Alpha-gal Syndrome (AGS)
2022 Case Definition
2022 Case Definition
CSTE Position Statement(s)
Alpha-gal Syndrome (AGS) is a hypersensitivity reaction to galactose-α-1,3-galactose (alpha-gal), found in non-primate mammalian meat and certain derivative products.1-5 Unlike typical food allergies, symptoms are often delayed by two hours or more after exposure and can arise suddenly following years of safe meat consumption.6–8 Evidence suggests that the bite of some tick species induces immunoglobulin E (IgE) antibodies to alpha-gal, sensitizing patients to subsequent alpha-gal exposures.1,9–12 Symptoms typically include abdominal cramping, urticaria, and anaphylaxis.8 Diagnosis relies on a history of symptoms following exposure to mammalian products, and an elevated serum IgE specific to alpha-gal.6 AGS has been reported worldwide13; in the United States, it is most closely associated with lone star tick (Amblyomma americanum) bites.10 Research has suggested that other tick species, including Ixodes spp., may also be associated with AGS development.14,15 Reports of AGS in the scientific literature have been increasing over the last decade, but the true burden of cases is unknown. Additionally, much of the country may be at risk given the expanding geographic range of lone star and other ticks.16 Responding to the increased diagnosis of cases and public interest, multiple states have expressed a desire to quantify the burden of AGS. The standardization of case definition and reporting criteria is necessary in order to characterize disease burden, compare interstate disease incidence, and monitor trends in patient demographics, morbidity, mortality, and geographic distribution of risk. This will inform public health recommendations and guidance. Preventing tick bites is the main strategy for AGS intervention1–3; disease surveillance could, therefore, inform activities to strengthen occupational health protocols of suspected risk groups and public health messaging regarding tick bite prevention behaviors, with the goal of reducing tick borne disease risk.11,17
- Acute onset of any one or more of the following allergic and/or gastrointestinal symptoms that occur 2–10 hours after ingestion of pork, beef, lamb, any other mammalian meat, or any mammalian-derived product (e.g. gelatin), OR within two hours after intramuscular, intravenous, or subcutaneous administration of alpha-gal-containing vaccination or medication:
- Abdominal pain
- Anaphylaxis as diagnosed by a provider
- Swelling of one or more of the following: lips, tongue, throat, face, eyelids, or other associated structures
- Shortness of breath
- Acute episode of hypotension*
- the absence of a clear alternative diagnosis.
* Normal values for systolic blood pressure vary by age. Hypotension is classified by systolic blood pressure <90 mmHg for ages 11+ years; < [70 mmHg + 2 x age] for ages 1 -10 years; <70 mmHg for ages less than 1 year.
Confirmatory laboratory evidence:
- Serum or plasma immunoglobulin E specific to alpha-gal (sIgE) ≥ 0.1 IU/mL or ≥ 0.1 kU/L.
Presumptive laboratory evidence:
- An allergy skin test result that is interpreted by the ordering provider as consistent with alpha-gal allergy based on sensitivity to one or more mammalian meats (e.g., pork, beef, lamb) or other mammalian-derived products.
Note: The categorical labels used here to stratify laboratory evidence are intended to support the standardization of case classifications for public health surveillance. The categorical labels should not be used to interpret the utility or validity of any laboratory test methodology.
Criteria to Distinguish a New Case from an Existing Case
A case should only be counted if not previously reported to public health authorities.
Meets confirmatory laboratory evidence with no clinical information available.
Meets clinical criteria AND presumptive laboratory evidence.
Meets clinical criteria AND confirmatory laboratory evidence.
- Hashizume H, Fujiyama T, Umayahara T, Kageyama R, Walls AF, Satoh T. Repeated Amblyomma testudinarium tick bites are associated with increased galactose-α-1,3-galactose carbohydrate IgE antibody levels: A retrospective cohort study in a single institution. J Am Acad Dermatol 2018;78(6):1135-1141.e3.
- Kim MS, Straesser MD, Keshavarz B, et al. IgE to galactose-α-1,3-galactose wanes over time in patients who avoid tick bites. J Allergy Clin Immunol Pract 2020;8(1):364-367.e2.
- Prose R, Breuner NE, Johnson TL, Eisen RJ, Eisen L. Contact Irritancy and Toxicity of Permethrin-Treated Clothing for Ixodes scapularis, Amblyomma americanum, and Dermacentor variabilis Ticks (Acari: Ixodidae). J Med Entomol 2018;55(5):1217–24.
- Galili U. The alpha-gal epitope and the anti-Gal antibody in xenotransplantation and in cancer immunotherapy. Immunol Cell Biol 2005;83(6):674–86.
- Hilger C, Fischer J, Wölbing F, Biedermann T. Role and Mechanism of Galactose-Alpha-1,3-Galactose in the Elicitation of Delayed Anaphylactic Reactions to Red Meat. Curr Allergy Asthma Rep 2019;19(1):3.
- Commins SP, Satinover SM, Hosen J, et al. Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-α-1,3-galactose. Journal of Allergy and Clinical Immunology 2009;123(2):426-433.e2.
- Platts-Mills TAE, Li R, Keshavarz B, Smith AR, Wilson JM. Diagnosis and Management of Patients with the α-Gal Syndrome. The Journal of Allergy and Clinical Immunology: In Practice 2020;8(1):15-23.e1.
- Commins SP, Jerath MR, Cox K, Erickson LD, Platts-Mills T. Delayed anaphylaxis to alpha-gal, an oligosaccharide in mammalian meat. Allergology International 2016;65(1):16–20.
- Mitchell CL, Lin F-C, Vaughn M, Apperson CS, Meshnick SR, Commins SP. Association between lone star tick bites and increased alpha-gal sensitization: evidence from a prospective cohort of outdoor workers. Parasites Vectors 2020;13(1):470.
- Commins SP, James HR, Kelly LA, et al. The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose. J Allergy Clin Immunol 2011;127(5):1286-1293.e6.
- Fischer J, Lupberger E, Hebsaker J, et al. Prevalence of type I sensitization to alpha-gal in forest service employees and hunters. Allergy 2017;72(10):1540–7.
- Gonzalez-Quintela A, Dam Laursen AS, Vidal C, Skaaby T, Gude F, Linneberg A. IgE antibodies to alpha-gal in the general adult population: relationship with tick bites, atopy, and cat ownership. Clin Exp Allergy 2014;44(8):1061–8.
- van Nunen S. Tick-induced allergies: mammalian meat allergy, tick anaphylaxis and their significance. Asia Pac Allergy 2015;5(1):3–16.
- Young I, Prematunge C, Pussegoda K, Corrin T, Waddell L. Tick exposures and alpha-gal syndrome: A systematic review of the evidence. Ticks and Tick-borne Diseases 2021;12(3):101674.
- Crispell G, Commins SP, Archer-Hartman SA, et al. Discovery of Alpha-Gal-Containing Antigens in North American Tick Species Believed to Induce Red Meat Allergy. Front Immunol 2019;10:1056.
- Eisen RJ, Eisen L, Beard CB. County-Scale Distribution of Ixodes scapularis and Ixodes pacificus (Acari: Ixodidae) in the Continental United States. J Med Entomol 2016;53(2):349–86.
- Bellamy P. Sanderson WT, Winter K, Stringer JW, Kussainov N, Commins SP. Prevalence of alpha-gal sensitization among Kentucky timber harvesters and forestry and wildlife practitioners. The Journal of Allergy and Clinical Immunology: In Practice. 2020; S2213-2198(20)31353-2.