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.

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To date, non-chemotherapy drug-induced severe neutropenia (neutrophil count of ≤0.5 x 10/L) also called idiosyncratic drug-induced agranulocytosis is little discussed in the literature. In the present paper, we report and discuss the clinical data and management of this rare disorder. Areas covered: To do this, we carried out a review of the literature using PubMed database of the US National Library of Medicine. We also used data from the American Society of Hematology educational books, textbooks of Hematology and Internal medicine, and information gleaned from international meetings. Expert opinion: Idiosyncratic agranulocytosis remains a potentially serious adverse event due 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. In this context, several prognostic factors have been identified that may be helpful when identifying 'susceptible' patients. Old age (>65 years), septicemia or shock, renal failure, and a neutrophil count ≤0.1 × 10/L have been consensually accepted as poor prognostic factors. In our experience, modern management with pre-established procedures, intravenous broad-spectrum antibiotics and hematopoietic growth factors (particularly G-CSF) is likely to improve the prognosis. Thus with appropriate management, the mortality rate is currently between 5 to 10%.

Introduction: Idiosyncratic drug-induced neutropenia and agranulocytosis is seldom discussed in the literature, especially for new drugs such as biotherapies outside the context of oncology. In the present paper, we report and discuss the clinical data and management of this relatively rare disorder, with a focus on biotherapies used in autoimmune and auto-inflammatory diseases. Materials and methods: A review of the literature was carried out using the PubMed database of the US National Library of Medicine. We searched for articles published between January 2010 and May 2019 using the following key words or associations: “drug-induced neutropenia”, “drug-induced agranulocytosis”, and “idiosyncratic agranulocytosis”. We included specific searches on several biotherapies used outside the context of oncology, including: tumor necrosis factor (TNF)-alpha inhibitors, anti-CD20 agents, anti-C52 agents, interleukin (IL) 6 inhibitors, IL 1 inhibitors, and B-cell activating factor inhibitor. Results: Idiosyncratic neutropenia remains a potentially serious adverse event due 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 with grade 3 or 4 neutropenia (neutrophil count (NC) ≤ 0.5 × 109/L and ≤ 0.1 × 109/L, respectively). Over the last 20 years, several drugs have been strongly associated with the occurrence of idiosyncratic neutropenia, including antithyroid drugs, ticlopidine, clozapine, sulfasalazine, antibiotics such as trimethoprim-sulfamethoxazole, and deferiprone. Transient grade 1–2 neutropenia (absolute blood NC between 1.5 and 0.5 × 109/L) related to biotherapy is relatively common with these drugs. An approximate 10% prevalence of such neutropenia has been reported with several of these biotherapies (e.g., TNF-alpha inhibitors, IL6 inhibitors, and anti-CD52 agents). Grade 3–4 neutropenia or agranulocytosis and clinical manifestations related to sepsis are less common, with only a few case reports to date for most biotherapies. Special mention should be made of late onset and potentially severe neutropenia, especially following anti-CD52 agent therapy. During drug therapy, several prognostic factors have been identified that may be helpful when identifying ‘susceptible’ patients. Older age (>65 years), septicemia or shock, renal failure, and a neutrophil count ≤0.1 × 109/L have been identified as poor prognostic factors. Idiosyncratic neutropenia should be managed depending on clinical severity, with permanent/transient discontinuation or a lower dose of the drug, switching from one drug to another of the same or another class, broad-spectrum antibiotics in cases of sepsis, and hematopoietic growth factors (particularly G-CSF). Conclusion: Significant progress has been made in recent years in the field of idiosyncratic drug-induced neutropenia, leading to an improvement in their prognosis (currently, mortality rate between 5 and 10%). Clinicians must continue their efforts to improve their knowledge of these adverse events with new drugs as biotherapies.