightly dusky and mottled in appearance (Fig 1). No signs of infection were present. It was noted that the patient's feet were firmly pressed against the footboard of the hospital bed and not properly offloaded. Z-flow boots for offloading of the feet were placed on at this time, and local wound care with betadine paint every other day was started. The plan was to await demarcation of the gangrene to determine if the skin would become viable or ultimately require an amputation.Fig 1 Partial thickness gangrene in bilateral feet on hospital day 35. All necrotic areas were dry and stable in appearance with no associated fluctuance or crepitus, no malodor, no surrounding edema or erythema, and no signs of infection.
Throughout the hospital course, increased necrosis was noted to the left plantar forefoot (Fig 2). Based on the stable nature and partial-thickness depth of the gangrene, the prognosis for healing and prevention of limb and toe loss was favorable. The patient was discharged to acute rehabilitation after a 55-day duration of stay. The plan was to continue wearing offloading boots, wound care with betadine paint every other day, and regular follow-up with podiatry to monitor demarcation. Unfortunately, the patient was lost to follow-up. The patient was called for follow-up, and family revealed that he had moved to the Dominican Republic and that his foot wounds healed without requiring amputation.Fig 2 Partial thickness gangrene in bilateral feet on hospital day 45. Increased necrosis of the left plantar forefoot gangrene, which was dry and stable in appearance.
Discussion
The cause of pedal gangrene in this patient was likely multifactorial, including the use of ECMO and vasopressors, prone positioning without proper offloading, and the hypercoagulable nature of COVID-19. Here, we delve further into the role of prone positioning and ECMO in the development of pedal tissue necrosis and discuss the other contributing factors.
Prone positioning can optimize oxygenation in patients with worsening hypoxemia.4 However, necrosis can develop at pressure points without proper offloading. Intubated patients typically remain prone for 12 to 16 hours per day, increasing the probability of developing pressure wounds.4 Risk factors for the development of prone-related pressure injuries include high body mass index, male sex, and age greater than 60 years, two of which pertain to this patient.5,6 Although the dorsal feet and toes are main pressure points in the prone position, no studies have detailed lower extremity wounds secondary to prolonged prone positioning.
Patients who remain hypoxic despite prone positioning may require ECMO support. The use of ECMO throughout the pandemic has steadily increased with promising results.7,8 However, patient selection is stringent and is reserved for those younger than 65 years, with a body mass index of less than 40, who are not immunocompromised, and who have been on mechanical ventilation for fewer than 10 days.7,9 Therefore, this patient was an ideal candidate. Limb ischemia can result from ECMO owing to vessel damage during cannulation, preexisting atherosclerotic disease, and prolonged vasopressor use.10 Prior case series on pedal complications after ECMO show gangrene occurring more readily in younger patients, possibly secondary to smaller caliber vessels and fewer collaterals.10, 11, 12 Patients are typically on ECMO for 1 to 3 weeks, and the risk of ischemia increases with prolonged duration (13 days in this patient).3,13
Coagulopathy and limb ischemia in the setting of COVID-19 is widely recognized.14, 15, 16 Studies have reported on the hypercoagulable effects of COVID-19 resulting in the development of acute limb ischemia and digital gangrene despite anticoagulation.15, 16, 17 Low-intensity heparin infusion is recommended in critically ill patients with COVID-19 and has been associated with survival benefit.16,18,19 This finding is reflected in our hospital's anticoagulation protocol.
Vasopressors are associated with the development of digital gangrene, because they create peripheral vasoconstriction to perfuse organs during hemodynamic instability.20 This patient was on vasopressors (epinephrine injection, phenylephrine, and norepinephrine infusions) for 30 days. Vasopressor-induced digital necrosis is a known side effect reported in the literature, often reported as being bilateral and symmetrical in the toes.21, 22, 23 Atrial fibrillation has also been associated with toe necrosis owing to showering of microemboli, although less likely in this patient owing to the short duration of arrhythmia.24
The lack of adequate offloading perhaps played the largest role in the development of pedal gangrene in this patient. Constant pressure to an area creates capillary occlusion, ultimately leading to tissue ischemia owing to inadequate oxygenation.25 Therefore, proper offloading in the bed is of great importance. Heel offloading boots have been found to decrease heel contact forces and can alleviate pressure from the footboard.25 Placing a pillow underneath the shins or positioning the feet off the end of the bed can alleviate pressure on the dorsal feet and toes when the patient is prone. Pressure redistribution support surfaces and prophylactic silicone dressings over bony prominences as well as frequent repositioning can also prevent these injuries.4 At our institution, the podiatry, vascular, and wound care teams have since revised the prone positioning protocol to address offloading of the lower extremities and feet.
Conclusions
We have presented this case to highlight the importance of proper offloading to decrease pressure necrosis injuries from occurring in patients with COVID-19. In patients who are prone positioned and on ECMO and vasopressor support, the risk of developing these wounds is only exacerbated. Efforts to decrease lower extremity pressure wounds are paramount in decreasing the rates of partial and total limb loss.
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33688601 | 19,951,856 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'No adverse event'. | Using Machine Learning Imputed Outcomes to Assess Drug-Dependent Risk of Self-Harm in Patients with Bipolar Disorder: A Comparative Effectiveness Study.
BACKGROUND
Incomplete suicidality coding in administrative claims data is a known obstacle for observational studies. With most of the negative outcomes missing from the data, it is challenging to assess the evidence on treatment strategies for the prevention of self-harm in bipolar disorder (BD), including pharmacotherapy and psychotherapy. There are conflicting data from studies on the drug-dependent risk of self-harm, and there is major uncertainty regarding the preventive effect of monotherapy and drug combinations.
OBJECTIVE
The aim of this study was to compare all commonly used BD pharmacotherapies, as well as psychotherapy for the risk of self-harm, in a large population of commercially insured individuals, using self-harm imputation to overcome the known limitations of this outcome being underrecorded within US electronic health care records.
METHODS
The IBM MarketScan administrative claims database was used to compare self-harm risk in patients with BD following 65 drug regimens and drug-free periods. Probable but uncoded self-harm events were imputed via machine learning, with different probability thresholds examined in a sensitivity analysis. Comparators included lithium, mood-stabilizing anticonvulsants (MSAs), second-generation antipsychotics (SGAs), first-generation antipsychotics (FGAs), and five classes of antidepressants. Cox regression models with time-varying covariates were built for individual treatment regimens and for any pharmacotherapy with or without psychosocial interventions ("psychotherapy").
RESULTS
Among 529,359 patients, 1.66% (n=8813 events) had imputed and/or coded self-harm following the exposure of interest. A higher self-harm risk was observed during adolescence. After multiple testing adjustment (P≤.012), the following six regimens had higher risk of self-harm than lithium: tri/tetracyclic antidepressants + SGA, FGA + MSA, FGA, serotonin-norepinephrine reuptake inhibitor (SNRI) + SGA, lithium + MSA, and lithium + SGA (hazard ratios [HRs] 1.44-2.29), and the following nine had lower risk: lamotrigine, valproate, risperidone, aripiprazole, SNRI, selective serotonin reuptake inhibitor (SSRI), "no drug," bupropion, and bupropion + SSRI (HRs 0.28-0.74). Psychotherapy alone (without medication) had a lower self-harm risk than no treatment (HR 0.56, 95% CI 0.52-0.60; P=8.76×10-58). The sensitivity analysis showed that the direction of drug-outcome associations did not change as a function of the self-harm probability threshold.
CONCLUSIONS
Our data support evidence on the effectiveness of antidepressants, MSAs, and psychotherapy for self-harm prevention in BD.
BACKGROUND
ClinicalTrials.gov NCT02893371; https://clinicaltrials.gov/ct2/show/NCT02893371.
Introduction
Self-harming behavior is a public and mental health concern of increasing prevalence, which contributes to US hospitalization rates, morbidity, and mortality due to completed suicides. There is a clear temporal and causal link between self-injury and suicide attempts, with both being part of a “suicidality” spectrum and the former being a robust prospective predictor of the latter [1]. In 2018, suicide was the 10th leading cause of death in the general US population, reaching a rate of 14.2 per 100,000 standard population [2]. A previous study reported that the risk ratio of suicide in mental disorders was as high as 7.5 (95% CI 6.6-8.6) and in mood disorders was even higher at 12.3 (95% CI 8.9-17.1) [3]. A recent systematic review showed that bipolar disorder (BD) may be associated with the highest suicide risk among all psychiatric disorders, with over 15%-20% of deaths attributed to suicide and the standardized suicide rate being 20 to 30-fold greater than in the general population (0.2-0.4 per 100 person-years) [4]. Another review found that up to 20% of individuals with BD end their life by suicide and 20%-60% attempt suicide at least once in their lifetime [5]. The reported proportion of suicide attempts and completed suicides among individuals with BD varies from 5:1 in males over 45 years to 85:1 in females under 30 years [6].
Since suicide is an extreme form of self-harming behavior, proper recognition and management of patients presenting with self-inflicted injury are of tremendous importance to prevent lethal outcomes, especially among patients with mood disorders. The factors affecting self-harm risk should be of particular importance for studying suicidality, especially given that the self-inflicted nature of physical trauma/poisoning is often hidden owing to poor patient rapport, provider screening, and data recording.
Incomplete suicidality coding in administrative claims data is a known obstacle for observational studies. It was shown that only 19% of suicide attempts mentioned in primary care clinical notes were coded in International Classification of Diseases-9-Clinical Modification (ICD-9-CM) [7]. Our data from a large-scale observational study on imputing self-harm phenotypes in individuals with major mental illness (MMI) showed that only 1 in 19 self-harm events were coded in the billing records [8]. In addition, a methodological challenge is that ICD-9-CM coding does not robustly distinguish between suicide attempts (implying a desire to die), self-inflicted injury without suicidal intention, and suicide. While ICD-10-CM can distinguish these, many suicide attempts will be classified only under intentional self-harm. Given that all these acts are within the spectrum of self-damaging behavior, we will refer to them collectively as “self-harm.” Thus, we use “self-harm”/“self-harming behavior” as the broadest term covering all forms of self-damaging acts (not thoughts alone), including not only suicide attempts, but also any intentional harm regardless of intent to die. In contrasting this self-harm study with the literature, we recognized that most of the latter was focused more narrowly on attempted and/or completed suicides.
With most of the negative outcomes missing from the data, it is challenging to assess the evidence on treatment strategies for the prevention of self-harm in BD, including pharmacotherapy and psychotherapy. There are conflicting data from studies on the drug-dependent risk of self-harm, and there is still major uncertainty regarding the preventive effect of monotherapy and drug combinations. The benefits of lowering suicidality risk were reported for lithium [9], mood-stabilizing anticonvulsants (MSAs) [10], antidepressants [11-13], and second-generation antipsychotics (SGAs) [14] in the mentally ill population. Several studies demonstrated the benefits of continuous MSA use (either alone or as an adjunct) for suicide risk reduction [15,16]. However, two recent meta-analyses showed no clear benefits of lithium [17] or valproate [18] use for preventing suicidality in patients with mood disorders. The STEP-BD study failed to find any relationship between lithium, MSA, or antipsychotic use and suicidality [19]. The US Food and Drug Administration (FDA) issued warnings for increased suicidality risk with antidepressants [20] and antiepileptic drugs [21].
Two recent meta-analyses showed that psychotherapy is associated with a reduced risk of attempting suicide, but more equivocal evidence on self-harm [22,23]; however, data on psychotherapy-dependent self-harm in adults and subjects with BD are lacking. This provokes further questions on its relative effectiveness when compared with BD medications.
The aim of this study was to provide a comprehensive comparison of all commonly used BD pharmacotherapies, as well as psychotherapy for the risk of self-harm in a large population of commercially insured individuals, using self-harm imputation to overcome the known limitations of this outcome being underrecorded within US electronic health care record systems.
Methods
A retrospective observational study was conducted using the IBM MarketScan commercial claims and encounters (CCAE) administrative claims data and MarketScan Medicare data on 1.3 million US inpatients and outpatients with BD for the years 2003 to 2016 [24]. The database contained records of provider visits, diagnoses, procedures, outpatient prescription fills, laboratory test orders (but not results), and patient age, sex, and state of residence. The data handling was similar to that in our previous studies on the drug-dependent risk of kidney disorders and diabetes mellitus in BD [25,26], with the additional step of combining data for patients who were covered in both the CCAE and Medicare databases through their patient identifier. The relevant PostgreSQL queries and source code for data transformations and machine learning (ML) are available online [27]. The study protocol was approved by the University of New Mexico Human Research Review Committee (Institutional Review Board number 16-243).
Given that the majority of suicide attempts and self-harm events are not coded at the point of care, we employed ML to build a classification model of self-harm being present or absent, based on billing codes during emergency room (ER) or inpatient provider visits. For that purpose, we constructed a “meta-visit” by merging consecutive outpatient/inpatient/ER visits, with no gaps between visits, which allowed us to capture the medical activity associated with a given event that could have involved multiple points of care. A self-harm phenotype was defined by the presence during a meta-visit of one or more of the ICD-10-CM codes or ICD-9-CM codes listed in Multimedia Appendix 1. These encompass all codes for intentional self-harm or suicide attempts by any means, including poisoning. If one or more of these codes was present during a meta-visit, the meta-visit was labeled as class 1; otherwise, it was labeled as class 0.
Our earlier imputation model on over 10 million patients aged ≤65 years with MMI (schizophrenia, schizoaffective disorder, BD, and major depressive disorder) from CCAE was validated with several approaches, including via a clinician-derived “gold standard,” and it identified 10.1 times more self-harm events with probability over 0.5 than were originally coded or 19 times more self-harm events based on summed probabilities [8]. In this study, we applied the previously developed ML modeling approach to an extended set of psychiatric patients of all ages, including those in the CCAE and Medicare databases. We first selected 11 million individuals with any MMI diagnosis (635,722,756 meta-visits) and performed ML on a subset of 26,392,236 meta-visits in which an inpatient or ER visit was present, using five-fold cross-validation. Covariates included age, sex, start year of the meta-visit, and the presence/absence of non–self-harm billing codes. ICD-9-CM and ICD-10-CM diagnosis codes were mapped to their Systematized Nomenclature of Medicine (SNOMED) equivalents (and all ancestors thereof) using the Observational Medical Outcomes Partnership (OMOP) vocabulary as of October 24, 2020 [28]. Procedure codes based on ICD-9-CM Volume 3 (ICD-9-CM V3), ICD-10-Procedure Coding System (ICD-10-PCS), and Current Procedural Technology, Fourth Edition (CPT-4) were mapped to ICD-10-PCS concepts (and all ancestors thereof). Overall, 190,919 covariates were added into the ML process described previously [8]. A threshold probability over 0.5 from the resulting cross-validated model estimates of self-harm was chosen to label self-harm as “present” for our main model, but sensitivity analyses were run for threshold probabilities greater than 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, 0.95, and only coded self-harm (probability=1.0).
We then used the categorization of 26 million meta-visits to assign whether or not self-harm occurred following treatment exposure in a subset of 529,359 patients with two or more diagnoses of BD and no other MMI, who satisfied our data staging and inclusion/exclusion criteria (see below). Since there are approximately 28 attempts for every suicide death [29] and attempts are a subset of self-harm, selection of self-harm as the outcome allowed us to greatly increase the power of our subsequent comparative effectiveness study.
It should be noted that our ML approach was trained only on meta-visits with an inpatient/ER component since there was a negligible number of self-harm events coded during the purely outpatient meta-visits (about 1 in 100,000).
The patient inclusion criterion was two or more ICD-9-CM/ICD-10-CM diagnostic codes for BD (296.(0-1)*, 296.(4-8)*, F30*, or F31*) from 2003 to 2016. The exclusion criterion was the diagnosis of major depressive disorder, schizophrenia, or schizoaffective disorder at any time during the observation period. The onset of intellectual disability, autism spectrum disorder, mental illness of organic origin, or Parkinson disease, and use of antidementia drugs after the index exposure were considered as censoring events.
A patient was included in the analysis based on the following first observed sequence of events (Figure 1): (1) A minimum of 12 months of observation (used to compute pretreatment covariates); (2) Index visit (meta-visit with at least one BD diagnostic code); (3) Index exposure (the first day of exposure [drug regimen or “no drug”] observable on the last day of the index visit); (4) Time-varying drug exposure period (series of time intervals in which distinct regimens [including “no drug”] were prescribed); and (5) Outcomes of interest (the first meta-visit with newly observed coded and/or imputed self-harm and right censoring defined as any hospitalization/ER meta-visit without coded and/or imputed self-harm, or the end of patient observation).
Figure 1 Prespecified sequence of events. (1) One year before the index exposure; (2) Index visit (any meta-visit with a diagnosis of bipolar disorder); (3) Index exposure (the first day of exposure [drugs of interest or no drugs of interest] observable on the last day of the index visit); (4) Time-varying drug exposure period (series of time intervals in which distinct regimens [including “no drug”] were prescribed); (5) Outcome (the first meta-visit with coded and/or imputed self-harm or a censoring event).
The observation period ended for patients upon self-harm–unrelated hospitalization/ER meta-visit, because data on pharmacotherapy were not available during these types of visits, making it challenging to quantify psychotropic treatment time intervals. Additionally, hospitalization itself can affect the risk of self-harm.
The start and stop times were recorded for each treatment exposure period. Two Cox regression models for self-harm were built. One model compared 64 pharmacotherapies (as well as “no drug”) to lithium, and the other model compared any drug (as a single category) with or without psychosocial interventions to “no treatment” (neither pharmacotherapy nor psychosocial interventions).
The idea to include “no drug” and “no treatment” in the list of comparators in our study came from patients with BD who participated in several focus groups and were engaged in designing this research [30,31]. Doing so allowed us to address patient questions regarding the safety and effectiveness of avoiding pharmacotherapy.
To ensure sufficient power to detect significant self-harm risk differences and assure convergence of Cox regression, each drug regimen was required to have 1000 or more treatment intervals and to have five or more defined cases of coded and/or imputed self-harm following exposure [32]. Because of this latter restriction, for the sensitivity analyses, the lower threshold sensitivity Cox models will have more drugs analyzed than the higher threshold ones.
The following 11 drug classes were included in the analysis: lithium, first-generation antipsychotics (FGAs), SGAs, third-generation antipsychotics (TGAs; partial agonists of dopamine receptors, aripiprazole, and brexpiprazole), MSAs, monoamine oxidase inhibitor antidepressants, noradrenergic and specific serotonergic antidepressants (NASSAs; represented by mirtazapine only), norepinephrine-dopamine reuptake inhibitors (NDRIs; represented by bupropion only), serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), and tri- and tetracyclic antidepressants (see Multimedia Appendix 2 for the full list of drugs).
MSAs, SGAs, and TGAs were studied as a class when used during a polypharmacy regimen exposure interval and as individual drugs when considering monotherapy time intervals. SGAs common enough for individual analysis were risperidone, olanzapine, quetiapine, ziprasidone, asenapine, paliperidone, and lurasidone. The individual MSAs studied were valproate, carbamazepine, oxcarbazepine, and lamotrigine. Of the two TGAs, only aripiprazole was common enough to be studied individually.
Combinations of two, three, or four of the 11 drug classes (represented usually by one drug from each class) with the requisite 1000 or more treatment intervals and five or more self-harm events were included in the regression model, and drug regimens without those requisites were grouped under the categories “polypharmacy 2,” “polypharmacy 3,” and “polypharmacy 4” (for uncommon combinations of two, three, and four or more classes, respectively). Enough instances of within-class polypharmacy were present among MSAs and SGAs to include “multi-MSA” and “multi-SGA” variables. Monotherapies without the requisite 1000 exposure intervals (clozapine, brexpiprazole, and iloperidone) were combined into the category “uncommon monotherapy.”
Treatment in the main time-varying Cox regression model was represented as one or more exposure intervals, with all drug categories mutually exclusive and collectively exhaustive, using lithium monotherapy as the reference. The rules to distinguish between polypharmacy and overlapping drug regimen switch are described in our previous study of a similar design [25].
Among the covariates included in the main Cox regression model (not to be confused with the ML covariates) were patient age, sex, BD episode index visit characteristics (severity, mood polarity, and psychotic features, if documented), comorbid mental and physical conditions, including “external injury” codes evidencing noniatrogenic trauma, medication prescriptions filled (other than drugs of interest) and mental health procedures performed 1 year before (but not including) the index exposure, hospital/ER admissions 1 year prior to the index exposure, and types of visits composing the index meta-visit (inpatient/ER/outpatient).
Patient age and the number of unique BD drugs previously tried by the patient were fitted in both Cox regression models using a smoothing spline to account for nonlinear risk of self-harm.
“Psychotherapy” included 227 procedure codes indicating psychosocial intervention (individual, group, or family psychotherapy, crisis intervention, substance abuse–focused treatment, hypnosis, biofeedback, etc) [27].
We developed two time-varying Cox regression models. In the first (main) model comparing 64 treatments and “no drug” to lithium, psychotherapy was coded as a binary time-varying covariate (indicating whether at least one of the 227 procedure codes was present during the current drug/“no drug” exposure period). In the second regression model, all drug regimens were united into a single category (“pharmacotherapy”), and psychotherapy was combined with pharmacotherapy in a time-varying covariate with the following four categories: “pharmacotherapy alone,” “psychotherapy alone,” “psychotherapy and pharmacotherapy,” and “no psychotherapy and no pharmacotherapy” (ie, “no treatment”), with “no psychotherapy and no pharmacotherapy” as the reference.
Given the multiple treatment comparators chosen and the time-varying nature of the treatment covariates in our design, propensity score matching was not feasible for bias correction. Instead, we used a resolution IV fractional factorial design of experiments [33] (whereby main effects are aliased with three-way interactions and two-way interactions are aliased with two-way interactions) to select an appropriate subset of the 78 pretreatment covariates to control for bias. Rather than assessing whether the pretreatment covariates were associated with the outcome, we assessed in a form of sensitivity analysis whether their inclusion or exclusion impacted the hazard ratio (HR) estimates for the treatments with respect to the outcome. If so, inclusion of the variable in the model would be needed for addressing bias. If not, the variable, while possibly associated with the outcome, would nevertheless be unimportant for accurate assessment of treatment risk, and could be excluded to reduce the degrees of freedom of the model and thereby increase power. The time-varying treatment variables were included in each model, but the pretreatment covariates were included or excluded according to the factorial design across 512 different runs (plus a reference run with no pretreatment covariates) to determine which covariates had the largest impact on the drug HR coefficients. The 513 runs generated a 513×66 matrix Y of coefficients for 66 drugs over the 513 runs. The design matrix X was a 513×78 matrix of +1/−1 values corresponding to whether the given pretreatment covariate was included/excluded in a given run. Then, for each of the 66 column vectors (Yi) of Y, a multiple linear regression was run with Yi as the dependent variable and the 78 column vectors of X as the independent variables. We counted how many times each of the 78 covariates was significant at P<.05/66 over those 66 models to rank candidate covariates for our model. We discarded 26 covariates that were not significant in any of the 66 models. We then built our main Cox regression model using this set of covariates plus the treatment covariates and performed a backward elimination procedure on the pretreatment covariates, iteratively dropping the covariates that were significant in the fewest models and stopping the elimination procedure when a highly significant covariate was found (neoplasm). One drug was subsequently removed from the analysis owing to lack of events when some coding errors were corrected. We also generated an L2-norm of each row of X with the reference run row to form a vector Y’ for regression with the design matrix X to assess how much the incorporation of pretreatment covariates changed all drug covariate estimates in order to understand the largest potential sources of bias. The final set of covariates selected for the first Cox model was used in the second Cox model.
The study used the following software: PostgreSQL version 10.4 (PostgreSQL Global Development Group) and R version 3.4.0 (R Foundation for Statistical Computing), including the Cox regression coxph() function from the survival (2.42-6) package and the FrF2 (1.7-2) package for fractional factorial design. All hypothesis tests were two-sided.
Results
The following self-harm classification results were observed for our MMI ML model on meta-visits based on five-fold cross-validation (probability [p] cutoff of 0.5): self-harm coded and imputed (p>0.5; N=93,311); self-harm coded but not imputed (p≤0.5; N=3717); self-harm not coded but imputed (N=1,029,058); and self-harm neither coded nor imputed (N=25,266,150) (area under the curve [AUC]=0.99; Matthews correlation coefficient [MCC]=0.28; sensitivity=0.962; specificity=0.961). The following self-harm classification results were observed when the model was applied to meta-visits for only BD cases meeting our eligibility criteria: self-harm coded and imputed (p>0.5; N=488); self-harm coded but not imputed (p≤0.5; N=37); self-harm not coded but imputed (N=8288); and self-harm neither coded nor imputed (N=520,546) (AUC=0.994; MCC=0.225; sensitivity=0.930; specificity=0.984). Thus, an extra 8288 meta-visits with imputed self-harm were added to our analytical pipeline in addition to the 525 (488+37) meta-visits that had coded self-harm for a total of 8813 persons with self-harm.
The sample sizes at different stages of the study are shown in Multimedia Appendix 3. A total of 529,359 patients met the eligibility criteria and had the prespecified sequence of events. Of them, 98.3% were censored and 1.66% (n=8813 events) had imputed and/or coded self-harm.
During the observation period after the index visit, the annual incidence of self-harm (p>0.5) was 0.013 (0.016 for all drug exposure intervals with or without psychotherapy and 0.011 for “no drug” intervals with or without psychotherapy), based on 632,512 years of observation. By summing the probabilities, during the observation period after the index visit for all exposures, the annual incidence of self-harm was 0.027 over 632,512 years of patient observation.
The 515 observed treatment regimens were collapsed to 17 monotherapies, three monoclass therapies, “no drug,” and 45 drug combinations that fit the selection criteria.
The first Cox regression model comparing 65 treatment regimens to lithium showed that 11 treatments had a significantly higher risk of self-harm (P<.05, no multiple testing correction) (Table 1). The top “high-risk” treatments were “tri/tetracyclic antidepressants + SGA” (HR 2.33, 95% CI 1.28-4.26; P=5.73×10-3), “SSRI + FGA” (HR 2.26, 95% CI 1.16-4.38; P=1.61×10-2), “FGA + MSA” (HR 1.82, 95% CI 1.15-2.89; P=1.12×10-2), and FGA monoclass therapy (HR 1.69, 95% CI 1.19-2.39; P=3.20×10-3).
Nine regimens had significantly lower risk of self-harm over lithium alone (P<.05, no multiple testing correction), including monotherapies with MSAs valproate (HR 0.71, 95% CI 0.61-0.84; P=4.57×10-5) and lamotrigine (HR 0.74, 95% CI 0.65-0.85; P=1.13×10-5), SGAs risperidone (HR 0.68, 95% CI 0.56-0.83; P=1.82×10-4) and aripiprazole (HR 0.70, 95% CI 0.59-0.84; P=9.40×10-5), and antidepressant classes SNRI (HR 0.65, 95% CI 0.51-0.83; P=5.51×10-4), SSRI (HR 0.61, 95% CI 0.53-0.71; P=6.05×10-11), and NDRI (bupropion) (HR 0.50, 95% CI 0.39-0.65; P=1.18×10-7), as well as the combination of NDRI with SSRI (HR 0.28, 95% CI 0.13-0.60; P=1.0×10-3) and the “no drug” regimen.
Of the 11 polypharmacy regimens with risk significantly different from that of lithium, only bupropion + SSRI had lower risk (HR 0.28, 95% CI 0.13-0.60; P=1.00×10-3). Nine of the remaining 10 high-risk polypharmacy regimens contained an antipsychotic (either SGA or FGA, or both), with the exception being lithium + MSA (HR 1.35, 95% CI 1.09-1.67; P=5.32×10-3). The “no drug” exposure intervals were associated with a significantly lower risk of subsequent self-harm versus lithium monotherapy (HR 0.56, 95% CI 0.50-0.63; P=2.79×10-22).
To correct for multiple comparisons, we used the Benjamini-Yekutieli procedure to reduce the false discovery rate. This correction yielded 15 regimens with a statistically significant different risk of self-harm versus lithium at a 5% false-discovery rate (which corresponded to a P value cutoff ≤.012). Six of them were of higher risk (tri/tetracyclic antidepressants + SGA, FGA + MSA, FGA, SNRI + SGA, lithium + MSA, and lithium + SGA) and nine were of lower risk than lithium (lamotrigine, valproate, risperidone, aripiprazole, SNRI, SSRI, “no drug,” bupropion, and bupropion + SSRI).
Our sensitivity analysis revealed that overall most of the “high-risk” drug regimens maintained their HR values above 1 across a wide range of self-harm probability thresholds (40%-70%) (Figure 2). Only one regimen (tri/tetracyclic antidepressants + SGA) demonstrated significantly higher risk of self-harm versus lithium, across all 10 tested probability thresholds.
Table 1 Cox regression model comparing 64 pharmacotherapies and “no drug” to lithium for the risk of subsequent coded and/or imputed self-harm in patients with bipolar disorder of all ages.
Covariatesa HRb,c Lower 95% Upper 95% P value Patients
(N=529,359) Intervals (N=1,749,468) Events (N=8813)
Tri/tetracyclic antidepressants + SGAd,e 2.33 1.28 4.26 5.73×10-3 180 1044 11
SSRIf + FGAg,e 2.26 1.16 4.38 1.61×10-2 195 1014 9
FGA + MSAh,e 1.82 1.15 2.89 1.12×10-2 481 2448 19
SSRI + lithium + MSA + SGAe 1.72 1.00 2.97 4.96×10-2 192 1424 14
FGA monoclass therapye 1.69 1.19 2.39 3.20×10-3 1069 5853 35
SNRIi + SGAe 1.59 1.18 2.14 2.27×10-3 1466 6803 50
SNRI + MSA + SGAe 1.56 1.06 2.29 2.25×10-2 805 4200 29
Asenapine 1.50 0.77 2.90 2.31×10-1 160 1494 9
Lithium + MSA + SGAe 1.42 1.07 1.90 1.52×10-2 1143 7748 57
Lurasidone 1.42 0.97 2.07 7.25×10-2 459 3919 29
NDRIj + SSRI + MSA + SGA 1.40 0.66 2.96 3.84×10-1 170 1251 7
SSRI + lithium + SGA 1.39 0.94 2.05 9.85×10-2 725 3898 28
NDRI + lithium + MSA 1.38 0.65 2.93 3.95×10-1 193 1438 7
Aripiprazole + MSA + SGA 1.38 0.86 2.22 1.87×10-1 411 2641 18
Lithium + MSAe 1.35 1.09 1.67 5.32×10-3 2763 18,728 116
Lithium + SGAe 1.34 1.11 1.62 2.86×10-3 3757 18,980 155
Polypharmacy 4k 1.33 0.97 1.82 7.60×10-2 1274 8867 47
SSRI + MSA + SGAe 1.31 1.05 1.62 1.52×10-2 3153 16,322 118
NDRI + MSA + SGA 1.25 0.86 1.81 2.47×10-1 836 5558 30
Aripiprazole + SGA 1.22 0.79 1.88 3.72×10-1 715 3987 22
NASSAl + SGA 1.20 0.62 2.33 5.86×10-1 321 1457 9
NDRI + lithium 1.16 0.74 1.80 5.18×10-1 728 4559 21
Tri/tetracyclic antidepressants 1.15 0.71 1.88 5.66×10-1 693 4130 17
SSRI + lithium + MSA 1.10 0.66 1.82 7.10×10-1 499 3,514 16
Uncommon monotherapy 1.09 0.49 2.45 8.29×10-1 169 1205 6
NDRI + SSRI + MSA 1.08 0.68 1.72 7.44×10-1 720 4754 19
SSRI + lithium 1.06 0.81 1.39 6.61×10-1 2457 13,235 64
MSA + SGA 1.05 0.91 1.21 5.15×10-1 13,348 67,185 421
Lithium (reference) 1.00 N/Am N/A N/A 13,759 66,760 351
Polypharmacy 3n 1.00 0.79 1.25 9.66×10-1 3794 23,234 95
NDRI + aripiprazole + MSA 0.99 0.51 1.91 9.67×10-1 254 2316 9
Lithium + aripiprazole + MSA 0.97 0.50 1.89 9.30×10-1 227 1797 9
SNRI + lithium 0.97 0.54 1.72 9.06×10-1 529 2814 12
SSRI + SGA 0.96 0.80 1.15 6.36×10-1 7896 33,503 188
SSRI + MSA 0.95 0.81 1.11 5.32×10-1 12,315 58,789 286
Quetiapine 0.95 0.82 1.10 5.03×10-1 13,795 60,422 342
Aripiprazole + MSA 0.94 0.76 1.17 5.90×10-1 3401 21,368 108
Ziprasidone 0.94 0.71 1.24 6.63×10-1 2381 11,773 58
Multi-SGA 0.93 0.56 1.57 7.94×10-1 677 3479 15
Lithium + aripiprazole 0.92 0.60 1.42 7.19×10-1 665 4268 22
SNRI + MSA 0.90 0.68 1.20 4.80×10-1 2939 13,995 58
FGA + lithium 0.89 0.40 1.99 7.73×10-1 315 1472 6
NDRI + SGA 0.89 0.62 1.27 5.07×10-1 1408 8336 33
Multi-MSA 0.87 0.61 1.24 4.49×10-1 1451 8792 34
SSRI + aripiprazole 0.85 0.64 1.14 2.83×10-1 2285 11,695 52
Olanzapine 0.84 0.66 1.07 1.57×10-1 4040 16,759 83
NASSA + MSA 0.82 0.42 1.60 5.65×10-1 438 2313 9
NDRI + MSA 0.82 0.64 1.05 1.20×10-1 3460 21,294 74
Oxcarbazepine 0.81 0.65 1.02 6.91×10-2 4436 20,633 97
Carbamazepine 0.74 0.54 1.02 6.45×10-2 2284 10,662 42
Lamotriginee 0.74 0.65 0.85 1.13×10-5 28,624 131,786 549
NDRI + aripiprazole 0.73 0.41 1.30 2.91×10-1 564 4038 12
Valproatee 0.71 0.61 0.84 4.57×10-5 14,718 61,544 253
SSRI + aripiprazole + MSA 0.70 0.43 1.15 1.56×10-1 784 5148 17
Aripiprazolee 0.70 0.59 0.84 9.40×10-5 8872 47,373 186
Polypharmacy 2o 0.68 0.46 1.01 5.32×10-2 2017 11,269 28
Risperidonee 0.68 0.56 0.83 1.82×10-4 7084 28,302 138
SNRIe 0.65 0.51 0.83 5.51×10-4 6120 27,921 78
NASSA 0.65 0.38 1.08 9.77×10-2 950 4964 15
Paliperidone 0.61 0.29 1.30 2.03×10-1 292 1858 7
SSRIe 0.61 0.53 0.71 6.05×10-11 30,138 131,895 381
NDRI + SSRI + SGA 0.60 0.25 1.45 2.57×10-1 345 2079 5
“No drug”e 0.56 0.50 0.63 2.79×10-22 299,295 621,467 3694
NDRI (bupropion)e 0.50 0.39 0.65 1.18×10-7 6005 35,433 72
SNRI + aripiprazole 0.45 0.19 1.09 7.85×10-2 457 2765 5
NDRI (bupropion) +SSRIe 0.28 0.13 0.60 1.00×10-3 1263 7496 7
Prior self-harme 3.32 2.68 4.11 3.17×10-28 704 1652 70
Alcohol/substance abuse or dependencee 1.92 1.81 2.03 7.17×10-106 57,392 149,679 1065
Deliriume 1.69 1.36 2.10 1.92×10-6 1694 4086 60
Prior hospitalizatione 1.63 1.54 1.72 1.78×10-64 131,613 342,122 1905
Mental procedure before index exposuree 1.50 1.42 1.58 3.43×10-50 81,943 247,474 841
Liver diseasee 1.49 1.29 1.71 4.27×10-8 9063 23,559 121
Unknown polarity of index mood episodee 1.33 1.24 1.43 1.67×10-15 307,243 1,000,348 2447
Conduct disordere 1.26 1.14 1.39 3.65×10-6 13,728 39,657 255
Seizure disordere 1.18 1.11 1.25 2.07×10-7 90,276 307,887 667
External injurye 1.12 1.06 1.19 2.31×10-5 117,722 338,635 1350
Pulmonary disorder 1.12 0.99 1.26 7.60×10-2 18,960 48,974 160
Depression during the index meta-visite 1.10 1.02 1.18 1.52×10-2 72,386 245,707 487
Male sexe 1.07 1.03 1.12 1.46×10-3 227,507 733,963 1966
Exposure to sedative or antianxiety druge 1.06 1.00 1.12 4.24×10-2 130,186 431,040 929
Number of prior unique BDp drugs tried (linear component of spline fit)e 1.02 1.01 1.04 4.17×10-3 N/A N/A N/A
Psychotic features present during the index meta-visit 1.01 0.92 1.11 7.73×10-1 23,846 78,579 345
Age (linear component of spline fit)e 0.98 0.97 0.98 6.99×10-201 N/A N/A N/A
Exposure to central nervous system stimulant 0.95 0.88 1.01 9.62×10-2 55,140 195,116 396
BD type II during the index meta-visite 0.93 0.87 0.99 2.49×10-2 90,741 331,720 497
Manic episode during the index meta-visite 0.92 0.85 0.99 3.40×10-2 82,955 250,285 512
Exposure to glucocorticoidse 0.83 0.77 0.89 1.04×10-7 80,626 246,182 472
Exposure to antibacterial agentse 0.80 0.76 0.84 3.77×10-17 144,933 453,129 951
Exposure to sex hormonese 0.79 0.74 0.85 3.08×10-10 67,550 217,335 372
Neoplasme 0.77 0.70 0.85 1.70×10-7 42,628 130,488 220
Psychotic features unknown during the index meta-visite 0.67 0.63 0.72 2.85×10-30 401,789 1,295,408 2709
Psychotherapy (psychosocial interventions)e 0.59 0.57 0.62 1.12×10-114 249,328 704,937 1369
Outpatient visit present during the index meta-visite 0.56 0.50 0.63 4.69×10-23 522,232 1,732,715 3475
Age (nonlinear components of the spline model)e N/A N/A N/A 4.58×10-32 N/A N/A N/A
Number of prior unique BD drugs tried (nonlinear components of spline fit)e N/A N/A N/A 1.21×10-9 N/A N/A N/A
aCovariates labeled “prior” are related to the 1-year period before the index exposure.
bCovariates are sorted by their hazard ratio value.
cHR: hazard ratio.
dSGA: second-generation antipsychotic.
eCovariates with significant P values (<.05; no multiple testing correction).
fSSRI: selective serotonin reuptake inhibitor.
gFGA: first-generation antipsychotic.
hMSA: mood stabilizing anticonvulsant.
iSNRI: serotonin-norepinephrine reuptake inhibitor.
jNDRI: norepinephrine-dopamine reuptake inhibitor (represented by bupropion only).
kPolypharmacy 4: uncommon combination of four or more bipolar disorder drug classes.
lNASSA: noradrenergic and specific serotonergic antidepressant (represented by mirtazapine only).
mN/A: not applicable.
nPolypharmacy 3: uncommon combination of three bipolar disorder drug classes.
oPolypharmacy 2: uncommon combination of two bipolar disorder drug classes.
pBD: bipolar disorder.
Figure 2 Sensitivity analysis for the “low-risk” and “high-risk” covariates in the first regression model comparing individual exposure regimens for the risk of self-harm. The X-axis shows 13 covariates and the respective 20%-100% self-harm thresholds chosen to impute the outcome. The Y-axis shows the respective hazard ratios (colored dots) and 95% CIs (colored lines). Varied intensity magenta is used to represent the range of 20%-40% self-harm probability thresholds, black is used to represent the 50% threshold of the main model, and varied intensity green is used to represent the 60%-100% probability threshold used. Missing estimates are due to lack of sufficient outcomes for a regimen to be included (observed in the higher probability threshold models). MSA: mood-stabilizing anticonvulsant; NDRI: norepinephrine-dopamine reuptake inhibitor; nodrug: period free from any of the studied bipolar disorder drugs; SGA: second-generation antipsychotic; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.
For most of the “low-risk” drugs, the HR values were below 1 at any self-harm probability threshold, except for 90%-100% (very likely to be self-harm or actually coded). Bupropion alone or in combination with SSRI had a significant association with lower self-harm risk across all tested thresholds. As expected, the higher the probability of self-harm, the larger were the respective HR CIs owing to fewer events observed. The results of the sensitivity analysis for all exposure covariates in this model, as well as the nondrug covariates, can be found in Multimedia Appendix 4, Multimedia Appendix 5, Multimedia Appendix 6, and Multimedia Appendix 7.
When assessing the largest sources of bias, four variables were highly significantly associated with shifting the estimates of all the treatment coefficients, based on the regression of Y’ versus X, including the number of prior unique BD drugs tried, psychotherapy, alcohol/substance abuse or dependence, and outpatient visit present during the index meta-visit. These four were among the covariates with the top five most significant (P<.05/66) associations over the 66 Yi versus X regressions performed on individual treatment estimates in our variable selection procedure. A total of 29 pretreatment covariates were incorporated in the model to adjust for potential bias in treatment risk estimates.
In the main Cox model, documentation of prior coded self-harm had the highest HR value among all nondrug covariates (HR 3.32, 95% CI 2.68-4.11; P=3.17×10-28). A set of mental conditions, including delirium, substance/alcohol abuse and dependence, conduct disorder, and procedures related to mental health services were associated with a significantly higher risk of self-harm (HR 1.26-1.92, P<.05). Previous hospitalizations, liver disease, and seizures were also associated with elevated self-harm risk when present (HR 1.18-1.63, P<.05). Exposure to antianxiety and sedative drugs showed a modest risk of self-harm (HR 1.06, 95% CI 1.00-1.12; P=4.24×10-2). Additionally, index visit depression was modestly associated with self-harm risk (HR 1.10, 95% CI 1.02-1.18; P=1.52×10-2).
Multiple factors had significantly lower self-harm risk, including index manic mood episodes, BD type II, use of antibacterial agents and glucocorticoids, exposure to sex hormones, and neoplasm diagnosis (HR 0.77-0.93; P<.05). Psychotherapy during the exposure period was strongly associated with a lower risk of self-harm (HR 0.59, 95% CI 0.57-0.62; P=1.12×10-114). The lowest HR value for self-harm was associated with an outpatient visit being present during the index meta-visit (HR 0.56, 95% CI 0.50-0.63; P=4.69×10-23) (Table 1).
When self-harm risk was plotted as a function of the number of different unique drugs of interest tried in the past, we observed that HR values slightly decreased after intervals with one and two drugs used, but then started to rise with the number of agents used (Figure 3).
Figure 4 shows the risk of self-harm as a function of patient age. It demonstrates that HR values were much higher in adolescence, dropped after the 20s, and leveled off with older age.
Figure 3 The hazard ratio of coded and/or imputed self-harm as a function of the number of different unique drugs of interest used by the patient in the year prior to the index visit plus up to the prior treatment interval. The graph represents a smoothing spline, with the reference being zero prior drugs. The blue dotted lines represent 95% CIs.
Figure 4 The hazard ratio of coded and/or imputed self-harm as a function of patient age. The graph represents a smoothing spline, with the reference being age 50 years. The blue dotted lines represent 95% CIs.
In the second Cox regression model with all BD drugs grouped under the “pharmacotherapy” category, the risk of self-harm was the lowest following “psychotherapy alone” intervals, compared with “no treatment” (HR 0.56, 95% CI 0.52-0.60; P=8.76×10-58) (Table 2). The combination “psychotherapy + pharmacotherapy” had a somewhat lower risk of self-harm (HR 0.88, 95% CI 0.83-0.95; P=3.80×10-4), but pharmacotherapy alone was associated with a significantly higher risk compared with “no treatment” (HR 1.38, 95% CI 1.30-1.48; P=1.09×10-22).
Table 2 Cox regression model comparing “pharmacotherapy” (as a single category) and “psychotherapy” (psychosocial interventions) to “no treatment” (no drugs and no psychotherapy) for the risk of subsequent coded and/or imputed self-harm in patients with bipolar disorder of all ages.
Covariatesa HRb,c Lower 95% Upper 95% P value Patients (N=529,359) Intervals (N=1,749,468) Events (N=8813)
Pharmacotherapy alone (any drug regimen)d 1.38 1.30 1.48 1.09×10-22 122,898 651,191 2819
Any drug and psychotherapyd 0.88 0.83 0.95 3.80×10-4 107,166 476,810 2300
Psychotherapy aloned 0.56 0.52 0.60 8.76×10-58 142,162 228,127 1183
No treatment (reference) 1.00 N/Ae N/A N/A 157,133 393,340 2511
Prior self-harmd 3.32 2.68 4.10 3.34×10-28 704 1652 70
Alcohol/substance abuse or dependenced 1.91 1.80 2.03 2.48×10-105 57,392 149,679 1065
Deliriumd 1.68 1.35 2.08 2.74×10-6 1694 4086 60
Previous hospitalizationd 1.61 1.52 1.71 3.21×10-62 131,613 342,122 1905
Prior mental health procedured 1.49 1.41 1.57 2.90×10-49 81,943 247,474 841
Liver diseased 1.48 1.29 1.71 4.30×10-8 9063 23,559 121
Unknown polarity of index mood episoded 1.35 1.25 1.45 2.33×10-16 307,243 1,000,348 2447
Conduct disorderd 1.25 1.13 1.38 9.03×10-6 13,728 39,657 255
Seizure disorderd 1.17 1.10 1.25 4.56×10-7 90,276 307,887 667
Pulmonary disorder 1.12 0.99 1.26 6.69×10-2 18,960 48,974 160
External injury 1.12 1.06 1.18 4.79×10-5 117,722 338,635 1350
Depression during the index visitd 1.09 1.01 1.17 3.15×10-2 72,386 245,707 487
Male sexd 1.08 1.04 1.13 3.96×10-4 227,507 733,963 1966
Number of prior unique BDf drugs tried (linear component of spline fit)d 1.07 1.06 1.09 2.99×10-24 N/A N/A N/A
Exposure to sedative antianxiety 1.05 0.99 1.11 1.10×10-1 130,186 431,040 929
Psychotic features present 1.03 0.93 1.13 6.01×10-1 23,846 78,579 345
Age (linear component of spline fit)d 0.98 0.98 0.98 5.17×10-194 N/A N/A N/A
Exposure to central nervous system stimulantd 0.93 0.87 0.99 2.15×10-2 55,140 195,116 396
BD type II during the index meta-visitd 0.92 0.86 0.98 6.72×10-3 90,741 331,720 497
Manic episode during the index meta-visitd 0.91 0.84 0.98 1.45×10-2 82,955 250,285 512
Exposure to glucocorticoidsd 0.82 0.77 0.88 2.18×10-8 80,626 246,182 472
Exposure to antibacterial agentsd 0.78 0.74 0.83 2.65×10-19 144,933 453,129 951
Exposure to sex hormonesd 0.78 0.73 0.84 3.77×10-11 67,550 217,335 372
Neoplasmd 0.76 0.69 0.84 4.76×10-8 42,628 130,488 220
Psychotic features unknown during the index meta-visitd 0.66 0.62 0.71 8.75×10-33 401,789 1,295,408 2709
Outpatient visit present during the index meta-visitd 0.56 0.50 0.62 3.19×10-24 522,232 1,732,715 3475
Age (nonlinear components of spline model)d N/A N/A N/A 3.00×10-33 N/A N/A N/A
Number of prior unique BD drugs tried (nonlinear components of spline fit)d N/A N/A N/A 4.47×10-12 N/A N/A N/A
aCovariates labeled “prior” are related to the 1-year period before the index exposure.
bCovariates are sorted by their hazard ratio value.
cHR: hazard ratio.
dCovariates with significant P values (<.05).
eN/A: not applicable.
fBD: bipolar disorder.
The sensitivity analysis showed that most of the “high-risk” variables maintained their HR values above 1 at a wide range of self-harm probability thresholds, except for very high thresholds (>80%-90%). Prior self-harm and pharmacotherapy alone (without psychosocial interventions) had significantly high HR values across all tested self-harm probability thresholds. The “low-risk” variables mostly maintained their HR values below 1 with different self-harm probability thresholds (except for 80%-100%). Five variables had significantly lower risk of self-harm across all tested thresholds compared with no treatment at all. They were psychotherapy alone, prior self-harm, outpatient visit present during the index meta-visit, exposure to sex hormones, and use of antibacterial agents. As in the first model, the higher was the probability of self-harm, the wider were the CIs owing to fewer events (Figure 5).
Figure 5 Sensitivity analysis for the “low-risk” and “high-risk” covariates in the second regression model comparing pharmacotherapy (as a single exposure category) and psychotherapy for the risk of self-harm. The X-axis shows 27 covariates and the respective 20%-100% self-harm probability thresholds chosen to impute the outcome. The Y-axis shows the respective hazard ratios (HRs) (colored dots) and CIs (colored lines). Varied intensity magenta is used to represent the range of 20%-40% self-harm probability thresholds, black is used to represent the 50% threshold of the main model, and varied intensity green is used to represent the 60%-100% probability threshold used. The covariate “prior coded self-harm” is separated out with a different HR scale in the far right, since the HR values were extremely high at the 100% (coded) probability threshold. BD: bipolar disorder; CNS: central nervous system; Drug: any of the bipolar disorder drugs of interest.
Discussion
Principal Findings
Given the use of imputed self-harm (in addition to formally coded) as the primary outcome in our study, it is worthwhile to compare the coded and imputed annual incidence of self-harm in our data with that of the literature. In a recent UK study [34], within 25,965 person-years of observation in a cohort of 6671 patients with pharmacologically treated BD, who were aged 16 years or above, the annual incidence of hospitalized self-harm was 3774 per 100,000 person-years at risk (PYAR). The coded self-harm in our BD cohort of all ages was only 83 per 100,000 PYAR. This would constitute 1:45-fold underrecording, if US rates of self-harm are comparable to UK rates. Our earlier estimate [8] that only 1 in 19 self-harm events was coded (within meta-visits having an inpatient and/or ER component) may not have been sufficiently pessimistic. In contrast to the strikingly low rates of coded self-harm in our study data, the estimates of coded + imputed self-harm used for our main model were more reassuring, with 1393 self-harm events per 100,000 PYAR. When summing the probabilities over all meta-visits, our estimate of the level of self-harm was 2839 per 100,000 PYAR, which is 75% of the UK estimate and is probably still low. Our sensitivity analysis revealed a range of 525 (formally coded only) to 20,226 (coded + imputed with >20% probability) self-harm events corresponding to a range of 83 to 3198/100,000 PYAR. It is important to note that because HRs are relative measures, they may be stably estimated across a broad range of imputation thresholds, with the advantage of more power for lower thresholds.
Our findings suggest that exposure to FGAs and some multidrug combinations were associated with 1.31 to 2.33 higher risks of self-harm compared with lithium; however, these associations were possibly observed owing to multiple-testing type I error. Drug-free intervals (“no drug”) had one of the lowest HR values in our first regression model compared with lithium (HR 0.56, 95% CI 0.50-0.63; P=2.79×10−22). According to a recent literature review, there is strong converging evidence indicating that long-term lithium treatment lowers deaths by suicide in patients with BD [4], which can be attributed to its possible serotonergic effect [35]. One explanation for the better performance of the “no drug” regimen in our study versus lithium could be indication bias, as drug-free periods can be associated with stable remission or asymptomatic states.
Self-harm risk reduction was significant with monotherapies involving the MSAs valproate and lamotrigine, the atypical antipsychotics risperidone and aripiprazole, the antidepressant bupropion, and monoclass treatment with SNRI and SSRI antidepressants. There are conflicting data in the literature on antidepressant-dependent suicidality in mood disorders, with reports on both the increased [36] and decreased risks of suicidal behavior [11,37]. In 2004, antidepressants received an FDA black box warning owing to increased suicidal thoughts and behaviors in adolescents on antidepressants versus placebo in FDA approval–seeking trials [20], and this warning was extended to include young adults in 2007 [38]. It is still not entirely clear whether a presumed increased suicidality risk in antidepressant users is due to drugs failing to prevent deterioration involving the natural illness course, due to their activating effect, or due to manic switch with subsequent mood phase inversion. In contrast, a 27-year prospective study on mood disorders showed that the risk of suicide attempts or suicides was reduced by 20% among participants taking antidepressants (HR 0.80, 95% CI 0.68-0.95; P=.011) [12]. Subsequent findings of the same authors showed that suicidality risk was reduced by 54% in individuals with BD type I and by 35% in those with BD type II while on antidepressants, compared with propensity-matched unexposed intervals [13]. While our study generated evidence on a more broadly defined set of “self-harm” acts, our data support the findings of the relative safety of SSRI and SNRI antidepressants compared with lithium and even with “no drug” in relation to suicidality in BD.
SGAs were previously shown to be associated with a reduced risk of suicide in patients with schizophrenia [14], although two recent international observational studies demonstrated the inferiority of quetiapine and olanzapine compared with lithium for self-harm prevention [34], and even an increased risk of completed suicide among BD patients taking antipsychotics [39]. Our data showed that the SGA risperidone is associated with a significantly lower self-harm risk in patients with BD. There is evidence suggesting that the beneficial effect of antipsychotics in BD may be explained by reduced impulsivity and risk taking [40].
Similar to studies on antidepressants, there are conflicting data on the MSA-dependent risk of self-harm in BD. While some studies reported an equally beneficial effect of MSAs (divalproex and carbamazepine) to lithium for BD suicidality prevention [10], others reported a significantly safer profile for lithium [41]. The majority of MSAs received an FDA warning of increased suicidal thoughts and behaviors in 2008 [42], based on a meta-analysis of 11 drugs [21]. Several studies failed to find any significant changes in suicidality risk according to antiepileptic drug intake [18,37]. However, a large pharmacoepidemiologic study found significantly lower rates of suicide attempts following MSA use, compared with the period before treatment, and showed that MSA monotherapy was significantly protective relative to no pharmacologic treatment (3 per 1000 vs 15 per 1000 person-years) [43]. Our findings support the evidence of a beneficial role of MSAs in self-harm prevention in BD management. Unlike the other data [34], our data showed that valproate is superior to lithium in terms of the association with reduced self-harm risk.
Given that 10 of the 11 “high-risk” exposures in our study were polypharmacy regimens, we made efforts to address the possible indication bias of multidrug regimens being given to patients who are treatment-resistant, by modeling the risk of self-harm as a function of the number of unique BD drugs filled in the year prior to the index visit plus those drugs tried from the index visit up to the current treatment interval. We fit this within the Cox regression model using a smoothing spline with no prior drugs set as the reference (Figure 3). The risk of self-harm was significantly lower in individuals treated with one to five different BD drugs in the year prior to the index visit, compared with individuals who had no prior drugs in the observed period of time. One explanation for this finding is that several “trial and error” attempts eventually result in better control over illness symptoms. However, self-harm risk was significantly higher in patients who received eight or more unique BD drugs, compared with drug-naive subjects, evidencing drug-resistant cases. At the same time, the rapidly expanding range of 95% CI corresponding to 8 to 20 drugs indicates limited sample sizes in this range. Overall, given that our self-harm risk estimates for the drugs account for prior treatment complexity and that the magnitude of this factor’s impact on risk was modest, it seems unlikely that a presumed polypharmacy-dependent increase in self-harm risk in patients with BD is fully explained by drug resistance or disease severity. However, we may not have fully corrected for indication biases. In particular, we did not model drug exposures prior to the year before the index visit.
Our sensitivity analysis showed that the direction of drug-outcome associations did not change as a function of the threshold of self-harm probability, while HR CIs were much more narrow when the outcome was imputed rather than coded. This provides evidence that using ML-imputed outcomes is a promising approach to increase power to perform comparative effectiveness studies, particularly when a phenotype is sparsely coded.
The presence of an outpatient encounter during the index meta-visit (with or without an adjacent hospitalization/ER visit) was associated with the lowest risk of self-harm. This can be explained by more accessible or comprehensive health care services provided, as evidenced by a patient visiting his/her outpatient provider during a crisis.
As was expected, our data suggested that psychosocial interventions may decrease the risk of self-harm in patients with BD. A recent meta-analysis showed that patients who received psychotherapy were less likely to subsequently attempt suicide [22]. However, a surprising finding from our second Cox regression model was that the HR of self-harm was lower following time intervals with psychotherapy alone, rather than when psychotherapy was combined with pharmacotherapy. This could be explained by indication bias, since drug-free patients could be asymptomatic or in stable remission. Another explanation is that pharmacotherapy was a very heterogeneous category combining “low-risk” and “high-risk” regimens together. There was insufficient power to perform a per-drug analysis of adjunctive psychotherapy.
The study limitations include nonrandomized assignment of patients to treatment groups; no patient data availability prior to the insurance enrollment date, as well as prior to 2003; unmeasured indication or other biases (eg, personality traits, coping strategies, environmental stressors, and support systems); and no correction for medication dosage, route of administration, or release mechanism.
Conclusions
The risk of self-harm varied more than eight-fold among different BD drug regimens. Exposure to antidepressant or MSA monotherapy was associated with a significantly lower risk of subsequent self-harm compared with lithium. Psychotherapy was strongly associated with a decreased risk of self-harm in patients with BD. ML imputation of self-harm can enhance the power for comparative effectiveness studies of BD treatments. The risk of self-harm was the highest during adolescence. Our data support the evidence that prior self-harm is one of the strongest predictors of future self-harm.
This work was supported by the Patient-Centered Outcomes Research Institute (PCORI) (award CER-1507-3160) and was part of the research project “Longitudinal comparative effectiveness of bipolar disorder therapies” (ClinicalTrials.gov identifier: NCT02893371). The study protocol was approved by the University of New Mexico Human Research Review Committee (Institutional Review Board number 16-243). PCORI funding was used for database access and salaries for all members of the research team who, in turn, contributed to study design, data collection, analysis and interpretation, writing of the article, and the decision to submit the article for publication. The views in this publication are solely the responsibility of the authors and do not necessarily represent the views of PCORI, its Board of Governors, or the Methodology Committee. We dedicate this article to our dear friend and coauthor, Dr Nathaniel G Hurwitz, who passed away during its preparation. He worked on this project as a labor of love, both for us and for all those affected by bipolar disorder.
Appendix
Multimedia Appendix 1 List of self-harm billing codes.
Multimedia Appendix 2 Drugs of interest analyzed either individually or as part of a composite class.
Multimedia Appendix 3 Sample size based on data staging. BD: bipolar disorder; ER: emergency room; MMI: major mental illness.
Multimedia Appendix 4 Sensitivity analysis for the first third of drug covariates (sorted by their hazard ratio from low to high) in the regression model comparing individual exposure regimens for the risk of self-harm. The X-axis shows drug covariates and the respective 20%-100% self-harm thresholds chosen to impute the outcome. The Y-axis shows the respective hazard ratios (colored dots) and CIs (colored lines). Varied intensity magenta is used to represent the range of 20%-40% self-harm probability thresholds, black is used to represent the 50% threshold of the main model, and varied intensity green is used to represent the 60%-100% probability threshold used. MSA: mood-stabilizing anticonvulsant; NDRI: norepinephrine-dopamine reuptake inhibitor; SGA: second-generation antipsychotic; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.
Multimedia Appendix 5 Sensitivity analysis for the second third of drug covariates (sorted by their hazard ratio from low to high) in the regression model comparing individual exposure regimens for the risk of self-harm. The X-axis shows drug covariates and the respective 20%-100% self-harm thresholds chosen to impute the outcome. The Y-axis shows the respective hazard ratios (colored dots) and CIs (colored lines). Varied intensity magenta is used to represent the range of 20%-40% self-harm probability thresholds, black is used to represent the 50% threshold of the main model, and varied intensity green is used to represent the 60%-100% probability threshold used. MSA: mood-stabilizing anticonvulsant; NDRI: norepinephrine-dopamine reuptake inhibitor; SGA: second-generation antipsychotic; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.
Multimedia Appendix 6 Sensitivity analysis for the last third of drug covariates (sorted by their hazard ratio from low to high) in the regression model comparing individual exposure regimens for the risk of self-harm. The X-axis shows drug covariates and the respective 20%-100% self-harm thresholds chosen to impute the outcome. The Y-axis shows the respective hazard ratios (colored dots) and CIs (colored lines). Varied intensity magenta is used to represent the range of 20%-40% self-harm probability thresholds, black is used to represent the 50% threshold of the main model, and varied intensity green is used to represent the 60%-100% probability threshold used. MSA: mood-stabilizing anticonvulsant; NDRI: norepinephrine-dopamine reuptake inhibitor; SGA: second-generation antipsychotic; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.
Multimedia Appendix 7 Sensitivity analysis for the nondrug covariates in the regression model comparing individual exposure regimens for the risk of self-harm. The X-axis shows nondrug covariates and the respective 20%-100% self-harm thresholds chosen to impute the outcome. The Y-axis shows the respective hazard ratios (HRs) (colored dots) and CIs (colored lines). Varied intensity magenta is used to represent the range of 20%-40% self-harm probability thresholds, black is used to represent the 50% threshold of the main model, and varied intensity green is used to represent the 60%-100% probability threshold used. The covariate “prior coded self-harm” is separated out with a different HR scale in the far right, since the HR values were extremely high at 100% (coded) probability threshold. MSA: mood-stabilizing anticonvulsant; NDRI: norepinephrine-dopamine reuptake inhibitor; SGA: second-generation antipsychotic; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.
Abbreviations
AUC area under curve
BD bipolar disorder
CCAE commercial claims and encounters
ER emergency room
FDA US Food and Drug Administration
FGA first-generation antipsychotic
HR hazard ratio
ICD International Classification of Diseases
MCC Matthews correlation coefficient
ML machine learning
MMI major mental illness
MSA mood-stabilizing anticonvulsant
NASSA noradrenergic and specific serotonergic antidepressant
NDRI norepinephrine-dopamine reuptake inhibitor
PYAR person-years at risk
SGA second-generation antipsychotic
SNRI serotonin-norepinephrine reuptake inhibitor
SSRI selective serotonin reuptake inhibitor
TGA third-generation antipsychotic
Authors' Contributions: AN: study design, data analysis and interpretation, and manuscript writing; PK: study design, data analysis, and manuscript editing; NRL: study design and data analysis; NGH: study design and data interpretation; AJM: data extraction and analysis; DCC: data extraction and analysis; YZ: data analysis and interpretation, and manuscript editing; SJN: study design, data interpretation, and manuscript editing; ASC: study design and manuscript editing; BK: study design, data analysis and interpretation, and manuscript editing; MT: study design, data interpretation, and manuscript editing; DJP: study design, data interpretation, and manuscript editing; CGL: study coordination, study design, data analysis and interpretation, and manuscript writing and editing.
Conflicts of Interest: MT was a full-time employee at Lilly (1997 to 2008). He has received honoraria from or consulted for Abbott, Actavis, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Johnson & Johnson, Otsuka, Merck, Sunovion, Forest, Gedeon Richter, Roche, Elan, Alkermes, Allergan, Lundbeck, Teva, Pamlab, Wyeth, and Wiley Publishing. His spouse was a full-time employee at Lilly (1998-2013). AN, AJM, NGH, BK, YZ, SJN, ASC, DJP, CGL, DCC, PK, and NRL report no relevant financial relationships with commercial interests. | ARIPIPRAZOLE | DrugsGivenReaction | CC BY | 33688834 | 19,918,177 | 2021-04-21 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Adverse drug reaction'. | Influences on pathologic complete response in breast cancer patients after neoadjuvant chemotherapy.
Pathologic complete response is associated with longer disease-free survival and better overall survival after neoadjuvant chemotherapy in breast cancer patients. We, therefore, evaluated factors influencing pathologic complete response.
Patients receiving neoadjuvant chemotherapy from 2015 to 2018 at the Saarland University Hospital were included. Patients' age, tumor stage, tumor biology, genetic mutation, recurrent cancer, discontinuation of chemotherapy, and participation in clinical trials were extracted from electronic medical records. Binary logistic regression was performed to evaluate the influence of these factors on pathologic complete response.
Data of 183 patients were included. The median patient's age was 54 years (22-78). The median interval between diagnosis and onset of chemotherapy was 28 days (14-91); between end of chemotherapy and surgery 28 days (9-57). Sixty-two patients (34%) participated in clinical trials for chemotherapy. A total of 86 patients (47%) achieved pathologic complete response. Patient's age, genetic mutation, recurrent cancers, or discontinuation of chemotherapy (due to side effects) and time intervals (between diagnosis and onset of chemotherapy, as well as between end of chemotherapy and surgery) did not influence pathologic complete response. Patients with high Ki67, high grading, Her2 positive tumors, as well as patients participating in clinical trials for chemotherapy had a higher chance of having pathologic complete response. Patients with Luminal B tumors had a lower chance for pathologic complete response.
Particularly patients with high risk cancer and patients, participating in clinical trials benefit most from chemotherapy. Therefore, breast cancer patients can be encouraged to participate in clinical trials for chemotherapy.
pmcIntroduction
Neoadjuvant chemotherapy (NACT) has changed its role for only inoperable and locally advanced breast cancer to a treatment used in early stages of breast cancer [1]. Particularly patients at high risk, like patients with Her2 positive and triple-negative breast cancer benefit from receiving NACT [2, 3]. Pathological complete response (pCR) is associated with a better outcome, meaning that patients having pCR have longer disease-free survival and better overall survival [5].
The definition of pCR varies in individual studies (ypT0/ypTis/ypN0). However, it could be shown that no residual invasive cancer in the breast and axilla is associated with better outcomes compared with no residual cancer in the breast alone [4]. Von Minckwitz et al. even detected a longer disease-free survival in patients with no invasive and no in situ carcinoma in the breast and axilla [5]. Also, tumor subtypes influence the achievement of pCR and thus a better outcome. For example, LeVasseur et al. detected that patients with triple negative tumors had longer relapse-free-survival and breast cancer-specific survival when achieving pCR after NACT [6].
As pCR plays an important role in the outcome of breast cancer, several studies already evaluated possible influencing factors, like age of the patients [7, 8], tumor biology [9] or genetic mutation [10]. The majority of the cited studies analyzed data that was previously collected as part of NACT trials. But patients who are included in clinical studies are mostly a selected collective due to in- and exclusion criteria with fewer previous illnesses, or of a certain subtype or tumor size. For this reason, we wanted to analyze possible influencing factors on pCR in “real-world-data”.
Although, some factors such as age, tumor biology or genetic mutation cannot be influenced directly, it is still important to identify possible risk factors to maybe establish further follow-up therapies or intensified aftercare. We, therefore, determined various clinical factors from electronic patient records and evaluated their influence on the probability of pCR. Parts of the registry were used for two other analyzes before [11, 12]. We could show that especially inpatient and outpatient presentations of the patients delayed therapy onset of NACT and surgery [11, 12].
Patients and methods
Data collection
All patients receiving NACT due to newly diagnosed breast cancer between 2015 to 2018 at the Department of Gynecology, Saarland University Medical Center, were included in the study. The primary endpoint was pCR after NACT. pCR was defined as no residual tumor in the breast and axilla (ypT0, N0). It includes no residual Tis (Carcinoma in situ). Date of diagnosis was defined as the date of core biopsy. Patients’ age, tumor stage, eventual multi-centricity, and tumor biology were recorded. It was distinguished whether the patients received NACT as standard therapy or in a clinical trial. Mainly GAIN II [13], Gepar Octo [14], and Gepar X [15] were addressed from 2015 to 2018 in the Saarland University Medical Center as clinical trials. The time interval between diagnosis and onset of chemotherapy, as well as between end of chemotherapy and surgery, was recorded. The type of operation and duration of hospitalization were documented. Patients who had an indication for BRCA testing according to the guidelines of the German AGO Mamma and the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) were tested for a BRCA mutation. Their recommendations are based on an analysis of 21,401 families [16]. It was registered whether patients had a genetic mutation (BRCA) or recurrent cancer. Recurrent cancer was defined as local recurrence of breast cancer. Patients with local recurrence were included in the study regardless of their previous therapy. If patients discontinued chemotherapy due to therapy complications or disease progress, it was recorded as well.
Data management and statistics
Patients’ data were reviewed in the hospital’s digital documentation system (SAP, Walldorf, Germany). Data were collected using Microsoft Excel 2010® (Microsoft, Redmond, USA). Further statistics were performed with SPSS 24.0 (IBM, Armonk, USA). Quantitative parameters (e.g., patients age, days) are given as median and range. Qualitative parameters (e.g., tumor stage) are presented as frequencies. Binary logistic regression was performed to determine the influence of multiple factors on pCR. Possible influencing factors were age, study participation, tumor biology, genetic mutation (BRCA), recurrent cancer, discontinuation of chemotherapy (due to side effects), days between diagnosis and begin of chemotherapy as well as days between end of chemotherapy and operation. All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from every individual participant included in the study.
Results
Between 2015 and 2018, a total of 205 patients received NACT due to newly diagnosed breast cancer at the Saarland University Medical Center. Twenty-two patients had to be excluded because of insufficient data so that the data of 183 patients were analyzed. The patients median age was 54 years (22–78). The median time between diagnosis and begin of NACT was 28 days (14–91). Between the end of NACT and operation, median time was 28 days (9–57).
Tumor stage and biology, as well as histological subtype and grading are illustrated in Table 1. Twenty-eight patients (15%) had multicentricity. BRCA mutation (9 patients, 5%) and recurrent cancers (7 patients, 4%) were rare. Sixty-two patients (34%) received study therapies: GAIN II (12%), Gepar Octo (10%), GeparX (9%), others (5%). Patients participating in clinical studies had a higher percentage of triple negative tumors (42%) compared to patients without study treatment (26%). Her2 positive tumors are less frequent in the study group (34%), compared to standard therapy regimen (39%). Furthermore, Grading and Ki67 values are higher in patients participating in clinical trials (Grading G3 67% vs. 53%, Ki67 50% vs. 40%). All patients received an Anthracycline and Taxane-based chemotherapy. Fifty-four patients of the Her2 positive group (79%) received chemotherapy in combination with Trastuzumab and Pertuzumab, 21% received chemotherapy in combination with Trastuzumab alone. All patients with triple-negative carcinoma additionally received carboplatin. Thirty-four patients (19%) discontinued NACT. Twenty patients (11%) skipped only the last or the last two chemotherapy doses, whereas 14 patients (8%) received three or more than three doses less. The reasons for a premature discontinuation of chemotherapy were equally distributed in both groups; the major part (16%) due to side effects (polyneuropathy 7%, changes in laboratory values as increased liver values or cytopenia 6%, others 3%). Four patients (2%) discontinued NACT because of tumor progression.Table 1 Tumor characteristics
TNM-stage Absolute frequencies (n) Cumulative frequencies (%)
Staging
ypT
0 89 48.6
1 56 30.6
2 16 8.7
3 7 3.8
4 5 2.7
X 10 5.6
ypN
0 56 30.6
1 26 14.2
2 15 8.2
3 3 1.6
Pre-therapeutic
pN0 (sentinal node) 83 45.4
pN+ 100 54.6
Tumor biology Absolute frequencies (n) Cumulative frequencies (%)
Tumor biology
NST (invasive carcinoma of no special type) 173 94.5
Others 10 5.5
Histological subtype Absolute frequencies (n) Cumulative frequencies (%)
Histology
Luminal A
HR+, Her2 neg, Ki67 ≤ 15% 8 4.4
Luminal B
HR+, Her2 neg, Ki67 > 15% 50 27.3
Her2 positive, HR positive 48 26.2
Her2 positive, HR negative 20 11.0
Triple negative 57 31.1
Grading Absolute frequencies (n) Cumulative frequencies (%)
Grading
G1 2 1.1
G2 74 40.4
G3 105 57.4
X 2 1.1
HR hormone receptor
Most patients received breast-conserving therapy (63%), followed by mastectomy (22%) and oncoplastic surgery (15%). Implants or expander was used for 24 patients (13%). The median time of hospitalization during the operation was 4 days (1–22). Patients with breast-conserving therapy had a median time of hospitalization of 3 days (1–14), patients undergoing mastectomy 6 days (2–17) and patients with oncoplastic surgery 7 days (2–22).
A total of 86 patients (47%) had pCR. The patients age, genetic mutation, recurrent cancer, or discontinuation of chemotherapy (due to side effects) did not influence pCR. Likewise, time between diagnosis and onset of NACT, or time between end of NACT and surgery, had no influence on pCR. Patients participating in clinical trials for NACT, higher tumor grade, high Ki67 and Her2 positive tumors had increased chances of having pCR. Patients with Luminal B tumors had a lower chance of achieving pCR. No pCR was detected in the Luminal A group. In patients with triple negative tumors, a trend could be observed. They seem to have more often pCR, although not statistically significant. Influences on pCR are shown in Table 2.Table 2 Influences on pCR by binary logistic regression
Parameter Odds ratio
Exp (B) P 95% confidence interval
Age 1.022 0.096 0.996–1.048
Time interval
Diagnosis-NACT
0.990 0.450 0.965–1.016
Time interval
NACT-operation
0.982 0.285 0.949–1.016
Study participation 2.355 0.009 1.244–4.458
Genetic mutation 2.203 0.275 0.533–9.103
Recurrent cancers 0.410 0.294 0.077–2.171
Discontinuation of NACT 1.929 0.115 0.852–4.371
Ki67 1.031 < 0.001 1.016–1.047
Grading 4.201 < 0.001 2.206–7.999
Triple negative 1.493 0.219 0.788–2.827
Her2 positive
HR positive
2.053 0.045 1.015–4.150
Her2 positive
HR negative
4.500 0.006 1.526–13.273
Luminal B 0.297 0.001 0.144–0.616
Bold values represents statistically significant
Discussion
This study presents several influences on pCR, with increased chances in patients participating in studies for NACT, having a high Ki67, high grading or Her2 positive tumors. Tumor subtypes like Luminal A and B had decreased chances of pCR.
Age had no influence on pCR in the current study. In contrast, other studies reported that young age is positively associated with pCR [7]. A cutoff value of 40 years was proposed under which the chances of pCR may be higher [17]. However, pCR can also be achieved in elderly patients, especially for Her2 positive patients [8]. So, age alone should not be an indication for NACT.
Neither time between diagnosis and onset of NACT, nor time between the end of chemotherapy and surgery influenced pCR. Consistently, exceeding a presumed cut-off of 4 weeks for onset of NACT or surgery did not influence pCR and disease-free or overall survival independent of histopathological subgroups [18]. However, it was suspected that patients without pCR could benefit from early surgery [18]. At least time intervals up to 8 weeks between NACT and surgery seem not to influence outcomes [19]. In the present study, the median time from diagnosis to NACT and NACT to surgery was about a month with only a minor part exceeding 8 weeks, which complies with German guidelines [20]. This limits the ability to assess the influence of longer time intervals on pCR. However, our results suggest that therapy intervals seem to have a negligible influence on pCR.
More than a third of our patients participated in clinical trials. Study participants for NACT had more than twice as high a chance to achieve pCR. In addition to higher chances for pCR in patients participating in clinical trials, mastectomy rates were lower [21]. However, one must take into account that the patients who are included in clinical studies are mostly a selected collective. On the one hand, this means that there is a disproportionate part of those patients who have a higher probability to achieve pCR due to tumor biology (e.g. high grading and high Ki67). On the other hand, study patients have fewer previous illnesses due to in- and exclusion criteria which can otherwise lead to premature discontinuation of therapy, dose reduction or longer therapy breaks. In the present study, patients receiving NACT in clinical trials had higher rates of Ki67 and higher grading compared to patients receiving standard therapy. This might be the reason for higher pCR rates in the study participants. Furthermore, there was a higher percentage with triple negative tumors in the study group comparing to standard treatment. However, the rate of Her2 positive tumors (which are also associated with higher rates of pCR) was lower in patients participating in clinical trials. Nevertheless, we should encourage our patients to participate in clinical trials. Besides contributing to therapy improvements, they most likely benefit from new therapies. Possible disadvantages of trial participation, such as delaying the onset of NACT or surgery, could be excluded [11, 12].
Only 5% of our patients had a proven genetic mutation (BRCA) for which a superior response to NACT was previously described [10]. Particularly when BRCA positive patients have triple-negative tumors, better outcomes are suspected [22]. We could not prove a significant influence of genetic mutation on pCR.
Likewise, there was no influence of local recurrent cancers on pCR. To our knowledge, this is the first study analyzing a possible influence of local recurrent cancers on the pCR rate. However, no distinction was made whether patients already received prior chemotherapy. In contrast to that, there are analyses describing the association of pCR after NACT on the recurrence of locoregional cancer. An analysis of 10,075 women showed that the local recurrence rate after chemotherapy was higher in patients with non-pCR (9.5% in 67 months) [23].
Discontinuation of chemotherapy due to intolerable side effects did not influence pCR. Patients discontinuing NACT due to disease progress were not included. In general, guidelines recommend the completion of chemotherapy [20]. Our results imply that discontinuation of chemotherapy may not substantially lower chances for pCR. However, it should be considered that this might be due to the small sample size and that most patients only discontinued before the last or the last two chemotherapy doses. Nevertheless, a detrimental effect of early termination of chemotherapy cannot be excluded. Peripheral neurotoxicity was the most common reason why patients had to discontinue chemotherapy (7%). Unfortunately, therapeutic options like pharmacological treatments are limited [24]. Thus, only dose reduction or discontinuation are current options [24]. Nevertheless, premature discontinuation of NACT seems to be uncritical, especially when a good clinical response was already proven. Further studies are needed to confirm our findings.
Ki67 and high grading were associated with high pCR rates (P < 0.001). As Ki67 increases by 1, the probability of a pCR increases by 1.031. This is consistent with findings that especially highly aggressive tumors have a good response to chemotherapy [5, 25]. Triple-negative tumors tend to have better pCR rates without reaching statistical significance. Other studies already showed that triple-negative tumors (as aggressive tumors) were associated with higher pCR rates after NACT [5, 7]. Her2 positive tumors showed higher chances for pCR in our study. This has also been demonstrated in previous studies [26, 27]. It could be shown that patients with Her2 positive, hormone receptor (HR) negative tumors showed the highest rates of pCR. With this tumor biology (Her2+, HR−) the chance to achieve pCR was 4.5 times higher than in other tumor subtypes. Von Minckwitz et al. and Harbeck et al. also observed that Her2 positive tumors respond particularly well to NACT when hormone receptor status is negative [5, 28]. In the present study, even tumors with Her2 positive, hormone receptor positive tumors had a twice as high chance to achieve pCR (P = 0.045). This effect could not be shown in all previous studies [5]. One reason for this might be the change in Her2 directed therapy, as the addition of pertuzumab to trasuzumab and NACT led to a more frequent pCR rate [29, 30]. In the present study, most patients (79%) received Trastuzumab and Pertuzumab. Only a minor part (21%) received Trastuzumab alone.
The subtype Luminal B was associated with a lower chance for pCR. Available data seem contradictory. pCR seems to appear more likely in young patients with hormone receptor-positive, Her2 negative breast cancer [7]. However, large analyzes of 13,939 women showed that the lowest rate of pCR was achieved for Luminal A, followed by Luminal B subtypes, whereas pCR rates of triple-negative and Her2 positive were comparatively higher [27]. Also, patients with progesterone negativity showed higher pCR rates [9]. Taken together, high Ki67, high grading and Her2 positive tumors are notably associated with higher pCR. No pCR was detected in the Luminal A group. This seems not to be surprisingly, as Luminal A cancers are not appropriate for NACT and normally show the lowest rates of pCR [27]. In this analysis, the four patients with Luminal A cancers had locally advanced tumors and received chemotherapy therefore neoadjuvant.
This study has limitations. It is single centric, and thus clinical pathways may differ to other centers. However, data were collected from a certified tertiary breast care center, ensuring that therapies are state of the art. The sample size is small, but many other studies are based on registers obtained from clinical trials for new therapy regimes [5, 7–9, 18, 21], which implies selection bias due to specific inclusion criteria. Our data more likely represents “real-world-data”.
Conclusion
Particularly patients with aggressive tumors (high Ki67, high grading, Her2 positive tumors) had better response rates on NACT. These patients should receive chemotherapy in a neoadjuvant setting. Furthermore, patients participating in clinical trials had higher pCR rates after NACT. Besides contributing to therapy improvements, they most likely benefit from new therapies. We should thus encourage our patients to participate in clinical trials.
Author contribution
All authors contributed to the study conception and design. Material preparation and data collection were performed by Carolin Müller, Lisa Jung and Sarah Huwer. The data analysis was performed by Carolin Müller. The first draft of the manuscript was written by Carolin Müller and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Availability of data and material
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Conflict of interest
All of the authors (Carolin Müller, Gilda Schmidt, Stephanie Juhasz-Böss, Lisa Jung, Sarah Huwer, Erich-Franz Solomayer, Ingolf Juhasz-Böss) declare that they have no conflict of interest.
Ethical approval
This research study was conducted retrospectively from data obtained for clinical purposes. All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Ethics committee of the Saarland Physicians’ chamber) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from every individual participant included in the study. Trial registration number: 207/10 (Ethics committee of the Saarland Physicians’ chamber). This article does not contain any studies with animals performed by any of the authors.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CARBOPLATIN, PERTUZUMAB, TRASTUZUMAB | DrugsGivenReaction | CC BY | 33689016 | 19,047,528 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cytopenia'. | Influences on pathologic complete response in breast cancer patients after neoadjuvant chemotherapy.
Pathologic complete response is associated with longer disease-free survival and better overall survival after neoadjuvant chemotherapy in breast cancer patients. We, therefore, evaluated factors influencing pathologic complete response.
Patients receiving neoadjuvant chemotherapy from 2015 to 2018 at the Saarland University Hospital were included. Patients' age, tumor stage, tumor biology, genetic mutation, recurrent cancer, discontinuation of chemotherapy, and participation in clinical trials were extracted from electronic medical records. Binary logistic regression was performed to evaluate the influence of these factors on pathologic complete response.
Data of 183 patients were included. The median patient's age was 54 years (22-78). The median interval between diagnosis and onset of chemotherapy was 28 days (14-91); between end of chemotherapy and surgery 28 days (9-57). Sixty-two patients (34%) participated in clinical trials for chemotherapy. A total of 86 patients (47%) achieved pathologic complete response. Patient's age, genetic mutation, recurrent cancers, or discontinuation of chemotherapy (due to side effects) and time intervals (between diagnosis and onset of chemotherapy, as well as between end of chemotherapy and surgery) did not influence pathologic complete response. Patients with high Ki67, high grading, Her2 positive tumors, as well as patients participating in clinical trials for chemotherapy had a higher chance of having pathologic complete response. Patients with Luminal B tumors had a lower chance for pathologic complete response.
Particularly patients with high risk cancer and patients, participating in clinical trials benefit most from chemotherapy. Therefore, breast cancer patients can be encouraged to participate in clinical trials for chemotherapy.
pmcIntroduction
Neoadjuvant chemotherapy (NACT) has changed its role for only inoperable and locally advanced breast cancer to a treatment used in early stages of breast cancer [1]. Particularly patients at high risk, like patients with Her2 positive and triple-negative breast cancer benefit from receiving NACT [2, 3]. Pathological complete response (pCR) is associated with a better outcome, meaning that patients having pCR have longer disease-free survival and better overall survival [5].
The definition of pCR varies in individual studies (ypT0/ypTis/ypN0). However, it could be shown that no residual invasive cancer in the breast and axilla is associated with better outcomes compared with no residual cancer in the breast alone [4]. Von Minckwitz et al. even detected a longer disease-free survival in patients with no invasive and no in situ carcinoma in the breast and axilla [5]. Also, tumor subtypes influence the achievement of pCR and thus a better outcome. For example, LeVasseur et al. detected that patients with triple negative tumors had longer relapse-free-survival and breast cancer-specific survival when achieving pCR after NACT [6].
As pCR plays an important role in the outcome of breast cancer, several studies already evaluated possible influencing factors, like age of the patients [7, 8], tumor biology [9] or genetic mutation [10]. The majority of the cited studies analyzed data that was previously collected as part of NACT trials. But patients who are included in clinical studies are mostly a selected collective due to in- and exclusion criteria with fewer previous illnesses, or of a certain subtype or tumor size. For this reason, we wanted to analyze possible influencing factors on pCR in “real-world-data”.
Although, some factors such as age, tumor biology or genetic mutation cannot be influenced directly, it is still important to identify possible risk factors to maybe establish further follow-up therapies or intensified aftercare. We, therefore, determined various clinical factors from electronic patient records and evaluated their influence on the probability of pCR. Parts of the registry were used for two other analyzes before [11, 12]. We could show that especially inpatient and outpatient presentations of the patients delayed therapy onset of NACT and surgery [11, 12].
Patients and methods
Data collection
All patients receiving NACT due to newly diagnosed breast cancer between 2015 to 2018 at the Department of Gynecology, Saarland University Medical Center, were included in the study. The primary endpoint was pCR after NACT. pCR was defined as no residual tumor in the breast and axilla (ypT0, N0). It includes no residual Tis (Carcinoma in situ). Date of diagnosis was defined as the date of core biopsy. Patients’ age, tumor stage, eventual multi-centricity, and tumor biology were recorded. It was distinguished whether the patients received NACT as standard therapy or in a clinical trial. Mainly GAIN II [13], Gepar Octo [14], and Gepar X [15] were addressed from 2015 to 2018 in the Saarland University Medical Center as clinical trials. The time interval between diagnosis and onset of chemotherapy, as well as between end of chemotherapy and surgery, was recorded. The type of operation and duration of hospitalization were documented. Patients who had an indication for BRCA testing according to the guidelines of the German AGO Mamma and the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) were tested for a BRCA mutation. Their recommendations are based on an analysis of 21,401 families [16]. It was registered whether patients had a genetic mutation (BRCA) or recurrent cancer. Recurrent cancer was defined as local recurrence of breast cancer. Patients with local recurrence were included in the study regardless of their previous therapy. If patients discontinued chemotherapy due to therapy complications or disease progress, it was recorded as well.
Data management and statistics
Patients’ data were reviewed in the hospital’s digital documentation system (SAP, Walldorf, Germany). Data were collected using Microsoft Excel 2010® (Microsoft, Redmond, USA). Further statistics were performed with SPSS 24.0 (IBM, Armonk, USA). Quantitative parameters (e.g., patients age, days) are given as median and range. Qualitative parameters (e.g., tumor stage) are presented as frequencies. Binary logistic regression was performed to determine the influence of multiple factors on pCR. Possible influencing factors were age, study participation, tumor biology, genetic mutation (BRCA), recurrent cancer, discontinuation of chemotherapy (due to side effects), days between diagnosis and begin of chemotherapy as well as days between end of chemotherapy and operation. All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from every individual participant included in the study.
Results
Between 2015 and 2018, a total of 205 patients received NACT due to newly diagnosed breast cancer at the Saarland University Medical Center. Twenty-two patients had to be excluded because of insufficient data so that the data of 183 patients were analyzed. The patients median age was 54 years (22–78). The median time between diagnosis and begin of NACT was 28 days (14–91). Between the end of NACT and operation, median time was 28 days (9–57).
Tumor stage and biology, as well as histological subtype and grading are illustrated in Table 1. Twenty-eight patients (15%) had multicentricity. BRCA mutation (9 patients, 5%) and recurrent cancers (7 patients, 4%) were rare. Sixty-two patients (34%) received study therapies: GAIN II (12%), Gepar Octo (10%), GeparX (9%), others (5%). Patients participating in clinical studies had a higher percentage of triple negative tumors (42%) compared to patients without study treatment (26%). Her2 positive tumors are less frequent in the study group (34%), compared to standard therapy regimen (39%). Furthermore, Grading and Ki67 values are higher in patients participating in clinical trials (Grading G3 67% vs. 53%, Ki67 50% vs. 40%). All patients received an Anthracycline and Taxane-based chemotherapy. Fifty-four patients of the Her2 positive group (79%) received chemotherapy in combination with Trastuzumab and Pertuzumab, 21% received chemotherapy in combination with Trastuzumab alone. All patients with triple-negative carcinoma additionally received carboplatin. Thirty-four patients (19%) discontinued NACT. Twenty patients (11%) skipped only the last or the last two chemotherapy doses, whereas 14 patients (8%) received three or more than three doses less. The reasons for a premature discontinuation of chemotherapy were equally distributed in both groups; the major part (16%) due to side effects (polyneuropathy 7%, changes in laboratory values as increased liver values or cytopenia 6%, others 3%). Four patients (2%) discontinued NACT because of tumor progression.Table 1 Tumor characteristics
TNM-stage Absolute frequencies (n) Cumulative frequencies (%)
Staging
ypT
0 89 48.6
1 56 30.6
2 16 8.7
3 7 3.8
4 5 2.7
X 10 5.6
ypN
0 56 30.6
1 26 14.2
2 15 8.2
3 3 1.6
Pre-therapeutic
pN0 (sentinal node) 83 45.4
pN+ 100 54.6
Tumor biology Absolute frequencies (n) Cumulative frequencies (%)
Tumor biology
NST (invasive carcinoma of no special type) 173 94.5
Others 10 5.5
Histological subtype Absolute frequencies (n) Cumulative frequencies (%)
Histology
Luminal A
HR+, Her2 neg, Ki67 ≤ 15% 8 4.4
Luminal B
HR+, Her2 neg, Ki67 > 15% 50 27.3
Her2 positive, HR positive 48 26.2
Her2 positive, HR negative 20 11.0
Triple negative 57 31.1
Grading Absolute frequencies (n) Cumulative frequencies (%)
Grading
G1 2 1.1
G2 74 40.4
G3 105 57.4
X 2 1.1
HR hormone receptor
Most patients received breast-conserving therapy (63%), followed by mastectomy (22%) and oncoplastic surgery (15%). Implants or expander was used for 24 patients (13%). The median time of hospitalization during the operation was 4 days (1–22). Patients with breast-conserving therapy had a median time of hospitalization of 3 days (1–14), patients undergoing mastectomy 6 days (2–17) and patients with oncoplastic surgery 7 days (2–22).
A total of 86 patients (47%) had pCR. The patients age, genetic mutation, recurrent cancer, or discontinuation of chemotherapy (due to side effects) did not influence pCR. Likewise, time between diagnosis and onset of NACT, or time between end of NACT and surgery, had no influence on pCR. Patients participating in clinical trials for NACT, higher tumor grade, high Ki67 and Her2 positive tumors had increased chances of having pCR. Patients with Luminal B tumors had a lower chance of achieving pCR. No pCR was detected in the Luminal A group. In patients with triple negative tumors, a trend could be observed. They seem to have more often pCR, although not statistically significant. Influences on pCR are shown in Table 2.Table 2 Influences on pCR by binary logistic regression
Parameter Odds ratio
Exp (B) P 95% confidence interval
Age 1.022 0.096 0.996–1.048
Time interval
Diagnosis-NACT
0.990 0.450 0.965–1.016
Time interval
NACT-operation
0.982 0.285 0.949–1.016
Study participation 2.355 0.009 1.244–4.458
Genetic mutation 2.203 0.275 0.533–9.103
Recurrent cancers 0.410 0.294 0.077–2.171
Discontinuation of NACT 1.929 0.115 0.852–4.371
Ki67 1.031 < 0.001 1.016–1.047
Grading 4.201 < 0.001 2.206–7.999
Triple negative 1.493 0.219 0.788–2.827
Her2 positive
HR positive
2.053 0.045 1.015–4.150
Her2 positive
HR negative
4.500 0.006 1.526–13.273
Luminal B 0.297 0.001 0.144–0.616
Bold values represents statistically significant
Discussion
This study presents several influences on pCR, with increased chances in patients participating in studies for NACT, having a high Ki67, high grading or Her2 positive tumors. Tumor subtypes like Luminal A and B had decreased chances of pCR.
Age had no influence on pCR in the current study. In contrast, other studies reported that young age is positively associated with pCR [7]. A cutoff value of 40 years was proposed under which the chances of pCR may be higher [17]. However, pCR can also be achieved in elderly patients, especially for Her2 positive patients [8]. So, age alone should not be an indication for NACT.
Neither time between diagnosis and onset of NACT, nor time between the end of chemotherapy and surgery influenced pCR. Consistently, exceeding a presumed cut-off of 4 weeks for onset of NACT or surgery did not influence pCR and disease-free or overall survival independent of histopathological subgroups [18]. However, it was suspected that patients without pCR could benefit from early surgery [18]. At least time intervals up to 8 weeks between NACT and surgery seem not to influence outcomes [19]. In the present study, the median time from diagnosis to NACT and NACT to surgery was about a month with only a minor part exceeding 8 weeks, which complies with German guidelines [20]. This limits the ability to assess the influence of longer time intervals on pCR. However, our results suggest that therapy intervals seem to have a negligible influence on pCR.
More than a third of our patients participated in clinical trials. Study participants for NACT had more than twice as high a chance to achieve pCR. In addition to higher chances for pCR in patients participating in clinical trials, mastectomy rates were lower [21]. However, one must take into account that the patients who are included in clinical studies are mostly a selected collective. On the one hand, this means that there is a disproportionate part of those patients who have a higher probability to achieve pCR due to tumor biology (e.g. high grading and high Ki67). On the other hand, study patients have fewer previous illnesses due to in- and exclusion criteria which can otherwise lead to premature discontinuation of therapy, dose reduction or longer therapy breaks. In the present study, patients receiving NACT in clinical trials had higher rates of Ki67 and higher grading compared to patients receiving standard therapy. This might be the reason for higher pCR rates in the study participants. Furthermore, there was a higher percentage with triple negative tumors in the study group comparing to standard treatment. However, the rate of Her2 positive tumors (which are also associated with higher rates of pCR) was lower in patients participating in clinical trials. Nevertheless, we should encourage our patients to participate in clinical trials. Besides contributing to therapy improvements, they most likely benefit from new therapies. Possible disadvantages of trial participation, such as delaying the onset of NACT or surgery, could be excluded [11, 12].
Only 5% of our patients had a proven genetic mutation (BRCA) for which a superior response to NACT was previously described [10]. Particularly when BRCA positive patients have triple-negative tumors, better outcomes are suspected [22]. We could not prove a significant influence of genetic mutation on pCR.
Likewise, there was no influence of local recurrent cancers on pCR. To our knowledge, this is the first study analyzing a possible influence of local recurrent cancers on the pCR rate. However, no distinction was made whether patients already received prior chemotherapy. In contrast to that, there are analyses describing the association of pCR after NACT on the recurrence of locoregional cancer. An analysis of 10,075 women showed that the local recurrence rate after chemotherapy was higher in patients with non-pCR (9.5% in 67 months) [23].
Discontinuation of chemotherapy due to intolerable side effects did not influence pCR. Patients discontinuing NACT due to disease progress were not included. In general, guidelines recommend the completion of chemotherapy [20]. Our results imply that discontinuation of chemotherapy may not substantially lower chances for pCR. However, it should be considered that this might be due to the small sample size and that most patients only discontinued before the last or the last two chemotherapy doses. Nevertheless, a detrimental effect of early termination of chemotherapy cannot be excluded. Peripheral neurotoxicity was the most common reason why patients had to discontinue chemotherapy (7%). Unfortunately, therapeutic options like pharmacological treatments are limited [24]. Thus, only dose reduction or discontinuation are current options [24]. Nevertheless, premature discontinuation of NACT seems to be uncritical, especially when a good clinical response was already proven. Further studies are needed to confirm our findings.
Ki67 and high grading were associated with high pCR rates (P < 0.001). As Ki67 increases by 1, the probability of a pCR increases by 1.031. This is consistent with findings that especially highly aggressive tumors have a good response to chemotherapy [5, 25]. Triple-negative tumors tend to have better pCR rates without reaching statistical significance. Other studies already showed that triple-negative tumors (as aggressive tumors) were associated with higher pCR rates after NACT [5, 7]. Her2 positive tumors showed higher chances for pCR in our study. This has also been demonstrated in previous studies [26, 27]. It could be shown that patients with Her2 positive, hormone receptor (HR) negative tumors showed the highest rates of pCR. With this tumor biology (Her2+, HR−) the chance to achieve pCR was 4.5 times higher than in other tumor subtypes. Von Minckwitz et al. and Harbeck et al. also observed that Her2 positive tumors respond particularly well to NACT when hormone receptor status is negative [5, 28]. In the present study, even tumors with Her2 positive, hormone receptor positive tumors had a twice as high chance to achieve pCR (P = 0.045). This effect could not be shown in all previous studies [5]. One reason for this might be the change in Her2 directed therapy, as the addition of pertuzumab to trasuzumab and NACT led to a more frequent pCR rate [29, 30]. In the present study, most patients (79%) received Trastuzumab and Pertuzumab. Only a minor part (21%) received Trastuzumab alone.
The subtype Luminal B was associated with a lower chance for pCR. Available data seem contradictory. pCR seems to appear more likely in young patients with hormone receptor-positive, Her2 negative breast cancer [7]. However, large analyzes of 13,939 women showed that the lowest rate of pCR was achieved for Luminal A, followed by Luminal B subtypes, whereas pCR rates of triple-negative and Her2 positive were comparatively higher [27]. Also, patients with progesterone negativity showed higher pCR rates [9]. Taken together, high Ki67, high grading and Her2 positive tumors are notably associated with higher pCR. No pCR was detected in the Luminal A group. This seems not to be surprisingly, as Luminal A cancers are not appropriate for NACT and normally show the lowest rates of pCR [27]. In this analysis, the four patients with Luminal A cancers had locally advanced tumors and received chemotherapy therefore neoadjuvant.
This study has limitations. It is single centric, and thus clinical pathways may differ to other centers. However, data were collected from a certified tertiary breast care center, ensuring that therapies are state of the art. The sample size is small, but many other studies are based on registers obtained from clinical trials for new therapy regimes [5, 7–9, 18, 21], which implies selection bias due to specific inclusion criteria. Our data more likely represents “real-world-data”.
Conclusion
Particularly patients with aggressive tumors (high Ki67, high grading, Her2 positive tumors) had better response rates on NACT. These patients should receive chemotherapy in a neoadjuvant setting. Furthermore, patients participating in clinical trials had higher pCR rates after NACT. Besides contributing to therapy improvements, they most likely benefit from new therapies. We should thus encourage our patients to participate in clinical trials.
Author contribution
All authors contributed to the study conception and design. Material preparation and data collection were performed by Carolin Müller, Lisa Jung and Sarah Huwer. The data analysis was performed by Carolin Müller. The first draft of the manuscript was written by Carolin Müller and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Availability of data and material
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Conflict of interest
All of the authors (Carolin Müller, Gilda Schmidt, Stephanie Juhasz-Böss, Lisa Jung, Sarah Huwer, Erich-Franz Solomayer, Ingolf Juhasz-Böss) declare that they have no conflict of interest.
Ethical approval
This research study was conducted retrospectively from data obtained for clinical purposes. All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Ethics committee of the Saarland Physicians’ chamber) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from every individual participant included in the study. Trial registration number: 207/10 (Ethics committee of the Saarland Physicians’ chamber). This article does not contain any studies with animals performed by any of the authors.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CARBOPLATIN, PERTUZUMAB, TRASTUZUMAB | DrugsGivenReaction | CC BY | 33689016 | 19,047,528 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatic enzyme increased'. | Influences on pathologic complete response in breast cancer patients after neoadjuvant chemotherapy.
Pathologic complete response is associated with longer disease-free survival and better overall survival after neoadjuvant chemotherapy in breast cancer patients. We, therefore, evaluated factors influencing pathologic complete response.
Patients receiving neoadjuvant chemotherapy from 2015 to 2018 at the Saarland University Hospital were included. Patients' age, tumor stage, tumor biology, genetic mutation, recurrent cancer, discontinuation of chemotherapy, and participation in clinical trials were extracted from electronic medical records. Binary logistic regression was performed to evaluate the influence of these factors on pathologic complete response.
Data of 183 patients were included. The median patient's age was 54 years (22-78). The median interval between diagnosis and onset of chemotherapy was 28 days (14-91); between end of chemotherapy and surgery 28 days (9-57). Sixty-two patients (34%) participated in clinical trials for chemotherapy. A total of 86 patients (47%) achieved pathologic complete response. Patient's age, genetic mutation, recurrent cancers, or discontinuation of chemotherapy (due to side effects) and time intervals (between diagnosis and onset of chemotherapy, as well as between end of chemotherapy and surgery) did not influence pathologic complete response. Patients with high Ki67, high grading, Her2 positive tumors, as well as patients participating in clinical trials for chemotherapy had a higher chance of having pathologic complete response. Patients with Luminal B tumors had a lower chance for pathologic complete response.
Particularly patients with high risk cancer and patients, participating in clinical trials benefit most from chemotherapy. Therefore, breast cancer patients can be encouraged to participate in clinical trials for chemotherapy.
pmcIntroduction
Neoadjuvant chemotherapy (NACT) has changed its role for only inoperable and locally advanced breast cancer to a treatment used in early stages of breast cancer [1]. Particularly patients at high risk, like patients with Her2 positive and triple-negative breast cancer benefit from receiving NACT [2, 3]. Pathological complete response (pCR) is associated with a better outcome, meaning that patients having pCR have longer disease-free survival and better overall survival [5].
The definition of pCR varies in individual studies (ypT0/ypTis/ypN0). However, it could be shown that no residual invasive cancer in the breast and axilla is associated with better outcomes compared with no residual cancer in the breast alone [4]. Von Minckwitz et al. even detected a longer disease-free survival in patients with no invasive and no in situ carcinoma in the breast and axilla [5]. Also, tumor subtypes influence the achievement of pCR and thus a better outcome. For example, LeVasseur et al. detected that patients with triple negative tumors had longer relapse-free-survival and breast cancer-specific survival when achieving pCR after NACT [6].
As pCR plays an important role in the outcome of breast cancer, several studies already evaluated possible influencing factors, like age of the patients [7, 8], tumor biology [9] or genetic mutation [10]. The majority of the cited studies analyzed data that was previously collected as part of NACT trials. But patients who are included in clinical studies are mostly a selected collective due to in- and exclusion criteria with fewer previous illnesses, or of a certain subtype or tumor size. For this reason, we wanted to analyze possible influencing factors on pCR in “real-world-data”.
Although, some factors such as age, tumor biology or genetic mutation cannot be influenced directly, it is still important to identify possible risk factors to maybe establish further follow-up therapies or intensified aftercare. We, therefore, determined various clinical factors from electronic patient records and evaluated their influence on the probability of pCR. Parts of the registry were used for two other analyzes before [11, 12]. We could show that especially inpatient and outpatient presentations of the patients delayed therapy onset of NACT and surgery [11, 12].
Patients and methods
Data collection
All patients receiving NACT due to newly diagnosed breast cancer between 2015 to 2018 at the Department of Gynecology, Saarland University Medical Center, were included in the study. The primary endpoint was pCR after NACT. pCR was defined as no residual tumor in the breast and axilla (ypT0, N0). It includes no residual Tis (Carcinoma in situ). Date of diagnosis was defined as the date of core biopsy. Patients’ age, tumor stage, eventual multi-centricity, and tumor biology were recorded. It was distinguished whether the patients received NACT as standard therapy or in a clinical trial. Mainly GAIN II [13], Gepar Octo [14], and Gepar X [15] were addressed from 2015 to 2018 in the Saarland University Medical Center as clinical trials. The time interval between diagnosis and onset of chemotherapy, as well as between end of chemotherapy and surgery, was recorded. The type of operation and duration of hospitalization were documented. Patients who had an indication for BRCA testing according to the guidelines of the German AGO Mamma and the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) were tested for a BRCA mutation. Their recommendations are based on an analysis of 21,401 families [16]. It was registered whether patients had a genetic mutation (BRCA) or recurrent cancer. Recurrent cancer was defined as local recurrence of breast cancer. Patients with local recurrence were included in the study regardless of their previous therapy. If patients discontinued chemotherapy due to therapy complications or disease progress, it was recorded as well.
Data management and statistics
Patients’ data were reviewed in the hospital’s digital documentation system (SAP, Walldorf, Germany). Data were collected using Microsoft Excel 2010® (Microsoft, Redmond, USA). Further statistics were performed with SPSS 24.0 (IBM, Armonk, USA). Quantitative parameters (e.g., patients age, days) are given as median and range. Qualitative parameters (e.g., tumor stage) are presented as frequencies. Binary logistic regression was performed to determine the influence of multiple factors on pCR. Possible influencing factors were age, study participation, tumor biology, genetic mutation (BRCA), recurrent cancer, discontinuation of chemotherapy (due to side effects), days between diagnosis and begin of chemotherapy as well as days between end of chemotherapy and operation. All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from every individual participant included in the study.
Results
Between 2015 and 2018, a total of 205 patients received NACT due to newly diagnosed breast cancer at the Saarland University Medical Center. Twenty-two patients had to be excluded because of insufficient data so that the data of 183 patients were analyzed. The patients median age was 54 years (22–78). The median time between diagnosis and begin of NACT was 28 days (14–91). Between the end of NACT and operation, median time was 28 days (9–57).
Tumor stage and biology, as well as histological subtype and grading are illustrated in Table 1. Twenty-eight patients (15%) had multicentricity. BRCA mutation (9 patients, 5%) and recurrent cancers (7 patients, 4%) were rare. Sixty-two patients (34%) received study therapies: GAIN II (12%), Gepar Octo (10%), GeparX (9%), others (5%). Patients participating in clinical studies had a higher percentage of triple negative tumors (42%) compared to patients without study treatment (26%). Her2 positive tumors are less frequent in the study group (34%), compared to standard therapy regimen (39%). Furthermore, Grading and Ki67 values are higher in patients participating in clinical trials (Grading G3 67% vs. 53%, Ki67 50% vs. 40%). All patients received an Anthracycline and Taxane-based chemotherapy. Fifty-four patients of the Her2 positive group (79%) received chemotherapy in combination with Trastuzumab and Pertuzumab, 21% received chemotherapy in combination with Trastuzumab alone. All patients with triple-negative carcinoma additionally received carboplatin. Thirty-four patients (19%) discontinued NACT. Twenty patients (11%) skipped only the last or the last two chemotherapy doses, whereas 14 patients (8%) received three or more than three doses less. The reasons for a premature discontinuation of chemotherapy were equally distributed in both groups; the major part (16%) due to side effects (polyneuropathy 7%, changes in laboratory values as increased liver values or cytopenia 6%, others 3%). Four patients (2%) discontinued NACT because of tumor progression.Table 1 Tumor characteristics
TNM-stage Absolute frequencies (n) Cumulative frequencies (%)
Staging
ypT
0 89 48.6
1 56 30.6
2 16 8.7
3 7 3.8
4 5 2.7
X 10 5.6
ypN
0 56 30.6
1 26 14.2
2 15 8.2
3 3 1.6
Pre-therapeutic
pN0 (sentinal node) 83 45.4
pN+ 100 54.6
Tumor biology Absolute frequencies (n) Cumulative frequencies (%)
Tumor biology
NST (invasive carcinoma of no special type) 173 94.5
Others 10 5.5
Histological subtype Absolute frequencies (n) Cumulative frequencies (%)
Histology
Luminal A
HR+, Her2 neg, Ki67 ≤ 15% 8 4.4
Luminal B
HR+, Her2 neg, Ki67 > 15% 50 27.3
Her2 positive, HR positive 48 26.2
Her2 positive, HR negative 20 11.0
Triple negative 57 31.1
Grading Absolute frequencies (n) Cumulative frequencies (%)
Grading
G1 2 1.1
G2 74 40.4
G3 105 57.4
X 2 1.1
HR hormone receptor
Most patients received breast-conserving therapy (63%), followed by mastectomy (22%) and oncoplastic surgery (15%). Implants or expander was used for 24 patients (13%). The median time of hospitalization during the operation was 4 days (1–22). Patients with breast-conserving therapy had a median time of hospitalization of 3 days (1–14), patients undergoing mastectomy 6 days (2–17) and patients with oncoplastic surgery 7 days (2–22).
A total of 86 patients (47%) had pCR. The patients age, genetic mutation, recurrent cancer, or discontinuation of chemotherapy (due to side effects) did not influence pCR. Likewise, time between diagnosis and onset of NACT, or time between end of NACT and surgery, had no influence on pCR. Patients participating in clinical trials for NACT, higher tumor grade, high Ki67 and Her2 positive tumors had increased chances of having pCR. Patients with Luminal B tumors had a lower chance of achieving pCR. No pCR was detected in the Luminal A group. In patients with triple negative tumors, a trend could be observed. They seem to have more often pCR, although not statistically significant. Influences on pCR are shown in Table 2.Table 2 Influences on pCR by binary logistic regression
Parameter Odds ratio
Exp (B) P 95% confidence interval
Age 1.022 0.096 0.996–1.048
Time interval
Diagnosis-NACT
0.990 0.450 0.965–1.016
Time interval
NACT-operation
0.982 0.285 0.949–1.016
Study participation 2.355 0.009 1.244–4.458
Genetic mutation 2.203 0.275 0.533–9.103
Recurrent cancers 0.410 0.294 0.077–2.171
Discontinuation of NACT 1.929 0.115 0.852–4.371
Ki67 1.031 < 0.001 1.016–1.047
Grading 4.201 < 0.001 2.206–7.999
Triple negative 1.493 0.219 0.788–2.827
Her2 positive
HR positive
2.053 0.045 1.015–4.150
Her2 positive
HR negative
4.500 0.006 1.526–13.273
Luminal B 0.297 0.001 0.144–0.616
Bold values represents statistically significant
Discussion
This study presents several influences on pCR, with increased chances in patients participating in studies for NACT, having a high Ki67, high grading or Her2 positive tumors. Tumor subtypes like Luminal A and B had decreased chances of pCR.
Age had no influence on pCR in the current study. In contrast, other studies reported that young age is positively associated with pCR [7]. A cutoff value of 40 years was proposed under which the chances of pCR may be higher [17]. However, pCR can also be achieved in elderly patients, especially for Her2 positive patients [8]. So, age alone should not be an indication for NACT.
Neither time between diagnosis and onset of NACT, nor time between the end of chemotherapy and surgery influenced pCR. Consistently, exceeding a presumed cut-off of 4 weeks for onset of NACT or surgery did not influence pCR and disease-free or overall survival independent of histopathological subgroups [18]. However, it was suspected that patients without pCR could benefit from early surgery [18]. At least time intervals up to 8 weeks between NACT and surgery seem not to influence outcomes [19]. In the present study, the median time from diagnosis to NACT and NACT to surgery was about a month with only a minor part exceeding 8 weeks, which complies with German guidelines [20]. This limits the ability to assess the influence of longer time intervals on pCR. However, our results suggest that therapy intervals seem to have a negligible influence on pCR.
More than a third of our patients participated in clinical trials. Study participants for NACT had more than twice as high a chance to achieve pCR. In addition to higher chances for pCR in patients participating in clinical trials, mastectomy rates were lower [21]. However, one must take into account that the patients who are included in clinical studies are mostly a selected collective. On the one hand, this means that there is a disproportionate part of those patients who have a higher probability to achieve pCR due to tumor biology (e.g. high grading and high Ki67). On the other hand, study patients have fewer previous illnesses due to in- and exclusion criteria which can otherwise lead to premature discontinuation of therapy, dose reduction or longer therapy breaks. In the present study, patients receiving NACT in clinical trials had higher rates of Ki67 and higher grading compared to patients receiving standard therapy. This might be the reason for higher pCR rates in the study participants. Furthermore, there was a higher percentage with triple negative tumors in the study group comparing to standard treatment. However, the rate of Her2 positive tumors (which are also associated with higher rates of pCR) was lower in patients participating in clinical trials. Nevertheless, we should encourage our patients to participate in clinical trials. Besides contributing to therapy improvements, they most likely benefit from new therapies. Possible disadvantages of trial participation, such as delaying the onset of NACT or surgery, could be excluded [11, 12].
Only 5% of our patients had a proven genetic mutation (BRCA) for which a superior response to NACT was previously described [10]. Particularly when BRCA positive patients have triple-negative tumors, better outcomes are suspected [22]. We could not prove a significant influence of genetic mutation on pCR.
Likewise, there was no influence of local recurrent cancers on pCR. To our knowledge, this is the first study analyzing a possible influence of local recurrent cancers on the pCR rate. However, no distinction was made whether patients already received prior chemotherapy. In contrast to that, there are analyses describing the association of pCR after NACT on the recurrence of locoregional cancer. An analysis of 10,075 women showed that the local recurrence rate after chemotherapy was higher in patients with non-pCR (9.5% in 67 months) [23].
Discontinuation of chemotherapy due to intolerable side effects did not influence pCR. Patients discontinuing NACT due to disease progress were not included. In general, guidelines recommend the completion of chemotherapy [20]. Our results imply that discontinuation of chemotherapy may not substantially lower chances for pCR. However, it should be considered that this might be due to the small sample size and that most patients only discontinued before the last or the last two chemotherapy doses. Nevertheless, a detrimental effect of early termination of chemotherapy cannot be excluded. Peripheral neurotoxicity was the most common reason why patients had to discontinue chemotherapy (7%). Unfortunately, therapeutic options like pharmacological treatments are limited [24]. Thus, only dose reduction or discontinuation are current options [24]. Nevertheless, premature discontinuation of NACT seems to be uncritical, especially when a good clinical response was already proven. Further studies are needed to confirm our findings.
Ki67 and high grading were associated with high pCR rates (P < 0.001). As Ki67 increases by 1, the probability of a pCR increases by 1.031. This is consistent with findings that especially highly aggressive tumors have a good response to chemotherapy [5, 25]. Triple-negative tumors tend to have better pCR rates without reaching statistical significance. Other studies already showed that triple-negative tumors (as aggressive tumors) were associated with higher pCR rates after NACT [5, 7]. Her2 positive tumors showed higher chances for pCR in our study. This has also been demonstrated in previous studies [26, 27]. It could be shown that patients with Her2 positive, hormone receptor (HR) negative tumors showed the highest rates of pCR. With this tumor biology (Her2+, HR−) the chance to achieve pCR was 4.5 times higher than in other tumor subtypes. Von Minckwitz et al. and Harbeck et al. also observed that Her2 positive tumors respond particularly well to NACT when hormone receptor status is negative [5, 28]. In the present study, even tumors with Her2 positive, hormone receptor positive tumors had a twice as high chance to achieve pCR (P = 0.045). This effect could not be shown in all previous studies [5]. One reason for this might be the change in Her2 directed therapy, as the addition of pertuzumab to trasuzumab and NACT led to a more frequent pCR rate [29, 30]. In the present study, most patients (79%) received Trastuzumab and Pertuzumab. Only a minor part (21%) received Trastuzumab alone.
The subtype Luminal B was associated with a lower chance for pCR. Available data seem contradictory. pCR seems to appear more likely in young patients with hormone receptor-positive, Her2 negative breast cancer [7]. However, large analyzes of 13,939 women showed that the lowest rate of pCR was achieved for Luminal A, followed by Luminal B subtypes, whereas pCR rates of triple-negative and Her2 positive were comparatively higher [27]. Also, patients with progesterone negativity showed higher pCR rates [9]. Taken together, high Ki67, high grading and Her2 positive tumors are notably associated with higher pCR. No pCR was detected in the Luminal A group. This seems not to be surprisingly, as Luminal A cancers are not appropriate for NACT and normally show the lowest rates of pCR [27]. In this analysis, the four patients with Luminal A cancers had locally advanced tumors and received chemotherapy therefore neoadjuvant.
This study has limitations. It is single centric, and thus clinical pathways may differ to other centers. However, data were collected from a certified tertiary breast care center, ensuring that therapies are state of the art. The sample size is small, but many other studies are based on registers obtained from clinical trials for new therapy regimes [5, 7–9, 18, 21], which implies selection bias due to specific inclusion criteria. Our data more likely represents “real-world-data”.
Conclusion
Particularly patients with aggressive tumors (high Ki67, high grading, Her2 positive tumors) had better response rates on NACT. These patients should receive chemotherapy in a neoadjuvant setting. Furthermore, patients participating in clinical trials had higher pCR rates after NACT. Besides contributing to therapy improvements, they most likely benefit from new therapies. We should thus encourage our patients to participate in clinical trials.
Author contribution
All authors contributed to the study conception and design. Material preparation and data collection were performed by Carolin Müller, Lisa Jung and Sarah Huwer. The data analysis was performed by Carolin Müller. The first draft of the manuscript was written by Carolin Müller and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Availability of data and material
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Conflict of interest
All of the authors (Carolin Müller, Gilda Schmidt, Stephanie Juhasz-Böss, Lisa Jung, Sarah Huwer, Erich-Franz Solomayer, Ingolf Juhasz-Böss) declare that they have no conflict of interest.
Ethical approval
This research study was conducted retrospectively from data obtained for clinical purposes. All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Ethics committee of the Saarland Physicians’ chamber) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from every individual participant included in the study. Trial registration number: 207/10 (Ethics committee of the Saarland Physicians’ chamber). This article does not contain any studies with animals performed by any of the authors.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CARBOPLATIN, PERTUZUMAB, TRASTUZUMAB | DrugsGivenReaction | CC BY | 33689016 | 19,047,528 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neoplasm progression'. | Influences on pathologic complete response in breast cancer patients after neoadjuvant chemotherapy.
Pathologic complete response is associated with longer disease-free survival and better overall survival after neoadjuvant chemotherapy in breast cancer patients. We, therefore, evaluated factors influencing pathologic complete response.
Patients receiving neoadjuvant chemotherapy from 2015 to 2018 at the Saarland University Hospital were included. Patients' age, tumor stage, tumor biology, genetic mutation, recurrent cancer, discontinuation of chemotherapy, and participation in clinical trials were extracted from electronic medical records. Binary logistic regression was performed to evaluate the influence of these factors on pathologic complete response.
Data of 183 patients were included. The median patient's age was 54 years (22-78). The median interval between diagnosis and onset of chemotherapy was 28 days (14-91); between end of chemotherapy and surgery 28 days (9-57). Sixty-two patients (34%) participated in clinical trials for chemotherapy. A total of 86 patients (47%) achieved pathologic complete response. Patient's age, genetic mutation, recurrent cancers, or discontinuation of chemotherapy (due to side effects) and time intervals (between diagnosis and onset of chemotherapy, as well as between end of chemotherapy and surgery) did not influence pathologic complete response. Patients with high Ki67, high grading, Her2 positive tumors, as well as patients participating in clinical trials for chemotherapy had a higher chance of having pathologic complete response. Patients with Luminal B tumors had a lower chance for pathologic complete response.
Particularly patients with high risk cancer and patients, participating in clinical trials benefit most from chemotherapy. Therefore, breast cancer patients can be encouraged to participate in clinical trials for chemotherapy.
pmcIntroduction
Neoadjuvant chemotherapy (NACT) has changed its role for only inoperable and locally advanced breast cancer to a treatment used in early stages of breast cancer [1]. Particularly patients at high risk, like patients with Her2 positive and triple-negative breast cancer benefit from receiving NACT [2, 3]. Pathological complete response (pCR) is associated with a better outcome, meaning that patients having pCR have longer disease-free survival and better overall survival [5].
The definition of pCR varies in individual studies (ypT0/ypTis/ypN0). However, it could be shown that no residual invasive cancer in the breast and axilla is associated with better outcomes compared with no residual cancer in the breast alone [4]. Von Minckwitz et al. even detected a longer disease-free survival in patients with no invasive and no in situ carcinoma in the breast and axilla [5]. Also, tumor subtypes influence the achievement of pCR and thus a better outcome. For example, LeVasseur et al. detected that patients with triple negative tumors had longer relapse-free-survival and breast cancer-specific survival when achieving pCR after NACT [6].
As pCR plays an important role in the outcome of breast cancer, several studies already evaluated possible influencing factors, like age of the patients [7, 8], tumor biology [9] or genetic mutation [10]. The majority of the cited studies analyzed data that was previously collected as part of NACT trials. But patients who are included in clinical studies are mostly a selected collective due to in- and exclusion criteria with fewer previous illnesses, or of a certain subtype or tumor size. For this reason, we wanted to analyze possible influencing factors on pCR in “real-world-data”.
Although, some factors such as age, tumor biology or genetic mutation cannot be influenced directly, it is still important to identify possible risk factors to maybe establish further follow-up therapies or intensified aftercare. We, therefore, determined various clinical factors from electronic patient records and evaluated their influence on the probability of pCR. Parts of the registry were used for two other analyzes before [11, 12]. We could show that especially inpatient and outpatient presentations of the patients delayed therapy onset of NACT and surgery [11, 12].
Patients and methods
Data collection
All patients receiving NACT due to newly diagnosed breast cancer between 2015 to 2018 at the Department of Gynecology, Saarland University Medical Center, were included in the study. The primary endpoint was pCR after NACT. pCR was defined as no residual tumor in the breast and axilla (ypT0, N0). It includes no residual Tis (Carcinoma in situ). Date of diagnosis was defined as the date of core biopsy. Patients’ age, tumor stage, eventual multi-centricity, and tumor biology were recorded. It was distinguished whether the patients received NACT as standard therapy or in a clinical trial. Mainly GAIN II [13], Gepar Octo [14], and Gepar X [15] were addressed from 2015 to 2018 in the Saarland University Medical Center as clinical trials. The time interval between diagnosis and onset of chemotherapy, as well as between end of chemotherapy and surgery, was recorded. The type of operation and duration of hospitalization were documented. Patients who had an indication for BRCA testing according to the guidelines of the German AGO Mamma and the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) were tested for a BRCA mutation. Their recommendations are based on an analysis of 21,401 families [16]. It was registered whether patients had a genetic mutation (BRCA) or recurrent cancer. Recurrent cancer was defined as local recurrence of breast cancer. Patients with local recurrence were included in the study regardless of their previous therapy. If patients discontinued chemotherapy due to therapy complications or disease progress, it was recorded as well.
Data management and statistics
Patients’ data were reviewed in the hospital’s digital documentation system (SAP, Walldorf, Germany). Data were collected using Microsoft Excel 2010® (Microsoft, Redmond, USA). Further statistics were performed with SPSS 24.0 (IBM, Armonk, USA). Quantitative parameters (e.g., patients age, days) are given as median and range. Qualitative parameters (e.g., tumor stage) are presented as frequencies. Binary logistic regression was performed to determine the influence of multiple factors on pCR. Possible influencing factors were age, study participation, tumor biology, genetic mutation (BRCA), recurrent cancer, discontinuation of chemotherapy (due to side effects), days between diagnosis and begin of chemotherapy as well as days between end of chemotherapy and operation. All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from every individual participant included in the study.
Results
Between 2015 and 2018, a total of 205 patients received NACT due to newly diagnosed breast cancer at the Saarland University Medical Center. Twenty-two patients had to be excluded because of insufficient data so that the data of 183 patients were analyzed. The patients median age was 54 years (22–78). The median time between diagnosis and begin of NACT was 28 days (14–91). Between the end of NACT and operation, median time was 28 days (9–57).
Tumor stage and biology, as well as histological subtype and grading are illustrated in Table 1. Twenty-eight patients (15%) had multicentricity. BRCA mutation (9 patients, 5%) and recurrent cancers (7 patients, 4%) were rare. Sixty-two patients (34%) received study therapies: GAIN II (12%), Gepar Octo (10%), GeparX (9%), others (5%). Patients participating in clinical studies had a higher percentage of triple negative tumors (42%) compared to patients without study treatment (26%). Her2 positive tumors are less frequent in the study group (34%), compared to standard therapy regimen (39%). Furthermore, Grading and Ki67 values are higher in patients participating in clinical trials (Grading G3 67% vs. 53%, Ki67 50% vs. 40%). All patients received an Anthracycline and Taxane-based chemotherapy. Fifty-four patients of the Her2 positive group (79%) received chemotherapy in combination with Trastuzumab and Pertuzumab, 21% received chemotherapy in combination with Trastuzumab alone. All patients with triple-negative carcinoma additionally received carboplatin. Thirty-four patients (19%) discontinued NACT. Twenty patients (11%) skipped only the last or the last two chemotherapy doses, whereas 14 patients (8%) received three or more than three doses less. The reasons for a premature discontinuation of chemotherapy were equally distributed in both groups; the major part (16%) due to side effects (polyneuropathy 7%, changes in laboratory values as increased liver values or cytopenia 6%, others 3%). Four patients (2%) discontinued NACT because of tumor progression.Table 1 Tumor characteristics
TNM-stage Absolute frequencies (n) Cumulative frequencies (%)
Staging
ypT
0 89 48.6
1 56 30.6
2 16 8.7
3 7 3.8
4 5 2.7
X 10 5.6
ypN
0 56 30.6
1 26 14.2
2 15 8.2
3 3 1.6
Pre-therapeutic
pN0 (sentinal node) 83 45.4
pN+ 100 54.6
Tumor biology Absolute frequencies (n) Cumulative frequencies (%)
Tumor biology
NST (invasive carcinoma of no special type) 173 94.5
Others 10 5.5
Histological subtype Absolute frequencies (n) Cumulative frequencies (%)
Histology
Luminal A
HR+, Her2 neg, Ki67 ≤ 15% 8 4.4
Luminal B
HR+, Her2 neg, Ki67 > 15% 50 27.3
Her2 positive, HR positive 48 26.2
Her2 positive, HR negative 20 11.0
Triple negative 57 31.1
Grading Absolute frequencies (n) Cumulative frequencies (%)
Grading
G1 2 1.1
G2 74 40.4
G3 105 57.4
X 2 1.1
HR hormone receptor
Most patients received breast-conserving therapy (63%), followed by mastectomy (22%) and oncoplastic surgery (15%). Implants or expander was used for 24 patients (13%). The median time of hospitalization during the operation was 4 days (1–22). Patients with breast-conserving therapy had a median time of hospitalization of 3 days (1–14), patients undergoing mastectomy 6 days (2–17) and patients with oncoplastic surgery 7 days (2–22).
A total of 86 patients (47%) had pCR. The patients age, genetic mutation, recurrent cancer, or discontinuation of chemotherapy (due to side effects) did not influence pCR. Likewise, time between diagnosis and onset of NACT, or time between end of NACT and surgery, had no influence on pCR. Patients participating in clinical trials for NACT, higher tumor grade, high Ki67 and Her2 positive tumors had increased chances of having pCR. Patients with Luminal B tumors had a lower chance of achieving pCR. No pCR was detected in the Luminal A group. In patients with triple negative tumors, a trend could be observed. They seem to have more often pCR, although not statistically significant. Influences on pCR are shown in Table 2.Table 2 Influences on pCR by binary logistic regression
Parameter Odds ratio
Exp (B) P 95% confidence interval
Age 1.022 0.096 0.996–1.048
Time interval
Diagnosis-NACT
0.990 0.450 0.965–1.016
Time interval
NACT-operation
0.982 0.285 0.949–1.016
Study participation 2.355 0.009 1.244–4.458
Genetic mutation 2.203 0.275 0.533–9.103
Recurrent cancers 0.410 0.294 0.077–2.171
Discontinuation of NACT 1.929 0.115 0.852–4.371
Ki67 1.031 < 0.001 1.016–1.047
Grading 4.201 < 0.001 2.206–7.999
Triple negative 1.493 0.219 0.788–2.827
Her2 positive
HR positive
2.053 0.045 1.015–4.150
Her2 positive
HR negative
4.500 0.006 1.526–13.273
Luminal B 0.297 0.001 0.144–0.616
Bold values represents statistically significant
Discussion
This study presents several influences on pCR, with increased chances in patients participating in studies for NACT, having a high Ki67, high grading or Her2 positive tumors. Tumor subtypes like Luminal A and B had decreased chances of pCR.
Age had no influence on pCR in the current study. In contrast, other studies reported that young age is positively associated with pCR [7]. A cutoff value of 40 years was proposed under which the chances of pCR may be higher [17]. However, pCR can also be achieved in elderly patients, especially for Her2 positive patients [8]. So, age alone should not be an indication for NACT.
Neither time between diagnosis and onset of NACT, nor time between the end of chemotherapy and surgery influenced pCR. Consistently, exceeding a presumed cut-off of 4 weeks for onset of NACT or surgery did not influence pCR and disease-free or overall survival independent of histopathological subgroups [18]. However, it was suspected that patients without pCR could benefit from early surgery [18]. At least time intervals up to 8 weeks between NACT and surgery seem not to influence outcomes [19]. In the present study, the median time from diagnosis to NACT and NACT to surgery was about a month with only a minor part exceeding 8 weeks, which complies with German guidelines [20]. This limits the ability to assess the influence of longer time intervals on pCR. However, our results suggest that therapy intervals seem to have a negligible influence on pCR.
More than a third of our patients participated in clinical trials. Study participants for NACT had more than twice as high a chance to achieve pCR. In addition to higher chances for pCR in patients participating in clinical trials, mastectomy rates were lower [21]. However, one must take into account that the patients who are included in clinical studies are mostly a selected collective. On the one hand, this means that there is a disproportionate part of those patients who have a higher probability to achieve pCR due to tumor biology (e.g. high grading and high Ki67). On the other hand, study patients have fewer previous illnesses due to in- and exclusion criteria which can otherwise lead to premature discontinuation of therapy, dose reduction or longer therapy breaks. In the present study, patients receiving NACT in clinical trials had higher rates of Ki67 and higher grading compared to patients receiving standard therapy. This might be the reason for higher pCR rates in the study participants. Furthermore, there was a higher percentage with triple negative tumors in the study group comparing to standard treatment. However, the rate of Her2 positive tumors (which are also associated with higher rates of pCR) was lower in patients participating in clinical trials. Nevertheless, we should encourage our patients to participate in clinical trials. Besides contributing to therapy improvements, they most likely benefit from new therapies. Possible disadvantages of trial participation, such as delaying the onset of NACT or surgery, could be excluded [11, 12].
Only 5% of our patients had a proven genetic mutation (BRCA) for which a superior response to NACT was previously described [10]. Particularly when BRCA positive patients have triple-negative tumors, better outcomes are suspected [22]. We could not prove a significant influence of genetic mutation on pCR.
Likewise, there was no influence of local recurrent cancers on pCR. To our knowledge, this is the first study analyzing a possible influence of local recurrent cancers on the pCR rate. However, no distinction was made whether patients already received prior chemotherapy. In contrast to that, there are analyses describing the association of pCR after NACT on the recurrence of locoregional cancer. An analysis of 10,075 women showed that the local recurrence rate after chemotherapy was higher in patients with non-pCR (9.5% in 67 months) [23].
Discontinuation of chemotherapy due to intolerable side effects did not influence pCR. Patients discontinuing NACT due to disease progress were not included. In general, guidelines recommend the completion of chemotherapy [20]. Our results imply that discontinuation of chemotherapy may not substantially lower chances for pCR. However, it should be considered that this might be due to the small sample size and that most patients only discontinued before the last or the last two chemotherapy doses. Nevertheless, a detrimental effect of early termination of chemotherapy cannot be excluded. Peripheral neurotoxicity was the most common reason why patients had to discontinue chemotherapy (7%). Unfortunately, therapeutic options like pharmacological treatments are limited [24]. Thus, only dose reduction or discontinuation are current options [24]. Nevertheless, premature discontinuation of NACT seems to be uncritical, especially when a good clinical response was already proven. Further studies are needed to confirm our findings.
Ki67 and high grading were associated with high pCR rates (P < 0.001). As Ki67 increases by 1, the probability of a pCR increases by 1.031. This is consistent with findings that especially highly aggressive tumors have a good response to chemotherapy [5, 25]. Triple-negative tumors tend to have better pCR rates without reaching statistical significance. Other studies already showed that triple-negative tumors (as aggressive tumors) were associated with higher pCR rates after NACT [5, 7]. Her2 positive tumors showed higher chances for pCR in our study. This has also been demonstrated in previous studies [26, 27]. It could be shown that patients with Her2 positive, hormone receptor (HR) negative tumors showed the highest rates of pCR. With this tumor biology (Her2+, HR−) the chance to achieve pCR was 4.5 times higher than in other tumor subtypes. Von Minckwitz et al. and Harbeck et al. also observed that Her2 positive tumors respond particularly well to NACT when hormone receptor status is negative [5, 28]. In the present study, even tumors with Her2 positive, hormone receptor positive tumors had a twice as high chance to achieve pCR (P = 0.045). This effect could not be shown in all previous studies [5]. One reason for this might be the change in Her2 directed therapy, as the addition of pertuzumab to trasuzumab and NACT led to a more frequent pCR rate [29, 30]. In the present study, most patients (79%) received Trastuzumab and Pertuzumab. Only a minor part (21%) received Trastuzumab alone.
The subtype Luminal B was associated with a lower chance for pCR. Available data seem contradictory. pCR seems to appear more likely in young patients with hormone receptor-positive, Her2 negative breast cancer [7]. However, large analyzes of 13,939 women showed that the lowest rate of pCR was achieved for Luminal A, followed by Luminal B subtypes, whereas pCR rates of triple-negative and Her2 positive were comparatively higher [27]. Also, patients with progesterone negativity showed higher pCR rates [9]. Taken together, high Ki67, high grading and Her2 positive tumors are notably associated with higher pCR. No pCR was detected in the Luminal A group. This seems not to be surprisingly, as Luminal A cancers are not appropriate for NACT and normally show the lowest rates of pCR [27]. In this analysis, the four patients with Luminal A cancers had locally advanced tumors and received chemotherapy therefore neoadjuvant.
This study has limitations. It is single centric, and thus clinical pathways may differ to other centers. However, data were collected from a certified tertiary breast care center, ensuring that therapies are state of the art. The sample size is small, but many other studies are based on registers obtained from clinical trials for new therapy regimes [5, 7–9, 18, 21], which implies selection bias due to specific inclusion criteria. Our data more likely represents “real-world-data”.
Conclusion
Particularly patients with aggressive tumors (high Ki67, high grading, Her2 positive tumors) had better response rates on NACT. These patients should receive chemotherapy in a neoadjuvant setting. Furthermore, patients participating in clinical trials had higher pCR rates after NACT. Besides contributing to therapy improvements, they most likely benefit from new therapies. We should thus encourage our patients to participate in clinical trials.
Author contribution
All authors contributed to the study conception and design. Material preparation and data collection were performed by Carolin Müller, Lisa Jung and Sarah Huwer. The data analysis was performed by Carolin Müller. The first draft of the manuscript was written by Carolin Müller and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Availability of data and material
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Conflict of interest
All of the authors (Carolin Müller, Gilda Schmidt, Stephanie Juhasz-Böss, Lisa Jung, Sarah Huwer, Erich-Franz Solomayer, Ingolf Juhasz-Böss) declare that they have no conflict of interest.
Ethical approval
This research study was conducted retrospectively from data obtained for clinical purposes. All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Ethics committee of the Saarland Physicians’ chamber) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from every individual participant included in the study. Trial registration number: 207/10 (Ethics committee of the Saarland Physicians’ chamber). This article does not contain any studies with animals performed by any of the authors.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CARBOPLATIN, PERTUZUMAB, TRASTUZUMAB | DrugsGivenReaction | CC BY | 33689016 | 19,047,528 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Influences on pathologic complete response in breast cancer patients after neoadjuvant chemotherapy.
Pathologic complete response is associated with longer disease-free survival and better overall survival after neoadjuvant chemotherapy in breast cancer patients. We, therefore, evaluated factors influencing pathologic complete response.
Patients receiving neoadjuvant chemotherapy from 2015 to 2018 at the Saarland University Hospital were included. Patients' age, tumor stage, tumor biology, genetic mutation, recurrent cancer, discontinuation of chemotherapy, and participation in clinical trials were extracted from electronic medical records. Binary logistic regression was performed to evaluate the influence of these factors on pathologic complete response.
Data of 183 patients were included. The median patient's age was 54 years (22-78). The median interval between diagnosis and onset of chemotherapy was 28 days (14-91); between end of chemotherapy and surgery 28 days (9-57). Sixty-two patients (34%) participated in clinical trials for chemotherapy. A total of 86 patients (47%) achieved pathologic complete response. Patient's age, genetic mutation, recurrent cancers, or discontinuation of chemotherapy (due to side effects) and time intervals (between diagnosis and onset of chemotherapy, as well as between end of chemotherapy and surgery) did not influence pathologic complete response. Patients with high Ki67, high grading, Her2 positive tumors, as well as patients participating in clinical trials for chemotherapy had a higher chance of having pathologic complete response. Patients with Luminal B tumors had a lower chance for pathologic complete response.
Particularly patients with high risk cancer and patients, participating in clinical trials benefit most from chemotherapy. Therefore, breast cancer patients can be encouraged to participate in clinical trials for chemotherapy.
pmcIntroduction
Neoadjuvant chemotherapy (NACT) has changed its role for only inoperable and locally advanced breast cancer to a treatment used in early stages of breast cancer [1]. Particularly patients at high risk, like patients with Her2 positive and triple-negative breast cancer benefit from receiving NACT [2, 3]. Pathological complete response (pCR) is associated with a better outcome, meaning that patients having pCR have longer disease-free survival and better overall survival [5].
The definition of pCR varies in individual studies (ypT0/ypTis/ypN0). However, it could be shown that no residual invasive cancer in the breast and axilla is associated with better outcomes compared with no residual cancer in the breast alone [4]. Von Minckwitz et al. even detected a longer disease-free survival in patients with no invasive and no in situ carcinoma in the breast and axilla [5]. Also, tumor subtypes influence the achievement of pCR and thus a better outcome. For example, LeVasseur et al. detected that patients with triple negative tumors had longer relapse-free-survival and breast cancer-specific survival when achieving pCR after NACT [6].
As pCR plays an important role in the outcome of breast cancer, several studies already evaluated possible influencing factors, like age of the patients [7, 8], tumor biology [9] or genetic mutation [10]. The majority of the cited studies analyzed data that was previously collected as part of NACT trials. But patients who are included in clinical studies are mostly a selected collective due to in- and exclusion criteria with fewer previous illnesses, or of a certain subtype or tumor size. For this reason, we wanted to analyze possible influencing factors on pCR in “real-world-data”.
Although, some factors such as age, tumor biology or genetic mutation cannot be influenced directly, it is still important to identify possible risk factors to maybe establish further follow-up therapies or intensified aftercare. We, therefore, determined various clinical factors from electronic patient records and evaluated their influence on the probability of pCR. Parts of the registry were used for two other analyzes before [11, 12]. We could show that especially inpatient and outpatient presentations of the patients delayed therapy onset of NACT and surgery [11, 12].
Patients and methods
Data collection
All patients receiving NACT due to newly diagnosed breast cancer between 2015 to 2018 at the Department of Gynecology, Saarland University Medical Center, were included in the study. The primary endpoint was pCR after NACT. pCR was defined as no residual tumor in the breast and axilla (ypT0, N0). It includes no residual Tis (Carcinoma in situ). Date of diagnosis was defined as the date of core biopsy. Patients’ age, tumor stage, eventual multi-centricity, and tumor biology were recorded. It was distinguished whether the patients received NACT as standard therapy or in a clinical trial. Mainly GAIN II [13], Gepar Octo [14], and Gepar X [15] were addressed from 2015 to 2018 in the Saarland University Medical Center as clinical trials. The time interval between diagnosis and onset of chemotherapy, as well as between end of chemotherapy and surgery, was recorded. The type of operation and duration of hospitalization were documented. Patients who had an indication for BRCA testing according to the guidelines of the German AGO Mamma and the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) were tested for a BRCA mutation. Their recommendations are based on an analysis of 21,401 families [16]. It was registered whether patients had a genetic mutation (BRCA) or recurrent cancer. Recurrent cancer was defined as local recurrence of breast cancer. Patients with local recurrence were included in the study regardless of their previous therapy. If patients discontinued chemotherapy due to therapy complications or disease progress, it was recorded as well.
Data management and statistics
Patients’ data were reviewed in the hospital’s digital documentation system (SAP, Walldorf, Germany). Data were collected using Microsoft Excel 2010® (Microsoft, Redmond, USA). Further statistics were performed with SPSS 24.0 (IBM, Armonk, USA). Quantitative parameters (e.g., patients age, days) are given as median and range. Qualitative parameters (e.g., tumor stage) are presented as frequencies. Binary logistic regression was performed to determine the influence of multiple factors on pCR. Possible influencing factors were age, study participation, tumor biology, genetic mutation (BRCA), recurrent cancer, discontinuation of chemotherapy (due to side effects), days between diagnosis and begin of chemotherapy as well as days between end of chemotherapy and operation. All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from every individual participant included in the study.
Results
Between 2015 and 2018, a total of 205 patients received NACT due to newly diagnosed breast cancer at the Saarland University Medical Center. Twenty-two patients had to be excluded because of insufficient data so that the data of 183 patients were analyzed. The patients median age was 54 years (22–78). The median time between diagnosis and begin of NACT was 28 days (14–91). Between the end of NACT and operation, median time was 28 days (9–57).
Tumor stage and biology, as well as histological subtype and grading are illustrated in Table 1. Twenty-eight patients (15%) had multicentricity. BRCA mutation (9 patients, 5%) and recurrent cancers (7 patients, 4%) were rare. Sixty-two patients (34%) received study therapies: GAIN II (12%), Gepar Octo (10%), GeparX (9%), others (5%). Patients participating in clinical studies had a higher percentage of triple negative tumors (42%) compared to patients without study treatment (26%). Her2 positive tumors are less frequent in the study group (34%), compared to standard therapy regimen (39%). Furthermore, Grading and Ki67 values are higher in patients participating in clinical trials (Grading G3 67% vs. 53%, Ki67 50% vs. 40%). All patients received an Anthracycline and Taxane-based chemotherapy. Fifty-four patients of the Her2 positive group (79%) received chemotherapy in combination with Trastuzumab and Pertuzumab, 21% received chemotherapy in combination with Trastuzumab alone. All patients with triple-negative carcinoma additionally received carboplatin. Thirty-four patients (19%) discontinued NACT. Twenty patients (11%) skipped only the last or the last two chemotherapy doses, whereas 14 patients (8%) received three or more than three doses less. The reasons for a premature discontinuation of chemotherapy were equally distributed in both groups; the major part (16%) due to side effects (polyneuropathy 7%, changes in laboratory values as increased liver values or cytopenia 6%, others 3%). Four patients (2%) discontinued NACT because of tumor progression.Table 1 Tumor characteristics
TNM-stage Absolute frequencies (n) Cumulative frequencies (%)
Staging
ypT
0 89 48.6
1 56 30.6
2 16 8.7
3 7 3.8
4 5 2.7
X 10 5.6
ypN
0 56 30.6
1 26 14.2
2 15 8.2
3 3 1.6
Pre-therapeutic
pN0 (sentinal node) 83 45.4
pN+ 100 54.6
Tumor biology Absolute frequencies (n) Cumulative frequencies (%)
Tumor biology
NST (invasive carcinoma of no special type) 173 94.5
Others 10 5.5
Histological subtype Absolute frequencies (n) Cumulative frequencies (%)
Histology
Luminal A
HR+, Her2 neg, Ki67 ≤ 15% 8 4.4
Luminal B
HR+, Her2 neg, Ki67 > 15% 50 27.3
Her2 positive, HR positive 48 26.2
Her2 positive, HR negative 20 11.0
Triple negative 57 31.1
Grading Absolute frequencies (n) Cumulative frequencies (%)
Grading
G1 2 1.1
G2 74 40.4
G3 105 57.4
X 2 1.1
HR hormone receptor
Most patients received breast-conserving therapy (63%), followed by mastectomy (22%) and oncoplastic surgery (15%). Implants or expander was used for 24 patients (13%). The median time of hospitalization during the operation was 4 days (1–22). Patients with breast-conserving therapy had a median time of hospitalization of 3 days (1–14), patients undergoing mastectomy 6 days (2–17) and patients with oncoplastic surgery 7 days (2–22).
A total of 86 patients (47%) had pCR. The patients age, genetic mutation, recurrent cancer, or discontinuation of chemotherapy (due to side effects) did not influence pCR. Likewise, time between diagnosis and onset of NACT, or time between end of NACT and surgery, had no influence on pCR. Patients participating in clinical trials for NACT, higher tumor grade, high Ki67 and Her2 positive tumors had increased chances of having pCR. Patients with Luminal B tumors had a lower chance of achieving pCR. No pCR was detected in the Luminal A group. In patients with triple negative tumors, a trend could be observed. They seem to have more often pCR, although not statistically significant. Influences on pCR are shown in Table 2.Table 2 Influences on pCR by binary logistic regression
Parameter Odds ratio
Exp (B) P 95% confidence interval
Age 1.022 0.096 0.996–1.048
Time interval
Diagnosis-NACT
0.990 0.450 0.965–1.016
Time interval
NACT-operation
0.982 0.285 0.949–1.016
Study participation 2.355 0.009 1.244–4.458
Genetic mutation 2.203 0.275 0.533–9.103
Recurrent cancers 0.410 0.294 0.077–2.171
Discontinuation of NACT 1.929 0.115 0.852–4.371
Ki67 1.031 < 0.001 1.016–1.047
Grading 4.201 < 0.001 2.206–7.999
Triple negative 1.493 0.219 0.788–2.827
Her2 positive
HR positive
2.053 0.045 1.015–4.150
Her2 positive
HR negative
4.500 0.006 1.526–13.273
Luminal B 0.297 0.001 0.144–0.616
Bold values represents statistically significant
Discussion
This study presents several influences on pCR, with increased chances in patients participating in studies for NACT, having a high Ki67, high grading or Her2 positive tumors. Tumor subtypes like Luminal A and B had decreased chances of pCR.
Age had no influence on pCR in the current study. In contrast, other studies reported that young age is positively associated with pCR [7]. A cutoff value of 40 years was proposed under which the chances of pCR may be higher [17]. However, pCR can also be achieved in elderly patients, especially for Her2 positive patients [8]. So, age alone should not be an indication for NACT.
Neither time between diagnosis and onset of NACT, nor time between the end of chemotherapy and surgery influenced pCR. Consistently, exceeding a presumed cut-off of 4 weeks for onset of NACT or surgery did not influence pCR and disease-free or overall survival independent of histopathological subgroups [18]. However, it was suspected that patients without pCR could benefit from early surgery [18]. At least time intervals up to 8 weeks between NACT and surgery seem not to influence outcomes [19]. In the present study, the median time from diagnosis to NACT and NACT to surgery was about a month with only a minor part exceeding 8 weeks, which complies with German guidelines [20]. This limits the ability to assess the influence of longer time intervals on pCR. However, our results suggest that therapy intervals seem to have a negligible influence on pCR.
More than a third of our patients participated in clinical trials. Study participants for NACT had more than twice as high a chance to achieve pCR. In addition to higher chances for pCR in patients participating in clinical trials, mastectomy rates were lower [21]. However, one must take into account that the patients who are included in clinical studies are mostly a selected collective. On the one hand, this means that there is a disproportionate part of those patients who have a higher probability to achieve pCR due to tumor biology (e.g. high grading and high Ki67). On the other hand, study patients have fewer previous illnesses due to in- and exclusion criteria which can otherwise lead to premature discontinuation of therapy, dose reduction or longer therapy breaks. In the present study, patients receiving NACT in clinical trials had higher rates of Ki67 and higher grading compared to patients receiving standard therapy. This might be the reason for higher pCR rates in the study participants. Furthermore, there was a higher percentage with triple negative tumors in the study group comparing to standard treatment. However, the rate of Her2 positive tumors (which are also associated with higher rates of pCR) was lower in patients participating in clinical trials. Nevertheless, we should encourage our patients to participate in clinical trials. Besides contributing to therapy improvements, they most likely benefit from new therapies. Possible disadvantages of trial participation, such as delaying the onset of NACT or surgery, could be excluded [11, 12].
Only 5% of our patients had a proven genetic mutation (BRCA) for which a superior response to NACT was previously described [10]. Particularly when BRCA positive patients have triple-negative tumors, better outcomes are suspected [22]. We could not prove a significant influence of genetic mutation on pCR.
Likewise, there was no influence of local recurrent cancers on pCR. To our knowledge, this is the first study analyzing a possible influence of local recurrent cancers on the pCR rate. However, no distinction was made whether patients already received prior chemotherapy. In contrast to that, there are analyses describing the association of pCR after NACT on the recurrence of locoregional cancer. An analysis of 10,075 women showed that the local recurrence rate after chemotherapy was higher in patients with non-pCR (9.5% in 67 months) [23].
Discontinuation of chemotherapy due to intolerable side effects did not influence pCR. Patients discontinuing NACT due to disease progress were not included. In general, guidelines recommend the completion of chemotherapy [20]. Our results imply that discontinuation of chemotherapy may not substantially lower chances for pCR. However, it should be considered that this might be due to the small sample size and that most patients only discontinued before the last or the last two chemotherapy doses. Nevertheless, a detrimental effect of early termination of chemotherapy cannot be excluded. Peripheral neurotoxicity was the most common reason why patients had to discontinue chemotherapy (7%). Unfortunately, therapeutic options like pharmacological treatments are limited [24]. Thus, only dose reduction or discontinuation are current options [24]. Nevertheless, premature discontinuation of NACT seems to be uncritical, especially when a good clinical response was already proven. Further studies are needed to confirm our findings.
Ki67 and high grading were associated with high pCR rates (P < 0.001). As Ki67 increases by 1, the probability of a pCR increases by 1.031. This is consistent with findings that especially highly aggressive tumors have a good response to chemotherapy [5, 25]. Triple-negative tumors tend to have better pCR rates without reaching statistical significance. Other studies already showed that triple-negative tumors (as aggressive tumors) were associated with higher pCR rates after NACT [5, 7]. Her2 positive tumors showed higher chances for pCR in our study. This has also been demonstrated in previous studies [26, 27]. It could be shown that patients with Her2 positive, hormone receptor (HR) negative tumors showed the highest rates of pCR. With this tumor biology (Her2+, HR−) the chance to achieve pCR was 4.5 times higher than in other tumor subtypes. Von Minckwitz et al. and Harbeck et al. also observed that Her2 positive tumors respond particularly well to NACT when hormone receptor status is negative [5, 28]. In the present study, even tumors with Her2 positive, hormone receptor positive tumors had a twice as high chance to achieve pCR (P = 0.045). This effect could not be shown in all previous studies [5]. One reason for this might be the change in Her2 directed therapy, as the addition of pertuzumab to trasuzumab and NACT led to a more frequent pCR rate [29, 30]. In the present study, most patients (79%) received Trastuzumab and Pertuzumab. Only a minor part (21%) received Trastuzumab alone.
The subtype Luminal B was associated with a lower chance for pCR. Available data seem contradictory. pCR seems to appear more likely in young patients with hormone receptor-positive, Her2 negative breast cancer [7]. However, large analyzes of 13,939 women showed that the lowest rate of pCR was achieved for Luminal A, followed by Luminal B subtypes, whereas pCR rates of triple-negative and Her2 positive were comparatively higher [27]. Also, patients with progesterone negativity showed higher pCR rates [9]. Taken together, high Ki67, high grading and Her2 positive tumors are notably associated with higher pCR. No pCR was detected in the Luminal A group. This seems not to be surprisingly, as Luminal A cancers are not appropriate for NACT and normally show the lowest rates of pCR [27]. In this analysis, the four patients with Luminal A cancers had locally advanced tumors and received chemotherapy therefore neoadjuvant.
This study has limitations. It is single centric, and thus clinical pathways may differ to other centers. However, data were collected from a certified tertiary breast care center, ensuring that therapies are state of the art. The sample size is small, but many other studies are based on registers obtained from clinical trials for new therapy regimes [5, 7–9, 18, 21], which implies selection bias due to specific inclusion criteria. Our data more likely represents “real-world-data”.
Conclusion
Particularly patients with aggressive tumors (high Ki67, high grading, Her2 positive tumors) had better response rates on NACT. These patients should receive chemotherapy in a neoadjuvant setting. Furthermore, patients participating in clinical trials had higher pCR rates after NACT. Besides contributing to therapy improvements, they most likely benefit from new therapies. We should thus encourage our patients to participate in clinical trials.
Author contribution
All authors contributed to the study conception and design. Material preparation and data collection were performed by Carolin Müller, Lisa Jung and Sarah Huwer. The data analysis was performed by Carolin Müller. The first draft of the manuscript was written by Carolin Müller and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Availability of data and material
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Conflict of interest
All of the authors (Carolin Müller, Gilda Schmidt, Stephanie Juhasz-Böss, Lisa Jung, Sarah Huwer, Erich-Franz Solomayer, Ingolf Juhasz-Böss) declare that they have no conflict of interest.
Ethical approval
This research study was conducted retrospectively from data obtained for clinical purposes. All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Ethics committee of the Saarland Physicians’ chamber) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from every individual participant included in the study. Trial registration number: 207/10 (Ethics committee of the Saarland Physicians’ chamber). This article does not contain any studies with animals performed by any of the authors.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CARBOPLATIN, PERTUZUMAB, TRASTUZUMAB | DrugsGivenReaction | CC BY | 33689016 | 19,047,528 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Polyneuropathy'. | Influences on pathologic complete response in breast cancer patients after neoadjuvant chemotherapy.
Pathologic complete response is associated with longer disease-free survival and better overall survival after neoadjuvant chemotherapy in breast cancer patients. We, therefore, evaluated factors influencing pathologic complete response.
Patients receiving neoadjuvant chemotherapy from 2015 to 2018 at the Saarland University Hospital were included. Patients' age, tumor stage, tumor biology, genetic mutation, recurrent cancer, discontinuation of chemotherapy, and participation in clinical trials were extracted from electronic medical records. Binary logistic regression was performed to evaluate the influence of these factors on pathologic complete response.
Data of 183 patients were included. The median patient's age was 54 years (22-78). The median interval between diagnosis and onset of chemotherapy was 28 days (14-91); between end of chemotherapy and surgery 28 days (9-57). Sixty-two patients (34%) participated in clinical trials for chemotherapy. A total of 86 patients (47%) achieved pathologic complete response. Patient's age, genetic mutation, recurrent cancers, or discontinuation of chemotherapy (due to side effects) and time intervals (between diagnosis and onset of chemotherapy, as well as between end of chemotherapy and surgery) did not influence pathologic complete response. Patients with high Ki67, high grading, Her2 positive tumors, as well as patients participating in clinical trials for chemotherapy had a higher chance of having pathologic complete response. Patients with Luminal B tumors had a lower chance for pathologic complete response.
Particularly patients with high risk cancer and patients, participating in clinical trials benefit most from chemotherapy. Therefore, breast cancer patients can be encouraged to participate in clinical trials for chemotherapy.
pmcIntroduction
Neoadjuvant chemotherapy (NACT) has changed its role for only inoperable and locally advanced breast cancer to a treatment used in early stages of breast cancer [1]. Particularly patients at high risk, like patients with Her2 positive and triple-negative breast cancer benefit from receiving NACT [2, 3]. Pathological complete response (pCR) is associated with a better outcome, meaning that patients having pCR have longer disease-free survival and better overall survival [5].
The definition of pCR varies in individual studies (ypT0/ypTis/ypN0). However, it could be shown that no residual invasive cancer in the breast and axilla is associated with better outcomes compared with no residual cancer in the breast alone [4]. Von Minckwitz et al. even detected a longer disease-free survival in patients with no invasive and no in situ carcinoma in the breast and axilla [5]. Also, tumor subtypes influence the achievement of pCR and thus a better outcome. For example, LeVasseur et al. detected that patients with triple negative tumors had longer relapse-free-survival and breast cancer-specific survival when achieving pCR after NACT [6].
As pCR plays an important role in the outcome of breast cancer, several studies already evaluated possible influencing factors, like age of the patients [7, 8], tumor biology [9] or genetic mutation [10]. The majority of the cited studies analyzed data that was previously collected as part of NACT trials. But patients who are included in clinical studies are mostly a selected collective due to in- and exclusion criteria with fewer previous illnesses, or of a certain subtype or tumor size. For this reason, we wanted to analyze possible influencing factors on pCR in “real-world-data”.
Although, some factors such as age, tumor biology or genetic mutation cannot be influenced directly, it is still important to identify possible risk factors to maybe establish further follow-up therapies or intensified aftercare. We, therefore, determined various clinical factors from electronic patient records and evaluated their influence on the probability of pCR. Parts of the registry were used for two other analyzes before [11, 12]. We could show that especially inpatient and outpatient presentations of the patients delayed therapy onset of NACT and surgery [11, 12].
Patients and methods
Data collection
All patients receiving NACT due to newly diagnosed breast cancer between 2015 to 2018 at the Department of Gynecology, Saarland University Medical Center, were included in the study. The primary endpoint was pCR after NACT. pCR was defined as no residual tumor in the breast and axilla (ypT0, N0). It includes no residual Tis (Carcinoma in situ). Date of diagnosis was defined as the date of core biopsy. Patients’ age, tumor stage, eventual multi-centricity, and tumor biology were recorded. It was distinguished whether the patients received NACT as standard therapy or in a clinical trial. Mainly GAIN II [13], Gepar Octo [14], and Gepar X [15] were addressed from 2015 to 2018 in the Saarland University Medical Center as clinical trials. The time interval between diagnosis and onset of chemotherapy, as well as between end of chemotherapy and surgery, was recorded. The type of operation and duration of hospitalization were documented. Patients who had an indication for BRCA testing according to the guidelines of the German AGO Mamma and the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) were tested for a BRCA mutation. Their recommendations are based on an analysis of 21,401 families [16]. It was registered whether patients had a genetic mutation (BRCA) or recurrent cancer. Recurrent cancer was defined as local recurrence of breast cancer. Patients with local recurrence were included in the study regardless of their previous therapy. If patients discontinued chemotherapy due to therapy complications or disease progress, it was recorded as well.
Data management and statistics
Patients’ data were reviewed in the hospital’s digital documentation system (SAP, Walldorf, Germany). Data were collected using Microsoft Excel 2010® (Microsoft, Redmond, USA). Further statistics were performed with SPSS 24.0 (IBM, Armonk, USA). Quantitative parameters (e.g., patients age, days) are given as median and range. Qualitative parameters (e.g., tumor stage) are presented as frequencies. Binary logistic regression was performed to determine the influence of multiple factors on pCR. Possible influencing factors were age, study participation, tumor biology, genetic mutation (BRCA), recurrent cancer, discontinuation of chemotherapy (due to side effects), days between diagnosis and begin of chemotherapy as well as days between end of chemotherapy and operation. All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from every individual participant included in the study.
Results
Between 2015 and 2018, a total of 205 patients received NACT due to newly diagnosed breast cancer at the Saarland University Medical Center. Twenty-two patients had to be excluded because of insufficient data so that the data of 183 patients were analyzed. The patients median age was 54 years (22–78). The median time between diagnosis and begin of NACT was 28 days (14–91). Between the end of NACT and operation, median time was 28 days (9–57).
Tumor stage and biology, as well as histological subtype and grading are illustrated in Table 1. Twenty-eight patients (15%) had multicentricity. BRCA mutation (9 patients, 5%) and recurrent cancers (7 patients, 4%) were rare. Sixty-two patients (34%) received study therapies: GAIN II (12%), Gepar Octo (10%), GeparX (9%), others (5%). Patients participating in clinical studies had a higher percentage of triple negative tumors (42%) compared to patients without study treatment (26%). Her2 positive tumors are less frequent in the study group (34%), compared to standard therapy regimen (39%). Furthermore, Grading and Ki67 values are higher in patients participating in clinical trials (Grading G3 67% vs. 53%, Ki67 50% vs. 40%). All patients received an Anthracycline and Taxane-based chemotherapy. Fifty-four patients of the Her2 positive group (79%) received chemotherapy in combination with Trastuzumab and Pertuzumab, 21% received chemotherapy in combination with Trastuzumab alone. All patients with triple-negative carcinoma additionally received carboplatin. Thirty-four patients (19%) discontinued NACT. Twenty patients (11%) skipped only the last or the last two chemotherapy doses, whereas 14 patients (8%) received three or more than three doses less. The reasons for a premature discontinuation of chemotherapy were equally distributed in both groups; the major part (16%) due to side effects (polyneuropathy 7%, changes in laboratory values as increased liver values or cytopenia 6%, others 3%). Four patients (2%) discontinued NACT because of tumor progression.Table 1 Tumor characteristics
TNM-stage Absolute frequencies (n) Cumulative frequencies (%)
Staging
ypT
0 89 48.6
1 56 30.6
2 16 8.7
3 7 3.8
4 5 2.7
X 10 5.6
ypN
0 56 30.6
1 26 14.2
2 15 8.2
3 3 1.6
Pre-therapeutic
pN0 (sentinal node) 83 45.4
pN+ 100 54.6
Tumor biology Absolute frequencies (n) Cumulative frequencies (%)
Tumor biology
NST (invasive carcinoma of no special type) 173 94.5
Others 10 5.5
Histological subtype Absolute frequencies (n) Cumulative frequencies (%)
Histology
Luminal A
HR+, Her2 neg, Ki67 ≤ 15% 8 4.4
Luminal B
HR+, Her2 neg, Ki67 > 15% 50 27.3
Her2 positive, HR positive 48 26.2
Her2 positive, HR negative 20 11.0
Triple negative 57 31.1
Grading Absolute frequencies (n) Cumulative frequencies (%)
Grading
G1 2 1.1
G2 74 40.4
G3 105 57.4
X 2 1.1
HR hormone receptor
Most patients received breast-conserving therapy (63%), followed by mastectomy (22%) and oncoplastic surgery (15%). Implants or expander was used for 24 patients (13%). The median time of hospitalization during the operation was 4 days (1–22). Patients with breast-conserving therapy had a median time of hospitalization of 3 days (1–14), patients undergoing mastectomy 6 days (2–17) and patients with oncoplastic surgery 7 days (2–22).
A total of 86 patients (47%) had pCR. The patients age, genetic mutation, recurrent cancer, or discontinuation of chemotherapy (due to side effects) did not influence pCR. Likewise, time between diagnosis and onset of NACT, or time between end of NACT and surgery, had no influence on pCR. Patients participating in clinical trials for NACT, higher tumor grade, high Ki67 and Her2 positive tumors had increased chances of having pCR. Patients with Luminal B tumors had a lower chance of achieving pCR. No pCR was detected in the Luminal A group. In patients with triple negative tumors, a trend could be observed. They seem to have more often pCR, although not statistically significant. Influences on pCR are shown in Table 2.Table 2 Influences on pCR by binary logistic regression
Parameter Odds ratio
Exp (B) P 95% confidence interval
Age 1.022 0.096 0.996–1.048
Time interval
Diagnosis-NACT
0.990 0.450 0.965–1.016
Time interval
NACT-operation
0.982 0.285 0.949–1.016
Study participation 2.355 0.009 1.244–4.458
Genetic mutation 2.203 0.275 0.533–9.103
Recurrent cancers 0.410 0.294 0.077–2.171
Discontinuation of NACT 1.929 0.115 0.852–4.371
Ki67 1.031 < 0.001 1.016–1.047
Grading 4.201 < 0.001 2.206–7.999
Triple negative 1.493 0.219 0.788–2.827
Her2 positive
HR positive
2.053 0.045 1.015–4.150
Her2 positive
HR negative
4.500 0.006 1.526–13.273
Luminal B 0.297 0.001 0.144–0.616
Bold values represents statistically significant
Discussion
This study presents several influences on pCR, with increased chances in patients participating in studies for NACT, having a high Ki67, high grading or Her2 positive tumors. Tumor subtypes like Luminal A and B had decreased chances of pCR.
Age had no influence on pCR in the current study. In contrast, other studies reported that young age is positively associated with pCR [7]. A cutoff value of 40 years was proposed under which the chances of pCR may be higher [17]. However, pCR can also be achieved in elderly patients, especially for Her2 positive patients [8]. So, age alone should not be an indication for NACT.
Neither time between diagnosis and onset of NACT, nor time between the end of chemotherapy and surgery influenced pCR. Consistently, exceeding a presumed cut-off of 4 weeks for onset of NACT or surgery did not influence pCR and disease-free or overall survival independent of histopathological subgroups [18]. However, it was suspected that patients without pCR could benefit from early surgery [18]. At least time intervals up to 8 weeks between NACT and surgery seem not to influence outcomes [19]. In the present study, the median time from diagnosis to NACT and NACT to surgery was about a month with only a minor part exceeding 8 weeks, which complies with German guidelines [20]. This limits the ability to assess the influence of longer time intervals on pCR. However, our results suggest that therapy intervals seem to have a negligible influence on pCR.
More than a third of our patients participated in clinical trials. Study participants for NACT had more than twice as high a chance to achieve pCR. In addition to higher chances for pCR in patients participating in clinical trials, mastectomy rates were lower [21]. However, one must take into account that the patients who are included in clinical studies are mostly a selected collective. On the one hand, this means that there is a disproportionate part of those patients who have a higher probability to achieve pCR due to tumor biology (e.g. high grading and high Ki67). On the other hand, study patients have fewer previous illnesses due to in- and exclusion criteria which can otherwise lead to premature discontinuation of therapy, dose reduction or longer therapy breaks. In the present study, patients receiving NACT in clinical trials had higher rates of Ki67 and higher grading compared to patients receiving standard therapy. This might be the reason for higher pCR rates in the study participants. Furthermore, there was a higher percentage with triple negative tumors in the study group comparing to standard treatment. However, the rate of Her2 positive tumors (which are also associated with higher rates of pCR) was lower in patients participating in clinical trials. Nevertheless, we should encourage our patients to participate in clinical trials. Besides contributing to therapy improvements, they most likely benefit from new therapies. Possible disadvantages of trial participation, such as delaying the onset of NACT or surgery, could be excluded [11, 12].
Only 5% of our patients had a proven genetic mutation (BRCA) for which a superior response to NACT was previously described [10]. Particularly when BRCA positive patients have triple-negative tumors, better outcomes are suspected [22]. We could not prove a significant influence of genetic mutation on pCR.
Likewise, there was no influence of local recurrent cancers on pCR. To our knowledge, this is the first study analyzing a possible influence of local recurrent cancers on the pCR rate. However, no distinction was made whether patients already received prior chemotherapy. In contrast to that, there are analyses describing the association of pCR after NACT on the recurrence of locoregional cancer. An analysis of 10,075 women showed that the local recurrence rate after chemotherapy was higher in patients with non-pCR (9.5% in 67 months) [23].
Discontinuation of chemotherapy due to intolerable side effects did not influence pCR. Patients discontinuing NACT due to disease progress were not included. In general, guidelines recommend the completion of chemotherapy [20]. Our results imply that discontinuation of chemotherapy may not substantially lower chances for pCR. However, it should be considered that this might be due to the small sample size and that most patients only discontinued before the last or the last two chemotherapy doses. Nevertheless, a detrimental effect of early termination of chemotherapy cannot be excluded. Peripheral neurotoxicity was the most common reason why patients had to discontinue chemotherapy (7%). Unfortunately, therapeutic options like pharmacological treatments are limited [24]. Thus, only dose reduction or discontinuation are current options [24]. Nevertheless, premature discontinuation of NACT seems to be uncritical, especially when a good clinical response was already proven. Further studies are needed to confirm our findings.
Ki67 and high grading were associated with high pCR rates (P < 0.001). As Ki67 increases by 1, the probability of a pCR increases by 1.031. This is consistent with findings that especially highly aggressive tumors have a good response to chemotherapy [5, 25]. Triple-negative tumors tend to have better pCR rates without reaching statistical significance. Other studies already showed that triple-negative tumors (as aggressive tumors) were associated with higher pCR rates after NACT [5, 7]. Her2 positive tumors showed higher chances for pCR in our study. This has also been demonstrated in previous studies [26, 27]. It could be shown that patients with Her2 positive, hormone receptor (HR) negative tumors showed the highest rates of pCR. With this tumor biology (Her2+, HR−) the chance to achieve pCR was 4.5 times higher than in other tumor subtypes. Von Minckwitz et al. and Harbeck et al. also observed that Her2 positive tumors respond particularly well to NACT when hormone receptor status is negative [5, 28]. In the present study, even tumors with Her2 positive, hormone receptor positive tumors had a twice as high chance to achieve pCR (P = 0.045). This effect could not be shown in all previous studies [5]. One reason for this might be the change in Her2 directed therapy, as the addition of pertuzumab to trasuzumab and NACT led to a more frequent pCR rate [29, 30]. In the present study, most patients (79%) received Trastuzumab and Pertuzumab. Only a minor part (21%) received Trastuzumab alone.
The subtype Luminal B was associated with a lower chance for pCR. Available data seem contradictory. pCR seems to appear more likely in young patients with hormone receptor-positive, Her2 negative breast cancer [7]. However, large analyzes of 13,939 women showed that the lowest rate of pCR was achieved for Luminal A, followed by Luminal B subtypes, whereas pCR rates of triple-negative and Her2 positive were comparatively higher [27]. Also, patients with progesterone negativity showed higher pCR rates [9]. Taken together, high Ki67, high grading and Her2 positive tumors are notably associated with higher pCR. No pCR was detected in the Luminal A group. This seems not to be surprisingly, as Luminal A cancers are not appropriate for NACT and normally show the lowest rates of pCR [27]. In this analysis, the four patients with Luminal A cancers had locally advanced tumors and received chemotherapy therefore neoadjuvant.
This study has limitations. It is single centric, and thus clinical pathways may differ to other centers. However, data were collected from a certified tertiary breast care center, ensuring that therapies are state of the art. The sample size is small, but many other studies are based on registers obtained from clinical trials for new therapy regimes [5, 7–9, 18, 21], which implies selection bias due to specific inclusion criteria. Our data more likely represents “real-world-data”.
Conclusion
Particularly patients with aggressive tumors (high Ki67, high grading, Her2 positive tumors) had better response rates on NACT. These patients should receive chemotherapy in a neoadjuvant setting. Furthermore, patients participating in clinical trials had higher pCR rates after NACT. Besides contributing to therapy improvements, they most likely benefit from new therapies. We should thus encourage our patients to participate in clinical trials.
Author contribution
All authors contributed to the study conception and design. Material preparation and data collection were performed by Carolin Müller, Lisa Jung and Sarah Huwer. The data analysis was performed by Carolin Müller. The first draft of the manuscript was written by Carolin Müller and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Availability of data and material
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Conflict of interest
All of the authors (Carolin Müller, Gilda Schmidt, Stephanie Juhasz-Böss, Lisa Jung, Sarah Huwer, Erich-Franz Solomayer, Ingolf Juhasz-Böss) declare that they have no conflict of interest.
Ethical approval
This research study was conducted retrospectively from data obtained for clinical purposes. All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Ethics committee of the Saarland Physicians’ chamber) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from every individual participant included in the study. Trial registration number: 207/10 (Ethics committee of the Saarland Physicians’ chamber). This article does not contain any studies with animals performed by any of the authors.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CARBOPLATIN, PERTUZUMAB, TRASTUZUMAB | DrugsGivenReaction | CC BY | 33689016 | 19,047,528 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Decreased appetite'. | Pancreaticoduodenectomy combined with splenectomy for a patient with pancreatic cancer and pancytopenia due to liver cirrhosis: Case report.
The incidence of patients with liver cirrhosis (LC) is increasing. Patients with LC are known to have a greater risk of postoperative morbidity and mortality than patients without LC. A treatment option such as pancreaticoduodenectomy (PD) has not been validated to be safe for these patients, especially those with pancytopenia due to portal hypertension (PH). Providing an effective treatment option for these patients is essential.
METHODS
Herein, we describe a patient with pancreatic cancer with pancytopenia due to LC that was successfully treated with PD combined with splenectomy. The patient was a 70-year-old woman who was referred to our hospital for evaluation of a mass in the pancreatic head after she developed obstructive jaundice. She was diagnosed with T2N0M0, Stage IB pancreatic cancer and pancytopenia due to PH associated with LC. She received 2 cycles of adjuvant gemcitabine/S-1 chemotherapy and underwent radical subtotal stomach-preserving pancreaticoduodenectomy with splenectomy to improve her pancytopenia. Histopathological examination of the resected specimen revealed an R0 resection showing an Evans grade IIa histological response. Her pancytopenia improved rapidly after surgery.
Strict indications for PD, haemostatic control of intraoperative bleeding, and optimal perioperative management were important for preventing hepatic decompensation in this patient. Splenectomy is effective for thrombocytopenia due to LC; however, attention to postoperative complications such as overwhelming post-splenectomy infection and portal vein thrombosis is required.
CONCLUSIONS
For patients with pancreatic cancer with pancytopenia due to LC, PD combined with splenectomy plus optimal perioperative management is effective.
1 Introduction
Patients with liver cirrhosis (LC) have been recognized to have a greater risk of postoperative morbidity and mortality than patients without LC [1,2]. The safety of pancreaticoduodenectomy (PD) for patients with chronic hepatic dysfunction due to LC has not been validated. The risk of pancreaticoduodenectomy (PD) for patients increases with the progression of LC, because of the development of pancytopenia due to portal hypertension (PH) and secondary hypersplenism.
Perioperative chemotherapy has played an increasingly important role in the treatment of patients with pancreatic cancer (PC). Therefore, it is important to provide appropriate treatment options, including chemotherapy, for a patient with PC and pancytopenia due to LC. Herein we describe a patient with PC with pancytopenia due to LC who was successfully treated by PD combined with splenectomy, which enabled the safe postoperative administration of chemotherapy. We report this case in accordance with the 2020 SCARE criteria [3].
2 Case report
A 70-year-old woman with obstructive jaundice underwent percutaneous transhepatic biliary drainage instead of endoscopic biliary drainage because of her duodenal stenosis. She was then referred to our hospital for evaluation of a pancreatic head lesion that had been identified on an abdominal computed tomography (CT) scan performed when her jaundice had been discovered. She had a past history of endovascular aneurysmal repair (EVAR) for an abdominal aortic aneurysm one year previously and an appendectomy followed by surgery for an ileus when she was 10 years of age. Her family history was negative for pancreatic cancer and genetic disorders. She was 151 cm tall and weighed 60 kg. Her body-mass index was 26.3. The results of her physical examination were unremarkable.
Laboratory analysis revealed pancytopenia (white blood cell count 2710/μL, red blood cell count 366 × 104/μL, haemoglobin 10.9 g/dL, platelet count 89 × 103/μL) and CA19−9 3909 U/mL). She was negative for hepatitis B surface antigen and anti-hepatitis C virus antibody. Her Child-Pugh score and Model for End-stage Liver Disease (MELD) score were Grade 5A and 9, respectively [[4], [5], [6]]. Enhanced multidetector-row computed tomography (CT) revealed a 25-mm hypovascular tumour in the pancreatic groove, which had invaded the duodenum and lower bile duct (Fig. 1a). No other metastases involving distant organs were seen. Dullness of the hepatic margins was observed, and the spleen appeared enlarged, with a maximum diameter of 15 cm, suggesting portal hypertension (PH) (Fig. 1b). Endoscopic ultrasound-guided fine needle aspiration was performed. The cytopathological findings revealed pancreatic adenocarcinoma. Based on the 8th edition of the UICC criteria, the findings were diagnosed to be T2N0M0, Stage IB pancreatic carcinoma.Fig. 1 Pretreatment coronal enhanced computed tomography images.
a) Hypovascular 25-mm tumour (white arrow) in the pancreatic groove invading the duodenum and lower bile duct.
b) Splenomegaly with a maximum splenic diameter of 15 cm, which suggests portal hypertension.
Fig. 1
In accordance with the findings of the phase 2/3 Prep-02/JSAP05 trial [7], the patient underwent neoadjuvant gemcitabine/S-1 (GS) chemotherapy (gemcitabine [800 mg/m2] on days 1, 8 and S-1 [100 mg/m2] on days 1–14 of a 21-day cycle) repeated every 3 weeks for 2 cycles. Because of the patient’s pretreatment pancytopenia (neutrophil count 2250/μL), gemcitabine and S-1 were reduced by 200 mg/m2/day to 800 mg/m2/day, and 20 mg/m2/day to 100 mg/m2/day, respectively. Even after the dose reduction, neutropenia (neutrophil count 1340/μL) was observed during 1 cycle of GS, and chemotherapy was withheld until the neutropenia was resolved. Although the patient’s serum CA 19−9 level decreased after 2 cycles of GS chemotherapy, it remained elevated (CA 19−9 1064 U/mL). After 2 cycles, the primary tumour had slightly decreased to a diameter of 24 mm. Since the level of her CA19−9 tumour marker remained elevated, her risk of postoperative recurrence after PD was high. However, if the tumour recurred, the administration of intensive chemotherapy such as FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) and gemcitabine/nab-paclitaxel regimens would be difficult because of the patient’s pancytopenia. Therefore, we elected to perform a splenectomy in addition to the PD to improve her pancytopenia.
Splenectomy for splenomegaly with PH occasionally results in loss of a large amount of blood, which requires a large transfusion. The transfusion leads to oedema of the intestinal wall, which can increase the difficulty of performing a PD. Therefore, we decided to perform the PD followed by splenectomy.
The intraoperative findings revealed a liver with a granular surface and dullness of the liver’s edge (Fig. 2). We performed extensive detachment of the adhesions due to the patient’s previous appendectomy and subsequent surgery for an ileus, and found that detaching the hepatoduodenal ligament was difficult because of her repeated preoperative episodes of cholangitis. Since the collateral hepatic circulation that had developed bled easily, haemostasis was performed safely by ligation. After the PD, we began the splenectomy. We first detached and ligated the splenic artery (SA) at the upper edge of the pancreatic body to shrink the spleen and reduce the amount of blood loss. The splenic vein (SV) was also ligated, but the splenic hilum bled heavily because of tension on the SV. Haemostasis was performed by ligation while elevating the splenic hilum from the dorsal side. Finally, we performed a radical subtotal stomach-preserving PD with splenectomy, and lymph node dissections of groups 1 and 2 that included the hepatoduodenal ligament caudal to the hilar plate. The operative time was 12 h and 7 min, and the volume of blood loss was 1990 mL.Fig. 2 Intraoperative image.
Intraoperative findings show the dullness of the liver’s edge and its granular surface.
Fig. 2
The excised specimens showed a solid tumour in the pancreatic head which had invaded the duodenum and bile duct (Fig. 3a), and splenomegaly (Fig. 3b). The histopathological diagnosis was invasive ductal carcinoma with severe venous invasion and moderate nerve infiltration, ypT2N0M0, ypStage IB pancreatic cancer, as based on the 8th Edition of the UICC criteria and grade IIa as based on the Evans classification [8] (Fig. 4).Fig. 3 Macroscopic views of the resected specimens.
a) Macroscopic image of the resected specimen shows a mass in the pancreatic head, which has invaded the duodenum and bile duct.
b) The resected spleen is enlarged.
Fig. 3
Fig. 4 Photomicrograph (haematoxylin-and-eosin stain).
Malignant cells (arrows) have invaded the bile ducts (arrowheads).
Fig. 4
The patient’s pancytopenia improved rapidly after surgery. The platelet count increased rapidly after splenectomy, peaking at 681,000/μL on postoperative day (POD) 16, and then decreasing to the normal range (Fig. 5). However, the patient developed atelectasis and splenic vein thrombosis, which were considered Grade II complications in accordance with the Clavien-Dindo classification. The patient received high-flow nasal oxygen therapy and noninvasive positive-pressure ventilation, including bilevel positive airway pressure, and was prescribed an anticoagulant agent for the thrombosis. The patient was moved out of the intensive care unit on POD 5, and discharged on POD 30. After having received adjuvant chemotherapy with S-1 for 2 months due to the anorexia, the patient underwent blood tests and CT scans every 3 months. Nine months after her PD, a liver metastasis was detected, for which she received chemotherapy. She has remained alive for 13 months after her PD.Fig. 5 Graph of platelet and white blood cell counts over the patient’s hospital course.
GS: Neoadjuvant gemcitabine/S-1 chemotherapy
Adjuvant S-1: Adjuvant S-1 chemotherapy
Fig. 5
3 Discussion
The outcomes of surgery in patients with LC have been reported to vary, based not only on the degree of damage to the liver but also the invasiveness of the surgery [9]. The reported mortality of major abdominal surgery for patients with LC is 35% [10]. The Child-Pugh classification and the MELD score have been useful for estimating the risk of surgical mortality. According to the Child-Pugh classification, the mortality rates for major abdominal surgery have been 10%, 30%, and 76%–82% for Child-Pugh classifications A, B, and C, respectively [11]. Whereas, according to the MELD score, the 30-day mortalities after surgery were reported to be 6% for MELD < 8 and 50% for MELD > 20 [12]. However, until now, to our best knowledge, only a few studies have been published on the outcomes of PD in patients with LC. A retrospective multicentre study reported that PH and a serum aspartate aminotransferase (AST) of <50 IU/L were significant independent risk factors for hepatic decompensation, and an AST of < 50 IU/L and an AST-to-platelet-ratio index (APRI) ≥ 1.0 for a patient with a Child-Pugh B classification may be indications that PD can be performed [13]. At the first visit, our patient’s AST value, APRI value, and Child-Pugh score were 57 IU/L, 1.6, and 5A, respectively. After 2 cycles of GS, her preoperative AST and APRI values had decreased to 22 IU/L and 0.5, respectively. Therefore, our patient had appropriate indications for undergoing a PD. Her postoperative Child-Pugh score has remained 5–6 (Class A), with no increase in the APRI (Table 1). The increase in the postoperative MELD score was considered to be due to her anorexia associated with S1 adjuvant chemotherapy.Table 1 Table of perioperative Child-Pugh and MELD scores and APRI score.
Table 1 Pre-treatment After 2 cycles of GS POM1 POM2 POM3 POM4 POM5 POM6
Child-Pugh score 5 5 5 5 5 6 6 5
MELD score 9 3 1 0 1 3 5 3
APRI 1.6 0.5 0.2 0.1 0.1 0.1 0.1 0.1
APRI: AST-to-platelet-ratio index.
GS: Neoadjuvant gemcitabine/S-1 chemotherapy.
POM: Postoperative month.
Pancytopenia has a wide range of aetiologies, including malignancies (leukaemia, malignant lymphoma, myelodysplastic syndrome, myeloma), autoimmune conditions (aplastic anaemia, systemic lupus erythematosus [SLE]), hypersplenism due to LC, drugs, infections, and nutritional deficiencies, so the evaluation of a patient with pancytopenia requires a comprehensive approach [14]. Regarding the patient’s thrombocytopenia, the causes of thrombocytopenia often overlap with the causes of pancytopenia [15]. Because our patient did not have lymphadenopathy, SLE, recent extensive thrombosis, blasts or atypical cells at peripheral blood tests, abnormal findings in her bone marrow, abnormal lymph nodes on CT or PET-CT, signs of infection, recent changes in oral medication, or a history of gastrectomy, we excluded malignancies, autoimmune conditions, drug reactions, infections, and nutritional deficiencies from the differential diagnosis. CT showed dullness of the hepatic margins, splenomegaly, and presence of a collateral circulation; we concluded that her pancytopenia, including her thrombocytopenia, was caused by hypersplenism due to LC. Therefore, we did not think that a bone-marrow biopsy was a priority, compared with preoperative chemotherapy for pancreatic cancer.
Thrombocytopenia (platelet count < 150,000/μL) [16] can occur with the progression of LC. The production of thrombopoietin and sequestration of platelets in the spleen are the main mechanisms involved in the development of thrombocytopenia [17]. The treatments for thrombocytopenia due to LC have included platelet transfusions, medications, embolization of the SA, and splenectomy [18]. With our patient’s elevated CA19−9 level, the risk of recurrence of her pancreatic cancer was considered high, and we elected to add treatment for improving her pancytopenia in order to enable the safe administration of chemotherapy after her recurrence. Platelet transfusion was not performed because of her splenomegaly and because of the possibility of platelet sequestration followed by destruction. We did not administer a thrombopoietin receptor agonist such as eltrombopag, which is effective for thrombocytopenia, because the patient required treatment not only for her thrombocytopenia but also for her pancytopenia. Whether a partial splenic artery embolization (PSAE) or splenectomy should have been performed has been controversial. The complications of PSAE include peritonitis, splenic abscess, and portal vein thrombosis. Additionally, PSAE is an invasive procedure, with both significant cost and uncertain long-term benefits. These limitations make PSAE an unsuitable option for many patients with advanced LC [17]. Furthermore, Miyake et al. reported that platelet counts after splenectomy were significantly increased over platelet counts after PSAE [19]. On the other hand, although splenectomy is an effective option for improving pancytopenia, it is also invasive and occasionally results in massive loss of blood. Additionally, the main complications after splenectomy are overwhelming post-splenectomy infections (OPSIs), approximately 80% of which are pneumococcal, and portal vein thrombosis. The reported incidence of portal vein thrombosis after splenectomy for splenomegaly has ranged from 9% to 29% [17].
For our patient, we debated about performing a splenectomy. Ligation or embolization of the SA was also considered, but we considered the effect of those procedures to be limited, because the blood supply of the spleen was delivered via collateral circulation, including the left gastric artery, the stomach wall, and the middle colic artery [20,21]. Therefore, we decided to perform a splenectomy, which seemed to provide the most reliable effect of increasing the blood cell count for the chemotherapy after recurrence of pancreatic cancer [19]. After confirmation that there were no distant metastases after neoadjuvant chemotherapy, we finally performed a radical PD combined with splenectomy following the approval by a multidisciplinary team a few days before the surgery. The patient also received postoperative pneumococcal vaccine to prevent OPSI before she underwent chemotherapy. However, the vaccine should have been administered before surgery in this high-risk patient.
With regard to preoperative chemotherapy, Karl et al. reported the usefulness and low toxicity of chemotherapy administered by intra-arterial infusion, including isolated abdominal perfusion [22]. However, our patient also had an abdominal aortic aneurysm with type 2 endoleak despite her previous EVAR, so catheterization was considered to be difficult. Additionally, her pretreatment CA19−9 level was very high (CA19−9 3909 U/mL), suggesting the possibility of micrometastases. Therefore, we elected to perform dose-reduced systemic chemotherapy for the early treatment and suppression of micrometastatic disease.
To our best knowledge, when limited to cases of PD synchronous with splenectomy for PC with pancytopenia due to LC, a total of 2 cases have been reported, including our case [23]. As in our patient, who lost a large volume of blood, Futagawa et al. reported a large blood loss (1700 mL). In patients with LC, bleeding occurs readily because of PH and decreased coagulability, and there is concern that hepatic function may deteriorate because of blood transfusions. Therefore, the control of intraoperative bleeding by reliable haemostasis is important. Furthermore, in patients with PH in whom collateral circulation develops, attention must be paid to the extent of lymph node dissection. Dissection of the hepatoduodenal ligament interrupts the collateral circulation, which can lead to refractory ascites and hepatic decompensation. Group 1 and 2 lymph node dissections were performed for our patient, who did not develop hepatic decompensation. However, careful planning that takes into consideration a patient’s overall condition and degree of liver damage is needed before surgery for these patients.
When PD is performed for a patient with LC, prevention of hepatic decompensation, which is directly is associated with mortality, is the most important consideration. Optimal perioperative management may decrease morbidity and mortality following surgery. Perioperative management for patients with LC includes nutritional management, control of refractory ascites and glucose levels, and correction of coagulopathy. These measures can help in preventing infection, hepatic encephalopathy and hepatic decompensation [24]. In our case, enteral nutrition therapy was started immediately after surgery for nutritional management and the prevention of postoperative infections [25]. In addition, since patients with LC who undergo PD, which is a highly invasive procedure, have increased risk of postoperative morbidity and mortality, careful monitoring and follow up are essential.
4 Conclusions
Strict indications for PD, control of intraoperative bleeding, and optimal perioperative management are important for preventing hepatic decompensation. Even for patients with PC and pancytopenia due to LC, PD combined with splenectomy is an effective treatment option.
Declaration of Competing Interest
The authors declare that they have no competing interests.
Funding
This study did not receive any specific grants from funding agencies in the public, commercial, and not-for-profit sectors.
Ethical approval
This study was exempt from ethical approval at our institution.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
HT (certified by the Japanese Society of Gastroenterological Surgery) performed the surgery on this patient. IH, HT, KM, and TH managed the postoperative course of this patient. HT and HI wrote the manuscript. All authors have read and approved the final manuscript.
Registration of research studies
Not Applicable.
Guarantor
Hideharu Tanaka (Corresponding author and guarantor).
Provenance and peer review
Not commissioned, externally peer-reviewed.
Availability of data and materials
Not applicable.
Acknowledgements
The authors wish to thank JAM Post for the editing of a draft of this manuscript. | GEMCITABINE, GIMERACIL\OTERACIL\TEGAFUR | DrugsGivenReaction | CC BY | 33689973 | 19,088,732 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metastases to liver'. | Pancreaticoduodenectomy combined with splenectomy for a patient with pancreatic cancer and pancytopenia due to liver cirrhosis: Case report.
The incidence of patients with liver cirrhosis (LC) is increasing. Patients with LC are known to have a greater risk of postoperative morbidity and mortality than patients without LC. A treatment option such as pancreaticoduodenectomy (PD) has not been validated to be safe for these patients, especially those with pancytopenia due to portal hypertension (PH). Providing an effective treatment option for these patients is essential.
METHODS
Herein, we describe a patient with pancreatic cancer with pancytopenia due to LC that was successfully treated with PD combined with splenectomy. The patient was a 70-year-old woman who was referred to our hospital for evaluation of a mass in the pancreatic head after she developed obstructive jaundice. She was diagnosed with T2N0M0, Stage IB pancreatic cancer and pancytopenia due to PH associated with LC. She received 2 cycles of adjuvant gemcitabine/S-1 chemotherapy and underwent radical subtotal stomach-preserving pancreaticoduodenectomy with splenectomy to improve her pancytopenia. Histopathological examination of the resected specimen revealed an R0 resection showing an Evans grade IIa histological response. Her pancytopenia improved rapidly after surgery.
Strict indications for PD, haemostatic control of intraoperative bleeding, and optimal perioperative management were important for preventing hepatic decompensation in this patient. Splenectomy is effective for thrombocytopenia due to LC; however, attention to postoperative complications such as overwhelming post-splenectomy infection and portal vein thrombosis is required.
CONCLUSIONS
For patients with pancreatic cancer with pancytopenia due to LC, PD combined with splenectomy plus optimal perioperative management is effective.
1 Introduction
Patients with liver cirrhosis (LC) have been recognized to have a greater risk of postoperative morbidity and mortality than patients without LC [1,2]. The safety of pancreaticoduodenectomy (PD) for patients with chronic hepatic dysfunction due to LC has not been validated. The risk of pancreaticoduodenectomy (PD) for patients increases with the progression of LC, because of the development of pancytopenia due to portal hypertension (PH) and secondary hypersplenism.
Perioperative chemotherapy has played an increasingly important role in the treatment of patients with pancreatic cancer (PC). Therefore, it is important to provide appropriate treatment options, including chemotherapy, for a patient with PC and pancytopenia due to LC. Herein we describe a patient with PC with pancytopenia due to LC who was successfully treated by PD combined with splenectomy, which enabled the safe postoperative administration of chemotherapy. We report this case in accordance with the 2020 SCARE criteria [3].
2 Case report
A 70-year-old woman with obstructive jaundice underwent percutaneous transhepatic biliary drainage instead of endoscopic biliary drainage because of her duodenal stenosis. She was then referred to our hospital for evaluation of a pancreatic head lesion that had been identified on an abdominal computed tomography (CT) scan performed when her jaundice had been discovered. She had a past history of endovascular aneurysmal repair (EVAR) for an abdominal aortic aneurysm one year previously and an appendectomy followed by surgery for an ileus when she was 10 years of age. Her family history was negative for pancreatic cancer and genetic disorders. She was 151 cm tall and weighed 60 kg. Her body-mass index was 26.3. The results of her physical examination were unremarkable.
Laboratory analysis revealed pancytopenia (white blood cell count 2710/μL, red blood cell count 366 × 104/μL, haemoglobin 10.9 g/dL, platelet count 89 × 103/μL) and CA19−9 3909 U/mL). She was negative for hepatitis B surface antigen and anti-hepatitis C virus antibody. Her Child-Pugh score and Model for End-stage Liver Disease (MELD) score were Grade 5A and 9, respectively [[4], [5], [6]]. Enhanced multidetector-row computed tomography (CT) revealed a 25-mm hypovascular tumour in the pancreatic groove, which had invaded the duodenum and lower bile duct (Fig. 1a). No other metastases involving distant organs were seen. Dullness of the hepatic margins was observed, and the spleen appeared enlarged, with a maximum diameter of 15 cm, suggesting portal hypertension (PH) (Fig. 1b). Endoscopic ultrasound-guided fine needle aspiration was performed. The cytopathological findings revealed pancreatic adenocarcinoma. Based on the 8th edition of the UICC criteria, the findings were diagnosed to be T2N0M0, Stage IB pancreatic carcinoma.Fig. 1 Pretreatment coronal enhanced computed tomography images.
a) Hypovascular 25-mm tumour (white arrow) in the pancreatic groove invading the duodenum and lower bile duct.
b) Splenomegaly with a maximum splenic diameter of 15 cm, which suggests portal hypertension.
Fig. 1
In accordance with the findings of the phase 2/3 Prep-02/JSAP05 trial [7], the patient underwent neoadjuvant gemcitabine/S-1 (GS) chemotherapy (gemcitabine [800 mg/m2] on days 1, 8 and S-1 [100 mg/m2] on days 1–14 of a 21-day cycle) repeated every 3 weeks for 2 cycles. Because of the patient’s pretreatment pancytopenia (neutrophil count 2250/μL), gemcitabine and S-1 were reduced by 200 mg/m2/day to 800 mg/m2/day, and 20 mg/m2/day to 100 mg/m2/day, respectively. Even after the dose reduction, neutropenia (neutrophil count 1340/μL) was observed during 1 cycle of GS, and chemotherapy was withheld until the neutropenia was resolved. Although the patient’s serum CA 19−9 level decreased after 2 cycles of GS chemotherapy, it remained elevated (CA 19−9 1064 U/mL). After 2 cycles, the primary tumour had slightly decreased to a diameter of 24 mm. Since the level of her CA19−9 tumour marker remained elevated, her risk of postoperative recurrence after PD was high. However, if the tumour recurred, the administration of intensive chemotherapy such as FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) and gemcitabine/nab-paclitaxel regimens would be difficult because of the patient’s pancytopenia. Therefore, we elected to perform a splenectomy in addition to the PD to improve her pancytopenia.
Splenectomy for splenomegaly with PH occasionally results in loss of a large amount of blood, which requires a large transfusion. The transfusion leads to oedema of the intestinal wall, which can increase the difficulty of performing a PD. Therefore, we decided to perform the PD followed by splenectomy.
The intraoperative findings revealed a liver with a granular surface and dullness of the liver’s edge (Fig. 2). We performed extensive detachment of the adhesions due to the patient’s previous appendectomy and subsequent surgery for an ileus, and found that detaching the hepatoduodenal ligament was difficult because of her repeated preoperative episodes of cholangitis. Since the collateral hepatic circulation that had developed bled easily, haemostasis was performed safely by ligation. After the PD, we began the splenectomy. We first detached and ligated the splenic artery (SA) at the upper edge of the pancreatic body to shrink the spleen and reduce the amount of blood loss. The splenic vein (SV) was also ligated, but the splenic hilum bled heavily because of tension on the SV. Haemostasis was performed by ligation while elevating the splenic hilum from the dorsal side. Finally, we performed a radical subtotal stomach-preserving PD with splenectomy, and lymph node dissections of groups 1 and 2 that included the hepatoduodenal ligament caudal to the hilar plate. The operative time was 12 h and 7 min, and the volume of blood loss was 1990 mL.Fig. 2 Intraoperative image.
Intraoperative findings show the dullness of the liver’s edge and its granular surface.
Fig. 2
The excised specimens showed a solid tumour in the pancreatic head which had invaded the duodenum and bile duct (Fig. 3a), and splenomegaly (Fig. 3b). The histopathological diagnosis was invasive ductal carcinoma with severe venous invasion and moderate nerve infiltration, ypT2N0M0, ypStage IB pancreatic cancer, as based on the 8th Edition of the UICC criteria and grade IIa as based on the Evans classification [8] (Fig. 4).Fig. 3 Macroscopic views of the resected specimens.
a) Macroscopic image of the resected specimen shows a mass in the pancreatic head, which has invaded the duodenum and bile duct.
b) The resected spleen is enlarged.
Fig. 3
Fig. 4 Photomicrograph (haematoxylin-and-eosin stain).
Malignant cells (arrows) have invaded the bile ducts (arrowheads).
Fig. 4
The patient’s pancytopenia improved rapidly after surgery. The platelet count increased rapidly after splenectomy, peaking at 681,000/μL on postoperative day (POD) 16, and then decreasing to the normal range (Fig. 5). However, the patient developed atelectasis and splenic vein thrombosis, which were considered Grade II complications in accordance with the Clavien-Dindo classification. The patient received high-flow nasal oxygen therapy and noninvasive positive-pressure ventilation, including bilevel positive airway pressure, and was prescribed an anticoagulant agent for the thrombosis. The patient was moved out of the intensive care unit on POD 5, and discharged on POD 30. After having received adjuvant chemotherapy with S-1 for 2 months due to the anorexia, the patient underwent blood tests and CT scans every 3 months. Nine months after her PD, a liver metastasis was detected, for which she received chemotherapy. She has remained alive for 13 months after her PD.Fig. 5 Graph of platelet and white blood cell counts over the patient’s hospital course.
GS: Neoadjuvant gemcitabine/S-1 chemotherapy
Adjuvant S-1: Adjuvant S-1 chemotherapy
Fig. 5
3 Discussion
The outcomes of surgery in patients with LC have been reported to vary, based not only on the degree of damage to the liver but also the invasiveness of the surgery [9]. The reported mortality of major abdominal surgery for patients with LC is 35% [10]. The Child-Pugh classification and the MELD score have been useful for estimating the risk of surgical mortality. According to the Child-Pugh classification, the mortality rates for major abdominal surgery have been 10%, 30%, and 76%–82% for Child-Pugh classifications A, B, and C, respectively [11]. Whereas, according to the MELD score, the 30-day mortalities after surgery were reported to be 6% for MELD < 8 and 50% for MELD > 20 [12]. However, until now, to our best knowledge, only a few studies have been published on the outcomes of PD in patients with LC. A retrospective multicentre study reported that PH and a serum aspartate aminotransferase (AST) of <50 IU/L were significant independent risk factors for hepatic decompensation, and an AST of < 50 IU/L and an AST-to-platelet-ratio index (APRI) ≥ 1.0 for a patient with a Child-Pugh B classification may be indications that PD can be performed [13]. At the first visit, our patient’s AST value, APRI value, and Child-Pugh score were 57 IU/L, 1.6, and 5A, respectively. After 2 cycles of GS, her preoperative AST and APRI values had decreased to 22 IU/L and 0.5, respectively. Therefore, our patient had appropriate indications for undergoing a PD. Her postoperative Child-Pugh score has remained 5–6 (Class A), with no increase in the APRI (Table 1). The increase in the postoperative MELD score was considered to be due to her anorexia associated with S1 adjuvant chemotherapy.Table 1 Table of perioperative Child-Pugh and MELD scores and APRI score.
Table 1 Pre-treatment After 2 cycles of GS POM1 POM2 POM3 POM4 POM5 POM6
Child-Pugh score 5 5 5 5 5 6 6 5
MELD score 9 3 1 0 1 3 5 3
APRI 1.6 0.5 0.2 0.1 0.1 0.1 0.1 0.1
APRI: AST-to-platelet-ratio index.
GS: Neoadjuvant gemcitabine/S-1 chemotherapy.
POM: Postoperative month.
Pancytopenia has a wide range of aetiologies, including malignancies (leukaemia, malignant lymphoma, myelodysplastic syndrome, myeloma), autoimmune conditions (aplastic anaemia, systemic lupus erythematosus [SLE]), hypersplenism due to LC, drugs, infections, and nutritional deficiencies, so the evaluation of a patient with pancytopenia requires a comprehensive approach [14]. Regarding the patient’s thrombocytopenia, the causes of thrombocytopenia often overlap with the causes of pancytopenia [15]. Because our patient did not have lymphadenopathy, SLE, recent extensive thrombosis, blasts or atypical cells at peripheral blood tests, abnormal findings in her bone marrow, abnormal lymph nodes on CT or PET-CT, signs of infection, recent changes in oral medication, or a history of gastrectomy, we excluded malignancies, autoimmune conditions, drug reactions, infections, and nutritional deficiencies from the differential diagnosis. CT showed dullness of the hepatic margins, splenomegaly, and presence of a collateral circulation; we concluded that her pancytopenia, including her thrombocytopenia, was caused by hypersplenism due to LC. Therefore, we did not think that a bone-marrow biopsy was a priority, compared with preoperative chemotherapy for pancreatic cancer.
Thrombocytopenia (platelet count < 150,000/μL) [16] can occur with the progression of LC. The production of thrombopoietin and sequestration of platelets in the spleen are the main mechanisms involved in the development of thrombocytopenia [17]. The treatments for thrombocytopenia due to LC have included platelet transfusions, medications, embolization of the SA, and splenectomy [18]. With our patient’s elevated CA19−9 level, the risk of recurrence of her pancreatic cancer was considered high, and we elected to add treatment for improving her pancytopenia in order to enable the safe administration of chemotherapy after her recurrence. Platelet transfusion was not performed because of her splenomegaly and because of the possibility of platelet sequestration followed by destruction. We did not administer a thrombopoietin receptor agonist such as eltrombopag, which is effective for thrombocytopenia, because the patient required treatment not only for her thrombocytopenia but also for her pancytopenia. Whether a partial splenic artery embolization (PSAE) or splenectomy should have been performed has been controversial. The complications of PSAE include peritonitis, splenic abscess, and portal vein thrombosis. Additionally, PSAE is an invasive procedure, with both significant cost and uncertain long-term benefits. These limitations make PSAE an unsuitable option for many patients with advanced LC [17]. Furthermore, Miyake et al. reported that platelet counts after splenectomy were significantly increased over platelet counts after PSAE [19]. On the other hand, although splenectomy is an effective option for improving pancytopenia, it is also invasive and occasionally results in massive loss of blood. Additionally, the main complications after splenectomy are overwhelming post-splenectomy infections (OPSIs), approximately 80% of which are pneumococcal, and portal vein thrombosis. The reported incidence of portal vein thrombosis after splenectomy for splenomegaly has ranged from 9% to 29% [17].
For our patient, we debated about performing a splenectomy. Ligation or embolization of the SA was also considered, but we considered the effect of those procedures to be limited, because the blood supply of the spleen was delivered via collateral circulation, including the left gastric artery, the stomach wall, and the middle colic artery [20,21]. Therefore, we decided to perform a splenectomy, which seemed to provide the most reliable effect of increasing the blood cell count for the chemotherapy after recurrence of pancreatic cancer [19]. After confirmation that there were no distant metastases after neoadjuvant chemotherapy, we finally performed a radical PD combined with splenectomy following the approval by a multidisciplinary team a few days before the surgery. The patient also received postoperative pneumococcal vaccine to prevent OPSI before she underwent chemotherapy. However, the vaccine should have been administered before surgery in this high-risk patient.
With regard to preoperative chemotherapy, Karl et al. reported the usefulness and low toxicity of chemotherapy administered by intra-arterial infusion, including isolated abdominal perfusion [22]. However, our patient also had an abdominal aortic aneurysm with type 2 endoleak despite her previous EVAR, so catheterization was considered to be difficult. Additionally, her pretreatment CA19−9 level was very high (CA19−9 3909 U/mL), suggesting the possibility of micrometastases. Therefore, we elected to perform dose-reduced systemic chemotherapy for the early treatment and suppression of micrometastatic disease.
To our best knowledge, when limited to cases of PD synchronous with splenectomy for PC with pancytopenia due to LC, a total of 2 cases have been reported, including our case [23]. As in our patient, who lost a large volume of blood, Futagawa et al. reported a large blood loss (1700 mL). In patients with LC, bleeding occurs readily because of PH and decreased coagulability, and there is concern that hepatic function may deteriorate because of blood transfusions. Therefore, the control of intraoperative bleeding by reliable haemostasis is important. Furthermore, in patients with PH in whom collateral circulation develops, attention must be paid to the extent of lymph node dissection. Dissection of the hepatoduodenal ligament interrupts the collateral circulation, which can lead to refractory ascites and hepatic decompensation. Group 1 and 2 lymph node dissections were performed for our patient, who did not develop hepatic decompensation. However, careful planning that takes into consideration a patient’s overall condition and degree of liver damage is needed before surgery for these patients.
When PD is performed for a patient with LC, prevention of hepatic decompensation, which is directly is associated with mortality, is the most important consideration. Optimal perioperative management may decrease morbidity and mortality following surgery. Perioperative management for patients with LC includes nutritional management, control of refractory ascites and glucose levels, and correction of coagulopathy. These measures can help in preventing infection, hepatic encephalopathy and hepatic decompensation [24]. In our case, enteral nutrition therapy was started immediately after surgery for nutritional management and the prevention of postoperative infections [25]. In addition, since patients with LC who undergo PD, which is a highly invasive procedure, have increased risk of postoperative morbidity and mortality, careful monitoring and follow up are essential.
4 Conclusions
Strict indications for PD, control of intraoperative bleeding, and optimal perioperative management are important for preventing hepatic decompensation. Even for patients with PC and pancytopenia due to LC, PD combined with splenectomy is an effective treatment option.
Declaration of Competing Interest
The authors declare that they have no competing interests.
Funding
This study did not receive any specific grants from funding agencies in the public, commercial, and not-for-profit sectors.
Ethical approval
This study was exempt from ethical approval at our institution.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
HT (certified by the Japanese Society of Gastroenterological Surgery) performed the surgery on this patient. IH, HT, KM, and TH managed the postoperative course of this patient. HT and HI wrote the manuscript. All authors have read and approved the final manuscript.
Registration of research studies
Not Applicable.
Guarantor
Hideharu Tanaka (Corresponding author and guarantor).
Provenance and peer review
Not commissioned, externally peer-reviewed.
Availability of data and materials
Not applicable.
Acknowledgements
The authors wish to thank JAM Post for the editing of a draft of this manuscript. | GEMCITABINE, GIMERACIL\OTERACIL\TEGAFUR | DrugsGivenReaction | CC BY | 33689973 | 19,088,732 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenia'. | Pancreaticoduodenectomy combined with splenectomy for a patient with pancreatic cancer and pancytopenia due to liver cirrhosis: Case report.
The incidence of patients with liver cirrhosis (LC) is increasing. Patients with LC are known to have a greater risk of postoperative morbidity and mortality than patients without LC. A treatment option such as pancreaticoduodenectomy (PD) has not been validated to be safe for these patients, especially those with pancytopenia due to portal hypertension (PH). Providing an effective treatment option for these patients is essential.
METHODS
Herein, we describe a patient with pancreatic cancer with pancytopenia due to LC that was successfully treated with PD combined with splenectomy. The patient was a 70-year-old woman who was referred to our hospital for evaluation of a mass in the pancreatic head after she developed obstructive jaundice. She was diagnosed with T2N0M0, Stage IB pancreatic cancer and pancytopenia due to PH associated with LC. She received 2 cycles of adjuvant gemcitabine/S-1 chemotherapy and underwent radical subtotal stomach-preserving pancreaticoduodenectomy with splenectomy to improve her pancytopenia. Histopathological examination of the resected specimen revealed an R0 resection showing an Evans grade IIa histological response. Her pancytopenia improved rapidly after surgery.
Strict indications for PD, haemostatic control of intraoperative bleeding, and optimal perioperative management were important for preventing hepatic decompensation in this patient. Splenectomy is effective for thrombocytopenia due to LC; however, attention to postoperative complications such as overwhelming post-splenectomy infection and portal vein thrombosis is required.
CONCLUSIONS
For patients with pancreatic cancer with pancytopenia due to LC, PD combined with splenectomy plus optimal perioperative management is effective.
1 Introduction
Patients with liver cirrhosis (LC) have been recognized to have a greater risk of postoperative morbidity and mortality than patients without LC [1,2]. The safety of pancreaticoduodenectomy (PD) for patients with chronic hepatic dysfunction due to LC has not been validated. The risk of pancreaticoduodenectomy (PD) for patients increases with the progression of LC, because of the development of pancytopenia due to portal hypertension (PH) and secondary hypersplenism.
Perioperative chemotherapy has played an increasingly important role in the treatment of patients with pancreatic cancer (PC). Therefore, it is important to provide appropriate treatment options, including chemotherapy, for a patient with PC and pancytopenia due to LC. Herein we describe a patient with PC with pancytopenia due to LC who was successfully treated by PD combined with splenectomy, which enabled the safe postoperative administration of chemotherapy. We report this case in accordance with the 2020 SCARE criteria [3].
2 Case report
A 70-year-old woman with obstructive jaundice underwent percutaneous transhepatic biliary drainage instead of endoscopic biliary drainage because of her duodenal stenosis. She was then referred to our hospital for evaluation of a pancreatic head lesion that had been identified on an abdominal computed tomography (CT) scan performed when her jaundice had been discovered. She had a past history of endovascular aneurysmal repair (EVAR) for an abdominal aortic aneurysm one year previously and an appendectomy followed by surgery for an ileus when she was 10 years of age. Her family history was negative for pancreatic cancer and genetic disorders. She was 151 cm tall and weighed 60 kg. Her body-mass index was 26.3. The results of her physical examination were unremarkable.
Laboratory analysis revealed pancytopenia (white blood cell count 2710/μL, red blood cell count 366 × 104/μL, haemoglobin 10.9 g/dL, platelet count 89 × 103/μL) and CA19−9 3909 U/mL). She was negative for hepatitis B surface antigen and anti-hepatitis C virus antibody. Her Child-Pugh score and Model for End-stage Liver Disease (MELD) score were Grade 5A and 9, respectively [[4], [5], [6]]. Enhanced multidetector-row computed tomography (CT) revealed a 25-mm hypovascular tumour in the pancreatic groove, which had invaded the duodenum and lower bile duct (Fig. 1a). No other metastases involving distant organs were seen. Dullness of the hepatic margins was observed, and the spleen appeared enlarged, with a maximum diameter of 15 cm, suggesting portal hypertension (PH) (Fig. 1b). Endoscopic ultrasound-guided fine needle aspiration was performed. The cytopathological findings revealed pancreatic adenocarcinoma. Based on the 8th edition of the UICC criteria, the findings were diagnosed to be T2N0M0, Stage IB pancreatic carcinoma.Fig. 1 Pretreatment coronal enhanced computed tomography images.
a) Hypovascular 25-mm tumour (white arrow) in the pancreatic groove invading the duodenum and lower bile duct.
b) Splenomegaly with a maximum splenic diameter of 15 cm, which suggests portal hypertension.
Fig. 1
In accordance with the findings of the phase 2/3 Prep-02/JSAP05 trial [7], the patient underwent neoadjuvant gemcitabine/S-1 (GS) chemotherapy (gemcitabine [800 mg/m2] on days 1, 8 and S-1 [100 mg/m2] on days 1–14 of a 21-day cycle) repeated every 3 weeks for 2 cycles. Because of the patient’s pretreatment pancytopenia (neutrophil count 2250/μL), gemcitabine and S-1 were reduced by 200 mg/m2/day to 800 mg/m2/day, and 20 mg/m2/day to 100 mg/m2/day, respectively. Even after the dose reduction, neutropenia (neutrophil count 1340/μL) was observed during 1 cycle of GS, and chemotherapy was withheld until the neutropenia was resolved. Although the patient’s serum CA 19−9 level decreased after 2 cycles of GS chemotherapy, it remained elevated (CA 19−9 1064 U/mL). After 2 cycles, the primary tumour had slightly decreased to a diameter of 24 mm. Since the level of her CA19−9 tumour marker remained elevated, her risk of postoperative recurrence after PD was high. However, if the tumour recurred, the administration of intensive chemotherapy such as FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) and gemcitabine/nab-paclitaxel regimens would be difficult because of the patient’s pancytopenia. Therefore, we elected to perform a splenectomy in addition to the PD to improve her pancytopenia.
Splenectomy for splenomegaly with PH occasionally results in loss of a large amount of blood, which requires a large transfusion. The transfusion leads to oedema of the intestinal wall, which can increase the difficulty of performing a PD. Therefore, we decided to perform the PD followed by splenectomy.
The intraoperative findings revealed a liver with a granular surface and dullness of the liver’s edge (Fig. 2). We performed extensive detachment of the adhesions due to the patient’s previous appendectomy and subsequent surgery for an ileus, and found that detaching the hepatoduodenal ligament was difficult because of her repeated preoperative episodes of cholangitis. Since the collateral hepatic circulation that had developed bled easily, haemostasis was performed safely by ligation. After the PD, we began the splenectomy. We first detached and ligated the splenic artery (SA) at the upper edge of the pancreatic body to shrink the spleen and reduce the amount of blood loss. The splenic vein (SV) was also ligated, but the splenic hilum bled heavily because of tension on the SV. Haemostasis was performed by ligation while elevating the splenic hilum from the dorsal side. Finally, we performed a radical subtotal stomach-preserving PD with splenectomy, and lymph node dissections of groups 1 and 2 that included the hepatoduodenal ligament caudal to the hilar plate. The operative time was 12 h and 7 min, and the volume of blood loss was 1990 mL.Fig. 2 Intraoperative image.
Intraoperative findings show the dullness of the liver’s edge and its granular surface.
Fig. 2
The excised specimens showed a solid tumour in the pancreatic head which had invaded the duodenum and bile duct (Fig. 3a), and splenomegaly (Fig. 3b). The histopathological diagnosis was invasive ductal carcinoma with severe venous invasion and moderate nerve infiltration, ypT2N0M0, ypStage IB pancreatic cancer, as based on the 8th Edition of the UICC criteria and grade IIa as based on the Evans classification [8] (Fig. 4).Fig. 3 Macroscopic views of the resected specimens.
a) Macroscopic image of the resected specimen shows a mass in the pancreatic head, which has invaded the duodenum and bile duct.
b) The resected spleen is enlarged.
Fig. 3
Fig. 4 Photomicrograph (haematoxylin-and-eosin stain).
Malignant cells (arrows) have invaded the bile ducts (arrowheads).
Fig. 4
The patient’s pancytopenia improved rapidly after surgery. The platelet count increased rapidly after splenectomy, peaking at 681,000/μL on postoperative day (POD) 16, and then decreasing to the normal range (Fig. 5). However, the patient developed atelectasis and splenic vein thrombosis, which were considered Grade II complications in accordance with the Clavien-Dindo classification. The patient received high-flow nasal oxygen therapy and noninvasive positive-pressure ventilation, including bilevel positive airway pressure, and was prescribed an anticoagulant agent for the thrombosis. The patient was moved out of the intensive care unit on POD 5, and discharged on POD 30. After having received adjuvant chemotherapy with S-1 for 2 months due to the anorexia, the patient underwent blood tests and CT scans every 3 months. Nine months after her PD, a liver metastasis was detected, for which she received chemotherapy. She has remained alive for 13 months after her PD.Fig. 5 Graph of platelet and white blood cell counts over the patient’s hospital course.
GS: Neoadjuvant gemcitabine/S-1 chemotherapy
Adjuvant S-1: Adjuvant S-1 chemotherapy
Fig. 5
3 Discussion
The outcomes of surgery in patients with LC have been reported to vary, based not only on the degree of damage to the liver but also the invasiveness of the surgery [9]. The reported mortality of major abdominal surgery for patients with LC is 35% [10]. The Child-Pugh classification and the MELD score have been useful for estimating the risk of surgical mortality. According to the Child-Pugh classification, the mortality rates for major abdominal surgery have been 10%, 30%, and 76%–82% for Child-Pugh classifications A, B, and C, respectively [11]. Whereas, according to the MELD score, the 30-day mortalities after surgery were reported to be 6% for MELD < 8 and 50% for MELD > 20 [12]. However, until now, to our best knowledge, only a few studies have been published on the outcomes of PD in patients with LC. A retrospective multicentre study reported that PH and a serum aspartate aminotransferase (AST) of <50 IU/L were significant independent risk factors for hepatic decompensation, and an AST of < 50 IU/L and an AST-to-platelet-ratio index (APRI) ≥ 1.0 for a patient with a Child-Pugh B classification may be indications that PD can be performed [13]. At the first visit, our patient’s AST value, APRI value, and Child-Pugh score were 57 IU/L, 1.6, and 5A, respectively. After 2 cycles of GS, her preoperative AST and APRI values had decreased to 22 IU/L and 0.5, respectively. Therefore, our patient had appropriate indications for undergoing a PD. Her postoperative Child-Pugh score has remained 5–6 (Class A), with no increase in the APRI (Table 1). The increase in the postoperative MELD score was considered to be due to her anorexia associated with S1 adjuvant chemotherapy.Table 1 Table of perioperative Child-Pugh and MELD scores and APRI score.
Table 1 Pre-treatment After 2 cycles of GS POM1 POM2 POM3 POM4 POM5 POM6
Child-Pugh score 5 5 5 5 5 6 6 5
MELD score 9 3 1 0 1 3 5 3
APRI 1.6 0.5 0.2 0.1 0.1 0.1 0.1 0.1
APRI: AST-to-platelet-ratio index.
GS: Neoadjuvant gemcitabine/S-1 chemotherapy.
POM: Postoperative month.
Pancytopenia has a wide range of aetiologies, including malignancies (leukaemia, malignant lymphoma, myelodysplastic syndrome, myeloma), autoimmune conditions (aplastic anaemia, systemic lupus erythematosus [SLE]), hypersplenism due to LC, drugs, infections, and nutritional deficiencies, so the evaluation of a patient with pancytopenia requires a comprehensive approach [14]. Regarding the patient’s thrombocytopenia, the causes of thrombocytopenia often overlap with the causes of pancytopenia [15]. Because our patient did not have lymphadenopathy, SLE, recent extensive thrombosis, blasts or atypical cells at peripheral blood tests, abnormal findings in her bone marrow, abnormal lymph nodes on CT or PET-CT, signs of infection, recent changes in oral medication, or a history of gastrectomy, we excluded malignancies, autoimmune conditions, drug reactions, infections, and nutritional deficiencies from the differential diagnosis. CT showed dullness of the hepatic margins, splenomegaly, and presence of a collateral circulation; we concluded that her pancytopenia, including her thrombocytopenia, was caused by hypersplenism due to LC. Therefore, we did not think that a bone-marrow biopsy was a priority, compared with preoperative chemotherapy for pancreatic cancer.
Thrombocytopenia (platelet count < 150,000/μL) [16] can occur with the progression of LC. The production of thrombopoietin and sequestration of platelets in the spleen are the main mechanisms involved in the development of thrombocytopenia [17]. The treatments for thrombocytopenia due to LC have included platelet transfusions, medications, embolization of the SA, and splenectomy [18]. With our patient’s elevated CA19−9 level, the risk of recurrence of her pancreatic cancer was considered high, and we elected to add treatment for improving her pancytopenia in order to enable the safe administration of chemotherapy after her recurrence. Platelet transfusion was not performed because of her splenomegaly and because of the possibility of platelet sequestration followed by destruction. We did not administer a thrombopoietin receptor agonist such as eltrombopag, which is effective for thrombocytopenia, because the patient required treatment not only for her thrombocytopenia but also for her pancytopenia. Whether a partial splenic artery embolization (PSAE) or splenectomy should have been performed has been controversial. The complications of PSAE include peritonitis, splenic abscess, and portal vein thrombosis. Additionally, PSAE is an invasive procedure, with both significant cost and uncertain long-term benefits. These limitations make PSAE an unsuitable option for many patients with advanced LC [17]. Furthermore, Miyake et al. reported that platelet counts after splenectomy were significantly increased over platelet counts after PSAE [19]. On the other hand, although splenectomy is an effective option for improving pancytopenia, it is also invasive and occasionally results in massive loss of blood. Additionally, the main complications after splenectomy are overwhelming post-splenectomy infections (OPSIs), approximately 80% of which are pneumococcal, and portal vein thrombosis. The reported incidence of portal vein thrombosis after splenectomy for splenomegaly has ranged from 9% to 29% [17].
For our patient, we debated about performing a splenectomy. Ligation or embolization of the SA was also considered, but we considered the effect of those procedures to be limited, because the blood supply of the spleen was delivered via collateral circulation, including the left gastric artery, the stomach wall, and the middle colic artery [20,21]. Therefore, we decided to perform a splenectomy, which seemed to provide the most reliable effect of increasing the blood cell count for the chemotherapy after recurrence of pancreatic cancer [19]. After confirmation that there were no distant metastases after neoadjuvant chemotherapy, we finally performed a radical PD combined with splenectomy following the approval by a multidisciplinary team a few days before the surgery. The patient also received postoperative pneumococcal vaccine to prevent OPSI before she underwent chemotherapy. However, the vaccine should have been administered before surgery in this high-risk patient.
With regard to preoperative chemotherapy, Karl et al. reported the usefulness and low toxicity of chemotherapy administered by intra-arterial infusion, including isolated abdominal perfusion [22]. However, our patient also had an abdominal aortic aneurysm with type 2 endoleak despite her previous EVAR, so catheterization was considered to be difficult. Additionally, her pretreatment CA19−9 level was very high (CA19−9 3909 U/mL), suggesting the possibility of micrometastases. Therefore, we elected to perform dose-reduced systemic chemotherapy for the early treatment and suppression of micrometastatic disease.
To our best knowledge, when limited to cases of PD synchronous with splenectomy for PC with pancytopenia due to LC, a total of 2 cases have been reported, including our case [23]. As in our patient, who lost a large volume of blood, Futagawa et al. reported a large blood loss (1700 mL). In patients with LC, bleeding occurs readily because of PH and decreased coagulability, and there is concern that hepatic function may deteriorate because of blood transfusions. Therefore, the control of intraoperative bleeding by reliable haemostasis is important. Furthermore, in patients with PH in whom collateral circulation develops, attention must be paid to the extent of lymph node dissection. Dissection of the hepatoduodenal ligament interrupts the collateral circulation, which can lead to refractory ascites and hepatic decompensation. Group 1 and 2 lymph node dissections were performed for our patient, who did not develop hepatic decompensation. However, careful planning that takes into consideration a patient’s overall condition and degree of liver damage is needed before surgery for these patients.
When PD is performed for a patient with LC, prevention of hepatic decompensation, which is directly is associated with mortality, is the most important consideration. Optimal perioperative management may decrease morbidity and mortality following surgery. Perioperative management for patients with LC includes nutritional management, control of refractory ascites and glucose levels, and correction of coagulopathy. These measures can help in preventing infection, hepatic encephalopathy and hepatic decompensation [24]. In our case, enteral nutrition therapy was started immediately after surgery for nutritional management and the prevention of postoperative infections [25]. In addition, since patients with LC who undergo PD, which is a highly invasive procedure, have increased risk of postoperative morbidity and mortality, careful monitoring and follow up are essential.
4 Conclusions
Strict indications for PD, control of intraoperative bleeding, and optimal perioperative management are important for preventing hepatic decompensation. Even for patients with PC and pancytopenia due to LC, PD combined with splenectomy is an effective treatment option.
Declaration of Competing Interest
The authors declare that they have no competing interests.
Funding
This study did not receive any specific grants from funding agencies in the public, commercial, and not-for-profit sectors.
Ethical approval
This study was exempt from ethical approval at our institution.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
HT (certified by the Japanese Society of Gastroenterological Surgery) performed the surgery on this patient. IH, HT, KM, and TH managed the postoperative course of this patient. HT and HI wrote the manuscript. All authors have read and approved the final manuscript.
Registration of research studies
Not Applicable.
Guarantor
Hideharu Tanaka (Corresponding author and guarantor).
Provenance and peer review
Not commissioned, externally peer-reviewed.
Availability of data and materials
Not applicable.
Acknowledgements
The authors wish to thank JAM Post for the editing of a draft of this manuscript. | GEMCITABINE, GIMERACIL\OTERACIL\TEGAFUR | DrugsGivenReaction | CC BY | 33689973 | 19,088,732 | 2021-04 |
What is the weight of the patient? | Pancreaticoduodenectomy combined with splenectomy for a patient with pancreatic cancer and pancytopenia due to liver cirrhosis: Case report.
The incidence of patients with liver cirrhosis (LC) is increasing. Patients with LC are known to have a greater risk of postoperative morbidity and mortality than patients without LC. A treatment option such as pancreaticoduodenectomy (PD) has not been validated to be safe for these patients, especially those with pancytopenia due to portal hypertension (PH). Providing an effective treatment option for these patients is essential.
METHODS
Herein, we describe a patient with pancreatic cancer with pancytopenia due to LC that was successfully treated with PD combined with splenectomy. The patient was a 70-year-old woman who was referred to our hospital for evaluation of a mass in the pancreatic head after she developed obstructive jaundice. She was diagnosed with T2N0M0, Stage IB pancreatic cancer and pancytopenia due to PH associated with LC. She received 2 cycles of adjuvant gemcitabine/S-1 chemotherapy and underwent radical subtotal stomach-preserving pancreaticoduodenectomy with splenectomy to improve her pancytopenia. Histopathological examination of the resected specimen revealed an R0 resection showing an Evans grade IIa histological response. Her pancytopenia improved rapidly after surgery.
Strict indications for PD, haemostatic control of intraoperative bleeding, and optimal perioperative management were important for preventing hepatic decompensation in this patient. Splenectomy is effective for thrombocytopenia due to LC; however, attention to postoperative complications such as overwhelming post-splenectomy infection and portal vein thrombosis is required.
CONCLUSIONS
For patients with pancreatic cancer with pancytopenia due to LC, PD combined with splenectomy plus optimal perioperative management is effective.
1 Introduction
Patients with liver cirrhosis (LC) have been recognized to have a greater risk of postoperative morbidity and mortality than patients without LC [1,2]. The safety of pancreaticoduodenectomy (PD) for patients with chronic hepatic dysfunction due to LC has not been validated. The risk of pancreaticoduodenectomy (PD) for patients increases with the progression of LC, because of the development of pancytopenia due to portal hypertension (PH) and secondary hypersplenism.
Perioperative chemotherapy has played an increasingly important role in the treatment of patients with pancreatic cancer (PC). Therefore, it is important to provide appropriate treatment options, including chemotherapy, for a patient with PC and pancytopenia due to LC. Herein we describe a patient with PC with pancytopenia due to LC who was successfully treated by PD combined with splenectomy, which enabled the safe postoperative administration of chemotherapy. We report this case in accordance with the 2020 SCARE criteria [3].
2 Case report
A 70-year-old woman with obstructive jaundice underwent percutaneous transhepatic biliary drainage instead of endoscopic biliary drainage because of her duodenal stenosis. She was then referred to our hospital for evaluation of a pancreatic head lesion that had been identified on an abdominal computed tomography (CT) scan performed when her jaundice had been discovered. She had a past history of endovascular aneurysmal repair (EVAR) for an abdominal aortic aneurysm one year previously and an appendectomy followed by surgery for an ileus when she was 10 years of age. Her family history was negative for pancreatic cancer and genetic disorders. She was 151 cm tall and weighed 60 kg. Her body-mass index was 26.3. The results of her physical examination were unremarkable.
Laboratory analysis revealed pancytopenia (white blood cell count 2710/μL, red blood cell count 366 × 104/μL, haemoglobin 10.9 g/dL, platelet count 89 × 103/μL) and CA19−9 3909 U/mL). She was negative for hepatitis B surface antigen and anti-hepatitis C virus antibody. Her Child-Pugh score and Model for End-stage Liver Disease (MELD) score were Grade 5A and 9, respectively [[4], [5], [6]]. Enhanced multidetector-row computed tomography (CT) revealed a 25-mm hypovascular tumour in the pancreatic groove, which had invaded the duodenum and lower bile duct (Fig. 1a). No other metastases involving distant organs were seen. Dullness of the hepatic margins was observed, and the spleen appeared enlarged, with a maximum diameter of 15 cm, suggesting portal hypertension (PH) (Fig. 1b). Endoscopic ultrasound-guided fine needle aspiration was performed. The cytopathological findings revealed pancreatic adenocarcinoma. Based on the 8th edition of the UICC criteria, the findings were diagnosed to be T2N0M0, Stage IB pancreatic carcinoma.Fig. 1 Pretreatment coronal enhanced computed tomography images.
a) Hypovascular 25-mm tumour (white arrow) in the pancreatic groove invading the duodenum and lower bile duct.
b) Splenomegaly with a maximum splenic diameter of 15 cm, which suggests portal hypertension.
Fig. 1
In accordance with the findings of the phase 2/3 Prep-02/JSAP05 trial [7], the patient underwent neoadjuvant gemcitabine/S-1 (GS) chemotherapy (gemcitabine [800 mg/m2] on days 1, 8 and S-1 [100 mg/m2] on days 1–14 of a 21-day cycle) repeated every 3 weeks for 2 cycles. Because of the patient’s pretreatment pancytopenia (neutrophil count 2250/μL), gemcitabine and S-1 were reduced by 200 mg/m2/day to 800 mg/m2/day, and 20 mg/m2/day to 100 mg/m2/day, respectively. Even after the dose reduction, neutropenia (neutrophil count 1340/μL) was observed during 1 cycle of GS, and chemotherapy was withheld until the neutropenia was resolved. Although the patient’s serum CA 19−9 level decreased after 2 cycles of GS chemotherapy, it remained elevated (CA 19−9 1064 U/mL). After 2 cycles, the primary tumour had slightly decreased to a diameter of 24 mm. Since the level of her CA19−9 tumour marker remained elevated, her risk of postoperative recurrence after PD was high. However, if the tumour recurred, the administration of intensive chemotherapy such as FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) and gemcitabine/nab-paclitaxel regimens would be difficult because of the patient’s pancytopenia. Therefore, we elected to perform a splenectomy in addition to the PD to improve her pancytopenia.
Splenectomy for splenomegaly with PH occasionally results in loss of a large amount of blood, which requires a large transfusion. The transfusion leads to oedema of the intestinal wall, which can increase the difficulty of performing a PD. Therefore, we decided to perform the PD followed by splenectomy.
The intraoperative findings revealed a liver with a granular surface and dullness of the liver’s edge (Fig. 2). We performed extensive detachment of the adhesions due to the patient’s previous appendectomy and subsequent surgery for an ileus, and found that detaching the hepatoduodenal ligament was difficult because of her repeated preoperative episodes of cholangitis. Since the collateral hepatic circulation that had developed bled easily, haemostasis was performed safely by ligation. After the PD, we began the splenectomy. We first detached and ligated the splenic artery (SA) at the upper edge of the pancreatic body to shrink the spleen and reduce the amount of blood loss. The splenic vein (SV) was also ligated, but the splenic hilum bled heavily because of tension on the SV. Haemostasis was performed by ligation while elevating the splenic hilum from the dorsal side. Finally, we performed a radical subtotal stomach-preserving PD with splenectomy, and lymph node dissections of groups 1 and 2 that included the hepatoduodenal ligament caudal to the hilar plate. The operative time was 12 h and 7 min, and the volume of blood loss was 1990 mL.Fig. 2 Intraoperative image.
Intraoperative findings show the dullness of the liver’s edge and its granular surface.
Fig. 2
The excised specimens showed a solid tumour in the pancreatic head which had invaded the duodenum and bile duct (Fig. 3a), and splenomegaly (Fig. 3b). The histopathological diagnosis was invasive ductal carcinoma with severe venous invasion and moderate nerve infiltration, ypT2N0M0, ypStage IB pancreatic cancer, as based on the 8th Edition of the UICC criteria and grade IIa as based on the Evans classification [8] (Fig. 4).Fig. 3 Macroscopic views of the resected specimens.
a) Macroscopic image of the resected specimen shows a mass in the pancreatic head, which has invaded the duodenum and bile duct.
b) The resected spleen is enlarged.
Fig. 3
Fig. 4 Photomicrograph (haematoxylin-and-eosin stain).
Malignant cells (arrows) have invaded the bile ducts (arrowheads).
Fig. 4
The patient’s pancytopenia improved rapidly after surgery. The platelet count increased rapidly after splenectomy, peaking at 681,000/μL on postoperative day (POD) 16, and then decreasing to the normal range (Fig. 5). However, the patient developed atelectasis and splenic vein thrombosis, which were considered Grade II complications in accordance with the Clavien-Dindo classification. The patient received high-flow nasal oxygen therapy and noninvasive positive-pressure ventilation, including bilevel positive airway pressure, and was prescribed an anticoagulant agent for the thrombosis. The patient was moved out of the intensive care unit on POD 5, and discharged on POD 30. After having received adjuvant chemotherapy with S-1 for 2 months due to the anorexia, the patient underwent blood tests and CT scans every 3 months. Nine months after her PD, a liver metastasis was detected, for which she received chemotherapy. She has remained alive for 13 months after her PD.Fig. 5 Graph of platelet and white blood cell counts over the patient’s hospital course.
GS: Neoadjuvant gemcitabine/S-1 chemotherapy
Adjuvant S-1: Adjuvant S-1 chemotherapy
Fig. 5
3 Discussion
The outcomes of surgery in patients with LC have been reported to vary, based not only on the degree of damage to the liver but also the invasiveness of the surgery [9]. The reported mortality of major abdominal surgery for patients with LC is 35% [10]. The Child-Pugh classification and the MELD score have been useful for estimating the risk of surgical mortality. According to the Child-Pugh classification, the mortality rates for major abdominal surgery have been 10%, 30%, and 76%–82% for Child-Pugh classifications A, B, and C, respectively [11]. Whereas, according to the MELD score, the 30-day mortalities after surgery were reported to be 6% for MELD < 8 and 50% for MELD > 20 [12]. However, until now, to our best knowledge, only a few studies have been published on the outcomes of PD in patients with LC. A retrospective multicentre study reported that PH and a serum aspartate aminotransferase (AST) of <50 IU/L were significant independent risk factors for hepatic decompensation, and an AST of < 50 IU/L and an AST-to-platelet-ratio index (APRI) ≥ 1.0 for a patient with a Child-Pugh B classification may be indications that PD can be performed [13]. At the first visit, our patient’s AST value, APRI value, and Child-Pugh score were 57 IU/L, 1.6, and 5A, respectively. After 2 cycles of GS, her preoperative AST and APRI values had decreased to 22 IU/L and 0.5, respectively. Therefore, our patient had appropriate indications for undergoing a PD. Her postoperative Child-Pugh score has remained 5–6 (Class A), with no increase in the APRI (Table 1). The increase in the postoperative MELD score was considered to be due to her anorexia associated with S1 adjuvant chemotherapy.Table 1 Table of perioperative Child-Pugh and MELD scores and APRI score.
Table 1 Pre-treatment After 2 cycles of GS POM1 POM2 POM3 POM4 POM5 POM6
Child-Pugh score 5 5 5 5 5 6 6 5
MELD score 9 3 1 0 1 3 5 3
APRI 1.6 0.5 0.2 0.1 0.1 0.1 0.1 0.1
APRI: AST-to-platelet-ratio index.
GS: Neoadjuvant gemcitabine/S-1 chemotherapy.
POM: Postoperative month.
Pancytopenia has a wide range of aetiologies, including malignancies (leukaemia, malignant lymphoma, myelodysplastic syndrome, myeloma), autoimmune conditions (aplastic anaemia, systemic lupus erythematosus [SLE]), hypersplenism due to LC, drugs, infections, and nutritional deficiencies, so the evaluation of a patient with pancytopenia requires a comprehensive approach [14]. Regarding the patient’s thrombocytopenia, the causes of thrombocytopenia often overlap with the causes of pancytopenia [15]. Because our patient did not have lymphadenopathy, SLE, recent extensive thrombosis, blasts or atypical cells at peripheral blood tests, abnormal findings in her bone marrow, abnormal lymph nodes on CT or PET-CT, signs of infection, recent changes in oral medication, or a history of gastrectomy, we excluded malignancies, autoimmune conditions, drug reactions, infections, and nutritional deficiencies from the differential diagnosis. CT showed dullness of the hepatic margins, splenomegaly, and presence of a collateral circulation; we concluded that her pancytopenia, including her thrombocytopenia, was caused by hypersplenism due to LC. Therefore, we did not think that a bone-marrow biopsy was a priority, compared with preoperative chemotherapy for pancreatic cancer.
Thrombocytopenia (platelet count < 150,000/μL) [16] can occur with the progression of LC. The production of thrombopoietin and sequestration of platelets in the spleen are the main mechanisms involved in the development of thrombocytopenia [17]. The treatments for thrombocytopenia due to LC have included platelet transfusions, medications, embolization of the SA, and splenectomy [18]. With our patient’s elevated CA19−9 level, the risk of recurrence of her pancreatic cancer was considered high, and we elected to add treatment for improving her pancytopenia in order to enable the safe administration of chemotherapy after her recurrence. Platelet transfusion was not performed because of her splenomegaly and because of the possibility of platelet sequestration followed by destruction. We did not administer a thrombopoietin receptor agonist such as eltrombopag, which is effective for thrombocytopenia, because the patient required treatment not only for her thrombocytopenia but also for her pancytopenia. Whether a partial splenic artery embolization (PSAE) or splenectomy should have been performed has been controversial. The complications of PSAE include peritonitis, splenic abscess, and portal vein thrombosis. Additionally, PSAE is an invasive procedure, with both significant cost and uncertain long-term benefits. These limitations make PSAE an unsuitable option for many patients with advanced LC [17]. Furthermore, Miyake et al. reported that platelet counts after splenectomy were significantly increased over platelet counts after PSAE [19]. On the other hand, although splenectomy is an effective option for improving pancytopenia, it is also invasive and occasionally results in massive loss of blood. Additionally, the main complications after splenectomy are overwhelming post-splenectomy infections (OPSIs), approximately 80% of which are pneumococcal, and portal vein thrombosis. The reported incidence of portal vein thrombosis after splenectomy for splenomegaly has ranged from 9% to 29% [17].
For our patient, we debated about performing a splenectomy. Ligation or embolization of the SA was also considered, but we considered the effect of those procedures to be limited, because the blood supply of the spleen was delivered via collateral circulation, including the left gastric artery, the stomach wall, and the middle colic artery [20,21]. Therefore, we decided to perform a splenectomy, which seemed to provide the most reliable effect of increasing the blood cell count for the chemotherapy after recurrence of pancreatic cancer [19]. After confirmation that there were no distant metastases after neoadjuvant chemotherapy, we finally performed a radical PD combined with splenectomy following the approval by a multidisciplinary team a few days before the surgery. The patient also received postoperative pneumococcal vaccine to prevent OPSI before she underwent chemotherapy. However, the vaccine should have been administered before surgery in this high-risk patient.
With regard to preoperative chemotherapy, Karl et al. reported the usefulness and low toxicity of chemotherapy administered by intra-arterial infusion, including isolated abdominal perfusion [22]. However, our patient also had an abdominal aortic aneurysm with type 2 endoleak despite her previous EVAR, so catheterization was considered to be difficult. Additionally, her pretreatment CA19−9 level was very high (CA19−9 3909 U/mL), suggesting the possibility of micrometastases. Therefore, we elected to perform dose-reduced systemic chemotherapy for the early treatment and suppression of micrometastatic disease.
To our best knowledge, when limited to cases of PD synchronous with splenectomy for PC with pancytopenia due to LC, a total of 2 cases have been reported, including our case [23]. As in our patient, who lost a large volume of blood, Futagawa et al. reported a large blood loss (1700 mL). In patients with LC, bleeding occurs readily because of PH and decreased coagulability, and there is concern that hepatic function may deteriorate because of blood transfusions. Therefore, the control of intraoperative bleeding by reliable haemostasis is important. Furthermore, in patients with PH in whom collateral circulation develops, attention must be paid to the extent of lymph node dissection. Dissection of the hepatoduodenal ligament interrupts the collateral circulation, which can lead to refractory ascites and hepatic decompensation. Group 1 and 2 lymph node dissections were performed for our patient, who did not develop hepatic decompensation. However, careful planning that takes into consideration a patient’s overall condition and degree of liver damage is needed before surgery for these patients.
When PD is performed for a patient with LC, prevention of hepatic decompensation, which is directly is associated with mortality, is the most important consideration. Optimal perioperative management may decrease morbidity and mortality following surgery. Perioperative management for patients with LC includes nutritional management, control of refractory ascites and glucose levels, and correction of coagulopathy. These measures can help in preventing infection, hepatic encephalopathy and hepatic decompensation [24]. In our case, enteral nutrition therapy was started immediately after surgery for nutritional management and the prevention of postoperative infections [25]. In addition, since patients with LC who undergo PD, which is a highly invasive procedure, have increased risk of postoperative morbidity and mortality, careful monitoring and follow up are essential.
4 Conclusions
Strict indications for PD, control of intraoperative bleeding, and optimal perioperative management are important for preventing hepatic decompensation. Even for patients with PC and pancytopenia due to LC, PD combined with splenectomy is an effective treatment option.
Declaration of Competing Interest
The authors declare that they have no competing interests.
Funding
This study did not receive any specific grants from funding agencies in the public, commercial, and not-for-profit sectors.
Ethical approval
This study was exempt from ethical approval at our institution.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
HT (certified by the Japanese Society of Gastroenterological Surgery) performed the surgery on this patient. IH, HT, KM, and TH managed the postoperative course of this patient. HT and HI wrote the manuscript. All authors have read and approved the final manuscript.
Registration of research studies
Not Applicable.
Guarantor
Hideharu Tanaka (Corresponding author and guarantor).
Provenance and peer review
Not commissioned, externally peer-reviewed.
Availability of data and materials
Not applicable.
Acknowledgements
The authors wish to thank JAM Post for the editing of a draft of this manuscript. | 60 kg. | Weight | CC BY | 33689973 | 19,088,732 | 2021-04 |
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