Integrated humoral and inflammatory signatures predict outcomes in severe COVID ‐19: a 14‐day longitudinal analysis

Background: Severe COVID-19 is marked by profound immune dysregulation, yet the interplay between humoral and inflammatory responses that determines clinical outcomes in critically ill patients remains incompletely understood. We evaluated longitudinal antibody and soluble immune mediator profiles to identify prognostic signatures associated with survival in severe COVID-19. Methods: In this prospective longitudinal study, peripheral blood samples were collected from 30 unvaccinated adults with severe COVID-19 admitted to the intensive care unit (ICU) and 30 healthy controls. Serum concentrations of SARS-CoV-2-specific IgM, IgG and IgA antibodies (S1, RBD and N) and 27 cytokines, chemokines and growth factors were quantified at ICU admission (D0), Day 7 (D7) and Day 14 (D14) using Luminex multiplex assays. Patients were classified according to clinical outcome: discharge (DIS) or death (DEA). Results: DIS and DEA patients exhibited distinct immunological trajectories. DEA patients showed early elevations of IgM anti-N and IgM anti-RBD at D0, accompanied by increased IFN-γ. At D7, persistently elevated TNF-α and FGF-basic differentiated nonsurvivors, while by D14, higher levels of CXCL8, CCL4, CXCL10 and G-CSF were strongly associated with mortality. In contrast, DIS patients exhibited more coordinated immune regulation, including sustained IL-13 production and higher IgA anti-S1 and IgA anti-RBD levels. Conclusions: Integrated humoral and inflammatory signatures, particularly early IgM anti-N/anti-RBD responses and sequential increases in IFN-γ, TNF-α, FGF-basic, CXCL8, CCL4, CXCL10 and G-CSF, highlight immune signatures associated with poor outcomes. IL-13 and coordinated antibody interactions may reflect protective immune pathways. These findings highlight the prognostic value of multidimensional immune monitoring in severe COVID-19.