预测社区获得性肺炎患者接受糖皮质激素辅助治疗的获益情况：一项基于随机试验的数据驱动分析

Predicting benefit from adjuvant therapy with corticosteroids in community-acquired pneumonia: a data-driven analysis of randomised trials.

作者信息

Smit Jim M, Van Der Zee Philip A, Stoof Sara C M, Van Genderen Michel E, Snijders Dominic, Boersma Wim G, Confalonieri Paola, Salton Francesco, Confalonieri Marco, Shih Mei-Chiung, Meduri Gianfranco U, Dequin Pierre-François, Le Gouge Amélie, Lloyd Melanie, Karunajeewa Harin, Bartminski Grzegorz, Fernández-Serrano Silvia, Suárez-Cuartín Guillermo, van Klaveren David, Briel Matthias, Schönenberger Christof M, Steyerberg Ewout W, Gommers Diederik A M P J, Bax Hannelore I, Bos Wilem Jan W, van de Garde Ewoudt M W, Wittermans Esther, Grutters Jan C, Blum Claudine A, Christ-Crain Mirjam, Torres Antoni, Motos Ana, Reinders Marcel J T, Van Bommel Jasper, Krijthe Jesse H, Endeman Henrik

机构信息

Department of Intensive Care, Erasmus MC-University Medical Center Rotterdam, Rotterdam, Netherlands; Pattern Recognition & Bioinformatics Group, Delft University of Technology, Delft, Netherlands.

Department of Intensive Care, Erasmus MC-University Medical Center Rotterdam, Rotterdam, Netherlands; Department of Pulmonary Medicine, Erasmus MC-University Medical Center Rotterdam, Rotterdam, Netherlands.

出版信息

Lancet Respir Med. 2025 Mar;13(3):221-233. doi: 10.1016/S2213-2600(24)00405-3. Epub 2025 Jan 29.

DOI:10.1016/S2213-2600(24)00405-3

PMID:39892408

Abstract

BACKGROUND

Despite several randomised controlled trials (RCTs) on the use of adjuvant treatment with corticosteroids in patients with community-acquired pneumonia (CAP), the effect of this intervention on mortality remains controversial. We aimed to evaluate heterogeneity of treatment effect (HTE) of adjuvant treatment with corticosteroids on 30-day mortality in patients with CAP.

METHODS

In this individual patient data meta-analysis, we included RCTs published before July 1, 2024, comparing adjuvant treatment with corticosteroids versus placebo in patients hospitalised with CAP. The primary endpoint was 30-day all-cause mortality, collected across all trials, and analyses followed the intention-to-treat principle. We analysed HTE using risk and effect modelling. For risk modelling, patients were classified as having less severe or severe CAP based on the pneumonia severity index (PSI), comparing PSI class I-III versus class IV-V. For effect modelling, we trained a corticosteroid-effect model on six trials and externally validated it using data from two trials, received after model preregistration. This model classified patients into two groups: no predicted benefit and predicted benefit from adjuvant treatment with corticosteroids. The literature search was registered on PROSPERO, CRD42022380746.

FINDINGS

We included eight RCTs with 3224 patients. Across all eight trials, 246 (7·6%) patients died within 30 days (106 [6·6%] of 1618 in the corticosteroid group vs 140 [8·7%] of 1606 in the placebo group; odds ratio [OR] 0·72 [95% CI 0·56-0·94], p=0·017). The corticosteroid-effect model, which selected C-reactive protein (CRP), showed significant HTE during external validation in the two most recent trials. In these trials, 154 (11·4%) of 1355 patients died within 30 days (88 [13·1%] of 671 in the placebo group vs 66 [9·6%] of 684 in the corticosteroid group; OR 0·71 [95% CI 0·50-0·99], p=0·044). Among patients predicted to have no benefit (CRP ≤204 mg/L, n=725), no significant effect was observed (OR 0·98 [95% CI 0·63-1·50]), whereas for those with predicted benefit (CRP >204 mg/L, n=630), 39 (13·0%) of 301 patients died in the placebo group compared with 20 (6·1%) of 329 in the corticosteroid group (0·43 [0·25-0·76], p=0·026). No significant HTE was found between less severe CAP (PSI class I-III, n=229) and severe CAP (PSI class IV-V, n=1126). Corticosteroid therapy significantly increased hyperglycaemia risk (44 [12·8%] of 344 in the placebo group vs 84 [24·8%] of 339 in the corticosteroid group; OR 2·50 [95% CI 1·63-3·83], p<0·0001) and hospital re-admission risk (30 [3·7%] of 814 in the placebo group vs 57 [7·0%] of 819 in the corticosteroid group; 1·95 [1·24-3·07], p=0·0038).

INTERPRETATION

Overall, adjuvant therapy with corticosteroids significantly reduces 30-day mortality in patients hospitalised with CAP. The treatment effect varied significantly among subgroups based on CRP concentrations, with a substantial mortality reduction observed only in patients with high baseline CRP.

FUNDING

None.

摘要

背景

尽管有多项关于社区获得性肺炎（CAP）患者使用皮质类固醇辅助治疗的随机对照试验（RCT），但这种干预措施对死亡率的影响仍存在争议。我们旨在评估皮质类固醇辅助治疗对CAP患者30天死亡率的治疗效果异质性（HTE）。

方法

在这项个体患者数据荟萃分析中，我们纳入了2024年7月1日前发表的RCT，比较皮质类固醇辅助治疗与安慰剂在CAP住院患者中的疗效。主要终点是所有试验中收集的30天全因死亡率，分析遵循意向性治疗原则。我们使用风险和效应模型分析HTE。对于风险建模，根据肺炎严重程度指数（PSI）将患者分为轻度或重度CAP，比较PSI I-III级与IV-V级。对于效应建模，我们在六项试验中训练了皮质类固醇效应模型，并使用模型预注册后从两项试验中获得的数据进行外部验证。该模型将患者分为两组：无预测获益组和皮质类固醇辅助治疗有预测获益组。文献检索已在PROSPERO上注册，注册号为CRD42022380746。

结果

我们纳入了八项RCT，共3224例患者。在所有八项试验中，246例（7.6%）患者在30天内死亡（皮质类固醇组1618例中的106例[6.6%] vs安慰剂组1606例中的140例[8.7%]；比值比[OR] 0.72 [95% CI 0.56-0.94]，p = 0.017）。选择C反应蛋白（CRP）的皮质类固醇效应模型在两项最新试验的外部验证中显示出显著的HTE。在这些试验中，1355例患者中有154例（11.4%）在30天内死亡（安慰剂组671例中的88例[13.1%] vs皮质类固醇组684例中的66例[9.6%]；OR 0.71 [95% CI 0.50-0.99]，p = 0.044）。在预测无获益的患者（CRP≤204 mg/L，n = 725）中，未观察到显著效果（OR 0.98 [95% CI 0.63-1.50]），而对于有预测获益的患者（CRP>204 mg/L，n = 630），安慰剂组301例中有39例（13.0%）死亡，皮质类固醇组329例中有20例（6.1%）死亡（0.43 [0.25-0.76]，p = 0.026）。在轻度CAP（PSI I-III级，n = 229）和重度CAP（PSI IV-V级，n = 1126）之间未发现显著的HTE。皮质类固醇治疗显著增加了高血糖风险（安慰剂组344例中的44例[12.8%] vs皮质类固醇组339例中的84例[24.8%]；OR 2.50 [95% CI 1.63-3.83]，p<0.0001）以及医院再入院风险（安慰剂组814例中的30例[3.7%] vs皮质类固醇组819例中的57例[7.0%]；1.95 [1.24-3.07]，p = 0.0038）。