The current report contains several new observations. First, the patients report anaphylaxis, angioedema, or urticaria associated with eating mammalian meat 3 to 6 hours earlier. This represents a departure from the conventional food allergy paradigm and might provide an explanation as to why the clinical implications of IgE antibodies to carbohydrate epitopes have not been well characterized to date.21
Skin responses do occur with appropriate testing, indicating that IgE antibodies to α-gal are present on mast cells, and therefore the delay in symptoms is likely due to digestion, processing, or both of the antigen.
Second, we have been able to relate distinct clinical symptoms to the newly described IgE antibody specific for α-gal. The α-gal epitope is abundantly expressed on cells and tissues of nonprimate mammals,15,22
making it potentially more clinically relevant than the previously described cross-reactive carbohydrate determinant motifs of xylose and core-3-linked fucose.23
Screening of sera from the 24 patients with IgE antibodies to α-gal revealed that only 3 of the 24 had cross-reactivity to bromelain, which contains both xylose and core-3-linked fucose (data not shown). Moreover, sera with high titer-specific IgE antibodies to bromelain did not contain IgE antibodies to α-gal (data not shown). α-Gal has not been previously described as a potential food allergen, and its elucidation might explain earlier published reports of delayed food (meat) allergy,24
or an observed reactivity to beef in children allergic to cow’s milk.26
Third, in this cohort of patients with similar histories, symptoms, and serum IgE antibody profiles, we found that conventional SPTs with commercial reagents were insufficient for diagnosis. In fact, a wheal response of less than 4 mm to beef, pork, and lamb performed by using an accepted SPT method with widely used extracts could lead to incorrect guidance for patients, a serious issue when anaphylaxis is the result. Moreover, given the titer of IgE antibodies to α-gal, both SPTs and intradermal tests produce smaller-diameter wheals than would be expected with a protein food allergen, such as peanut. There are several possible explanations for the intermediate skin test responses. It has been suggested that antibodies to relatively uncharged carbohydrate epitopes would have low affinity.27
Alternatively, the distribution of the α-gal epitope on the intact proteins might not be suitable for cross-linking IgE antibodies on the surface of a mast cell. Despite the obvious logistic challenges, SPTs with freshly prepared food extracts offer an alternative approach with increased diagnostic benefits. We are currently pursuing data to demonstrate positive double-blind, placebo-controlled food challenge results in these patients to document symptoms and the time delay described. If we are able to do so, then the potential exists for using intradermal tests to foods because these patients would meet the proposed criteria.28
Finally, most patients reported the onset of symptoms within the last 2 to 3 years, challenging the notion that the incidence of adult-onset mammalian meat allergy is rare.
Screening serum samples from multiple geographic locales has revealed a distinct regional distribution of IgE antibodies to α-gal. To date, we have found patients in Virginia, North Carolina, Tennessee, Arkansas, and Missouri, a distribution that roughly correlates with the higher incidence of cetuximab hypersensitivity reactions.11,29,30
This population is enriched, however, and other data suggest that the prevalence of IgE antibodies to α-gal in central Virginia might be approximately 10%. Thus our current data cannot be used to calculate the prevalence of IgE antibodies to α-gal in patients with symptoms, nor does it provide evidence about what percentage of patients with IgE antibodies to α-gal will have symptoms.
Initial attempts to clarify the possible causes of development of IgE antibodies to α-gal included investigation of parasitic infections as an inciting event. Sera from patients with documented helminth infections, however, do not consistently contain IgE antibodies to α-gal (data not shown). Interestingly, more than 80% of the patients in the present cohort report being bitten by ticks before having symptoms; a similar scenario has been recently described in a group of Australian patients.31
Therefore the implications of IgE antibodies to α-gal might extend well beyond the southeastern United States, and we are pursuing the possibility that bites from ticks or tick larvae of the genus Amblyomma
are responsible for triggering the production of IgE antibodies to α-gal.
It has recently been reported that some patients with cat allergy have IgE antibodies that bind to a carbohydrate epitope on cat IgA, a major component of cat epithelium–derived allergy extracts.32
Further preliminary investigation suggests that these IgE antibodies are binding to an α-gal moiety on cat IgA (M. van Hage, personal communication). Moreover, IgE antibodies to α-gal might explain the clinical observation in Europe of an association between allergy to epithelia and allergy to meat (pork-cat syndrome),33
as well as the reported observation of cross-reactivity among beef, pork, and pet dander in patients with milk allergy.34
The significant correlation between IgE to cat and IgE antibodies to α-gal is not because patients with IgE to α-gal have cat allergy; in fact, only 3 of the 24 patients report allergic symptoms to cats, and these correspond to patients with IgE to Fel d 1. Rather, the presence of α-gal moieties on epithelia is responsible for the consistently positive cat (and dog) values, and this is supported by the absorption data showing that preincubation with α-gal or beef thyroglobulin removed this IgE antibody (). This apparent incongruence between ImmunoCAP results and clinical symptoms is also evident in the context of cow’s milk because most patients tolerate milk despite positive skin test results and serum titers (geometric mean, 2.80 IU/mL). Ten of the 24 patients reported symptoms to cow’s milk, however, and the distinction between cow’s milk reactions and the lack of cat/dog allergic symptoms in the setting of seropositivity for each likely is because of the ingestion versus inhalant routes of exposure. Although avoidance of mammalian meat is certainly the recommendation, patients do not appear to require complete avoidance of all mammalian products (ie, the aforementioned tolerance of cow’s milk in 14/24 patients). In fact, some patients even report the ability to tolerate small amounts of mammalian meat on occasion without symptoms but then might react to a single piece of bacon, raising the possibility that portion size, processing, preparation, and/or cut of meat might influence the production of a reaction. Another possibility is that a bovine allergen distinct from α-gal is responsible for producing the reactions these patients have experienced.
In conclusion, we have described a cohort of patients with IgE antibodies to α-gal who experience delayed symptoms of anaphylaxis, angioedema, or urticaria after eating mammalian meat. This report of severe food allergy related to IgE antibodies to a carbohydrate epitope is novel, and in keeping with the lack of immediate oral symptoms, skin testing in these patients often produces a wheal response of less than 4 mm. There are 2 major questions that will require further research, the first of which might require controlled food challenges. Why are reactions to meat delayed for several hours? What insult or exposure induces the production of IgE antibodies to α-gal in these adult patients?
Clinical implications: In patients with IgE antibodies to the carbohydrate α-gal, eating beef, pork, or lamb is associated with delayed anaphylaxis, urticaria, or angioedema and often a less than 4-mm response on SPTs.