Respiratory burden in post-acute COVID-19 sequelae: a longitudinal study of airway and systemic inflammation and clinical outcomes

Background: It is unclear why patients with post-acute coronavirus disease 2019 sequelae (PACS) often present with persistent respiratory symptoms. We hypothesised that autoimmune inflammatory biomarkers may be associated with the persistence and/or resolution of these symptoms. We performed symptom-based unsupervised cluster analysis to evaluate airway and systemic immune responses in PACS participants over time. Methods: Individuals with confirmed SARS-CoV-2 infection, a persistent range of PACS symptoms for >12 weeks and no previous diagnosis of chronic lung disease were recruited and assessed at a 6-month follow-up. Assessments included St George's Respiratory Questionnaire (SGRQ), pulmonary function testing, 6-min walk test and analysis of blood and sputum inflammatory markers. Results: Unsupervised clustering based on SGRQ domains of 85 PACS individuals revealed four clusters. Cluster 1 (14%) reported no impairment and normal lung function, whereas clusters 2 (24%) and 3 (36%) were moderately symptomatic. Cluster 3 had a greater proportion of reduced lung function. Cluster 4 (26%) reported severe impairment across all SGRQ domains, with significantly lower 6-min walk distance, dyspnoea and fatigue. Clusters 3 and 4 had evidence of systemic inflammation (C-reactive protein and anti-SS-B/La). Sputum analysis showed no evidence of airway inflammation in any cluster. After 6 months, improved symptoms in 43% of individuals correlated with increased forced expiratory volume in 1 s percentage predicted and low serum interleukin-8 (p<0.05) over time. Multivariate regression suggested that a reduction in serum anti-SS-B/La IgG over 6 months was associated with improvement of SGRQ impact (t=3.17, p=0.003) and activity (t=2.04, p=0.005). Conclusions: A subset of previously healthy PACS patients have clinically relevant respiratory burden as identified by unbiased SGRQ domain analysis associated with systemic inflammation and autoantibodies.