Review article
Idiosyncratic drug-induced agranulocytosis: Update of an old disorder

https://doi.org/10.1016/j.ejim.2006.07.012Get rights and content

Abstract

In this paper, we review the literature on idiosyncratic drug-induced agranulocytosis, a rare but life-threatening potential adverse event of most drugs. Articles were identified through MEDLINE searches (1966–2005). Additional references were localized through a review of textbooks on hematology and internal medicine, and information gleaned from international meetings. Additional unpublished data from our cohort with drug-induced agranulocytosis at the University Hospital of Strasbourg, France, were also considered. Searches were done using the following key words: “agranulocytosis”, “drug-induced agranulocytosis”, and “idiosyncratic agranulocytosis” and were restricted to: English- and French-language, human subjects, clinical trial, review, and guidelines. All of the papers and abstracts were reviewed by at least two senior researchers who selected the data used in the study.

What we found is that, over the last 20 years, the incidence of idiosyncratic drug-induced agranulocytosis has remained stable – 2.4–15.4 cases per million – despite the emergence of new causative drugs, mainly antibiotics, antiplatelet agents, and antithyroid drugs. To date, drug-induced agranulocytosis remains a serious adverse event due to the frequency of severe sepsis with severe deep infections (such as pneumonia), septicemia, and septic shock in about two-thirds of all patients. In this setting, old age (> 65 years), septicemia or shock, metabolic disorders such as renal failure, and a neutrophil count below 0.1 × 109/L are poor prognostic factors. Nevertheless, with appropriate management using pre-established procedures, with intravenous broad-spectrum antibiotic therapy, and hematopoietic growth factors, the mortality rate is currently around 5%. Given the increased life expectancy and subsequent longer exposure to drugs, as well as the development of new agents, health care professionals should be aware of this adverse event and its management.

Introduction

In 1922, Schultz first proposed the term ‘agranulocytosis’ for cases of severe pharyngeal infectious symptoms, concomitantly with a lack of granulocytes in the blood [1]. Yet, agranulocytosis is marked by a profound decrease in the number of, or an absolute lack of, granulocytes in circulating blood, classically resulting in a neutrophil count below 0.5 × 109/L [2], [3]. The criteria used to assess causality are reported in Table 1 [4], [5]. In the majority of patients, the neutrophil count is below 0.1 × 109/L. Patients with such severe neutropenia are likely to experience life-threatening, and sometimes fatal, infections. Most, but not all, instances of agranulocytosis result from exposure to drugs (idiosyncratic drug-induced agranulocytosis), and either the drug itself or a metabolite may be causative. Other common causes of agranulocytosis in adult patients are listed in Table 2 [2], [6].

In the present paper, we report and discuss the current literature and our own experience with idiosyncratic drug-induced agranulocytosis.

Section snippets

Search strategy

A bibliographic search was performed on the PubMed database of the US National Library of Medicine for articles published from January 1966 to December 2005 using the following key words or associations: “agranulocytosis”, “drug-induced agranulocytosis”, and “idiosyncratic agranulocytosis”. We restricted ourselves to English- or French-language publications published from January 1, 1966 to December 31, 2005; human subjects; clinical trials, reviews, or guidelines. All of the English and French

Pathophysiology

Clinical observations, studies in volunteers and patients, and laboratory experiments suggest that idiosyncratic drug-induced agranulocytosis is mediated by immuno-allergic and toxic mechanisms [2], [7]. However, the mechanisms that cause neutropenia are not completely understood. In many cases, neutropenia occurs after prolonged exposure, resulting in decreased granulocyte production by hypoplastic bone marrow. In other cases, repeated but intermittent exposure is needed. This suggests an

Epidemiological data

In Europe, the annual incidence of idiosyncratic drug-induced agranulocytosis is between 3.4 and 5.3 cases per million population [7], [17]. In the USA, Strom et al. reported rates ranging from 2.4 to 15.4 per million per year [18]. In our experience (observational study), from 1996 to 2003, the annual incidence of symptomatic idiosyncratic drug-induced agranulocytosis remained stable, with approximately 6 cases per million population [19]. It is worth noting that this incidence remains stable

Drugs involved and risk factors

Drugs that are most often associated with idiosyncratic agranulocytosis are shown in Table 3 [2], [3], [7], [19], [23], [24], [25]. For the majority of these compounds, the risk appears to be very small. However, for such drugs as antithyroid drugs, ticlopidine, clozapine, sulfasalazine, gold salts, penicillamine, and phenylbutazone, the risk may be higher [2], [3], [26], [27]. For example, for antithyroid drugs, a risk of 3 per 10,000 users has been reported [28]. Nevertheless, inconsistent

Clinical manifestations

Historical case reports of idiosyncratic drug-induced agranulocytosis have described edema, necrosis, and obstruction of the pharynx, followed within days by prostration, coma, and death [1], [6]. Presently, patients usually present high fever, sore throat, several deep infections, and a general sensation of malaise, often including chills, myalgia, and/or arthralgia [2], [7], [19], [23]. Most patients (> 60%) develop septicemia while some have evidence of severe pneumonia as well as anorectal,

Hematological data

Besides a granulocyte blood count under 0.5 × 109/L, hemoglobin (Hb) and platelet (Pla) counts are usually normal [6]. However, in elderly patients, associated hematological abnormalities are frequent: anemia (Hb < 120 g/L) in at least 30% of patients and thrombocytopenia (Pla < 150 × 109/L) in 10% of patients [19], [20]. Thus, especially in the elderly, bone marrow examination is routinely required to exclude an underlying pathology [20]. The bone marrow typically shows a normal or mildly reduced

Differential diagnosis

Differential diagnosis of idiosyncratic drug-induced agranulocytosis in adults includes a limited number of conditions (Table 2) [2], [3], [6]. The most relevant differential diagnoses include: (i) nutritional deficiencies (cobalamin and folate deficiencies); (ii) neutropenia secondary to severe sepsis (especially viral); (iii) neutropenia appearing as the first manifestation of a bone marrow failure, such as myelodysplastic syndromes; or (iv) neutropenia associated with hypersplenism [2], [3],

Prognosis and mortality rate

Up until 20 years ago, the mortality rate for idiosyncratic drug-induced agranulocytosis was 10–16% in European studies [2], [7], [32], [33], but this rate has recently dropped to 5–10%, probably due to improvements in the recognition, management, and treatment of this condition [2], [41], [42]. The highest mortality rate is observed in older patients (> 65 years), as well as in those experiencing renal failure (defined as a serum creatine level > 120 μmol/L), bacteriemia, or shock at diagnosis

Management with a focus on the usefulness of hematopoietic growth factors

The management of idiosyncratic drug-induced agranulocytosis begins with the immediate withdrawal of any potentially causative drug [2], [7]. The patient's medication history must be carefully and chronologically obtained in order to focus on the suspected agent(s). In our opinion, for drugs with a known but rare association with agranulocytosis, the rarity and unpredictability of the reaction does not make routine monitoring worthwhile [2]. However, routine monitoring for agranulocytosis is

Conclusions

Over the last 20 years, the annual incidence of life-threatening, idiosyncratic drug-induced agranulocytosis has remained stable (about 3–16 cases per million), despite the emergence of new causative drugs, especially antibiotics, antiplatelet agents, antithyroid drugs, neuroleptics, anti-epileptic agents, and nonsteroidal anti-inflammatory agents. Idiosyncratic drug-induced agranulocytosis is often a serious adverse event due to the frequency of severe infections (such as deep infections,

Learning points

  • –

    Idiosyncratic drug-induced agranulocytosis is a rare disorder with an incidence of 2.4–15.4 cases per million. New causative drugs are emerging, mainly antibiotics, antiplatelet agents, and antithyroid drugs.

  • –

    Idiosyncratic drug-induced agranulocytosis remains a potential serious adverse event due to the frequency of severe sepsis with severe deep infections (e.g., pneumonia), septicemia, and septic shock in some two-thirds of all hospitalized patients.

  • –

    Old age (> 65 years), septicemia or shock,

Acknowledgement

We are indebted to Helen Fotherghill, who kindly edited the English of the text.

Members of the Groupe d'études des agranulocytoses médicamenteuses des Hôpitaux Universitaires de Strasbourg

We are indebted to Professors JM Brogard, JF Blicklé, M Imler, JL Schlienger, B Goichot, JC Weber, D Storck, G Kaltenbach, F Kuntzmann, J Sibilia, JL Kuntz, D Lipsker, P Wolff, S Rohr and C Meyer (Hôpitaux Universitaires de Strasbourg, France) and to Doctors E Noel, S Affenberger, A Ruellan, AE Perrin, F

References (49)

  • W. Schultz

    Ueber eigenartige halserkrankungen

    Dtsch Med Wochenschr

    (1922)
  • E. Andrès et al.

    Non-chemotherapy drug-induced agranulocytosis: experience of the Strasbourg teaching hospital (1985–2000) and review of the literature

    Clin Lab Haematol

    (2002)
  • N.S. Young et al.

    Agranulocytosis

  • E. Andrès et al.

    Agranulocytoses médicamenteuses: données actuelles

    Ann Biol Clin

    (2003)
  • C. Bénichou et al.

    Standardization of definitions and criteria for causality assessment of adverse drug reactions. Drug-induced blood cytopenias: report of an international consensus meeting

    Nouv Rev Fr Hematol

    (1993)
  • D.C. Dale et al.

    Chronic neutropenia

    Medicine (Baltimore)

    (1979)
  • W.N. Patton et al.

    Idiosyncratic drug-induced haematological abnormalities: incidence, pathogenosis, management and avoidance

    Drug Safety

    (1994)
  • F.H. Claas

    Immune mechanisms leading to drug-induced blood dyscrasias

    Eur J Haematol

    (1996)
  • A. Salama et al.

    Immune-mediated agranulocytosis related to drugs and their metabolites: mode of sensitization and heterogeneity of antibodies

    Br J Haematol

    (1989)
  • L.J. Lewitt

    Chlorpropamide-induced pure white cell aplasia

    Blood

    (1987)
  • B. Nyfeler et al.

    The lymphocyte transformation test for the diagnosis of drug allergy: sensitivity and specificity

    Clin Exp Allergy

    (1997)
  • N.S. Young

    Drug-related blood dyscrasias

    Eur J Haematol

    (1996)
  • I. Mosyagin et al.

    Impact of myeloperoxidase and NADPH-oxydase polymorphism in drug-induced agranulocytosis

    J Clin Psychopharmacol

    (2004)
  • E. Andrès et al.

    Drug-associated agranulocytosis: experience at Strasbourg Teaching Hospital

    Arch Intern Med

    (1999)

    • Cited by (61)

    View all citing articles on Scopus
    View full text
    Copyright © 2006 Elsevier B.V. All rights reserved.