Alpha-Gal, Anaphylaxis & Tryptase: Why This Blood Test Matters

Why Tryptase Testing Matters When Evaluating Mast Cell Activation and Anaphylaxis

Patients experiencing flushing, a racing heart, shortness of breath, dizziness, throat sensations, trembling, nausea, or a feeling that something terrible is happening may understandably believe they are having a severe allergic reaction. The challenge is that several of these symptoms can occur with both anaphylaxis and a panic or hyperventilation episode.

For this reason, a careful medical history, examination, and appropriate laboratory testing can be very important; especially when episodes are recurrent or the diagnosis is uncertain. Anxiety and panic attacks are specifically recognized in international anaphylaxis guidance as conditions that can mimic anaphylaxis.

What Is Tryptase? Tryptase is an enzyme found primarily within mast cells, immune cells involved in allergic and inflammatory reactions. When substantial systemic mast-cell activation occurs, as can happen during anaphylaxis, tryptase may be released into the bloodstream.

Measuring serum tryptase during an episode and comparing it with the patient's normal baseline can therefore provide objective evidence that mast cells were significantly activated. Tryptase is currently considered the most mast-cell-specific laboratory mediator routinely used to document systemic mast-cell activation.

Timing Is Extremely Important A tryptase level obtained days or weeks after an episode cannot tell us what was happening during the reaction. When possible, current allergy guidance recommends obtaining an acute serum tryptase within approximately 2 hours of the beginning of symptoms. A separate baseline tryptase should be obtained when the patient is well, generally at least 24 hours after complete resolution of the event. Tryptase typically rises after significant systemic mast-cell activation, reaches its highest concentration relatively early in the reaction, and then begins falling over the next several hours. This is why obtaining the blood sample at the correct time is so important.

It Is the Change From Baseline That Matters A common misconception is that the laboratory's normal reference range alone determines whether mast-cell activation occurred. It does not. Current consensus criteria compare the acute tryptase with that individual patient's own baseline tryptase. A commonly used criterion for significant systemic mast-cell activation is: Acute tryptase > (baseline tryptase × 1.2) + 2 ng/mL This is often called the “20% + 2” rule.

Example If a patient's normal baseline tryptase is 5 ng/mL: 5 × 1.2 = 6 6 + 2 = 8 ng/mL An acute tryptase rising above approximately 8 ng/mL would therefore meet this laboratory criterion for significant systemic mast-cell activation, even though the result might still appear close to or within some laboratories' reference ranges.

This illustrates why simply asking, “Was the tryptase high?” may be the wrong question. The better question is: “Did the tryptase rise significantly above this patient's normal baseline?” Why This Can Be Helpful When Panic Attacks Are Suspected Panic attacks and anaphylaxis can share symptoms such as: • Rapid heartbeat • Chest tightness • Shortness of breath • Lightheadedness • Trembling • Tingling • Nausea • A sensation of throat tightness • Intense fear or a feeling that something terrible is happening International anaphylaxis guidance includes anxiety and panic attacks among the recognized differential diagnoses of suspected anaphylaxis. However, anaphylaxis is more likely to produce objective findings resulting from systemic allergic mediator release, which can include hives, flushing, angioedema, wheezing or bronchospasm, vomiting or diarrhea, and significant cardiovascular changes such as hypotension. Importantly, not every patient with anaphylaxis develops hives or other skin findings.

An appropriately timed rise in tryptase can add valuable objective evidence that significant mast-cell activation occurred during the episode. Conversely, repeated episodes with properly timed tryptase measurements showing no significant change from baseline may prompt the treating physician to consider other explanations for the patient's symptoms. It should not automatically be assumed that those symptoms are psychological. Other cardiovascular, respiratory, neurologic, gastrointestinal, endocrine, autonomic, and allergic disorders may also mimic portions of an anaphylactic reaction.

A Normal Tryptase Does NOT Completely Rule Out Anaphylaxis This is one of the most important points for patients to understand. Anaphylaxis is a clinical diagnosis.

A patient can experience genuine anaphylaxis without demonstrating a diagnostic increase in serum tryptase. Therefore, a normal tryptase should never be used by itself to tell a patient that an allergic reaction did not occur. Tryptase is best viewed as supporting evidence, particularly when the diagnosis is uncertain. Likewise, emergency treatment should never be delayed while waiting for a tryptase result. When clinical anaphylaxis is suspected, treatment is based on the patient's symptoms and examination, with intramuscular epinephrine remaining the critical first-line therapy.

Tryptase and Mast Cell Activation Syndrome The term Mast Cell Activation Syndrome (MCAS) is sometimes used very broadly. Current consensus literature recommends considerably more stringent criteria.

Symptoms alone do not establish MCAS. A proper evaluation generally looks for compatible recurrent systemic symptoms together with objective evidence of mast-cell mediator release during an episode, and an appropriate clinical response to therapies directed at mast-cell mediators. The event-related increase in tryptase is one of the best-established objective laboratory measurements for demonstrating systemic mast-cell activation. The 20% + 2 rule was specifically developed so that meaningful mast-cell activation could be detected regardless of whether a patient's normal baseline tryptase is low, average, or elevated.

Other mast-cell mediator studies, including urinary metabolites of histamine, prostaglandins, and leukotrienes, may sometimes be considered by an allergist or mast-cell specialist when appropriate.

What About a High Baseline Tryptase? An elevated baseline tryptase is a different issue from an acute rise during a reaction. Persistently elevated baseline tryptase can occur for several reasons and does not by itself prove that a patient is experiencing ongoing mast-cell activation or MCAS. Depending upon the degree of elevation and the patient's history, further evaluation may be appropriate for conditions such as hereditary alpha-tryptasemia or a clonal mast-cell disorder such as systemic mastocytosis.

This is another reason both measurements can be useful:

1. Acute tryptase; obtained during the suspected reaction
2. Baseline tryptase; obtained when the patient is well The relationship between those two values often provides considerably more information than either number alone.

The Goal Is an Accurate Diagnosis For patients who have experienced a frightening reaction, the goal should never be to simply label every event as either “anaphylaxis” or “anxiety.” The goal is to determine as accurately as possible what actually happened. An accurate diagnosis can prevent two very different problems: A patient with genuine anaphylaxis should not have a potentially dangerous reaction dismissed as panic or anxiety.

At the same time, a patient experiencing panic, hyperventilation, vasovagal episodes, or another medical condition should not have to live believing that every episode represents life-threatening anaphylaxis. When clinically appropriate, obtaining an acute tryptase and comparing it with a properly obtained baseline tryptase can provide an important objective piece of that diagnostic puzzle.

Important Safety Information If symptoms suggest possible anaphylaxis, particularly difficulty breathing, significant throat or tongue swelling, faintness or low blood pressure, or rapidly developing symptoms involving multiple body systems; do not wait for laboratory testing before seeking emergency treatment. Tryptase helps physicians investigate what occurred. It is not a substitute for emergency treatment and should never delay epinephrine when anaphylaxis is suspected.

References

1. Golden DBK, et al. Anaphylaxis: A 2023 Practice Parameter Update. Annals of Allergy, Asthma & Immunology. 2024. Joint Task Force on Practice Parameters / AAAAI-ACAAI.
2. Wang J, et al. Anaphylaxis in Practice: A Guide to the 2023 Practice Parameter Update. AAAAI. 2024.
3. Cardona V, et al. World Allergy Organization Anaphylaxis Guidance 2020. World Allergy Organization Journal. 2020;13:100472.
4. Valent P, et al. Why the 20% + 2 Tryptase Formula Is a Diagnostic Gold Standard for Severe Systemic Mast Cell Activation and Mast Cell Activation Syndrome. International Archives of Allergy and Immunology. 2019;180:44–51.
5. Valent P, et al. Proposed Diagnostic Algorithm for Patients With Suspected Mast Cell Activation Syndrome. Journal of Allergy and Clinical Immunology: In Practice. 2019;7:1125–1133.
6. Gülen T. Using the Right Criteria for MCAS. Current Allergy and Asthma Reports. 2024.
7. Beyens M, et al. Diagnostic Significance of Tryptase for Suspected Mast Cell Disorders. 2023.