Rodrigo Chamira, Leonardi-Bee Jo, Nguyen-Van-Tam Jonathan, Lim Wei Shen
Department of Respiratory Medicine, Nottingham University Hospitals Trust, City Campus, Hucknall Road, Nottingham, Nottinghamshire, UK, NG5 1PB.
Cochrane Database Syst Rev. 2016 Mar 7;3:CD010406. doi: 10.1002/14651858.CD010406.pub2.
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.
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 (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.
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 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.
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.
AUTHORS' 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.
流感的特效治疗仅限于神经氨酸酶抑制剂和金刚烷类药物。皮质类固醇在脓毒症及相关病症中显示出有益效果，这很可能归因于其抗炎和免疫调节特性。尽管皮质类固醇常用于治疗重症流感，但其潜在益处或危害仍存在不确定性。
考虑到皮质类固醇在用药时间和剂量上的差异，系统评价皮质类固醇作为辅助治疗在流感治疗中的有效性和潜在不良反应。
我们检索了Cochrane系统评价数据库（2015年第5期）、医学索引数据库（1946年至2015年6月第1周）、荷兰医学文摘数据库（1974年至2015年6月）、护理学与健康领域数据库（1981年至2015年6月）、拉丁美洲及加勒比地区健康科学数据库（1982年至2015年6月）、科学引文索引数据库（1985年至2015年6月），以及过去三年主要传染病和微生物学会议的摘要和纳入文章的参考文献。
我们纳入了比较皮质类固醇治疗与未使用皮质类固醇治疗流感或流感样疾病的随机对照试验、半随机对照试验和观察性研究。我们未根据发表语言、流感亚型、临床环境或参与者年龄对研究进行限制。我们分两个阶段选择符合条件的研究：先顺序检查标题和摘要，然后阅读全文。
两对综述作者独立提取数据并评估偏倚风险。在适当情况下，我们使用随机效应荟萃分析模型汇总效应估计值。我们使用I²统计量评估异质性，并使用推荐分级的评估、制定与评价（GRADE）框架评估证据质量。
我们确定了19项符合条件的研究（共3459名个体），均为观察性研究；13项研究（1917名个体）适合纳入死亡率的荟萃分析。其中，12项研究了感染2009甲型H1N1流感病毒（H1N1pdm09）的患者。在纽卡斯尔 - 渥太华量表的“可比性领域”中，偏倚风险最大，这与潜在的指示性混杂因素一致。死亡率的具体数据质量非常低。所报告的皮质类固醇使用剂量很高，且其使用指征报告不充分。荟萃分析显示，皮质类固醇治疗与死亡率增加相关（比值比（OR）为3.06，95%置信区间（CI）为1.58至5.92）。对四项研究中调整后的死亡率估计值进行的汇总亚组分析发现了类似的关联（OR为2.82，95%CI为1.61至4.92）。三项研究报告了与皮质类固醇治疗相关的医院获得性感染几率更高；所有这些都是未调整的估计值，我们将这些数据的质量评为非常低。
我们未找到任何关于皮质类固醇辅助治疗流感的完整随机对照试验。观察性研究提供的现有证据质量非常低，指示性混杂是一个主要的潜在问题。尽管我们发现皮质类固醇辅助治疗与死亡率增加相关，但对这一结果的解释应谨慎。鉴于在脓毒症和肺炎的皮质类固醇辅助治疗临床试验中报告了改善的结果，包括死亡率降低，因此需要更多高质量的研究（包括随机对照试验和观察性研究）。目前，在本综述中我们没有足够的证据来确定皮质类固醇对流感患者的有效性。
