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Objective: In this article, we report and discuss the clinical presentation and management of idiosyncratic drug-induced agranulocytosis (neutrophil count <0.5 × 10(9)/l)., Results/conclusions: Idiosyncratic drug-induced agranulocytosis remains a potentially serious adverse event owing to the frequency of severe sepsis with severe deep tissue infections (e.g., pneumonia), septicemia and septic shock in approximately two-thirds of all hospitalized patients. However, several prognostic factors have recently been identified that may be helpful in practice to identify 'susceptible' patients. Old age (>65 years), septicemia or shock, metabolic disorders such as renal failure and a neutrophil count below 0.1 × 10(9)/l are currently consensually accepted as poor prognostic factors. In this potentially life-threatening disorder, modern management with broad-spectrum antibiotics and hematopoietic growth factors (particularly granulocyte colony-stimulating factor) is likely to improve prognosis. Thus, with appropriate management, the mortality rate from idiosyncratic drug-induced agranulocytosis is currently approximately 5%.

Drug-induced agranulocytosis (neutrophil count <0.5 x 10(9)/l) is a rare haematological complication with an incidence of no more than 10 cases per million inhabitants per year in Europe. Over the past few years there has been a steady decline in mortality rate, (currently at <5%), which can be partly explained by earlier recognition and the improved clinical management of associated intercurrent infections that may lead to severe sepsis if left untreated. The true impact of the use of haematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), on the decreased mortality rate remains unknown. Yet, most studies show that these molecules, especially G-CSF, reduce the duration of agranulocytosis, antibiotic course and length of hospital stay. Their use is particularly recommended in patients with poor prognostic factors, such as a neutrophil count <0.1 x 10(9)/l, age over 65 years, severe infection or multiple co-morbidities. In all cases, the drug responsible for causing the agranulocytosis must be discontinued and remain permanently contraindicated. The appropriate Medicines Regulatory Agency must also be notified of the adverse event.

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%.

Purpose of Review: Idiosyncratic drug-induced agranulocytosis or acute neutropenia is an adverse event resulting in a neutrophil count of under 0.5 x 10/l. Patients with such severe neutropenia are likely to experience life-threatening and sometimes fatal infections., Recent Findings: Over the last 20 years, the incidence of idiosyncratic drug-induced agranulocytosis or acute neutropenia has remained stable at 2.4-15.4 cases per million, despite the emergence of new causative drugs: antibiotics (beta-lactam and cotrimoxazole), antiplatelet agents (ticlopidine), antithyroid drugs, sulfasalazine, neuroleptics (clozapine), antiepileptic agents (carbamazepine), nonsteroidal anti-inflammatory agents and dipyrone. Drug-induced agranulocytosis remains a serious adverse event due to the occurrence of severe sepsis with severe deep infections (such as pneumonia), septicemia and septic shock in around two thirds of patients. In this setting, old age (>65 years), septicemia or shock, metabolic disorders such as renal failure, and a neutrophil count under 0.1 x 10/l are poor prognostic factors. Nevertheless with appropriate management using preestablished procedures, with intravenous broad-spectrum antibiotic therapy and hematopoietic growth factors, the mortality rate is currently around 5%., Summary: Given the increased life expectancy and subsequent longer exposure to drugs, as well as the development of new agents, healthcare professionals should be aware of this adverse event and its management.

Objective: the aim of this study is to determine the clinical characteristics of drug-induced agranulocytosis in rheumatology., Patients and Method: it is a retrospective monocentric study, including all cases of rheumatologic drug-induced agranulocytosis followed between January 1985 and December 2005., Results: eight female and 4 men, mean age 62.5 years (range: 17-79), were included in the present study. The causative drugs were: anti-inflammatory agents (n=5, 41.6%), methotrexate (n=3, 25%), sulfasalazine (n=2, 16.6%), noramidopyrine (n=1) and dapsone (n=1). Main clinical features included infectious disorders in 9 cases (75%) with 4 cases of septicemia (33.3%) and 2 cases of septic shock (16.6%). The mean neutrophils count was 0.132 x 10(9)/L (range, 0-0.4). Outcome was favorable in 11 patients (91.6%). One patient died of septic complications., Conclusion: in rheumatology, drug-induced agranulocytosis is a rare but life-threatening disorder.

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).

Objectives: We studied clinical factors that may influence the duration of hematological recovery to reach neutrophil counts and thus, indirectly, the prognosis in patients with life-threatening drug-induced agranulocytosis (DIA)., Methods: Using univariate and multivariate analyses with Cox's proportional hazard models, we determined the prognostic factors for hematological recovery, defined as neutrophil counts>0.5 and>1.5.10(9)/L, in 91 patients with established life-threatening DIA., Results: Multivariable analysis showed that neutrophil count<0.1.10(9)/L (at diagnosis) and infection profile: severe infections or septic shock, adversely influenced the neutrophil recovery (for the two neutrophil levels). Hematopoietic growth factors were significantly associated with rapid hematological recovery (for the two neutrophil levels). Documented microbial infections and antiplatelet DIA were also associated with rapid hematological recovery (for a neutrophil count>1.5.10(9)/L)., Conclusion: Our findings demonstrate that in life-threatening DIA, hematological recovery is mainly dependent of the neutrophil level, the type of infections and the utilization of hematopoietic growth factors.

Agranulocytosis is a life-threatening disorder in any age, but particularly so in elderly patients who are receiving, on average, a larger number of drugs than younger patients. Drug-induced agranulocytosis still remains a rare event, with an annual incidence rate of approximately 3-12 cases per million population. This disorder frequently occurs as an adverse reaction to drugs, particularly antibacterials, antiplatelet agents, antithyroid drugs, antipsychotics or antiepileptic drugs, and NSAIDs. Although patients experiencing drug-induced agranulocytosis may initially be asymptomatic, the severity of the neutropenia usually translates into the onset of severe sepsis that requires intravenous broad-spectrum antibacterial therapy. In this setting, haematopoietic growth factors have been shown to shorten the duration of neutropenia. Thus, with appropriate management, the mortality rate of idiosyncratic drug-induced agranulocytosis is now 5-10%. However, given the increased life expectancy and subsequent longer exposure to drugs, as well as the development of new agents, physicians should be aware of this complication and its management., (Copyright 2004 Adis Data Information BV)

Objective: To report on an uncommon association of agranulocytosis in primary Sjögren's syndrome (SS)., Methods: The clinical, haematological, and immunological features of seven patients with primary SS associated with a chronic (>6 months) agranulocytosis, and the outcome of the patients, were analysed., Results: Patients were white women with an unexplained agranulocytosis. They all had non-erosive arthritis and three had a thrombocytopenia or Evan's syndrome. In three patients, transient or durable expansion of T lymphocytes was present in the peripheral blood or in the bone marrow, but evolved independently from neutrophil counts. There was no paroxysmal nocturnal haemoglobinuria clone or antibodies to neutrophil surface antigens. In vitro bone marrow culture was normal (four patients) or showed a decrease in colony forming unit-granulocyte monocyte (CFU-GM) and colony forming unit-erythroblast (CFU-E) (one patient). Serum levels of soluble Fas ligand (sFasL) were normal, and granulocyte-colony stimulating factor (G-CSF) concentrations were either normal or raised. One patient was treated with steroids associated with intravenous immunoglobulins and achieved a lasting response. Two other patients were treated with steroids and methotrexate, with poor efficacy. Short courses of subcutaneous G-CSF produced a transient and mild response in all three patients. Complete recovery of the neutrophils occurred temporarily during pregnancy in two patients. After a mean follow up of 34.8 months (range 6-139) all patients were alive and none developed serious infections., Conclusion: A subset of patients with primary SS and non-destructive arthritis may develop a chronic but well tolerated agranulocytosis that is usually poorly responsive to steroids and oral methotrexate.

Purpose: Elderly patients with nonchemotherapy drug-induced agranulocytosis present commonly with severe infections, and have a mortality of at least 20%. We studied whether granulocyte colony-stimulating factor (G-CSF), a hematopoietic growth factor that shortens the duration of neutropenia, is useful in these patients., Subjects and Methods: We studied 54 patients > or =65 years of age who had drug-induced agranulocytosis, some of whom had been treated with G-CSF. We determined the times until hematologic recovery (defined as a neutrophil count >1.5 x 10(9)/L), tolerance of G-CSF, and clinical outcomes., Results: Of the 54 patients, 20 received G-CSF. Two patients who had not been treated with G-CSF died of uncontrolled septic shock and extensive pneumonia. The mean (+/- SD) time until hematologic recovery was significantly less in patients treated with G-CSF (6.6 +/- 3.9 days vs. 8.8 +/- 4.9 days, P <0.04). Compliance with G-CSF therapy was good; only mild flu-like symptoms and transient bone pain were reported in 12 patients., Conclusion: Our findings suggest that G-CSF therapy may be beneficial in the management of drug-induced agranulocytosis in elderly patients.

Agranulocytosis is a life-threatening disorder that frequently occurs as an adverse reaction to drugs. The overall incidence of nonchemotherapy drug-induced agranulocytosis (DIA) ranges from 2.6 to 10 cases per million patients exposed to drugs per year. Although patients experiencing DIA may initially be asymptomatic, the severity of the neutropenia usually leads to severe sepsis, requiring intravenous broad-spectrum antibiotic therapy. In this setting, old age, septicaemia, shock, and the metabolic complications of infection, such as renal failure, are poor prognostic variables. The severity of neutropenia (< 0.1 x 10(9))/l) and its duration (> 10 days) may also impact negatively on the outcome. With appropriate management using pre-established procedures, the mortality rate is now around 5%. Haematopoietic growth factors have been shown to shorten the duration of neutropenia in DIA. However, it has yet to be determined whether their use translates into a better outcome in DIA patients experiencing sepsis. DIA still remains a rare event. However, given the increased life expectancy and subsequent longer exposure to drugs, as well as the development of new agents, physicians should be aware of this complication and its management.

Drug-induced agranulocytosis (DIA) is often caused by antithyroid drugs. We retrospectively studied the use of granulocyte colony-stimulating factor (G-CSF) therapy in antithyroid-DIA. Data for 20 patients (10 treated with G-CSF) with antithyroid-DIA (neutrophil count <0.5x10(9)/l) were extracted from a cohort study of DIA patients (n=110). G-CSF (300 microg/day subcutaneously) was used where the neutrophil count was <0.1x10(9)/l, or the patient was aged >70 years, or there were severe features of infection or underlying disease. Mean patient age was 62 years (range 34-87); sex ratio (M/F) was 0.05. Carbimazole (n=19) and benzylthiouracile (n=1) were the causative drugs, at mean doses of 30 mg/day (range 20-60) and 100 mg/day (range 50-150), respectively, for a mean of 37 days (range 31-90). Antithyroid drugs were prescribed for Graves' disease (n=8), thyrotoxicosis related to amiodarone intake (n=6) and multinodular goitre (n=6). Clinical features included isolated fever (n=7), pneumonia (n=5), septicaemia or septic shock (n=5) and acute tonsillitis (n=3). Mean neutrophil count was 0.07+/-0.1x10(9)/l. No patient died. Mean durations of haematological recovery, antibiotic therapy and hospitalization were significantly reduced with G-CSF: 6.8+/-4 days vs. 11.6+/-5; 7.5+/-3.8 days vs. 12+/-4.5; and 7.3+/-4.8 days vs. 13+/-6.1, respectively (all p<0.05). G-CSF induced flu-like symptoms in 30% of patients, but reduced overall costs.

Purpose: Our study was aimed at determining the role of hematopoietic growth factor in drug-induced agranulocytosis., Methods: Fifty-five cases of drug-induced agranulocytosis were reviewed and subdivided retrospectively into a G-CSF group (n = 15) and an untreated group (n = 40). Mortality and hematological recovery (number of days required for neutrophil counts to exceed 1.5 x 10(9)/L) were studied in the two groups., Results: The mean granulocyte count was 0.09 x 10(9)/L. All patients presented infection. In the G-CSF group, no mortality (0% versus 5%, P = 0.85) and a shorter recovery time (8.1 versus 9.5 days P = 0.39) were observed. No significant difference between the two groups was observed in either the duration of antibiotic therapy (9.3 days in the G-CSF group versus 10.1 days in the untreated group, P = 0.51) or duration of hospitalization (10 days in the treated group versus 11 days in the G-CSF group, P = 0.46)., Conclusion: Our results as well as a literature review indicate that G-CSF could decrease the time to hematological recovery and perhaps reduce mortality. However, the exact role of hematopoietic growth factors requires further investigations.

Background/Introduction: Few data is currently available on neutropenia and agranulocytosis related to drug intake. Aim: We report here data on 203 patients with established idiosyncratic drug-induced agranulocytosis, followed up in a referral centre within a university hospital. Design: Data from 203 patients with idiosyncratic drug-induced agranulocytosis were retrospectively reviewed. Methods: All cases were extracted from a cohort study on agranulocytosis in the Strasbourg University Hospital (Strasbourg, France). Results: The mean age was 61.6 years old (range: 18-95), the gender ratio (F/M) was 1.3. Several comorbidities were present in 63.5%. The most frequent causative drugs were: antibiotics (49.3%), especially b-lactams and cotrimoxazole; antithyroid drugs (16.7%); neuroleptic and anti-epileptic agents (11.8%); antiviral agents (7.9%); and platelet aggregation inhibitors as ticlopidine and acid acetylsalicylic (6.9%). The main primary clinical manifestations during hospitalization included: isolated fever (26.3%); septicaemia (13.9%); documented pneumonia (13.4%); sore throat and acute tonsillitis (9.3%); and septic shock (6.7%). The mean neutrophil count at nadir was 0.148 × 109/L (range: 0-0.48). All febrile patients were treated with broad-spectrum antibiotics and 107 (52.7%) with hematopoietic growth factors. The mean duration of haematological recovery (neutrophil count ⩾1.5 × 109/L) was 7.8 (range: 2-20). This mean duration was reduced to 2.1 days (range: 2-16) (p=0.057) with hematopoietic growth factors. Outcome was favourable in 91.6% of patients; seventeen died. Thirty-seven patients (18.2%) required intensive care. Discussion/Conclusion: The present study demonstrated that idiosyncratic drug-induced agranulocytosis is a relative rare events; that antibiotics, antithyroid, neuroleptic and anti-epileptic agents, and platelet aggregation inhibitors are the main incriminated drug classes; that agranulocytosis typically serious, with at least 50% exhibiting severe sepsis and a mortality rate <10%; and that modern management of such disorder may reduce the infection-related mortality. [ABSTRACT FROM AUTHOR]

Abstract: 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 <0.5×109/l, in serious forms <0,1×109/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). [Copyright &y& Elsevier]