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Alpha-Gal Syndrome:
Overview, Diagnosis, and Treatment

About Alpha-Gal Syndrome

 
Alpha-Gal syndrome is a form of delayed allergic reaction to mammalian red meat.17

  • The allergic sensitization is to Galactose-α-1,3-galactose (α-Gal or alpha-Gal), a sugar molecule found in mammalian meat.1 
  • It is a tick-related allergy, with increase in serum IgE to alpha-Gal demonstrated following a bite specifically from the Lone Star tick (Amblyomma americanum) in the United States.2, 23
  • Thus, the syndrome can appear suddenly in people who have tolerated meat for years.3
  • Skin-prick tests for mammalian meat extracts often give weak or negative results for alpha-Gal sensitization, making alpha-Gal sIgE component testing a preferred diagnostic method for alpha-Gal sensitization.5,6

 
Unlike in most protein-based food allergies, where symptoms often appear within minutes of ingestion, symptom onset in alpha-Gal syndrome is typically delayed by 3 to 6 hours or more.6,7 This contributes to diagnostic confusion, as patients suffering from the syndrome struggle to connect their reaction to meat consumed hours before.

3 to 6 hours

Symptoms can appear 3 to 6 hours or more after the consumption of mammalian (red) meat.6,7

Common alpha-Gal symptoms include:1,4,8

  • Generalized skin reactions and itching (pruritus and urticaria)
  • Angioedema
  • Nausea, diarrhea, or indigestion (before the onset of other symptoms)
  • Anaphylaxis

The greater the number of tick bites, the greater the risk of developing an alpha-Gal sensitization.2

Alpha-Gal syndrome: a delayed diagnosis

In one study, almost 80 percent of patients with alpha-Gal syndrome weren’t diagnosed for more than seven years.9 This is due to a variety of factors, from the relatively recent discovery of the syndrome, to the common sudden adult onset, to the delay in symptom expression.
 
Like all food allergies, diagnosing a red meat or alpha-Gal allergy starts with a physical examination and, of critical importance, a food-allergy-focused patient history.10,11

This history can then be used to guide testing decisions and results interpretation. This systematic approach can help determine whether the reported history of food allergy, combined with laboratory data, points to a possible case of alpha-Gal syndrome, or whether other diagnostic pathways should be considered.

 

Who should be tested?

Alpha-Gal syndrome is more common in the southeastern and midwestern United States than in other parts of the country.2 This is likely because bites from the Lone Star tick are the predominant cause of the syndrome, and that is where the ticks are most populous.2 Although the exact prevalence of the disease is unknown, it is thought that prevalence is growing—an estimated 10 percent of some U.S. populations may have increased IgE levels of alpha-Gal.12
 

Distribution of cases of alpha-Gal syndrome in the USA

> 100 cases

41 - 99 cases

5 - 40 cases

1 - 4 cases

0 cases

Lone Star tick region
(Amblyomma Americanum)

Adapted from Platts-Mills T. The Alpha-gal Syndrome: IgE responses to galactose alpha-1,3-galactose induced by bites from lone star ticks.. Presentation presented at AAAI; 2019.

Reduced quality of life

Patients with alpha-Gal syndrome frequently go undiagnosed. However, they’re experiencing symptoms that can range from confusing and unpleasant to deadly. So while they remain undiagnosed, they are likely to make many increased emergency room and provider visits, searching for answers they don’t always get.9 All of this leads to them living in confusion, pain, and fear.

Common allergic triggers

Alpha-Gal is present in all mammals except for humans and old-world monkeys.13 Therefore, mammalian (red) meats such as beef, pork, and lamb are the most common triggers. 

But derivatives of red meat can be hiding in a variety of foods that aren’t always clearly labeled, like gelatin-containing foods and dairy.15,18 These derivatives can also be found in many medications and biologic therapies, of which patients need to be aware.14-18

There are also cofactors that relate to anaphylaxis and may increase risk or severity of reaction, including:
 

  • Non-steroidal anti-inflammatory drugs
  • Exercise
  • Alcohol
  • Recent tick bite(s)17,20
Click to View Allergic Trigger Risks

Not all triggers are equally likely to cause a reaction—see the chart above for triggers ranked from higher to lower risk.17

 

Cross-reactivity21,26

Some cross-reactivity occurs during skin-prick testing and the use of immunoassays with meat extracts and other animal-derived antigens. There are three conditions in which cross-reactivity occurs when testing with meat allergens:

  • When patients have a positive to one meat, they may show a reaction to another mammalian meat because of cross-reactivity
  • Cross-reactivity between meat and other foods from animal origin such as milk and egg. The prevalence of meat allergy in children with an identified milk allergy can be as high as 20%.
  • There is also cross-reactivity between meat and animal dander because of the albumins present in animal tissue. This is the reason for the pork-cat syndrome phenomena where patients can be allergic to pork and also have an allergy to the cat albumin Fel d 2.

Most patients with alpha-Gal syndrome could also have positive results to cat and dog extracts and cow’s milk.21,26

What is component testing?

What is component testing?

When it comes to alpha-Gal syndrome, skin-prick testing (SPT) with commercial meat extracts and raw meats may not reliable. The results are often negative or ambiguous, with weak skin reactions.4,5 In a series of 25 patients with IgE sensitization to alpha-Gal and allergic symptoms after consuming pork kidney, mammalian meat, or gelatin, only two had positive SPT results to commercially available extracts from pork, beef, lamb, or horse meat.19

 
This is where testing with allergen components comes in. With alpha-Gal allergen component blood testing, providers have access to a quantitative and reliable measure of specific IgE sensitization that can help aid in this especially challenging diagnosis.

Component testing can lead to:

  • Improved diagnosis of alpha-Gal mediated red meat allergy
  • Earlier diagnosis for appropriate lifestyle modifications
  • Clarity on cause of symptoms6

 
Component testing can also help distinguish cross-reactive patients whose symptoms are caused by pork-cat syndrome from those with alpha-Gal associated meat allergy, helping patients to understand if they need to avoid pork (as in pork-cat syndrome) or red meat altogether (as in alpha-Gal syndrome).21
 

It’s not just knowledge you’ll be giving them, but peace of mind, too.

Testing Confidence

Testing Increases Diagnostic Confidence

Adding diagnostic testing to aid in a differential diagnosis has been shown to increase confidence in diagnosis to 90 percent.i,ii Conventionally, a diagnosis of allergic or autoimmune disease relies on the case history and a physical examination. However, adding diagnostic testing to aid in a differential diagnosis has been shown to increase confidence in diagnosis.i,ii Diagnostic testing can also help to improve the patient’s quality of life and productivity, reduce costs associated with absenteeism, and optimize use of medication, in addition to decreasing unscheduled healthcare visits.iii,iv 

i. Duran-Tauleria E, Vignati G, Guedan MJ, et al. The utility of specific immunoglobulin E measurements in primary care. Allergy. 2004;59 (Suppl78):35-41.
ii. NiggemannB, Nilsson M, Friedrichs F. Paediatric allergy diagnosis in primary care is improved by in vitro allergen specific IgE testing. Pediatr Allergy Immunol. 2008;19:325-331
iii. Welsh N, et al. The Benefits of Specific Immunoglobulin E Testing in the Primary Care Setting. J Am Pharm Assoc. 2006;46:627.
iv. Szeinbach SL, Williams B, Muntendam P, et al. Identification of allergic disease among users of antihistamines. J Manag Care Pharm. 2004; 10 (3): 234-238

Learn more about testing.

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Management and care of patients with
alpha-Gal syndrome

Avoidance of mammalian (red) meat consumption is essential for alpha-Gal-sensitized patients. Management is focused on the avoidance of red meat, as well as further tick bites. Some patients may need to also eliminate dairy and gelatin-containing products from their diets.17
 
However, the serum level of alpha-Gal-specific IgE and thus the patient’s sensitization may decrease over time after a tick bite. Some patients who avoid subsequent tick bites for one to two years may be able to tolerate red meat again.23

 

 

Organ meat is associated with some of the highest allergic reactions in alpha-Gal syndrome.17

By diagnosing patients earlier, it is possible to reduce the unnecessary burden of alpha-Gal Syndrome.

References
  1. Alpha-gal Allergy [Internet]. Centers for Disease Control and Prevention. Centers for Disease Control and Prevention; 2019. Retrieved June 2020. https://www.cdc.gov/ticks/alpha-gal/index.html
  2. Commins SP, James HR, Kelly LA, Pochan SL, Workman LJ, Perzanowski MS, et al. The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-alpha-1,3-galactose. J Allergy Clin Immunol. 2011 May;127(5):1286-93.
  3. Steinke JW, Platts-Mills TA, Commins SP. The alpha-gal story: lessons learned from connecting the dots. J Allergy Clin Immunol. 2015;135(3):589‐597. doi:10.1016/j.jaci.2014.12.1947
  4. Kennedy JL, Stallings AP, Platts-Mills TA, Oliveira WM, Workman L, James HR, et al. Galactose-alpha-1,3-galactose and delayed anaphylaxis, angioedema, and urticaria in children. Pediatrics. 2013 May;131(5):e1545-52.
  5. Michel S, Scherer K, Heijnen IA, Bircher AJ. Skin prick test and basophil reactivity to cetuximab in patients with IgE to alpha-gal and allergy to red meat. Allergy. 2014 Mar;69(3):403-5.
  6. Commins SP, Satinover SM, Hosen J, Mozena J, Borish L, Lewis BD, et al. Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-alpha-1,3-galactose. J Allergy Clin Immunol. 2009  Feb;123(2):426-33.
  7. Commins SP, Platts-Mills TA. Delayed anaphylaxis to red meat in patients with IgE specific for galactose alpha-1,3-galactose (alpha-gal). Curr Allergy Asthma Rep. 2013  Feb;13(1):72-7.
  8. Tripathi A, Commins SP, Heymann PW, Platts-Mills TA. Delayed anaphylaxis to red meat masquerading as idiopathic anaphylaxis. J Allergy Clin Immunol Pract. 2014 May-Jun;2(3):259-65.
  9. Flaherty MG, Kaplan SJ, Jerath MR. Diagnosis of life-threatening alpha-gal food allergy appears to be patient driven. J Prim Care Community
  10. Burks AW, Tank M, Sicherer S, et al. ICON: Food allergy. J Allergy Clin Immunol. 2012;129:906-920. 
  11. Sicherer SH, Sampson HA. Food allergy: A review and update on epidemiology, pathogenesis, diagnosis, prevention, and management. J Allergy Clin Immunol. 2018 Jan;141(1):41-58
  12. Jackson WL. Mammalian meat allergy following a tick bite: a case report. Oxf Med Case Reports. 2018 Feb 21;2018(2):omx098. doi: 10.1093/omcr/omx098. PMID: 29492269; PMCID: PMC5822700.Health 
  13. Macher BA, Galili U. The Galα1, 3Galβ1, 4GlcNAc-R (α-Gal) epitope: a carbohydrate of unique evolution and clinical relevance. Biochimica Biophysica Acta (BBA)-General Subjects. 2008;1780(2):75-88.
  14. Mullins RJ, James H, Platts-Mills TA, Commins S. The relationship between red meat allergy and sensitization to gelatin and galactose-alpha-1,3-galactose. J Allergy Clin Immunol. 2012 May;129(5):1334-42.
  15. Caponetto P, Fischer J, Biedermann T. Gelatin-containing sweets can elicit anaphylaxis in a patient with sensitization to galactose-alpha-1,3-galactose. J Allergy Clin Immunol Pract. 2013 May-Jun;1(3):302-3.
  16. Stone CA, Jr., Hemler JA, Commins SP, et al. Anaphylaxis after zoster vaccine: Implicating alpha-gal allergy as a possible mechanism. J Allergy Clin Immunol. 2017;139(5):1710-1713.e1712.
  17. Platts-Mills T, Li R, Keshavarz B, Smith A, Wilson J. Diagnosis and Management of Patients with the α-Gal Syndrome. Journal of Allergy and Clinical Immunology: In Practice. 2020;8(1):15-23.e1.
  18. Van Nunen S. Galactose-alpha-1, 3-galactose, mammalian meat and anaphylaxis: a world- wide phenomenon? Curr Treat Options Allergy. 2014;1(3):262-77.
  19. Fischer J, Hebsaker J, Caponetto P, Platts-Mills TA, Biedermann T. Galactose-alpha-1, 3-galactose sensitization is a prerequisite for pork-kidney allergy and cofactor-related mammalian meat anaphylaxis. J Allergy Clin Immunol. 2014;134(3):755-9.
  20. Wolbing F, Fischer J, Koberle M, Kaesler S, Biedermann T. About the role and underlying mechanisms of cofactors in anaphylaxis. Allergy. 2013 Sep;68(9):1085-92.
  21. García B, Lizaso M. Cross-reactivity syndromes in food allergy. J Investig Allergol Clin Immunol. 2011;21(3):162-70.
  22. Kaplan AC, Carson MP. Diagnosing meat allergy after tick bite without delay. J Am Board Fam Med. 2018;31(4):650-652.
  23. Berg EA, Platts-Mills TA, Commins SP. Drug allergens and food - the cetuximab and galactose-alpha-1,3-galactose story. Ann Allergy Asthma Immunol. 2014 Feb;112(2):97-101.
  24. Geographic distribution of ticks that bite humans | CDC [Internet]. Centers for Disease Control and Prevention. 2020 [cited 2020 Jul 7]. Available from: https://www.cdc.gov/ticks/geographic_distribution.html
  25. Platts-Mills T. The Alpha-gal Syndrome:​ IgE responses to galactose alpha-1,3-galactose induced by bites from lone star ticks.​. Presentation presented at AAAAI; 2019.
  26. Restani P, Fiocchi A, Beretta B, Velona T, Giovannini M, Galli CL. Meat allergy: III--Proteins involved and cross-reactivity between different animal species. J Am Coll Nutr. 1997 Aug;16(4):383-9.