Non-chemotherapy drug-induced neutropenia: key points to manage the challenges

Abstract

Non-chemotherapy idiosyncratic drug-induced neutropenia (IDIN) is a relatively rare but potentially fatal disorder that occurs in susceptible individuals, with an incidence of 2.4 to 15.4 cases per million population. Affected patients typically experience severe neutropenia within several weeks to several months after first exposure to a drug, and mortality is ∼5%. The drugs most frequently associated with IDIN include metamizole, clozapine, sulfasalazine, thiamazole, carbimazole, amoxicillin, cotrimoxazole, ticlopidine, and valganciclovir. The idiosyncratic nature of IDIN, the lack of mouse models and diagnostic testing, and its low overall incidence make rigorous studies to elucidate possible mechanisms exceptionally difficult. An immune mechanism for IDIN involving neutrophil destruction by hapten (drug)-specific antibodies and drug-induced autoantibodies is frequently suggested, but strong supporting evidence is lacking. Although laboratory testing for neutrophil drug-dependent antibodies is rarely performed because of the complexity and low sensitivity of tests currently in use, these assays could possibly be enhanced by using reactive drug metabolites in place of the parent drug. Patients typically experience acute, severe neutropenia, or agranulocytosis (<0.5 × 10⁹ neutrophils/L) and symptoms of fever, chills, sore throat, and muscle and joint pain. Diagnosis can be difficult, but timely recognition is critical because if left untreated, there is an increase in mortality. Expanded studies of the production and mechanistic role of reactive drug metabolites, genetic associations, and improved animal models of IDIN are essential to further our understanding of this important disorder.

Figure 1.

Hapten and danger hypotheses of IDIN immune mechanism. (1) Native drug in the bloodstream enters neutrophils, liver macrophages, and other cells. (2) Drug is oxidized to reactive metabolite(s). (3) Reactive drug (hapten) forms a covalent link with endogenous proteins, forming drug–protein adducts. (4) Drug–protein adducts are taken up by antigen- presenting cells (APCs) and peptide-drug presented in context of class II HLA to T helper (T_H) cells that engage through T-cell receptor (TCR): Signal 1. (5) Stressed neutrophils or other cells release danger signals that activate APCs. (6) B7 on activated APCs engages CD28 on T_H cell for co-stimulus that is Signal 2. (7) The activated T_H cell provides signals to B cells to produce drug-dependent neutrophil antibodies against drug/hapten and to stimulate hapten-specific cytotoxic T cells (T_c): Immune response. (8) Drug-dependent neutrophil antibodies bind drug–protein adducts on neutrophil membrane that cause neutrophil destruction/clearance. (9) In the absence of danger signals, there is no Signal 2, resulting in immune tolerance.

Figure 2.

Fluorescence histograms generated from immunofluorescence detection of immunoglobulin G (IgG) drug-dependent neutrophil antibodies by flow cytometry. Isolated normal donor neutrophils were incubated with patient’s serum and washed; neutrophil-bound antibodies were detected with fluorescent anti-human IgG. Results shown are for serum from a patient exposed to quinine with drug-induced neutropenia incubated with neutrophils showing higher IgG fluorescence (median fluorescence intensity [MdFI] = 315) with quinine (dark histogram) compared with patient’s serum incubated with neutrophils and buffer/no drug (light histogram, MdFI = 59), indicating the presence of quinine drug-dependent neutrophil antibodies. MdFI values are shown for each histogram.