Clinical Microbiology: Open Access

Abstract

The Mechanisms of Adverse Reactions to Oseltamivir: Part II. Delayed Type Reactions

Rokuro Hama

Oseltamivir is recommended for treatment and prophylaxis of Influenza in persons at higher risk for Influenza complications such as individuals with diabetes, neuropsychiatric illnesses, and respiratory, cardiac, renal, hepatic or hematological diseases. However, a recent systematic review reported that reduction of antibody production, renal disorders, hyperglycemia, psychiatric disorders, and QT prolongation may be related to Oseltamivir use. The underlying mechanisms of these effects are reviewed. There is decisive evidence that administration of a clinically compatible dose of Oseltamivir in mice challenged by a respiratory syncytial virus (RSV) that lacks a neuraminidase gene showed symptom-relieving effects and inhibition of viral clearance. These effects were accompanied by decreased level of T cell surface sialoglycosphingolipid (ganglioside) GM1 that is regulated by the endogenous neuraminidase in response to viral challenge. Clinical and non-clinical evidence supports the view that the usual dose of Oseltamivir suppresses pro-inflammatory cytokines such as interferon-gamma, interleukin-6, and tumor necrosis factor-alpha almost completely in experimentally infected Influenza viruses in humans with partial suppression of viral shedding. Animal toxicity tests support the clinical evidence with regard to renal and cardiac disorders (bradycardia and QT prolongation) and do not disprove the metabolic effect. Reduction of antibody production and cytokine induction and renal, metabolic, cardiac, and prolonged psychiatric disorders after Oseltamivir use may be related to inhibition of the host’s endogenous neuraminidase. While the usual clinical dose of Zanamivir may not have this effect, a higher dose or prolonged administration of Zanamivir and other neuraminidase inhibitors may induce similar delayed reactions, including reduction of antibody and/or cytokine production.