Distinct Cytokine Signatures and Antibody Neutralization Capacity Differentiate Post-Acute Sequelae of COVID-19 From Recovered Individuals Despite Comparable T Cell Responses.

High prevalence of post-acute sequelae of COVID-19 (PASC/long COVID) has led to the determination of the pathophysiology of PASC. In a hospital-based cross-sectional survey, we assessed the clinical and immunological parameters in a set of 67 PASC and 81 recovered individuals from COVID-19 (N-PASC), to identify the immune biomarkers associated with the mechanistic cornerstone of this condition. PASC had higher chronic comorbidities, hospitalization, and ICU admissions during the COVID-19 pandemic compared to the N-PASC group. Though comparable SARS-CoV-2-specific antibodies were detected across the groups, their functionality (NAbs) was significantly higher in the N-PASC. PASC patients exhibited features of immune dysregulation, characterized by altered coordination between cellular and humoral immune responses despite broadly comparable cytokine profiles and T-cell responses. ROC analysis in hospitalized PASC and hospitalized N-PASC subjects sampled at 1, 2, and 3 years post COVID-19 supported the utility of IL-6 as a biomarker for long-term inflammatory activity. Higher FGF-basic levels in the hospitalized PASC compared to non-hospitalized PASC highlighted a potential association between elevated growth factor signaling and severity-related immune dysregulation, tissue damage that may have utility as a biomarker candidate. Our analysis supports a dysregulated crosstalk between humoral and cellular immunity in PASC patients, which could be leading to inflammation and persistent clinical symptoms associated with this debilitating condition. In conclusion, comparable T-cell and cytokine responses among long COVID and recovered individuals suggest that persistent symptoms are unlikely to be driven by impaired antiviral immunity, underscoring the potential role of immune dysregulation.