Red Meat Allergies After Lone Star Tick (Amblyomma americanum) Bites

James H. Diaz, MD, DrPH

Disclosures

South Med J. 2020;113(6):267-274. 

In This Article

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Global Epidemiology of Red Meat Allergy After Tick Bites

Red meat allergies have occurred after hard tick (Family Ixodidae) bites on every continent except Antarctica, with most cases reported from Australia and the United States.[8,9] van Nunen reported diagnosing two patients per week with red meat allergy and anaphylaxis following Australian paralysis tick bites.[8] The 0.12% prevalence of red meat anaphylaxis after paralysis tick bites in the region exceeded the 0.10% prevalence of peanut-mediated anaphylaxis.[8] van Nunen proposed that the increasing prevalence of red meat allergy after tick bites in Australia was the result of an increasing number of zoonotic reservoir hosts for ticks, especially bandicoots and other small mammals.[8]

In the United States, Commins and Platts-Mills reported a seroprevalence in excess of 1000 individuals with red meat allergy after tick bites and estimated that >5000 individuals had similar but undiagnosed conditions in the Southeast, where the Lone Star tick (Amblyomma americanum) is the predominant regional tick-biting species (Figure 1).[9] Similar to the Australian experience, US investigators proposed that the increasing prevalence of red meat allergy after tick bites in the United States was the result of an increase in the white-tailed deer population, the preferred zoonotic reservoir hosts for A americanum in the Southeast (Figure 2).[10]

Figure 1.

Amblyomma americanum, the North American Lone Star tick. (A) Female, (B) male, (C) nymph, dorsal views. Photograph from the Centers for Disease Control and Prevention.

Figure 2.

Geographic distribution range of Amblyomma americanum, the North American Lone Star tick. Illustration from the Centers for Disease Control and Prevention.

In most cases, the predominant regional tick vector of red meat allergy is suspected by its geographic distribution or confirmed by expert identification or molecular methods (Table 2).[2–4,11–19] Only one predominant regional tick species usually serves as the responsible vector of red meat allergy, now known as the α-gal syndrome.[19] For example, the paralysis tick is responsible for >95% of the cases of red meat allergy after tick bites in Australia. Kwak et al, however, reported a rare case of mammalian meat allergy following multiple bites by another Australian tick species, Ixodes (Endopalpiger) australiensis (Table 2).[19]

Meat Allergies From α-gal Sensitization

When Landsteiner first identified the four major blood group antigens in 1900, he also discovered that humans possessed additional blood group B-like antibodies.[20] These antibodies were directed against an oligosaccharide epitope found on nonprimate, mammalian red blood cells.[20,21] Later, immunologists identified this epitope as α-gal, an IgG immunoglobulin.[20,21] Although all meat-eating primates, including humans, possess IgG α-gal antibodies to mammalian meat, the serum concentration of these antibodies is low (<1% of circulating Ig), and red meat allergies are rare (≤3% of foodborne allergies).[20,21]

Red meat allergies have been reported following antigenic sensitization to α-gal in meat by cow's milk, yogurt, and cheese; by exposures to oral or intravenous bovine and porcine albumin preparations; and by prior allergic reactions to foods containing bovine- or porcine-derived gelatin (Table 3).[14,16,22] Gelatin is a manufactured mammalian meat product composed of hydrolyzed collagen processed from cattle bones, cowhide, and pig skin.[14,16,22]

α-gal-containing Monoclonal Antibodies and Meat Allergies

Medical oncologists engaged in early clinical trials of cetuximab in several southeastern states during the period 2004–2007, describing hypersensitivity reactions, including fatal anaphylaxis, within 5 to 10 minutes of initial infusion.[23–26] Cetuximab is a monoclonal antibody developed in mouse cell lines (SP2/0) that targets the epidermal growth factor receptor in metastatic colorectal and head and neck cancers.[23–26]

In 2017, Chitnavis and coauthors reported the first case of anaphylaxis during the initial intravenous infusion of infliximab in a patient with Crohn disease and a history of meat allergy confirmed by intradermal skin testing with positive reactions to beef, lamb, and pork and negative reactions to chicken, turkey, cow's milk, and fish.[27] Like cetuximab, infliximab is a monoclonal antibody that is glycosylated with α-gal in mouse cell lines (SP2/0). Infliximab targets tumor necrosis factor-α, a key cytokine causing inflammation in Crohn disease and ulcerative colitis. Because further infliximab therapy was contraindicated, the authors administered vedolizumab to the patient without adverse effects. Vedolizimab is a nonglycosylated monoclonal antibody produced in Chinese hamster ovaries, which may produce low levels of α-gal IgE antibodies, but has not caused anaphylaxis.

α-gal Sensitization and Meat Allergies After Tick Bites

In 2009, Commins et al reported a series of 24 patients from the southeastern United States who experienced delayed symptoms of urticaria, angioedema, or anaphylaxis 3 to 6 hours after eating beef, pork, or lamb.[3] All of the patients were intradermal skin test positive to meat but not to chicken extracts.[3] Subsequent radioallergosorbent testing detected IgE antibodies specific for α-gal and confirmed α-gal in red meat as the responsible allergen in all of the patients. Several patients reported prior tick bites and resided in the same states as patients with cetuximab allergies (Arkansas, Missouri, Tennessee, Virginia, and North Carolina).[3,20,23–27]

In 2009, van Nunen et al also described an association between paralysis tick bites and delayed, IgE-mediated mammalian meat allergies in Australia, and suggested that α-gal was again the responsible epitope as in cetuximab allergy.[4] As in the Australian experience, US investigators observed the regional overlaps between the predominant tick species, such as A americanum, and red meat allergy cases, and between the cetuximab allergy cases and IgE antibodies specific for α-gal after tick bites (Figure 1).[4,6,9,20]

Additional evidence in support of A americanum bites as the cause of IgE antibody production specific for α-gal allergy to red meat in the United States was provided by a small case series of three patients.[5] In this series, all three subjects reported tick bites in A americanum tick-endemic regions of the United States, and two subjects were bitten by positively identified A americanum.[5] In all three cases, IgE assays demonstrated statistically significant correlations between human IgE antibodies to α-gal and to salivary proteins derived from A americanum (P < 0.001).[5]

When ticks inject small amounts of α-gal into the circulation during bloodfeeding, the animal-derived antigen promotes the development of IgE-mediated anti-α-gal-antibodies.[28,29] This immunological reaction sensitizes some people to an IgE-mediated allergic response on reexposures to α-gal antigens during monoclonal antibody immunotherapy infusions for cancer or following the ingestion of red meats, dairy products, or gelatin-containing foods.[14,16,19,22–27] The exact incubation period for sensitization to red meat is unknown, but it has been estimated to range from 1 to 3 months based on prior case reports.[14,16,19,22–27]

Although the common denominator between meat allergies and prior tick bites or monoclonal antibody therapy is IgE-mediated α-gal hypersensitivity, the incubation periods from the initiating events to the onset of allergic manifestations differ for unknown reasons. The cetuximab and infliximab infusion reactions are immediate in onset, like other drug-induced allergies.[22–26] The onset of red meat allergies is delayed by ≥2 to 3 hours, unlike other foodborne allergies.[11,12,17,28,30] Investigators have suggested that this delay in onset of hypersensitivity reactions after red meat consumption is related to the time required for intestinal absorption and lymphatic delivery of α-gal epitopes into the circulation to trigger IgE-mediated allergic reactions.[11,12,17,28,30]

Risk Factors for Meat Allergies After Tick Bites

In 2018, Carter et al identified IgE antibodies to α-gal in 6 of 70 patients with idiopathic anaphylaxis, all of whom reported prior tick bites and lived in A americanum–endemic US states (Figure 2).[18] All 6 patients in the study were male and had non-B blood types. Two of the 6 patients, who experienced more severe anaphylactic reactions, had systemic mastocytosis, a hematological condition that is characterized by increased mast cell counts, high serum tryptase levels, and a predisposition to insect venom-induced allergic reactions. After adopting red meat–free diets, all 6 patients experienced no further episodes of unexplained anaphylaxis for follow-up periods ranging from 18 months to 3 years.

Although asthma is not an established risk factor for red meat allergy after tick bites, preexisting atopic allergies to cat dander and to other furred animal dander also may serve as potential risk factors because the sensitizing epitope in animal dander is α-gal, which triggers the production of α-gal-specific IgE.[20]

More recently, another relatively common risk factor for red meat allergy after tick bites was described in patients with bovine and porcine bioprosthetic heart valves.[31,32] In 2013, Naso and co-investigators identified the α-gal epitope in glutaraldehyde-fixed bioprosthetic heart valves and warned that histocompatibility or hypersensitivity reactions could occur in patients with α-gal allergies.[31] Table 4 summarizes the risk factors for red meat allergy in α-gal-sensitized patients.

Clinical Manifestations of Meat Allergies After Tick Bites

In most cases, patients with mammalian meat allergies will have a history of tick bites.[6,30] Patients present with delayed allergic manifestations from 2 to 10 hours after ingesting cooked or raw mammalian meat, often at night.[3,6,9,11,12,17,28] Anaphylaxis with syncope, hypotension, and stridor characterize up to 60% of initial presentations, with the remainder characterized by combinations of pruritic urticarial reactions, angioedema, diarrhea, and abdominal pain.[3,6,9,11,12,17,28] A gelatin allergy may precede a mammalian meat allergy. Manifestations may be immediate if the exposure is to intravenous gelatin-containing plasma expanders or delayed if the exposure is to foodborne gelatin in desserts or to gelatin in medications.[14,22]

Laboratory Diagnosis of Meat Allergies After Tick Bites

The most specific serological tests to support a clinical diagnosis of the α-gal syndrome include blood antigen group typing; total serum IgE levels by chemiluminescence assay (normal mean 32 IU/mL); and specific IgE levels to beef, pork, and lamb extracts by fluoro-enzyme immunoassay (positive IgE reaction level to α-gal ≥0.35 IU/mL).[9,10,18] If such tests are unavailable, then cetuximab skin prick or intradermal skin testing also will confirm the diagnosis of α-gal sensitivity and IgE-mediated red meat allergy.[18,25,30] Systemic mastocytosis also should be ruled out by measuring serum tryptase levels by fluoro-enzyme immunoassay (normal levels ≤11.5 ng/mL).[18] Skin prick or intradermal skin tests with extracts of beef, lamb, pork, chicken, turkey, fish, and cat and dog dander also are recommended to establish the best meatless diets and to rule out coexisting dander allergy.[18,25,30]

Several investigators have recommended pretesting for IgE antibodies to α-gal for all patients with histories of red meat allergies or tick bites before the initiation of therapy with monoclonal antibody biologics, such as cetuximab for metastatic cancer and infliximab for inflammatory bowel disease.[27] In these cases, several laboratory tests are recommended, including the IgE western blotting test with cetuximab, the CD63-expression-based basophil activation test, and the α-gal-specific IgE test using bovine thyroglobulin (ImmunoCap, Thermo Fisher, Waltham, MA). The ImmunoCap test is regarded as the most specific test for identifying patients with IgE antibodies to α-gal.[27]

Management of Meat Allergies After Tick Bites

The therapeutic management of mammalian meat allergic reactions is no different from the treatment of anaphylaxis, angioedema, and urticaria resulting from exposures to other foodborne allergens.[6,8,18,20,30] The cornerstone of therapeutic management for acute anaphylaxis with syncope, shock, laryngeal edema, stridor, wheezing, and respiratory distress is subcutaneous epinephrine to restore blood pressure and reverse bronchoconstriction.[6,18,20,30] Oral or parenteral H-1 and H-2 blocking antihistamines are indicated for symptomatic relief from pruritic urticarial reactions.[6,8,18,20,30] Oral or parenteral corticosteroids are indicated to reduce ongoing swelling from angioedema.[6,8,18,20,30] Nongelatin-containing intravenous fluids, plasma expanders, and electrolytes are indicated to reverse hypovolemia and restore circulatory volume in reactions with gastrointestinal involvement and severe diarrhea, usually without vomiting.[6,8,18,20,30]

Patients with α-gal sensitivity should avoid all red meat, including beef, lamb, pork, goat, rabbit, horse, kangaroo, venison, and other game meats and organ meats; all gelatin-containing foods and drugs; and cancer immunotherapy with intravenous cetuximab and infliximab.[6,8,18,20,30] Some food sensitivities may wane over a prolonged period during which mammalian meat may be reintroduced gradually into one's diet.[8,20,30]

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