Is IgG (Immunoglobulin G) and IgA (Immunoglobulin A) sensitivity testing useful in patients suspected of having a mast cell disorder?

IgG and IgA Sensitivity Testing in Suspected Mast Cell Disorders

IgG and IgA sensitivity testing is NOT useful or recommended for diagnosing mast cell disorders, including systemic mastocytosis or mast cell activation syndrome. These tests are not part of any established diagnostic criteria and have no validated role in the evaluation of mast cell disorders.

Recommended Diagnostic Testing for Mast Cell Disorders

The diagnostic workup for suspected mast cell disorders should focus on validated markers of mast cell activation and clonality, not immunoglobulin sensitivity testing:

Initial Laboratory Evaluation

Serum Tryptase Measurement:

• Obtain baseline serum tryptase when the patient is completely asymptomatic to establish a personal reference value 1, 2
• During suspected mast cell activation episodes, collect acute serum tryptase 1-4 hours after symptom onset 1, 2
• A diagnostic increase requires ≥20% above baseline PLUS an absolute increase of ≥2 ng/mL 1, 2
• Persistently elevated baseline tryptase (>20 ng/mL) is a minor diagnostic criterion for systemic mastocytosis and warrants bone marrow evaluation 1, 3

Molecular Testing for Clonality

KIT D816V Mutation Analysis:

• Use highly sensitive allele-specific oligonucleotide quantitative PCR (ASO-qPCR) on peripheral blood as initial screening 1, 2, 3
• This mutation is detected in >80% of systemic mastocytosis patients when applied to bone marrow 1, 3
• Next-generation sequencing myeloid panels have only ~5% sensitivity for KIT D816V and are NOT recommended for this purpose 1, 3
• If peripheral blood testing is negative but clinical suspicion remains high, proceed to bone marrow testing 1, 3

Additional Mediator Testing

Urinary Metabolites (when serum tryptase is difficult to obtain or negative):

• 24-hour urine collection for N-methylhistamine (more reliable than direct histamine measurement) 2, 3
• Leukotriene E4 (peaks in 0-6 hour collections and can guide leukotriene antagonist therapy) 2, 3
• 11β-prostaglandin F2α (peaks in 0-3 hour collections and correlates with anaphylactic severity) 2, 3

Bone Marrow Evaluation

Indications for bone marrow biopsy:

• Persistently elevated baseline serum tryptase >20 ng/mL 1, 3
• Adult-onset mastocytosis in the skin 1
• Positive peripheral blood KIT D816V mutation 3
• Clinical features suggesting systemic mastocytosis 1, 3

Required bone marrow analyses:

• Aspirate and core biopsy to assess for multifocal dense infiltrates of ≥15 mast cells (major diagnostic criterion) 1
• Immunohistochemistry with tryptase, CD117, CD25, and optionally CD30 1
• Flow cytometry for CD117, CD25, CD2, and optionally CD30 1
• KIT D816V mutation testing on bone marrow if peripheral blood negative 1, 3
• Chromosome analysis, especially in suspected associated hematologic neoplasm 1
• Reticulin and collagen staining to assess bone marrow fibrosis 1

Clinical Context for Testing

When to suspect mast cell disorders:

• Episodic symptoms involving 2 or more physiological systems (cutaneous, GI, cardiac, respiratory, neuropsychiatric) 1
• Symptoms include visceral and somatic pain, pruritus, flushing, sweating, urticaria, angioedema, wheezing, tachycardia, abdominal cramping, vomiting, nausea, diarrhea 1
• Recurrent anaphylaxis without clear trigger 1
• Adult-onset mastocytosis in the skin 1

Tests NOT Recommended

The following tests have no validated role in mast cell disorder diagnosis:

• IgG or IgA sensitivity testing (not mentioned in any guideline or validated diagnostic criteria)
• Plasma or urine histamine levels (use N-methylhistamine instead) 2
• Heparin (not validated as a marker) 2
• Chromogranin A (resides in neuroendocrine cells, not mast cells) 2

Common Pitfalls

Overdiagnosis is a significant problem:

• In a prospective study, only 2% of patients with suspected MCAS actually met diagnostic criteria 4
• Many patients self-diagnose based on internet information without meeting validated criteria 5, 4
• Depression and anxiety disorders are frequent comorbidities that can mimic or amplify symptoms 4

Critical diagnostic requirements:

• All three criteria must be met for MCAS diagnosis: (1) episodic symptoms affecting ≥2 organ systems, (2) documented mediator elevation, and (3) response to mast cell-targeted therapy 6, 5
• Stringent diagnostic criteria must be fulfilled to confirm mast cell involvement with certainty 5

Referral Recommendations

Refer to allergy specialist or mast cell disease research center when:

• MCAS diagnosis is supported through clinical and/or laboratory features 1
• Additional specialized testing is needed (urinary N-methylhistamine, leukotriene E4, 11β-prostaglandin F2α) 1
• Symptoms remain refractory to first-line therapy 7