Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data

Abstract

International audienceSummaryBackground Neuraminidase inhibitors were widely used during the 2009–10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection. Methods We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling. Findings We included data for 29 234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0·81; 95% CI 0·70–0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41–0·56; p<0·0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37–0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each day's delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1·23] [95% CI 1·18–1·28]; p<0·0001 for the increasing HR with each day's delay). Interpretation We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection. Funding F Hoffmann-La Roche

Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09‐related pneumonia: an individual participant data meta‐analysis

“…Our other findings that NAI treatment at any time versus no NAI, and later NAI treatment compared with no NAI, universally increased the risks of IRP, contrast sharply with previous observational data on hospitalised influenza patients which found that NAI treatment (irrespective of timing) and later antiviral therapy (initiated >48 hours after illness onset) may improve a range of clinical outcomes 19, 23, 24, 25, 26, 27, 28. Essentially similar observations were made for ‘any pneumonia’.…”

Viral load is strongly associated with length of stay in adults hospitalised with viral acute respiratory illness

“…This suggests that in contrast to healthy adults with uncomplicated viral infection (where viral load peaks quickly and declines rapidly) for hospitalised adults with complicated respiratory viral illness, the viral load remains an important determinant of clinical outcome at this later time point and is therefore potentially modifiable with effective antiviral therapy. This is consistent with a number of observational studies of hospitalised adults with influenza showing reduction in viral loads and clinical benefits from neuraminidase inhibitors even when started beyond 48 hours of symptom duration [29][30][31]. Although not explored in this study a high viral load is also suggestive of increased infectiousness and an increased risk of nosocomial spread and so patients with a high viral load detected on admission to hospital would represent a priority group for side room isolation and enhanced infection control practices.…”

Comparison of the three waves of avian influenza A(H7N9) virus circulation since live poultry markets were permanently closed in the main urban areas in Zhejiang Province, July 2014‐June 2017

“…The reduced time between illness onset and antiviral treatment was in agreement with an observed declining trend of fatality of H7N9 cases. As the antiviral treatment was recommended as early as possible and considered to be more effective if initiated within 48 hours from illness onset,26, 27 the median time of 5 days for this period in the most recent wave indicates that there are still rooms for improvements that could potentially reduce future mortality of H7N9 infection by a significant amount. Meanwhile, the strengthening of health education programs and awareness training related to H7N9 should be deemed as essential, as a cost‐effective way of achieving early hospital visits, early diagnostics, and early antiviral treatment.…”