Immunological and clinical markers of post-acute sequelae of COVID-19: Insights from mild and severe cases six months post-infection

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SUMMARY Post-acute sequelae of COVID-19 (PASC) is a complex and multifaceted clinical challenge requiring to emphasize its underlying pathophysiological mechanisms. This study assessed hundreds of virological, serological, immunological, and tissue damage biomarkers in two patient cohorts who experienced mild (n=270) or severe (n=188) COVID-19, 6 to 9 months post-initial infection, and in which 40% and 57.4% of patients, respectively, developed PASC. Blood analysis showed that mains differences observed in humoral, viral, and biological biomarkers were associated with the initial COVID-19 severity, rather than being specifically linked to PASC. However, patients with PASC displayed altered CD4 + and CD8 + memory T-cell subsets, with higher cytokine-secreting cells and increased terminally differentiated CD45RA + effector memory T cells (TEMRA). Elevated SARS-CoV-2-specific T cells responsive to nucleocapsid/membrane proteins with a TEMRA phenotype were also observed. A random forest model identified these features and initial symptom duration as top variables discriminating PASC, achieving over 80% classification accuracy. Highlights Nine months post-initial SARS-CoV-2 infection, over 40% of patients developed PASC Regardless of PASC, the initial disease form influenced the main immune differences PASC led to altered memory T-cell subsets with elevated TEMRA phenotype PASC presence is associated with disease form, initial symptom count and duration

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