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Anesthetic Clinical Pharmacology

What Does a Red Meat Allergy Have to Do With Anesthesia? Perioperative Management of Alpha-Gal Syndrome

Dunkman, W. Jonathan MD*; Rycek, Wendy PharmD; Manning, Michael W. MD, PhD*

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doi: 10.1213/ANE.0000000000003460
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Abstract

Patients with alpha-gal syndrome express IgE antibodies to the carbohydrate galactose-α-1,3-galactose (alpha-gal), an oligosaccharide found in the meat and tissues of noncatarrhine mammals. Alpha-gal allergy has been implicated in 2 distinct forms of anaphylaxis. IgE antibodies to alpha-gal were first identified in patients experiencing immediate-onset anaphylaxis to the monoclonal antibody cetuximab. It subsequently became clear that these antibodies were also responsible for a meat allergy presenting as delayed-onset anaphylaxis 3–6 hours after ingestion of mammalian meat products. Further study has indicated that the production of IgE to alpha-gal is triggered by a bite from the lone star tick (Amblyomma americanum), endemic to the southeastern United States.1–5 This allergy may be formally reported in a number of ways in the patient’s medical record, or it may be informally reported by the patient as this syndrome could at first appear to be an irrelevant food allergy and may not be well documented, requiring vigilance on the part of the anesthesiologist.

In 2007, O’Neil et al6 reported significant hypersensitivity reactions to cetuximab in 22% of a cohort from Tennessee and North Carolina compared to 1.2% in the general population. In 2008, Chung et al7 also reported IgE antibodies to cetuximab in 20% of healthy control subjects from Tennessee. In 2011, Commins et al8 reported IgE to alpha-gal in 18%–22% of patients in random populations from Tennessee, North Carolina, and Virginia. While the incidence of clinically significant alpha-gal syndrome in the general population is unknown and probably not this high, these data do point to a fairly high overall incidence in certain regions of the southeastern United States.

In an effort to better understand this unusual and recently described syndrome and its ramifications in the perioperative environment, we performed a review of the literature to identify all relevant articles in the existing literature. Initial searches were performed on PubMed, and additional articles were identified by following up on references for identified papers in a serial fashion. Target articles provided both background on this syndrome in general and any reports of reactions to medications or medical devices related to alpha-gal syndrome.

REVIEW

Alpha-Gal

Figure 1.
Figure 1.:
Glycan structures of alpha-gal and human blood groups. Used with permission from Platts-Mills et al3 and Bircher et al.9

Alpha-gal is an oligosaccharide found on the surface of most mammalian cells and is similar to the B blood group antigen (Figure 1).3,9 Until recently, this substance was best known as a major antigenic barrier to xenotransplantation. Alpha-gal is synthesized by the enzyme alpha-1,3-galactosyltransferase, which is present in most mammals although absent in humans and other members of the catarrhine group of primates. Catarrhine primates include the old-world monkeys and apes (gibbons, orangutans, gorillas, chimpanzees, and humans). As humans do not produce alpha-gal, they naturally produce IgG and IgM to alpha-gal, which represent the dominant mechanism of hyperacute rejection in xenotransplantation. However, IgE to alpha-gal causes alpha-gal syndrome. IgE to alpha-gal has only recently been recognized and seems to require a specific trigger to stimulate production.1,3,4

Cetuximab

Figure 2.
Figure 2.:
Structure of cetuximab highlighting alpha-gal location in red. Used with permission from Platts-Mills et al3 and Bircher et al.9

IgE to alpha-gal was first recognized in a group of patients with cancer experiencing immediate hypersensitivity reactions on the first infusion of the monoclonal antibody cetuximab. Cetuximab (Erbitux; Bristol-Myers Squibb, New York City, NY and ImClone Systems, Bridgewater, NJ) is a monoclonal antibody specific for the epidermal growth factor receptor and used in the treatment of metastatic colorectal cancer and head and neck cancer. Shortly after this drug went into clinical use in March 2006, there were frequent reports of immediate hypersensitivity reactions in patients in the southeastern United States. While rates of hypersensitivity reactions were low (<1%) in most centers in the Northeast, 1 study found 22% of patients treated with cetuximab in Tennessee and North Carolina experienced a severe hypersensitivity reaction.6 It was determined that these reactions were due to preexisting IgE antibodies to the oligosaccharide alpha-gal, which is located on the Fab portion of cetuximab (Figure 2).3,5,7,9 These reactions tended to develop rapidly, during or ≤20 minutes after the infusion, and to be quite severe, including several fatalities.4

Red Meat Allergy

From 2006 to 2008, a number of patients being evaluated for recurrent urticaria, angioedema, and/or anaphylaxis also tested positive for IgE to alpha-gal. Although there was often no clear immediate trigger, many patients reported that their symptoms occurred 4–6 hours after eating red meat (beef, pork, or lamb). Although initial skin prick tests with commercial meat abstracts produced minimal wheals, the compelling histories prompted additional testing, which showed positive intradermal skin tests and eventually revealed IgE antibodies directed to alpha-gal. These patients were densely clustered in the southeastern United States, the same geographic distribution as the reactions to cetuximab.10 This is a new syndrome and may not be routinely tested in all centers. However, recognition is increasing, and testing is increasingly frequent at centers with a high regional incidence. The immunoassay for IgE to alpha-gal is commercially available and well documented in the literature, but it is not US Food and Drug Administration approved.11

Unlike traditional IgE-mediated food hypersensitivities, a delay occurs between meat consumption and symptoms. The precise cause of this delay is unclear, but the prevailing view is that it is related to the digestion, absorption, and transit of the relevant glycoproteins and/or glycolipids. Symptoms typically begin 3–6 hours after eating meat, although some patients report a shorter delay, often associated with exercise, alcohol consumption, or food with a high alpha-gal content, such as pork kidney and sausage casing. The most common early symptom is itching, and many patients report gastrointestinal symptoms such as nausea, diarrhea, or indigestion. These early symptoms then progress to urticaria, angioedema, or anaphylaxis. Given a typical dinner time and the time course of this process, many patients report reactions late at night or awakening them from sleep, and they often present to emergency departments between 11 pm and 2 am. The presentation is somewhat variable from patient to patient and even from exposure to exposure for the same patient. Not every exposure leads to a clinical reaction, although affected patients will report some reaction to most exposures, and avoidance of red meat clearly leads to an absence of reactions. This allergy develops some time in adult life, with patients reporting long histories of tolerating meat products before developing these reactions. Consistent with known alpha-gal production, triggers include the meat and tissues of noncatarrhine mammals, typically beef, pork, and lamb. Patients do not report reactions or have positive allergy tests to nonmammalian food animals such as chicken, turkey, or fish.1,2,4,10 Most patients will have positive IgE assays toward cow’s milk but will usually still tolerate consumption of milk and other dairy products.12

Anecdotal experience indicates that some individuals’ hypersensitivity may recede with time in the absence of recurrent exposure.1 However, the absence of a recent reaction to meat products is no guarantee that a patient will not react to substances in the perioperative period.

Ticks

As more patients presented with alpha-gal syndrome, researchers established that the regional distribution of alpha-gal syndrome most closely matched that of tick-borne illnesses and the range of the lone star tick, Amblyomma americanum, in particular. In addition, many patients reported that they spent a lot of time outdoors, and several patients reported that they believed their red meat allergy had started after a tick bite.

In 2011, Commins et al8 (specifically, author Dr Platts-Mills) reported prospective studies of the response to tick bites in 3 subjects, epidemiologic evidence that these IgE antibodies are present where tick bites are common, a correlation between IgE antibodies to tick proteins and IgE antibodies to alpha-gal, and evidence for the expanding range of the lone star tick, concluding that lone star tick bites are the predominant and possibly only cause of IgE to alpha-gal8 (Figures 313,14 and 45,14,15). The role of the tick bite in triggering this allergy explains why it develops later in life in previously unaffected individuals.

Figure 3.
Figure 3.:
Lone star tick photo.14 Image by Micheal L. Levin, PhD, available from Centers for Disease Control and Prevention13 in the public domain.
Figure 4.
Figure 4.:
Geographic distribution of lone star tick, Amblyomma americanum. 5 , 14 Available from Centers for Disease Control and Prevention15 in the public domain.

Tick bites are known to be immunogenic and play a role in a number of diseases. There appears to be something about the bite of Amblyomma americanum that induces such a rapid and vigorous IgE response to alpha-gal, although it is not known what this factor is. Theories include a response to the normal constituents of the tick’s saliva, residual mammalian glycoproteins or glycolipids containing alpha-gal present in the tick from a previous blood meal, or the presence of another as yet undescribed organism living in the tick.4

The recent discovery and increasing recognition of alpha-gal syndrome parallel the rise in population and range of Amblyomma americanum, which in turn is related to the rise of the whitetail deer population in the eastern United States over the past several decades. Ixodes scapularis, the main tick vector for Lyme disease, does not appear to induce alpha-gal syndrome, which is almost unheard of in the northeastern United States where whitetail deer and Ixodes scapularis, but not Amblyomma americanum, is common.3,4,8

In addition to the growing group of patients described in the southeastern United States, groups of patients with alpha-gal syndrome have been described worldwide, including in Australia,16,17 Europe,18–24 Asia,25–27 and Central America.28,29 In each case, sensitization via a tick bite, production of IgE to alpha-gal, and a subsequent allergic reaction to red meat have been described, although the relevant tick species vary with location.1–3

Reported Reactions to Drugs and Devices

In addition to the reactions to cetuximab and red meat, which helped define this syndrome, there is growing recognition of allergic reactions in these patients to other drugs and medical devices that contain the alpha-gal epitope. Many of these reactions result from inactive substances that are part of the manufacturing or preparation process, such as gelatin or stearic acid.

Allergy testing shows a strong positive correlation among responses to gelatin, red meat, and alpha-gal, suggesting that alpha-gal may mediate some previously recognized gelatin allergies. Alpha-gal has been implicated in reactions to gelatin-containing products such as Gelofusine, Haemaccel, vaginal fenticonazole, zoster vaccine, influenza vaccine, and even candies.17,20,30–33

Magnesium stearate (a form of stearic acid) is used to facilitate the manufacturing of many drugs and may be contained in the final product. It can be derived from either bovine or plant sources. Researchers in New Jersey have reported a patient with known alpha-gal allergy and allergic reactions to numerous drugs (acetaminophen, naproxen, lisinopril, hydrocodone/acetaminophen, clonidine) in preparations that contain magnesium stearate. Magnesium stearate was the 1 inactive ingredient common among all of the allergies, and the patient tolerated some of the same drugs in other forms not containing magnesium stearate.34

Patients with alpha-gal syndrome may also react to recombinant human proteins produced in nonprimate mammals. In a recent series looking at IgE reactivity in patients with meat, dairy, or gelatin allergies, 5 of 9 patients with IgE to alpha-gal demonstrated specific IgE for activated recombinant human coagulation factor VII (rhFVII, eptacog alpha, NovoSeven; Novo Nordisk, Plainsboro, NJ) produced in baby hamster kidney cells.35

Pharmaceutical-grade heparin is derived from porcine (intestine) or bovine (lung) sources and has attracted attention as a possible alpha-gal allergy trigger. It is likely to contain alpha-gal, but the widespread use of heparin combined with relatively few reports of reactions suggests that clinically significant reactions are uncommon, although they do occur. The likelihood of a reaction may be dependent on the source, processing, and purity, as well as the dose of heparin. Many of the reported reactions have been related to high-dose heparin associated with cardiac bypass.33

In patients with known alpha-gal syndrome, 1 group has reported success in several cases by pretreating with steroids and antihistamines before heparin administration. They also propose a heparin challenge the evening before the procedure. Due to variability among manufactured heparin lots, they advocate using heparin from the same lot as that administered during the heparin challenge for the surgery.36

Bioprosthetic heart valves are often constructed with bovine or porcine pericardium and are another potential concern. Researchers in Virginia reported 3 cases of patients with alpha-gal syndrome who underwent valve replacement with bioprosthetic valves. Two of the 3 experienced perioperative hypersensitivity reactions, but all 3 ultimately tolerated valve replacement. They suggest that decellularized valves, which have been shown to have no detectable alpha-gal, should be considered for patients with alpha-gal syndrome.37 Others have reported premature deterioration of bioprosthetic valves in patients who subsequently developed alpha-gal syndrome.38

IMPLICATIONS FOR THE ANESTHESIOLOGIST

Identification of Patients

The first challenge to provide safe anesthesia care for these patients is proper identification of a patient with alpha-gal syndrome. The recent identification of this syndrome, its somewhat unusual nature, and limited awareness of this new entity mean that patients may present with a variety of diagnoses or clues that need to be recognized as actually representing alpha-gal syndrome. As awareness increases, patients may present for surgery with an identified alpha-gal allergy, but it may also be described as a meat allergy, red meat allergy, beef/pork allergy, or quadruped allergy. This allergy may be formally reported in the patient’s medical record or informally reported by the patient as this syndrome could at first appear to be an irrelevant food allergy and may not be well documented. Patients with cancer may report an allergy to cetuximab, specifically anaphylaxis on the first administration of cetuximab, although any IgE-mediated symptoms should be taken seriously. Some patients may have a medic alert bracelet. Any of these presenting clues should prompt further questioning and a high suspicion for alpha-gal syndrome, particularly in the southeastern United States. A history of a tick bite may be helpful and confirmatory but should not be considered necessary. When identified, every attempt should be made to properly document this syndrome in the patient’s medical record and take appropriate precautions.

Our Research on Drugs and Devices

As our institution has recognized more patients with alpha-gal syndrome presenting to our operating rooms for a wide variety of procedures, our pharmacists have compiled alpha-gal information about as many drugs as possible to help guide our perioperative prescribing. Many of the potential conflicts arise from inactive compounds such as stearic acid, lactic acid, glycerin, and gelatin contained in a specific preparation rather than from the active drug itself, making identification particularly challenging (Table 1). Stearic acid and lactic acid can be derived from either animal or plant sources. If derived from an animal source, they may contain alpha-gal. However, the same substance derived from a plant source should be alpha-gal free. Many manufacturers do not report or do not know the full lineage of each substance used in their products. Manufacturers do not currently report alpha-gal content in package inserts or test for alpha-gal in the final product. Inactive ingredient information can change at any time, and the US Food and Drug Administration does not require manufacturers to disseminate this information.34 It is important to note that the same drug from different manufacturers or in different preparations might be safe in 1 instance and not in another.

Table 1.
Table 1.:
Common Inactive Ingredients That May Contain Alpha-Gal and Examples of Medications in Which They Are Found

As such, careful attention must be paid to each drug given to a patient with alpha-gal syndrome. We have particularly found many conflicts with oral medications often given before surgery that contain gelatin, magnesium stearate, stearic acid, or lactic acid. We have also found many instances where the ultimate source of a substance such as lactic acid cannot be determined, and we have typically chosen to consider these unsafe for patients with alpha-gal syndrome.

Our pharmacists have worked hard to obtain information on as many medications as possible; however, it is an ongoing effort. The pharmacy maintains an active list of commonly used perioperative medications and alpha-gal content. The list is updated as formulations change or more information becomes available (Figure 5). Alpha-gal content can vary among manufacturers and even among lots of a medication, so an accurate list will vary from institution to institution based on the unique mix of suppliers. The abridged table included here provides an example of how our pharmacy tracks and presents this information, but it should not be taken as a universal reference for alpha-gal content.

Figure 5.
Figure 5.:
Abridged example of table tracking alpha-gal content in common perioperative medications.

As with the reactions to red meat, allergic reactions to medications can be quite variable in both severity and timing, probably due at least in part to the amount of alpha-gal in the medication and the route of administration. Intravenous administration is likely to result in a shorter time to symptoms, as is seen with reactions to cetuximab, while oral administration may result in a delayed reaction, as is seen with reactions to red meat. Severity may depend on the amount of alpha-gal, the titer of a given patient’s alpha-gal IgE, and other poorly understood cofactors. Some patients tolerate many drugs containing some alpha-gal, while others react quite severely, including life-threatening anaphylaxis. Ultimately, the risk versus benefit of each drug must be considered on a case-by-case basis.

Because of its mammalian origin, albumin is often raised as a potential trigger for alpha-gal syndrome. However, pharmaceutical albumin is derived from human plasma and should be alpha-gal free and safe for these patients.

Heparin is porcine or bovine in origin, and we consider this unsafe for patients with alpha-gal syndrome, although the cases discussed present some possibilities for mitigating the risk in these patients and provide examples of safe use. Alternatives for anticoagulation include bivalirudin and argatroban; however, the pharmacokinetics of these drugs, relative lack of experience compared to heparin, and lack of active reversal options present challenges.

Other products used in the perioperative environment need to be evaluated carefully, including catgut sutures, biologic mesh, bovine pericardium, heart valves, and topical hemostatic agents. When these products are considered, discussion with the entire perioperative team should occur before surgery.

MANAGEMENT

As with any allergy, the primary goal should be the avoidance of triggering agents. As discussed, both identifying patients with alpha-gal syndrome and identifying potential triggers can be a challenge. In the absence of specific testing to the contrary, a history of hypersensitivity reaction to cetuximab or meat should be considered likely to be an alpha-gal mediated and the patient treated with appropriate precautions.

When a patient with alpha-gal syndrome is identified, it is important to identify this specifically and clearly in the medical record. Hospitals should work with their electronic medical record (EMR) providers to have “galactose-alpha-1,3-galactose” or “alpha-gal” specifically added to their bank of possible allergens. These patients can then have “alpha-gal” specifically listed as an allergen. This strategy will identify these patients clearly to providers and avoid the need to list multiple redundant but less precise allergens on the allergy list (meat, red meat, beef, pork, cetuximab, etc). This is important given the preponderance of low severity reactions listed as allergies on patients’ charts and the resulting alert fatigue among providers.39 Without clear documentation, most anesthesia providers may perceive alpha-gal syndrome as a cluster of standard food allergies and overlook its true importance. Ideally, the EMR should be updated regularly by the pharmacy and nutritional services to provide allergy alerts to those food and medical products that may contain alpha-gal. If building these alerts proves impractical because of the number of drugs that may contain alpha-gal and their changing status between suppliers and lots, hospitals might choose instead to maintain an offline but current up-to-date list of medications’ alpha-gal content. The provider can then identify the patient with alpha-gal syndrome from the EMR, request the current version of this list from the pharmacy, and use this to guide perioperative prescribing. This system identifies the allergy clearly and provides up-to-date information to guide prescribing.

Treatment for patients experiencing symptoms thought to be related to an alpha-gal hypersensitivity is like treatment for hypersensitivity in general and includes H1 and H2 blockers, corticosteroids, albuterol, epinephrine, and other supportive care as indicated. The offending agent should be discontinued, although this may not be possible, particularly in a delayed reaction to an oral medication.

On a systems level, hospitals, particularly in the southeastern United States, should encourage education of all relevant providers on this relatively new syndrome, develop a means of clearly identifying patients with known alpha-gal syndrome, and maintain a formulary specific list of medications’ alpha-gal content as available. Although alpha-gal syndrome is a growing challenge for patients and health care providers in general, we in the perioperative environment must be particularly vigilant given the number of different medications we give in a short period of time in a complex environment to ensure the safety of our patients.

DISCLOSURES

Name: W. Jonathan Dunkman, MD.

Contribution: This author helped with research and manuscript preparation.

Name: Wendy Rycek, PharmD.

Contribution: This author helped with pharmacy research, table preparation, and manuscript editing.

Name: Michael W. Manning, MD, PhD.

Contribution: This author helped prepare the manuscript.

This manuscript was handled by: Ken B. Johnson, MD.

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