Heterogeneity of Immunological, Coagulation and Complement Clustering to Viral Challenge and Clinical Relevance

Differences in immune responses affect viral illness outcomes, but the combined contributions of inflammation, coagulation, and complement pathway heterogeneity to disease stratification remain unclear. We analyzed infectious, immunological, coagulation, and complement responses at admission (t0) and assessed their associations with cerebrovascular and coagulation comorbidities. Ninety-six PCR-confirmed SARS-CoV-2 patients were sampled at <24 h (t1), 48 h (t2), and seven days (t3). COVID-19-specific immunity (Spec-IMM cluster) was measured by serum IgG, IgM, and IgA against S and N proteins; nonspecific immune activity (NONspec-IMM domain) used white blood cell (WBC) count, procalcitonin, IL-6, and ferritin. Complement activation (COMP cluster) Complement Factor H (CFH) levels, C5a, TCC, and clusterin. Coagulation (COAG clusters) was assessed using platelet count, D-dimer, and INR. Three clusters within each biological domain were compared for clinical features, outcomes, and organ injury trajectories. Clustering based on inflammatory markers revealed three distinct subgroups that differed in clinical severity and resource use. ICU admission, ECMO, length of stay, and organ dysfunction scores varied between clusters; WBC counts differed consistently and IL-6 only at baseline, while ferritin and procalcitonin showed no stable differences. Clustering by coagulation or complement parameters had limited clinical relevance, as most outcomes, including survival rates and organ dysfunction, were similar across groups. Adaptive immune responses (IgG levels) and other injury markers displayed minimal or transient cluster differences without consistent patterns. Nonspecific inflammatory responses, particularly leukocyte changes, more reliably identify COVID-19 host patterns than coagulation or complement activation alone.