Reframing ME/CFS: toward a unified mechanistic model of chronic post-infectious diseases, 2026, Watton and Prusty

[Chandelier]

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

Watton, Paul; Prusty, Bhupesh K.

Abstract​

Background​

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.

Main body​

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.

Conclusion​

ME/CFS is thus reframed here as a disorder of impaired adaptive capacity within post-infectious disease biology.

Web | DOI | Journal of Translational Medicine

 

[Colleen Steckel]

This paper made the important point that research on patients at rest may miss many of the disease signals. Researchers who push patients into post-exertional neuroimmune exhaustion (a crash) need to be sure they are informing patients about the dangers.

Informed consent is needed... but researchers need to know how dangerous it can be to push patients past their energy production envelope.

We need researchers to recognize that results based on patients at rest are not reliable.

Good to see Prusty is recognizing the:

• persistent immune dysregulation
• mitochondrial and metabolic reprogramming
• endothelial and microvascular dysfunction
• abnormal coagulation
• lipid-mediated signalling
• extracellular vesicle communication
• viral protein-associated immune activation.

I would love my doctor to read this paper...

 

[Jonathan Edwards]

Good to see Prusty is recognizing the:

Is it? None of those have been reliably established as far as I know. The one thing we do not need is a folklore of pseudoscience built around wishful thinking about pathology.

 

[Utsikt]

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.

Something has to keep the disease active so you experience PEM when you do go above your limits, so surely that something must be measurable as well (in theory).

They seem to be arguing that you can’t take the absence of evidence of abnormalities at resting state as evidence of the absence of abnormalities in the same measurements during/after «stress», which is just plain obvious. This is how asthma and allergies are diagnosed, you provoke it and see what happens.

So I’m not sure what this paper adds?

The table of potential treatments in the supplementary files includes ~50 treatments ranging for Rituximab to magnesium.

For Ritux they write:

Negative phase III outcome; heterogeneous responses; does not target plasma cells; infection risk and immunosuppression; findings support subgroup heterogeneity rather than universal efficacy.

Given that Fluge and Mella were very clear that you can completely shut the door on Ritux being effective for anyone, my cynicism would say that this tells you what you need to know about their rigour and level of scrutiny when assessing the evidence..