Global Consensus-2 Criteria Expand Recognition of Mast Cell Activation Syndrome
Recognition of mast cell activation syndrome (MCAS) has increased substantially since publication of the Global Consensus-2 (Consensus-2) diagnostic criteria, according to a review published in the Journal of Visualized Experiments (JoVE).
In “Progress in Mast Cell Activation Syndrome: The Global Consensus-2 Diagnostic Criteria at Six Years”, Afrin and colleagues evaluate developments in the field and argue that broader diagnostic recognition has improved identification of patients with mast-cell–mediated disease. The review also highlights ongoing debate between Consensus-2 and more restrictive international consensus criteria used by many allergy and immunology specialists.
Study Findings
The authors report that awareness and diagnosis of MCAS have expanded significantly during the 6 years since publication of the Consensus-2 criteria. MCAS is characterized by inappropriate mast cell activation resulting in multisystem symptoms that may affect the skin, gastrointestinal tract, cardiovascular system, respiratory tract, and nervous system. Unlike systemic mastocytosis, MCAS does not require abnormal mast cell accumulation in tissues.
According to the review, increasing clinical experience has supported recognition of MCAS as a potentially common disorder that may coexist with other mast cell diseases. The authors contend that some patients with clinically significant mast cell activation remain undiagnosed when more restrictive diagnostic frameworks are applied.
A major focus of the article is the distinction between Consensus-2 and international consensus diagnostic criteria. Consensus-2 adopts a broader, clinically oriented approach that considers the limitations of currently available laboratory testing and emphasizes overall clinical presentation. In contrast, international consensus criteria place greater emphasis on objective biochemical evidence of mast cell activation, particularly an event-related increase in serum tryptase meeting the formula of baseline × 1.2 + 2 ng/mL.
Under the international consensus framework, diagnosis generally requires recurrent severe systemic symptoms involving at least 2 organ systems, objective laboratory evidence of mast cell activation, and clinical improvement with mast cell-targeted therapy. The authors argue that while these criteria provide high specificity, they may exclude patients whose laboratory abnormalities are difficult to capture despite having clinically significant disease.
Clinical Implications
The debate between Consensus-2 and international consensus criteria reflects a broader challenge in medicine: balancing diagnostic sensitivity with specificity.
Proponents of Consensus-2 argue that broader criteria may reduce underdiagnosis and allow earlier treatment for patients with chronic multisystem symptoms attributable to mast cell activation. Because mast cell mediators can fluctuate rapidly and laboratory testing is often performed outside symptomatic episodes, some patients may not meet strict biochemical thresholds despite substantial clinical evidence of mast cell involvement.
Supporters of international consensus criteria emphasize the importance of objective biomarker confirmation to minimize overdiagnosis and maintain diagnostic rigor. These criteria are particularly valuable in research settings and in evaluating patients with severe episodic reactions resembling anaphylaxis.
For clinicians, the review underscores the importance of comprehensive patient assessment. Regardless of the diagnostic framework used, evaluation should include consideration of alternative diagnoses and related disorders, including systemic mastocytosis, hereditary alpha-tryptasemia, allergic disease, dysautonomia, endocrine disorders, medication reactions, and gastrointestinal conditions.
The JoVE review suggests that broader diagnostic recognition has improved identification of affected patients, while continued debate regarding optimal diagnostic standards highlights the need for additional research to refine evidence-based approaches to diagnosis and management.
Reference:
Afrin LB, Ackerley MB, Bluestein LS, et al. Progress in mast cell activation syndrome: the global consensus-2 diagnostic criteria at six years. J Vis Exp. 2025. doi:10.3791/68572.
