Infection-Driven Immune Remodeling in Post-Viral Chronic Disease: Multicenter Cross-Sectional, Prospective Cohort Analyses of Fibronectin and Fibronectin-Reactive IgM

Background: Post-viral chronic illnesses, including post-COVID syndrome and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), share disabling multisystem symptoms and, critically, the absence of validated diagnostic biomarkers. Fibronectin (Fn1) circulates at high abundance and participates in immune complex biology and tissue remodeling, while natural IgM supports homeostatic clearance pathways that may restrain autoimmunity. We hypothesized that disruption of the Fn1-natural IgM axis would be detectable in serum and clinically informative in post-viral chronic disease.

Methods: We quantified circulating Fn1 and Fn1-associated IgM signals in serum using ELISA-based assays across multiple cohorts: post-COVID participants from a German multicenter cohort (exploration and validation cohorts), ME/CFS cohorts from Germany with external validation cohorts from Sweden and the UK, and healthy controls (including pre-pandemic controls) and disease controls. We summarized immune-matrix imbalance using the log2-transformed IgM-Fn1/Fn1 ratio. Primary analyses evaluated the association of the ratio with post-COVID status relative to healthy controls in independent German cohorts, adjusting for age and sex. Secondary analyses assessed ME/CFS associations across countries. A smaller German post-COVID subgroup with paired follow-up samples was assessed longitudinally.

Findings: Across German cohorts, post-COVID status was consistently associated with a lower IgM-Fn1/Fn1 ratio compared with healthy controls, with marked separation across symptom-defined subgroups. In regression models, lower IgM-Fn1/Fn1 ratio values were independently associated with higher odds of post-COVID status in both the exploration and validation cohorts after adjustment for age and sex. Associations with ME/CFS were cohort-dependent: a lower ratio was observed in the Swedish ME/CFS cohort compared with healthy controls, while the UK cohort showed no material separation. In a selected post-COVID follow-up subgroup enriched for more severe baseline illness, the IgM-Fn1/Fn1 ratio declined within individuals over time despite largely stable symptom burden and quality-of-life metrics.

Interpretation: An interpretable serum immune-matrix imbalance metric, the IgM-Fn1/Fn1 ratio, robustly distinguishes post-COVID syndrome from healthy status across independent German cohorts and shows heterogeneous associations with ME/CFS across countries. These data are consistent with disrupted natural antibody-linked homeostatic regulation after viral infection and support prospective studies to define temporal dynamics, sources of heterogeneity, and clinical utility in biomarker-guided stratification.