**5. Epidemiology and causative drugs**

Idiosyncratic agranulocytosis is a rare disorder. In Europe, the annual incidence of such events is between 1.6 and 9.2 cases per million populations [2, 4]. In the USA, reported ranges from 2.4 to 15.4 per million per year. In our experience, the incidence remains unchanged, despite the withdrawn of incriminated drugs (which carry a high-risk), and increased levels of medical awareness and pharmacovigilance [5]. Older patients are thought to be at greater risk for to drug-induced neutropenia, probably because of increased medication use.

ticlopidine, the risk is more than 100-fold higher. Clozapine induces agranulocytosis in almost 1% of patients, particularly in the first three months of treatment, with older patients

Idiosyncratic Drug-Induced Severe Neutropenia and Agranulocytosis: State of the Art

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In our single-center cohort from the GREAT team (n = 203), the most frequent causative drugs are: antibiotics (49.3%), especially ß-lactams and cotrimoxazole; antithyroid drugs (16.7%); neuroleptic and anti-epileptic agents (11.8%); antiviral agents (7.9%); and platelet aggregation inhibitors (6.9%), especially ticlopidine [5]. Since 1990–2000, no case of noramidopyrine- and ticlopidine-induced agranulocytosis is reported in the literature. Recently, several new drugs have been listed as causative agents for severe neutropenia and agranulocytosis, for example,

The pathogenesis of drug-induced neutropenia is a heterogeneous process, which is not yet fully understood [2, 3]. Clinical observations, studies in volunteers and laboratory experiments have suggested that this disorder is mediated by immune allergic and toxic mechanisms. In many cases, neutropenia occurs after prolonged drug exposure, resulting in decreased granulocyte production by hypoplastic bone marrow. In other cases repeated, intermittent exposure is implicated. This suggests an immune mediated mechanism, although this hypothesis

Direct damage, either to the microenvironment of the bone marrow or myeloid precursors, plays a significant role in most other cases [3]. Complex metabolic pathways that metabolize drugs and other chemicals are regulated by genetic factors. Genetic polymorphism results in heterogeneity of expression of the various enzymes, which generate or destroy intermediate

Other mechanisms, involving cytotoxic T cells, haptens, auto-immunity, and oxidative modification of the drug have also been considered [3]. The impact of myeloperoxidase and NADPH-oxidase polymorphism in drug-induced neutropenia and agranulocytosis have also been studied. Clozapine appears to accelerate the process of apoptosis, thought to be due to depletion of ATP and reduced glutathione, which renders the neutrophils highly susceptible

Initially, symptomatic patients with idiosyncratic drug-induced severe neutropenia or agranulocytosis usually present with fever, which often is the earliest and sometimes the only sign during evolution. This later is often associated with general malaise, often including chills [2, 3]. In this setting, symptoms may appear either immediately or insidiously, depending on the time course of neutropenia development. Symptomatic patients are commonly present at discovery

acyclovir, ganciclovir, lamotrigine, terbinafine or deferiprone [2, 5].

**6. Mechanisms of idiosyncratic drug-induced neutropenia**

and females being at a higher risk [2, 5].

is not entirely confirmed.

toxic compounds [3].

to oxidant-induced apoptosis [3].

**7. Clinical manifestations**

Almost all classes of drugs have been implicated as "causative," but for the majority, the risk appears to be very small (**Table 2**) [2, 5]. However, for drugs such as antithyroid drugs, ticlopidine, clozapine, phenothiazines, sulfasalazine, trimethoprim-sulfametoxazole (cotrimoxazole), and dipyrone or sulfasalazine, the risk may be higher. For antithyroid drugs (propyl-thiouracil and méthimazole), a risk of 3 per 10,000 users has been reported. For


**Table 2.** Drugs implicated in the occurrence of idiosyncratic agranulocytosis.

ticlopidine, the risk is more than 100-fold higher. Clozapine induces agranulocytosis in almost 1% of patients, particularly in the first three months of treatment, with older patients and females being at a higher risk [2, 5].

In our single-center cohort from the GREAT team (n = 203), the most frequent causative drugs are: antibiotics (49.3%), especially ß-lactams and cotrimoxazole; antithyroid drugs (16.7%); neuroleptic and anti-epileptic agents (11.8%); antiviral agents (7.9%); and platelet aggregation inhibitors (6.9%), especially ticlopidine [5]. Since 1990–2000, no case of noramidopyrine- and ticlopidine-induced agranulocytosis is reported in the literature. Recently, several new drugs have been listed as causative agents for severe neutropenia and agranulocytosis, for example, acyclovir, ganciclovir, lamotrigine, terbinafine or deferiprone [2, 5].
