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

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 alpha-tryptasemia (H alpha T) (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 H alpha T (n = 33), indolent systemic mastocytosis (ISM) (n = 52), and ISM + H alpha T (n = 12). Mature tryptase levels were measured in H alpha T (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 H alpha T, 30% (16/53) of ISM, and 25% (3/12) of ISM 1 H alpha T patients from validation cohorts met the 20 + 2 rule despite absent immediate hypersensitivity symptoms; mature tryptase was noncontributory among individuals with H alpha T 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 H alpha T and ISM. Conclusions: Using an acute tryptase/BST ratio of 1.685 improves specificity of measured changes among individuals with H alpha T and ISM while maintaining high sensitivity for confirmation of anaphylaxis.