Alpha-Gal (Mammalian Meat) Allergy: Implications for Pharmacists

MAY 27, 2015
Indrani Kar, PharmD; Min Gong, PharmD candidate; Christine Muglia, MD; Catherine A. Monteleone, MD; and Evelyn R. Hermes-DeSantis, PharmD, BCPS
What Is Alpha-gal and Mammalian Meat Allergy?
Alpha-gal (galactose-alpha-1,3-galactose), a mammalian oligosaccharide, has recently been implicated in delayed anaphylaxis reactions to mammalian meat. First described in 2009, the alpha-gal allergy (red meat or mammalian allergy) is a novel form of IgE-mediated anaphylaxis; unlike most anaphylaxis, this reaction is delayed. Individuals with high IgE titers to alpha-gal have experienced urticaria, angioedema, and anaphylaxis symptoms 3 to 6 hours after ingesting mammalian meat (beef, pork, lamb, venison, goat, and bison), which is rich in alpha-gal.1
 
Many animal by-products may contain the alpha-gal epitope. Animal by-products derived from turkey, chicken, and fish, however, do not.2 Whereas the alpha-gal epitope is also present in cat IgA, a monoclonal antibody found in cat dander, cat exposure has not been associated with allergic reactions. However, patients with the alpha-gal allergy have shown positive skin and blood tests to cat IgA.1
 
The alpha-gal allergy affects both children and adults.3 The severity of the allergy and the allergy itself may recede over time.1
 
Evolution of Alpha-gal
Humans do not naturally produce alpha-gal epitopes, as the alpha-1,3-glycosyltransferase enzyme is inactivated in humans, old world monkeys, and apes. Other mammals, like new world monkeys, placental mammals, marsupials, and prosimians, however, produce alpha-gal and the enzyme. Humans produce IgG2 anti-gal naturally, which protects them against normal bacteria flora in the gut that produces the alpha-gal epitope.4 Patients with blood group B or AB have fewer anti-gal antibodies and therefore may be less likely to develop the mammalian meat allergy (or develop a milder reaction).5 Research suggests that exposure to the alpha-gal epitope in a tick bite may cause normal anti-gal antibody formation to switch from IgG2 to the IgE involved in the delayed anaphylaxis response to the specific types of mammalian meat previously mentioned.5,6
 
Prevalence and Location
Experts estimates that thousands of Americans have the alpha-gal allergy,7 with a causal relationship between lone star tick bites and these anaphylactic reactions. Individuals bitten by lone star ticks can develop IgE antibodies to alpha-gal. The highest infestations of lone star ticks occur in the eastern states.8  
 
Pharmacist’s Role
To prevent anaphylaxis, affected patients should avoid any medication, supplements, foods, etc that may contain the alpha-gal epitope; this is their only treatment option. A comprehensive list of medications containing alpha-gal or animal by-products is unavailable at this time. Alpha-gal allergy testing is commercially available and requires a serum sample.
 
As previously mentioned, many animal by-products may contain the alpha-gal epitope. Gelatin, derived from beef, is one .9 Animal-derived magnesium stearate is another. Cetuximab, a chimeric mouse–human IgG1 monoclonal antibody against epidermal growth factor receptor, contains the alpha-gal epitope in its Fab arm portion and has been known to cause the alpha-gal allergy.11 Additional medications, inactive ingredients, and procedures are also known to contain or utilize the alpha-gal epitope such as:
  •  Creon 102
  • Protein powders with whey2
  • Xenograft surgery6
 The issue with xenograft surgery has been resolved by using knock-out pigs lacking the alpha-gal epitope.4
 
To obtain information on animal by-product content, health care providers must contact manufacturers. Manufacturers do not currently report alpha-gal content in their package inserts or test for alpha-gal content in products. Inactive ingredient information can change at any time, and the FDA does not require manufacturers to disseminate this information. To prevent unnecessary exposure to alpha-gal, pharmacists should ensure that alpha-gal allergic patients avoid meat-containing medications. To provide timely patient care, alpha-gal information needs to be readily available, which is an area in which pharmacists can make an impact.10
 
Drug Information Service Contribution
At an academic medical center, a patient with the alpha-gal allergy with allergic reactions to antihypertensive medications presented to an immunologist.12 The medications contained gelatin and magnesium stearate. The drug information service proceeded to create an alpha-gal content database to support the selection of an appropriate antihypertensive pharmacotherapy regimen for patients who have the alpha-gal allergy. Pharmacists contacted manufacturers with the broadest range of antihypertensive medications, and asked, “Do your products contain galactose-alpha-1,3-galactose, alpha-gal, mammalian meat, or any animal by-products?” No manufacturers tested for the presence of alpha-gal in their product, but animal by-product content was available. All manufacturers took more than 24 hours to respond, and some required 1 or more call-back attempts.
 
Based on correspondence with manufacturers, the Table lists medications that do not contain animal by-products, suggesting they are alpha-gal-free. The drug information service continues to review and add medications to its database. It has reviewed hyperlipidemia medications, narcotics, and dermatologic creams to date.
 
Table: Medications that Do Not Contain Animal By-products (per the manufacturer)
Medication Manufacturer
Amlodipine Qualitest
Atenolol Mylan, Sandoz
Losartan potassium tablet, film coated Sandoz
Valsartan tablet Sandoz
Oxycodone liquid Lannett
Clotrimazole Natureplex
 
Although alpha-gal content cannot be completely ruled out, products without animal by-products theoretically may be used to safely treat patients with a documented alpha-gal allergy. One limitation of this database is that manufacturers do not routinely test for alpha-gal, so definitive conclusions cannot be drawn. However, the lack of information is intrinsic to the subject matter and not a database flaw.
 
The rising incidence and the serious nature of the alpha-gal allergy underscores the importance of properly managing patients. There is a need for more information on this topic. This database simplifies the task of verifying critical information and promotes timely decision making. The flexible design also allows for expansion to offer a complete reference. In the future, this database aims to compile all alpha-gal–related information into 1 central location for all medication classes.10
 
Conclusion
Pharmacists should be cognizant of patients presenting with anaphylaxis symptom, with a history of exposure to ticks and of consuming mammalian meats. The delay in symptom presentation may be attributed to the time required to digest meats. As pharmacists, knowing a patient’s full history will enhance recognition of the allergy.
 
Resources for pharmacists include the Alpha-Gal Allergy Awareness Web site (www.alpha-gal.org). The Robert Wood Johnson University Hospital drug information service database is available for use by pharmacists by calling 732-937-8842.
 
Additional research is required on the effect of alpha-gal in medications for patients with the alpha-gal allergy. Pharmacists, especially in the emergency department and ambulatory care settings who see patients with tick bites, should be aware of this allergy and medication’s potential to elicit symptoms.
 

Indrani Kar, PharmD, is a drug information resident at the Ernest Mario School of Pharmacy at Rutgers University and Robert Wood Johnson University Hospital in New Brunswick, New Jersey. Min Gong is a PharmD candidate at Ernest Mario School of Pharmacy. Christine Muglia, MD, is a second-year internal medicine resident at Robert Wood Johnson Medical School.
Catherine A. Monteleone, MD, is a professor of medicine at Robert Wood Johnson Medical School. Evelyn R. Hermes-DeSantis, PharmD, BCPS, is director, Drug Information Service, and a clinical professor, at Robert Wood Johnson University Hospital, Ernest Mario School of Pharmacy.

References
  1. 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 Res. 2013;13(1):72-77. doi: 10.1007/s11882-012-0315-y.
  2. Alpha-gal basics. Alpha-Gal Allergy Awareness website. http://alpha-gal.org. Published 2014. January 9, 2015.
  3. Kennedy JL, Stallings AP, Platts-Mills TA, et al. Galactose-α-1,3-galactose and delayed anaphylaxis, angioedema, and urticaria in children. Pediatrics. 2013;131(5):e1545-e1552. doi: 10.1542/peds.2012-2585.
  4. Tanemura M, Miyoshi E, Nagano H, et al. Role of α-gal epitope/anti-Gal antibody reaction in immunotherapy and its clinical application in pancreatic cancer. Cancer Sci. 2013;104(3):282-290. doi: 10.1111/cas.12084.
  5. Rispens T, Derksen NI, Commins SP, Platts-Mills TA, Aalberse RC. IgE production to α-gal is accompanied by elevated levels of specific IgG1 antibodies and low amounts of IgE to blood group B. PLos One. 2013;8(2):e55566. doi: 10.1371/journal.pone.0055566.
  6. Galili U. Anti-gal: an abundant human natural antibody of multiple pathogeneses and clinical benefits. Immunology. 2013;140(1):1-11. doi: 10.1111/imm.12110.
  7. Van Nunen S. Galactose-alpha-1,3-galactose, mammalian meat and anaphylaxis: a world-wide phenomenon? Curr Treat Options Allergy. 2014;1:262-277.
  8. Stromdahl EY, Hickling GJ. Beyond lyme: aetiology of tick-borne human diseases with emphasis on the south-eastern United States. Zoonoses Public Health. 2012;59(suppl 2):48-64. doi: 10.1111/j.1863-2378.2012.01475.x.
  9. 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;129(5):1334-1342.e1.. doi: 10.1016/j.jaci.2012.02.038.
  10. Gong M, Kar I, Monteleone CA, Hermes-DeSantis ER. Database creation of alpha-gal content in medications for patient care. Poster presented at American Society of Hospital Pharmacists’ Midyear Clinical Meeting; December 9, 2014; Anaheim, CA.
  11. Berg EA, Platts-Mills TA, Commins SP. Drug allergens and food – the cetuximab and galactose- α-1,3-galactose story. Ann Allergy Asthma Immunol. 2014;112(2):97-101. doi: 10.1016/j.anai.2013.11.014.
  12. Muglia C, Kar I, Gong M, Hermes-DeSantis E, Monteleone C. Anaphylaxis to medications containing meat by-products in an alpha-gal sensitized individual. J Allergy Clin Immunol Pract. 2015; In process.


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