Hereditary α-Tryptasemia Linked to Greater Risk of Drug-Induced Anaphylaxis

In a recent study, patients with hereditary α-tryptasemia (HαT) had a 13% prevalence of drug-induced anaphylaxis.1

“This is the first report investigating HαT and α-tryptase genotypes as a risk factor for potentially life-threatening reactions in patients with drug allergy or hypersensitivity to biological agents,” wrote investigators, led by Peter Korošec, MD, from the University Clinic of Respiratory and Allergic Diseases in Slovenia.

HαT, caused by extra copies of the TPSAB1 gene that increases α-tryptase and leads to high tryptase levels, occurs in approximately 5% of people in Western Europe and in the United States.2 Those with this genetic trait have a 50% chance of passing it down to their child, and 90% of people in the general population with increased baseline serum tryptase have HαT.

Studies have yet to show what function pro-tryptases serve in human health or disease in this patient population. Many symptoms are associated with HαT, including chronic skin flushing, itching, hives, bee sting allergy, dizziness, difficulty maintaining a normal pulse, chronic head, back, or joint pain, skeletal abnormalities, heartburn, IBS, food and drug reactions or intolerances, and sleep disturbances.3 However, it can be challenging to prove what symptoms caused HαT because of how common it is.2

Investigators sought to determine the impact of tryptase genotypes on drug-induced anaphylaxis.1 They also examined inciting agents causing the anaphylaxis and the severity of reactions.

“Our study suggests that increased germline copies of α-tryptase-encoding sequences at TPSAB1 are more prevalent among patients with anaphylaxis to drugs, and in both a discovery and validation cohort, the presence of HαT was associated with anaphylaxis to antibiotic and/or mAb,” investigators wrote.

The prospective discovery cohort included 99 patients, from a referral center in Slovenia, with drug-induced anaphylaxis who underwent tryptase genotyping by droplet digital PCR. The validation cohort included 26 patients from the Czech Republic.

HαT was associated with drug-induced anaphylaxis in 13% (n = 13) of the discovery cohort and 15% in the validation cohort (n = 4). Everyone with increased BST levels (11.6 to 21.9 ng/mL; n=14) in the discovery and validation cohort had HαT.

The study showed HαT had a greater prevalence in individuals with antibiotic- or mAb-induced anaphylaxis from both cohorts (26%) compared to those with anaphylaxis induced by NMBAs (n = 23), NSAIDs (n = 18), contrast (n = 3), chlorhexidine (n = 7), or other drugs (n = 10) (7%) odds ratio [OR] 4.1; 95% confidence interval [CI], 1.3 – 11.1; P = .02). Reactions were mostly severe (68%) grade 3 or 4, followed by grade 2 (17%) and grade 1 (15%).

“We found that the number of subjects with drug-induced anaphylaxis and H⍺T was more than twice that of the general population, and these findings are remarkably similar to previous data on adult patients with idiopathic anaphylaxis (17%) and severe Hymenoptera venom-triggered anaphylaxis (8.6%),” investigators wrote.

Additionally, patients with no α-tryptase had fewer HαT traits than in the general population, and those with more ⍺-tryptase copies had more severe reactions. Participants with 3 ⍺-tryptase copies had the greatest prevalence of severe anaphylaxis (73%), compared with 59% in participants with 1 to 2 copies and 58% in those without any copies.

“These initial data are interesting and justify looking at tryptase genotyping in other cohorts to evaluate any potential role for genotyping in clinical evaluation,” investigators wrote. “While the understanding of HαT as a modifier of mast cell-mediated reactions is currently nascent, our evolving data suggests that in patients with antibiotics or mAb-induced anaphylaxis, HαT may be more common…further studies are needed to evaluate if individuals with HαT are at higher risk of developing drug-induced anaphylaxis.

References

1. Korošec P, Lyons JJ, Svetina M, Koudová M, Bittóová M, Zidarn M, Sedláčková L, Rijavec M, Kopač P. Hereditary α-tryptasemia is associated with anaphylaxis to antibiotics and monoclonal antibodies. J Allergy Clin Immunol Pract. 2025 Apr 14:S2213-2198(25)00369-1. doi: 10.1016/j.jaip.2025.04.013. Epub ahead of print. PMID: 40239920.

2. Hereditary Alpha Tryptasemia (HaT). https://tmsforacure.org/hereditary-alpha-tryptasemia/. Accessed April 28, 2025.

3. Hereditary Alpha Tryptasemia and Hereditary Alpha Tryptasemia Syndrome FAQ. National Institute of Allergy and Infectious Diseases. https://www.niaid.nih.gov/research/hereditary-alpha-tryptasemia-faq. Accessed April 28, 2025.