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Mammalian meat–induced anaphylaxis: Clinical relevance of anti–galactose-α-1,3-galactose IgE confirmed by means of skin tests to cetuximab

2009; Elsevier BV; Volume: 124; Issue: 3 Linguagem: Inglês

10.1016/j.jaci.2009.06.014

1097-6825

S. Jacquenet, D.A. Moneret‐Vautrin, Bernard E. Bihain,

Mast cells and histamine

To the Editor: Severe anaphylaxis is often associated with food allergy. Classically, the diagnosis of food allergy is established through a careful evaluation of a patient's allergy history, including skin tests and in vitro tests. If the specific trigger cannot be established, then the patient might be diagnosed with idiopathic anaphylaxis, which is a major concern for both the patient and the physician. Some of these cases are due to rare food allergies.1Stricker W.E. Anorve-Lopez E. Reed C.E. Food skin testing in patients with idiopathic anaphylaxis.J Allergy Clin Immunol. 1986; 77: 516-519Abstract Full Text PDF PubMed Scopus (87) Google Scholar Recently, a new specific IgE to galactose-α-1,3-galactose (α-gal) was shown to be linked with anaphylaxis or angioedema reactions to mammalian meats.2Chung C.H. Mirakhur B. Chan E. Le Q.T. Berlin J. Morse M. et al.Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose.N Engl J Med. 2008; 358: 1109-1117Crossref PubMed Scopus (1173) Google Scholar, 3Commins S.P. Satinover S.M. Hosen J. Mozena J. Borish L. Lewis B.D. et al.Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-alpha-1,3-galactose.J Allergy Clin Immunol. 2009; 123: 426-433Abstract Full Text Full Text PDF PubMed Scopus (507) Google Scholar The present study reports on 2 cases of anaphylaxis to mammalian meats, which were evaluated by using an in-house α-gal IgE immunoassay4Erwin E.A. Custis N.J. Satinover S.M. Perzanowski M.S. Woodfolk J.A. Crane J. et al.Quantitative measurement of IgE antibodies to purified allergens using streptavidin linked to a high-capacity solid phase.J Allergy Clin Immunol. 2005; 115: 1029-1035Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar and novel intradermal tests (IDTs) to cetuximab. Cetuximab is an mAb presenting the α-gal oligosaccharide in the Fab portion of the heavy chain. Two patients were referred to our department in 2008 with idiopathic anaphylaxis diagnoses after undergoing inconclusive allergy tests. Patient 1 was a 53-year-old man who had an anaphylactic shock in 2006 ninety minutes after consuming pork offal. He experienced recurrent episodes of delayed urticaria 4 hours after ingesting pork, beef, and horse, lamb, and rabbit meats. Consumption of milk and poultry did not result in allergic reactions. The patient had asthma in childhood. Patient 2 was a 48-year-old woman who experienced an anaphylactic shock in 2004 two hours after eating a meal that included pork offal (kidney) and 7 episodes of urticaria that occurred at night. Retrospectively, the anamnesis indicated that she had consumed mammalian meat 6 hours before the allergic reaction. She consumed milk and poultry without incident. In childhood the patient had atopic dermatitis. She had 2 pets (a cat and a dog) and used to go horseback riding. Both patients had a background of atopy with sensitization to Dermatophagoides pteronyssinus. The total IgE levels measured were 38 kU/L for patient 1 and 454 kU/L for patient 2. The serum tryptase levels were normal in both patients. Prick-in-prick tests were performed to raw and cooked mammalian meats, as well as to 30 common foods. Both patients had slightly positive prick-in-prick test results, these being only to raw beef and pork kidney (Table I).Table IPrick-in-prick tests and IDT results for 3 patients (in millimeters)Patient 1Patient 2Pork-cat syndrome (control subject)Negative control to saline000Positive control to 9% codeine2.563Raw beef meat330Cooked beef meat2.500Raw and cooked veal meat0nd2.5Raw and cooked pork meat01.5 and 00Pork kidney2.52.50Raw and cooked lamb meat000Raw rabbit meat2nd2.5Cooked rabbit meat1ndNdOther food allergens000Cetuximab, 5 μg/ml990A positive prick-in-prick test result was a 3-mm-diameter wheal when the negative control produced negative results and the 9% codeine control result was positive. Open table in a new tab A positive prick-in-prick test result was a 3-mm-diameter wheal when the negative control produced negative results and the 9% codeine control result was positive. IDTs to cetuximab (Erbitux; Merck Serono, Geneva, Switzerland) were conducted at concentrations of 5, 50, and 500 μg/mL. For both patients, the IDT results were positive at the lowest concentration (5 μg/mL) and produced a mean wheal diameter of 9 mm (ie, the reaction was 3 times larger than the wheal of injection; Fig 1). Increased concentrations of cetuximab elicited impressive skin reactivity. Eight control subjects with atopy who were suspected of having meat allergies were also evaluated with IDTs to cetuximab. One of these control subjects had allergic rhinitis to cat and allergy to pork meat, referred to as "pork-cat syndrome," that was mediated by specific IgE antibodies to serum albumin. All 8 control subjects had negative results to cetuximab up to 500 μg/mL. Specific IgE antibodies were present for beef, pork, and rabbit meat in both patients (Table II). Specific IgE antibody levels to α-gal were measured, as described by Chung et al,2Chung C.H. Mirakhur B. Chan E. Le Q.T. Berlin J. Morse M. et al.Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose.N Engl J Med. 2008; 358: 1109-1117Crossref PubMed Scopus (1173) Google Scholar and were 4.82 kU/L in patient 1 and 0.28 kU/L in patient 2. Five control sera were tested; all were negative for IgE antibodies to α-gal. Both patients exhibited specific IgE antibodies to cat epithelia in the absence of IgE to Fel d 1, and patient 2 showed only a slight sensitization to cat albumin. Both patients had negative results for IgE antibodies to pork albumin. In contrast, the control subject with pork-cat syndrome had specific IgE antibodies that were greater than 100 kU/L against cat albumin and 9.41 kU/L against pork albumin but had no anti–α-gal IgE antibodies (Table II).Table IISpecific IgE levels (in kilounits per liter) in 3 subjects as measured with ImmunoCAP (Phadia, Uppsala, Sweden)Patient 1Patient 2Pork-cat syndrome (control subject)Beef3.43206.11BSANDND10.8Pork2.38136.48Pork serum albumin<0.10 100Cat albumin 100Fel d 1<0.10<0.103.01α-Gal4.820.28<0.10 Open table in a new tab Allergies to meats are rarely identified. The Circle for Clinical and Biological Investigations in Food Allergy (CICBAA) databank has recorded 1037 documented food allergies and contains data on 14 cases of allergies to mammalian meats, including 10 (1.3%) of 726 cases in children and 4 (1.2%) of 311 cases in adults. In children beef allergies were implicated in 8 cases and were associated with pork allergies in 2 cases and with milk allergies in 2 cases. Two cases in children were isolated pork allergies. In adults allergies to pork were reported 3 times and were associated with allergies to rabbit meat in 2 cases. BSA is the most common allergen that explains cross-allergies between milk and beef and lamb.5Restani P. Ballabio C. Tripodi S. Fiocchi A. Meat allergy.Curr Opin Allergy Clin Immunol. 2009; 9: 265-269Crossref PubMed Scopus (65) Google Scholar Other identified allergens were more rare; these included gamma globulins, tropomyosin, and actin.5Restani P. Ballabio C. Tripodi S. Fiocchi A. Meat allergy.Curr Opin Allergy Clin Immunol. 2009; 9: 265-269Crossref PubMed Scopus (65) Google Scholar In pork-cat syndrome the allergen is pork albumin, which can cross-react with cat albumin because of its 82% amino acid sequence homology.6Drouet M. Sabbah A. Le Sellin J. Bonneau J.C. Gay G. Dubois-Gosnet C. [Fatal anaphylaxis after eating wild boar meat in a patient with pork-cat syndrome].Allerg Immunol (Paris). 2001; 33: 163-165PubMed Google Scholar, 7Hilger C. Kohnen M. Grigioni F. Lehners C. Hentges F. Allergic cross-reactions between cat and pig serum albumin. Study at the protein and DNA levels.Allergy. 1997; 52: 179-187Crossref PubMed Scopus (98) Google Scholar In addition, specific allergens could be involved in allergies to offal that contrast with a tolerance to meats of similar origin.8Llatser R. Polo F. De La Hoz F. Guillaumet B. Alimentary allergy to pork. Crossreactivity among pork kidney and pork and lamb gut.Clin Exp Allergy. 1998; 28: 1021-1025Crossref PubMed Scopus (28) Google Scholar Mammalian meat allergies can be related to sensitization to the α-gal oligosaccharide epitope, a glycosylation modification in nonprimate mammalian proteins.2Chung C.H. Mirakhur B. Chan E. Le Q.T. Berlin J. Morse M. et al.Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose.N Engl J Med. 2008; 358: 1109-1117Crossref PubMed Scopus (1173) Google Scholar, 3Commins S.P. Satinover S.M. Hosen J. Mozena J. Borish L. Lewis B.D. et al.Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-alpha-1,3-galactose.J Allergy Clin Immunol. 2009; 123: 426-433Abstract Full Text Full Text PDF PubMed Scopus (507) Google Scholar, 9Macher B.A. Galili U. The Galalpha1,3Galbeta1,4GlcNAc-R (alpha-Gal) epitope: a carbohydrate of unique evolution and clinical relevance.Biochim Biophys Acta. 2008; 1780: 75-88Crossref PubMed Scopus (323) Google Scholar However, the clinical relevance of IgE antibodies against α-gal is unclear. Hence in patient 2 an allergic reaction is not observed after each meal containing meat. Although the level of specific IgE antibodies was low in this patient, strong skin sensitization was observed on the IDTs to cetuximab. The lack of a correlation between allergen consumption and the reaction might be linked to variability in meat digestion, as altered by the association of other food variables, which is known as the matrix effect. Pork-cat syndrome has been shown to be due to cross-reactivity between cat and pork albumins.7Hilger C. Kohnen M. Grigioni F. Lehners C. Hentges F. Allergic cross-reactions between cat and pig serum albumin. Study at the protein and DNA levels.Allergy. 1997; 52: 179-187Crossref PubMed Scopus (98) Google Scholar The control subject with this syndrome had no specific IgE antibodies to α-gal. This result is consistent with the theory that only protein epitopes are implicated in pork-cat syndrome and with the fact that albumins are not glycosylated. The strong skin reactivity observed might depend on several parameters. First, there are 2 α-gal epitopes per molecule of cetuximab, making cetuximab a divalent molecule that can bridge a membrane IgE. These epitopes are presented opportunistically to membrane IgE antibodies, with a constant distance between the 2 epitopes that is determined by the Fab. Second, the intradermal injection of this cetuximab offers a huge quantity of accessible epitopes. Injection of 0.05 mL of 5 μg/mL cetuximab offers a total of 1012 cetuximab molecules and, consequently, 2 × 1012 α-gal molecules. Third, the measured skin reactivity demonstrates that numerous specific IgE antibodies are present on mast cells. Therefore skin sensitization can be much higher than the circulating specific IgE level predicts. The reactive concentration of cetuximab, as measured with the IDT, was estimated to be 100-fold greater in the 7 control subjects than in the allergic patients (500 vs 5 μg/mL, respectively). Therefore this diagnostic tool could be used to accurately identify mammalian meat allergies in patients given diagnoses of idiopathic anaphylaxis and eosinophilic esophagitis, gastroenteritis, or colitis.10Spergel J.M. Eosinophilic esophagitis in adults and children: evidence for a food allergy component in many patients.Curr Opin Allergy Clin Immunol. 2007; 7: 274-278Crossref PubMed Scopus (131) Google Scholar We thank Shama M. Satinover and Dr Thomas Platts-Mills for the technical information used to measure the specific IgE antibodies to α-gal.