Timing dependent associations of acute phase laboratory and antibody parameters with post-acute sequelae of SARS-CoV-2 infection in unvaccinated individuals

Introduction Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) affects a substantial minority of individuals after acute COVID-19, and immune dysregulation is widely implicated in its pathogenesis. Reported associations between SARS-CoV-2-specific antibody responses and PASC have nonetheless been inconsistent. Because antibody levels change rapidly in the weeks after symptom onset, the timing of sampling may itself account for much of this heterogeneity, yet few studies have examined humoral responses along the time axis from symptom onset in combination with routinely available hematological, biochemical, and coagulation parameters. Methods Eight hundred seventy-two serial serum samples were retrospectively analyzed from 213 unvaccinated individuals experiencing their first SARS-CoV-2 infection, sampled between April 2020 and June 2021, before vaccine rollout and before the emergence of Omicron; 13 individuals subsequently met the World Health Organization definition of PASC. Sixty-seven parameters, comprising antiviral antibodies, autoantibodies and immune markers, complete blood count, biochemistry and coagulation tests, were compared between groups within four windows defined by days since symptom onset: ≤ 7, 8–14, 15–28, and > 28 days. Results The pattern of association shifted markedly across windows. Within seven days of onset, innate inflammatory and coagulation markers predominated. Between days 8 and 14, when adaptive humoral responses first become measurable, red cell indices differed between groups, with lower mean corpuscular hemoglobin concentration remaining significant when each patient contributed a single value. Anti-spike IgM levels tended to be higher in individuals who later developed PASC, although the difference was not statistically significant. Exploratory multivariable models combining humoral and hematological features discriminated better than either domain alone, although the small number of PASC cases precludes any claim of predictive validity. Discussion These findings identify days 8–14 after symptom onset as a potentially informative window during which acute-phase laboratory parameters, and possibly early humoral responses, differ between individuals who do and do not subsequently develop PASC, and suggest that the timing and quality of the early antibody response, rather than antibody magnitude measured at a single late time point, merit systematic investigation in PASC.