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Reframing ME/CFS: toward a unified mechanistic model of chronic post-infectious diseases

Paul Watton1, Bhupesh K Prusty2

  • 1Independent Scientist, Overton Lodge, Coach Road, Overton, Nr. Ashover, Chesterfield, Derbyshire, S45 0JN, UK.

Journal of Translational Medicine
|May 23, 2026
PubMed
Abstract

Insights

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex illness involving immune, metabolic, and vascular systems. Research reframes ME/CFS as a disorder of impaired adaptive capacity, moving beyond historical psychosocial models.

Area of Science:

  • Immunology
  • Systems Biology
  • Post-Infectious Syndromes

Background:

  • ME/CFS is a severe multisystem illness characterized by post-exertional malaise (PEM), cognitive dysfunction, and autonomic disturbances.
  • Historically, lack of biomarkers and diagnostic clarity led to psychosocial frameworks dominating ME/CFS research and clinical practice.
  • Limited investigative capacity hindered understanding of ME/CFS pathophysiology.

Purpose of the Study:

  • To review the shift in understanding ME/CFS from early observations to contemporary biological frameworks.
  • To reframe ME/CFS based on recent advances in systems biology and Long-COVID research.
  • To highlight the state-dependent nature of ME/CFS pathology revealed under physiological stress.

Main Methods:

  • Review of systems biology advances, particularly those accelerated by Long-COVID research.
  • Analysis of contemporary biological frameworks for understanding post-infectious syndromes.
  • Charting the evolution of ME/CFS research from historical to modern perspectives.

Main Results:

  • Advances implicate persistent immune dysregulation, metabolic reprogramming, and endothelial dysfunction in ME/CFS.
  • Long-COVID research has transformed the understanding of post-infectious syndromes, including ME/CFS.
  • Pathology in ME/CFS is state-dependent and becomes apparent under physiological stress.

Conclusions:

  • ME/CFS is reframed as a disorder of impaired adaptive capacity within post-infectious disease biology.
  • Contemporary biological frameworks offer a more mechanistic interpretation of ME/CFS.
  • Understanding ME/CFS requires considering its complex interplay with physiological stress.
Keywords:
Immune dysregulationImpaired physiological resilienceMitochondrial and metabolic reprogrammingPost-Exertional Malaise (PEM)Post-infectious disease biology

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