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Meta-Analysis
. 2019 Feb 24;2(2):CD010406.
doi: 10.1002/14651858.CD010406.pub3.

Corticosteroids as adjunctive therapy in the treatment of influenza

Louise Lansbury  1 , Chamira Rodrigo, Jo Leonardi-Bee, Jonathan Nguyen-Van-Tam, Wei Shen Lim
Affiliations
Meta-Analysis

Corticosteroids as adjunctive therapy in the treatment of influenza

Louise Lansbury et al. Cochrane Database Syst Rev. .

Abstract

Background: Specific treatments for influenza are limited to neuraminidase inhibitors and adamantanes. Corticosteroids show evidence of benefit in sepsis and related conditions, most likely due to their anti-inflammatory and immunomodulatory properties. Although commonly prescribed for severe influenza, there is uncertainty over their potential benefits or harms. This is an update of a review first published in 2016.

Objectives: To systematically assess the effectiveness and potential adverse effects of corticosteroids as adjunctive therapy in the treatment of influenza, taking into account differences in timing and doses of corticosteroids.

Search methods: We searched CENTRAL (2018, Issue 9), which includes the Cochrane Acute Respiratory infections Group's Specialised Register, MEDLINE (1946 to October week 1, 2018), Embase (1980 to 3 October 2018), CINAHL (1981 to 3 October 2018), LILACS (1982 to 3 October 2018), Web of Science (1985 to 3 October 2018), abstracts from the last three years of major infectious disease and microbiology conferences, and references of included articles. We also searched the World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, and the ISRCTN registry on 3 October 2018.

Selection criteria: We included randomised controlled trials (RCTs), quasi-RCTs, and observational studies that compared corticosteroid treatment with no corticosteroid treatment for influenza or influenza-like illness. We did not restrict studies by language of publication, influenza subtypes, clinical setting, or age of participants. We selected eligible studies in two stages: sequential examination of title and abstract, followed by full text.

Data collection and analysis: Two review authors independently extracted data and assessed risk of bias. We pooled estimates of effect using a random-effects model, where appropriate. We assessed heterogeneity using the I2 statistic and assessed the certainty of the evidence using the GRADE framework.

Main results: This updated review includes 30 studies (one RCT with two arms and 29 observational studies) with a total of 99,224 participants. We included 19 studies in the original review (n = 3459), all of which were observational, with 13 studies included in the meta-analysis for mortality. We included 12 new studies in this update (one RCT and 11 observational studies), and excluded one study in the original review as it has been superceded by a more recent analysis. Twenty-one studies were included in the meta-analysis (9536 individuals), of which 15 studied people infected with 2009 influenza A H1N1 virus (H1N1pdm09). Data specific to mortality were of very low quality, based predominantly on observational studies, with inconsistent reporting of variables potentially associated with the outcomes of interest, differences between studies in the way in which they were conducted, and with the likelihood of potential confounding by indication. Reported doses of corticosteroids used were high, and indications for their use were not well reported. On meta-analysis, corticosteroid therapy was associated with increased mortality (odds ratio (OR) 3.90, 95% confidence interval (CI) 2.31 to 6.60; I2 = 68%; 15 studies). A similar increase in risk of mortality was seen in a stratified analysis of studies reporting adjusted estimates (OR 2.23, 95% CI 1.54 to 3.24; I2 = 0%; 5 studies). An association between corticosteroid therapy and increased mortality was also seen on pooled analysis of six studies which reported adjusted hazard ratios (HRs) (HR 1.49, 95% CI 1.09 to 2.02; I2 = 69%). Increased odds of hospital-acquired infection related to corticosteroid therapy were found on pooled analysis of seven studies (pooled OR 2.74, 95% CI 1.51 to 4.95; I2 = 90%); all were unadjusted estimates, and we graded the data as of very low certainty.

Authors' conclusions: We found one RCT of adjunctive corticosteroid therapy for treating people with community-acquired pneumonia, but the number of people with laboratory-confirmed influenza in the treatment and placebo arms was too small to draw conclusions regarding the effect of corticosteroids in this group, and we did not include it in our meta-analyses of observational studies. The certainty of the available evidence from observational studies was very low, with confounding by indication a major potential concern. Although we found that adjunctive corticosteroid therapy is associated with increased mortality, this result should be interpreted with caution. In the context of clinical trials of adjunctive corticosteroid therapy in sepsis and pneumonia that report improved outcomes, including decreased mortality, more high-quality research is needed (both RCTs and observational studies that adjust for confounding by indication). The currently available evidence is insufficient to determine the effectiveness of corticosteroids for people with influenza.

PubMed Disclaimer

Conflict of interest statement

Louise Lansbury is Head of the WHO Collaborating Centre for Pandemic Influenza and Research at the University of Nottingham, which has a grant pending from the World Health Organization to provide technical assistance for the prevention and control of seasonal influenza. The study is unrelated to the submitted work. LL's salary is funded by the National Institute for Health Research.

Chamira Rodrigo was employed by Nottingham University Hospitals NHS Trust (NUH), and not a commercial organisation during his time as a clinical research fellow. NUH received unrestricted funding from Pfizer and the National Institute for Health Research (NIHR) for unrelated research, to which he contributed as a research investigator.

Professor Jo Leonardi‐Bee was a co‐applicant on an educational grant from Hoffmann‐La Roche to carry out research in the area of pandemic influenza. Hoffmann‐La Roche did not support any aspects of this work. JLB undertook consultancy work for the UK Food Standards Agency in 2013‐2015, and for a Breast Milk Substitute manufacturer in 2017, to help them design a healthcare claim trial.

Jonathan Nguyen‐Van‐Tam: The University of Nottingham Health Protection Research Group currently holds an unrestricted educational grant for influenza research from F. Hoffmann‐La Roche. The aforementioned funding received from F. Hoffmann‐La Roche did not support any aspect of this work. JNVT has received consultancy fees from two biopharmaceutical entities that have no licensed products anywhere in the world, as well as fees related to medico‐legal work on influenza, and royalties related to academic work. He is a former employee of SmithKline Beecham plc (now GlaxoSmithKline), Roche Products Ltd, and Aventis‐Pasteur MSD (now Sanofi‐Pasteur MSD), all prior to 2005, with no outstanding pecuniary interests by way of shareholdings, share options, or accrued pension rights. He is currently on secondment to the Department of Health and Social Care (UK Government).

Wei Shen Lim's institution has received an unrestricted investigator‐initiated research grant from Pfizer in support of a study in pneumococcal pneumonia that is unrelated to the submitted work; WSL is the Chief Investigator of the study. WSL's institution has received research funding from the National Institute for Health Research for a clinical trial of corticosteroids in pandemic influenza; WSL is the Chief Investigator.

Figures

1
1
Study flow diagram for the 2018 update search. We included 12 new studies in the update and excluded 1 study in the original version of the review (Diaz 2012), as it had been superceded by a more recent analysis.
2
2
Forest plot of comparison: 1 Corticosteroid therapy versus no corticosteroid therapy, Outcome: 1.1 Death following admission, hospitalised participants ‐ mortality ‐ studies reporting odds ratios.
3
3
Forest plot of comparison: 1 Corticosteroid therapy versus no corticosteroid therapy, Outcome: 1.2 Death following admission, hospitalised participants ‐ mortality ‐ studies reporting hazard ratios.
4
4
Funnel plot of studies reporting mortality.
5
5
Forest plot of comparison: 1 Corticosteroid therapy versus no corticosteroid therapy, Outcome: 1.3 Hospital‐acquired infection in hospitalised participants.
See this image and copyright information in PMC

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