tetano
Editor, Senior Moderator
Clin Microbiol Infect
. 2026 May 9:S1198-743X(26)00235-1.
doi: 10.1016/j.cmi.2026.05.002. Online ahead of print.
Early antifungal prophylaxis fails to prevent influenza-associated pulmonary aspergillosis in the ICU: a target trial emulation
Peng Li[SUP] 1 [/SUP], Shengnan Xu[SUP] 2 [/SUP], Chao Chen[SUP] 3 [/SUP], Xingang Hu[SUP] 4 [/SUP], Yajun Li[SUP] 4 [/SUP], Jinlai Wang[SUP] 2 [/SUP], Leilei Guo[SUP] 5 [/SUP], Bo Qiao[SUP] 6 [/SUP], Yuanyuan Li[SUP] 7 [/SUP], Yansheng Zhou[SUP] 8 [/SUP], Xiufeng Hu[SUP] 9 [/SUP], Yanyan Guo[SUP] 10 [/SUP], Bin Hu[SUP] 11 [/SUP], Sangang Zheng[SUP] 12 [/SUP], Junping Liu[SUP] 13 [/SUP], Pengli Fan[SUP] 14 [/SUP], Jiangfeng Zhang[SUP] 15 [/SUP], Junzhe Bao[SUP] 16 [/SUP], Mingjie Sun[SUP] 17 [/SUP]
Affiliations
Objectives: To evaluate whether early antifungal prophylaxis reduces the incidence of influenza-associated pulmonary aspergillosis (IAPA) in critically ill adults with influenza.
Methods: We emulated a target trial using a multicenter cohort of critically ill adults with influenza from 48 ICUs (2023-2025). The intervention was antifungal prophylaxis within 24 hours of ICU admission versus no prophylaxis. We used directed acyclic graphs and inverse probability of treatment weighting (IPTW) to control for confounding. The primary outcome was IAPA incidence after the first 48 hours of ICU stay. Secondary outcomes included hepatotoxicity, nephrotoxicity, 14-day non-death ICU discharge, and 28-day all-cause mortality.
Results: Among 2919 eligible patients, 448 (15.3%) received early prophylaxis. The overall incidence of IAPA was 7.0%. In the crude analysis, IAPA occurred in 16 of 448 (3.6%) patients in the prophylaxis group versus 189 of 2471 (7.6%) in the no prophylaxis group, corresponding to a reduced hazard (HR 0.46, 95% CI 0.27-0.76). However, after IPTW adjustment to emulate randomization, prophylaxis showed no significant protective effect (HR 0.88, 95% CI 0.48-1.63; P=0.693). Subgroup analysis revealed significant effect modification by ICU-specific baseline IAPA incidence (P for interaction <0.001), with a protective association observed only in the highest incidence tertile (HR 0.28, 95% CI 0.08-0.91). Prophylaxis was associated with an increased risk of hepatotoxicity (adjusted OR 1.58, 95% CI 1.35-1.86; P<0.001) but showed no significant effect on nephrotoxicity, ICU discharge, or mortality.
Conclusions: Early antifungal prophylaxis did not reduce IAPA incidence overall and was associated with increased hepatotoxicity, without improving clinical outcomes. The observed heterogeneity across ICUs suggests that a universal prophylaxis strategy is not justified.
Keywords: Antifungal prophylaxis; Directed acyclic graphs; Influenza-associated pulmonary aspergillosis; Target trial emulation.
. 2026 May 9:S1198-743X(26)00235-1.
doi: 10.1016/j.cmi.2026.05.002. Online ahead of print.
Early antifungal prophylaxis fails to prevent influenza-associated pulmonary aspergillosis in the ICU: a target trial emulation
Peng Li[SUP] 1 [/SUP], Shengnan Xu[SUP] 2 [/SUP], Chao Chen[SUP] 3 [/SUP], Xingang Hu[SUP] 4 [/SUP], Yajun Li[SUP] 4 [/SUP], Jinlai Wang[SUP] 2 [/SUP], Leilei Guo[SUP] 5 [/SUP], Bo Qiao[SUP] 6 [/SUP], Yuanyuan Li[SUP] 7 [/SUP], Yansheng Zhou[SUP] 8 [/SUP], Xiufeng Hu[SUP] 9 [/SUP], Yanyan Guo[SUP] 10 [/SUP], Bin Hu[SUP] 11 [/SUP], Sangang Zheng[SUP] 12 [/SUP], Junping Liu[SUP] 13 [/SUP], Pengli Fan[SUP] 14 [/SUP], Jiangfeng Zhang[SUP] 15 [/SUP], Junzhe Bao[SUP] 16 [/SUP], Mingjie Sun[SUP] 17 [/SUP]
Affiliations
- PMID: 42114720
- DOI: 10.1016/j.cmi.2026.05.002
Objectives: To evaluate whether early antifungal prophylaxis reduces the incidence of influenza-associated pulmonary aspergillosis (IAPA) in critically ill adults with influenza.
Methods: We emulated a target trial using a multicenter cohort of critically ill adults with influenza from 48 ICUs (2023-2025). The intervention was antifungal prophylaxis within 24 hours of ICU admission versus no prophylaxis. We used directed acyclic graphs and inverse probability of treatment weighting (IPTW) to control for confounding. The primary outcome was IAPA incidence after the first 48 hours of ICU stay. Secondary outcomes included hepatotoxicity, nephrotoxicity, 14-day non-death ICU discharge, and 28-day all-cause mortality.
Results: Among 2919 eligible patients, 448 (15.3%) received early prophylaxis. The overall incidence of IAPA was 7.0%. In the crude analysis, IAPA occurred in 16 of 448 (3.6%) patients in the prophylaxis group versus 189 of 2471 (7.6%) in the no prophylaxis group, corresponding to a reduced hazard (HR 0.46, 95% CI 0.27-0.76). However, after IPTW adjustment to emulate randomization, prophylaxis showed no significant protective effect (HR 0.88, 95% CI 0.48-1.63; P=0.693). Subgroup analysis revealed significant effect modification by ICU-specific baseline IAPA incidence (P for interaction <0.001), with a protective association observed only in the highest incidence tertile (HR 0.28, 95% CI 0.08-0.91). Prophylaxis was associated with an increased risk of hepatotoxicity (adjusted OR 1.58, 95% CI 1.35-1.86; P<0.001) but showed no significant effect on nephrotoxicity, ICU discharge, or mortality.
Conclusions: Early antifungal prophylaxis did not reduce IAPA incidence overall and was associated with increased hepatotoxicity, without improving clinical outcomes. The observed heterogeneity across ICUs suggests that a universal prophylaxis strategy is not justified.
Keywords: Antifungal prophylaxis; Directed acyclic graphs; Influenza-associated pulmonary aspergillosis; Target trial emulation.