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Idiosyncratic adverse events to phenytoin therapy, such as agranulocytosis and acute liver failure, though rare, may be life-threatening. Simultaneous occurrence of both adverse events is exceedingly rare; only two cases have been reported in the literature to date. We describe such a case in a 15-year-old girl. Prompt haematological and hepatic recovery occurred after discontinuation of the drug. Given the widespread use of phenytoin in seizure disorders, clinicians prescribing this drug should be aware of its potential complications. Early recognition can considerably improve outcomes., Competing Interests: Declaration of conflicting interestsThe author declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Rationale: Pure white cell aplasia (PWCA) is a rare paraneoplastic syndrome that occurs in patients with thymomas. Currently, the pathogenesis and treatment of this disease remain in the exploratory stage., Patient Concerns: We report a 68-year-old woman with thymoma experienced PWCA involvement as her first presentation. The patient had high fever and agranulocytosis at the onset of the disease. The white blood cell count in the complete blood count was 1.9 × 109/L with a neutrophil of 0.1 × 109/L. The bone marrow aspirates showed decreased granulocyte proliferation. Computed tomography showed a large mass in the anterior mediastinum., Diagnoses: The final diagnosis of our patient was PWCA and thymoma., Interventions: She underwent a thymectomy and cyclosporine A administration during first remission., Outcomes: Long-term remission was achieved following the readministration of cyclosporine A after the disease recurrence., Lessons: PWCA or agranulocytosis with thymoma has been confirmed to be an extremely rare disease. Thymomas with PWCA correlate with autoimmunity. From this case study and the literature review, we concluded that the pathogenesis of thymomas in PWCA is mainly related to the activation of autoreactive T cells. Thymectomy and the immunosuppressive drug, cyclosporine A, were chosen for treatment. The patient's granulocyte levels were unable to recover after surgery because of the inability to promptly clear activated T cells. After surgery, cyclosporine A continued to take for a long time. Thymectomy combined with prolonged cyclosporine A administration may be an effective method for treating this rare disease., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Antithyroid drug (ATD)-induced agranulocytosis (TIA) is the most serious adverse effect during ATD treatment of Graves' disease (GD). Previously, the MICA gene was reported to be associated with TIA. MICA protein is an important ligand for the NKG2D protein, which is encoded by the KLRK1 gene and KLRC4-KLRK1 read-through transcription. This study further investigated the association between KLRC4-KLRK1 gene polymorphisms and susceptibility to TIA., Methods: Twenty-eight candidate single nucleotide polymorphisms (SNPs) on KLRC4-KLRK1 read-through transcription were evaluated by the iPLEX MassARRAY system in 209 GD control patients and 38 TIA cases., Results: A significant association of rs2734565 polymorphism with TIA was found (p=0.02, OR=1.80, 95% CI=1.09-2.96). The haplotype C-A-A-C-G, including rs2734565-C, was associated with a significantly higher risk of TIA (p=4.79E-09, OR=8.361, 95% CI=3.737-18.707). In addition, the interval time from hyperthyroidism to agranulocytosis onset was shorter in patients carrying the rs2734565-C allele than in non-carrying groups (45.00 (14.00-6570.00) d vs. 1080.00 (30.00-3600.00) d, p= 0.046), and the interval from ATD treatment to agranulocytosis onset was also shorter in patients carrying rs2734565-C allele (29.00 (13.00-75.00) d vs. 57.50 (21.00-240.00) d, p= 0.023)., Conclusions: The findings suggest that the KLRC4-KLRK1 gene polymorphism is associated with susceptibility and progression of ATD-induced agranulocytosis. Patients carrying the rs2734565-C allele had a higher susceptibility and faster onset time of TIA., Competing Interests: The authors declare that they have no competing interests., (Thieme. All rights reserved.)

Background: Clozapine is a very effective therapeutic option for schizophrenic disorders that have been refractory to most other therapies. This extremely positive aspect clashes easily with an adverse effect of the drug that is deemed to be a very dangerous one: agranulocytosis. We asked whether the mandatory strict hematological follow-up prescribed in the black box warning of clozapine's label is proportioned to the actual incidence of agranulocytosis, considering that is the main reason that such a drug is often used only late in the treatment course., Methods: We carried out a systematic review of reports examining clozapine administration and agranulocytosis incidence. We specifically selected those where mild and moderate neutropenia was not used as a trigger to stop administration of clozapine, to better estimate the sheer incidence of agranulocytosis when clozapine was continued even with mild hematological effect, where detected. We used PubMed, MEDLINE, EMBASE, Cochrane, and ScienceDirect databases to identify clinical studies conducted between January 1975 and April 2023., Results: We included 14 studies, mostly retrospective ones, that examined the incidence of hematological adverse effects in patients using clozapine. A total of 2354 subjects were included. The mean age of the subjects was 33.5 years. The mean duration of observation of subjects who took clozapine was 800 days, with a mean daily dose of 319.5 mg per day. Of the 2354 subjects examined, we found that 11 of them experienced agranulocytosis (0.47%)., Conclusions: These results suggest the evidence of a lower incidence of agranulocytosis than previously estimated and are in line with more recent meta-analyses. We may therefore think that clinical practice may demand a revision of the approach that both psychiatrists and supervising organizations often take when talking about clozapine., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Infection is the most common adverse event of acute lymphoblastic leukemia (ALL) treatment and is also one of the main causes of death., Methods: To investigate the clinical characteristics and risk factors of severe infections during the maintenance phase of ALL treatment, we conducted a retrospective study., Results: A total of 181 children were eligible and 46 patients (25.4%) suffered from 51 events of severe infection, most of which occurred in the first half year of the maintenance phase (52.9%). The most common infection was pulmonary infection (86.3%) followed by bloodstream infection (19.6%). The main symptoms of ALL patients with pulmonary infection were fever, cough, and shortness of breath. The main manifestations of computer tomography (CT) were ground glass shadow (56.8%), consolidation shadow (27.3%), and streak shadow (25%). Multivariate binary logistic regression analysis showed that agranulocytosis, agranulocytosis ≥7 days, anemia, and low globulin level were independent risk factors for severe infection during the maintenance phase (all p < 0.05)., Conclusions: Taken together, blood routine examinations and protein levels should be monitored regularly for ALL patients in the maintenance phase, especially in the first 6 months. For ALL patients with risk factors, preventive anti-infective or supportive therapies can be given as appropriate to reduce the occurrence of severe infections., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Dipyrone has been used as an analgesic for a century, but recently was proposed as a novel therapeutic strategy for the prevention and therapy of pulmonary hypertension (PH). The aim of this study was to analyze whether the risk for ventilation procedures and hospitalization was lower among patients with PH who used dipyrone compared to subjects who did not use dipyrone., Materials and Methods: Initially, patients with PH were retrieved from the TriNetX database, whereby subjects who used dipyrone were assigned to cohort I, and cohort II was formed by those individuals who did not use dipyrone. Both cohorts were matched for several variables. The outcomes were requirement for ventilation procedures and hospital admission, whereby the time window to record events was 5 years after diagnosis of PH. Subsequently, risk analysis was carried out, and risk ratio (RR) and odds ratio (OR) were calculated. In addition, the risk of agranulocytosis was determined for both cohorts., Results: Out of 741,875 individuals diagnosed with PH 4,282 and 737,593 patients were assigned to the cohorts I and II. After matching, each cohort accounted for 4,278 individuals. Among the cohorts I and II 10 and 187 individuals required ventilation procedures. The according risks of 0.2% vs. 4.4% were significantly different (p < 0.0001; Log-Rank test). RR and OR were 0.053 and 0.051. Within the cohorts I and II 10 and 1,195 subjects required hospital admission. The risks of hospitalization of 0,4% vs. 27.9% differed significantly (p < 0.0001). RR and OR were 0.016 and 0.012. Among the cohorts I and II 47 and 66 individuals were diagnosed with agranulocytosis, whereby no significance was found (p > 0.05)., Conclusions: The risk for ventilation measures and hospitalization among patients with PH was found to be significantly lower when dipyrone was used. Even though the underlying mechanisms remain unknown to date, they are supposedly mediated by an active metabolite of dipyrone. The obtained results appear to be promising for patients suffering from PH. Hence, the present study may encourage further research., Competing Interests: Declaration of competing interest SP, RP, BG and WMK are holders of a patent on metamizole use for PH., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Clozapine is considered the most effective antipsychotic for schizophrenia, but it can cause neutropenia and even agranulocytosis. We describe the first case in Hong Kong involving the use of filgrastim, a recombinant form of human granulocyte colony-stimulating factor, to enable clozapine continuation therapy for a severely ill patient with treatment-resistant schizoaffective disorder who developed recurrent neutropenia after almost 20 years of continuous clozapine therapy. Therefore, clinical vigilance is important, regardless of clozapine treatment duration. Filgrastim can facilitate long-term clozapine therapy in patients with clozapine-induced neutropenia., Competing Interests: All authors have disclosed no conflicts of interest.

Background: The impact of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in acute myeloid leukemia (AML) is still controversial. The purpose of this study is to explore the impact of rhG-CSF administration on clinical efficacy and immune cell subsets after initial induction chemotherapy in AML., Methods: The clinical efficacy and immune cell subsets were compared in the newly diagnosed patients with AML according to whether rhG-CSF was used after initial induction chemotherapy. Next, rhG-CSF stimulation experi-ments on leukemia cell lines and primary leukemia blasts were performed in vitro., Results: There was no statistical difference between control group and rhG-CSF therapy group in complete remission rate and relapse free survival. The duration of agranulocytosis was significantly shortened in rhG-CSF therapy group compared with control group. The percentage of circulating monocytic myeloid-derived suppressor cells (M-MDSCs) and regulatory T cells (Tregs) were significantly increased after the administration of rhG-CSF. Furthermore, it was found that rhG-CSF did not promote the proliferation of leukemia cell lines and primary leukemia blasts, but increased the proportion of M-MDSCs and Tregs in vitro., Conclusions: Administration of rhG-CSF after initial induction therapy of AML does not affect the clinical remission and relapse rate, but reduces the duration of agranulocytosis and increases the proportion of M-MDSCs and Tregs.

Aim: To investigate the efficacy and safety of preoperative neoadjuvant therapy (PD-1 inhibitor plus nab-PTX and nedaplatin) for resectable stage III lung squamous cell carcinoma (SCC) patients., Methods: Patients with locally advanced lung SCC (stage IIIA, IIIB) who received PD-1 inhibitor combined with nab-PTX and NED between February 2019 and June 2021 in Weihai Municipal Hospital were included and underwent surgical treatment 4 weeks after 2-4 cycles neoadjuvant therapy. The rate of resection R0, the effective rate, the complete pathological remission rate (pCR) and the rate of major pathological remission (MPR) were observed., Results: A total of 14 initially unresectable male patients with lung SCC were included and received neoadjuvant treatment after evaluation. Nine out of 14 patients (64.3%) experienced treatment-related adverse events (TRAE), among which 8 (57.1%) experienced grade (G) I-II TRAEs including nausea, vomiting, fatigue, constipation, elevated ALT and AST, hyperthyroidism, hypothyroidism, rash, granulocytopenia, and thrombocytopenia, and 1 (7.1%) experienced grade III-V TRAEs (G), including granulocytopenia and atelectasis. Thirteen patients (92.86%) achieved RECIST-assessed partial remission (PR), while 1 patient (7.14%) achieved stable disease (SD) on imaging assessment after neoadjuvant treatment and continued to be progression-free for 26 months. Of the 11 patients who underwent resection, all were alive and recurrence/progression-free. MPR and pCR were observed in 2 (18.18%) and 9 (81.82%), respectively. IHC results exhibited that all NSCLC patients exhibited positive PD-L1 expression (9/14, TPS ≥50% or greater; 5/14, 1% < TPS < 50%). Two were negative for ALK, EGFR, and ros-1, and the rest were not examined for driver oncogene mutation., Conclusion: The neoadjuvant therapy of the PD-1 inhibitor combined with nab-PTX and NED demonstrated remarkable therapeutic efficacy and good safety on stage III lung SCC without increasing the risk of TRAE, mortality and surgery-related complications, or impede surgery feasibility., Competing Interests: The authors declare no conflicts of interest in this work., (© 2022 Xu et al.)

Objective: To investigate the safety of COVID-19 vaccination in patients on clozapine as regards plasma clozapine concentration and haematological parameters., Methods: We conducted a multicentre observational cohort study from 22 February 2021 to 2 September 2021. Primary outcomes were clinically relevant increase in clozapine blood levels (>100 μg/L increase compared to baseline) and clozapine alert levels (>1000 μg/L). Secondary outcomes were granulocytopenia, leukocytopenia and lymphocytopenia. Outcomes were measured approximately 5 days after the first and (where applicable) second dose of COVID-19 vaccine., Results: This study included 139 patients. Compared to baseline, clozapine blood levels increased significantly (ES = 0.28, p = 0.003) after the second vaccination. Clinically relevant increases in clozapine blood levels occurred in 20/92 patients (22%) and in 16/56 patients (29%) during the first and second phases, respectively. Clozapine alert levels developed in one patient (1%) following the first dose and in three patients (5%) after the second dose. In both phases, changes in white blood cells (WBC) were limited to mild granulocytopenia (3% and 5%), moderate granulocytopenia (1% and 0%) and leukocytopenia (2% and 3%) without cause for extra monitoring according to the guideline., Conclusion: In general, as regards WBC counts COVID-19 vaccination seems to be safe in patients with SMI. Changes in WBC had no clinical implications. Psychoeducation on the symptoms of clozapine intoxication is recommended, especially in patients with clozapine blood levels approaching the upper limit of the therapeutic range. Increase in the C-reactive protein (CRP) level can signal inflammation rapidly and help to prevent clozapine intoxication following vaccination., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Clozapine is the most efficacious treatment for schizophrenia and is associated with lower overall mortality than are other antipsychotic drugs, despite the risk of agranulocytosis. Preliminary reports over the past 10 years suggest a possible risk of haematological malignancies, but the issue has remained unsettled. We aimed to study the risk of haematological malignancies associated with use of clozapine and other antipsychotics., Methods: We did a nationwide case-control (and cohort) study of people with schizophrenia, using prospectively gathered data from Finnish national registers. A nested case-control study was constructed by individually matching cases of lymphoid and haematopoietic tissue malignancy with up to ten controls without cancer by age, sex, and time since first schizophrenia diagnosis. For the case-control study, we restricted inclusion criteria to malignancies diagnosed on a histological basis, and excluded individuals outside of the age range 18-85 years, and any patients that had a previous malignancy. Analyses were done using conditional logistic regression adjusting for comorbid conditions., Findings: For the case-control study 516 patients with a first-time diagnosis of lymphoid and haematopoietic tissue malignancy during years 2000-17 and diagnosed after their first diagnosis of schizophrenia were identified. 102 patients were excluded due to diagnosis that was without a histological basis, five patients were excluded because of their age, and 34 were excluded for a previous malignancy, resulting in 375 patients being matched to controls. We selected up to ten controls without cancer (3734 in total) for each case from the base cohort of people with schizophrenia. For the cohort study, data for 55 949 people were included for analysis. Cumulative incidence of haematological malignancies during the mean follow-up of 12·3 years (SD 6·5) was 102 (0·7%) cases among 13 712 patients who had used clozapine (corresponding to event rate of 61 cases per 100 000 person-years), and during mean follow-up of 12·9 years (SD 7·2) was 235 (0·5%) malignancies among 44 171 patients having used other antipsychotic medication than clozapine (corresponding to 41 cases per 100 000 person-years). Of the 375 individuals with haematological malignancies (305 lymphomas, 42 leukaemia, 22 myelomas, 6 unspecified) observed from 2000-17, 208 (55%) were males and 167 (45%) were female. Ethnicity data were not available. Compared with non-use of clozapine (most had used other antipsychotics and a few had used no antipsychotics), clozapine use was associated with increased odds of haematological malignancies in a dose-response manner (adjusted odds ratio 3·35, [95% CI 2·22-5·05] for ≥5000 defined daily dose cumulative exposure, p<0·0001). Exposure to other antipsychotic drugs was not associated with increased odds. A complementary analysis showed that the clozapine-related risk increase was specific for haematological malignancies, because no such finding was observed for other malignancies. Over 17 years of follow-up of the base cohort, 37 deaths occurred due to haematological malignancy among patients exposed to clozapine (26 with ongoing use at time of haematological malignancy diagnosis, and 11 in patients who did not use clozapine at the exact time of their cancer diagnosis), whereas only three deaths occurred due to agranulocytosis., Interpretation: Unlike other antipsychotics, long-term clozapine use is associated with increased odds of haematological malignancies. Long-term clozapine use has a higher effect on mortality due to lymphoma and leukaemia than due to agranulocytosis. However, acknowledging that the absolute risk is small compared with the previously observed absolute risk reduction in all-cause mortality is important. Our results suggest that patients and caregivers should be informed about warning signs of haematological malignancies, and mental health clinicians should be vigilant for signs and symptoms of haematological malignancy in patients treated with clozapine., Funding: The Finnish Ministry of Social Affairs and Health and Academy of Finland., Competing Interests: Declaration of interests JT, HT, and AT have participated in research projects funded by grants from Janssen-Cilag and Eli Lilly to their employing institution. JT has been a consultant or advisor to or has received honoraria from: Eli Lilly, Evidera, Janssen-Cilag, Lundbeck, Orion, Otsuka, Mediuutiset, Sidera, and Sunovion. JSB is supported by a National Health and Medical Research Council (NHMRC) Boosting Dementia Research Leadership Fellowship and has received grant funding or consulting funds from the NHMRC, Victorian Government Department of Health and Human Services, Dementia Australia Research Foundation, Yulgilbar Foundation, Aged Care Quality and Safety Commission, Dementia Centre for Research Collaboration, Pharmaceutical Society of Australia, GlaxoSmithKline Supported Studies Programme, Amgen, and several aged care provider organisations unrelated to this work. All grants and consulting funds were paid to the employing institution. HT reports personal fees from Janssen-Cilag and Otsuka. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Clozapine has been shown to be an effective and well-tolerated treatment for Parkinson disease (PD) psychosis as well as for refractory tremor in PD. Doses used are generally less than one tenth those used in treating schizophrenia. While the risk of leukopenia and agranulocytosis are reported to be independent of dose, that belief is based on the use of doses used in refractory schizophrenia. There are no published data on the risk of agranulocytosis in patients taking extremely low doses of clozapine., Case Report: This 87-year-old man with diabetes and PD experienced a granulocyte count drop from normal, 3900, at dose initiation, to 0, at the ninth week of treatment taking clozapine 12.5 mg twice daily for refractory tremor. He recovered without developing an infection., Conclusions: This is the first known reported case of agranulocytosis due to clozapine used at an extremely low dose. This report underscores the importance of blood monitoring, even at extremely low doses, although the exact risk remains unknown., Competing Interests: Conflicts of Interest and Source of Funding: Karger Press, Cambridge University Press; MedLink—royalties. EPI-Q, Practicing Clinicians Exchange—consulting. Salary support only was provided by the Butler Hospital., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Schizophrenia is one of the major neuropsychiatric disorders affecting people worldwide. Unfortunately, currently available antipsychotic medications possess several side effects. Among them, clozapine is one of the atypical antipsychotics prescribed in schizophrenia wing to its blocking effect on dopamine (D2) and serotonin (5-HT 1c ) receptors. However, it has been recently reserved for resistant schizophrenia due to its several side effects. The current research aimed at investigating potential naringin add-on benefit to cease the main side effects of clozapine in ketamine-induced psychosis in rats. In this study, schizophrenia was induced in rats via ketamine administration that could promote neuropathological patterns of schizophrenia. Afterwards, clozapine and naringin were administered to rats in order to improve such effects induced by ketamine. Clozapine administration promoted weight gain, hyperglycemia, dyslipidemia, and agranulocytosis. However, naringin was able to reduce such adverse effects when added to clozapine treatment. Naringin increased total leukocyte count preventing agranulocytosis either when administered alone or in combination with clozapine. In addition, via its metabolic activities, naringin treatment lowered serum total cholesterol and triglycerides levels. Moreover, naringin prevented weight gain when administered. Finally, naringin reduced serum glucose level preventing hyperglycemia associated with clozapine treatment. Collectively, these findings may suggest that naringin possesses a potential add-on benefit to clozapine in treatment of schizophrenia., (© 2021 Wiley Periodicals, LLC.)

Tazobactam / piperacillin (TAZ / PIPC) is an injectable combination drug consisting of a broad-spectrum penicillin and a β-lactamase inhibitor. This antimicrobial has a wide spectrum of efficacy against both Gram-positive bacteria and anaerobes. Adverse events usually present as diarrhea or liver dysfunction ; agranulocytosis has not been reported in Japanese patients with puerperal disorders. However, we report a 32-year-old Japanese woman who received TAZ / PIPC to treat an intraperitoneal infection that developed after complications related to transvaginal delivery. Within 14 days of beginning TAZ / PIPC therapy, the patient developed agranulocytosis, indicated by a white blood cell count of 1900 cells / µL and a neutrophil count of 475 cells / µL. We discontinued TAZ / PIPC at this point and changed the antimicrobial to meropenem. Seven days later, her white blood cell count increased to 3700 cells / µL (neutrophil count : 1684 cells / µL), and the intraperitoneal infection resolved. Patients receiving TAZ / PIPC should be monitored periodically for agranulocytosis as well as for diarrhea and liver dysfunction. J. Med. Invest. 68 : 368-371, August, 2021.

Background: Clozapine remains the only medication licensed for treating refractory schizophrenia. However, it remains underutilized in part due to concerns regarding adverse events., Sources of Data: Published literature., Areas of Agreement: Common adverse events during clozapine treatment include sedation, hypersalivation, postural hypotension, dysphagia, gastrointestinal hypomotility, weight gain, diabetes mellitus and dyslipidaemia. Rare but serious events include agranulocytosis, cardiomyopathy, myocarditis, pneumonia, paralytic ileus and seizure., Areas of Controversy: It remains unclear how best to minimize clozapine-induced morbidity/mortality (i) during dose titration, (ii) from hypersalivation and (iii) from gastrointestinal hypomotility. It is also unclear how clozapine pharmacokinetics are affected by (i) gastrointestinal hypomotility, (ii) systemic infection and (iii) passive exposure to cigarette smoke. Whether monthly haematological monitoring needs to continue after 12 months of uninterrupted therapy is also a subject of debate., Growing Points: There is a need for better management of serious clozapine-related adverse events in addition to agranulocytosis. There is also a need for better education of patients and carers, general practitioners, A&E and ITU staff and others of the problems posed in using clozapine safely., Areas Timely for Developing Research: There is a need for more research on assessing clozapine dosage (i) as patients get older, (ii) with respect to exposure to cigarette smoke and (iii) optimizing response if adverse events or other factors limit dosage., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Clozapine is the most effective antipsychotic drug for schizophrenia, yet it can cause life-threatening adverse drug reactions, including myocarditis. The aim of this study was to determine whether schizophrenia patients with clozapine-induced myocarditis have a genetic predisposition compared with clozapine-tolerant controls. We measured different types of genetic variation, including genome-wide single-nucleotide polymorphisms (SNPs), coding variants that alter protein expression, and variable forms of human leucocyte antigen (HLA) genes, alongside traditional clinical risk factors in 42 cases and 67 controls. We calculated a polygenic risk score (PRS) based on variation at 96 different genetic sites, to estimate the genetic liability to clozapine-induced myocarditis. Our genome-wide association analysis identified four SNPs suggestive of increased myocarditis risk (P < 1 × 10 -6 ), with odds ratios ranging 5.5-13.7. The SNP with the lowest P value was rs74675399 (chr19p13.3, P = 1.21 × 10 -7 ; OR = 6.36), located in the GNA15 gene, previously associated with heart failure. The HLA-C*07:01 allele was identified as potentially predisposing to clozapine-induced myocarditis (OR = 2.89, 95% CI: 1.11-7.53), consistent with a previous report of association of the same allele with clozapine-induced agranulocytosis. Another seven HLA alleles, including HLA-B*07:02 (OR = 0.25, 95% CI: 0.05-1.2) were found to be putatively protective. Long-read DNA sequencing provided increased resolution of HLA typing and validated the HLA associations. The PRS explained 66% of liability (P value = 9.7 × 10 -5 ). Combining clinical and genetic factors together increased the proportion of variability accounted for (r 2 0.73, P = 9.8 × 10 -9 ). However, due to the limited sample size, individual genetic associations were not statistically significant after correction for multiple testing. We report novel candidate genetic associations with clozapine-induced myocarditis, which may have potential clinical utility, but larger cohorts are required for replication.

Objective: Estimation of the bone marrow haemopoietic status depending on the reasons and duration of breaks in a standard chemotherapy (BFM-ALL protocol) to predict the course of acute lymphoblastic leukemia (ALL) in chil- dren exposed to low doses of ionizing radiation after the Chornobyl accident., Materials and Methods: The ALL patients (n = 34) were examined within 5 stages of a program chemotherapy. The clinical symptoms, hemogram and myelogram data were analyzed. The radiation dose on bone marrow, initial leuko- cyte count, variants and prognosis of ALL course were accounted. Days of the stopped chemotherapy, type and fre- quency of complications (septic processes, febrile neutropenia, toxic hepatitis, granulocytopenia degree), and the prognosis of disease course (child living status, i.e. alive or died) were estimated., Results: There were abnormal differentiation processes and high percentage of lymphoblasts (86.2 ± 3.3) % in bone marrow in the 1st acute period. Hematological remission was established in all patients on the 33rd day of chemothe- rapy. In a half of cases the haematopoietic recovery occurred by a granulocyte-monocyte type. One third of patients presenting an erythroid type of haemopoiesis died later. The inverse correlation was found between the number of myelocaryocytes and disease prognosis (rs = -0.49). Breaks in chemotherapy for various reasons were recorded. The number of patients with granulocytopenia was greater at the phase 1 and 2 of protocol I and protocol M application, coinciding with a higher incidence of complications. An inverse correlations between the prediction of ALL course and sum of days of breaks between the protocol M and phase 1 of protocol II (rs = -0.56), as well as the duration of the phase 2 of protocol II (rs = -0.62) were found. The radiation dose on bone marrow was (5.37 ± 1.23) mSv. No relationship was found between the radiation doses, ALL variants and disease course., Conclusions: Prognosis of ALL course in children depends on the type of haemopoietic recovery and reasons of breaks in a standard chemotherapy. Interaction between the haemopoiesis functioning and microenvironment and that of their regulation are the key mechanisms of above-mentioned abnormalities, which is the basis for further research., (V. G. Bebeshko, K. M. Bruslova, N. M. Tsvetkova, L. O. Lyashenko, T. I. Pushkariova, L. O. Gonchar, I. V. Tryhlib, S. M. Yatsemirskyi, Yu. M. Samson, V. G. Boyarskyi, K. V. Grischenko, V. M. Polyanska, I. V. Dmytrenko.)

A 26-year-old man with history of schizophrenia was admitted for neutropaenia. He was started on clozapine 3 months prior to admission. As a result he had weekly monitoring of his blood counts and on day of admission was noted to have an absolute neutrophil count (ANC) of 450 cells/μL. He was admitted for clozapine-induced agranulocytosis. Clozapine was held and the patient was started on granulocyte colony-stimulating factor (G-CSF) filgrastim and received two doses without any signs of ANC recovery. On further review, it was noted that the absolute monocyte count (AMC) was also low and tracked with the trend of ANC. We then theorised that the impact of clozapine was on a haematopoietic precursor (colony-forming unit granulocyte-macrophage, CFU-GM) which gives rise to both monocytic and myeloid lineages. Therefore, sargramostim GM-CSF was started. After two doses, the ANC and AMC started trending up and by the third dose, both counts had fully recovered. He was discharged from the hospital and there are no plans to rechallenge with clozapine. Thus, we demonstrate a case of monocytopenia accompanying clozapine-induced agranulocytosis with successful use of GM-CSF. At least in this case, the target of the clozapine injury appears to be the CFU-GM, explaining the rapid and full response to GM-CSF after lack of response to G-CSF., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Agranulocytosis from antimicrobial therapy with ceftriaxone is rare. We report a case of agranulocytosis resulting from ceftriaxone noted more than 3 weeks into therapy., Case Presentation: A 72-year-old woman who was started on ceftriaxone for septic arthritis of the left knee 3 weeks before presentation was admitted to the hospital after being found to be neutropenic on outpatient laboratory analysis. Her absolute neutrophil count on admission was 0/μL. The cause of the agranulocytosis was suspected to be ceftriaxone. The drug was stopped, and she was started on granulocyte colony-stimulating factor with gradual resolution of the neutropenia., Discussion: Serious adverse effects of ceftriaxone therapy, such as agranulocytosis, must be monitored for, especially in patients who are receiving prolonged therapy or high doses. Once this cause of agranulocytosis is identified, ceftriaxone therapy should be stopped; if the patient is febrile, an infectious disease workup should be performed and antibiotics should be started; and granulocyte colony-stimulating factor should be administered with daily monitoring of the absolute neutrophil count.

Background Dipyrone is a non-narcotic analgesic/antipyretic widely used in some countries but prohibited in others due to suspected risk of agranulocytosis. The primary goal of this study was to evaluate hematological alterations in healthy adult volunteers after treatment with dipyrone. Methods The study enrolled 30 healthy volunteers of both genders, aged 19-37 years. They received tablets containing 500 mg of dipyrone sodium to be used four times daily for 7 consecutive days. Before the first administration, arterial pressure was measured and blood was collected in order to evaluate hematological baseline parameters. On the 8th day after the beginning of treatment, the volunteers had their blood pressure assessed once more and underwent a second blood draw. Total and specific leukocyte counts, creatinine, urea, aspartate aminotransferase (AST), alanine aminotransferase (ALT), erythrocytes, and platelets were quantitatively determined. Results No statistically significant difference was observed among total or specific leukocyte counts. Number of platelets, erythrocytes, hemoglobin, and hematocrit decreased after treatment. Diastolic pressure, mean arterial pressure (MAP), and urea concentration declined, while creatinine, AST, and ALT showed no significant alterations. It is noteworthy that, even for parameters that showed statistically significant changes, the highest and lowest values remained within the normal ranges. Conclusions Although dipyrone has historically been associated with agranulocytosis, leukocyte counts remained practically unchanged after oral administration of dipyrone. On the other hand, the present study adds evidence that dipyrone is able to produce statistically relevant decrease in number of platelets, erythrocytes, hemoglobin, and hematocrit in healthy adults, even after short-term treatment.

Granulocytopenia is defined as a decrease of peripheral blood granulocytes below lower limit of normal range. Patients with severe granulocytopenia - agranulocytosis exhibit < 0.5 × 109/l granulocytes in peipheral blood. Granulocytopenia may result from congenital or acquired defective production of granulocyte precursors or it may be a consequence of increased destruction of mature granulocytes, most frequently caused by immune mechanisms. Investigation of origin of granulocytopenia must be connected with exclusion of etiological agents causing secondary neutropenia (infections, autoimmune disorders, drugs, LGL syndrome). Patients with > 0.5 × 109/l of granulocytes usually do not exhibit clinical symptoms unless they do not suffer from a concomitant disease (especially immunodeficiency). Patients with severe granulocytopenia are indicated for supportive treatment and for administration of G-CSF. Children with severe congenital neutropenia (SCN) are at risk of later development of MDS or AML and are candidates for SCT when signs of disease progression appears. Key words: diagnosis - granulocytopenia - growth factors - pathogenesis - transplantation -treatment.

Mycoplasma pneumoniae is a common respiratory pathogen which may cause haematological manifestations including haemolytic anaemia and thrombocytopaenia. Severe neutropaenia is rare with very few cases reported in the literature. An 85-year-old man was transferred to our facility with agranulocytosis in the context of an infective exacerbation of chronic obstructive pulmonary disease with positive serological testing for M. pneumoniae. No alternative infective, autoimmune or lymphoproliferative cause of the neutropaenia was identified. Granulocyte autoantibody testing was performed with a positive result for neutrophil-bound IgG and IgM autoantibodies and significant agglutination reactions. The patient was treated with azithromycin and granulocyte colony-stimulating factor which resulted in a sustained resolution of his neutropaenia., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose of Review: Clozapine-induced agranulocytosis/granulocytopenia (CIAG) is an uncommon condition, but potentially fatal in consequences. The pathogenesis, despite multiple experiments, is not fully elucidated. The current theory suggests reactive oxygen species - nitrenium ion as the most important factor of CIAG. In this review, mechanism and monitoring of CIAG will be discussed., Recent Findings: The mechanism of CIAG seems to have an autoimmune background, rather than toxic. Clozapine has a high potential to undergo biochemical activation to nitrenium ion. The role of the primary metabolite of clozapine - N-desmethylclozapine - is in decline. Nitrenium ion is mainly synthesized by CYP3A4, CYP2D6, and myeloperoxidase system in leukocytes. An important component of CIAG pathogenesis is genetic aberration in human leukocyte antigen genes, and also genes associated with apoptosis and ubiquitination. Clozapine monitoring regimes differ between countries. US-derived clozapine Risk Evaluation and Mitigation Strategy is the most tolerant in the aspect of blood parameter thresholds. Therefore, it provides the opportunities for physician to continue the treatment and also to rechallenge the drug after the episode of CIAG., Summary: Each patient with the episode of CIAG should be assessed individually, with special attention to risk factors and drug-drug interactions. Upon that, the decision about clozapine rechallenge or withdrawal should be made.

Although anti-neutrophil antibodies (ANAs) often exist and immunoreaction may be involved in agranulocytosis, few reports have so far described ANA-positive cases of agranulocytosis with an unknown etiology. We herein describe the case of a 69-year-old woman who presented with ANA-positive agranulocytosis. In this case, both the withdrawal of the drugs that had possibly caused neutropenia and the use of granulocyte-colony stimulating factor (G-CSF) were ineffective treatment measures. Approximately 2 weeks after the discontinuation of the suspected drugs, we initiated corticosteroid pulse therapy; the neutrophil count recovered by day 19 of steroid therapy. High-dose methylprednisolone therapy should thus be considered for patients demonstrating ANA-positive agranulocytosis with an unknown etiology that is refractory to G-CSF treatment.

Introduction: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe toxidermia that can lead to death from multivisceral failure. We report a case of DRESS associated with febrile agranulocytosis in a child., Observation: An 8-year-old child was hospitalized for diffuse maculopapular exanthema with edema of the extremities and face associated with cheilitis and febrile agranulocytosis. This symptomatology began 1month after the introduction of carbamazepine for partial epilepsy. The clinical picture was a multisystemic disease with colitis, interstitial pneumonitis, hepatic cytolysis, and hepatocellular insufficiency. HHV7 viral reactivation and increased eosinophils (20%) in the myelogram were demonstrated, providing the diagnosis of DRESS. The progression was favorable after carbamazepine therapy was stopped and systemic corticosteroids were administered., Discussion: DRESS syndrome is a disorder that is unfamiliar to pediatricians. Its association with agranulocytosis is rare and the absence of hypereosinophilia contributed to diagnostic difficulties in this case. The multisystemic failure, the reactivation of HHV7, the increase of eosinophils in the myelogram, and the favorable progression under systemic corticosteroid therapy contributed greatly to the diagnosis. A cutaneous biopsy was not considered necessary for the diagnosis in the case reported herein., Conclusion: DRESS syndrome is rarely associated with agranulocytosis, but its diagnosis must be quickly raised so that the incriminated drug can be interrupted., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Purpose/background: Clozapine is associated with hematological abnormalities, notably neutropenia, which may progress to agranulocytosis. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been used to reduce the frequency and duration of clozapine-associated neutropenia. This review aims to explore the use, efficacy, and tolerability of these cytokines in the treatment of clozapine-associated agranulocytosis., Methods/procedures: We conducted a systematic review of published interventional and observational studies, case series, and case reports where G-CSF/GM-CSF was used to treat clozapine-associated agranulocytosis., Findings/results: We identified 29 reports (40 patients). The median duration of neutrophil recovery time after stopping clozapine and starting cytokine treatment was 7 days (range, 2-13 days) for those with agranulocytosis (absolute neutrophil count < 0.5 × 10 cells/L). Ninety-four percent (n = 29) had no serious adverse reactions, and no deaths occurred., Implications/conclusions: Our findings indicate that G-CSF/GM-CSF use is well tolerated and suggest that G-CSF can sometimes be safely used to reduce the duration of neutropenia associated with clozapine use. However, the interpretation of this outcome is difficult, given the likely publication bias for positive outcomes in case reports.

Thionamides, such as methimazole and propylthiouracil, are used for the management of hyperthyroidism. Agranulocytosis is a rare adverse effect of thionamides and elderly patients are especially vulnerable. Here we discuss a case of an 80-year-old woman who developed agranulocytosis and pneumonia approximately 4 weeks after starting low dose methimazole therapy. Despite aggressive treatment with broad-spectrum antibiotics and granulocyte colony stimulating factor, she developed multiorgan failure and died. Our goals are to identify risk factors common to elderly patients and hopefully improve outcomes in this population when prescribed thionamides., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

We report on a 77-year-old male patient with neutropenic fever as a result of a newly diagnosed agranulocytosis. The patient was taking metamizole, which is a well known cause of agranulocytosis. The diagnosis of metamizole-induced agranulocytosis as an underestimated side-effect of metamizole could be confirmed by a bone marrow biopsy. The bone marrow and the blood count recovered completely after stopping the therapy with metamizole and administration of granulocyte colony-stimulating factor (G-CSF).

Infectious mononucleosis secondary to Epstein-Barr virus typically follows a relatively benign and self-limited course. A small subset of individuals may develop further progression of disease including hematologic, neurologic, and cardiac abnormalities. A mild transient neutropenia occurring during the first weeks of acute infection is a common finding however in rare cases a more profound neutropenia and agranulocytosis may occur up to 6weeks following the onset of initial symptoms. We describe the case of an 18-year-old woman who presented 26days following an acute infectious mononucleosis diagnosis with agranulocytosis and fever. No source of infection was identified and the patient had rapid improvement in her symptoms and resolution of her neutropenia. The presence of fever recurrence and other non-specific symptoms in individuals 2-6weeks following acute infectious mononucleosis symptom onset may warrant further assessment for this uncommon event., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The monoclonal anti-immunoglobulin E (IgE) antibody, omalizumab, was the first drug approved for use in patients with chronic idiopathic/spontaneous urticaria (CIU/CSU) who remain symptomatic despite H 1 -antihistamine treatment. Omalizumab binds to free IgE, which lowers free IgE levels and causes FcεRI receptors on basophils and mast cells to be downregulated. It has been shown to improve symptoms of CIU/CSU, but its mechanism of action is not currently understood. Potential mechanisms in CIU/CSU include reducing mast cell releasability, reversing basopenia and improving basophil IgE receptor function, reducing activity of IgG autoantibodies against FcεRI and IgE, reducing activity of IgE autoantibodies against an antigen or autoantigen that has yet to be definitively identified, reducing the activity of intrinsically 'abnormal' IgE, and decreasing in vitro coagulation abnormalities associated with disease activity. However, none of these theories alone or in combination fully account for the pattern of symptom improvement seen with omalizumab therapy, and therefore, no one mechanism is likely to be the definitive mechanism of action. Additional research is needed to further clarify the involvement of omalizumab in relieving symptoms associated with the complex, multifactorial pathogenesis of CIU/CSU., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Agranulocytosis is a rare but serious complication of antithyroid drug therapy, and an up-to-date understanding of this topic is important. Both direct toxicity and immune-mediated responses have been described as possible mechanisms. Some major susceptibility loci have recently been identified, which may lead the diagnosis of agranulocytosis into a genomic era. Onset is acute and patients present with symptoms and signs of infection together with high fever. Clinical suspicion is pivotal and should prompt blood sampling. An absolute neutrophil count of <500/μl in the presence of antithyroid drugs establishes the diagnosis. The causative drug should immediately be stopped to prevent further damage. Treatment includes broad-spectrum antibiotics and granulocyte-colony stimulation factor in selected patients. Later, patients will need definitive treatment for hyperthyroidism, usually with radioactive iodine or surgery. The best way to avoid the mortality associated with antithyroid drug-induced agranulocytosis is patient education.

Chronic lymphocytic leukemia (CLL) is frequently associated with autoimmune complications such as autoimmune hemolytic anemia, immune thrombocytopenia, pure red cell aplasia, and autoimmune granulocytopenia. It is critical to diagnose cytopenias from these secondary complications of CLL accurately, since prognosis and therapy are substantially different from patients who have cytopenias due to extensive bone marrow infiltration by CLL. The pathogenesis of autoimmune cytopenias in CLL is complex; and it involves antigen presentation by CLL cells to polyclonal B cells resulting in production of autoantibody, and alteration of the T cell milieu tilting the balance in favor of an autoimmune response. Traditional therapy of autoimmune complications in CLL consists of immunosuppression with corticosteroids and/or anti-CD20 monoclonal antibodies. In patients who have a suboptimal response, treating the underlying CLL is generally effective in ameliorating secondary cytopenias. Although novel oral therapies such as ibrutinib, idelalisib, and venetoclax have been shown to be extremely effective in the management of CLL, prospective data from larger numbers of patients with longer follow-up are needed prior to recommending their routine use in the management of autoimmune cytopenias in CLL.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease that presents with sicca symptoms of the main mucosal surfaces. Patients with pSS have a broad spectrum of laboratory features, such as cytopenias and hypergammaglobulinemia. Although hematological abnormalities are usually seen in pSS patients, agranulocytosis and autoimmune hemolytic anemia (AIHA) are rare. Here we describe a 40-year-old woman with pSS who developed both agranulocytosis and mixed-type AIHA. An increased risk of malignancies has also been reported in pSS patients with hematological changes. Although there is no evidence of malignancies, this patient should be closely followed up in case of developing lymphoma., (© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

Leukopenia is a considerably common complication of tocilizumab [TCZ] and rituximab [RTX] therapy. RTX-induced leukopenia typically exhibits delayed onset. While agranulocytosis has been reported linked to RTX treatment of lymphoma, this complication rarely occurs in rheumatoid arthritis (RA) treatment and, to our knowledge, has never been reported in association with TCZ therapy. We herein report four agranulocytosis cases in three patients, with the first two cases suspected to be secondary to human parvovirus B19 (PVB19) infection. Agranulocytosis manifested in the first patient 2 months following a third RTX course. Bone marrow (BM) polymerase chain reaction (PCR) was positive for PVB19. The patient relapsed after three TCZ courses, with her PCR again positive for PVB19. Both episodes resolved under granulocyte-macrophage colony-stimulating factor (GM-CSF). In the second patient, agranulocytosis manifested after the 74th TCZ course. Bone marrow PCR was positive for PVB19, and the evolution was favorable under intravenous immunoglobulin administration. The third case was a 53-year-old female patient with seropositive RA who presented agranulocytosis after the first infusion of her fourth RTX course. Unfortunately, no PCR PVB19 was made on myelogram. Evolution was favorable after 5 days of GM-CSF. PVB19 infection should be investigated in patients suffering from agranulocytosis manifesting during biotherapy. In cases manifesting from the 15th day of RTX treatment onwards, hemogram must be conducted before readministering the infusion., Competing Interests: Compliance with ethical standards Disclosures None.

Immune checkpoint inhibitors are novel agents in the process of revolutionising cancer care. These agents have become a very appealing therapeutic alternative since they are much better tolerated than cytotoxic therapy, due to their relatively favorable toxicity profile. However, adverse events associated with these agents usually involve the immune system and can have serious implications jeopardising survival. Herein we report the first case of immune-mediated agranulocytosis due to Nivolumab therapy. The patient suffered from Staphylococcus infection during her agranulocytosis which only responded to high dose corticosteroid therapy., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Antithyroid drug (ATD)-induced agranulocytosis is a rare but life-threatening disease. Clinical features of ATD-induced agranulocytosis and outcomes remain incompletely understood., Method: Patients with clinically diagnosed ATD-induced agranulocytosis were retrospectively studied, involving 9690 patients who were referred for radioiodine treatment during a 15-year period (2000-2015) in China. There were 114 cases of agranulocytosis attributable to ATD included, and their clinical characteristics and therapy outcomes were analyzed., Results: The female-to-male ratio of ATD-induced agranulocytosis was 10.4:1. The mean age (±standard deviation) of the patients with ATD-induced agranulocytosis was 41.7 ± 12.3 years. The methimazole and propylthiouracil doses given at the onset were 22.9 ± 8.0 mg/day and 253.6 ± 177.5 mg/day, respectively. ATD-induced agranulocytosis occurred in 45.1%, 74.3%, and 88.5% of patients within 4, 8, and 12 weeks of the onset of ATD therapy, respectively. Fever (78.9%) and sore throat (72.8%) were the most common symptoms when agranulocytosis was diagnosed. The mean recovery time of agranulocytosis was 13.41 ± 7.14 days. Recovery time in the granulocyte colony-stimulating factor (G-CSF)-treated group (12.7 ± 6.0 days) did not differ from that in the group not treated with G-CSF (16.4 ± 10.6 days; p = 0.144). Treatment with (131)I was successful in 87/98 patients (88.8%). The success rate of (131)I was equivalent (p = 1.000) between the groups receiving methimazole (88.2%, 75/85) and propylthiouracil (92.3%, 12/13)., Conclusions: This largest single-institution study in China shows that ATD-induced agranulocytosis tends to occur within the first 12 weeks after the onset of ATD therapy. For patients with ATD-induced agranulocytosis, G-CSF does not improve the recovery time of agranulocytosis, and (131)I is an optimal treatment approach.

Drug-induced agranulocytosis is a rare haematological disorder considered as severe adverse drug reaction. Due to its low incidence, the number of studies are low and the variability of clinical features and presentation in hospitalized patients is rarely described. Awe performed an observational, transversal and retrospective study in the haematology and toxicology unit in a tertiary hospital located in Spain (Valencia) (1996-2010) in order to assess its incidence, the drugs involved, the management and outcomes of drug-induced agranulocytosis. Twenty-one cases of agranulocytosis were retrieved. All of them presented severe and symptomatic agranulocytosis (fever and infection). The most common drug associated with drug-induced agranulocytosis was metamizole administration but other drugs belonging to different pharmacological classes as well (carbimazol, sulfasalazine, bisoprolol, itraconazole, amitryptiline, ketorolac and claritomicine+cefuroxime). No differences between sex and age were found in relationship with the manifestations or course of agranulocytosis. In contrast, a significantly negative association was found between age of patients and the percentage of increase in neutrophil count. Administration of human granulocyte colony-stimulating factor did not significantly enhance the recovery of the process or the restoration of leucocytes count, suggesting a limited utility in this type of agranulocytosis., (© The Author(s) 2015.)