TY - JOUR
T1 - Predicting benefit from adjuvant therapy with corticosteroids in community-acquired pneumonia
T2 - a data-driven analysis of randomised trials
AU - Smit, Jim M.
AU - Van Der Zee, Philip A.
AU - Stoof, Sara C.M.
AU - Van Genderen, Michel E.
AU - Snijders, Dominic
AU - Boersma, Wim G.
AU - Confalonieri, Paola
AU - Salton, Francesco
AU - Confalonieri, Marco
AU - Shih, Mei Chiung
AU - Meduri, Gianfranco U.
AU - Dequin, Pierre François
AU - Le Gouge, Amélie
AU - Lloyd, Melanie
AU - Karunajeewa, Harin
AU - Bartminski, Grzegorz
AU - Fernández-Serrano, Silvia
AU - Suárez-Cuartín, Guillermo
AU - van Klaveren, David
AU - Briel, Matthias
AU - Schönenberger, Christof M.
AU - Steyerberg, Ewout W.
AU - Gommers, Diederik A.M.P.J.
AU - Bax, Hannelore I.
AU - Bos, Wilem Jan W.
AU - van de Garde, Ewoudt M.W.
AU - Wittermans, Esther
AU - Grutters, Jan C.
AU - Blum, Claudine A.
AU - Christ-Crain, Mirjam
AU - Torres, Antoni
AU - Motos, Ana
AU - Reinders, Marcel J.T.
AU - Van Bommel, Jasper
AU - Krijthe, Jesse H.
AU - Endeman, Henrik
N1 - Publisher Copyright:
© 2025 Elsevier Ltd
PY - 2025/1/29
Y1 - 2025/1/29
N2 - 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], pinteraction=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.
AB - 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], pinteraction=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.
UR - http://www.scopus.com/inward/record.url?scp=85216461339&partnerID=8YFLogxK
U2 - 10.1016/S2213-2600(24)00405-3
DO - 10.1016/S2213-2600(24)00405-3
M3 - Article
C2 - 39892408
AN - SCOPUS:85216461339
SN - 2213-2600
VL - 13
SP - 221
EP - 233
JO - The Lancet Respiratory Medicine
JF - The Lancet Respiratory Medicine
IS - 3
ER -