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Annals of Internal Medicine May 2007Nonchemotherapy drug-induced agranulocytosis is a rare adverse reaction that is characterized by a decrease in peripheral neutrophil count to less than 0.5 x 10(9)... (Review)
Review
BACKGROUND
Nonchemotherapy drug-induced agranulocytosis is a rare adverse reaction that is characterized by a decrease in peripheral neutrophil count to less than 0.5 x 10(9) cells/L due to immunologic or cytotoxic mechanisms.
PURPOSE
To systematically review case reports of drugs that are definitely or probably related to agranulocytosis.
DATA SOURCES
English-language and German-language reports in MEDLINE (1966 to 2006) or EMBASE (1989 to 2006) and in bibliographies of retrieved articles.
STUDY SELECTION
Published case reports of patients with nonchemotherapy drug-induced agranulocytosis.
DATA EXTRACTION
One reviewer abstracted details about cases and assessed causality between drug intake and agranulocytosis by using World Health Organization assessment criteria.
DATA SYNTHESIS
Causality assessments of 980 reported cases of agranulocytosis were definite in 56 (6%), probable in 436 (44%), possible in 481 (49%), and unlikely in 7 (1%). A total of 125 drugs were definitely or probably related to agranulocytosis. Drugs for which more than 10 reports were available (carbimazole, clozapine, dapsone, dipyrone, methimazole, penicillin G, procainamide, propylthiouracil, rituximab, sulfasalazine, and ticlopidine) accounted for more than 50% of definite or probable reports. Proportions of fatal cases decreased between 1966 and 2006. More patients with a neutrophil count nadir less than 0.1 x 10(9) cells/L had fatal complications than did those with a neutrophil count nadir of 0.1 x 10(9) cells/L or greater (10% vs. 3%; P < 0.001). Patients treated with hematopoietic growth factors had a shorter median duration of neutropenia (8 days vs. 9 days; P = 0.015) and, among asymptomatic patients at diagnosis, had a lower proportion of infectious or fatal complications (14% vs. 29%; P = 0.030) than patients without such treatment.
LIMITATIONS
Case reports cannot provide rates of drug-induced complications, sometimes incompletely assess or describe important details, and sometimes emphasize atypical features and outcomes.
CONCLUSIONS
Many drugs can cause nonchemotherapy drug-induced agranulocytosis. Case fatality may be decreasing over time with the availability of better treatment.
Topics: Agranulocytosis; Drug-Related Side Effects and Adverse Reactions; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Risk Factors
PubMed: 17470834
DOI: 10.7326/0003-4819-146-9-200705010-00009 -
La Revue Du Praticien May 2015
Review
Topics: Agranulocytosis; Diagnosis, Differential; Disease Progression; Drug Hypersensitivity; Emergencies; Humans
PubMed: 26165115
DOI: No ID Found -
Current Opinion in Hematology Jan 2018Clozapine-induced agranulocytosis/granulocytopenia (CIAG) is an uncommon condition, but potentially fatal in consequences. The pathogenesis, despite multiple... (Review)
Review
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.
Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans
PubMed: 28984748
DOI: 10.1097/MOH.0000000000000391 -
Expert Opinion on Drug Safety May 2007Acute agranulocytosis is a rare, potentially life-threatening condition, which is attributable to drugs in > 70% of cases. Agranulocytosis is characterised by a... (Review)
Review
Acute agranulocytosis is a rare, potentially life-threatening condition, which is attributable to drugs in > 70% of cases. Agranulocytosis is characterised by a peripheral neutrophil count < 0.5 x 10(9)/l. It often manifests with a severe sore throat, but isolated fever, pneumonia or septicaemia are not uncommon. Agranulocytosis may be caused by many drugs. High-risk drugs include antithyroid drugs, clozapine, ticlopidine, sulfasalazine, dipyrone, trimethoprim/sulfamethoxazole, carbamazepine and probably rituximab. Suspect drugs should be stopped immediately. In febrile patients, blood cultures and, where indicated, site-specific cultures should be obtained and treatment with empirical broad spectrum antibiotics started. Haematopoietic growth factors should be considered in patients with poor prognostic factors (e.g., a neutrophil count < 0.1 x 10(9)/l), severe clinical infection or severe underlying disease or comorbidity. Case fatality has decreased to ~ 5% in recent years, probably owing to improved intensive care treatment and increased alertness of physicians to this severe adverse reaction.
Topics: Acute Disease; Agranulocytosis; Anti-Bacterial Agents; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Incidence; Prognosis
PubMed: 17480181
DOI: 10.1517/14740338.6.3.323 -
Medical Toxicology and Adverse Drug... 1988Agranulocytosis is a rare but potentially serious adverse side effect of many drugs. Although it was recognised as an idiosyncratic type of drug reaction more than 50... (Review)
Review
Agranulocytosis is a rare but potentially serious adverse side effect of many drugs. Although it was recognised as an idiosyncratic type of drug reaction more than 50 years ago, its pathogenesis is still not fully understood. Drug-related antibodies are responsible for the neutropenia in the so-called 'immune' or 'aminopyrine' type of agranulocytosis. In contrast to former assumptions, the disappearance of leucocytes is not only due to rapid destruction of circulation cells, but it can result also from failure of the production of granulopoetic cells. In some other groups of drugs there is no evidence of immune-mediated disease, but direct toxicity to bone marrow cells has been observed using biochemical methods or inhibition of the growth of granulopoetic colonies in semisolid culture media. Until now it has not been possible to define the enzymatic abnormality which could explain this metabolic type of idiosyncrasy. The quantification of the incidence of potentially drug-induced agranulocytosis in general, and in particular its association with single drugs, requires studies on large populations and the use of strict epidemiological methodology to prevent reporting of grossly biased results. Data from recent case control studies show definitely lower risks for some relevant groups of drugs than formerly appreciated. As expected, agranulocytosis has been observed in association with some recently introduced drugs. This underlines the necessity for continued postmarketing monitoring of potential haematological side effects and for further case control studies to furnish data to aid prescribing physicians and health authorities in decision-making.
Topics: Agranulocytosis; Drug-Related Side Effects and Adverse Reactions; Epidemiologic Methods; Female; Humans; Male; Risk Factors
PubMed: 3063921
DOI: 10.1007/BF03259896 -
Drug and Therapeutics Bulletin Jul 1997Drug-induced agranulocytosis is a rare, potentially fatal idiosyncratic reaction that can occur unpredictably with a wide variety of drugs when taken in a conventional... (Review)
Review
Drug-induced agranulocytosis is a rare, potentially fatal idiosyncratic reaction that can occur unpredictably with a wide variety of drugs when taken in a conventional dose. In this article, we discuss its diagnosis and management and we consider the drugs most commonly involved and ways of minimising risk. We do not consider the dose-related granulocytopenia that commonly complicates treatment with cytotoxic and other myelosuppressant drugs, nor the rarer reaction, aplastic anaemia.
Topics: Agranulocytosis; Granulocyte Colony-Stimulating Factor; Humans; Opportunistic Infections; Recombinant Proteins
PubMed: 9282424
DOI: 10.1136/dtb.1997.35749 -
Presse Medicale (Paris, France : 1983) Sep 2008Idiosyncratic drug-induced agranulocytosis is a potential adverse event of most drugs, rare but life-threatening. Its annual incidence does not exceed 10 cases per... (Review)
Review
Idiosyncratic drug-induced agranulocytosis is a potential adverse event of most drugs, rare but life-threatening. Its annual incidence does not exceed 10 cases per million population in Europe and has remained stable over the past two decades. Its pathogenesis is poorly understood. The principal drugs associated with it are antithyroid drugs, antibiotics including trimethoprim, sulfamethoxazole, and beta-lactamines, ticlopidine, sulfasalazine and dipyrone. Clinical presentation is highly variable but a severe infection is observed in more than one third of cases. Poor prognostic factors include a neutrophil count under 100/mm(3), age > 65 years, septicemia or shock, and severe comorbidity. Improvement in the management of infectious complications and the use of hematopoietic growth factors in severe cases helps explain that mortality rate has fallen to less than 5%.
Topics: Agranulocytosis; Humans
PubMed: 18644319
DOI: 10.1016/j.lpm.2008.03.013 -
Nihon Rinsho. Japanese Journal of... Nov 2001
Review
Topics: Agranulocytosis; Anti-Bacterial Agents; Cause of Death; Drug-Related Side Effects and Adverse Reactions; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Japan; Macrophage Colony-Stimulating Factor; Prognosis
PubMed: 11808154
DOI: No ID Found -
Drugs in R&D Mar 2017Agranulocytosis 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... (Review)
Review
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.
Topics: Agranulocytosis; Antithyroid Agents; Humans; Risk Factors
PubMed: 28105610
DOI: 10.1007/s40268-017-0172-1 -
La Revue de Medecine Interne Mar 2006Agranulocytosis is a life-threatening disorder that frequently occurs as an adverse reaction to drugs. (Review)
Review
BACKGROUND
Agranulocytosis is a life-threatening disorder that frequently occurs as an adverse reaction to drugs.
CURRENT DATA
Idiosyncratic drug-induced agranulocytosis is characterized by a neutrophil count <0.5x10(9)/l, in serious forms <0,1x10(9)/l that currently occurs especially in association with antibiotics, antithyroid drugs ant ticlopidine (>60% of the incriminated drugs). The overall incidence of idiosyncratic agranulocytosis ranges from 2.4 to 15.4 cases per million patients exposed to drugs per year. Although patients experiencing idiosyncratic agranulocytosis may be asymptomatic (50%), the severity of the neutropenia usually leads to severe sepsis: fever of unknown origin, septicemia, septic shock or localized documented infections such as sore throat, various cutaneous infections or pneumonia. Nevertheless, the mortality rate of idiosyncratic agranulocytosis is now around 5% with appropriate management.
PERSPECTIVES
In the future, management of drug-induced agranulocytosis may include pre-established procedures using in critically situations, broad-spectrum antibiotic therapy and hematopoietic growth factors (G-CSF).
Topics: Agranulocytosis; Anti-Bacterial Agents; Antithyroid Agents; Diagnosis, Differential; Fever; Fibrinolytic Agents; Humans; Neutropenia; Survival Rate; Ticlopidine
PubMed: 16043267
DOI: 10.1016/j.revmed.2005.06.008