o215 Alpha-Gal

Summary

α-Gal-associated meat allergy is a recently described syndrome in which individuals who have been bitten by ticks of the Ixodidae family become sensitized to the carbohydrate determinant galactose-α-1,3-galactose (α-Gal). The resulting IgE antibodies react with α-Gal epitopes on mammalian meat, resulting in an allergic reaction and in some cases anaphylaxis after eating meat or gelatin. A distinctive feature of this allergy is the delayed onset of symptoms, which occurs 2-6 hours after eating meat. The delayed symptom onset is thought to reflect the appearance of glycolipid α-Gal moieties, which are believed to be involved in the allergic reaction, in the bloodstream.

Diagnosis of α-Gal-associated meat allergy may not be straightforward, especially in children, as the syndrome can be confused with protein-based meat allergies. While negative skin prick test (SPT) results are unreliable, the syndrome can be confirmed by correlating clinical history with the measurement of IgE antibodies to α-Gal. If α-Gal sIgE results represent >2% of total sIgE, a diagnosis of meat allergy is very likely (1). Serum tryptase testing can help identify people who may have more severe reactions to tick bites (2). Finally, testing for the presence of IgE to α-Gal could identify a risk factor for medical treatment with cetuximab, eating gelatin-containing substances, or using artificial bovine blood in areas where hard body ticks are common, particularly in individuals with a history of a tick bite or demonstrated allergy to mammalian meat or gelatin (1).

Environmental Characteristics

Worldwide distribution

To date, cases of α-Gal-associated meat allergy have been reported in the southeastern (27) northeastern and upper midwestern US (3), Australia (4) Asia (5) and in several European countries, including France (6-8) Spain(9), Germany(10), Switzerland (11), and Sweden (12), Italy (13).

On all continents, the ticks responsible for sensitization to α-Gal belong to the Ixodidae family of hard ticks, with each continent harboring its native species. In the US, bites from the Lone Star tick Amblyomma americanum (Figure 1) are the predominant, if not exclusive, cause of α-Gal sensitization (14). There is a significant correlation between IgE to Lone Star tick bites and antibodies to α-Gal (15). Warming temperatures and the availability of desirable hosts favor the continued range expansion of Lone Star ticks (3), with reported sightings from Maine to Florida, in Wisconsin (16), and as far west as Texas, Oklahoma and Colorado (17). Borrelia burgdorferi, the bacterium that ticks carry causes Lyme disease, does not appear to induce IgE to α-Gal and its bites are not associated with itching (15). In Australia, the suspected tick is Ixodes holocyclus (7, 18), whereas in Europe it is Ixodes ricinus (19) ,and Hematophagous ixodidae in Asia (20).

The prevalence of detectable IgE antibodies to α-Gal is highest in areas where Ixodidae ticks are common. In Sweden, around 10% of 143 healthy blood donors in the greater Stockholm area had IgE antibodies to α-Gal, compared with only 0.7% in the north of the country where tick bites are rare (12). It is, however, unclear exactly what proportion of sensitized individuals experience allergic symptoms after eating mammalian meat. Commins and Platts-Mills estimated that around 10% of individuals with detectable α-Gal antibodies may display red meat allergy (21). The prevalence of IgE to α-Gal among Danish and Spanish adults was estimated at 5.5% and 8.1%, respectively, for levels ≥0.1 kUA/L, and at 1.8% and 2.2%, respectively, for levels ≥0.35 kUA/L (22). Based on a survey of 1,000 Americans, 7.7% reported a history of an anaphylactic reaction, with an estimated 5.1% of that population having “probable anaphylaxis” and 1.6% “very likely” anaphylaxis (23), 218 of the reported cases met the criteria for anaphylaxis, and 85 were associated with a definitive cause; α-Gal was cited in 28/85 (33%) of cases with a known cause, more frequently than other food allergies (24/85 cases, 28%).

Adult onset originally appeared to be a characteristic of α-Gal-associated meat allergy (24). In a series of 29 patients with α-Gal-associated meat allergy in Japan, 21 were over 60 years of age (5). Nevertheless, cases of α-Gal-associated meat allergy have also been observed in children (15, 25). In a case series of 51 children ages 4-17 years, who had possible delayed allergic reactions to mammalian foods, 45 had high serum IgE levels to α-Gal, which correlated with beef IgE levels (15). Questioning revealed a history of symptoms 3-6 hours after eating meat and of tick bites. Among adults and children, and atopic and non-atopic individuals, the levels of α-Gal IgE and the severity of reactions were similar (26)

Blood group phenotype

The B blood group phenotype appears to confer a protective effect against the production of high levels of IgE to α-Gal, with a strong relationship between α-Gal-associated meat allergy and absence of the B blood group phenotype (12, 26, 27)

A study of the relationship between the B blood group phenotype and IgG and IgE responses to α-Gal found that none of the subjects with the B phenotype expressed IgE to α-Gal (28). Among 39 Swedish patients with delayed meat allergy, only two (5%) had blood group B or AB, which is significantly lower than the expected overall prevalence of 18% in the Swedish population (12). The same study reported that in a group of healthy blood donors and patients with Lyme disease with detectable IgE to α-Gal, the levels of IgE against α-Gal were very low among those with the blood group B phenotype (12). The mechanism of this protective effect has not been fully elucidated. However, the structure of the α-Gal epitope is closely related to that of the blood group B antigen, and it appears that the presence of the group B antigen induces tolerance and eliminates most B cell clones that could otherwise interact with tick-derived α-Gal antigens (28).

In addition, Wilson et al (1) have found indications that a-Gal sensitization could be a risk factor for coronary artery disease. This need to be further studied. 

Figure 1. Structure of galactose-a1,3-galactose.

Prevention and Therapy

Management of α-Gal-associated meat allergy (29)

The primary management strategy is avoiding mammalian meat, especially fatty cuts.

• Avoid meats, including beef, pork, lamb, horse, goat, rabbit, squirrel, and venison.
• Avoid mammalian organs such as liver, intestine, heart, and kidney (especially pork kidney) and other mammalian products including lard, suet, and pork rinds.
• Gelatin has reportedly caused severe reactions, either as jelly sweets and marshmallows or as intravenous preparations.

Although most patients tolerate dairy products and gelatin, patients who continue to have unexplained symptoms may also be advised to avoid dairy foods and gelatin.

Avoid additional tick bites by staying away from tick-infested areas, wearing protective clothing, or using products containing N, N-diemethyl-meta-toluamide may make some patients less prone to symptomatic reactions.

Molecular Aspects

Biochemistry

The α-Gal epitope (Galα1-3Galβ1-4GlcNAc-R, or Gaα1- 3Galα1-3GlcNAc-R) is a unique carbohydrate structure present in all mammals except humans and Old World monkeys (Figure 2), where it exists on the cell surface as both glycolipids and glycoproteins (30). The onset of clinical symptoms in α-Gal-associated meat allergy corresponds with basophil activation, implying that it coincides with the appearance of the antigen in the bloodstream (31). Lipids enter the bloodstream 3–4 hours after a meal, suggesting that the delay in symptom onset could reflect the time required for absorption and digestion of glycolipid α-Gal antigens (21). The observation that fatty meats provoke more consistent and severe reactions is also consistent with the notion that glycolipids may play an important role (21, 31). This hypothesis is further supported by evidence that glycolipids can elicit a robust immune response in humans (32). However, a recent screen of IgE-binding proteins from beef and pork, using sera from Japanese patients with α-Gal-associated meat allergy, identified α-Gal on the glycoproteins laminin γ-1 and the collagen α 1 (VI) chain as likely common IgE-reactive proteins in these patients with beef allergy (5). 

Figure 2. Levels of a-Gal-specific IgE increase after tick bites and decline with time after the bite. Adapted from (14).

Comparison with other meat allergies

Meat allergy

Despite a high level of meat consumption in developed countries, allergy to meat is uncommon (33, 34) it is normally outgrown during the first years of life and is rare in adults (35). Meat allergy has been estimated to occur in around 3% to >7% of children and adults with food allergies (36, 37). Allergy to beef is the most commonly reported form of meat allergy, affecting 1.5 to 6.5% of children with atopic dermatitis or food allergies (35, 38) which corresponds to a prevalence of around 0.3% in the general population (39).

Table 1. Features of α-Gal-mediated meat allergy, protein-mediated meat allergy (40-42), and pork-cat syndrome (43, 44)

Patients with meat allergy are often sensitized to cross-reactive proteins, such as serum albumin, gamma globulins, tropomyosins, and actin (40). Consequently, many patients show cross-reactivity to animal danders in SPT and immunoassays (40, 47) and a high proportion of beef-allergic patients also show clinical cross-reactions to cow’s milk (35). In contrast with α-Gal-associated meat allergy, symptoms in individuals sensitized to protein epitopes usually appear immediately after meat is eaten (41, 42) (Table 1). 

Diagnostic Relevance

Disease Severity

Delayed onset of symptoms is the most clinically distinguishing characteristic of α-Gal-associated meat allergy compared with protein-based meat allergies. However, accurate information on the timing of symptom onset is not always available from the patient.

Exposure

Alpha-Gal is present in all mammals except for humans and old-world monkeys (30). Therefore, red meats such as beef, pork, and lamb are the most common triggers. But derivatives of red meat can be hiding in a variety of foods that aren’t always clearly labeled, like gelatin-containing foods and dairy. These derivatives can also be found in many medications and biologic therapies of which patients need to be aware(1, 4).

Not all triggers are equally likely to cause a reaction—see the chart below for triggers ranked from higher to lower risk. 

Table 2.  Adapted from (1) 

There are also cofactors that may increase the risk or severity of the reaction, including:

• Non-steroidal anti-inflammatory drugs
• Exercise
• Alcohol
• Recent tick bites (1, 45)

Compiled By

Reviewer: Dr. Christian Fischer

Last reviewed: October 2020