Nonchemotherapy drug-induced agranulocytosis in children detected by a prospective pharmacovigilance program

ABSTRACT

Objectives: A prospective evaluation of nonchemotherapy drug-induced agranulocytosis (DIA) cases, which are infrequent in the pediatric population. We characterize agranulocytosis cases and assess lab test differences between drug- and nondrug-induced agranulocytosis. Methods: Through our Prospective Pharmacovigilance Program from Laboratory Signals at Hospital we detected pediatric agranulocytosis cases from July 2007 to December 2010. This program estimates the incidence, drug causality, clinical features, outcomes of DIA pediatric cases, and assesses laboratory differences with respect to non-DIA. Results: We detected 662 agranulocytosis in 308 pediatric patients, of which 14 were caused by nonchemotherapy drugs. The incidence rate of DIA for 10,000 pediatric patients was 3.92 (Poisson 95% confidence interval 1.09–8.77); 78.6% of DIA cases occurred in patients younger than 3 years. The final outcome was recovery without sequela in all cases. The pharmacologic group most frequently implicated was antimicrobial drugs (11 drugs), 7 of which were beta-lactams. The drugs most frequently suspected were cefotaxime and vancomycin (3 cases each). We found 3 drugs (cloperastine, codeine, and enoxaparin) not previously described to induce DIA. Automatic linear modeling (n = 56, R² = 45.2%) showed a significant inverse association with platelets (R² = 17.5%), hemoglobin, and alanine transaminase, and a direct association with red cell distribution (R² = 16.2%). A generalized linear model (Type III, n = 1188; DIA, n = 86; likelihood ratio chi-squared = 156.16) retained eosinophils (p <.001), platelets (p <.001), total serum proteins (p <.001), and hemoglobin (p =.039). Conclusions: We found a higher incidence of DIA in children than previously described. Our findings also suggest an immune-mediated destruction or myeloid toxicity, possibly facilitated by an increase in drug exposure.

KEYWORDS:

• Adverse drug reactions
• children
• drug-induced neutropenia
• pharmacovigilance
• surveillance

Acknowledgments

The authors would like to thank Juliette Siegfried and her team at ServingMed.com for editing the manuscript. The study was conducted as part of the routine work of the Risk Management Units of LPUH. No financial assistance was received to support this study.

Conflicts of interest

The authors have no conflicts of interest to disclose relevant to this article.