Defining baseline variability of serum tryptase levels improves accuracy in identifying anaphylaxis

Abstract

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. We sought to define a serum tryptase change that distinguishes baseline variability from anaphylaxis on the basis of intraindividual variation in BST. 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. 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. Aratio 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. 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.