BEYOND ACUTE INFECTION: A REVIEW OF VIRAL PERSISTENCE AND IMMUNE DYSREGULATION AS THE PATHOPHYSIOLOGICAL NEXUS OF LONG COVID PHENOTYPES

Abstract

Long COVID, or Post-Acute Sequelae of SARS-CoV-2 infection (PASC), represents a significant global health challenge affecting millions worldwide. This review synthesizes recent mechanistic evidence to propose that the pathophysiological nexus of Long COVID’s diverse clinical phenotypes lies in the interplay between SARS-CoV-2 viral persistence and subsequent chronic immune dysregulation. Moving beyond hypotheses of residual acute damage, we detail the evidence for viral components, particularly the Spike protein, persisting in tissue reservoirs like the gut, nervous system, and vasculature for months post-infection. This persistent antigen serves as a continuous trigger for a self-perpetuating cycle of immune dysfunction, characterized by chronic inflammation, T-cell exhaustion, autoantibody production, and mast cell activation. A central downstream consequence is a systemic microvascular coagulopathy, driven by the formation of fibrin amyloid microclots that resist fibrinolysis, leading to tissue hypoxia and bioenergetic failure through mitochondrial dysfunction. This mechanistic pathway—from viral persistence to immune dysregulation and microvascular damage—explains the multi-system symptomatology, including fatigue, cognitive impairment, and cardiovascular complications. We conclude that this biological framework validates Long COVID as a distinct disease entity, mandates a shift towards biomarker-driven diagnosis, and provides a rationale for targeted, combination therapies addressing viral persistence, immune dysregulation, and microclotting to mitigate this growing burden of chronic disease.