**4. Definition**

Neutropenia is defined by a neutrophil count <1.5 × 10<sup>9</sup>

188 Hematology - Latest Research and Clinical Advances

**2. Search strategy**

a short narrative review.

acute leukemia.

between 1.5 and 0.5 × 109

**3. Etiologies of severe neutropenia**

/L (<1.2 × 109

degree of neutropenia predicts the risk of serious bacterial infections. Severe neutropenia is characterized by a profound decrease of circulating neutrophils in case of an absolute lack of

Schultz first introduced the term "agranulocytosis" in 1922, for cases of acute and severe pharyngeal infections, associated with a lack of granulocytes in the blood in relation to drug intake [2]. Such unpredictable event, named "idiosyncratic," is typically serious, with around

In this chapter, we report and discuss the diagnosis and management of idiosyncratic drug-

A literature search was performed on the *PubMed* database of the *US National Library of Medicine* and *Scholar Google*. We searched for articles published between January 2010 and March 2018, using the following keywords or associations: "*drug-induced neutropenia,*" "*drug-induced agranulocytosis,*" "*idiosyncratic neutropenia*" and "*idiosyncratic agranulocytosis*"; restrictions included: English- or French-language publications; published from January 1, 2010 to February 31, 2018; human subjects; clinical trials, review articles or guidelines. All of the English and French abstracts were reviewed by at least two senior researchers from our work group (*GRoupes d'Etudes des Agranulocytoses médicamenTeuses* (GREAT) des *Hôpitaux Universitaires de Strasbourg* (HUS), Strasbourg, France). After rigorous selection, only 15 papers were selected and analyzed. The latter was used to write this paper in the form of

*American Society of Hematology* educational books, textbooks of Hematology and Internal

In adults, the diagnosis of acute and severe neutropenia (neutrophil count of <0.5 × 109

includes a limited number of conditions [1]. In fact, the main differential diagnoses outside the context of treatment of cancer with chemotherapy (e.g., alkylating agents, antimetabolites, etc.) or radiotherapy, include myelodysplastic syndromes, especially in elderly patients, and

All other conditions induced moderate neutropenia, with an absolute neutrophil count

sepsis, particularly viral infections or bacterial infections (severe Gram-negative infections with Salmonella sp., tuberculosis, Brucella sp.); and neutropenia associated with

/L. These conditions mainly include: neutropenia secondary to

medicine, and information gleaned from international meetings were also used.

circulating neutrophils, classically resulting in a neutrophil count of <0.5 × 109

50% of cases exhibiting severe sepsis, and a mortality rate of 10–20% [2, 3].

induced, or drug-associated, severe neutropenia, and agranulocytosis.

/L in black people). The

/L [1, 2].

/L

To date, drug-induced, or drug associated, severe neutropenia, or agranulocytosis is defined at least by a neutrophil count of <0.5 × 109 /L, which occurs as a result of exposure to drugs [3]. The presence of fever and sepsis signs is usual, even required, for some authors. In the majority of patients, the neutrophil count is under 0.1 × 109 /L.

All drugs may be the causative agents, particularly: chemotherapy, immune modulator agents or biotherapies. Other daily drugs may also be more rarely incriminated. Such event is called "idiosyncratic" drug-induced neutropenia and agranulocytosis [2, 3]. Either the drug itself or one of its metabolites may be the causative agent.

Currently, the recommended criteria for diagnosing blood cytopenias and for implicating a drug as a causative agent in neutropenia are derived from an international consensus meeting [2, 4]. These criteria are outlined in **Table 1**. As idiosyncratic severe neutropenia and agranulocytosis are life-threatening conditions, no patient was re-challenged with the incriminated drug ("theoretical method of reference").


\*Immunoglobulins, interferon, anti-TNF antibodies, anti-CD20 (rituximab).

**Table 1.** Criteria for idiosyncratic drug-induced agranulocytosis.
