Deciphering the compartmentalized host response in sepsis secondary to community-acquired pneumonia

Abstract

Sepsis, currently defined as a complex condition resulting from a dysregulated host response to infection leading to lethal organ dysfunction, is a major global health concern and a leading cause of both morbidity and mortality worldwide. Emerging evidence suggests that immune compartmentalization, variation in the immune response between the circulation and the tissue microenvironment, plays a vital role in the clinical trajectory of sepsis. In sepsis secondary to community-acquired pneumonia (CAP), distinct immune cell distribution and localization of cytokine production may contribute to divergent inflammatory signatures between bronchoalveolar lavage fluid (BALF) and plasma. This project aims to identify compartment-specific immune responses which would aid in further uncovering the pathophysiology of pneumosepsis. This project was a prospective observational single-center study in the intensive care unit (ICU) within Mater Dei Hospital, Malta, forming part of the Molecular Endotype-Specific Dynamics of Lung Endothelial Barrier Integrity in Sepsis (MENDSEP) study. Peripheral blood and BALF samples were obtained from 29 consenting critically ill patients diagnosed with sepsis secondary to CAP (pneumosepsis) between 2023 and 2025. In addition, 16 age, sex, and co-morbidity-matched controls were recruited from the community and from St Vincent de Paul Residence (SVPR). The levels of various cytokines and markers in blood and BALF of septic samples were quantified using multiplex immunoassays. Cytokine analysis revealed marked immune compartmentalization in pneumosepsis. Pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), anti-inflammatory cytokines (IL-10) and anti-viral interferons (IFN-α, IFN-β, IFN-γ) were all found to be significantly enriched in BALF relative to plasma (p<0.001), indicating localized inflammatory and antiviral activity. Conversely, angiopoietin-2 (Ang-2) and the Ang-2:Ang-1 ratio were elevated in the circulation, representing systemic endothelial dysfunction. These findings underscore the compartmentalized nature of the immune response in sepsis, with localized pulmonary inflammation alongside systemic endothelial dysfunction. This study lays the groundwork to further elucidate the complex pathophysiology of sepsis, in improving early diagnosis, and the development of compartment-specific therapeutic targets.