Alpha-gal Information

What Is Alpha-gal Syndrome (AGS)?

Alpha-gal syndrome also known as alpha-gal allergy or mammalian meat allergy, is a severe and potentially life-threatening allergy. It involves an IgE antibody response to galactose-alpha-1,3-galactose (alpha-gal), a sugar found in all mammals except for old world monkeys, apes, and humans (1). Alpha-gal syndrome was first described in 2008 (2). It is poorly understood within the medical community, because of its recent discovery and its varied and atypical presentation.

A Paradigm-Shifting Allergy

AGS differs from typical allergies in significant ways.

  • It is believed to be triggered by tick bites (3).
  • It is one of only two life-threatening carbohydrate allergies (4)
  • It causes atypical and delayed-onset symptoms (1,5,6).
  • The allergy component of AGS is only one dimension of an immune response with deeper implications (7).

“…there are also patients who have episodes of abdominal pain without any skin involvement. Those cases are a problem because the possibility of food allergy is not obvious, and they can be severe… Other diagnoses that arise less commonly are arthritis and chronic pruritis. Distinguishing [AGS] from chronic hives can be challenging (6).”

A Growing Threat to Public Health

  • The number of people being diagnosed with AGS is rising (8) as tick populations swell and their ranges expand (3,9).  Models suggest that this expansion will continue (10).
  • AGS is already a common allergy in some regions of the U.S. (11).
  • Throughout the South and much of the eastern U.S., AGS is the leading cause of adult-onset allergy and anaphylaxis (12).
  • Due to a lack of physician awareness (13), AGS is underdiagnosed and commonly misdiagnosed (14).
  • Diagnosis tends to be patient-driven, even in areas where AGS is prevalent (14).

In one recent study of anaphylaxis, AGS was found to be the number one trigger, accounting for 33% of the cases with a definitive cause. The number two cause was all other food allergies combined, at 28%. In the same study, recognition of AGS led to a reduction in the percentage of anaphylaxis cases without a definitive cause from 59% to 35% of total cases (44).

For more information about the growing AGS epidemic see An Emerging Epidemic

 

What Is Alpha-gal?

Galactose-alpha-1,3-galactose, or alpha-gal for short, is an oligosaccharide, or sugar. It is a common component of the glycolipids and glycoproteins produced by all mammals except for old world monkeys, apes, and humans. It is also produced by gut bacteria and many human pathogens.

Alpha-gal is also called the “alpha-gal linkage.” The “alpha-gal epitope” is the part of the alpha-gal antigen that antibodies attach to.

 

Galactose-alpha-1,3-galactose (alpha-gal)

How Do You Get Alpha-gal Syndrome?

  • Alpha-gal syndrome is believed to be triggered by the bite of certain species of ticks. In different parts of the world, different tick species are responsible (15).
  • In North America, the bite of the Lone Star Tick (Amblyomma americanum) thought to be the trigger (16).
  • It is likely that additional as of yet unidentified tick species (8), maybe other ectoparasites, like chiggers (17), and possibly even endoparasites (3,18) can trigger AGS.
  • Alpha-gal has been found in the saliva of Black-Legged Ticks (Ixodes scapularis) (8). It is likely that Black-legged Ticks can trigger AGS, as do other species in their genus, but this has yet to be demonstrated.
  • The Asian Longhorned Tick (Haemaphysalis longicornis), recently introduced in the U.S., is known to trigger AGS in Asia (19). As of yet, it has not been tied to any cases in the U.S, but it seems likely that it will be.
  • Only some people who are bitten by ticks that can trigger AGS actually develop it (6).
  • Even if you have been bitten by ticks before and did not develop AGS, a future bite could trigger it (3)..
  • Repeated tick bites are associated with a rise in alpha-gal IgE (20).
  • Multiple tick bites are associated with the onset AGS (3). Many patients report that they were bitten by ticks for many years, and then after being bitten by multiple ticks at once, they developed AGS.

What Is Alpha-gal Found In?

Alpha-gal is found in the tissues, cells, and fluids of mammals (1) as well as products containing mammalian-derived ingredients. These include (but are not limited to):

  • Mammalian meat (1), such as beef, pork, lamb, bison, venison, goat, rabbit, squirrel, groundhog, moose, elk, kangaroo, antelope, buffalo, etc.
  • Mammalian organs, including liver (21), kidneys, and intestines contain even more alpha-gal than mammalian meat (222324, 25, 26, 27)
  • Milk, dairy products (1,22) gelatin (27,28), and other foods with mammalian-derived ingredients, including many processed foods (2229)
  • Other mammalian products and byproducts
  • Cetuximab (a drug that played a role in the discovery of AGS) (30, 31), heparin, pancreatic and other enzyme replacements (36), drugs with gelatin capsules or mammalian-derived inactive ingredients, like some magnesium stearate, and many perioperative, prescription and OTC drugs (632, 3334, 353637, 38)
  • Many vaccines, including those that contain gelatin such as Zostavax and MMR and others (2835363940414243)
  • Many medical products and devices, including (but not limited to) some bioprosthetic heart valves (4546, 47, 48, 49), antivenoms (5051), plasma volume substitutes (28, 52), hemostatic agents (53), catgut sutures, topicals, adhesives, etc. (6,32, 3334, 3536,).
  • Many personal care and household products, such as those containing “hydrolyzed protein” (gelatin), lanolin, glycerin, collagen, and tallow.
  • Airborne particles, such as fumes from cooking meat

The food additive carrageenan is not made from mammals, it is made from red algae, but it contains the alpha-gal linkage/epitope (54, 55).

  • Although in a laboratory setting, three forms of carrageenan did not inhibit the binding of IgE to alpha-gal (56), it is well-known within the AGS community that many of us react to it. Anecdotal reports suggest that reactions to carrageenan can be severe and tend to have a more rapid onset than our reactions to alpha-gal in mammalian products.

What Foods Do Not Have Alpha-gal in Them?

Alpha-gal is NOT found in:

  • Fish or seafood.
  • Birds, like chicken, turkey, quail, and emu.
  • Reptiles, like snakes, crocodiles, and lizards or amphibians, like frogs
  • Plants, including all fruits, vegetables, and grains. Note that algae are not plants, and some algae do contain alpha-gal.
  • Some of these foods may be injected with, or otherwise contaminated by, mammalian products, byproducts, or carrageenan, especially chicken, turkey, and seafood.
  • Some people with AGS report reacting to canned tuna (6,), for reasons that are not clear, but may be related to fillers or contamination with dolphin.

References

1. Commins, S. P., et al. (2009). “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 123(2): 426-433.e422.

2.  Commins, S. P., et al. (2008). Anaphylaxis and IgE Antibodies to Galactose-Alpha-1,3-Galactose (alphaGal): Insight from the Identification of Novel IgE ab to Carbohydrates on Mammalian ProteinsJournal of Allergy and Clinical Immunology, Volume 121, Issue 2, S25.

3. Commins, S. P., et al. (2011). “The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose.” Journal of Allergy and Clinical Immunology 127(5): 1286-1293.e1286.

4. Soh, J. Y., et al. (2015). “Carbohydrates as food allergens.” Asia Pac Allergy 5(1): 17-24.

5. Levin, M., et al. (2019). “Galactose alpha-1,3-galactose phenotypes: Lessons from various patient populations.” Ann Allergy Asthma Immunol 122(6): 598-602.

6. Platts-Mills, T. A., et al. (2019). “Diagnosis and management of patients with the alpha-Gal syndrome.” J Allergy Clin Immunol Pract.

7. Commins, S. P. (2016). “Invited Commentary: Alpha-Gal Allergy: Tip of the Iceberg to a Pivotal Immune Response.” Curr Allergy Asthma Rep 16(9): 61.

8. Crispell, G., et al. (2019). “Discovery of Alpha-Gal-Containing Antigens in North American Tick Species Believed to Induce Red Meat Allergy.” Front Immunol 10: 1056.

9. Monzón, J. D., et al. (2016). “Population and Evolutionary Genomics of Amblyomma americanum, an Expanding Arthropod Disease Vector.” Genome Biology and Evolution 8(5): 1351-1360.

10. Raghavan RK, et al. Peterson AT, Cobos ME, Ganta R, Foley D (2019).  Current and Future Distribution of the Lone Star Tick, Amblyomma americanum (L.) (Acari: Ixodidae) in North America. PLOS ONE 14(1): e0209082.

11. Wilson, J. M. and T. A. E. Platts-Mills (2019). “Red meat allergy in children and adults.” Curr Opin Allergy Clin Immunol 19(3): 229-235.

12. Commins, S.P. (2018). Interview on “More people developing red meat allergy from tick bites.” CBS News

13. Flaherty, M. G., et al. (2018). “Patients’ Health Information Practices and Perceptions of Provider Knowledge in the Case of the Newly Discovered Alpha-gal Food Allergy.” Journal of Patient Experience.

14. Flaherty, M. G., et al. (2017). “Diagnosis of Life-Threatening Alpha-Gal Food Allergy Appears to Be Patient Driven.” Journal of Primary Care & Community Health 8(4): 345-348.

15. Cabezas-Cruz, A., et al. (2019). “Environmental and Molecular Drivers of the alpha-Gal Syndrome.” Front Immunol 10: 1210.

16. Commins, S. P. and T. A. E. Platts-Mills (2013). “Tick bites and red meat allergy.” Curr Opin Allergy Clin Immunol 13(4): 354-359.

17. Stoltz, L. P., et al. (2019). “Could chiggers be contributing to the prevalence of galactose-alpha-1,3-galactose sensitization and mammalian meat allergy?” J Allergy Clin Immunol Pract 7(2): 664-666.

18. Arkestål, K et al. (2011). “Impaired allergy diagnostics among parasite-infected patients caused by IgE antibodies to the carbohydrate epitope galactose-α1,3-galactose.” Journal of Allergy and Clinical Immunology Journal of Allergy and Clinical Immunology 127(4): 1024-1028

19. Chinuki, Y., et al. (2016). “Haemaphysalis longicornis tick bites are a possible cause of red meat allergy in Japan. Allergy 71(3): 421-425.

20. Hashizume, H., et al. (2018). “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 78(6): 1135-1141.e1133.

21. Bianchi, John (2019). Personal communication

22. Morisset, M., et al. (2012). “Anaphylaxis to pork kidney is related to IgE antibodies specific for galactose-alpha-1,3-galactose.” Allergy 67(5): 699-704.

23. Fischer, J., et al. (2014).Galactose-alpha-1,3-galactose sensitization is a prerequisite for pork-kidney allergy and cofactor-related mammalian meat anaphylaxis” Journal of Allergy and Clinical Immunology 134(3): 755 – 759

24. Fischer, J., et al. (2016). “Clinical spectrum of alpha-Gal syndrome: from immediate-type to delayed immediate-type reactions to mammalian innards and meat.” Allergo J Int 25: 55-62.

25. McPherson, T.B. et al. (2004). “Galα(1,3)Gal Epitope in Porcine Small Intestinal Submucosa.” Tissue Enggineering 6(3).

26. Fujiwara, M. and T. Araki (2019). “Immediate anaphylaxis due to beef intestine following tick bites.” Allergol Int 68(1): 127-129.

27. Caponetto, P., et al. (2013). “Gelatin-containing sweets can elicit anaphylaxis in a patient with sensitization to galactose-α-1,3-galactose.” The Journal of Allergy and Clinical Immunology: In Practice 1(3): 302-303.

28. Mullins, R. J., et al. (2012). “Relationship between red meat allergy and sensitization to gelatin and galactose-alpha-1,3-galactose.” Journal of Allergy and Clinical Immunology 129(5): 1334-U1217.

29. Kaman, K. and D. Robertson (2018). “ALPHA-GAL ALLERGY; MORE THAN MEAT?” Annals of Allergy, Asthma & Immunology 121(5): S115.

30. Chung, C.H. et al. (2008). “Cetuximab-Induced Anaphylaxis and IgE Specific for Galactose-α-1,3-Galactose.” N Engl J Med 358:1109-1117

31. Berg, E. A., et al. (2014). “Drug allergens and food-the cetuximab and galactose-alpha-1,3-galactose story.” Annals of Allergy Asthma & Immunology 112(2): 97-101.

32. Dunkman, W. J., et al. (2018). “What Does a Red Meat Allergy Have to Do With Anesthesia? Perioperative Management of Alpha-Gal Syndrome.” Anesth Analg.

33. Pfutzner, W. and K. Brockow (2018). “Perioperative drug reactions – practical recommendations for allergy testing and patient management.” Allergo J Int 27(4): 126-129.

34. Dewachter, P., et al. (2019). “Anesthetic management of patients with pre-existing allergic conditions: a narrative review.” Br J Anaesth 123(1): e65-e81.

35. Popescu, F. D., et al. (2019). “DRUG ALLERGIES DUE TO IgE SENSITIZATION TO alpha-GAL.” Farmacia 67(1): 43-49.

36. Swiontek, K., et al. (2019). “Drugs of porcine origin—A risk for patients with α-gal syndrome?” The Journal of Allergy and Clinical Immunology: In Practice 7(5): 1687-1690.e1683.

37.  Vidal C et al. (2016) Vaginal Capsules: An Unsuspected Probable Source of Exposure to α-GalJ Investig Allergol Clin Immunol 2016; Vol 26(6) : 388-389

38. Muglia, C., et al. (2015). “Anaphylaxis to medications containing meat byproducts in an alpha-gal sensitized individual.” Journal of Allergy and Clinical Immunology-in Practice 3(5): 796-797.

39. Akella, K., et al. (2017). “Alpha Gal-Induced Anaphylaxis to Herpes Zoster Vaccination.” CHEST 152(4): A6.

40. Bakhtiar, M., et al. (2017). “P66: ALLERGIC REACTION TO BOVINE GELATIN COLLOID: THE ROLE OF IMMUNOGLOBULIN E TOWARDS GALACTOSE-ALPHA-1,3-GALACTOSE: IMPLICATIONS BEYOND RED MEAT ALLERGIES.” Internal Medicine Journal 47(S5): 24-24.

41. Bradfisch, F., et al. (2019). “Case series of anaphylactic reactions after rabies vaccinations with gelatin sensitization.” Allergo J Int 28(4): 103-106.

42. Stone, C. A., Jr., et al. (2019). “Anaphylaxis after vaccination in a pediatric patient: further implicating alpha-gal allergy.” The Journal of Allergy and Clinical Immunology: In Practice 7(1): 322-324.e322.

43. Stone, C. A., Jr., et al. (2017). “Anaphylaxis after zoster vaccine: Implicating alpha-gal allergy as a possible mechanism.” Journal of Allergy and Clinical Immunology 139(5): 1710-1713.e1712.

44. Pattanaik, D., et al. (2018). “The changing face of anaphylaxis in adults and adolescents.” Annals of Allergy, Asthma & Immunology 121(5): 594-597.

45. Ankersmit, H. J., et al. (2017). “When meat allergy meets cardiac surgery: A driver for humanized bioprosthesis.” J Thorac Cardiovasc Surg 154(4): 1326-1327.

46. Hawkins, R. B., et al. (2016). “Premature Bioprosthetic Aortic Valve Degeneration Associated with Allergy to Galactose-Alpha-1,3-Galactose.” Journal of cardiac surgery 31(7): 446-448.

47. Kleiman, A. M., et al. (2017). “Delayed Anaphylaxis to Mammalian Meat Following Tick Exposure and Its Impact on Anesthetic Management for Cardiac Surgery: A Case Report.” A & a Case Reports 8(7): 175-177.

48. Mozzicato, S. M., et al. (2014). “Porcine or bovine valve replacement in 3 patients with IgE antibodies to the mammalian oligosaccharide galactose-alpha-1,3-galactose.” J Allergy Clin Immunol Pract 2(5): 637-638.

49. “Alpha-Gal Specific IgG Immune Response after Implantation of Bioprostheses.”

50. Fischer, J., et al. (2017). “Alpha-gal is a possible target of IgE-mediated reactivity to antivenom.” Allergy 72(5): 764-771.

51. Rizer, J., et al. (2017). “Acute hypersensitivity reaction to Crotalidae polyvalent immune Fab (CroFab) as initial presentation of galactose–1,3-galactose (-gal) allergy.” Clinical Toxicology 55(7): 668-669.

52. Farooque, S. et al. (2018). Anaphylaxis to intravenous gelatin‐based solutions: a case series examining clinical features and severity

53. Lied, G. A., et al. (2019). “Intraoperative anaphylaxis to gelatin-based hemostatic agents: a case report.” J Asthma Allergy 12: 163-167.

54. Tobacman, J. K. (2015). “The common food additive carrageenan and the alpha-gal epitope.” Journal of Allergy and Clinical Immunology 136(6): 1708-1709.

55. Martin Tanner, personal communication (2019).

56. Steinke, J.W. et al. (2015). “Reply to ‘The common food additive carrageenan and the alpha-gal epitope’.” Journal of Allergy and Clinical Immunology 136(6):1709–1710