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Corticosteroids as Adjunctive Therapy in the Treatment of Influenza

An Updated Cochrane Systematic Review and Meta-analysis

Lansbury, Louise E. MBBS, PhD1,2; Rodrigo, Chamira MRCP, PhD3; Leonardi-Bee, Jo PhD1; Nguyen-Van-Tam, Jonathan DM, FFPH, FRCPath, FRSPH, FRSB1; Lim, Wei Shen DM, FRCP2,3

doi: 10.1097/CCM.0000000000004093
Online Clinical Investigation: PDF Only
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Objectives: Corticosteroids may be beneficial in sepsis, but uncertainty remains over their effects in severe influenza. This systematic review updates the current evidence regarding corticosteroids in the treatment of influenza and examines the effect of dose on outcome.

Data Sources: Electronic databases (MEDLINE, EMBASE, CINAHL, LILACS, CENTRAL, and Web of Science) and trial registries were searched to October 2018 for randomized controlled trials, quasi-experimental designs, and observational cohort studies reporting corticosteroid versus no corticosteroid treatment in individuals with influenza.

Study Selection and Data Extraction: Two researchers independently assessed studies for inclusion. Risk of bias was assessed using the Cochrane Risk of Bias tool (randomized controlled trials) or Newcastle-Ottawa Scale (observational studies). Where appropriate, we estimated the effect of corticosteroids by random-effects meta-analyses using the generic inverse variance method. Meta-regression analysis was used to assess the association of corticosteroid dose and mortality.

Data Synthesis: We identified 30 eligible studies, all observational apart from one randomized controlled trial. Twenty-one observational studies were included in the meta-analysis of mortality, which suggested an adverse association with corticosteroid therapy (odds ratio, 3.90; 95% CI, 2.31–6.60; 15 studies; adjusted hazard ratio, 1.49; 95% CI, 1.09–2.02; six studies). Risk of bias assessment was consistent with potential confounding by indication. Pooled analysis of seven studies showed increased odds of hospital-acquired infection in people treated with corticosteroids (unadjusted odds ratio, 2.74; 95% CI, 1.51–4.95). Meta-regression of the effect of dose on mortality did not reveal an association, but reported doses of corticosteroids in included studies were high (mostly > 40 mg methylprednisolone [or equivalent] per day).

Conclusions: Corticosteroid treatment in influenza is associated with increased mortality and hospital-acquired infection, but the evidence relates mainly to high corticosteroid doses and is of low quality with potential confounding by indication a major concern.

1Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom

2Nottingham Biomedical Research Centre NIHR, United Kingdom.

3Department of Respiratory Medicine, Nottingham University Hospitals Trust, Nottingham, United Kingdom.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by grants from National Institute for Health Research Nottingham Biomedical Research Centre, (Nottingham University Hospitals National Health Service Trust and University of Nottingham), Nottingham, United Kingdom.

This article is based on a Cochrane Review published in the Cochrane Database of Systematic Reviews (CDSR) 2019; issue 2, DOI: 10.1002/14651858.CD010406. (see www.cochranelibrary.com for information). Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and the CDSR should be consulted for the most recent version of the review.

Dr. Lansbury disclosed that this work is part of an ongoing program undertaken by the Nottingham Biomedical Research Centre funded by the National Institute for Health Research (NIHR); she is the Head of the World Health Organization Collaborating Centre for Pandemic Influenza and Research at the University of Nottingham, which has a grant from the World Health Organization to provide technical assistance for the prevention and control of seasonal influenza; she has salary support funded by the NIHR; and she received support for article research from the NIHR. Dr. Rodrigo received salaries funded, in part, by an unrestricted grant from Pfizer and the NIHR. Professor Leonardi-Bee disclosed that she was a coapplicant 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. She also undertook consultancy work for the U.K. Food Standards Agency in 2013–2015 and for a Breast Milk Substitute manufacturer in 2017 to help them design a healthcare claim trial. Professor Nguyen-Van-Tam’s institution received funding from the NIHR. He disclosed that the University of Nottingham Health Protection Research Group currently holds an unrestricted educational grant for influenza research from F. Hoffmann-La Roche, but this did not support any aspect of this work. He also disclosed that he is a former employee of SmithKline Beecham plc (now GlaxoSmithKline), Roche Products, 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 (U.K. government); he received support for article research from NIHR, Nottingham Biomedical Research Centre; and he disclosed off-label product use of corticosteroids. Professor Lim’s institution received funding from NIHR Biomedical Research Centre and Pfizer (unrestricted investigator-initiated research grant for pneumococcal pneumonia) and the NIHR (corticosteroids in pandemic influenza clinical trial).

This work was performed at the University of Nottingham, Nottingham, United Kingdom.

Address requests for reprints to: Louise E. Lansbury, MBBS, PhD, Department of Epidemiology and Public Health, University of Nottingham, Room B104 Clinical Sciences Building, City Hospital, Nottingham NG5 1PB, United Kingdom. E-mail: louise.lansbury@nottingham.ac.uk

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