This is day five of a five day series decoding the three most important studies from the past three years for five conditions. We previously covered PoTS, ME/CFS, Long-COVID and EDS. Today: Mast Cell Activation Syndrome.
A note before we begin that is worth stating clearly at the outset. MCAS is a condition surrounded by genuine scientific controversy, not about whether mast cell activation causes symptoms, it clearly does, but about how MCAS is defined, how it is diagnosed and how commonly it occurs in patients with PoTS and EDS. The studies below reflect that complexity honestly. Some findings will be validating and one will be particularly challenging. All of them are worth engaging with (in my opinion).
Study 1: The Harvard Paper That Said MCAS Is Underdiagnosed, Overdiagnosed, and Poorly Understood Simultaneously
Castells M, Giannetti MP, Hamilton MJ, et al. Mast cell activation syndrome: current understanding and research needs. Journal of Allergy and Clinical Immunology. 2024;154(2):255–263.
Published in the Journal of Allergy and Clinical Immunology in August 2024, this is the most comprehensive expert consensus paper on MCAS produced in the past decade. The author list reads like a who’s who of MCAS research, spanning Brigham and Women’s Hospital, Harvard Medical School, the NIH, alongside multiple leading autonomic and connective tissue specialists including Clair Francomano, one of the world’s leading EDS experts, together with Peter Novak, whose Long COVID autonomic research we have decoded previously.
The paper opens with a statement that is simultaneously validating for patients and sobering for clinicians: MCAS has gained increased attention from patients and medical providers, but there are many gaps in knowledge resulting in confusion about this clinical syndrome. The confusion is not a patient problem. It is a knowledge problem. The experts writing this paper are acknowledging that the field does not yet fully understand what MCAS is, what causes it, or how reliably it can be diagnosed.
What the paper identifies as established: mast cell activation drives genuine, measurable, systemic symptoms. Mast cells, when inappropriately activated, release a range of mediators including histamine, prostaglandins, tryptase, together with cytokines that affect vascular tone, pain signalling, gastrointestinal function, neurological function, immune regulation. The biological mechanisms are real. The clinical effects are real.
What the paper identifies as unresolved: the current diagnostic criteria require a rise in serum tryptase of 20% plus 2ng/mL above baseline during an episode. This is a stringent requirement that many patients with genuine mast cell-mediated symptoms will not meet. Recent studies attempting to systematically evaluate individuals with suspected MCAS found that fewer than 5% met strict criteria for primary or idiopathic MCAS. This does not mean 95% of people who think they have MCAS do not have mast cell-mediated symptoms. It means the diagnostic criteria are failing to capture the broader spectrum of mast cell involvement.
The paper calls specifically for expansion of validated biomarkers beyond serum tryptase, for better understanding of whether MCAS is a primary syndrome or a manifestation of other inflammatory or clonal disorders, together with urgent research into the underlying mechanisms that lead to mast cell activation in MCAS patients. It also makes the clinically important point that treatment response itself can be evidence of mast cell involvement: response to antihistamines, cromolyn sodium, or omalizumab supports a mast cell-mediated mechanism even when tryptase criteria are not met.
Study 2: The Systematic Review That Found No Clear Evidence for the PoTS/EDS/MCAS Trifecta
Farley M, Estrada-Mendizabal RJ, Gansert EA, et al. Prevalence of mast cell activation disorders and hereditary alpha tryptasemia among patients with postural orthostatic tachycardia syndrome and Ehlers-Danlos syndrome: a systematic review. Annals of Allergy, Asthma and Immunology. 2025;135:97–102.
This study from the Mayo Clinic, published in April 2025, is the one that will be uncomfortable for some readers. It is also one of the most important, because it asks a question the community has assumed the answer to for years: what is the actual evidence for the co-occurrence of MCAS with PoTS and EDS?
The researchers conducted a systematic search of four major medical databases, reviewed 200 records, excluded those that did not meet inclusion criteria, reviewed 92 full texts, along with applied strict diagnostic criteria throughout. They focused specifically on studies where MCAS was diagnosed using validated criteria rather than broader symptom-based definitions.
The conclusion: no studies using strict diagnostic criteria confirm a clear association between MCAS and PoTS or EDS. Despite anecdotal reports and individual studies suggesting potential overlap, most existing research lacked validated diagnostic standards and consistency.
This finding requires careful interpretation. It does not mean MCAS does not co-occur with PoTS and EDS. It means the existing research has not been rigorous enough to confirm that it does. Studies recruiting patients from allergy clinics, or using broader symptom-based MCAS criteria rather than the validated tryptase-based criteria, systematically inflate apparent prevalence. The authors explicitly note that use of unvalidated criteria may result in increased prevalence of reported cases, potentially creating misleading associations.
What this means practically: the PoTS/EDS/MCAS trifecta is widely discussed and many patients experience symptoms consistent with all three. The mechanism connecting them, including shared mast cell density in vascular tissue, connective tissue influence on mast cell activation, along with oestrogen-driven mast cell degranulation, is biologically plausible. But the rigorous epidemiological evidence confirming the trifecta at the population level does not yet exist. This is a gap in the research, not evidence that the connection is false.
Importantly, a 2025 study in Autonomic Neuroscience surveying 84 women with hEDS found that 32.1% had MCAS and 25% had all three conditions simultaneously. This is a positive finding from a different methodology. The tension between these results reflects the current state of the evidence: suggestive but not yet definitive, highly sensitive to the diagnostic criteria used.
Study 3: Six Years of the Consensus-2 Criteria: What Has Changed
Afrin LB, Blitshteyn S, Bluestein LS, et al. Progress in mast cell activation syndrome: the global consensus-2 diagnostic criteria at six years. Diagnostics. 2026. https://doi.org/10.1515/dx-2026-0016
Published in June 2026, this paper represents a six-year assessment of the broader consensus-2 diagnostic criteria for MCAS, developed by Lawrence Afrin and colleagues as an alternative to the strict tryptase-based criteria. The consensus-2 criteria require fewer criteria to be met and include a broader list of symptoms, making them more inclusive but also, as the Farley review noted, more susceptible to false positives.
The authors make a case that the broader criteria have brought appropriate diagnosis to many patients previously labelled with unexplained inflammatory syndromes or misdiagnosed as having somatisation or primary psychiatric disorders. They report that appropriate therapy for MCAS can dramatically improve quality of life, sometimes after decades of morbidity and disability despite extensive past workups and unhelpful treatments. They also note that concerns about overdiagnosis under consensus-2 have, in their clinical experience, not been realised.
This is an important claim and worth engaging with seriously. If the stricter tryptase criteria are failing to diagnose patients with genuine mast cell-mediated disease, and if broader criteria identify those patients and lead to treatments that work, then the broader criteria may be serving patients better even if they are less specific. The paper specifically highlights that a response to mast cell targeted therapy, whether antihistamines, sodium cromolyn, or mast cell stabilisers, is itself evidence of mast cell involvement.
The honest tension in MCAS research sits precisely here. The Castells Harvard paper calls for better biomarkers to capture patients the tryptase criteria miss. The Farley systematic review shows that studies using looser criteria create misleading prevalence estimates. The Afrin paper argues the broader criteria are clinically appropriate and improving lives. These are not contradictory positions in a fraudulent debate. They are legitimate scientific disagreements about how to balance sensitivity and specificity in the diagnosis of a heterogeneous condition with no single definitive biomarker. That debate is ongoing.
Honourable Mentions
The Diagnosis and Management of Patients with Mast Cell Activation Syndromes: Status 2026 (Gülen T, et al., Journal of Allergy and Clinical Immunology: In Practice, 2025) provides a comprehensive update on clinical management across the spectrum of mast cell disorders, distinguishing clearly between MCAS, systemic mastocytosis, along with anaphylaxis, which are frequently confused even in specialist settings.
The MCAS in ME/CFS study from the CCCFS cohort found that in 687 ME/CFS patients, those with an MCAS diagnosis showed significantly higher rates of orthostatic dysregulation, providing independent evidence that mast cell activation and autonomic dysfunction co-occur in ME/CFS patients specifically.
The AGA Clinical Practice Update (Lam C, et al., Gastroenterology, 2025) formally recognised the GI manifestations of MCAS for the first time, providing structured clinical pathways, acknowledging the interplay with PoTS and hEDS, along with recommending low histamine dietary approaches for symptom management.
The Bigger Picture
MCAS research in the past three years has moved in two directions simultaneously. The evidence for genuine mast cell-mediated disease in a subset of patients with PoTS, EDS, Long COVID and ME/CFS is growing. The evidence that the diagnostic criteria need significant refinement to capture that population accurately is equally growing. These two things are not in opposition. They are two parts of the same problem.
The community deserves both validation and rigour. Validation: mast cell activation is real, measurable, treatable in some patients. Rigour: the diagnostic criteria are imperfect, the epidemiology has been overstated in some publications, along with the field needs better biomarkers to confidently identify who has MCAS and who does not. Both can be true simultaneously. Holding both is how the science advances.
The views and opinions expressed in Dysautonomia Decoded are my own and do not represent those of my employer or any affiliated organisation.
References
Castells M, Giannetti MP, Hamilton MJ, et al. Mast cell activation syndrome: current understanding and research needs. Journal of Allergy and Clinical Immunology. 2024;154(2):255–263. https://doi.org/10.1016/j.jaci.2024.05.025
Farley M, Estrada-Mendizabal RJ, Gansert EA, et al. Prevalence of mast cell activation disorders and hereditary alpha tryptasemia among patients with postural orthostatic tachycardia syndrome and Ehlers-Danlos syndrome: a systematic review. Annals of Allergy, Asthma and Immunology. 2025;135:97–102. https://doi.org/10.1016/j.anai.2025.03.025
Afrin LB, Blitshteyn S, Bluestein LS, et al. Progress in mast cell activation syndrome: the global consensus-2 diagnostic criteria at six years. Diagnostics. 2026. https://doi.org/10.1515/dx-2026-0016
Gülen T, et al. Diagnosis and management of patients with mast cell activation syndromes: status 2026. Journal of Allergy and Clinical Immunology: In Practice. 2025. https://doi.org/10.1016/j.jaip.2025.11.014
Lam C, et al. AGA Clinical Practice Update on diagnosis and management of immune and mast cell mediated GI conditions. Gastroenterology. 2025.
The point about treatment response serving as clinical evidence is so vital. When strict tryptase criteria fail 95% of symptomatic patients, waiting for a lab spike while people suffer is bad medicine. Thank you for the well-written post!
Meg, thanks a lot for these five posts over five days! Great summaries of the most relevant outcomes from the papers, it really helps to choose which ones prioritise to read first.
I wish I could become a paid subscriber because your hard work is totally worth it. Oh, the joys of not being able to work nor receive benefits (over three years waiting to be assessed by the work & pensions department, the disability assessment was 'quicker' and got my blue badge).