Idiosyncratic Drug-induced Neutropenia Research Articles

Rates of severe neutropenia and infection risk in patients treated with deferiprone: 28 years of data

AbstractPatients treated with deferiprone for transfusional iron overload may experience idiosyncratic drug–induced neutropenia (IDIN) that may increase risk of infection. This analysis examined the rates of severe IDIN and risk of serious infections at different absolute neutrophil count (ANC) levels during deferiprone treatment. Events of severe IDIN (ANC <0.5 × 109/L) and associated serious infections from clinical trials and postmarketing setting were analyzed by discrete ANC levels: group 1, 0.2 × 109/L to 0.5 × 109/L; group 2, 0.1 × 109/L to 0.199 × 109/L; group 3, <0.1 × 109/L. In clinical trials, 22 events of severe IDIN occurred (group 1, n = 9; group 2, n = 3; group 3, n = 10), and rates of severe IDIN per 100 patient-years were 0.45 in group 1; 0.15 in group 2; and 0.50 in group 3 (1990.26 patient-years deferiprone exposure). All serious infections were in group 3 (3/10 [30.0%]). In the postmarketing setting, 176 events of severe IDIN were reported (group 1, n = 65; group 2, n = 20; group 3, n = 91) and rates of severe IDIN per 100 patient-years were 0.06 in group 1; 0.02 in group 2; and 0.08 in group 3 (111 570.24 patient-years deferiprone exposure). Rates of serious infection were 7.7% (5/65) in group 1; 10% (2/20) in group 2; and 13.2% (12/91) in group 3. Our findings suggest a high risk of serious infections with ANC <0.2 × 109/L during deferiprone treatment, a level consistent with the recent neutropenia guidelines.

Hydroxychloroquine-Induced Neutropenia in an Infant with Coronavirus-19 Disease

Hydroxychloroquine (HCQ)-induced neutropenia is very rare in children. Even though idiosyncratic HCQ-induced neutropenia is mentioned as a possible side effect reported in the adult population, no pediatric cases have been published in the literature. We present an infant with severe neutropenia after HCQ therapy during the early COVID-19 pandemic. A 2-month-old infant with severe neutropenia after HCQ therapy during the early COVID-19 pandemic. After the neutrophil count returned to normal within a week of stopping the HCQ, and all other possible causes were ruled out, the diagnosis of HCQ-induced neutropenia was made. This case appears to be the first reported pediatric patient with severe neutropenia following the administration of HCQ. HCQ should be used with caution in young infants and only when strongly indicated. Idiosyncratic drug-induced neutropenia is typically serious in infants and mandates prompt diagnosis and management. When patients begin treatment with a drug that can cause neutropenia, neutrophil counts must be carefully monitored, especially in the first 2 days. Furthermore, if neutropenia occurs, we recommend neutrophil monitoring until complete recovery.

Drug-Induced Neutropenia During Treatment of Non-Neoplastic Dermatologic Diseases: A Review.

Idiosyncratic drug-induced neutropenia (DIN) is a rare, potentially fatal adverse reaction. A literature search was performed on Pubmed and Embase, targeting articles indicating neutropenia as a complication during the treatment of non-neoplastic dermatological disorders. In 66 identified articles, the common incriminated drugs included conventional oral immunomodulators, topical cytotoxic agents, antibacterials, antifungals, biologics and targeted synthetic disease-modifying antirheumatic drugs, non-steroidal anti-inflammatory drugs, and retinoids, with dapsone being reported most often. The duration of drug exposure before the diagnosis of neutropenia varied, but mostly ranged from days to weeks. The majority of patients recovered after drug discontinuation and supportive management including antibiotics and granulocyte colony-stimulating factor, but fatal cases were reported. The proposed pathogenesis of DIN consists of direct drug toxicity and immune-mediated reaction. Certain genetic variants, individual variability in enzyme efficiency, and concomitant use of other drugs may increase the risk of DIN. Being familiar with the most commonly implicated agents and risk factors helps early identification and prompt management of this potentially fatal complication.

Idiosyncratic Drug-Induced Neutropenia and Agranulocytosis in Elderly Patients.

Agranulocytosis is a rare, but serious and life-threatening hematologic disorder in elderly patients. Idiosyncratic drug-induced agranulocytosis (IDIA) has been classically defined by a neutrophil count below 0.5 × 109/L. The annual incidence of IDIA in Europe is about 1.6–9.2 cases per million inhabitants. Increasing age and female sex have been considered as risk factors for the development of this condition. Besides, it is well known that older people take on average more drugs than younger people. This condition is most often associated with the intake of antibacterial agents, antiplatelets, antithyroids, antipsychotics, antiepileptics and nonsteroidal anti-inflammatory drugs (NSAIDs). Initially, agranulocytosis may present without symptoms, but may quickly progress to a severe infection and sepsis. The causative drug should be immediately stopped. In febrile patients, blood cultures and where indicated, site-specific cultures should be obtained and early treatment with empirical broad-spectrum antibiotics started. Even with adequate treatment, the mortality rate is higher in elderly patients reaching up to 20%. Hematopoietic growth factors have proven to be useful as they shorten the duration of neutropenia. However, data on neutropenia and agranulocytosis in the elderly meeting the criteria of evidence-based medicine are still poor in the literature. This review analyzes the results of our experience as well as other published studies of the universal literature.

State of Art of Idiosyncratic Drug-Induced Neutropenia or Agranulocytosis, with a Focus on Biotherapies.

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.

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

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.

Idiosyncratic drug-induced neutropenia & agranulocytosis.

Few data is currently available on neutropenia and agranulocytosis related to drug intake. We report here data on 203 patients with established idiosyncratic drug-induced agranulocytosis, followed up in a referral centre within a university hospital. Data from 203 patients with idiosyncratic drug-induced agranulocytosis were retrospectively reviewed. All cases were extracted from a cohort study on agranulocytosis in the Strasbourg University Hospital (Strasbourg, France) RESULTS: : The mean age was 61.6 years old (range: 18-95), the gender ratio (F/M) was 1.3. Several comorbidities were present in 63.5%. The most frequent causative drugs were: 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 as ticlopidine and acid acetylsalicylic (6.9%). The main primary clinical manifestations during hospitalization included: isolated fever (26.3%); septicaemia (13.9%); documented pneumonia (13.4%); sore throat and acute tonsillitis (9.3%); and septic shock (6.7%). The mean neutrophil count at nadir was 0.148 x 109/L (range: 0-0.48). All febrile patients were treated with broad-spectrum antibiotics and 107 (52.7%) with hematopoietic growth factors. The mean duration of haematological recovery (neutrophil count ≥1.5 x 109/L) was 7.8 (range: 2-20). This mean duration was reduced to 2.1 days (range: 2-16) (p = 0.057) with hematopoietic growth factors. Outcome was favourable in 91.6% of patients; seventeen died. Thirty-seven patients (18.2%) required intensive care. 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.

Understanding idiosyncratic drug-induced neutropenia

Understanding idiosyncratic drug-induced neutropenia

Reply to Andrès et al.

Dear Sir, I would like to offer the following comment to the letter by E. Andrès and colleagues (pp. 533–534, this issue). The authors support their decision to treat all patients with idiosyncratic drug-induced neutropenia with G-CSF by quoting a number of studies (Table 1). The issue is whether these studies provide evidence-based medicine criteria for decisions. The only randomized, controlled trial (RCT) (Ref. [2] in their list) could not document an effect of G-CSF on the recovery of neutrophils. This study can be classified as evidence level 1b or 2b, according to the NHS Research and Development criteria (http://cebm.jr2.ox.ac.uk). The studies by Andrès et al. and Sprikkelman et al. (Refs. [4–6] in their list) fit evidence level 4 or 3b, respectively. The meta-analysis of Beaushesne and Shalansky (Ref. [7] in their list) corresponds to level 5 because a meta-analysis cannot be better than the cited studies. Thus, the grade of recommendations against treatment with G-CSF corresponds to level A, and for treatment to levels C or D. The conclusion must be that the scientific community still lacks high-quality studies in this field. I would emphasize that it is prudent to evaluate the basis for the recommendations critically even for rare disorders, such as the idiosyncratic drug-induced neutropenia. Attempts have been made to analyse the pitfalls [1-3]. I believe that an international co-operative study, designed as a RCT, is the only answer to the question.

The effects of some drugs which cause agranulocytosis on protein synthesis in human granulocytes

The rate of protein synthesis by human granulocytes in vitro has been measured by the incorporation of [U- 14C]phenylalanine into the cell protein. The total phenylalanine concentration in the cells was measured in each experiment so that changes in the precursor pool specific radioactivity during the experiment could be allowed for. Cells were obtained from normal subjects, patients who had recovered from an episode of idiosyncratic drug-induced neutropenia, and from a case of idiopathic neutropenia. The effects of the following drugs which sometimes cause idiosyncratic neutropenia, on the rate of protein synthesis in human granulocytes in vitro has been studied: sodium aurothiomalate, phenylbutazone, carbimazole, methimazole, methylthiouracil, chlorpromazine, chloramphenicol, sulphamethoxazole and trimethoprim. The last two drugs were studied separately, and in combination in the proportions in which they are found in plasma during co-trimoxazole therapy. When used at the concentrations which are believed to represent the maximum in vivo concentrations in serum, none of the following affected the protein synthetic activity of normal human granulocytes in vitro: sodium aurothiomalate, phenylbutazone, methimazole, methylthiouracil, sulphamethoxazole and trimethoprim (the latter pair either separately or together as in co-trimoxazole). Chlorpromazine (1 × 10 −4 M) markedly inhibited protein synthesis by the cells of one normal subject out of the 10 who were studied. Higher concentrations (1 × 10 −3 M) of chlorpromazine virtually abolished protein synthesis in the cells of the two normal subjects studied. Chloramphenicol reduced the protein synthetic activity of normal human granulocytes. We obtained no evidence that protein synthesis by the granulocytes from patients who had experienced neutropenia due to sodium aurothiomalate (4 cases), chloramphenicol (2 cases), carbimazole (1 case), co-trimoxazole (1 case), methylthiouracil (1 case) were abnormally sensitive to inhibition by the drug which had caused the neutropenia.