de Brabander Justin, Michels Erik H A, Butler Joe M, Reijnders Tom D Y, van Engelen Tjitske S R, Leite Giuseppe G F, Paling Fleur P, Klarenbeek Augustijn M, Sie Daoud L S, Boyer Roxane E, Sweeney Timothy E, Bonten Marc J M, Timbermont Leen, Malhotra-Kumar Surbhi, Kluytmans Jan A J W, Peters-Sengers Hessel, van der Poll Tom
Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands.
Eur Respir J. 2025 Apr 24;65(4). doi: 10.1183/13993003.00592-2024. Print 2025 Apr.
Immune response dysregulation has been implicated in the development of intensive care unit (ICU)-acquired pneumonia. We aimed to determine differences in the longitudinal blood transcriptional response between patients who develop ICU-acquired pneumonia (cases) and those who do not (controls).
We performed a case-cohort study in mechanically ventilated trauma and surgery patients with ICU stays >2 days, enrolled in 30 hospitals across Europe. We collected blood for RNA sequencing at baseline, day 7 and (in cases) the day of pneumonia diagnosis. We performed gene set enrichment analysis and analysed longitudinal gene expression changes using linear mixed models. External validation was performed using an independent trauma cohort.
We enrolled 113 cases and 115 controls, with similar baseline characteristics. At baseline (median 2 days after ICU admission), cases showed upregulated gene pathways relating to innate immunity, haemostasis and metabolism, and downregulated adaptive immune pathways. These changes persisted at the day of pneumonia diagnosis (median 6 days, compared to day 7 in controls). In the longitudinal comparison, cases exhibited enhanced upregulation of innate immunity, adaptive immunity and haemostasis pathways, along with enhanced downregulation of metabolism pathways, relative to controls (all p<0.00001, except haemostasis p<0.05). These findings were largely externally validated. Cases had higher quantitative sepsis response signature scores (p<0.001), reflective of immune dysregulation.
Patients developing ICU-acquired pneumonia exhibit distinct blood transcriptional responses shortly after ICU admission and in the subsequent path to pneumonia, suggestive of broad immune dysfunction with both immunosuppressive and inflammatory features.
免疫反应失调与重症监护病房（ICU）获得性肺炎的发生有关。我们旨在确定发生ICU获得性肺炎的患者（病例组）与未发生者（对照组）之间血液转录反应的纵向差异。
我们在欧洲30家医院对入住ICU超过2天的机械通气创伤和手术患者进行了一项病例队列研究。我们在基线、第7天以及（病例组）肺炎诊断当天采集血液用于RNA测序。我们进行了基因集富集分析，并使用线性混合模型分析纵向基因表达变化。使用独立的创伤队列进行外部验证。
我们纳入了113例病例和115例对照，他们具有相似的基线特征。在基线时（ICU入院后中位数为2天），病例组显示与固有免疫、止血和代谢相关的基因通路上调，而适应性免疫通路下调。这些变化在肺炎诊断当天（中位数为6天，对照组为第7天）仍然存在。在纵向比较中，与对照组相比，病例组的固有免疫、适应性免疫和止血通路上调增强，代谢通路下调增强（所有p<0.00001，止血通路p<0.05除外）。这些发现大多在外部得到了验证。病例组的定量脓毒症反应特征评分更高（p<0.001），反映了免疫失调。
发生ICU获得性肺炎的患者在ICU入院后不久以及随后发生肺炎的过程中表现出独特的血液转录反应，提示存在具有免疫抑制和炎症特征的广泛免疫功能障碍。
