Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC).

Observed Findings

• PASC presents with heterogeneous symptoms affecting multiple organ systems including neurological, cardiovascular, immunological, and gastrointestinal dysfunction
• Several potential mechanisms may contribute to PASC including acute organ damage, persistent viral reservoirs, viral reactivation, dysbiosis, coagulation abnormalities, and autoimmunity
• Significant clinical and mechanistic overlap exists between PASC, ME/CFS, and POTS
• Dysautonomia and brainstem/vagus nerve dysfunction are proposed contributors to post-exertional malaise and other cardinal symptoms
• The individualized nature of PASC symptoms suggests multiple pathogenic pathways operating across patients

Inferred Conclusions

• PASC likely results from multiple distinct pathogenic mechanisms rather than a single cause, requiring personalized diagnostic and therapeutic approaches
• The similarities between PASC, ME/CFS, and POTS suggest shared pathobiological pathways that warrant integrated research strategies
• Future research must identify and validate specific mechanisms in individual patients to enable targeted interventions
• Integration of findings across multisystem investigations is necessary to understand the true nature and drivers of PASC

Remaining Questions