Alveolar dysregulation of host response in pneumonia and ARDS: implications for immune modulation and infection

Respiratory failure due to pneumonia and acute respiratory distress syndrome (ARDS) remains a major cause of morbidity and mortality in the intensive care unit. The alveolar compartment plays a central role in both pathogen clearance and tissue injury, yet its biology is poorly captured by systemic measurements. Growing evidence shows that dysregulation of alveolar host responses drives disease progression, shapes susceptibility to secondary infections, and influences recovery.

Community-, hospital-, and ventilator-associated pneumonia differ in microbial drivers and host responses, but all share a pattern of localized inflammation. In most cases, pathogens are rapidly controlled following antimicrobial treatment, while alveolar inflammation persists. This persistence likely reflects self-reinforcing cycles between epithelial injury, neutrophil activity, and monocyte-macrophage dysfunction. Mechanical ventilation further disrupts local defenses, promoting microbial overgrowth and ventilator-associated pneumonia.In ARDS, diffuse alveolar damage initiates an early influx of neutrophils and monocyte-derived macrophages. Although peripheral blood has been used to identify systemic inflammatory subphenotypes, molecular signatures in the alveolar compartment often differ and may provide complementary biological information. Patients may diverge into distinct alveolar immune trajectories, ranging from sustained alveolar hyperinflammation to immune exhaustion. These divergent trajectories influence downstream repair, determining whether patients achieve epithelial recovery or develop fibrotic remodeling.Alveolar immune dysregulation also creates a permissive niche for viral and fungal pathogens. Pulmonary reactivation of herpes simplex virus or cytomegalovirus and fungal infections with Aspergillus frequently occur in critically ill patients and may reflect impaired local host defense. These processes are associated with prolonged mechanical ventilation and illustrate how impaired alveolar defenses may sustain injury and propagate complications.

Pneumonia and ARDS share common pathways of alveolar immune dysregulation that are not adequately captured by systemic profiling alone. Integrating systemic and alveolar immune assessment, including their concordance and discordance, may improve patient stratification, facilitate identification of treatable traits, and support the development of more personalized, compartment-informed therapeutic strategies, including both immunomodulatory and pathogen-directed interventions. A more refined understanding of compartment-specific host responses will be key to advancing these approaches.