Defining baseline variability of serum tryptase levels improves accuracy in identifying anaphylaxis
Open accessAbstract
Background Acute increases of ≥20% + 2 ng/mL (20 + 2 rule) over basal serum tryptase (BST) is the recommended threshold supporting a clinical diagnosis of anaphylaxis. Prospective studies have demonstrated high sensitivity for this algorithm after parenteral exposure, but specificity has not been evaluated.Objective We sought to define a serum tryptase change that distinguishes baseline variability from anaphylaxis on the basis of intraindividual variation in BST.Methods Ninety-three total subjects with atopy (n = 62) or hereditary α-tryptasemia (HαT) (n = 31) and ≥2 BST measurements were identified. Sequential BST variability measurements were modeled and threshold ratios that optimized sensitivity and/or specificity determined. Models were tested in 22 individuals with physician-diagnosed anaphylaxis and validated in independent cohorts of individuals with HαT (n = 33), indolent systemic mastocytosis (ISM) (n = 52), and ISM + HαT (n = 12). Mature tryptase levels were measured in HαT (n = 19) and ISM (n = 20). An online application was developed for clinical use.Results As a result of BST variability, 9.7% (9/93) of primary cohort patients, and 18% (6/33) of HαT, 30% (16/53) of ISM, and 25% (3/12) of ISM + HαT patients from validation cohorts met the 20 + 2 rule despite absent immediate hypersensitivity symptoms; mature tryptase was noncontributory among individuals with HαT or ISM at baseline. A ratio of acute tryptase/BST exceeding 1.685 provided the optimized diagnostic rule for jointly maximizing sensitivity and specificity. Statistically significant improvement in specificity relative to the 20 + 2 rule was observed among individuals with elevated BST caused by HαT and ISM.Conclusions Using an acute tryptase/BST ratio of 1.685 improves specificity of measured changes among individuals with HαT and ISM while maintaining high sensitivity for confirmation of anaphylaxis.
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The monomeric forms of tryptase are secreted constitutively and can have some variability.
“The monomeric forms are secreted constitutively and can have some variability [23].”
From Diagnostic Significance of Tryptase for Suspected Mast Cell Disorders (2023) · cites this paper as [23]
The Results report that basal serum tryptase levels varied across repeated measurements, supporting the variability part of the claim. Our copy does not state that the variable tryptase was monomeric or that monomeric forms are secreted constitutively; the References list a study on spontaneous release of tryptase precursors, but that is not a finding established here. (LLM, conf=0.82)
Experimental — accuracy not yet measuredRecently, an acute-to-baseline tryptase ratio above 1.685 has been proposed to increase specificity in patients with indolent systemic mastocytosis and/or HαT as these patients can depict a variability in baseline tryptase without MCAS.
“Recently, an aST/bST ratio above 1.685 has been proposed to increase specificity in patients with ISM and/or HαT as these patients can depict a variability in bST without MCAS [23].”
From Diagnostic Significance of Tryptase for Suspected Mast Cell Disorders (2023) · cites this paper as [23]
The Abstract Results and Discussion support the proposed acute-to-baseline ratio of 1.685 and its improved specificity in people with ISM and/or HαT whose baseline tryptase varies. The Results describe baseline measurements taken without immediate hypersensitivity symptoms, but do not establish that the patients were free of MCAS; that part of the claim is more specific than the evidence. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThese authors proposed an acute tryptase value/BST ratio of 1.685 to improve specificity while maintaining high sensitivity.
“These authors proposed an acute tryptase value/BST ratio of 1.685 to improve specificity while maintaining high sensitivity (34).”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [34]
A recent study suggested the "20% + 2 formula" is not sufficiently performant when applied to patients with HαT and/or SM.
“a recent study suggested this approach to be not sufficiently performant when applied to patients with HαT and/or SM.”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [34]
An acute tryptase/BST ratio exceeding 1.6 is an optimized diagnostic rule with high sensitivity and specificity in SM and HαT, but the 20% of baseline + 2 ng/mL formula should be applied to cover all basal tryptase ranges.
“A ratio of acute tryptase/BST exceeding 1.6 provides an optimized diagnostic rule with high sensitivity and specificity in SM and HαT, but in order to cover all disorders (all ranges of basal tryptase), the 20% of baseline + 2 ng/mL formula should be applied.19”
From Mast cell activation syndrome: Current understanding and research needs (2024) · cites this paper as [19]
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References 23 · Cited by 91
- Authors
- Mateja, A., Wang, Q., Chovanec, J., Kim, J., Wilson, K. J., Schwartz, L. B., Glover, S. C., Carter, M. C., Metcalfe, D. D., Brittain, E., & Lyons, J. J.
- Affiliations
- Frederick National Laboratory for Cancer Research (US)
- National Institutes of Health (US)
- University of Mississippi Medical Center (US)
- Virginia Commonwealth University (US)
- Corresponding author
- Lyons, Jonathan J.
- ORCID
- Venue
- Journal of Allergy and Clinical Immunology
- Publisher
- Elsevier BV
- Published
- 2022-03
- Volume
- 149
- Issue
- 3
- Pages
- 1010-1017.e10
- ISSN
- 0091-6749 (ISSN-L)
- PMC
- PMC9126046
- OpenAlex
- W3194138138
- Cited by
- 91
- References
- 23
- Citations by year
- 2026: 18 · 2025: 19 · 2024: 18 · 2023: 19 · 2022: 16 · 2021: 1
- FWCI
- 5.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Allergy and Clinical Immunology (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- U.S. Public Health Service
- National Institutes of Health (75N91019F00130, 75N910D00024, R21DE028378)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
- Health Sciences › Medicine › Immunology and Allergy › Food Allergy and Anaphylaxis Research
- Health Sciences › Medicine › Pharmacology › Drug-Induced Adverse Reactions
- Keywords
- serum tryptase, anaphylaxis diagnosis, hereditary alpha-tryptasemia, indolent systemic mastocytosis, diagnostic specificity, atopy, web-based diagnostic tool
- MeSH terms
- Anaphylaxis, Humans, Mast Cells, Mastocytosis, Prospective Studies, Mastocytosis, Systemic, Tryptases
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