Understanding clozapine-related blood dyscrasias. Developments, genetics, ethnicity and disparity: it's a CIN.

Clozapine remains the gold standard intervention for treatment-resistant schizophrenia; however, it remains underused, especially for some minority groups. A significant impediment is concern about propensity to neutropenia. The aim of this article is to provide an update on current knowledge relating to: the pattern and incidence of severe blood dyscrasias; the effectiveness of current monitoring regimes in reducing harm; the mechanisms of and the distinctions between clozapine-induced neutropenia and agranulocytosis; benign ethnic neutropenia; and changes to the monitoring thresholds in the USA and other international variations. These all have implications for the practical use of clozapine; specifically, how barriers to initiating, maintaining and restarting clozapine can be understood and in many cases overcome, especially for patients from minority groups, potentially with simpler approaches than the use of lithium or G-CSF.

Time for a change to clozapine haematological monitoring.

OBJECTIVES: This paper critiques the haematological monitoring guidelines for clozapine. It describes the history of clozapine, as well as the pathophysiology and epidemiology of clozapine-induced neutropenia (CIN) and agranulocytosis (CIA). The paper appraises the extant literature on mandatory clozapine haematological monitoring. CONCLUSION: Contemporary Australian protocols for clozapine haematological monitoring are not consistent with the current evidence base. CIN and CIA are rare occurrences, and the associated risk of death is low. Potential modifications to existing guidelines include changing neutrophil thresholds for patients with benign ethnic neutropenia and reducing the frequency or removing haematological monitoring after two years of clozapine treatment.

Dose-dependent incidence of agranulocytosis in patients treated with methimazole and propylthiouracil.

Agranulocytosis is a serious adverse effect of methimazole (MMI) and propylthiouracil (PTU), and although there have been reports suggesting a dose-dependent incidence in relation to both drugs, the evidence has not been conclusive. The objective of our study was to determine whether the incidences of agranulocytosis induced by MMI and PTU exhibit dose-dependency. The subjects were 27,784 patients with untreated Graves' disease, 22,993 of whom were on an antithyroid drug treatment regimen for more than 90 days. Within this subset, 18,259 patients had been treated with MMI, and 4,734 had been treated with PTU. The incidence of agranulocytosis according to dose in the MMI group was 0.13% at 10 mg/day, 0.20% at 15 mg/day, 0.32% at 20 mg/day, and 0.47% at 30 mg/day, revealing a significant dose-dependent increase. In the PTU group, there were 0 cases of agranulocytosis at doses of 125 mg/day and below, 0.33% at 150 mg/day, 0.31% at 200 mg/day, and 0.81% at 300 mg/day, also revealing a significant dose-dependent increase. The incidence of agranulocytosis at MMI 15 mg and PTU 300 mg, i.e., at the same potency in terms of hormone synthesis inhibition, was 0.20% and 0.81%, respectively, and significantly higher in the PTU group. Our findings confirm a dose-dependent increase in the incidence of agranulocytosis with both drugs, but that at comparable thyroid hormone synthesis inhibitory doses PTU has a considerably higher propensity to induce agranulocytosis than MMI does.

Adverse hematological profiles associated with chlorpromazine antipsychotic treatment in male rats: Preventive and reversal mechanisms of taurine and coenzyme-Q10.

Chlorpromazine (CPZ) is one of the most effective antipsychotic drugs used for managing psychotic related disorders owing to its dopamine receptor blocking action. However, pharmacological investigations against CPZ's cytotoxic effect have remained scarce. Hence, this study investigated the preventive and reversal effects of taurine and coenzyme-Q10 (COQ-10), which are compounds with proven natural antioxidant properties, against CPZ-induced hematological impairments in male rats. In the preventive study, rats received oral saline (10 ml/kg), taurine (150 mg/kg/day), COQ-10 (10 mg/kg/day) or in combination for 56 days, alongside CPZ (30 mg/kg, p.o.) between days 29-56. In the reversal protocol, rats had CPZ repeatedly for 56 days before taurine and COQ-10 treatments or their combination from days 29-56. Rats were also given taurine (150 mg/kg/day), and COQ-10 (10 mg/kg/day) alone for 56 days. Serums were extracted and assayed for hematological, with oxidative and inflammatory markers. CPZ induced decreased red/white blood cells, erythropoietin, platelet count, packed cell volume and hemoglobin, neutrophil, and lymphocyte, which were prevented and reversed by taurine and COQ-10, or their combination. Taurine and COQ-10 improved mean corpuscular volume, hemoglobin concentration, with increased erythropoietin levels relative to CPZ groups. CPZ-induced increased malondialdehyde, tumor necrosis factor-alpha and interleukin-6 levels with decreased interleukin-10, glutathione, and superoxide-dismutase were prevented and reversed by taurine and COQ-10 in comparison with CPZ groups. Taurine and COQ-10 alone notably improved the antioxidant/anti-inflammatory status relative to controls. Among other mechanisms, taurine and COQ-10 abated CPZ-induced hematological deficiencies, via decreased serum levels of oxidative stress, and pro-inflammatory cytokines release, with increased antioxidants and anti-inflammation function.

Gingival Necrosis Related to Sepsis-Induced Agranulocytosis Due to Pseudomonas aeruginosa Bacteraemia: A Case Report.

Background: There have been no reports of sepsis-induced agranulocytosis causing gingival necrosis in otherwise medically healthy patients to the authors' best knowledge. Even though there are several case reports of gingival necrosis secondary to medication-induced agranulocytosis, they have not systematically described the natural progression of agranulocytosis-related gingival necrosis. Methods: This paper presents a case report of a 29-year-old female Indian patient with generalised gingival necrosis and constitutive signs of intermittent fever, nausea, and vomiting. She also complained of abdominal pains. Blood counts showed agranulocytosis, and the patient was admitted for a workup of the underlying cause. Parenteral broad-spectrum antibiotics were administered, which brought about clinical resolution. Results: Her gingival necrosis was attributed to sepsis-induced agranulocytosis triggered by Pseudomonas aeruginosa bacteraemia, and upon clinical recovery, spontaneous exfoliation left behind exposed bone. Secondary healing over the exposed alveolar bone was noted after a year-long follow-up, albeit with some residual gingival recession. Conclusions: Oral manifestations of gingival necrosis, when present with concomitant constitutive symptoms, could indicate a serious underlying systemic condition that could be potentially life-threatening if left untreated. Dentists should be cognizant of this possibility so that timely intervention is not delayed.

Agranulocytosis Associated With Psychiatric Polypharmacy: Lessons Learned From a Clinical Case.

Psychiatric polypharmacy involves the use of two or more psychotropic medications to manage a mental and emotional condition. The prevalence of psychotropic polypharmacy has been increasing since the 1990s and has been attributed to the rise in multiple psychiatric conditions presenting in one patient. However, as the prevalence of polypharmacy increases to maximize therapeutic advantages, so does the adverse effect profile of those drugs used in combination, leading to very life-threatening effects such as agranulocytosis. Thus, we report a case of agranulocytosis secondary to polypharmacy in a patient with a history of multiple complex psychiatric conditions.  The patient is a 20-year-old female with a past medical history of major depressive disorder, borderline personality disorder, post-traumatic stress disorder, anxiety disorder, hypothyroidism, and ulcerative colitis. Her psychiatric conditions were managed with multiple medications including chlorpromazine, and clozapine was recently added a month prior to admission. Upon admission, the patient was hemodynamically stable and febrile, with complaints of generalized body aches and myalgia. Laboratory results showed profound leukopenia with a white blood cell count of 1.0x103/uL and a neutrophil number of 0.02x103/uL. The patient was admitted to the hospital for neutropenic sepsis and was aggressively treated with intravenous antibiotics. Her clozapine and chlorpromazine were discontinued. In this report, we discuss the association between chlorpromazine and clozapine use and agranulocytosis, emphasizing the importance of regular monitoring and heightened awareness for patients on these medications. This case also underscores the necessity for cautious polypharmacy medication management in individuals with complex psychiatric conditions, highlighting the potential life-threatening consequences of polypharmacy in this population.

Possible nonimmunological toxicological mechanisms of vesnarinone-associated agranulocytosis in HL-60 cells: role of reduced glutathione as cytotoxic defense.

This study was conducted as part of an investigation into the cause of vesnarinone-associated agranulocytosis. When HL-60 cells were exposed to vesnarinone for 48 hr, little cytotoxicity was observed, although reduced glutathione (GSH) content decreased in a concentration-dependent manner. Significant cytotoxicity and reactive oxygen species (ROS) production were observed when intracellular GSH content was reduced by treatment with L-buthionine-(S, R)-sulphoximine. The involvement of myeloperoxidase (MPO) metabolism was suggested, as when HL-60 cells were exposed to a reaction mixture of vesnarinone-MPO/H2O2/Cl-, cytotoxicity was also observed. In contrast, the presence of GSH (1 mM) protected against these cytotoxic effects. Liquid chromatography-mass spectrometry analysis of the MPO/H2O2/Cl- reaction mixture revealed that vesnarinone was converted into two metabolites, (4-(3,4-dimethoxybenzoyl)piperazine [Metabolite 1: M1] and 1-chloro-4-(3,4-dimethoxybenzoyl)piperazine [Metabolite 2: M2]). M2 was identified as the N-chloramine form, a reactive metabolite of M1. Interestingly, M2 was converted to M1, which was accompanied by the conversion of GSH to oxidized GSH (GSSG). Furthermore, when HL-60 cells were exposed to synthetic M1 and M2 for 24 hr, M2 caused dose-dependent cytotoxicity, whereas M1 did not. Cells were protected from M2-derived cytotoxicity by the presence of GSH. In conclusion, we present the first demonstration of the cytotoxic effects and ROS production resulting from the MPO/H2O2/Cl- metabolic reaction of vesnarinone and newly identified the causative metabolite, M2, as the N-chloramine metabolite of M1, which induces cytotoxicity in HL-60 cells. Moreover, a protective role of GSH against the cytotoxicity was revealed. These findings suggest a possible nonimmunological cause of vesnarinone agranulocytosis.

Severe Clozapine-Induced Agranulocytosis, Pharmacodynamic Synergism, and Lithium Promyelocytic Effects in Granulocyte Colony-Stimulating Factor (G-CSF) Resistance or Delayed Response: A Case Report.

Clozapine-induced agranulocytosis is documented in multiple studies, but there is limited literature on treatment-resistant agranulocytosis, the synergistic effect of multiple agranulocytosis-inducing drugs, and lithium's promyelocytic effects. This case highlights these gaps by discussing a patient with an absolute neutrophil count of zero while being treated with Depakote, Haldol, and clozapine. This case proposes more research on lithium's promyelocytic effects, especially in patients who are unresponsive or have a delayed response to discontinuing offending agents and granulocyte colony-stimulating factor (G-CSF).

Comparison of agranulocytosis and anti-neutrophil cytoplasmic antibody-associated vasculitis caused by two antithyroid drugs: A pharmacovigilance study using the WHO international database.

BACKGROUND: Methimazole (MMI) and propylthiouracil (PTU) are commonly used for patients with thyrotoxicosis. Agranulocytosis and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is associated with high morbidity and mortality, requiring appropriate interventions. In this study, we compared adverse drug effects associated with MMI and PTU using a real-world large pharmacovigilance database. METHODS: We searched all Individual Case Safety Reports reported to be associated with MMI and PTU, from VigiBase between 1967 and June 2, 2021. We conducted disproportionality analysis (case/non-case analysis) to analyze the difference in reported adverse drug reactions (ADRs) between antithyroid drugs (case) and the entire database (non-cases). We further analyzed information for the cases of agranulocytosis and AAV. RESULTS: Among 11 632 cases of ADRs reported after MMI intake, agranulocytosis occurred in 1633 cases and AAV occurred in 41 cases. For 5055 cases of ADRs reported after PTU intake, agranulocytosis occurred in 459 cases and AAV occurred in 110 cases. Agranulocytosis occurred after a median of 28 days after PTU intake and 33 days after MMI intake. More than 95% of the agranulocytosis cases were classified as serious, but most of them (65.1% for PTU and 70.4% for MMI) were reported to have recovered after dechallenge actions; mostly drug withdrawal. AAV occurred after a median of 668 days after PTU intake, and 1162 days after MMI intake. CONCLUSIONS: This is a pharmacoepidemiological study investigating agranulocytosis and AAV caused by MMI and PTU. Through this research, we could provide more specific insights into a safe prescription of antithyroid drugs in a real-world setting.

Identifying causative medications for agranulocytosis: A case report of an older adult with cerebral infarction.

Key Clinical Message: Most drugs that cause adverse events are difficult to identify in critically ill patients undergoing polypharmacy. We share our experience in identifying the causative drug among four suspect drugs administered during emergency treatment. Abstract: We present the case of a 93-year-old man who was admitted for the treatment of cerebrovascular events. The patient was initially prescribed dual antiplatelet therapy with aspirin and clopidogrel along with lansoprazole, Hange-koboku-toh, and elobixibat. On day 36 after admission, the patient was found to have developed agranulocytosis. To improve his cerebrovascular prognosis, we first discontinued medications other than the anticoagulant medicines and initiated filgrastim. We discontinued clopidogrel 9 days after the discontinuation of the other medicines considering his low white blood cell count. One day after the discontinuation of clopidogrel, the agranulocytosis was alleviated. Considering the time course, clopidogrel, lansoprazole, Hange-koboku-toh, and elobixibat were suspected as the culprit medicines. This case highlights the considerable challenges encountered in clinical practice when attempting to identify the drugs responsible for agranulocytosis, particularly in patients on intensive medication therapy.

'Double whammy': An Unusual Co-occurrence of Idiosyncratic phenytoin-induced agranulocytosis and acute liver failure in a child.

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.

Pembrolizumab-induced agranulocytosis.

INTRODUCTION: With the widespread use of anti-programmed death-1 monoclonal antibodies, such as pembrolizumab, rare side effects appear in clinical practice. CASE REPORT: We report the case of a man diagnosed with non-keratinizing squamous lung carcinoma stage IVB with programmed death-ligand 1 70% who developed agranulocytosis 10 days after a single dose of pembrolizumab as monotherapy. MANAGEMENT AND OUTCOME: Pembrolizumab was discontinued immediately. Grade 4 neutrophil decrease is mentioned in the product information sheet as a rare side effect. The patient was admitted in poor physical condition with grade 4 neutropenic fever, mucositis and anemia. Agranulocytosis did not improve despite treatment with granulocyte colony-stimulating factor, intravenous corticosteroids and intravenous immunoglobulins. He experienced a rapid worsening and died 3 weeks after admission. The causal relationship between pembrolizumab and the appearance of agranulocytosis was determined as possible according to Naranjo's modified Karch and Lasagna's imputability algorithm. DISCUSSION: Hematologic immune-related adverse events are uncommon but important side effects among patients treated with immune checkpoint inhibitors. Agranulocytosis and neutropenia are infrequently reported but can be life-threatening. The main approach for agranulocytosis consists of intravenous corticosteroids, granulocyte colony-stimulating factors and blood products. Depending on bone marrow characteristics, treatments for refractory patients include intravenous immunoglobulins or cyclosporine. After an immune-related adverse event, benefits and risks must be considered before continuation with an immune checkpoint inhibitor. Detection and communication of adverse drug reactions to the Pharmacovigilance Systems have special relevance for rare side effects.

Current practice for clozapine-induced leukopenia in Japanese psychiatric hospitals: A nationwide survey.

Clozapine is an atypical antipsychotic used for treatment-resistant schizophrenia. In Japan, its use requires management by a blood monitoring system called the Clozaril Patient Monitoring Service (CPMS) for the early detection of serious side effects such as agranulocytosis, which is extremely rare. Monitoring services vary among the clozapine suppliers in different countries. Additionally, Japanese patients can be started on clozapine treatment exclusively through an 18-week inpatient admission at a psychiatric hospital capable of coordinating with a hematologist. One reported reason for the lack of widespread clozapine use in Japan is the difficulty in establishing collaboration with hematologists when agranulocytosis/leukopenia occurs. Hence, we conducted a nationwide web-based survey of CPMS-registered psychiatric facilities in Japan to determine the status of collaboration with hematology departments. Valid responses were received from the psychiatrists responsible for prescribing clozapine at 203 of the 547 facilities (response rate: 37.1 %). The largest number of psychiatric facilities (61 %) collaborated with hematologists at another facility with a psychiatry department, while psychiatrists in 32 % of the facilities worked with hematologists at their own facilities. Most patients with clozapine-induced agranulocytosis/leukopenia could be treated with clozapine discontinuation and follow-up in psychiatric inpatient units with the assistance of a hematologist. The actual workload of hematologists was limited, and the patients might experience the burden of repeated blood sampling. This study suggests that disseminating information regarding the status of collaborations with hematologists may promote the widespread use of clozapine in Japan. SHORT COMMENT FOR TWITTER: This study suggests that most patients with clozapine-induced agranulocytosis/leukopenia could be treated with clozapine discontinuation and follow-up in psychiatric inpatient units with the assistance of a hematologist.

Antithyroid Drug-Induced Agranulocytosis: A Case Report.

Agranulocytosis is a rare but life-threatening complication of methimazole and propylthiouracil, antithyroid drugs (ATDs) prescribed for the treatment of hyperthyroidism. We report the case of a 41-year-old female who presented to our institution with complaints of fevers, chills, sore throat, myalgias, and generalized weakness one month after treatment initiation with methimazole. A complete blood count at admission revealed agranulocytosis with an absolute neutrophil count of 0/µl. After discontinuation of the medication, she was treated with granulocyte-colony stimulating factor and intravenous broad-spectrum antibiotics, which improved her condition on day seven of hospitalization. Although agranulocytosis is a rare complication of antithyroid drugs, providers must maintain a high index of clinical suspicion as prompt diagnosis and treatment are essential. After the diagnosis is confirmed with an absolute neutrophil count <500/µl, management involves discontinuation of the offending agent and initiation of intravenous broad-spectrum antibiotics. Granulocyte-colony stimulating factor, commonly employed in addition to antibiotics, is a controversial treatment option and more research demonstrating its efficacy is necessitated. Preventing mortality associated with antithyroid drug-induced agranulocytosis is achieved through patient education at the time of ATD initiation.

Pure White Cell Aplasia Associated With Long-Term Unprotected Exposure to High Concentrations of Benzalkonium Chloride and 2-Phenoxyethanol.

Pure white cell aplasia (PWCA) is a very rare hematological disorder with a nearly total absence of granulocytes and their precursor cells. While the disease is rarely diagnosed incidentally in otherwise asymptomatic individuals, most patients suffer from sometimes life-threatening infections. Due to its very low incidence, the precise pathomechanism of PWCA still needs to be elucidated. While most cases reported in the literature have been associated with an underlying thymic or autoimmune disease, some other factors including the intake of certain drugs such as antimicrobial agents or immune checkpoint inhibitors have been identified as potential triggers. Since PWCA is commonly refractory to treatment with granulocyte colony-stimulating factors (G-CSF), the main focus lies in identifying and eliminating the underlying trigger. Here, we report a unique case where the development of PWCA in a 56-year-old man with an upper respiratory tract infection has to be attributed to the long-term unprotected exposure to an industrial detergent containing high concentrations of the preservatives benzalkonium chloride (BAC) and 2-phenoxyethanol (2-PE). As a matter of fact, certain hematotoxic potential has been described in the literature for both BAC and 2-PE.

Clozapine monitoring at a specialised psychiatric hospital: A retrospective chart review.

Background: Clozapine is the only Food and Drug Administration (FDA) and National Institute for Care and Excellence (NICE) approved drug for treatment-resistant schizophrenia (TRS). Its potentially life-threatening haematological side effects of neutropaenia and agranulocytosis mandate rigorous monitoring of neutrophil counts, presenting unique, Third-World population challenges. Aim: To describe the Clozapine white blood cell monitoring practice and outcomes in a local psychiatric hospital. Setting: At a specialist Psychiatry unit in Durban, KwaZulu-Natal, which follows a modified algorithm of the South African Standard Treatment Guidelines for Clozapine monitoring. Methods: A retrospective chart review composed of 120 patients on Clozapine treatment from 01 July 2018-31 December 2020. Demographic and clinical information was captured in a Redcap database. Descriptive statistics using categorical variables were used. Results: The study population was from a low socioeconomic background, with low levels of education and employment. A baseline neutrophil count was recorded in 58 files (48.3%). Clozapine was stopped in 6 out of the 120 patients due to 'neutropaenia' (absolute neutrophil counts ranging from 1.18 to 1.6); none developed agranulocytosis. Their duration of Clozapine treatment ranged from 2 weeks-15 years. Conclusion: Haematological monitoring frequency and documentation of patients receiving Clozapine were not in compliance with the hospital's adapted guidelines and may have resulted in the termination of treatment before true neutropaenia developed. Patients developed neutropaenia at low doses of Clozapine and after many years of treatment. Contribution: These results suggest local Clozapine monitoring guidelines should be more strictly adhered to.

Early Achromobacter xylosoxidans Endocarditis After the Valvular Mitral Replacement Complicated by an Agranulocytosis on B-lactams: A Case Report.

An immunocompetent 82-year-old woman developed endocarditis caused by an atypical organism called Achromobacter xylosoxidans, after a first valvular surgery. The intravenous antibiotic therapy with ceftazidime - 2 g every 8 hours during five weeks - a key part of the treatment, induced agranulocytosis as an adverse event. Cross-reactivity between antibiotics was suspected. Finally, the patient's cure was the result of a coordinated effort between medical and surgical professionals. Postoperative follow-up is six years.

Fosfomycin-induced agranulocytosis: a case report and review of the literature.

BACKGROUND: The intravenous form of fosfomycin, a bactericide antibiotic used to treat multiresistant bacterial infections is little prescribed. The most common reported adverse effects are hypokaliemia and hypernatremia. We describe a case of agranulocytosis, a rarely described side effect that may be fatal. CASE PRESENTATION: A 45 year-old woman was admitted to the intensive care unit for post-surgical meningitis following meningioma resection. Meropenem and vancomycin were first introduced. A DRESS-syndrom with meropenem was suspected. Neutropenia was diagnosed three days after the introduction of parenteral fosfomycin and agranulocytosis four days later. Eosinophilia was also observed. A bone marrow aspiration was performed showing a disappearance of the neutrophil granulocyte line and a significant eosinophilia. Meropenem was discontinued. Fosfomycin was maintained and filgrastim was added. As filgrastim had no effect, the relationship with fosfomycin was suspected, so it was then withheld. An increase of the neutrophil count was observed. Because of the complexity of the case, the unfavorable course of the illness and the urgent need for revision surgery, a rechallenge with fosfomycin was done followed by a decrease of the neutrophil count. CONCLUSION: This is the third paper reporting agranulocytosis induced by fosfomycin, and the first detailed description of a case. Based on chronological and semiological criteria and bibliographic data, the event was qualified as probable with the Naranjo adverse drug probability scale. Literature data is scarce. The summary of product characteristics mentions that only a few cases of transient neutropenia and agranulocytosis have been reported. An analysis of the FDA Adverse Event Reporting System Database highlighted a higher than expected frequency of agranulocytosis in patients treated with fosfomycin. Parenteral fosfomycin is often used in patients receiving other medications, so that it is rarely the only suspect. In our case, the results of the bone marrow aspiration, the sudden drop of the neutrophil count with concomitant eosinophilia and the absence of improvement despite the dose decrease, point towards an immuno-allergic mechanism. However, the overlap between the suspected DRESS induced by meropenem and the agranulocytosis do not allow to conclude with certainty on the causality. Awareness should be raised about this side effect.

Therapeutic Management and Long-Term Outcome of Hyperthyroidism in Patients with Antithyroid-Induced Agranulocytosis: A Retrospective, Multicenter Study.

BACKGROUND: Antithyroid drug-induced agranulocytosis (AIA) (neutrophils <500/µL) is a rare but serious complication in the treatment of hyperthyroidism. METHODOLOGY: Adult patients with AIA who were followed up at 12 hospitals in Spain were retrospectively studied. A total of 29 patients were studied. The etiology of hyperthyroidism was distributed as follows: Graves' disease (n = 21), amiodarone-induced thyrotoxicosis (n = 7), and hyperfunctioning multinodular goiter (n = 1). Twenty-one patients were treated with methimazole, as well as six patients with carbimazole and two patients with propylthiouracil. RESULTS: The median (IQR) time to development of agranulocytosis was 6.0 (4.0-11.5) weeks. The most common presenting sign was fever accompanied by odynophagia. All of the patients required admission, reverse isolation, and broad-spectrum antibiotics; moreover, G-CSF was administered to 26 patients (89.7%). Twenty-one patients received definitive treatment, thirteen patients received surgery, nine patients received radioiodine, and one of the patients required both treatments. Spontaneous normalization of thyroid hormone values occurred in six patients (four patients with amiodarone-induced thyrotoxicosis and two patients with Graves' disease), and two patients died of septic shock secondary to AIA. CONCLUSIONS: AIA is a potentially lethal complication that usually appears around 6 weeks after the initiation of antithyroid therapy. Multiple drugs are required to control hyperthyroidism before definitive treatment; additionally, in a significant percentage of patients (mainly in those treated with amiodarone), hyperthyroidism resolved spontaneously.