title: Corticosteroids as adjunctive therapy in the treatment of influenza.
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 benefit or harm.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  We searched CENTRAL (2015, Issue 5), MEDLINE (1946 to June week 1, 2015), EMBASE (1974 to June 2015), CINAHL (1981 to June 2015), LILACS (1982 to June 2015), Web of Science (1985 to June 2015), abstracts from the last three years of major infectious disease and microbiology conferences, and references of included articles.
  
  
  METHODS
  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.
  
  
  METHODS
  Two pairs of review authors independently extracted data and assessed risk of bias. We pooled estimates of effect using random-effects meta-analysis models, where appropriate. We assessed heterogeneity using the I(2) statistic and assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.
  
  
  RESULTS
  We identified 19 eligible studies (3459 individuals), all observational; 13 studies (1917 individuals) were suitable for inclusion in the meta-analysis of mortality. Of these, 12 studied patients infected with 2009 influenza A H1N1 virus (H1N1pdm09). Risk of bias was greatest in the 'comparability domain' of the Newcastle-Ottawa scale, consistent with potential confounding by indication. Data specific to mortality were of very low quality. 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) 3.06, 95% confidence interval (CI) 1.58 to 5.92). Pooled subgroup analysis of adjusted estimates of mortality from four studies found a similar association (OR 2.82, 95% CI 1.61 to 4.92). Three studies reported greater odds of hospital-acquired infection related to corticosteroid therapy; all were unadjusted estimates and we graded the data as very low quality.
  
  
  CONCLUSIONS
  We did not identify any completed RCTs of adjunctive corticosteroid therapy for treating influenza. The available evidence from observational studies is of very low quality with confounding by indication a major potential concern. Although we found that adjunctive corticosteroid therapy was 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). Currently, we do not have sufficient evidence in this review to determine the effectiveness of corticosteroids for patients with influenza.
authors.affiliation: Department of Respiratory Medicine, Nottingham University Hospitals Trust, City Campus, Hucknall Road, Nottingham, Nottinghamshire, UK, NG5 1PB.
authors.forename: Chamira
authors.initials: C
authors.lastname: Rodrigo
authors.forename: Jo
authors.initials: J
authors.lastname: Leonardi-Bee
authors.forename: Jonathan
authors.initials: J
authors.lastname: Nguyen-Van-Tam
authors.forename: Wei Shen
authors.initials: WS
authors.lastname: Lim
mesh_terms: D000305:Adrenal Cortex Hormones / Q000009:adverse effects / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects; D003428:Cross Infection / Q000209:etiology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D007251:Influenza, Human / Q000188:drug therapy* / Q000401:mortality; D007362:Intensive Care Units / Q000706:statistics & numerical data; D064887:Observational Studies as Topic
chemical_list: D000305:Adrenal Cortex Hormones