title: Nonchemotherapy drug-induced agranulocytosis in children detected by a prospective pharmacovigilance program.
abstract: OBJECTIVE
  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.
authors.affiliation: a Department of Clinical Pharmacology , La Paz University Hospital, IdiPAZ, School of Medicine, Autonomous University of Madrid , Madrid , Spain.
authors.forename: Nicolás
authors.initials: N
authors.lastname: Medrano-Casique
authors.affiliation: a Department of Clinical Pharmacology , La Paz University Hospital, IdiPAZ, School of Medicine, Autonomous University of Madrid , Madrid , Spain.
authors.forename: Hoi Y
authors.initials: HY
authors.lastname: Tong
authors.affiliation: a Department of Clinical Pharmacology , La Paz University Hospital, IdiPAZ, School of Medicine, Autonomous University of Madrid , Madrid , Spain.
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Borobia
authors.affiliation: a Department of Clinical Pharmacology , La Paz University Hospital, IdiPAZ, School of Medicine, Autonomous University of Madrid , Madrid , Spain.
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Carcas
authors.affiliation: a Department of Clinical Pharmacology , La Paz University Hospital, IdiPAZ, School of Medicine, Autonomous University of Madrid , Madrid , Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Frías
authors.affiliation: a Department of Clinical Pharmacology , La Paz University Hospital, IdiPAZ, School of Medicine, Autonomous University of Madrid , Madrid , Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Ramírez
mesh_terms: D000367:Age Factors; D000380:Agranulocytosis / Q000139:chemically induced / Q000175:diagnosis / Q000453:epidemiology / Q000628:therapy; D002439:Cefotaxime / Q000008:administration & dosage / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D003061:Codeine / Q000008:administration & dosage / Q000009:adverse effects*; D017984:Enoxaparin / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects*; D011446:Prospective Studies; D014640:Vancomycin / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D017984:Enoxaparin; D010880:Piperidines; C040282:cloperastine; D014640:Vancomycin; D002439:Cefotaxime; D003061:Codeine
keywords: Adverse drug reactions; children; drug-induced neutropenia; pharmacovigilance; surveillance