Review question
We reviewed the evidence regarding the effect of additional ('adjunctive') steroid treatment in individuals with influenza infection.
Background
The majority of individuals with influenza have a fever, headache, and cough and improve without any specific treatment. However, a small proportion of patients develop a more severe form of influenza that requires admission to a hospital intensive care unit. These patients are often prescribed steroids as part of their treatment, although the evidence supporting the use of steroids in these circumstances is controversial.
Study characteristics
We searched for studies comparing additional steroid treatment with no additional steroid treatment in individuals with influenza. The evidence is current to 3 October 2018. We identified a total of 30 studies with 99,224 individuals; one of these studies was a clinical trial. The majority of studies investigated adults admitted to hospital with pandemic influenza in 2009 and 2010.
Key results
We found one relevant clinical trial, but there were very few participants (n = 24) with laboratory-confirmed influenza. The certainty of the evidence available from existing observational studies was of very low. We found that people with influenza who received additional steroid treatment may have a greater risk of death compared to those who did not receive steroid treatment. Hospital-acquired infection was the main 'side effect' related to steroid treatment reported in the included studies; most studies reported a greater risk of hospital-acquired infection in the group treated with steroids. However, it was unclear whether patients with more severe influenza had been selected to receive steroid treatment. Consequently, we were unable to determine whether additional steroid treatment in people with influenza is truly harmful or not. Further clinical trials of additional steroids in the treatment of individuals with influenza are therefore warranted. In the meantime, the use of steroids in influenza remains a clinical judgement call.
Certainty of the evidence
In the one controlled trial there were only 24 participants with confirmed influenza infection, and there was under-representation of the sickest patients in the intensive care unit and with sepsis.
The rest of the evidence was from observational studies, and we classified the certainty of this evidence as very low. A major limitation was that the indications for corticosteroid therapy were not fully specified in many of the studies; corticosteroids may have been used as a final attempt in people with the most severe disease, or conversely they may have been used to treat less severe illnesses that occurred simultaneously such as asthma exacerbations. It was noted in some studies that there was high degree of association between the use of corticosteroids and the presence of potentially confounding factors such as disease severity and underlying illnesses, suggesting that confounding by the indication for corticosteroids was likely if not adjusted for when determining effect estimates. We noted inconsistent reporting of other important variables that may be related to influenza-related death across studies, including time to hospitalisation, the use and timing of antiviral drugs and antibiotics, and the type, dose, timing, and duration of corticosteroid therapy. Additionally, for studies in which this information was reported, there were differences between studies in the way that disease severity was measured, the time point at which death was assessed, and the proportions of cases and controls treated with antivirals and/or antibiotics and in the type, dose, timing, and duration of corticosteroid therapy.
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.
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.
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.
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.
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.
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.
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.