Multiple early factors anticipate post-acute COVID-19 sequelae

Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2–3 months later), integrated with clinical data and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific auto-antibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes, exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time, leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies. [Display omitted] •Longitudinal multi-omics associate PASC with auto-antibodies, viremia, and comorbidities•Reactivation of latent viruses during initial infection may contribute to PASC•Subclinical auto-antibodies negatively correlate with anti-SARS-CoV-2 antibodies•Gastrointestinal PASC uniquely present with post-acute expansion of cytotoxic T cells By correlating patient symptoms with in-depth profiling of blood cells and plasma components throughout COVID-19 infection, this study identifies factors that may predict sustained disease.