Alpha-gal Syndrome for Cardiologists and Cardiac Surgeons
Alpha-gal Syndrome for Cardiothoracic Surgeons
by Mehmet Oz, MD, FACS
Further Reading for Cardiologists and Cardiac Surgeons–Under Development
Hilger, C., et al. (2019). “Role and mechanism of galactose-alpha-1,3-galactose in the elicitation of delayed anaphylactic reactions to red meat.” Curr Allergy Asthma Rep 19(1): Article 3-Article 3.
Purpose of Review: The alpha-Gal (α-Gal) syndrome is characterized by the presence of IgE antibodies directed at the carbohydrate galactose-alpha-1,3-galactose (α-Gal). In this article, we review the presence of α-Gal in food and non-food sources; we discuss the evolutionary context of the antibody response to α-Gal and highlight immune responses to α-Gal and other carbohydrates. Recent findings: IgE antibodies have been associated with delayed allergy to red meat. In addition to food, drugs, and other products of animal origin are increasingly perceived as a risk for patients sensitized to α-Gal. The link between tick bites and anti-α-Gal IgE-antibody production that has been established first by epidemiological studies has now been confirmed in mouse models. Summary: The anti-α-Gal immune response is complex and characterized by a unique feature. IgM and IgG antibodies have been found to confer protection against pathogens whereas the IgE-response to α-Gal is detrimental and causes severe reactions upon exposure to mammalian meat and other products.
Research of Specific Relevance to Cardiologists and Cardiothoracic Surgeons
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.
A seemingly impossible relationship between cardiac surgery and meat allergy should have led to the manufacture of gal-deficient valves. Why? In January 2005, over a decade ago, we reported for the first time that recipients of bioprostheses developed an alpha-gal-specific humoral immune response.1, 2 It was then speculated that the degeneration of the bioprosthesis was associated with the presence of alpha-gal in the valve tissue. This insight was corroborated by multiple groups and, most important, proven in experimental animal work.3, 4, 5 There are limited reports of humans with a hypersensitivity reaction after biovalve implantation.6 Is there a possibility that allergy research may have relevance for cardiac surgery? Dr Patts Mills, FRS, from the Asthma and Allergic Disease Center at the Virginia Health System, was the first to report that humans with meat allergies (consumption of red meat that leads to delayed anaphylaxis, angioedema, and urticaria) have developed immunoglobulin (Ig)-E–specific antibodies against alpha-gal.
Crow, H., et al. (2019). “Red Meat Allergy Associated with NSTEMI.” American Journal of Medical Case Reports. (7)1: 13-15
Alpha-gal syndrome, also known as mammalian meat allergy, is characterized by a hypersensitivity reaction to galactose-alpha-1,3-galactose. Reactions typically manifest hours after consumption of red meat products such as beef, pork, and lamb. We describe the case of a 64-year-old male resident of rural Oklahoma who presented with anaphylaxis and myocardial infarction. The patient suffered complications that were attributed to porcine-derived heparin in the setting of undiagnosed alpha-gal syndrome. We describe the clinical course of this patient that lead to the diagnosis of alpha-gal syndrome to raise awareness of this disease.
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.
We present the cases of two patients with bioprosthetic aortic valves who developed an allergy to alpha-gal. Each had premature degeneration of their bioprosthesis and demonstrated rapidly increasing transvalvular gradients after development of their allergy. Each underwent successful replacement with a mechanical aortic valve within 1-2 years of symptom onset. doi: 10.1111/jocs.12764 (J Card Surg 2016;31:446-448).
Hawkins, R. B. and R. K. Ghanta (2017). “MAMMALIAN MEAT ALLERGY AND ADVANCES IN BIOPROSTHETIC VALVE TECHNOLOGY Reply.” Journal of Thoracic and Cardiovascular Surgery 154(4): 1327-+.
We read with interest the letter to the editor by Ankersmit and colleagues,1 ‘‘When Meat Allergy Meets Cardiac Surgery: A Driver for Humanized Bioprosthesis.’’ The University of Virginia has led the epidemiologic characterization of the mammalian meat allergy
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.
Hypersensitivity reactions to mammalian meat following tick exposure are increasing in prevalence and provide a unique challenge to anesthesiologists. The reactions, including anaphylaxis, are delayed and therefore may not be easily recognized and treated. The risk is especially high in cardiac surgery, where several potential triggers, including biological valves as well as heparin, are used frequently. In the presence of such hypersensitivity, prophylactic measures including preoperative testing and pharmacologic prophylaxis may be useful in modulating the immune response such that triggering agents may be used relatively safely. We present 3 patients with previous sensitization to meat protein following a tick bite with known allergic reactions to mammalian meat who presented for cardiac surgery involving exposure to potential allergens and discuss the perioperative management including possible prevention.
Mawhirt, S. L. and E. Banta (2019). “Successful intravenous heparin administration during coronary revascularization surgery in a patient with alpha-gal anaphylaxis history.” Ann Allergy Asthma Immunol.
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.
Wilson, J. M., et al. (2019). “IgE, alpha-Gal and atherosclerosis.” Aging (Albany NY) 11(7): 1900-1902.
Emerging evidence suggests a link between allergic disease and cardiovascular disease. The idea that there could be a connection between ‘allergies’ and heart disease is not readily apparent. Nonetheless, over the past 20 years research in mice and humans has linked hematopoietic cells and soluble factors that mediate allergic disease with coronary artery disease (CAD) [1,2]. Specifically, mast cells  and elevated levels of the Immunoglobulin E (IgE) isotype  have been associated with the presence and/or severity of CAD. However, despite these associations, no specific allergens or IgE responses to specific allergens, have been implicated in CAD . It was on this backdrop that a team of allergists and cardiologists collaborated to investigate the hypothesis that specific IgE to a novel oligosaccharide allergen present in mammalian meat could be a risk factor for CAD.
Wilson, J. M., et al. (2018). “IgE Sensitization to the Food Allergen Galactose-a-1,3-Galactose is Associated with Coronary Atherosclerosis.” Journal of Allergy and Clinical Immunology 141(2): AB146.
RATIONALE: The oligosaccharide galactose-a-1,3-galactose (a-Gal) is the target of IgE in cases of delayed anaphylaxis to red meat. Sensitization to a-Gal is more prevalent in the community than cases of delayed anaphylaxis and is particularly common in the southeastern United States, a region with high incidence of cardiovascular disease. Additionally, recent reports have linked mast cells and elevated total IgE with coronary artery disease. We sought to test the hypothesis that sensitization to a-Gal represents an independent risk factor for coronary atherosclerosis.
For additional information related to hospitalization and surgery click here.
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.
The bovine gelatin colloid is a recognized cause of adverse reactions, albeit uncommon. It is noteworthy that many patients with red‐meat‐derived gelatin allergy may have negative specific Immunoglobulin E (sIgE) antibody to the conventional red‐meat‐derived gelatin immunoassay. Bovine gelatin colloids have been shown to contain about 0.44 ± 0.2 mcg/g to 0.52 ± 0.1 mcg/g of galactose‐alpha‐1,3‐galactose (alpha‐gal). It has been demonstrated that sIgE towards the alpha‐gal moiety may cause life‐threatening anaphylactic reactions with wide ranging implications. We describe three patients with an allergic reaction to bovine gelatin colloid who had positive skin test to Gelofusine and sIgE to alpha‐gal but negative sIgE to bovine gelatin.
Dewachter, P., et al. (2019). “Anesthetic management of patients with pre-existing allergic conditions: a narrative review.” Br J Anaesth 123(1): e65-e81.
This narrative review seeks to distinguish the clinical patterns of pre-existing allergic conditions from other confounding non-allergic clinical entities, and to identify the potential related risks and facilitate their perioperative management. Follow-up investigation should be performed after a perioperative immediate hypersensitivity to establish a diagnosis and provide advice for subsequent anaesthetics, the main risk factor for perioperative immunoglobulin E (IgE)-mediated anaphylaxis being a previous uninvestigated perioperative immediate hypersensitivity reaction. The concept of cross-reactivity between drugs used in the perioperative setting and food is often quoted, but usually not supported by evidence. There is no reason to avoid propofol in egg, soy, or peanut allergy. The allergenic determinants have been characterized for fish, shellfish, and povidone iodine, but remain unknown for iodinated contrast agents. Iodinated drugs may be used in seafood allergy. Evidence supporting the risk for protamine allergy in fish allergy and in neutral protamine Hagedorn insulin use is lacking. Conversely, cross-reactivity to gelatin-based colloid may occur in alpha-gal syndrome. Atopy and allergic asthma along with other non-allergic conditions, such as NSAID-exacerbated respiratory disease, chronic urticaria, mastocytosis, and hereditary or acquired angioedema, are not risk factors for IgE-mediated drug allergy, but there is a perioperative risk associated with the potential for exacerbation of the various conditions.
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.
Over the past decade, there has been a growing awareness of a new allergic syndrome known as alpha-gal allergy or alpha-gal syndrome, commonly recognized as a red meat allergy. We performed a review of the literature to identify articles that provide both background on this syndrome in general and any reports of reactions to medications or medical devices related to alpha-gal syndrome. Alpha-gal syndrome results from IgE to the oligosaccharide galactose-alpha-1,3-galactose, expressed in the meat and tissues of noncatarrhine mammals. It is triggered by the bite of the lone star tick and has been implicated in immediate-onset hypersensitivity to the monoclonal antibody cetuximab and delayed-onset hypersensitivity reactions after the consumption of red meat. There is growing recognition of allergic reactions in these patients to other drugs and medical devices that contain alpha-gal. Many of these reactions result from inactive substances that are part of the manufacturing or preparation process such as gelatin or stearic acid. This allergy may be documented in a variety of ways or informally reported by the patient, requiring vigilance on the part of the anesthesiologist to detect this syndrome, given its serious implications. This allergy presents a number of unique challenges to the anesthesiologist, including proper identification of a patient with alpha-gal syndrome and selection of anesthetic and adjunctive medications that will not trigger this allergy.
Lied, G. A., et al. (2019). “Intraoperative anaphylaxis to gelatin-based hemostatic agents: a case report.” J Asthma Allergy 12: 163-167.
Surgiflo Haemostatic Matrix is an absorbable gelatin matrix hemostatic material that has been widely used in various surgical operations to assist hemostasis. Nonetheless, as biologically active agents (contains porcine gelatin), there is potential for allergic reactions to these products. Here, we report the case of a 71-year-old man who had intraoperative anaphylaxis with cardiovascular events to gelatin associated with the use of a topical hemostatic agent (Surgiflo). The patient reported a history of red meat allergy and tick bites during his allergological examination after anaphylaxis. He also had high levels of specific IgE antibodies towards alpha-gal. Special consideration should be given before administering bovine- or porcine-derived gelatin products during surgery to patients with animal-related allergies, such as alpha-gal or gelatin allergy and an atopic background.
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.
Background: We have observed patients clinically allergic to red meat and meat-derived gelatin. Objective: We describe a prospective evaluation of the clinical significance of gelatin sensitization, the predictive value of a positive test result, and an examination of the relationship between allergic reactions to red meat and sensitization to gelatin and galactose-alpha-1,3-galactose (alpha-Gal). Methods: Adult patients evaluated in the 1997-2011 period for suspected allergy/anaphylaxis to medication, insect venom, or food were skin tested with gelatin colloid. In vitro (ImmunoCAP) testing was undertaken where possible. Results: Positive gelatin test results were observed in 40 of 1335 subjects: 30 of 40 patients with red meat allergy (12 also clinically allergic to gelatin), 2 of 2 patients with gelatin colloid-induced anaphylaxis, 4 of 172 patients with idiopathic anaphylaxis (all responded to intravenous gelatin challenge of 0.02-0.4 g), and 4 of 368 patients with drug allergy. Test results were negative in all patients with venom allergy (n = 241), nonmeat food allergy (n = 222), and miscellaneous disorders (n = 290). ImmunoCAP results were positive to a-Gal in 20 of 24 patients with meat allergy and in 20 of 22 patients with positive gelatin skin test results. The results of gelatin skin testing and anti-alpha-Gal IgE measurements were strongly correlated (r = 0.46, P < .01). alpha-Gal was detected in bovine gelatin colloids at concentrations of approximately 0.44 to 0.52 mu g/g gelatin by means of inhibition RIA. Conclusion: Most patients allergic to red meat were sensitized to gelatin, and a subset was clinically allergic to both. The detection of a-Gal in gelatin and correlation between the results of a-Gal and gelatin testing raise the possibility that a-Gal IgE might be the target of reactivity to gelatin. The pathogenic relationship between tick bites and sensitization to red meat, alpha-Gal, and gelatin (with or without clinical reactivity) remains uncertain. (J Allergy Clin Immunol 2012;129:1334-42.)
Mullins, R. J. A. (2008). “Clinical Significance Of Sensitisation To Gelatine Colloids In 800 Patients.” Journal of Allergy and Clinical Immunology 121(2): S26.
RATIONALE: Gelatine is one of several meat-derived allergens. Evaluation of 2 index cases with anaphylaxis (Ax) to meat and intraoperative gelatine colloid prompted a prospective examination of the significance of gelatine sensitisation.
METHODS: Between 2000-7, 800 adults presenting with food (FAx)/other Ax, drug (DA), venom allergy (VA) plus control disorders underwent SPT and intradermal testing (IDT) with neat Haemaccel and Gelofusine. Where possible, ImmunoCap was used to measure gelatine IgE.
Peters, C., et al. (2016). “Anaphylaxie peranesthésique à la gélatine associée à une allergie alimentaire à l’alpha-gal.” Anesthésie & Réanimation 2(2): 123-125.
Résumé: Récemment, le galactose-α-1,3-galactose, également connu sous alpha-gal, un sucre présent chez la plupart des mammifères à l’exception des primates, a été identifié comme allergène responsable d’anaphylaxies immédiates lors de l’administration de cetuximab et d’anaphylaxies retardées après consommation de viandes de mammifères. Certaines personnes allergiques à la viande de mammifère montrent également une sensibilisation à la gélatine. Nous décrivons le cas d’un patient présentant à la fois une allergie aux abats de mammifères reposant sur une hypersensibilité IgE-dépendante à l’alpha-gal et une anaphylaxie à un substitut plasmatique à base de gélatine fluide modifiée (Geloplasma®).
Summary:Recently, galactose-α-1,3-galactose, also known as alpha-gal, an oligosaccharide found in all mammals except primates, has been identified as an allergen responsible of immediate anaphylaxis during cetuximab perfusion or late-onset anaphylaxis after consumption of mammal meat. Some subjects with mammal meat allergy also present gelatin sensitization. We describe the observation of a patient with an allergy to mammal kidneys due to an IgE-mediated alpha-gal allergy and an anaphylactic reaction to gelatin-based plasma substitute (Geloplasma®).
Platts-Mills, T. A., et al. (2019). “Diagnosis and management of patients with the alpha-Gal syndrome.” J Allergy Clin Immunol Pract.
The alpha-Gal syndrome has many novel features that are relevant to diagnosis and management. In most cases the diagnosis can be made on a history of delayed allergic reactions to red meat and the blood test for IgE to the oligosaccharide galactose-alpha-1,3-galactose (alpha-Gal). In general, the diagnosis also dictates the primary treatment, i.e. – avoiding mammalian meat and also dairy in some cases. In the USA the lone star tick is the primary cause of this disease but different ticks are responsible in other countries. Blood levels of IgE to alpha-Gal often drop in patients who avoid recurrent tick bites, but the rate of decline is variable. Similarly, the delay before reactions is variable and the severity of the allergic reactions is not predicted by the delay or the titer of specific IgE. Some mammalian-derived products are only relevant to select patient groups, such as heart valves, gelatin-based plasma expanders, and pancreatic enzymes. A minority of cases may benefit from avoiding a wide range of products that are prepared with mammalian-derived constituents, such as gelatin. This review focuses on the nature of the syndrome, common challenges in diagnosis and management, and also gaps in our current knowledge that would benefit from additional investigation.
Pfutzner, W. and K. Brockow (2018). “Perioperative drug reactions – practical recommendations for allergy testing and patient management.” Allergo J Int 27(4): 126-129.
Background: Allergy testing for perioperative drug reactions poses a particular diagnostic challenge. Neuromuscular blocking agents (NMBA) and antibiotics are among the most common triggers. In principle, however, any drug administered perioperatively is capable of causing a hypersensitivity reaction. Methods: This article is an overview of selected scientific articles and is based on research in PubMed, specialist databases, and guidelines. Results: Besides patient’s history and laboratory tests (the latter being feasible to only a limited extent), skin tests play a particularly important role. To obtain clinical relevant results, profound knowledge on the best point in time for testing, the drug concentrations to be used, how to perform tests correctly, and the assessment criteria is of special importance. Conclusion: Final outcomes of the diagnostic procedures should be providing thorough information of the patient about the findings, drugs that should be avoided in the future as well as alternative preparations, and, if necessary, preventive measures to be taken in the event of further surgical interventions.
Popescu, F. D., et al. (2019). “DRUG ALLERGIES DUE TO IgE SENSITIZATION TO alpha-GAL.” Farmacia 67(1): 43-49.
Serum specific IgE antibodies for non-primate mammalian carbohydrate galactose-alpha-1,3-galactose (alpha-Gal) are associated to alpha-Gal syndrome: delayed allergy to red meat manifested as anaphylaxis, angioedema or urticaria after ingestion of beef, pig or lamb meat, immediate-onset anaphylaxis at first parenteral exposure to drugs significantly containing alpha-Gal. IgE-mediated drug allergy in the alpha-Gal syndrome was reported for some therapeutic monoclonal antibodies, such as cetuximab, snake antivenom, and varicella-zoster vaccine, but there are risks also for colloid plasma volume substitutes, vaccines containing gelatin of porcine/bovine animal origin as an excipient, and drugs with porcine pancreatin or bovine-origin magnesium stearate.
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.
The a-gal syndrome is characterized by a delayed allergic reaction to mammalian meat associated with the presence of speciﬁc IgE antibodies to galactose-a-1,3-galactose.1 Sensitized patients are at risk upon ingestion of red meat, in particular pork kidney and innards.2 However, diverse other products of mammalian origin have been shown to carry the a-gal epitope and to trigger allergic symptoms, for example, therapeutic mAbs of rodent origin, bovine-derived gelatin colloids, as well as gelatin contained in drugs and sweets.3 Polyclonal antibody preparations such as antivenoms derived from horses have been shown to carry the a-gal epitope,4 and a case of hypersensitivity has been reported recently in an a-galesensitized patient.5 The high gelatin content of some vaccines has been attributed to anaphylaxis upon vaccination in 2 a-galeallergic patients,6,7 and the premature degradation of bioprosthetic heart valves has been associated with the presence of speciﬁc IgE in 2 patients.8