Tryptase Identified in Review as Most Reliable Anaphylaxis Biomarker

A systematic review showed tryptase is the most widely used biomarker for diagnosing anaphylaxis using the “Rule of Twos” diagnosis strategies, with histamine and urinary PGD2 displaying potential.1

“Tryptase, despite being considered the most reliable, exhibits a sensitivity of only 49%,” wrote investigators, led by Roy Khalaf, MD, from McGill University in Quebec, Canada. “Hence, more than half of true anaphylactic cases could be misclassified as false negatives.”

Clinical criteria play a key role in diagnosing anaphylaxis, but sometimes, they are not enough. Other conditions, such as acute urticaria, asthma exacerbations, and neuroendocrine tumors, may present with similar clinical symptoms, making it harder to diagnose anaphylaxis. Laboratory biomarkers could help confirm the diagnosis of anaphylaxis.

Research has identified biomarkers for food and venom-induced anaphylaxis. Since these triggers involve IgE-mediated mast cell activation, biomarkers include tryptase and histamine.2

Investigators aimed to evaluate the diagnostic utility of potential biomarkers for anaphylaxis.1 The team conducted a systematic review of 28 studies (17 cohort studies and 11 case-control studies) from Embase and Medline (2004 – 2024) that evaluated the diagnostic test accuracy of tryptase, histamine, platelet-activating factor (PAF), PAF-acetylhydrolase (PAF-AH), and urinary prostaglandin D2 (PGD2) in confirmed anaphylaxis cases.

Studies had a generally high quality, with low to moderate risk of bias. The primary concerns of these studies included potential selection bias, such as excluding severe cases or incomplete follow ups and the variability in diagnostic accuracy due to different strategies for evaluating biomarkers.

The review followed PRISMA-DTA guidelines and included 18,749 participants, with 3,329 (17.8%) who had confirmed anaphylaxis. The team collected data on basic demographics, age at reaction, anaphylaxis triggers, specific handling of biomarker, half-life of biomarker, study bias, and sensitivity and specificity.

Among participants with anaphylaxis, 33.9% were male and 15.7% were < 18 years. Triggers included food (13.9%), neuromuscular blocking agents (11.7%), unspecified perioperative causative agent (5.6%), unspecified drugs (4.9%), antibiotics (3.7%), and venom (3.6%). More than half had unspecified triggers resulting in anaphylaxis (56.8%).

Biomarker sampling was conducted in an outpatient clinic (n = 1480), perioperatively (n = 840), emergency departments (n = 654), during oral challenge tests (n = 191), unspecified (n = 153), and during immunotherapy (n = 11). Biomarkers were measured at a single time point, excluding tryptase values, which were evaluated at baseline in 1447 patients. For the other biomarkers, this limits the ability to assess trends over time.

Most of the studies (n = 24) reported evaluating tryptase as a biomarker for anaphylaxis, with a pooled sensitivity and specificity of 0.49 and 0.82, respectively. Tryptase was evaluated using ImmunoCAP measurement within 2 hours of reaction.

Histamine, assessed in 6 studies, also showed promise as a biomarker, with a pooled sensitivity and specificity of 0.76 and 0.69, respectively. The biomarkers of PAF, PAF-AH, and urinary PGD2 had limited data, though urinary PGD2 showed some potential despite limitations of practical challenges—these biomarkers were only studied in 1 study.

The review suggests fluctuations in serum tryptase levels are a reliable marker for diagnosing anaphylaxis. Research supports the “Rule of Twos” for confirming an anaphylaxis, where a patient has a tryptase level of 2ng/mL above baseline plus 1.2 times the baseline value. Other studies used tryptase values > 11.4 ng/mL to diagnose anaphylaxis, and another defined the “Rule of Twos” as 1.2 times the baseline tryptase value plus 2 ng/mL.

“Our findings reinforce that although tryptase is the most clinically useful biomarker, no single biomarker currently demonstrates sufficient sensitivity to be used in isolation, for diagnosing anaphylaxis,” investigators wrote. “The review highlights the need for continued validation of histamine, PDG2, PAF, and PAF-AH for the diagnosis of anaphylaxis.”

References

1. Khalaf R, Prosty C, Davalan W, Abrams E, Kaouache M, Ben-Shoshan M. Diagnostic Utility of Biomarkers in Anaphylaxis: A Systematic Review and Meta-Analysis. J Allergy Clin Immunol Pract. 2025 Apr 14:S2213-2198(25)00362-9. doi: 10.1016/j.jaip.2025.04.008. Epub ahead of print. PMID: 40239922.

2. Beck SC, Wilding T, Buka RJ, Baretto RL, Huissoon AP, Krishna MT. Biomarkers in Human Anaphylaxis: A Critical Appraisal of Current Evidence and Perspectives. Front Immunol. 2019 Apr 5;10:494. doi: 10.3389/fimmu.2019.00494. PMID: 31024519; PMCID: PMC6459955.