Mast Cell Activation Syndrome (MCAS): Diagnostic Approach and Treatment
Diagnostic Criteria
MCAS diagnosis requires simultaneous fulfillment of three mandatory criteria: (1) recurrent episodic symptoms affecting at least two organ systems concurrently, (2) documented elevation of mast cell mediators during symptomatic episodes on at least two separate occasions, and (3) demonstrable clinical improvement with mast cell-targeted therapy. 1
Clinical Presentation Requirements
Episodic, not chronic symptoms are essential—persistent daily symptoms between episodes argue against MCAS and suggest alternative diagnoses such as chronic urticaria, functional gastrointestinal disorders, or poorly controlled asthma 1
Symptoms must involve at least two organ systems simultaneously during acute episodes 1:
The prototypical presentation resembles idiopathic anaphylaxis with recurrent systemic reactions 2
Laboratory Confirmation
Serum tryptase measurement is the cornerstone of laboratory diagnosis 1:
Obtain baseline serum tryptase when completely asymptomatic to establish the patient's individual reference value 1
Collect acute serum tryptase 1–4 hours after symptom onset during an episode 1
Diagnostic threshold: tryptase must rise ≥20% above baseline PLUS an absolute increase of ≥2 ng/mL 1
This elevation must be documented on at least two separate symptomatic episodes 1
When tryptase testing is negative or unavailable, 24-hour urine collections provide alternative evidence 1:
N-methylhistamine (histamine metabolite): collect during symptomatic periods; more sensitive than direct histamine measurement 1
Leukotriene E4 (LTE4): peaks 0–6 hours after symptom onset; guides addition of leukotriene antagonists 1
11β-prostaglandin F2α: peaks 0–3 hours after onset; elevation suggests potential benefit from aspirin therapy 1
Critical Pitfall: Baseline Elevations Are Not Diagnostic
Chronically elevated baseline tryptase (>20 ng/mL) without episodic symptoms suggests systemic mastocytosis or hereditary α-tryptasemia, not MCAS 1
Elevated baseline urinary mediators without acute increases during symptomatic episodes do not fulfill diagnostic criteria 1
Exclusion of Secondary Causes
Before diagnosing primary or idiopathic MCAS, systematically exclude secondary triggers 1, 2, 3:
- IgE-mediated allergies (food, venom, environmental)
- Cofactor-dependent food allergy (exercise, NSAIDs, alcohol)
- NSAID hypersensitivity
- Drug reactions
- Infections or other inflammatory conditions
Clonality Assessment
For patients meeting MCAS criteria, evaluate for clonal mast cell disease 1:
KIT D816V mutation testing using highly sensitive allele-specific oligonucleotide quantitative PCR on peripheral blood 1
Bone marrow biopsy is indicated when:
TPSAB1 α-tryptase copy number testing (buccal swab) to diagnose hereditary α-tryptasemia, which mimics MCAS with chronically elevated tryptase and multisystem symptoms 1
Treatment Algorithm
First-Line Therapy
Initiate non-sedating H1 antihistamines at 2–4 times the standard FDA-approved dose combined with an H2 antagonist 1:
- H1 antihistamines: cetirizine, fexofenadine, or loratadine at 2–4× standard dosing 1
- H2 antagonist: famotidine for gastrointestinal symptoms and additional histamine blockade 1
- Assess response after 2–6 weeks before escalating therapy 1
Common pitfall: Standard-dose antihistamines are frequently insufficient; failure to use guideline-recommended 2–4× dosing contributes to perceived treatment resistance 1
Second-Line Add-On Therapies
If first-line therapy provides incomplete control, add agents sequentially based on mediator profile and symptom pattern 1:
Oral cromolyn sodium 200 mg four times daily for gastrointestinal symptoms or when antihistamine response is suboptimal; requires at least 1 month at full dose before efficacy can be judged 1
Leukotriene antagonist (montelukast 10 mg daily, zafirlukast, or zileuton) when urinary LTE4 is elevated or antihistamine response is inadequate; particularly effective for respiratory and dermatologic symptoms 1
Aspirin 325–650 mg twice daily for flushing or hypotensive episodes when urinary 11β-PGF2α is elevated; must be initiated in a controlled clinical setting due to risk of mast cell degranulation 1
Third-Line Therapies for Refractory Disease
Systemic corticosteroids: prednisone ≈0.5 mg/kg/day (≈50 mg) with slow taper over 1–3 months for severe refractory symptoms 1
Omalizumab (anti-IgE biologic) for patients remaining symptomatic despite optimal mediator-targeted therapy, particularly effective in preventing recurrent anaphylaxis 1
Cytoreductive therapies (interferon-α, cladribine) reserved for life-threatening manifestations unresponsive to antimediator drugs 1
Midostaurin (multikinase inhibitor) for advanced clonal MCAS with refractory symptoms; prophylactic ondansetron 30–60 minutes before dosing mitigates nausea 1
Therapeutic Response as Diagnostic Criterion
Demonstrable clinical improvement with mast cell-targeted therapy is mandatory for confirming MCAS diagnosis 1:
- Evaluate treatment efficacy over 2–6 weeks before considering escalation 1
- Lack of response should prompt reconsideration of the diagnosis 1
Emergency Management
All MCAS patients require two epinephrine auto-injectors (0.3 mg for adults) 1:
Instruct patients to use epinephrine for episodes meeting anaphylaxis criteria (involvement of ≥2 organ systems with cardiovascular or respiratory compromise) 2
Assume supine position immediately during hypotensive episodes to prevent cardiovascular collapse 1
Peri-Procedural Prophylaxis
Premedicate before surgery, invasive procedures, or contrast imaging 1:
- Prednisone 50 mg at 13 hours, 7 hours, and 1 hour before the procedure 1
- H1 and H2 antihistamines before the procedure 1
- Coordinate with surgical, anesthesia, and allergy teams; review prior anesthetic records 1
- Fentanyl or remifentanil are preferred opioids over morphine or codeine 1
- Do not withhold analgesics—untreated pain is a potent mast cell trigger 1
Expected Treatment Outcomes
Approximately one-third of patients achieve complete symptom resolution with first-line H1/H2 antihistamine combinations at 2–4× standard doses 1
Another one-third experience major symptom reduction after adding mast cell stabilizers or leukotriene antagonists 1
The remaining one-third show minor response and typically require combination regimens 1
Monitoring and Follow-Up
For stable MCAS, perform routine evaluation every 6–12 months 1:
- History, physical examination, and laboratory testing 1
- Symptom burden assessment using validated tools (Mast Cell Activation Symptom questionnaire, Mast Cell Quality of Life questionnaire) 1
- DEXA scan every 1–3 years for patients with osteopenia or osteoporosis 1
Prognosis
No progression to systemic mastocytosis was observed in a Mayo Clinic cohort of clonal MCAS patients followed >15 years 1
Data from indolent systemic mastocytosis indicate normal life expectancy, suggesting a generally favorable prognosis when disease remains indolent 1
Referral Indications
Refer to specialized mast cell disorder centers 1:
- Refractory symptoms despite optimal therapy
- Need for advanced diagnostic assays (urinary mediators, sensitive KIT testing, tryptase genotyping)
- Consideration of investigational therapies or enrollment in research studies