Post-acute sequelae of COVID-19: A disorder of impaired innate immune resolution – A narrative review

Post-acute sequelae of COVID-19 (PASC) affect millions of people worldwide and are increasingly recognized as a disorder of failed innate immune resolution rather than a persistent viral infection. Emerging evidence shows that residual SARS-CoV-2 antigens, host-derived alarmins, reactivated latent viruses, and mucosal microbiome-derived products from oral–nasopharyngeal and gut reservoirs sustain the chronic activation of pattern-recognition receptors, inflammasomes, and complement pathways. In parallel, deficits in specialized pro-resolving mediators, impaired efferocytosis, and persistent tissue injury prevent physiological termination of inflammation. These unresolved cues drive long-lasting epigenetic and metabolic reprogramming of hematopoietic stem cells and myeloid lineages, creating maladaptive trained immunity states characterized by hyper-responsiveness or exhaustion of these cells. Thromboinflammatory processes, including aberrant NETosis and sustained interface signalingling, further reinforce self-perpetuating inflammatory circuits. Together, these pathways give rise to reproducible molecular endotypes, including thromboinflammatory, interferon-driven, and neuroinflammatory phenotypes, which explain clinical heterogeneity. Framing PASC as a disorder of impaired immune resolution within a mucosal microbial viral context provides a unifying mechanistic scaffold for biomarker identification and host-directed therapies. This review proposes that restoring active resolution programs, rebalancing metabolic–epigenetic networks, and dismantling pathogenic innate feedback loops are promising strategies for reversing the chronic immune imprint of PASC. • PASC is a disorder of failed innate immune resolution. • Persistent stimuli (SARS-CoV-2, DAMPs, latent viruses, microbiota) drive chronic inflammation. • A deficit in pro-resolving mediators (SPMs) and efferocytosis blocks repair. • Maladaptive trained immunity epigenetically entrenches myeloid dysfunction. • Innate immune endotypes (e.g., thromboinflammatory) explain PASC heterogeneity.