Metabolic Dysfunction-Associated Steatotic Liver Disease Shapes a Distinct Semaphorin-Cytokine Immune Signature in Severe Community-Acquired Pneumonia.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a modulator of infection severity, yet its impact on the immune response in severe community-acquired pneumonia (sCAP) remains poorly understood. In this prospective cohort study of 108 adults with sCAP, we evaluated the prevalence and prognostic impact of MASLD and performed pathogen-stratified immune profiling of cytokines and semaphorins on hospital days 1 and 5. MASLD was present in 50% of patients and independently associated with early respiratory failure (OR 3.8) and vasopressor-dependent shock (OR 4.0), despite similar sCAP severity at baseline. MASLD patients exhibited distinct immune profiles, including elevated baseline serum levels of SEMA3A, SEMA7A, IL-2, IL-10, IL-17A, CXCL10, and TGF-β1, and reduced SEMA5A. By day 5, the MASLD group exhibited a greater decline in pro-inflammatory mediators compared to non-MASLD patients but failed to upregulate reparative mediators such as SEMA4D and TGF-β1, unlike the non-MASLD group. These kinetics may suggest a maladaptive immune response in MASLD, potentially consistent with early immune exhaustion. Immunokinetic patterns were pathogen-specific, including transient increase in IL-17A and IL-10 in Legionella and Mycoplasma infections, and CXCL10, IL-2, IL-17A, TGF-β1 and IL-10 in influenza. Serum IL-10, CXCL10, SEMA3F, SEMA4D and SEMA7A correlated with organ failure and sCAP complications. These findings underscore the clinical importance of the lung-liver axis and suggest that semaphorins could serve as valuable prognostic biomarkers for identifying high-risk patients.