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Drug Fever

A Descriptive Cohort Study from the French National Pharmacovigilance Database

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Abstract

Background: Although known as a rare adverse drug reaction (ADR), drug fever (DF) remains an important issue in medicine, with the risk of leading to inappropriate and potentially harmful diagnostic and therapeutic interventions. Only sparse data regarding DF have been published.

Objective: The aim of the study was to investigate which drugs were associated with DF, and report outcomes.

Methods: Cases of DF without skin reactions were selected from all ADRs reported from 1986 to 2007 in the French National Pharmacovigilance Database. Drugs potentially responsible for DF were assessed using a qualitative case-by-case analysis (Naranjo’s criteria) and quantitative measurement (proportional reporting ratio [PRR]). A drug was implicated as the cause of DF when the following criteria were validated: three or more cases and PRR of at least two with a Chi-squared value of at least four.

Results: A total of 167 DF cases involving 115 drugs were eligible. Based on the PRR, 22 drugs were significantly associated with DF. Antibacterials represented the most frequently reported drugs, including amikacin (PRR 39.6 [95% CI 23.6, 69.0], oxacillin (9.1 [3.6, 23.4]), cefotaxime (5.5 [2.0, 15.3]), ceftriaxone (5.4 [2.6, 11.3]), rifampicin (4.0 [1.8, 9.2]), vancomycin (4.0 [1.4, 11.5]), ciprofloxacin (3.1 [1.2, 8.0]), isoniazid (3.9 [1.4, 11.4]), pristinamycin (3.1 [1.0, 9.1]) and cotrimoxazole (2.6 [1.2, 5.8]). Median time [interquartile range] from drug administration to fever onset was 2 days [1.0–10.5]. A diagnosis of DF was made following cessation of the suspected drugs (3 days [1.0–11.5] after fever onset. Drug rechallenge was performed (38.0%), resulting in recurrence of DF in all cases. DF resulted in life-threatening events (0.6%), hospitalization or prolonged hospital stay (24.5%) and persistent disability (0.6%). Final outcome was favourable in 96.9% of cases after drug discontinuation.

Conclusion: Diagnosing DF is challenging. Based on this large series, antibacterials remain the major class of drugs responsible for DF.

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Acknowledgements

No sources of funding were used to conduct this study or prepare this manuscript. None of the authors has any conflict of interest.

The authors would like to acknowledge Jenny Lu, MD, from Toxikon Consortium, Chicago, IL, USA, for her review of this manuscript and François Maignen, from the European Medicines Agency, London, UK, for his methodological help. We appreciate the assistance of the French pharmacovigilance centers in our work.

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Authors and Affiliations

  1. Department of Internal Medicine, AP-HP, Ambroise Paré Hospital, 9 avenue Charles-de-Gaulle, 92100, Boulogne-Billancourt, France

    Dominique Vodovar &  Thomas Hanslik MD

  2. Medical and Toxicological Critical Care Department, AP-HP, Lariboisière Hospital, Paris, France

    Dominique Vodovar & Bruno Mégarbane

  3. Paris-Diderot University, Paris, France

    Dominique Vodovar & Bruno Mégarbane

  4. Regional Center of Pharmacovigilance, AP-HP, European Georges Pompidou Hospital, Paris, France

    Christine LeBeller & Agnes Lillo-Le-Louet

  5. Versailles-Saint Quentin University, Versailles, France

    Thomas Hanslik MD

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  1. Dominique Vodovar
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  2. Christine LeBeller
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Vodovar, D., LeBeller, C., Mégarbane, B. et al. Drug Fever. Drug Saf 35, 759–767 (2012). https://doi.org/10.1007/BF03261972

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