Algorithms in allergy: An algorithm for alpha‐Gal syndrome diagnosis and treatment, 2024 update
Authors: U. Darsow, A. Gelincik, U. Jappe, T. A. Platts‐Mills, D. Ünal, T. Biedermann
Journal: Allergy (2024)

Galactose α-1,3-galactose (alpha-Gal) syndrome, a delayed type I red meat (RM) allergy based on the production of specific IgE antibodies (sIgE) to the oligosaccharide alpha-Gal, is a unique entity. It is (A) an often severe and (B) mainly delayed anaphylaxis associated with a carbohydrate that shows no similarity with the classical carbohydrate determinants (CCD),1 and (C) is the only allergy that is considered a tick-borne disease without being positively correlated with tick borne infections.2-6 Due to its mammalian origin, alpha-Gal-IgE may induce allergy not only to the respective foods but also to drugs of mammalian origin (i.e., antivenom products, gelatin-containing plasma expanders) or derived from a production process that includes mammalian cells/tissue. Due to the complexity of this entity, the term alpha-Gal syndrome was coined. Persistent local reactions, itching for two or more weeks and recall urticaria after tick bites have been shown to represent a typical sign for sensitization, and furthermore indicated that tick bites are involved in the specific antibody production to alpha-Gal.4, 5, 7-10 In the United States, 2% of the population show elevated sIgE to alpha-Gal.11 In Europe, an overall prevalence of sensitization to alpha-Gal between 5.5% and 24.5% could be observed with significantly elevated sensitization rates in rural regions.12 As many as 44.4% of alpha-Gal-IgE-positive individuals were atopic,12 with increased alpha-Gal sIgE in patients with previous tick bites during the last year. Mammalian meat-induced delayed anaphylaxis was found in 8.6% of forest employees with alpha-gal-sIgE levels ≥0.35 kUA/L.3 The diagnosis of alpha-Gal syndrome is made by integrating history, specific sensitization and oral challenge test (Figure 1).13, 14 Urticaria/angioedema with gastrointestinal, cardiovascular and/or bronchial symptoms several hours (or faster, depending on cofactors and exposure) following the ingestion of RM, innards or other sources of alpha-Gal is suggestive. As an exclusive intestinal involvement of alpha-Gal syndrome may occur,14 it is an important differential diagnosis for inflammatory bowel diseases. Alpha-Gal syndrome may also present as occupational disease and has recently even been accepted as such by the authorities in Germany.15 In cases of anaphylaxis due to unknown causes, alpha-Gal syndrome is a plausible differential diagnosis. Unlike the traditional delayed allergic symptoms due to alpha-Gal allergy, early-onset of symptoms has also been reported after RM consumption with concomitant cofactors16-18 and innards. Insomuch that a 2-h cut-off has been proposed to time the discrimination between early-onset and delayed-onset alpha-Gal allergy.16, 18 Various sources of alpha-Gal exposure for example, in food are included in test systems for the management of cases,13 (Figure 1). Skin prick tests with fresh meat often show only weak positivity. Alpha-Gal-associated meat allergy can be delineated by the demonstration of specific IgE to alpha-Gal (alpha-galactosylated bovine thyroglobulin is mostly used in FEIA). On the other hand, IgE-detection on the basis of bovine thyroglobulin can be false negative.15, 19 The reason for false-negative results obtained with bovine thyroglobulin could be steric in nature so that patients' IgE cannot bind to the alpha-Gal epitope or due to the number of alpha-Gal epitopes on the protein used. This could be overcome by a different method including several different alpha-Gal-carrying proteins into routine diagnostics in the future as was convincingly shown by an accordingly designed multiplex assay.15, 19 The basophil activation test (BAT) was shown to distinguish patients with alpha-Gal syndrome from subjects with asymptomatic alpha-Gal sensitization: Basophil reactivity at distinct allergen concentrations, the % CD631/anti-FcεRI ratio across most allergen concentrations, the AUC of dose–response curves, and basophil allergen threshold sensitivity (CD-sens) with pork kidney extract were significantly higher in patients with alpha-gal syndrome compared with those in sensitized subjects.20 However, availability of BAT varies. Thus, oral challenge with preferably cooked porcine kidney including cofactors is necessary to prove the diagnosis.13 Management is based on avoidance (Figure 2). However, despite all efforts in avoidance, serious reactions may occur due to accidental ingestion.11 Oral immunotherapy (OIT) with mammalian meat was first successfully administered to two adult patients with alpha-Gal induced delayed RM allergy by Unal et al.21 Five years of experience on OIT to alpha-Gal of the same study group revealed that OIT can treat both early- and delayed-onset symptoms in alpha-Gal RM allergy with two different OIT protocols18 awaiting confirmation in further studies (Figure 2). It was observed that during the maintenance phase of OIT when patients are only exposed to occasional tick bites, they can reveal high serum alpha-gal sIgE levels and present systemic hypersensitivity reactions. We recommend measuring alpha-gal sIgE levels in patients exposed to tick bites and have a hypersensitivity reaction during the maintenance phase of OIT. It has been observed that loss of tolerance may occur in patients who give a break of more than 3 days during maintenance of RM OIT.22 The results of these studies show that there are risks associated with OIT, data should be carefully interpreted regarding the low patient numbers from only one country. Multicentre studies on larger patient cohorts are needed to further evaluate this procedure. U.D., A.G., U.J., T.P.M., D.Ü. and T.B. consensually prepared this manuscript. U.D.—Coordination and draft. Authors thank C. Kugler (Munich) for her contribution to dietary management. No special funding for this article. The authors declare no conflict of interest. Not applicable.