What are the next steps for a patient with elevated tryptase, potentially indicating mast cell activation or an allergic condition?

Elevated Tryptase at 22 μg/L: Next Steps

A tryptase level of 22 μg/L exceeds the diagnostic threshold of 20 μg/L and mandates bone marrow evaluation to assess for systemic mastocytosis, while simultaneously requiring immediate safety measures including prescription of two epinephrine auto-injectors and comprehensive trigger avoidance education. 1

Immediate Safety Measures

Before any diagnostic workup, ensure patient safety:

• Prescribe two epinephrine auto-injectors (0.3-0.5 mg) to carry at all times, even if the patient is currently asymptomatic 1, 2
• Provide Medic Alert identification documenting elevated tryptase and anaphylaxis risk 1
• Educate on trigger avoidance: temperature extremes, physical stimuli (pressure, friction), certain medications (NSAIDs, opioids, vancomycin, contrast media), alcohol, stress, exercise, and hot water 1, 3

Confirm True Baseline Elevation

The critical first step is determining whether this represents a true baseline or acute elevation:

• Repeat tryptase measurement when the patient is completely asymptomatic (>24 hours after any symptoms) to establish true baseline 1, 3
• If measured during or shortly after symptoms, the value may reflect recent mast cell degranulation even without recognized symptoms 1
• Acute tryptase peaks at 60-90 minutes after mast cell activation and persists up to 6 hours 1

If baseline tryptase remains >20 μg/L on repeat testing, proceed directly to bone marrow evaluation as this meets a minor diagnostic criterion for systemic mastocytosis 1, 4

Comprehensive Clinical Assessment

Systematically assess for subtle manifestations of mast cell mediator release across multiple organ systems 1:

Cutaneous Manifestations

• Urticaria, pruritus, flushing, angioedema (most common) 1
• Positive Darier's sign (wheal formation with stroking) occurs in 89-94% of cutaneous mastocytosis 1
• Bullae formation, particularly in mastocytoma cases 1

Gastrointestinal Symptoms

• Diarrhea, abdominal cramping, nausea, vomiting, bloating 1
• These respond to H2 antihistamines and cromolyn sodium 1

Cardiovascular Symptoms

• Hypotension, tachycardia, syncope, near-syncope, palpitations, vasomotor instability 1
• When occurring with at least one other organ system, indicates systemic anaphylaxis 1

Historical Red Flags

• Severe anaphylaxis to Hymenoptera (bee/wasp) stings is strongly associated with underlying mastocytosis 1
• Recurrent "idiopathic" anaphylaxis 1

Mandatory Bone Marrow Evaluation

A persistently elevated baseline tryptase >20 μg/L mandates bone marrow evaluation 1, 4, 5. The evaluation must include:

• Bone marrow aspiration and core biopsy 1
• Immunohistochemistry for CD117, CD25, and CD2 expression on mast cells 1
• KIT D816V mutation testing (present in >90% of systemic mastocytosis) 1
• Flow cytometry to assess mast cell immunophenotype 1

WHO Diagnostic Criteria for Systemic Mastocytosis

Requires either:

• Major criterion + one minor criterion, OR
• Three minor criteria 1

Major criterion: Dense mast cell infiltrate (≥15 mast cells in aggregates) in bone marrow or other extracutaneous organs 1

Minor criteria:

1. 25% of mast cells are spindle-shaped or atypical

2. KIT D816V mutation detected
3. Mast cells express CD25 and/or CD2
4. Baseline tryptase >20 μg/L 1

Consider Hereditary Alpha-Tryptasemia

Before assuming pathology, consider this benign genetic variant:

• Approximately 4-6% of the general population carry germline TPSAB1-α copy number gains, resulting in elevated baseline tryptase without systemic mastocytosis 1
• Associated symptoms include flushing, pruritus, dysautonomia, gastrointestinal symptoms, chronic pain, and joint hypermobility 1
• Genetic testing can confirm this diagnosis 1

Distinguish from Mast Cell Activation Syndrome (MCAS)

If bone marrow evaluation is negative for systemic mastocytosis, consider MCAS:

• Diagnostic criteria: Acute elevation >20% + 2 μg/L above baseline on at least 2 separate occasions 1, 4
• Symptoms must affect at least 2 organ systems concurrently 1
• Requires documentation of acute tryptase during symptomatic episodes: initial sample as soon as feasible, second at 1-2 hours after symptom onset, third at 24 hours or in convalescence 1, 3

Other Causes of Elevated Tryptase

Rule out alternative explanations 4, 6:

• Acute myelocytic leukemia
• Myelodysplastic syndromes
• Hypereosinophilic syndrome with FLP1L1-PDGFRA mutation
• End-stage renal failure
• Recent anaphylaxis (even without recognized symptoms)

Ongoing Management Strategy

Antimediator Therapy

If symptomatic, initiate 1:

• H1 antihistamines (cetirizine, diphenhydramine, or hydroxyzine)
• H2 antihistamines (ranitidine or famotidine)
• Cromolyn sodium for gastrointestinal symptoms
• Leukotriene receptor antagonists

Monitoring

• Annual tryptase monitoring for confirmed systemic mastocytosis to assess disease burden 1
• Instruct patient to maintain detailed symptom diary documenting episodic symptoms, timing, potential exposures, and activities 1

Specialist Referral

• Establish care with both allergy/immunology and hematology for multidisciplinary management 1
• Specialized clinics with collaboration between these specialties provide optimal care 3

Critical Caveat

Tryptase >200 ng/mL requires urgent hematology referral and possible hospitalization, as it strongly suggests advanced systemic mastocytosis or mast cell leukemia 1. Your patient at 22 μg/L does not meet this threshold but still requires systematic evaluation.