Characterizing the phenotypes of post-acute COVID-19 sequelae

Abstract

Individuals with post-acute COVID-19 sequelae (PACS) often experience a range of persistent symptoms, such as fatigue, dyspnea, and brain fog, which highlight the need for extensive phenotypic characterization due to the condition's heterogeneity. The clinical and inflammatory markers associated with these symptoms over time are not yet fully established, and there have been reports of circulating anti-nuclear autoantibodies (ANAs) and new autoimmune diseases in PACS patients. To address these gaps, we conducted a single-centre, longitudinal study (NCT:05459506) involving 118 PACS individuals without prior autoimmune disease, compared with 30 individuals with previous COVID-19 but no persistent symptoms (No-PACS), and 20 individuals with no SARS-CoV-2 infection (No-VIDS). PACS participants underwent rheumatological and, if needed, respiratory consult. We assessed inflammatory mediators and ANAs in serum and sputum, measured neuronal-specific autoantibodies, and used validated quality-of-life questionnaires, patient-reported outcomes (PROs), pulmonary function tests, and the 6-minute walk test to assess overall health and functioning. Participants were followed up after six months for longitudinal analysis. Our findings broadly categorized PACS participants into three main overlapping phenotypes based on PROs: inflammatory, respiratory, and neurocognitive. Within the inflammatory phenotype, a notable subset of PACS patients, previously healthy, exhibited autoimmune diseases with elevated pro-inflammatory cytokines and ANAs. Respiratory burden, identified using the validated St George’s Respiratory Questionnaire, was more closely associated with ongoing systemic inflammation and autoantibodies than with residual lung-localized inflammation. Over time, the inflammatory burden and levels of circulating autoantibodies generally decreased with symptom improvement. Presence of anti-neuronal-specific autoantibodies in PACS participants were indicative of a neurocognitive phenotype. This study highlights the role of systemic inflammation and autoimmunity across various PACS phenotypes. By identifying key markers and their changes over time, our findings pave the way for targeted research, improved diagnostics, and more effective treatments, ultimately advancing the management of PACS.