Rohrhofer et al. (2025)
- Authors: Johanna Rohrhofer, Lilian Ebner, Johannes Schweighardt, Michael Stingl, Eva Untersmayr.
- Institutes: Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; CerePrax, 1150 Vienna, Austria.
- Publisher: Diagnostics
- Link: DOI
Summary
This study provides strong evidence that a significant subgroup of ME/CFS patients, estimated at up to 25%, has clinically relevant mast cell activation (MCA). The research establishes a clear association between this MCA involvement and a higher prevalence of orthostatic intolerance (OI), particularly POTS. This is a crucial finding for patients, as it suggests that identifying MCA is key to personalizing treatment. The study showed that ME/CFS patients with both MCA and OI reported significant symptom improvement from mast cell-targeted therapies, offering a potential treatment pathway for this subgroup. This research underscores the importance of screening for MCA to better manage OI symptoms and improve outcomes for this patient cohort.
What was researched?
This study investigated how common mast cell activation (MCA) is in an Austrian cohort of ME/CFS patients. It also explored the clinical relevance of MCA and its relationship with orthostatic intolerance (OI), particularly postural orthostatic tachycardia syndrome (POTS).
Why was it researched?
Growing evidence suggests that mast cell activation (MCA) may contribute to ME/CFS symptoms , and researchers have noted an overlap in symptoms like orthostatic intolerance (OI) and POTS between ME/CFS and Mast Cell Activation Syndrome (MCAS). However, the extent to which MCA plays a role in the pathophysiology of OI within the ME/CFS population was still unknown. This research aimed to stratify patients to help identify subgroups and improve personalized treatment options.
How was it researched?
The researchers analyzed two data sets. The first was a large online questionnaire (CCCFS cohort) with 687 self-reporting ME/CFS patients from German-speaking regions. The second was a retrospective analysis of clinical data from 383 Austrian ME/CFS patients (ME/CFS-MCA cohort) from a specialized neurology practice. The data was analyzed to compare the prevalence of OI and treatment responses in patients with and without diagnosed or suspected mast cell activation.
What has been found?
The study found that MCA is a frequent comorbidity, with its prevalence increasing over the course of the disease; up to 25.3% of patients in one cohort met the criteria for clinically relevant MCA. In both patient cohorts, orthostatic intolerance (OI), and specifically POTS, was significantly more common in ME/CFS patients who also had MCA involvement. Patients with both MCAS and OI reported significant symptom improvement from mast cell-targeted treatment 💊 (). This subgroup also responded more frequently to IF-channel inhibitors 💊 (), but showed no significant difference in response to beta blockers, compared to patients without MCAS.
Discussion
The authors acknowledge several limitations, including the reliance on self-reported data in the first cohort and the retrospective (looking-back) design of the second. They also note that results from Austrian cohorts may not be fully generalizable to other populations. A key issue highlighted was the lack of laboratory testing for MCAS in most patients (only 3.1% in one cohort), even when clinically suspected, which underscores a gap in current diagnostic practices.
Conclusion & Future Work
The authors conclude that mast cell activation (MCA) is a frequent and clinically relevant comorbidity in ME/CFS that is strongly associated with a higher prevalence of OI, especially POTS. They suggest that stratifying ME/CFS patients based on MCA involvement is essential for tailoring personalized treatment approaches. Future research should use laboratory testing to validate these findings and explore the overlapping biological pathways.