Association of Inhaled Corticosteroids with Incident Pneumonia and Mortality in COPD Patients; Systematic Review and Meta-Analysis

Background: Inhaled corticosteroids are commonly prescribed for patients with severe COPD. They have been associated with increased risk of pneumonia but not with increased pneumonia-associated or overall mortality. Methods: To further examine the effects of inhaled corticosteroids on pneumonia incidence, and mortality in COPD patients, we searched for potentially relevant articles in PubMed, Medline, CENTRAL, EMBASE, Scopus, Web of Science and manufacturers' web clinical trial registries from 1994 to February 4, 2014. Additionally, we checked the included and excluded studies' bibliographies. We subsequently performed systematic review and meta-analysis of included randomized controlled trials and observational studies on the topic. Results: We identified 38 studies: 29 randomized controlled trials and nine observational studies. The estimated unadjusted risk of pneumonia was increased in randomized trials: RR 1.61; 95% CI 1.35–1.93, p < 0.001; as well as in observational studies: OR 1.89; 95% CI 1.39–2.58, p < 0·001. Six randomized trials and seven observational studies were useful in estimating unadjusted risk of pneumonia case-fatality: RR 0.91; 95% CI 0.52–1.59, p = 0.74; and OR 0.72; 95% CI 0.59–0.88, p = 0.001, respectively. Twenty-nine randomized trials and six observational studies allowed estimation of unadjusted risk of overall mortality: RR 0.95; 95% CI 0.85–1.05, p = 0.31; and OR 0.79; 95% CI 0.65–0.97, p = 0.02, respectively. Conclusions: Despite a substantial and significant increase in unadjusted risk of pneumonia associated with inhaled corticosteroid use, pneumonia fatality and overall mortality were found not to be increased in randomized controlled trials and were decreased in observational studies.

背景：吸入性糖皮质激素（Inhaled corticosteroids）是重度慢性阻塞性肺疾病（Chronic Obstructive Pulmonary Disease, COPD）患者的临床常用处方药物。现有研究表明，该类药物可升高肺炎发病风险，但并未增加肺炎相关死亡或全因死亡风险。
方法：为进一步探讨吸入性糖皮质激素对COPD患者肺炎发生率及死亡风险的影响，我们检索了1994年至2014年2月4日期间PubMed、Medline、CENTRAL、EMBASE、Scopus、Web of Science以及药企官方临床试验注册网站中的潜在相关文献；此外，我们还对纳入及排除研究的参考文献列表进行了追溯。随后，我们对该主题下纳入的随机对照试验（Randomized Controlled Trial）和观察性研究开展了系统评价与荟萃分析（Meta-analysis）。
结果：本研究共纳入38项研究，其中29项为随机对照试验，9项为观察性研究。随机对照试验分析显示，未校正的肺炎发病风险显著升高：相对危险度（Relative Risk, RR）=1.61，95%置信区间（95% Confidence Interval, 95%CI）为1.35~1.93，p<0.001；观察性研究分析亦得到相似结果：比值比（Odds Ratio, OR）=1.89，95%CI为1.39~2.58，p<0.001。针对肺炎病死率的未校正风险评估，共纳入6项随机对照试验与7项观察性研究，结果显示随机对照试验的RR=0.91，95%CI为0.52~1.59，p=0.74；观察性研究的OR=0.72，95%CI为0.59~0.88，p=0.001。针对全因死亡风险的评估，共纳入29项随机对照试验与6项观察性研究，随机对照试验分析显示RR=0.95，95%CI为0.85~1.05，p=0.31；观察性研究分析显示OR=0.79，95%CI为0.65~0.97，p=0.02。
结论：尽管吸入性糖皮质激素使用与未校正的肺炎发病风险显著且大幅升高相关，但随机对照试验结果显示其并未增加肺炎病死率与全因死亡风险，而观察性研究则显示二者风险有所降低。