Use of Neuraminidase Inhibitors for Treatment of Severe Influenza: Times Are Changing.

The desire for new and improved therapies to be in the pipeline, so commonly expressed in the era of antibiotic resistance, has been relevant to the development of influenza antivirals for decades. Oseltamivir and zanamivir, the first neuraminidase inhibitors, were licensed for therapy in 1999 and put into greater use in the late 2000s following widespread resistance to amantadine and rimantadine. In 2009, the Centers for Disease Control and Prevention (CDC) issued recommendations for neuraminidase inhibitors as alternatives. In the context of suboptimal use, the CDC has continued to advocate for prompt antiviral treatment for confirmed or suspected influenza. This was particularly true during the 2014–2015 influenza A/H3N2 season, when the circulation of a drifted strain throughout the United States led to low influenza vaccine effectiveness in the community, clearly increasing the need for appropriate therapy in a year when pneumonia and influenza mortality was elevated for 8 consecutive weeks [1]. Current treatment recommendations by the CDC [2] and the Infectious Diseases Society of America [3] call for treatment based on clinical suspicion of influenza, whether or not a positive influenza test is available at the time. This is reflective of the lack of sensitivity of many of the rapid influenza tests being used [4]. The goal of this empiric recommendation is to encourage early use of antivirals, particularly within the first 48 hours of symptoms when treatment has been shown to be most effective [5, 6]. Despite the recommendations, the use of neuraminidase inhibitors during and following the pandemic has been surprisingly low among hospitalized adults and even lower in outpatients. This is particularly true of oseltamivir, the only neuraminidase inhibitor that is orally bioavailable. Hesitancy surrounding neuraminidase inhibitors may stem from discussions of metaanalyses of randomized control trials on the use of antivirals primarily for mild to moderate illness [7–9]. Neuraminidase inhibitors have been shown in randomized controlled trials to be effective in shortening the duration of influenza illness [7–9] and have been shown in observational studies to be effective in reducing mortality in hospitalized patients [6]. One metaanalysis further identified a benefit of treatment among patients admitted to the intensive care unit as a secondary endpoint [7]. However, the randomized controlled trials that formed the basis for these analyses lacked sufficient data on treatment of hospitalized patients with severe influenza. This necessitates the use of data from large observational studies to support the development of recommendations [10]. Thus, studies of the effectiveness of oseltamivir when used for treatment of hospitalized patients have primarily been observational. One of the largest analyses to date is a metaanalysis conducted in 2014 by Muthuri et al [6] that showed that neuraminidase treatment reduced mortality overall and that this effect was greatest with prompt treatment. It appears that the use of antivirals to treat influenza is now on the rise. In this issue of Clinical Infectious Diseases, Appiah and colleagues present data on an apparent trend of increasing antiviral use among hospitalized children and adults. The data come from the Influenza Hospitalization Surveillance Network (FluSurv-NET), a national surveillance system in the United States that encompasses more than 250 hospitals and laboratories. Through this network, the authors were able to gather data on 48 456 laboratory-confirmed hospitalized cases of influenza over 5 seasons. A steady increase in antiviral treatment from 72% to 89% was observed in the overall population, with a marked increase in infants aged <1 year, in whom treatment increased from 51% to 82% over the 5-year period. The increase in the number of hospitalized individuals who are treated in alignment with recommendations is a positive development. Still, the authors’ analysis of who did not receive treatment sheds light on some interesting caveats. Most notably, children as a group were treated less often E D I T O R I A L C O M M E N T A R Y