Case Presentation Competition, 5 Back to Basics

Serotonin syndrome associated with clozapine withdrawal and concurrent selective serotonin reuptake inhibitor (SSRI) use has previously been reported. A 56-year-old female with schizophrenia was admitted for pyrexia, rigidity, and altered mental state after her second dose of clozapine restart. She had discontinued her long-term clozapine 2 weeks prior. She developed ventilatory failure, reduced consciousness, eye deviation, and worsening rigidity, requiring ICU support. Examination showed a right upper motor neurone syndrome with absent ankle reflexes. She had raised inflammatory markers and creatine kinase. Serum neuropathy, encephalitis screen, and COVID PCR were negative. Respiratory investigations were unfruitful. MRI head and spine did not show brain or cord signal change to correlate to signs. Lumbar puncture showed a quiet CSF, negative culture, viral PCR, and encephalitis antibodies. EEG showed bihemispheric background slowing. Despite clinical improvement, repeat examination showed persistent signs. She was diagnosed with serotonin syndrome after developing a bilateral tremor. Treatment with cyproheptadine correlated with an improvement in her signs, cognitive state, and EEG. Serotonin syndrome can present with reversible neuromuscular signs. With clozapine withdrawal, it can require a prolonged time course of recovery in contrast with classical serotonin syndrome. Cyprohepta- dine can cause agranulocytosis and this delays clozapine restart.

Clinical impact of reducing the frequency of clozapine monitoring: controlled mirror-image cohort study.

BACKGROUND: To minimise infection during COVID-19, the clozapine haematological monitoring interval was extended from 4-weekly to 12-weekly intervals in South London and Maudsley NHS Foundation Trust. AIMS: To investigate the impact of this temporary policy change on clinical and safety outcomes. METHOD: All patients who received clozapine treatment with extended (12-weekly) monitoring in a large London National Health Service trust were included in a 1-year mirror-image study. A comparison group was selected with standard monitoring. The proportion of participants with mild to severe neutropenia and the proportion of participants attending the emergency department for clozapine-induced severe neutropenia treatment during the follow-up period were compared. Psychiatric hospital admission rates, clozapine dose and concomitant psychotropic medication in the 1 year before and the 1 year after extended monitoring were compared. All-cause clozapine discontinuation at 1-year follow-up was examined. RESULTS: Of 569 participants, 459 received clozapine with extended monitoring and 110 controls continued as normal. The total person-years were 458 in the intervention group and 109 in the control group, with a median follow-up time of 1 year in both groups. During follow-up, two participants (0.4%) recorded mild to moderate neutropenia in the intervention group and one (0.9%) in the control group. There was no difference in the incidence of haematological events between the two groups (IRR = 0.48, 95% CI 0.02-28.15, P = 0.29). All neutropenia cases in the intervention group were mild, co-occurring during COVID-19 infection. The median number of admissions per patient during the pre-mirror period remained unchanged (0, IQR = 0) during the post-mirror period. There was one death in the control group, secondary to COVID-19 infection. CONCLUSIONS: There was no evidence that the incidence of severe neutropenia was increased in those receiving extended monitoring.

Agranulocytosis following intravenous immunoglobulin administration in a patient with Guillain-Barre Syndrome triggered by COVID-19: A case report

Neutropenia during recovery after coronavirus disease 2019 (COVID-19), as well as neutropenia after intravenous immunoglobulin (IVIG) administration are very rare hematological abnormalities. We report the first case of agranulocytosis following IVIG administration in patients with Guillain-Barre syndrome (GBS) triggered by COVID-19. A 62-year-old female patient was admitted to the Emergency Department due to progressive limb weakness and sensory disturbances that began two weeks before admission. Five weeks before admission she was treated for COVID-19 and has fully recovered. She was diagnosed with Guillain-Barre syndrome (GBS), and treatment with IVIG was started. Twenty hours after the first dose of IVIG, blood analysis showed neutropenia and thrombocytopenia, and after the fifth dose she developed agranulocytosis followed by mild increase in body temperature. Granulocyte colony-stimulating factor (G-CSF) was administered and after 12 hours the leukocyte lineage recovered. According to the previous findings, neutropenia after IVIG administration might be related to CD11b, and COVID-19 is associated with an increase in immature neutrophil populations in the later stages of the disease defined by their expression of CD11b. Meanwhile, some finding suggests that corticosteroid pretreatment prevent neutropenia after IVIG administration, which might be important because many patients with post-COVID GBS have been treated with corticosteroids for COVID-19. Copyright © 2022, ASEAN Neurological Association. All rights reserved.

TREATMENT OF ACUTE LYMPHOBLASTIC LEUKEMIA DURING COVID-19

Background: During the coronavirus pandemic, the risk of severe COVID-19 and mortality are higher in certain groups, in particular in patients with oncohematological diseases. Acute lymphoblastic leukemia (ALL) is a special group of oncohematological diseases in which mortality in the era of COVID-19 has increased 2-3 times. Currently, there is no consensus on the treatment of ALL during coronavirus infection. Aims: To determine the basic principles and features of the management of patients with ALL during COVID-19. Methods: 46 patients with ALL and COVID-19 (men 52.2%, women 47.8%) aged 18-74 years (median-44.5) were treated at the Moscow City Clinical Hospital 52 on 01.04.20-01.11.21. B-ALL was 58.7% (27 patients), T-ALL - 34.8% (16 patients), biphenotypic - 4.3% (2 patients), not defined - 2.2% (1 patient), Ph-positive ALL - 17.4% (8 patients). The status of the disease of patients upon admission to the Hospital differed: debut of ALL - 20 patients (43.5%), remission - 16 patients (34.8%), relapse and refractory course - 10 patients (21.7%). All patients were treated COVID-19 in accordance with the current guidelines for the prevention, diagnosis and treatment of COVID- 19 (interleukin 6 inhibitor, anticoagulant and antibacterial therapy, glucocorticoids (GCs), human immunoglobulin (IG) against COVID-19). According to vital indications and with stabilization of the patient's condition, 18 patients (39.1%) received chemotherapy (CT). Results: There were no deaths in the group of patients with remission of ALL. In patients with the debut of ALL, mortality was 45% (9 patients), in relapse and refractory course - 50% (5 patients) (p=0.005). Mortality in the group who did not receive CT was 35.7%, and in the group who received CT - 22.2%. 6 patients with Ph-positive ALL (75.0%) continued therapy with tyrosine kinase inhibitors (TKI). According to the protocol for the treatment of ALL, full doses of GCs (100%) and anthracyclines (ATC) (100%) were used, lumbar punctures (LP) and intrathecal (IT) injections of CT (100%) were continued. Due to the high risk of thrombotic complications in COVID-19 and asparaginase therapy, anticoagulant therapy was performed (100%). Prevention of pneumocystis pneumonia (PCP) (89.1%), antifungal (37.0%) and antibacterial (87.0%) therapy were carried out in the treatment of COVID-19. With the persistence of COVID-19 and the absence of antibodies to COVID-19, 2 patients received repeated transfusion of human IG against COVID-19. Summary/Conclusion: During the COVID-19 pandemic, patients in remission of ALL coronavirus infection are treated and controlled. Treatment of COVID-19 in patients with ALL is carried out according to general protocols for the treatment of COVID-19, taking into account the peculiarities of nosology (agranulocytosis, high risk of PCP and fungal infection with long-term therapy of GCs, persistence of COVID-19). When the patient's condition is stabilized, the issue of CT should be decided individually in each case, taking into account all the risks of ALL and COVID-19. During CT, use full doses of GCs, ATC. In patients with mild and moderate COVID-19, continue LP and IT injections of CT, therapy with TKI.

COURSE OF CORONAVIRUS INFECTION IN ONCOHEMATOLOGICAL PATIENTS IN THE POSTTRANSPLANT PERIOD

Background: In March 2020, specialists in the field of oncohematology faced the problem of severity of coronavirus infection in patients after high-dose course of chemotherapy and autologous or allogeneic bone marrow transplantation. This required a revision of a number of issues related to the selection of patients for bone marrow transplantation (BMT), the development of new preventive and therapeutic tactics aimed at the treatment of infectious and immunological complications in this category of patients, depending on the nature of the underlying disease, the status of the disease and the timing of the treatment. Aims: To assess the severity, the most typical complications and the COVID 19 severity aspects in patients in early and late post-transplant periods to develop the most optimal tactics for the prevention and treatment of COVID 19 in this group of patients. Methods: An analysis was made of patients after HSCT with active coronavirus infection from 2020 to 2021, hospitalized in the hematology department of the Moscow multidisciplinary hospital (the hospital was completely redesigned to work on the COVID19 profile). A total number of hospitalized patients after HSCT was 25: 4 patients after allogeneic transplantation, 21 -after autologous. According to the timing of HSCT, patients were divided into 2 groups -early post-transplant period (ETP) (2-90 days after HSCT) -14 patients, and late post-transplant period (LTP) (3-24 months) -11 patients. According to nosology, patients were divided into following groups: lymphomas -72%, MM -12%, AA and CML 8% each. All patients were admitted with a positive PCR test (0-7 days of COVID). COVID therapy was carried out according to the protocols adopted in the Russian Federation using antiviral drugs, biological therapy, corticosteroids, anticoagulants. If necessary, the required supportive therapy was carried out for this period of HSCT. Results: Severe COVID19 (CT 3-4 severity) was more often observed in patients in ETP (100%) than in LTP (45%) (p=0.021). The incidence of respiratory failure is 70% and 36% in ETP and LTP, respectively. According to the analysis in ETP, agranulocytosis was observed in 65% of cases, for LTP group -in 18% (p = 0.022). Development of severe infectious complications (bacterial, fungal and viral) was detected in 100% of patients in ETP, in 45% of patients in LTP (p = 0.002). Antifungal therapy was required in 100% of cases in ETP, and only in 27% of the LTP group (p=0.001). 90% of patients in both groups required biological therapy. Mortality in the group of patients in ETP was 35%, while no deaths were registered in the group of patients in LTP (p=0.027). Median of hospitalization period for ETP and LTP patients was 20 and 13 days, respectively. Summary/Conclusion: Patients in the early period after HSCT have a higher risk of developing lower respiratory tract infection, more likely to require antifungals, reserve group antibiotics, and have a greater risk of death from COVID-19. Biological therapy is not contraindicated in case of leukopenia and agranulocytosis in this group of patients.

Clozapine and Neutropenia in Patients with Schizophrenia and SARS-CoV-2 Infection.

Background: Clozapine (CLZ) is used for treatment-resistant schizophrenia (TRS). Adverse reactions to clozapine include neutropenia. In March 2020, WHO declared the COVID-19 pandemic and after, psychiatrists raised concerns regarding continuation of clozapine, due to multiple restrictions. We aimed to provide a study on the association between neutropenia and clozapine in patients with schizophrenia and COVID-19. Aim: To assess the neutrophil count in patients with schizophrenia treated with clozapine and infected with COVID-19. Methods: The study patients with schizophrenia, according to DSM-5, admitted to the Clinical Hospital of Psychiatry and Neurology Brasov, Romania, between April 2020 and October 2021. The inclusion criteria included positive RT-PCR (real-time PCR) test for COVID-19 and treatment with clozapine. We assessed three values of ANC (absolute neutrophil count): before COVID-19 infection (last ANC obtained at mandatory check), during infection and 1 month after resolution (first negative PCR test). Results: Of the 105 cases, 95 did not have neutropenia. Fifty-nine patients were males (62.1%), mean age was 43.5 years (SD = 12.1) with an average of clozapine treatment of 52.4 months (SD = 11.9). At baseline, they had a small reduction in the ANC mean value (4.41 × 109/l; SD = 2.22) which did not constitute a statistically significant decline from the prior to COVID-19 mean value of 4.66 × 109/l (SD = 2.34; p = 0.45). Values were also normal in the first month after negative PCR testing (4.45 × 109/l; SD = 2.35; p = 0.91). A total of 10 patients (9.5%) had neutropenia. The age, dose of clozapine and duration of treatment were not statistically different compared to the group without neutropenia. Conclusion: Psychiatrists and other health professionals should keep in mind that neutrophil count may decrease during COVID-19 infection in patients taking clozapine and in some cases, neutropenia may even occur. We assumed that neutropenia could be caused by COVID-19 and clozapine interaction.

Drug-induced blood dyscrasias with onset of respiratory symptoms

A patient, diagnosed with ulcerative colitis and rheumatoid arthritis and treated with mesalazine and hydroxychloroquine, presented with symptoms of catarrh similar to those of COVID-19. The pharmacotherapeutic monitoring service (PMS) provided to the patient allowed us to associate these symptoms with a side effect of the drug taken by the patient, i.e., blood dyscrasias. The intervention, carried out to inform the doctor while the patient was symptomatic, allowed the HCP to modify the treatment by reducing the doses of the drugs used until the condition was under control.

Final Results of CHRONOS19 Observational Study in Patients with Hematologic Disease and COVID-19 in Russia

Background: Research on the impact of COVID-19 on different patient populations has been of great value for the optimization of patient care since the start of the SARS-CoV-2 pandemic. Earlier, we reported the interim analysis of the immediate outcomes in patients (pts) with hematologic (hem) disease and COVID-19. Long-term results of the CHRONOS19 registry are now available. Methods: CHRONOS19 is an observational prospective cohort study among adult pts ((≥18 years) with hem diseases (malignant or non-malignant) and laboratory-confirmed or suspected (based on clinical symptoms and/or CT) COVID-19 in Russia. Data from 15 centers all over the country were collected on a web-based platform in a de-identified manner at 30, 90, and 180 days after COVID-19 was diagnosed. The primary endpoint was 30-day all-cause mortality. Secondary outcomes included COVID-19 complications, rate of ICU admission and mechanical ventilation, outcomes of hem disease in SARS-CoV-2 infected pts, overall survival, and risk factors for disease severity and mortality. Results: As of July 30, 2021, 666 pts were enrolled (females / males [n (%)]: 317 (48%) / 349 (52%);median [range] age: 56 [18-90] years. Disease types (malignant/non-malignant [n (%)]): 618 (93%) / 48 (7%), including AML 115 (17%), MM 113 (17%), NHL 106 (16%), CML / CMPD 92 (14%), ALL 52 (8%), CLL 50 (8%), MDS 25 (4%), HCL 23 (3%), HL 21 (3%), AA 16 (2%), APL 11 (2%), others 42 (6%);among them induction phase / remission / relapse or refractory / NA in 237 (35%) / 231 (35%) / 152 (23%) / 46 (7%) pts. Concomitant conditions were reported in 385 (58%) pts: cardiovascular 254 (66%), diabetes 76 (20%), obesity 57 (15%), pulmonary 41 (11%), chronic renal 44 (11%) or hepatic 33 (9%) disease, other 90 (23%). At a median follow-up of 7,5(1-19) months, 618 pts were evaluable for the primary outcome. Thirty-day all-cause mortality was 16% (100 pts died). Death due to COVID-19 complications occurred in 82 pts, 14 pts died due to progression of hem disease. Overall, 217 (33%) pts had severe disease, COVID-19 complications were detected in 458 (70%) pts, the most common were pneumonia in 425 (93%) pts, respiratory failure in 252 (55%) pts, multiple organ failure in 56 (12%) pts, cytokine storm in 52 (11%) pts, ARDS in 47 (10%) pts, and sepsis in 44 (10%) pts. The rate of ICU admission was 23% (145 pts) with high mortality in this group of pts (77%), 111 (17%) pts required mechanical ventilation, among them only 5 (4.5%) pts survived. Treatment of hem disease was changed, interrupted, or discontinued in 395 (60%) pts with a median delay of 4 weeks. At 30 days, the rate of relapse / progression of hem disease was 5% / 8% (24 / 40 of 517 evaluable pts). At the longer follow-up (90 and 180 days), relapse / progression occurred in another 9 / 23 pts. At the data cutoff, the median overall survival was not reached. Antibody detection was performed in 253 pts: 211 (84%) pts had IgG to SARS-CoV-2. In a univariate analysis, older age (> 60 years), myelotoxic agranulocytosis, transfusion dependence, diabetes among comorbidities, ARDS and other complications, except CRS, ICU and mechanical ventilation (Fig. 1) were associated with higher risks of mortality (p<0.05). The final results of the CHRONOS19 study will be presented. Conclusions: Patients with hem disease and COVID-19 have higher mortality than a general population with SARS-CoV-2 infection, predominantly due to COVID-19 complications. The longer-term follow-up did not reveal any concerns in terms of hem disease outcomes. [Formula presented] Disclosures: Vorobyev: Janssen, Roche, Sanofi, Takeda, Biocad, Abbvie: Other: Advisory Boards, Speakers Bureau;Astellas, Novartis, AstraZeneca: Speakers Bureau. Chelysheva: Pharmstandart: Speakers Bureau;Pfizer: Speakers Bureau;Bristol Myers Squibb: Speakers Bureau;Novartis Pharma: Speakers Bureau.

P.0912 Addressing barriers to clozapine use through Point Of Care Monitoring (POCM)

Introduction: Despite treatment guidelines for schizophrenia less than 25% of individuals with schizophrenia who meet Treatment Resistant Schizophrenia [TRS] criteria are actually receiving clozapine. On average, it takes 9 years before a patient is initiated on clozapine. Over this time, period patients will typically receive at least 7 different antipsychotics and 2/3 will have been prescribed 3 or more antipsychotics together. Treatment delay is correlated with impaired functionality, poorer outcome and greater disease burden and costs. Aims: Despite the effectiveness of clozapine, there is a reluctance to use it because of patient concerns, e.g., frequent blood tests;physician concerns, e.g., risk of agranulocytosis and lack of experience;system issues, e.g., registration and monitoring requirements;and medication complexity, e.g., dosing and titration [1]. This has been further impacted by the COVID-19 pandemic, with patients either not being initiated or switched because of concerns about difficulties in blood monitoring [2]. Clozapine utilization has been shown to increase with implementation of specific educational programs, audits, clozapine clinics and point of care testing [3] involvement of allied health care professionals such as pharmacists. We collected data on a unique pilot initiative using Point of Care Monitoring (POCM) to address the barrier of blood monitoring in a community setting. Methods: A POCM device (PRONTOTM) was approved in Canada in November 2019, which allows for real-time evaluation of white blood cell and neutrophil counts from a capillary sample. Patients registered to the Clozaril® Support and Assistance Network (CSAN) were switched from regular laboratory service to POCM conducted by on-site nursing staff in a group home setting. In a Quality Improvement (QI) project patients and staff were asked to evaluate their experiences. Results: A total of 152 POCM tests were conducted in 26 patients on clozapine who previously attended at a local laboratory. Overall adherence to CSAN monitoring was improved, and there was a high degree of patient acceptance and preference for POCM. The nursing staff reported high satisfaction and convenience with time saving. All patients switched to POCM have continued with it. Particular advantages included monitoring being carried out by consistent (and trusted) staff and the small sample size required. Conclusion: This is the first evaluation of POCM for clozapine in the community and potentially removes barriers to clozapine use given the simplicity, flexibility, rapidity, and convenience, as well as ease of use and decreased invasiveness. Patients were more cooperative and it is cost-effective as patients do not need to be transported to the laboratory. Further, POCM may contribute to the safer monitoring of clozapine patients in the current COVID environment. Improved patient care and increased adherence to monitoring results in potentially better outcomes. The next step is to demonstrate that patients can be safely initiated on clozapine in the community with POCM, thereby obviating the necessity of a hospital admission with associated cost and risk. Ultimately, the goal is the more appropriate use of clozapine with early and simple access consistent with treatment guidelines for schizophrenia. Conflict of interest Disclosure statement: I have received educational, research and tracvel grants and honoraria from Otsuka, Janssen, Mylan, HLS, Lundbeck, Novartis, Pfizer, Hoffmann La Roche, AbbeVie. Alkermes, and Kye

Clozapine, neutropenia and Covid-19: should clinicians be concerned? 3 months report.

BACKGROUND: Clozapine is among the most effective antipsychotics used for treatment resistant schizophrenia. Adverse reactions to clozapine include neutropenia. In March 2020, at the start of the Coronavirus -19 pandemic, clinicians raised concerns regarding continuation of antipsychotic treatment, and specifically of clozapine, in patients with coronavirus disease. We aimed here at providing a short report focusing on the association between neutropenia and clozapine in a case series of psychiatric inpatients diagnosed with COVID-19. PATIENTS & METHODS: We retrospectively inspected data of 10 patients on clozapine, admitted to Highgate Mental Health Centre, Camden & Islington NHS Foundation Trust, between March and July 2020; selection was based on their COVID-19 positive PCR test. We used a linear regression model to estimate whether there was a significant drop in the neutrophil count during SARS-CoV-2 infection.The analysis was done in R using a linear regression to the origin. RESULTS: Data were collected on 10 patients, of which 7 were males. During COVID-19 infection, neutrophils' count (ANC) was 4.13 â€‹× â€‹109/l (SD â€‹= â€‹2.70) which constituted a significant drop from a baseline value of 5.2 â€‹× â€‹109/l (SD â€‹= â€‹2.24). The mean relative reduction in ANC was -0.2729 (SD â€‹= â€‹0.1666). The beta value of 0.8377 obtained with the linear regression showed that ANC values during SARS-CoV-2 infection were 83.77% of the baseline ANC showing that within the two time points there was a decrease of 16.23%. The linear regression had a pvalue â€‹= â€‹8.96 â€‹× â€‹10-8 and an adjusted R2 of 95.94% which shows that the variability of the data is very well explained by the model. We also compared baseline ANC with ANC values approximately a month after resolution of the infection and results indicate that ANC values return to a 95% of baseline. CONCLUSIONS: Clinicians should bear in mind that a significant drop in neutrophils' count may occur in patients taking clozapine and affected from a SARS-CoV-2 infectionand that this drop is only transitory.

A possible increased risk of metamizole-associated neutropenia among COVID-19 patients.

Metamizole is commonly used as analgesic and antipyretic drug. The use of metamizole is prohibited in several countries due to its rare side effect of neutropenia and even agranulocytosis. Among the many symptoms of COVID-19, fever and diffuse pain predominant and therefore it can be assumed that metamizole may be widely used in the current epidemic period. So far, there have been no reports on the safety of metamizole in COVID-19 patients. We describe a series of 3 patients who developed severe neutropenia under metamizole treatment, raising a concern of a possible increased risk of this side effect among COVID-19 patients.

Clozapine: An Updated Overview of Pharmacogenetic Biomarkers, Risks, and Safety-Particularities in the Context of COVID-19.

BACKGROUND: clozapine (CLZ) use is precarious due to its neurological, cardiovascular, and hematological side effects; however, it is the gold standard in therapy-resistant schizophrenia (TRS) in adults and is underused. OBJECTIVE: to examine the most recent CLZ data on (a) side effects concerning (b) recent pharmacological mechanisms, (c) therapy benefits, and (d) the particularities of the COVID-19 pandemic. DATA SOURCES: a search was performed in two databases (PubMed and Web of Science) using the specific keywords "clozapine" and "schizophrenia", "side effects", "agranulocytosis", "TRS", or "bipolar affective disorder (BAF)" for the last ten years. STUDY ELIGIBILITY CRITERIA: clinical trials on adults with acute symptoms of schizophrenia or related disorders. RESULTS: we selected 37 studies, randomized controlled trials (RCTs), and clinical case series (CCS), centered on six main topics in the search area: (a) CLZ in schizophrenia, (b) CLZ in bipolar disorder, (c) side effects during the clozapine therapy, (d) CLZ in pregnancy, (e) CLZ in early-onset schizophrenia, and (f) CLZ therapy and COVID-19 infection. LIMITATIONS: we considered RCTs and CCS from two databases, limited to the search topics. Conclusions and implications of key findings: (a) clozapine doses should be personalized for each patient based on pharmacogenetics testing when available; the genetic vulnerability postulates predictors of adverse reactions' severity; patients with a lower genetic risk could have less frequent hematological monitoring; (b) a CLZ-associated risk of pulmonary embolism imposes prophylactic measures for venous thromboembolism; (c) convulsive episodes are not an indication for stopping treatment; the plasma concentration of clozapine is a better side effect predictor than the dosage; (d) COVID-19 infection may enhance clozapine toxicity, generating an increased risk of pneumonia. Therapy must be continued with the proper monitoring of the white blood count, and the clozapine dose decreased by half until three days after the fever breaks; psychiatrists and healthcare providers must act together.

Agranulocytosis Following COVID-19 Recovery.

Clinicians have continued to report on the clinical behavior and characteristics of patients with coronavirus disease 2019 (COVID-19) as our knowledge of the virus continues to mature. Herein, we report the case of a 39-year-old male with multiple comorbidities who became critically ill with COVID-19 infection, requiring mechanical ventilation and vasopressors, and then developed agranulocytosis following clinical improvement and resolution of symptoms of COVID infection. The period of agranulocytosis coincided with the development of thrombocytosis, and following resolution of agranulocytosis, the platelet count also normalized, suggesting a possible related mechanism. Interestingly, the patient was treated with TBO-filgrastim 480 mcg daily with a rapid reconstitution of neutrophils. While the mechanism of agranulocytosis remains unknown, we report, to our knowledge, the first known case of agranulocytosis following COVID-19 infection and its successful treatment with granulocyte colony-stimulating factor.

The effect of COVID-19 on absolute neutrophil counts in patients taking clozapine.

Clozapine is associated with haematological side effects, including neutropaenia, which can signal impending life-threatening agranulocytosis. Patients with COVID-19 infection frequently experience lymphopaenia, but not neutropaenia. We present 13 patients established on clozapine who developed COVID-19 infection. There were no significant differences in total white cell or neutrophil counts between pre-COVID-19, intra-COVID-19 or post-COVID-19 periods. We therefore suggest that patients who develop COVID-19 should generally have their clozapine treatment continued. Patients taking clozapine who develop neutroapaenia during COVID-19 infection should be investigated and monitored as in normal practice, because changes in neutrophil counts cannot be assumed to be due to the viral infection.

Management of clozapine treatment during the COVID-19 pandemic.

Clozapine is the only available treatment for refractory schizophrenia but its use involves frequent physical contact with healthcare workers for the purpose of mandatory blood monitoring. During the COVID-19 pandemic, patients taking clozapine will be self-isolating to reduce the risk of infection, not least because these patients are at high risk of serious illness and fatality because of high rates of diabetes, obesity and pulmonary disease and an increased risk of pneumonia. Problems may also arise because both clozapine-induced myocarditis and neutropenic sepsis share signs and symptoms with COVID-19 (fever, chest pain, dyspnoea, etc.). We recommend decreasing the frequency of physical contacts by extending the blood monitoring interval to 12 weeks in those patients taking clozapine for more than 1 year. To distinguish COVID-19 from clozapine-related physical adverse effects, we suggest an urgent antigen test alongside a full blood count. In those taking clozapine who develop COVID-19, we suggest continuing with clozapine whenever possible (even during ventilation), reducing the dose if necessary in line with blood assay results. Blood monitoring should continue but clozapine should only cease if there is a significant fall in neutrophils (COVID-19 is linked to lymphopenia but not neutropenia). To protect against the likelihood and severity of respiratory infection, we recommend the use of vitamin D in all clozapine patients. Initiation of clozapine is likely to remain problematic while the risk of infection remains, given the degree of physical contact required to assure safety.