Clinical meaning
Long COVID (post-acute sequelae of SARS-CoV-2 infection, or PASC) is a multisystem condition defined by symptoms persisting or developing 3 or more months after acute SARS-CoV-2 infection, lasting at least 2 months, and not attributable to an alternative diagnosis. The pathophysiology is multifactorial and involves several interconnected mechanisms. Viral persistence: SARS-CoV-2 RNA and spike protein have been detected in tissues (gut, brain, lymph nodes) months after acute infection, suggesting ongoing viral reservoirs that drive chronic immune activation. Immune dysregulation: Long COVID patients demonstrate persistent T-cell activation, elevated inflammatory cytokines (IL-6, TNF-alpha, interferon-gamma), reduced regulatory T-cell function, and development of autoantibodies — the immune profile resembles a chronic autoimmune-inflammatory state. Autoimmunity: molecular mimicry between SARS-CoV-2 spike protein and host proteins generates autoantibodies targeting G-protein coupled receptors, ACE2, and components of the autonomic nervous system, contributing to dysautonomia (POTS) and vascular dysfunction. Endothelial dysfunction and microclotting: SARS-CoV-2 damages vascular endothelium via ACE2 receptor binding, causing persistent endotheliopathy with elevated von Willebrand factor, complement activation, and formation of amyloid fibrin microclots that resist fibrinolysis and impair microvascular oxygen delivery — this mechanism likely underlies the persistent fatigue and exercise intolerance. Mitochondrial dysfunction: viral proteins impair mitochondrial electron transport chain function and oxidative phosphorylation, reducing cellular ATP production and contributing to the profound fatigue and post-exertional malaise (PEM) that characterize Long COVID and overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Neurological involvement: neuroinflammation from microglial activation, disruption of the blood-brain barrier, and direct viral neurotropism via olfactory nerve pathways contribute to brain fog, anosmia, and cognitive dysfunction. Latent virus reactivation: Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivation during acute COVID amplifies immune dysregulation and is associated with more severe Long COVID presentations.