Latest Findings on Mast Cell Activation Syndrome (MCAS)
Refined Diagnostic Criteria (2019–2026)
The diagnosis of MCAS requires three mandatory criteria to be met simultaneously: recurrent episodic symptoms affecting at least two organ systems, documented elevation of mast cell mediators during symptomatic episodes on at least two occasions, and clinical response to mast cell-targeted therapies. 1, 2
Clinical Presentation Requirements
Symptoms must be episodic, severe, and involve at least two organ systems concurrently—typically cardiovascular (hypotension, tachycardia, syncope), dermatologic (flushing, urticaria, angioedema, pruritus), gastrointestinal (cramping, diarrhea, nausea, vomiting), and respiratory (wheezing, dyspnea) systems. 1, 2
The prototypical presentation resembles idiopathic anaphylaxis with recurrent systemic reactions that meet anaphylaxis criteria. 3
Single organ involvement or chronic non-episodic symptoms do not meet diagnostic criteria for MCAS. 2
Laboratory Confirmation: Validated Mediator Testing
Serum tryptase remains the cornerstone biomarker, requiring both baseline measurement (when completely asymptomatic) and acute measurement (within 30–120 minutes of symptom onset). 1, 4, 2, 3
The diagnostic threshold is an increase ≥20% above the patient's personal baseline PLUS an absolute increase ≥2 ng/mL during symptomatic episodes. 1, 4
This calculation must be documented on at least two separate occasions to confirm the diagnosis. 2
24-hour urine collections provide alternative or complementary evidence when tryptase is difficult to obtain:
N-methylhistamine (histamine metabolite) is superior to direct histamine measurement and should be collected during symptomatic periods compared to baseline. 1, 4, 2
Leukotriene E4 (LTE4) peaks in 0–6 hour collections after episodes and guides leukotriene antagonist therapy. 1, 4
11β-prostaglandin F2α (PGD2 metabolite) peaks in 0–3 hour collections and correlates with anaphylactic severity; elevation indicates potential aspirin responsiveness. 1, 4
Critical pitfall: Elevated baseline values alone (without acute elevation during symptoms) do not confirm MCAS, nor do normal values exclude the diagnosis. 3
Genetic and Clonality Assessment (2019–2026)
Recent guidelines emphasize distinguishing primary (clonal) MCAS from idiopathic forms through genetic testing:
KIT D816V mutation testing using highly sensitive allele-specific oligonucleotide quantitative PCR (ASO-qPCR) on peripheral blood identifies clonal disease. 1, 4
If peripheral blood testing is negative but clinical suspicion remains high (elevated baseline tryptase >20 ng/mL, positive REMA or NIH scores), bone marrow biopsy should be performed with flow cytometry, immunohistochemistry, and KIT mutation analysis. 1, 4
TPSAB1 α-tryptase copy number variation (CNV) testing via buccal swab diagnoses hereditary α-tryptasemia, a newly recognized genetic condition (described 2016–2019) characterized by elevated baseline tryptase, multisystem symptoms (flushing, dysautonomia, gastrointestinal complaints, joint hypermobility), and symptom overlap with MCAS. 1, 4
Mandatory Treatment Response Criterion
Clinical improvement with mast cell-targeted therapy is a required diagnostic criterion, not merely a treatment goal. 1, 2
Patients must demonstrate measurable symptom reduction with H1 antihistamines, H2 antihistamines, mast cell stabilizers, or leukotriene modifiers. 2
Therapeutic response should be evaluated over a 2–6 week period before escalating therapy or reconsidering the diagnosis. 2
Exclusion of Secondary Causes
Before diagnosing primary or idiopathic MCAS, secondary causes must be systematically excluded: IgE-mediated allergies, cofactor-dependent food allergy, NSAID hypersensitivity, drug reactions, infections, and other conditions that trigger mast cell activation. 1, 4, 2, 3
Evidence-Based Treatment Advances (2018–2026)
First-Line Pharmacologic Therapy
Initiate non-sedating H1 antihistamines (cetirizine, fexofenadine, loratadine) at 2–4 times the standard FDA-approved dose combined with an H2 antihistamine (famotidine) to control histamine-mediated symptoms including flushing, pruritus, urticaria, tachycardia, and gastrointestinal discomfort. 1, 5
- Avoid chronic use of first-generation sedating antihistamines (diphenhydramine, hydroxyzine) in elderly patients due to anticholinergic-related cognitive decline. 5
Oral cromolyn sodium 200 mg four times daily is recommended for persistent gastrointestinal manifestations (diarrhea, abdominal pain, cramping, bloating) or inadequate antihistamine response. 1, 5
- Titrate using divided doses with weekly upward adjustments to improve tolerance; onset of action requires at least 1 month. 1, 5
Mediator-Targeted Therapy Based on Laboratory Profiles
Leukotriene antagonists (montelukast 10 mg daily, zafirlukast, or zileuton) should be added when urinary LTE4 is elevated or antihistamine response is suboptimal; these agents reduce bronchospasm, gastrointestinal symptoms, and synergize with H1 antihistamines for dermatologic manifestations. 1, 5
Aspirin 325–650 mg twice daily may reduce flushing and hypotensive episodes in patients with documented elevation of urinary 11β-prostaglandin F2α, but introduction must occur in a controlled clinical setting because aspirin can paradoxically provoke mast cell degranulation; contraindicated in NSAID hypersensitivity. 1, 2, 5
Additional Pharmacologic Options
Cyproheptadine (sedating H1 antihistamine with antiserotonergic activity) may alleviate gastrointestinal, musculoskeletal symptoms, and provide migraine prophylaxis. 5
Doxepin (potent H1/H2 antihistamine with tricyclic properties) can lessen central nervous system manifestations but may cause drowsiness, cognitive decline in older adults, and increased suicidal risk in younger patients. 5
Omalizumab (anti-IgE monoclonal antibody) has prevented anaphylactic episodes in reported MCAS cases, though evidence remains limited to case reports. 5
Corticosteroid Strategy
Reserve systemic corticosteroids for refractory disease: start prednisone ≈0.5 mg/kg/day (≈50 mg) and taper slowly over 1–3 months; long-term use is discouraged due to significant adverse effects. 1, 5
For procedures with prior mast cell activation, administer 50 mg prednisone at 13 hours, 7 hours, and 1 hour before the intervention to blunt peri-procedural activation. 5
Critical Safety and Emergency Management Updates
Anaphylaxis Preparedness
Prescribe two epinephrine auto-injectors (0.3 mg for adults) for every MCAS patient to carry at all times; 20–50% of patients with systemic mastocytosis experience systemic anaphylaxis, and MCAS patients face heightened risk. 1, 5
Instruct patients to assume a supine position promptly during hypotensive episodes to prevent cardiovascular collapse. 1, 5
Administer intramuscular epinephrine immediately for hypotension, laryngeal angioedema, or severe bronchospasm and transport by ambulance while remaining supine. 5
Peri-operative Management (NCCN 2018–2019)
Premedicate with H1 and H2 antihistamines plus corticosteroids before surgery, invasive procedures, or contrast imaging to prevent anaphylaxis. 1, 5
Ensure multidisciplinary coordination among surgical, anesthesia, and allergy teams; review prior anesthetic records and avoid known triggers. 1, 5
Preferred agents: propofol (induction), sevoflurane/isoflurane (inhalation), fentanyl or remifentanil (analgesia), lidocaine or bupivacaine (local), rocuronium or vecuronium (muscle relaxation). 5
Agents to avoid: atracurium, mivacurium, succinylcholine, morphine, codeine. 5
Pain Management Paradigm Shift
Do not withhold analgesics despite concerns about mast cell triggering; untreated pain itself is a potent trigger for mast cell degranulation. 1, 5
- Use fentanyl or remifentanil as safer opioid alternatives to morphine or codeine when opioid analgesia is required. 1, 5
Prognostic Insights and Natural History
There are no specific studies evaluating long-term prognosis of MCAS patients. 1
Some patients with clonal MCAS can progress to systemic mastocytosis (most likely indolent SM), but none of the patients in the Mayo Clinic cohort followed for more than 15 years developed mastocytosis. 1
Data regarding indolent SM demonstrate normal life expectancy. 1
Approximately one-third of MCAS patients experience complete resolution of symptoms with treatment, one-third have a major response, and one-third a minor response; a combination of drugs is usually necessary to achieve symptom control. 6
Unmet Needs and Future Research Directions
Whether precise measurement of additional mediators (platelet-activating factor, heparin, chymase, carboxypeptidase A3) will provide complementary and clinically useful insight requires further research. 1
Detection of somatic mutations of other genes that identify hyperactivatable mast cells would extend diagnostic tools and potentially indicate new therapeutic interventions targeting either the mutated gene product or the associated molecular pathway. 1
Newer therapies targeting signaling pathways (e.g., DCC2618, a selective inhibitor of D816V KIT in phase 1 trials for advanced SM; monoclonal antibodies targeting sialic acid-binding immunoglobulin-like lectin 8) remain investigational, and their long-term benefit/toxicity ratio for treating MCAS is undetermined. 1
Expanding access to key diagnostic tools—urinary mediator assays, sensitive KIT mutation testing, and tryptase genotyping—would facilitate and improve care. 3
Referral to specialized centers with expertise in mast cell activation disorders is strongly recommended to allow for a critical mass of patients to be enrolled in studies while providing the most up-to-date diagnostic procedures and treatment strategies. 1, 6