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Dr. Onyinye I. Iweala discusses a recently published review that provided updated recommendations for ordering tryptase tests, sharing her expert insights.

State‑of‑the‑art recommendations for clinician use and interpretation of mast cell tryptase tests were delineated in a review recently published online in Annals of Allergy, Asthma & Immunology.

“Rapidly evolving pathophysiology knowledge and management guidelines affect tryptase use in clinical practice, explaining the need for frequent updates,” lead author Moïse Michel, PharmD, PhD, and colleagues wrote. “Such updates often lack context on the pathophysiology and methods regarding mast cells and tryptase, thus hampering the practicing clinician’s ability to get the full picture from tryptase test results.”

According to the review, peripheral blood levels of tryptase—the most specific mast cell biomarker available in clinical laboratories—inform the diagnostic, prognostic, and therapeutic assessment of 3 clinical categories:(1) immediate hypersensitivity reactions; (2) clonal mast cell diseases and other myeloid malignancies, and as a biomarker for the efficacy of chemotherapeutics targeting mast cell survival; and (3) hereditary α‑tryptasemia.

Beyond updated recommendations for tryptase test use and interpretation, the review synthesized successive advances in mast cell and tryptase research through the lens of contemporary knowledge, outlined unmet tryptase use needs, and highlighted selected ongoing research poised to inform clinical practice soon.

Ordering Tryptase Tests: An Expert’s Insights

“This is a fantastic [review] that is very helpful in providing the historical, biological, diagnostic, and management contexts for measuring tryptase,” comments Onyinye I. Iweala, MD, PhD, an expert in mast cell disorders who was not involved in developing the review. Physician’s Weekly (PW) spoke with Dr. Iweala to gain insights into what clinicians need to know about ordering mast cell tryptase tests.

PW: In what situations is tryptase testing most useful?

Dr. Iweala: Comparing serum acute tryptase (sAT) drawn within 4 hours of anaphylaxis or mast cell degranulation event with serum baseline tryptase (sBT) gives allergists a method to confirm an anaphylactic event.

Tryptase testing is a screening test for systemic mastocytosis. sBT of 20 ug/L or higher is one of the minor criteria for systemic mastocytosis and typically increases the suspicion that a patient could have a primary clonal mast cell disorder. Of note, though uncommon, patients can have sBT levels within normal limits and still be diagnosed with systemic mastocytosis through other criteria.

The test can also screen for patients with the genetic condition hereditary α-tryptasemia. Patients with tryptases of 8 ug/L or higher may have this gene mutation. Patients with this genetic condition may be perfectly healthy or have primary or secondary mast cell disorders. They are at increased risk for severe mast cell-driven hypersensitivity responses.

Tracking tryptase levels over time in patients with primary clonal mast cell disorders or myeloid neoplasms before and during disease-targeted therapies can assess mast cell burden in systemic mastocytosis or neoplastic burden in myeloid neoplasms. In these situations, it is a good measure of response to therapy.

How does timing affect tryptase interpretation?

When using tryptase to confirm severe anaphylaxis occurrence, timing is critical. As the authors wrote, we can find peak levels of tryptase in the blood within 1 to 2 hours after the anaphylactic event, then tryptase levels decline over the next 24 hours. So, using tryptase to confirm that anaphylaxis has occurred works best if the blood for the tryptase test is drawn between 30 minutes and 4 hours after the start of the event.

Why is it important to measure both acute and baseline tryptase levels?

Measuring acute and baseline tryptase levels is most helpful in confirming an episode of anaphylaxis driven by mast cell degranulation.

What should clinicians consider when results are borderline or mildly elevated?

The reason for checking tryptase and the clinical context will determine how borderline or mildly elevated tryptases are interpreted. For example, in a person with a history of spontaneous anaphylaxis, or anaphylaxis after a bee sting or other stinging insect encounter, a borderline or mildly elevated tryptase will prompt providers to consider the possibility of the genetic mutation for hereditary α-tryptasemia potentially driving the tryptase increase. However, there may still be a suspicion for a clonal mast cell disorder, although it may not be as strong a suspicion as when the tryptase is significantly elevated (20 or higher).

Borderline or mildly elevated tryptase in trying to confirm anaphylaxis may be due to collecting the blood tryptase level sample outside the 30-minute to 4-hour window.

The article notes that “additional causes of elevated sBT level, mainly chronic kidney failure, reactional MC hyperplasia, or myeloid neoplasms need to be assessed, keeping in mind that sBT values up to 15 µg/L might lack immediate association with a clinical condition.”

What are the limitations of current tryptase testing?

When you order a tryptase level, you don’t get the results until days after you send off the test, by which time your patient’s symptoms have typically resolved. This makes tryptase a helpful test for the allergist/immunologist or the hematologist/oncologist seeing a patient in the outpatient setting, counseling them about whether they had confirmation that their symptoms were due to anaphylaxis. However, it is not as useful for an emergency department provider, an anesthesiologist, or an urgent care provider to quickly confirm that a patient is experiencing anaphylaxis.

What further related research do you recommend?

I recommend research that tries to answer these questions:

• Can point-of-care tryptase testing be developed?
• Is there a role for comparing the ratio of mature to immature tryptase in the serum during anaphylaxis? Would doing this result in a more sensitive test that could identify more people with mast cell activation disorders or food, drug, or other triggers that can induce anaphylaxis?
• Are there other markers besides tryptase (or in combination with tryptase) that should be measured as markers of mast cell burden or mast cell activation to improve the diagnosis of individuals with mast cell disorders?
• Are there mast cell-specific biomarkers that are not affected by chronic kidney disease?