Extensive immunological and inflammatory perturbation underpins the respiratory sequelae of post-acute COVID-19

Post-acute 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 CT), 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. R-PASC patients 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 R-PASC patients, whereas humoral responses showed minimal association with disease pathophysiology. Moreover, prolonged activation of complement classical and alternative pathway in R-PASC patients is associated with worsening respiratory parameters, while mannose-binding lectin (MBL) within the lectin pathway exhibits protective correlations with pulmonary tissue-function preservation. Overall, our study delineates the extensively perturbed immune–inflammation–organ dysfunction in R-PASC patients, thereby providing valuable insights into the pathogenesis of this condition and highlighting potential targets for therapeutic intervention.