What is chronic systemic mast cell activation and how is it treated?

Mast Cell Activation Syndrome: Recognition and Management

Yes, chronic systemic mast cell activation is a recognized medical entity called Mast Cell Activation Syndrome (MCAS), which presents with recurrent, episodic symptoms affecting multiple organ systems due to inappropriate mast cell mediator release. 1

What Defines MCAS

MCAS requires three mandatory diagnostic criteria to be met simultaneously 1, 2:

• Recurrent symptoms affecting at least 2 organ systems concurrently (cardiovascular, respiratory, dermatologic, gastrointestinal, or neurologic) 1
• Documented elevation of mast cell mediators during symptomatic episodes on at least two separate occasions 1, 2
• Clinical improvement with mast cell-targeted therapies (H1/H2 antihistamines, mast cell stabilizers, or leukotriene modifiers) 1, 2

The key distinguishing feature is that symptoms are episodic and recurrent, not persistent or chronic 1. Persistent daily symptoms should direct you toward alternative diagnoses like chronic urticaria or poorly controlled asthma 1.

Classification of MCAS Subtypes

Once diagnostic criteria are met, classify patients into three categories based on underlying pathology 1:

Primary MCAS (Clonal)

• KIT D816V mutation detected in peripheral blood or bone marrow 1, 3
• May progress to systemic mastocytosis, though this is uncommon 1
• Requires highly sensitive allele-specific oligonucleotide quantitative PCR (ASO-qPCR) for detection 3

Secondary MCAS (Reactive)

• Underlying IgE-mediated allergies, chronic inflammatory disorders, or neoplastic conditions trigger mast cell activation 1
• No KIT mutations present 1
• Normal mast cell morphology and immunophenotype 1

Idiopathic MCAS

• No identifiable trigger and no KIT mutations detected 1
• Diagnosis of exclusion rendered provisionally until specific cause identified 1

Hereditary Alpha-Tryptasemia

• TPSAB1 gene duplications/triplications causing elevated baseline tryptase 1
• Found in 4-6% of general population 1
• Associated with multisystem symptoms including flushing, dysautonomia, gastrointestinal symptoms, chronic pain, and joint hypermobility 1

Diagnostic Laboratory Testing

Serum Tryptase (Most Critical Test)

• Obtain baseline serum tryptase when completely asymptomatic to establish personal reference value 1, 3, 2
• Collect acute serum tryptase 1-4 hours after symptom onset during episodes 1, 3, 2
• Diagnostic threshold: ≥20% increase above baseline PLUS absolute increase ≥2 ng/mL 1, 3
• Persistently elevated baseline tryptase >20 ng/mL warrants bone marrow evaluation 1, 3

Urine Mediator Testing (24-hour collection)

• N-methylhistamine (histamine metabolite) is more reliable than direct histamine measurement 1, 3, 2
• Leukotriene E4 peaks in 0-6 hour collections and guides leukotriene antagonist therapy 1, 3, 2
• 11β-prostaglandin F2α peaks in 0-3 hour collections and correlates with anaphylaxis severity 1, 3

Genetic and Clonality Testing

• Peripheral blood KIT D816V mutation using ASO-qPCR to identify clonal MCAS 1, 3, 2
• Buccal swab for TPSAB1 α-tryptase copy number variation to diagnose hereditary α-tryptasemia 1, 3
• Bone marrow biopsy indicated if baseline tryptase persistently >20 ng/mL or high clinical suspicion for clonal disease 1, 3, 2

Tests NOT Recommended

• Plasma or urine histamine levels (use N-methylhistamine instead) 3
• Heparin (not validated as marker) 3
• Chromogranin A (resides in neuroendocrine cells, not mast cells) 3

Treatment Algorithm

First-Line Therapy (All Patients)

Start with combined H1 and H2 receptor antagonists at 2-4 times standard FDA-approved doses 1, 4:

• H1 antihistamines (nonsedating preferred): cetirizine 20-40 mg daily, loratadine 20-40 mg daily, or fexofenadine 360-480 mg daily 1
• H2 antihistamines: famotidine 40 mg twice daily or ranitidine 300 mg twice daily 1
• Avoid anticholinergic H1 antihistamines in elderly patients due to cognitive decline risk 4

Second-Line: Mast Cell Stabilizers

• Cromolyn sodium 200 mg four times daily for gastrointestinal symptoms (diarrhea, abdominal pain, nausea, vomiting) 1, 5
• Clinical improvement occurs within 2-6 weeks of treatment initiation 5
• FDA-approved for mastocytosis with documented efficacy for both cutaneous and systemic symptoms 5

Mediator-Specific Therapy

• Leukotriene antagonists (montelukast 10-20 mg daily or zileuton 600 mg four times daily) if urinary LTE4 elevated 1
• Aspirin 81-325 mg daily if prostaglandin metabolites elevated, but use with extreme caution as aspirin can trigger mast cell activation in some patients 1, 4
• Corticosteroids for refractory symptoms 1

Third-Line: Biologic Therapy

• Omalizumab (anti-IgE monoclonal antibody) for symptoms insufficiently controlled by conventional therapy, particularly recurrent anaphylaxis and severe skin symptoms 1, 4

Cytoreductive Therapy

• Reserved for advanced systemic mastocytosis (ASM, SM-AHN, MCL) with organ damage 1
• Midostaurin is the primary cytoreductive agent for advanced disease 1
• Not indicated for MCAS without systemic mastocytosis 1

Management of Acute Anaphylaxis

All patients must carry 2 epinephrine auto-injectors 1, 4:

• Immediately assume supine position 4
• Administer intramuscular epinephrine 0.3-0.5 mg (0.01 mg/kg in children, max 0.3 mg) 4
• Call emergency services 4
• Supplemental oxygen and IV fluids as needed 4
• Secondary management with chlorphenamine and hydrocortisone 4

Trigger Avoidance

Identify and eliminate specific triggers 1, 4:

• Insect venoms (consider venom immunotherapy) 1
• Temperature extremes (heat, cold) 1
• Mechanical irritation (friction, pressure) 1
• Alcohol 1
• Certain medications (NSAIDs, opioids, radiocontrast) 1
• Emotional stress and anxiety 1

Perioperative Management

Premedication is mandatory for all surgical, endoscopic, and invasive procedures to prevent anaphylaxis 1:

• Anxiolytics, antihistamines (H1 and H2), and corticosteroids administered preoperatively 1
• Coordinate with anesthesia and surgical teams 1
• Avoid known mast cell-triggering anesthetic agents 1

Critical Diagnostic Pitfalls

MCAS is substantially overdiagnosed 2. Do not diagnose based on:

• Nonspecific symptoms alone without documented mediator elevation 2
• Single organ system involvement 2
• Persistent daily symptoms (suggests alternative diagnosis) 1
• Elevated baseline tryptase alone without episodic symptoms 1

Exclude secondary causes first: IgE-mediated allergies, drug reactions, chronic inflammatory disorders, infections, and neoplastic conditions 1, 3.

Prognosis

Patients with idiopathic MCAS followed for >15 years did not develop mastocytosis 1. Patients with indolent systemic mastocytosis have normal life expectancy similar to age-matched general population 1. Treatment is symptom-based and typically lifelong, with adjustments based on mediator profiles and clinical response 1.