Long dismissed as psychosomatic, myalgic encephalomyelitis / chronic fatigue syndrome now has documented biological foundations — and the PMCHS mast cell terrain is likely a central mechanism.
Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a chronic multisystemic disease affecting 17 to 24 million people worldwide. Its defining symptom — post-exertional malaise (PEM) — is a massive, delayed worsening of symptoms after even minimal physical or cognitive effort, with a 12–48 hour delay. After a sustained conversation, a patient may be bedridden for several days.
For decades, medicine classified ME/CFS as a psychiatric or"functional" disorder. Robust biological data published in 2025 ended that debate: it is an organic, multisystemic disease with measurable biomarkers — and mast cells are at the heart of the mechanism.
The 2025 multisystemic study (Hanson et al.) formally documented an ATP/ADP deficit in immune cells of ME/CFS patients. This deficit is directly compatible with the PMCHS model: mast cells in a state of chronic hyperactivation are major energy consumers during repeated degranulation — they exhaust cellular energy reserves, explaining refractory fatigue even at rest.
The kynurenine/NAD⁺ pathway is also disrupted — IDO1, directly activatable by mast cells, diverts tryptophan from serotonin synthesis toward kynurenine production, contributing to the cognitive disorders and secondary depression documented in ME/CFS.
The same 2025 study documented via plasma proteomics: ↑ THBS1, VWF, FN1 (platelet aggregation, vascular remodelling) and ↓ CDH5 (VE-cadherin — endothelial barrier stability). This endothelial dysfunction profile with pro-thrombotic tendency is exactly what mast cells can induce via release of histamine, tryptase, and pro-coagulant factors — the same mechanism documented in Kounis syndrome and vascular PMCHS.
The 2025 study documents a significant ↓ in CD56ˡᵒʷCD16⁺ NK cells (mature cytotoxic NK cells) in ME/CFS patients. NK cells play a direct regulatory role on mast cells — their exhaustion removes a major brake on mast cell hyperactivation. It is a vicious cycle: hyperactivated mast cells exhaust NK cells, which can no longer regulate them, amplifying hyperactivation.
This study publishes for the first time a complete biological profile of ME/CFS across multiple systems simultaneously, formally refuting its psychiatric classification. The documented biomarkers converge with the PMCHS model:
"This study provides compelling evidence that ME/CFS is associated with dysfunction across multiple biological systems, challenging its dismissal as a psychological disorder."
Hanson et al., Nature Communications, 2025Specialist clinicians (Afrin, Molderings, Weinstock) estimate that a significant proportion of ME/CFS patients present an underlying undiagnosed mast cell activation syndrome. The symptomatic overlap is near-total — PEM, dysautonomia, brain fog, diffuse pain, multiple hypersensitivities are present in both pictures. The difference is often more contextual (documented viral trigger) than biological.
Within the PMCHS framework, ME/CFS represents a chronicisation phenotype: a pre-existing mast cell terrain, subjected to a sufficiently intense trigger (viral infection, surgery, trauma), tips into a state of permanent activation from which the system can no longer exit alone — lacking sufficient energy resources and autonomic regulation.
Afrin et al. 2020 · Weinstock 2023 · Molderings 2022⚠️ Critical point: Demyelination of vagal fibres by mast cell tryptase and chymase — documented in PMCHS — is likely one of the most important chronicisation mechanisms in ME/CFS. A demyelinated vagus nerve can no longer exert its cholinergic anti-inflammatory role via α7-nAChR, removing the last brake on mast cell hyperactivation. Low HRV (heart rate variability), documented in both conditions, is its indirect biomarker.
🔗 Link with Long Covid: Since 2020, Long Covid has become the main entry point into ME/CFS — between 10 and 30% of Long Covid patients develop a full ME/CFS picture. This is not a coincidence: SARS-CoV-2 massively activates mast cells, and in people with pre-existing PMCHS terrain, this activation may never extinguish. → See the Long Covid & PMCHS page
The most promising approaches in ME/CFS converge with the PMCHS protocol — confirming the shared mechanism.
⚠️ ME/CFS-specific warning: Graded exercise therapy (GET) is contraindicated in confirmed ME/CFS — it worsens PEM and accelerates chronification. This contraindication is now recognised by NICE (2021). Within the PMCHS framework, this contraindication has a mechanistic explanation: physical exertion triggers additional mast cell degranulation on an already depleted terrain.