Abstract
<title>Abstract</title> <p>The longitudinal immunological mechanisms driving the heterogeneous clinical phenotypes of Long COVID (LC) remain poorly understood. Here, we quantified 54 circulating immune biomarkers in 355 individuals followed for up to 24 months post-infection. Using joint factor analysis and Bayesian structural equation modelling, we demonstrate that despite clinical heterogeneity, the respiratory, chronic pain, and chronic fatigue-like LC phenotypes share a convergent immune signature. This signature is characterized by persistent upregulation of the Th17-associated cytokine IL-17F from 3 to 12 months. Early recovery phases were marked by down-regulated angiogenic factors, which later transitioned to sustained elevation of VEGF-C, fractalkine, eotaxin, and CTACK, indicating dysregulated vascular repair. While the neurosensorial phenotype lacked systemic immune perturbations, the chronic fatigue-like phenotype demonstrated a distinct, prolonged trajectory of active immune dysregulation driven by self-sustaining tissue remodelling rather than generalized hyperinflammation. These findings provide a longitudinal framework for understanding LC pathogenesis, identifying maladaptive immune-remodelling pathways as potential therapeutic targets in post-acute infection syndromes.</p>