Extensive Immunological and Inflammatory Perturbation Underpins the Respiratory Sequelae of Postacute COVID-19

Postacute sequelae of COVID-19 (PASC), a multisystem disorder with prevalent respiratory manifestations, affecting millions of individuals worldwide, yet the organ-/system-specific PASC pathogenesis and targeted interventions remain largely undefined. In this longitudinal cohort study of individuals followed up at 4 (n = 57) and 7 months (n = 54) after the Omicron BA.5 outbreak in China, we comprehensively analyzed physician-administered PASC symptom assessments, clinical respiratory evaluations (pulmonary function and chest computed tomography), immunological response profiles, and inflammatory markers. Our findings demonstrated that patients with respiratory system-specific PASC (R-PASC) endure long-term pulmonary function impairment (restrictive ventilation and diffusion dysfunction), sustained severe residual lung lesions (predominant fibrosis), and chronic systemic inflammatory responses. Patients with R-PASC exhibited enhanced SARS-CoV-2-specific T-cell responses, whereas in the control group, moderate-magnitude and polyfunctional virus-specific T-cell response correlated with improved lung function and alleviated inflammation. Sustained neutralizing antibody titers were also observed in patients with R-PASC, whereas humoral responses showed minimal association with disease pathophysiology. Moreover, prolonged activation of complement classical and alternative pathway in patients with R-PASC is associated with worsening respiratory parameters, whereas mannose-binding lectin within the lectin pathway exhibits protective correlations with pulmonary tissue function preservation. Overall, our study delineates the extensively perturbed immune-inflammation-organ dysfunction in patients with R-PASC, thereby providing valuable insights into the pathogenesis of this condition and highlighting potential targets for therapeutic intervention.