Abstract
BackgroundDrug-induced agranulocytosis is a recognized adverse drug event associated with serious infectious complications. Levamisole is an antihelminthic and immunomodulator withdrawn from North American markets in 2005 after reports of agranulocytosis. Previous studies of levamisole, suggest that the human leukocyte antigen (HLA)-B27 confers a genetic predisposition to this adverse drug event. Since 2009, emergency room visits due to agranulocytosis in individuals consuming levamisole-adulterated crack-cocaine have increased.MethodsWe performed a case–control study using a genotyping assay and novel gene chip to test the association between cocaine-associated agranulocytosis (CAA) and HLA-B27 and to identify pharmacokinetic and pharmacodynamic gene variants associated with the phenotype.ResultsFifty-one CAA cases were identified through a provincial physician reporting system between 2008 and 2011. We examined eight of these cases and 26 matched controls. Genotyping revealed a significant association between HLA-B27 and CAA (odds ratio [OR] 9.2, 95% confidence interval [CI], 1.54–54.6). We also observed a similar association with the HLA-B27 tag single nucleotide polymorphism rs4349859 (OR 9.2, 95% CI 1.5–54.6) and rs13202464 (OR 6.7, 95% CI 1.1–41). Further associations were identified with variants in the ARBCC12 (OR 10.0, 95% CI 2.7–36.8) and CYP11A1 (OR 7.4, 95% CI 2.1–26.6) genes, while a novel protective association was observed with variants in the ARDB1 gene (OR 0.06, 95% CI 0.007–0.46).ConclusionsWe confirmed the association of HLA-B27 with CAA and identified additional susceptibility variants. Health care providers should inform people who are identified as having CAA that it is genetically determined and can recur with continued cocaine use. The severity of infections and subsequent hospitalization, and the risk of recurrence may prompt health-promoting behaviour changes of the affected individuals. These genetic associations warrant the attention of public health and knowledge translation efforts to highlight the implications for susceptibility to this severe adverse drug event.
Highlights
Drug-induced agranulocytosis is a recognized adverse drug event associated with serious infectious complications
Relapse is common with approximately half of patients experiencing more than one episode of agranulocytosis associated with return to cocaine use [6]
Patient characteristics As of October 2011, 51 individuals with one or more episodes of cocaine-associated agranulocytosis (CAA) were reported through the British Columbia Centre for Disease Control (BCCDC) voluntary physician reporting system
Summary
Drug-induced agranulocytosis is a recognized adverse drug event associated with serious infectious complications. Suggest that the human leukocyte antigen (HLA)B27 confers a genetic predisposition to this adverse drug event. Since 2009, emergency room visits due to agranulocytosis in individuals consuming levamisole-adulterated crack-cocaine have increased. Reports of agranulocytosis in individuals using levamisole-adulterated cocaine first emerged in 2009 from Alberta and British Columbia (BC), Canada [6, 9] and New Mexico, USA [8] with later reports from other parts of Canada and the United States demonstrating a spectrum of pathology including cutaneous vasculopathy [10–13]. While no reported cases of levamisole-induced agranulocytosis could be identified from the period when the drug was used primarily as an antihelminthic agent, case reports emerged when its treatment profile broadened to include RA in the late 1970s and early 1980s [14, 15]. Initial findings amongst cases of cocaine-associated agranulocytosis (CAA) suggest a similar association with HLA-B27 [2, 15]
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