Spatially distinct immune signatures in ARDS of different bacterial origin

Background: Acute respiratory distress syndrome (ARDS) is a life-threatening respiratory failure. It can be triggered by infections such as bacterial pneumonia or as secondary condition upon acute pancreatitis. Although clinical symptoms are similar, immune responses vary depending on etiology. Understanding these immune signatures is critical for guiding personalized ARDS treatments. Methods: Bronchoalveolar fluid (BALf) and peripheral blood were collected at ICU admission from ARDS patients with Legionella (n=7-9), Streptococcus pyogenes (n=3-9), S. pneumoniae (n=7-14), or pancreatitis (n=5-7). A panel of 30 cytokines was analyzed in blood and BALf using LEGENDplex immuno-assays. To analyze the origin of the cytokine responses, excessive immune phenotyping of peripheral blood mononuclear cells was performed using multicolor spectral flow cytometry. Results: The mean age of patients was 57 years with 22.5% females. All patients required mechanical ventilation, with some on VV-ECMO. Immune signatures varied significantly by ARDS cause. In serum, S. pneumoniae infection showed broad inflammation with high IL-2, IL-4, IL-8, IL-12p70, IL-13, TNF-α, LT-α, CCL3, and CCL5 expression. In contrast Legionella infection triggered an interferon-γ driven response, while S. pyogenes induced a Th17 dominated profile. Control patients with pancreatitis showed milder systemic inflammation. In line, several immune cell clusters were distinct between ARDS subtypes including T cell and myeloid cell clusters. Notably, in BALf, cytokine profiles showed spatial differences compared with blood and all ARDS subtypes revealed a local chemokine expression with high IL-8, CXCL1, and CXCL10 in the lungs. Conclusion: Different ARDS etiology drives spatially distinct immune responses in blood and lungs. A deep understanding of systemic and local immune response pattern may help guide towards more precise immunotherapies. Publication History Article published online: 04 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany