Publication date: May 22, 2026
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe multisystem illness marked by post-exertional malaise (PEM), cognitive dysfunction, autonomic disturbance, and impaired physiological resilience. Historically, the absence of validated biomarkers, heterogeneous definitions, and limited investigative capacity have complicated mechanistic interpretation and contributed to the use of psychosocial and rehabilitative frameworks in clinical practice and in parts of the literature. Advances in systems biology, accelerated by Long-COVID research, have transformed our understanding of post-infectious syndromes, implicating persistent immune dysregulation, mitochondrial and metabolic reprogramming, endothelial and microvascular dysfunction, abnormal coagulation, lipid-mediated signalling, extracellular vesicle communication, and viral protein-associated immune activation. This review charts the shift from early post-infectious observations through psychosocial dominance to contemporary biological frameworks, emphasising that pathology is state-dependent and revealed under physiological stress. ME/CFS is thus reframed here as a disorder of impaired adaptive capacity within post-infectious disease biology.
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| Concepts | Keywords |
|---|---|
| Encephalomyelitis | Immune dysregulation |
| Mitochondrial | Impaired physiological resilience |
| Pathology | Post-Exertional Malaise (PEM) |
| Rehabilitative | Post-infectious disease biology |
| Viral |