Tick Talk: The Link Between Ticks and Red Meat Allergies

Ticks are the culprits behind illnesses such as Lyme disease, Rocky Mountain spotted fever, and babesiosis. Additionally, an unexpected association is found among ticks, a small oligosaccharide called alpha-gal, and red meat allergies. This association, in certain instances, can lead to severe anaphylactic reactions, posing a potential threat to life.

A recent article in the Annals of Emergency Medicine addressed alpha-gal as an increasingly prevalent trigger for anaphylaxis, stating that as many as 10% of patients diagnosed with idiopathic anaphylaxis have alpha-gal syndrome.^1,2

History
In 1991, Anthony Deutsch, MD, observed the link between tick bites and red meat allergies and presented his findings to the Georgia Allergy Society and the CDC. He documented a limited case series of 10 patients who experienced hives or anaphylaxis after consuming red meat several weeks to months after being bitten by ticks. Unfortunately, no additional statements or follow-ups were made for many years.³

In 2004, the FDA approved cetuximab, a chimeric mouse and human antibody against EGFR, used to treat colorectal cancer. However, post-market surveillance revealed that many patients developed allergic reactions, including anaphylaxis, to this drug. Concerns arose when these allergic reactions were noted to follow a geographic distribution.^1,4,5

In 2008, a paper in the New England Journal of Medicine identified galactose-alpha-1,3-galactose (i.e., alpha-gal) as the cause and confirmed the geographic distribution of allergic reactions to cetuximab; investigators documented allergic reactions in 0.6% of control subjects in Boston and 20% in Tennessee.⁶

In 2009, a team of allergists from Australia published a study involving 25 patients who had developed allergic reactions after consuming red meat. The study established a strong link between alpha-gal and red meat allergy, as all the patients had experienced tick bites before developing the allergy.⁷ Since then, additional reports from various regions around the globe have emerged. In the United States, red meat allergy from tick bites is mainly found in the southeastern region, which correlates with the North American lone star tick (Amblyomma americanum).^1,5,6

Pathophysiology
Galactose-alpha-1,3-galactose is an oligosaccharide attached to glycoproteins and glycolipids of cells and tissue of non-primate mammals.⁸ Humans do not have the enzyme (alpha 1,3-galactosyltransferase) to assemble alpha-gal from galactose.^8,10 A proposed teleological reason is found in a 1996 paper published in Nature, which showed that anti-gal antibodies in human serum quickly inactivate retroviruses produced from animal cells, thus protecting our distant ancestors from infections.⁹ The reason we lack this enzyme remains largely unknown, but it may have an evolutionary basis.

But what about ticks? Some studies have provided a molecular basis for endogenous alpha-gal synthesis in ticks, which appears to be the leading theory.¹⁰ Direct inoculation of alpha-gal from the saliva in a tick’s bite results in subsequent IgE-mediated allergic sensitization, leading to severe allergic reactions upon subsequent exposures to alpha-gal.^11,12 Allergists from the University of Virginia have hypothesized that tick bites might be the only cause of alpha-gal syndrome in the United States.¹

Clinical Presentation
The symptoms of alpha-gal syndrome are similar to those of a typical allergic reaction (i.e., urticaria and angioedema).¹ However, this condition differs from other allergic reactions, as it often includes more gastrointestinal symptoms such as nausea, vomiting, diarrhea, abdominal pain, and heartburn.¹³ These symptoms are believed to be caused by gut wall edema. The abdominal pain can be so severe that some patients have undergone surgical procedures, including exploratory laparotomy, appendectomy, and cholecystectomy, among others.^13,14 Apart from these symptoms, anaphylaxis caused by alpha-gal is similar to anaphylaxis caused by other factors.

Diagnosis
When diagnosing an allergic reaction caused by alpha-gal, the first step is being aware of the existence of this syndrome and considering it during the evaluation process. It is important to note that anaphylaxis from alpha-gal typically has a delayed onset, with symptoms occurring 2 to 8 hours after eating.¹⁵ This differs from typical anaphylaxis caused by other allergens, where symptoms usually appear within minutes.

To diagnose alpha-gal syndrome, a clinician can send a blood sample on a red-top tube to test for IgE antibodies to alpha-gal. A level greater than 0.1 IU/μL is said to be abnormal.^1,23 It is essential to note that this test will not result during the patient’s emergency department visit but can be very helpful during follow-up visits, as the ultimate treatment for alpha-gal is avoidance of possible exposures.

Treatment
In instances of anaphylaxis stemming from alpha-gal syndrome, immediate intervention mirrors standard procedures for any anaphylactic response, which include epinephrine, airway management, and resuscitation fluids.¹⁶ Monitor for a minimum of 6 hours; recognize that the potential for biphasic reactions may extend beyond this observation period.^16,17 Another consideration is the use of H1 and H2 blockers and steroids, as the allergen may persist in the digestive tract.¹

For patients exhibiting solely skin-related symptoms, there is no specific treatment protocol; however, antihistamines may be considered.¹ Upon discharge from the emergency department, patients should receive an epinephrine injector, training on its proper use, preventive measures, and clear return instructions.¹

Conclusion
According to a CDC study, alpha-gal syndrome may affect around 450,000 individuals in the United States. The incidence is expected to rise, likely due to climate changes favoring the expansion of tick populations.^18,19 A recent study revealed that 42% of health-care providers lacked awareness of the syndrome, and 35% were not confident in diagnosing and treating alpha-gal.²⁰ Emergency physicians need to be well-informed about this syndrome to consider it in the differential and, if feasible, initiate a diagnostic evaluation from the emergency department.¹

Given documented cases of fatal anaphylaxis resulting from alpha-gal syndrome, if suspicion arises, it is prudent to advise patients to avoid red meat and related mammalian products until they consult with an allergist.¹ A list of these products can be found on the CDC website; this information can be printed and given to the patient.

Other recommended actions include discharging patients with an epinephrine self-injector, providing education on its use, and elaborating on preventive measures to reduce the risk of exposure.

Emergency physicians should stay informed about this developing syndrome to ensure timely diagnosis and appropriate treatment.

Take-Home Points

• Alpha-gal syndrome is an allergy to an oligosaccharide found in non-primate mammals.
• It is estimated that as many as 10% of patients diagnosed with idiopathic anaphylaxis have alpha-gal syndrome.
• Awareness of this syndrome is essential in order to consider it in the differential.
• If feasible, a diagnostic evaluation can be started from the emergency department.

References 

1. Edlow JA. Alpha-Gal Syndrome: A Novel and Increasingly Common Cause of Anaphylaxis. Ann Emerg Med. 2023 Oct 11:S0196-0644(23)01187-3. doi: 10.1016/j.annemergmed.2023.08.491. Epub ahead of print. PMID: 37831041.
2. Carter MC, Ruiz-Esteves KN, Workman L, et al. Identification of alpha-gal sensitivity in patients with a diagnosis of idiopathic anaphylaxis. Allergy. 2018;73:1131-1134.
3. Steinke JW, Platts-Mills TA, Commins SP. The alpha-gal story: lessons learned from connecting the dots. J Allergy Clin Immunol. 2015 Mar;135(3):589-96; quiz 597. doi: 10.1016/j.jaci.2014.12.1947. PMID: 25747720; PMCID: PMC4600073.
4. O’Neil BH, Allen R, Spigel DR, Stinchcombe TE, Moore DT, Berlin JD, Goldberg RM. High incidence of cetuximab-related infusion reactions in Tennessee and North Carolina and the association with atopic history. J Clin Oncol. 2007 Aug 20;25(24):3644-8. doi: 10.1200/JCO.2007.11.7812. PMID: 17704414.
5. Mitchell CL, Lin FC, 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. Parasit Vectors. 2020 Sep 14;13(1):470. doi: 10.1186/s13071-020-04343-4. PMID: 32928302; PMCID: PMC7490856.
6. Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, Murphy BA, Satinover SM, Hosen J, Mauro D, Slebos RJ, Zhou Q, Gold D, Hatley T, Hicklin DJ, Platts-Mills TA. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008 Mar 13;358(11):1109-17. doi: 10.1056/NEJMoa074943. PMID: 18337601; PMCID: PMC2361129.
7. Van Nunen SA, O’Connor KS, Clarke LR, Boyle RX, Fernando SL. An association between tick bite reactions and red meat allergy in humans. Med J Aust. 2009 May 4;190(9):510-1. doi: 10.5694/j.1326-5377.2009.tb02533.x. PMID: 19413526.
8. Cabezas-Cruz A, Espinosa PJ, Alberdi P, et al. Tick galactosyltransferases are involved in α-Gal synthesis and play a role during Anaplasma phagocytophilum infection and Ixodes scapularis tick vector development. Sci Rep. 2018;8(1):14224. Published 2018 Sep 21. doi:10.1038/s41598-018-32664-z
9. Takeuchi Y, Porter CD, Strahan KM, Preece AF, Gustafsson K, Cosset FL, Weiss RA, Collins MK. Sensitization of cells and retroviruses to human serum by (alpha 1-3) galactosyltransferase. Nature. 1996 Jan 4;379(6560):85-8. doi: 10.1038/379085a0. PMID: 8538747. 
10. Platts-Mills TAE, Commins SP, Biedermann T, van Hage M, Levin M, Beck LA, Diuk-Wasser M, Jappe U, Apostolovic D, Minnicozzi M, Plaut M, Wilson JM. On the cause and consequences of IgE to galactose-α-1,3-galactose: A report from the National Institute of Allergy and Infectious Diseases Workshop on Understanding IgE-Mediated Mammalian Meat Allergy. J Allergy Clin Immunol. 2020 Apr;145(4):1061-1071. doi: 10.1016/j.jaci.2020.01.047. Epub 2020 Feb 10. PMID: 32057766; PMCID: PMC7301618.
11. 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
12. 12. Wen L, Zhou J, Yin J, et al. Delayed Anaphylaxis to Red Meat Associated With Specific IgE Antibodies to Galactose. Allergy Asthma Immunol Res. 2015;7(1):92-94. doi:10.4168/aair.2015.7.1.92
13. Commins SP. Diagnosis & management of alpha-gal syndrome: lessons from 2,500 patients. Expert Rev Clin Immunol. 2020;16(7):667-677. doi:10.1080/1744666X.2020.1782745
14. Commins SP. Invited Commentary: Alpha-Gal Allergy: Tip of the Iceberg to a Pivotal Immune Response. Curr Allergy Asthma Rep. 2016;16(9):61. doi:10.1007/s11882-016-0641-6
15. Keet CA, Wood RA. Food allergy and anaphylaxis. Immunol Allergy Clin North Am. 2007;27(2):193-vi. doi:10.1016/j.iac.2007.03.005
16. McHugh K, Repanshek Z. Anaphylaxis: Emergency Department Treatment. Emerg Med Clin North Am. 2022;40(1):19-32. doi:10.1016/j.emc.2021.08.004
17. Zilberstein J, McCurdy MT, Winters ME. Anaphylaxis. J Emerg Med. 2014;47(2):182-187. doi:10.1016/j.jemermed.2014.04.018
18. 1. Emerging tick bite-associated meat allergy potentially affects thousands. Centers for Disease Control and Prevention. July 27, 2023. https://www.cdc.gov/media/releases/2023/p0727-emerging-tick-bites.html.
19. Chacon Osorio GR, Palraj R, van Nunen S, White MJ. Newly Recognized α-Gal Syndrome in the Upper Midwestern United States. Mayo Clin Proc. 2022;97(9):1754-1755. doi:10.1016/j.mayocp.2022.07.003
20. Carpenter A, Drexler NA, McCormick DW, et al. Health Care Provider Knowledge Regarding Alpha-gal Syndrome – United States, March—May 2022. MMWR Morb Mortal Wkly Rep 2023;72:809—814 DOI: http://dx.doi.org/10.15585/mmwr.mm7230a1