What are institutional perioperative practices for patients with alpha-gal allergy?

Alpha-gal syndrome (AGS), also referred to as mammalian (or red) meat allergy, is a recently recognized allergic condition tied to tick bite exposure.^1,2 Saliva from the lone star tick (Ambylomma Americanum) contains the carbohydrate, galactose-α-1,3-galactose (alpha-gal), which is a component of the cell membrane in non-primate mammals such as cows, pigs, and sheep. Sensitization to alpha-gal, mediated through IgE, develops after the tick bite and subsequent exposure to alpha-gal-containing foods, food products, medications, and medical products, may lead to allergic reactions in some patients. A detailed overview of alpha-gal allergy, its epidemiology, and general considerations have previously been described in an FAQ written by this group in 2018. According to a 2023 CDC report, approximately 34,0000 suspected alpha-gal allergy cases were reported in the 8-year period between 2010 and 2018.³ However, this number has increased to about 13,000 to 18,000 every year between 2017 and 2022 for an approximate total of 90,000 cases over 6 years with a predominance occurring in those living in the southern, midwestern, and mid-Atlantic regions of the US.

Due to the increased recognition/awareness of alpha-gal allergy, recent reports have described a need to identify the presence of alpha-gal in products commonly used perioperatively due to the number of products used over a relatively short period of time in this setting.^4-7  The focus of this review is to summarize perioperative management practices from institutions that have seen a rise in the number of patients with alpha-gal allergy.

Preoperative Assessment
As part of the preoperative assessment, a patient history of any type of food, medication, or other intolerance or reaction should initiate further investigation.^4-7 Specific questions related to alpha-gal allergy include asking about red meat allergy and a previous allergic reaction to cetuximab, Zostavax (live varicella zoster), or yellow fever vaccine.⁵  Table 1 lists potential additional sources of alpha-gal.^4-7 Unlike typical anaphylactic reactions that occur immediately upon exposure, the allergic response to alpha-gal is typically delayed with initial symptoms first appearing up to 8 hours after exposure. Symptoms may be limited to the gastrointestinal (GI) tract or can include respiratory, cardiovascular, and systemic reactions such as urticaria, anaphylaxis, angioedema. Before attributing GI symptoms after food consumption to GI intolerance or asserting a diagnosis of idiopathic anaphylaxis, healthcare providers should rule out alpha-gal allergy through patient history and IgE testing. Since not all patients with positive alpha-gal IgE exhibit allergic reactions, a thorough patient history of reactions and rechallenges to suspected sources of allergens is required. According to some authors, alpha-gal IgE levels above 2 IU/mL increase the risk of severe allergic reactions.⁵ Risk factors for AGS include frequent outdoor activity in areas endemic to ticks, repeated tick bites, and non-B blood groups.

The information on products containing alpha-gal and their association with eliciting a reaction in patients with alpha-gal IgE is evolving and can change over time. As such, a comprehensive resource listing alpha-gal presence in specific products and their associated risk of an allergic reaction is lacking. Additional challenges include the lack of reporting of ingredient source (animal vs plant) by manufacturers, changes in the sources of ingredients over time, and differences between lots of the same medication from the same manufacturer. Several recent publications focused on perioperative considerations for patients with AGS provide general guidance as well as specific medications that require attention.^4-7

With multiple manufacturers of a single product, researching the ingredients of the specific product is important. Two sources that should be used to identify alpha-gal presence in a specific product is DailyMed and direct communication with the product manufacturer.⁴ An AGS online source for patients and providers also can assist with an initial search of information and products.  At a systems level, recommendations to identify and ensure safety for patient with AGS include:

• Increasing awareness and education of all health care providers^4-7
• Documentation of the allergy in the electronic chart and updating the electronic chart database to provide appropriate alerts^4,6,7
• Creation and maintenance of a formulary list of medications that contain alpha-gal^4,5,6
• Development of kits containing commonly used medications in the operative setting, for emergencies, and for codes that is periodically verified and appropriately labeled for use in patients with AGS⁴
• Allowing patients to bring home medications for administration instead of using a potentially different manufacturer’s product from the hospital pharmacy⁵

Medications used in the perioperative setting that have been reported to contain alpha-gal  are summarized in Table 1. Of note, the list is not comprehensive and is based on experience from institutions in high endemic tick bite areas such as Virginia, Tennessee, and North Carolina. Additionally, suggested alternatives are not available for most of these sources (other than avoidance) except for a few as noted in the table footnotes. Due to its frequent use in the surgical setting, several authors have described use of heparin or alternate methods for patients with AGS which are summarized below.

Heparin use in patients with alpha-gal allergy
Heparin is derived from porcine intestinal mucosa or bovine lung.^4-7 Despite the increased incidence of AGS and the animal-derived source of heparin, patients with documented AGS may not necessarily demonstrate a reaction to heparin. According to a retrospective case series of patients admitted to hospitals within a health care system in Virginia between Jan 2018 and July 2020, heparin or enoxaparin was administered during 57 visits to patients with documented AGS.⁹ A prophylactic dose of a heparin product was administered for 53 patient visits (93%). An allergic reaction occurred in 1 patient after receiving 2 doses of subcutaneous heparin 5000 units. The patient’s alpha-gal IgE level was 24.2 kU/L (reference range, 0.10 kU/L).  No reactions were observed from visits in which enoxaparin was administered.

Hawkins et al report the use of high dose intravenous (IV) heparin in 17 cardiac surgery patients with positive alpha-gal IgE of whom 4 (24%) experienced a severe allergic reaction compared to 1 of 13 patients (8%) with negative alpha-gal IgE.¹⁰ Neither heparin dose nor premedication with antihistamine and steroids differed between patients who experienced a reaction and those who had no reaction. Compared to those who did not experience an allergic reaction, patients with an allergic reaction had a significantly higher median alpha-gal IgE antibody level (75 vs 8 kU/L, respectively; p=0.006). All 4 patients with a reaction had an alpha-gal titer >50 kU/L which was measured within 90 days of surgery.

In a case report and literature review by Mawhirt et al, a patient with a reported alpha-gal allergy 6 years prior responded with negative skin prick sensitivity to beef and pork extracts as well as to porcine-derived heparin.¹¹ Additionally, prior to surgery, the patient reported a tolerance to dietary red meat over time since the initial allergy diagnosis. Premedication with corticosteroid and antihistamines followed by IV heparin was well tolerated. Eight other patients with a history of alpha-gal allergy demonstrated mixed results with use of IV heparin with 4 cases resulting in a reaction despite use of premedication in 2 cases. Heparin skin testing was conducted in 1 patient with a negative result, the patient received premedication, and no allergic reaction was reported. Koo et al also describe using intradermal skin testing to evaluate heparin and enoxaparin sensitivity along with alpha-gal IgE testing in patients with alpha-gal allergy to guide decisions on use or avoidance of heparin products.¹²

Successful use of bivalirudin as an alternative to heparin is described in a patient undergoing percutaneous coronary intervention (PCI) and left ventricular assist device (LVAD) replacement.¹³ The use of bivalirudin was chosen due to the patient’s history of AGS. Measurement of alpha-gal antibody levels or heparin skin testing was not performed.

McRae et al describe a heparin desensitization strategy prior to cardiac surgery in a patient with AGS with high alpha-gal IgE levels and a documented reaction to heparin flush.¹⁴ Prior to undergoing cardiopulmonary bypass surgery, the patient was given premedication with oral famotidine (20 mg twice daily) and cetirizine 10 mg twice daily. On the evening prior to surgery, a heparin desensitization protocol in the ICU was followed with increasing doses of heparin every 15 minutes over 4 hours and 30 minutes which the patient tolerated. Continuous monitoring along with availability of emergency management was ensured. The patient was able to receive required IV heparin doses without a reaction during the surgery.

Based on the available data, a suggested algorithm by Nourian et al can help guide the decision for heparin use in patients with AGS.⁴ When an alpha-gal IgE level is available, a risk category and associated action can be considered as shown in Table 2.  When alpha-gal levels are not available and a procedure is deemed urgent, patient history is used to determine the level of potential risk of a reaction. In cases of high suspicion, an alternate anticoagulant, heparin challenge, or immediate desensitization are options. Premedication and a heparin loading dose challenge can be considered for cases of low suspicion. Elective procedures should be postponed to obtain alpha-gal IgE levels, allergist consultation, and possible heparin skin testing. In all cases, alpha-gal IgE levels and an allergist consultation are recommended (either before or after the procedure).  Reports of reactions with enoxaparin in patients with AGS are limited and its use may be an alternative to consider for appropriate indications and patients at low to moderate risk.

Conclusion
Awareness and detection of AGS is increasing and the consequences of using products derived from or containing alpha-gal can range from no reaction to anaphylaxis. Until more evidence becomes available, health care providers, health care systems, and product manufacturers need to ensure availability and familiarity with medications and products that are alpha-gal free. Specific product details with respect to the source of active and inactive ingredients are needed. Appropriate alternate medications/products should be evaluated and made available. Keeping current on new information is important due to the changing nature of products and evolving clinical experience. In the case of heparin, several options include alternate anticoagulants, skin testing, and heparin desensitization and depend on alpha-gal IgE levels and urgency of the procedure. Although formal guidelines are not yet available, testing an alpha-gal IgE level can serve as a guide to the potential severity of the patient’s sensitivity and severity of a reaction if exposed to an alpha-gal containing product. Until more standard recommendations become available, utilizing these precautions in patients with AGS may help reduce the risk of an allergic reaction in the perioperative setting.

References

1. Jeimy S, Zhu R. Tick-borne red meat allergy (α-gal syndrome). CMAJ. 2023;195(38):E1305-E1306. doi: 10.1503/cmaj.231067.
2. Macdougall JD, Thomas KO, Iweala OI. The meat of the matter: understanding and managing alpha-gal syndrome. Immunotargets Ther. 2022;11:37-54. doi: 10.2147/ITT.S276872.
3. Thompson JM, Carpenter A, Kersh GJ, Wachs T, Commins SP, Salzer JS. Geographic distribution of suspected alpha-gal syndrome cases – United States, January 2017-December 2022. MMWR Morb Mortal Wkly Rep. 2023;72(30):815-820. doi: 10.15585/mmwr.mm7230a2.
4. Nourian MM, Stone CA Jr, Siegrist KK, Riess ML. Perioperative implications of patients with alpha gal allergies. J Clin Anesth. 2023;86:111056. doi: 10.1016/j.jclinane.2023.111056.
5. Wolaver W, Thakrar S, Thomas K, et al. Demystifying α-gal syndrome: identification and risk management in the perioperative setting. Curr Opin Anaesthesiol. 2021;34(6):761-765. doi: 10.1097/ACO.0000000000001066.
6. Wolfe RC, Blunt J. Perioperative considerations for the emerging alpha-gal allergy. J Perianesth Nurs. 2021;36(4):435-437. doi: 10.1016/j.jopan.2021.05.002.
7. Dunkman WJ, Rycek W, Manning MW. What does a red meat allergy have to do with anesthesia? Perioperative management of alpha-gal syndrome. Anesth Analg. 2019;129(5):1242-1248. doi: 10.1213/ANE.0000000000003460.
8. Tejan-Kamara AZ, Murhammer JM, Fingert JH. Alpha-gal syndrome (AGS) in a glaucoma suspect with narrow iridocorneal angles. Am J Ophthalmol Case Rep. 2023;29:101811. doi: 10.1016/j.ajoc.2023.101811.
9. Nwamara U, Kaplan MC, Mason N, Ingemi AI. A retrospective evaluation of heparin product reactions in patients with alpha-gal allergies.Ticks Tick Borne Dis. 2022;13(1):101869. doi: 10.1016/j.ttbdis.2021.101869.
10. Hawkins RB, Wilson JM, Mehaffey JH, Platts-Mills TAE, Ailawadi G. Safety of intravenous heparin for cardiac surgery in patients with alpha-gal syndrome. Ann Thorac Surg. 2021;111(6):1991-1997. doi: 10.1016/j.athoracsur.2020.07.050.
11. Mawhirt SL, Banta E. Successful intravenous heparin administration during coronary revascularization surgery in a patient with alpha-gal anaphylaxis history. Ann Allergy Asthma Immunol. 2019;123(4):399-401. doi: 10.1016/j.anai.2019.05.017.
12. Koo G, Plager J, Fahrenholz JM, Phillips E, Stone C Jr. Reactivity to heparin in patients with alpha-gal allergy: A potential role for skin testing? Ann Allergy Asthma Immunol. 2022;129(4):515-517. doi: 10.1016/j.anai.2022.07.010.
13. Radwan SS, Gill G, Ghazzal A, Malik A, Barnett C. Plaque rupture-induced myocardial infarction and mechanical circulatory support in alpha-gal allergy. Case Rep Cardiol. 2020;2020:5282843. doi: 10.1155/2020/5282843.
14. McRae AS, Tidwell WP, Patel S, Lombard FW. Heparin desensitisation prior to cardiopulmonary bypass in a patient with alpha-gal allergy. Anaesth Rep. 2022;10(2):e12203. doi: 10.1002/anr3.12203.

Prepared by:
Rita Soni, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

December 2023

The information presented is current as November 27, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.