First glimpses into the mechanisms of Long COVID.

Post-acute sequelae of COVID-19 (PASC), sometimes referred to as ‘Long COVID’, are observed in 30–70% of individuals post-SARS-CoV-2 infection. These can include loss of sense of smell, memory loss, fatigue, shortness of breath, gastrointestinal (GI) distress and other symptoms. Autoimmune processes and unresolved viral fragments have been proposed as causative, but experimental validation for these hypotheses is lacking. Now, a longitudinal multi-omic study of >300 patients by Su et al. reveals that some factors present at disease onset, such as pre-existing type 2 diabetes, latent EBV reactivation, circulating SARS-CoV-2 RNA fragments as well as specific autoantibodies, associate with specific PASC. The authors identified four different immune endotypes at 2–3 months post disease onset that differentially associate with PASC. Interestingly, they find that bystander activation of CMV-specific T cells during acute disease is associated with GI PASC. A second study by Vijayakumar et al. shows persistent immunological and proteomic abnormalities in the lungs of patients with ongoing respiratory symptoms after COVID-19, with continuing activation of CD8+ T cells and elevated levels of proteins associated with apoptosis, tissue repair and epithelial injury.