Review The Clinical Relevance of Mast Cell Activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2025, Rohrhofer et al

John Mac

John Mac

Senior Member (Voting Rights)

Abstract​

Background/Objectives: Growing evidence suggests that mast cell activation (MCA) may contribute to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a debilitating disorder characterized by persistent fatigue and post-exertional malaise (PEM). Particularly in relation to orthostatic intolerance (OI), including postural orthostatic tachycardia syndrome (POTS), this study aimed to investigate the prevalence and clinical relevance of MCA in an Austrian ME/CFS patient cohort.

Methods: Two data sets were analyzed. The CCCFS data set, a comprehensive, patient-centered online questionnaire consisting of 687 filled surveys, focuses on patient stratification. Self-reported clinical features, disease progression, and treatment responses were analyzed. Preliminary findings were validated in a second, retrospective study, analyzing data of 383 Austrian ME/CFS patients with regard to MCA involvement and OI.

Results: Among followed-up ME/CFS patients, MCA prevalence increased over the disease course, with up to 25.3% meeting the criteria for clinically relevant MCA. ME/CFS patients with Mast Cell Activation Syndrome (MCAS) and OI reported symptom alleviation significantly more often following mast cell-targeted treatment than those without MCAS (p < 0.0001). With regard to IF-channel inhibitors, ME/CFS patients diagnosed with MCAS responded more frequently than those without MCAS (p = 0.076), while no significant differences were observed in response to beta blockers (p = 0.637). In both cohorts, OI, particularly POTS, was significantly more common in patients with MCA involvement.

Conclusions: MCA appears to be a frequent and clinically relevant comorbidity in ME/CFS and is associated with a higher prevalence of OI, particularly POTS. Stratifying patients based on MCA involvement may support personalized treatment approaches and improve clinical outcomes.

 
John Mac said:
With regard to IF-channel inhibitors, ME/CFS patients diagnosed with MCAS responded more frequently than those without MCAS (p = 0.076)
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So they gave a medication that affects heart rhythm to patients who didn't even have the symptoms that it supposedly treats?
 
ME/CFS Science Blog said:
Looks like this is just based on self-reported questionnaires. Don't think one can study MCAS by just asking patients if they report certain symptoms or responses to treatment.
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Yes. Three of these authors, Rohrhofer, Stingl, and the senior author Eva Untersmayer, actually all did a study in 2024 looking for markers of mast cell activation - thread here.

There were no statistically significant differences in the two molecules measured between people with ME/CFS and healthy controls. So, either the authors were wrong about the biomarkers they chose, or people with ME/CFS probably don't have unusual levels of mast cell activation. There was no mention of the result in that 2024 paper's discussion.

Since then Eva Untersmayer seems to have pursued the mast cell angle for ME/CFS. Why, you might ask?

She is a clinician who sees ME/CFS patients, perhaps she believes that mast cell treatment helps her ME/CFS patients. She is also a director of a biotech company Desentum which is working on 'novel types of allergen immunotherapy products'. Yes, mast cells are very relevant to that company's products. I guess if you have a hammer, the world looks like a nail.
 
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