Publications

A searchable database of these publications is coming soon!

This research resource, in which we hope to include all the evidence-based research related to alpha-gal syndrome, was compiled by Matthew von Hendy of  Green Heron Research Resources. Matthew is an accomplished research librarian with more than 20 years of professional experience.  He has expertise in finding scientific, technical and health related information. He has worked at EPA, NASA and the National Academies of Sciences where his work was cited in 10 different National Academies reports.

Abdallah, M. A. and E. A. Larson (2018). “Delayed Anaphylaxis to Mammalian Meat: A Fascinating Disease and Captivating Story.” S D Med 71(10): 463-465.

Delayed anaphylaxis to mammalian meat is a newly recognized IgE-mediated syndrome associated with Lone Star tick bites. IgE-mediated anaphylaxis classically occurs within one hour of exposure to the allergen, which is typically a protein epitope. However, in this disease, circulating antibodies to a carbohydrate, alpha-gal (galactose-alpha-1,3-galactose), stimulate the anaphylactic cascade with hives, diarrhea, abdominal cramps, respiratory distress and anaphylactic shock developing after ingestion of beef, pork or lamb meat. The delayed onset of symptoms three to six hours after ingestion of meat is unique. Recognition and understanding of this disease are important for treating and educating patients with suggestive symptoms. Avoidance of red meat is the recommended therapy.

Abreu, C., et al. (2018). “Galactose-alpha-1,3-galactose allergy: a rare syndrome and an atypical presentation.” Eur Ann Allergy Clin Immunol 50(4): 190-192.

Summary: Allergies to red meat associated with galactose-alpha-1,3-galactose, commonly known as alpha-gal, are rare and have only recently been described. At this time, the literature reports only one case documented in Portugal. In this study, we report the case of a 76-year-old male with an immediate reaction following the ingestion of red meat. Rigorous diagnostic exams, including prick test, prick-to-prick tests, serum specific IgE and SDS-PAGE IgE-immunoblotting, were performed. The alpha-gal epitope IgE re-turned a value of 35.3 kUA/L, leading the authors to believe that this is an atypical case of alpha-gal allergy. 

Abreu, C., et al. (2015). “Anaphylaxis after consumption of red meat in patient with IgE antibodies specific for galactose-alpha-1,3-galactose.” Allergy 70: 616-617. 

Adams, C. B., et al. (2016). “Low rate of cetuximab hypersensitivity reactions in Northeast Tennessee: An Appalachian effect?” Journal of Oncology Pharmacy Practice 22(6): 784-789.

Purpose Cetuximab is a monoclonal antibody with a known risk of hypersensitivity reactions. Early studies showed hypersensitivity reaction rates of 3%, but there appears to be a higher incidence in the southeastern United States. To confirm the findings from nearby institutions that cetuximab-associated hypersensitivity reactions occur in approximately 20% of patients in the southeastern United States. Methods A retrospective chart review was conducted at Johnson City Medical Center in Johnson City, Tennessee. Each patient’s first infusion was analyzed for hypersensitivity reaction, as well as for demographic information such as allergy and smoking history, pre-medications, and malignancy type. Results Data from the first infusion of cetuximab were collected for a total of 71 patients with various malignancies. The overall rate of grade 3 or higher hypersensitivity reaction was 1.4%, and total rate of hypersensitivity reaction was 8.5%. These findings more closely correlate to the early clinical trials and package insert. Both severe (p=0.001) and any-grade (p=0.002) hypersensitivity reaction occurred less frequently in one Southeastern Appalachian medical center compared to academic medical centers directly to the east and west. Conclusions Patients in southern Appalachia may be less likely to develop cetuximab hypersensitivity reactions compared to surrounding areas in the Southeastern U.S. These results lend support to the theory that exposure to lonestar ticks (Amblyomma americanum) may be responsible for the development of IgE antibodies to cetuximab that cause hypersensitivity reactions. The development of quick and reliable bedside predictors of cetuximab hypersensitivity reactions may aid clinicians considering the use of cetuximab. 

Akella, K., et al. (2017). “Alpha Gal-Induced Anaphylaxis to Herpes Zoster Vaccination.” CHEST 152(4): A6.

Altmann, F. (2016). “Coping with cross-reactive carbohydrate determinants in allergy diagnosis.” Allergo J Int 25(4): 98-105.

A relevant proportion of allergy diagnosis is accomplished by in vitro determination of specific immunoglobulin E (sIgE) to extracts from suspected allergens. Such extracts inevitably contain glycoproteins, which may react with patients’ IgE. In the case of plant and insect allergens, the relevant epitope structure is an alpha-1,3-fucose on the Asn-linked sugar residue of so-called N-glycans. Due to their wide distribution, N-glycans carrying this epitope are known as “cross-reactive carbohydrate determinant(s)” (CCD[s]). About 15 years of awareness allow the conclusion that anti-CCD IgE does not cause noticeable clinical symptoms. In consequence, diagnostic results arising from CCD reactivity must be rated as false positives. With up to 30 % of CCD reactive patients, this can be regarded as a serious problem. Another cross-reactive carbohydrate determinant became notorious as a potential cause of anaphylactic reactions to a recombinant glycoprotein drug carrying alpha-1,3-galactose. This galactose-containing determinant (GalCD, galactose containing cross-reactive carbohydrate determinant) was supposed as a trigger for delayed allergic reactions to red meat in several cases. Thus, alpha-1,3-galactose may have clinical relevance in certain cases – possibly as a result of tick bites. Often, however, GalCDs probably cause false-positive results with milk and meat extracts. No clear evidence for the role of other non-human carbohydrate structures such as N-glycolylneuraminic acid as CCD has been presented so far. Remedies for sIgE based in vitro diagnosis come in the form of non-glycosylated recombinant allergen components or of specific CCD inhibitors. The high potential of recombinant allergens is optimally realized in the context of component resolved diagnosis using allergen arrays with more than 100 components, whereas CCD inhibitors increase the specificity of conventional extract-based diagnosis. Reagents for the detection and inhibition of CCDs from plants and insects have been developed, whereas tools for GalCDs of milk and meat lag behind.

Altrich, M. L., et al. (2015). “Alpha-Gal IgE Sensitization in the United States; Surveillance Update.” Journal of Allergy and Clinical Immunology 135(2, Suppl. S): AB37.

Galactose-alpha-1,3-galactose (alpha-gal), is a cross reactive carbohydrate moiety found in red meats such as beef, pork and lamb and is associated with a delayed IgE response. A link to lone star tick bites was established by researchers at the University of Virginia and although the mechanism of sensitization is not clearly elucidated, it remains the primary suspect.

Anemüller, W., et al. (2018). “Alpha-Gal-assoziierte verzögerte Anaphylaxie gegen rotes Fleisch als Berufskrankheit.” Der Hautarzt 69(10): 848-852.

Bei einem 30-jährigen Koch mit rezidivierenden verzögerten Angioödemen konnte anamnestisch und laborexperimentell als Ursache die Sensibilisierung gegen das Kohlenhydratepitop Galactose-alpha-(1,3)-Galactose (alpha-Gal) aufgedeckt werden. Mit der Diagnose einer verzögerten Anaphylaxie bei Sensibilisierung gegen alpha-Gal erfolgte aufgrund des beruflichen Bezuges die Meldung an die Berufsgenossenschaft mittels Hautarztbericht BK 5101. Hierauf wurde dem Patienten fristlos gekündigt. Als Konsequenz zeigten wir eine Berufskrankheit an. Diese Kasuistik stellt die Bedeutung der unterdiagnostizierten, potenziell lebensbedrohlichen Allergie gegen das Disaccharid alpha-Gal des roten Fleisches als Berufskrankheit dar.

English translation:

Alpha-gal associated delayed red meat anaphylaxis as an occupational disease

Abstract

In a 30-year-old chef with recurrent delayed angioedema history as well as the experimental detection of IgE antibodies to galactose-alpha (1,3) -galactose (alpha-gal) pointed to alpha gal as the causative agent. The diagnosis, therefore, was delayed by anaphylaxis due to alpha-gal. Because of the potential relationship to his profession, we have submitted a dermatologist’s report BK 5101 to the liability and insurance association, whereupon his contract of employment without notice. As a result, we reported an occupational disease. This case demonstrates underdiagnosed, potential life-threatening allergy to the disaccharide alpha gal in red meat as to occupational disease.

Ankersmit, H. J., et al. (2017). “When meat allergy meets cardiac surgery: A driver for humanized bioprosthesis.” J Thorac Cardiovasc Surg 154(4): 1326-1327.

A seemingly impossible relationship between cardiac surgery and meat allergy should have led to the manufacture of gal-deficient valves. Why? In January 2005, over a decade ago, we reported for the first time that recipients of bioprostheses developed an alpha-gal-specific humoral immune response. It was then speculated that the degeneration of the bioprosthesis was associated with the presence of alpha-gal in the valve tissue. This insight was corroborated by multiple groups and, most important, proven in experimental animal work. There are limited reports of humans with a hypersensitivity reaction after biovalve implantation.6 Is there a possibility that allergy research may have relevance for cardiac surgery? Dr Patts Mills, FRS, from the Asthma and Allergic Disease Center at the Virginia Health System, was the first to report that humans with meat allergies (consumption of red meat that leads to delayed anaphylaxis, angioedema, and urticaria) have developed immunoglobulin (Ig)-E–specific antibodies against alpha-gal

Apostolovic, D., et al. (2014). “Immunoproteomics of processed beef proteins reveal novel galactose-alpha-1,3-galactose-containing allergens.” Allergy 69(10): 1308-1315.

BACKGROUND: Red meat allergy presents a novel form of food allergy with severe delayed allergic reactions where IgE antibodies are directed against the carbohydrate alpha-Gal epitope. Food preparation and processing can influence the allergenicity of proteins. The aim of this study was to characterize the proteomic profile of different beef preparations and to investigate their alpha-Gal reactivity and potential allergenicity. METHODS: Extracts from raw, boiled, fried, and medium rare prepared beef were assessed by 2D PAGE for the comparison of protein profiles. IgE-binding proteins were identified using immunoblot-coupled proteomic analysis using sera from red meat-allergic patients. Presence of the alpha-Gal epitope was verified using anti-alpha-Gal antibody and IgE inhibition immunoblot with alpha-Gal. RESULTS: Multiple IgE-binding proteins were detected in the different beef preparations, many of which were also recognized by the anti-alpha-Gal antibody. Protein spots reacting with IgE in patient sera were analyzed by MS/MS, resulting in identification of 18 proteins with high identification scores. Seven of the 18 beef allergens identified using meat-allergic patient sera were also recognized by the anti-alpha-Gal monoclonal antibody, and four of them were stabile to thermal treatment. Furthermore, a dose-dependent inhibition of red meat-allergic patients’ IgE to beef by alpha-Gal was demonstrated. CONCLUSIONS: We show that the alpha-Gal epitope is commonly present in IgE-reactive beef proteins recognized by meat-allergic patients. Seven novel alpha-Gal-containing IgE-binding proteins were identified, of which four were stable to heat treatment. Thus, the allergenicity of red meat proteins is preserved even upon different thermal cooking.

Apostolovic, D., et al. (2015). “Red meat allergic patients have a selective IgE response to the alpha-Gal glycan.Allergy 70(11): 1497-1500.

Galactose-alpha-1,3-galactose (alpha-Gal) is a mammalian carbohydrate with significance in a novel type of food allergy. Patients with IgE against alpha-Gal report severe allergic symptoms 3-6 h after consumption of red meat. We investigated whether IgE from red meat allergic patients recognizes other mammalian glycans than alpha-Gal or glycans from the plant kingdom and insects of importance in allergy. We found that none of the 24 red meat allergic patients investigated had an IgE antibody response against the other abundant mammalian glycan N-glycolylneuraminic acid or against cross-reactive carbohydrate determinants from plant or venom sources (nCup a 1, nArt v 1, and MUXF3). Deglycosylation of an alpha-Gal-containing protein, bovine thyroglobulin, significantly reduced the IgE response. In conclusion, we show that red meat allergic patients have a selective IgE response to the alpha-Gal glycan found in red meat. Other common glycans reactive in allergic disease are not targets of red meat allergic patients’ IgE. 

Apostolovic, D., et al. (2019). “Red meat allergic patients have specific TH2 derived cellular and humoral responses against ixodes ricinus tick proteins supporting the link to alpha-gal allergy.” Allergy 74: 155-156.

Apostolovic, D., et al. (2017). “Peptidomics of an in vitro digested α-Gal carrying protein revealed IgE-reactive peptides.” Sci Rep 7(1): 5201.

The mammalian carbohydrate galactose-α1,3-galactose (α-Gal) causes a novel form of food allergy, red meat allergy, where patients experience severe allergic reactions several hours after red meat consumption. Here we explored gastric digestion of α-Gal glycoproteins using an in vitro model. Bovine thyroglobulin (BTG), a typical α-Gal carrying glycoprotein, was digested with pepsin. The resulting peptides were characterized by SDS PAGE, immunoblot and ImmunoCAP using sera from 20 red meat allergic patients. During pepsinolysis of BTG, a wide range of peptide bands was observed of which 14 to 17 kDa peptides remained stable throughout the gastric phase. The presence of the α-Gal epitope on the obtained peptides was demonstrated by an anti-α-Gal antibody and IgE from red meat allergic patients. The α-Gal digests were able to inhibit up to 86% of IgE reactivity to BTG. Importantly, basophil activation test demonstrated that the allergenic activity of BTG was retained after digestion in all four tested patients. Mass spectrometry-based peptidomics revealed that these peptides represent mostly internal and C-terminal parts of the protein, where the most potent IgE-binding α-Gal residues were identified at Asn1756, Asn1850 and Asn2231. Thus allergenic α-Gal epitopes are stable to pepsinolysis, reinforcing their role as clinically relevant food allergens.

Apostolovic, D., et al. (2019). “Allergenomics of the tick Ixodes ricinus reveals important alpha-Gal-carrying IgE-binding proteins in red meat allergy.” Allergy.           

Apostolovic, D., et al. (2018). “Immunoprofile of -Gal- and B-antigen-specific responses differentiates red meat-allergic patients from healthy individuals.” Allergy 73(7): 1525-1531.

Background: The galactose–1,3-galactose (-Gal) epitope is involved in red meat allergy. As -Gal is structurally similar to the blood group B-antigen, we explored the relationship between the immune responses to -Gal- and the B-antigen in red meat-allergic patients compared to healthy A/O or B blood donors. Methods: Sera from 51 red meat-allergic patients IgE-positive to -Gal and 102 healthy blood donors (51 blood group A/O; 51 blood group B) were included. -Gal- and B-antigen-specific IgE (ImmunoCAP) and IgG/IgG (1-4) (ELISA) responses were determined. Basophil activation tests were performed. Results: Fifteen healthy donors were IgE positive to -Gal, of which 3 had blood group B. The allergic patients had significantly higher -Gal IgE levels compared to the healthy donors. The majority of the allergic patients, but none of the healthy donors, had IgE against the B-antigen. Inhibition studies revealed cross-reactivity between -Gal and the B-antigen. The biological activity of the B-antigen was confirmed by basophil activation tests. Anti–Gal IgG (1) and IgG (4) levels were significantly higher in the patients compared to the healthy donors. Moreover, the IgG response to the B-antigen was comparable between the allergic patients and healthy A/O donors. Conclusion: Red meat-allergic patients showed significantly higher -Gal IgE, IgG (1), and IgG (4) levels, reflecting a Th2 response, compared to healthy blood donors. Blood group B donors had significantly reduced antibody responses to -Gal, due to similarities with the B-antigen, resulting in a lower risk of sensitization to -Gal and development of red meat allergy.

Apostolovic, D., et al. (2016). “The red meat allergy syndrome in Sweden.” Allergo Journal 25(2): 29-34.

In the last decade, a novel type of food allergy presenting with severe allergic reactions several hours after consumption of red meat has been recognized. The allergic responses are due to IgE antibodies directed against the carbohydrate epitope galactose-α-1,3-galactose (α-Gal) found in mammalian meat. This review presents the red meat allergy syndrome in Sweden, discusses the features of the immune response to carbohydrates, and highlights the presence of heat-stable α-Gal-containing proteins in meat.

Araujo, R. N., et al. (2016). “Amblyomma sculptum tick saliva: alpha-Gal identification, antibody response and possible association with red meat allergy in Brazil.” Int J Parasitol 46(3): 213-220.

            The anaphylaxis response is frequently associated with food allergies, representing a significant public health hazard. Recently, exposure to tick bites and production of specific IgE against alpha-galactosyl (alpha-Gal)-containing epitopes has been correlated to red meat allergy. However, this association and the source of terminal, non-reducing alpha-Gal-containing epitopes have not previously been established in Brazil. Here, we employed the alpha-1,3-galactosyltransferase knockout mouse (alpha 1,3-GalT-KO) model and bacteriophage Q beta-virus like particles (Q beta-VLPs) displaying Gal alpha 1,3Gal beta 1,4GlcNAc (Gal alpha 3LN) epitopes to investigate the presence of alpha-Gal-containing epitopes in the saliva of Amblyomma sculptum, a species of the Amblyomma cajennense complex, which represents the main tick that infests humans in Brazil. We confirmed that the alpha-1,3-galactosyltransferase knockout animals produce significant levels of anti-alpha-Gal antibodies against the Gal alpha 1,3Gal beta 1,4GlcNAc epitopes displayed on Q beta-virus like particles. The injection of A. sculptum saliva or exposure to feeding ticks was also found to induce both IgG and IgE anti-alpha-Gal antibodies in alpha-1,3-galactosyltransferase knockout mice, thus indicating the presence of alpha-Gal containing epitopes in the tick saliva. The presence of alpha-Gal-containing epitopes was confirmed by ELISA and immunoblotting following removal of terminal alpha-Gal epitopes by alpha-galactosidase treatment. These results suggest for the first known time that bites from the A. sculptum tick may be associated with the unknown etiology of allergic reactions to red meat in Brazil. (C) 2016 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved. 

Archer-Hartmann, S. A., et al. (2018). “Tick Bites and Hamburgers: N-Glycosylation analysis of saliva and salivary glands from the ticks responsible for Alpha-Gal Syndrome.” Glycobiology 28(12): 1080-1081. 

Arkestal, K., et al. (2011). “Impaired allergy diagnostics among parasite-infected patients caused by IgE antibodies to the carbohydrate epitope galactose-alpha 1,3-galactose.” J Allergy Clin Immunol 127(4): 1024-1028.

            BACKGROUND: The carbohydrate epitope galactose-alpha 1,3-galactose (alpha-Gal) is abundantly expressed on nonprimate mammalian proteins. We have recently shown that alpha-Gal is responsible for the IgE binding to cat IgA, a newly identified cat allergen (Fel d 5). OBJECTIVE: We sought to investigate the diagnostic relevance of IgE antibodies to Fel d 5 and alpha-Gal among parasite-infected patients from central Africa without cat allergy compared with patients with cat allergy from the same region. METHODS: Sera from 47 parasite-infected patients and 31 patients with cat allergy were analyzed for total IgE and IgE antibodies against cat dander extract (CDE) by using the ImmunoCAP system. Inhibition assay was performed with alpha-Gal on solid phase-bound CDE. The presence of IgE specific for the major cat allergen Fel d 1, Fel d 5, and alpha-Gal was analyzed by means of ELISA. RESULTS: Among the 47 parasite-infected patients, 85% had IgE antibodies against alpha-Gal (OD; median, 0.175; range, 0.102-1.466) and 66% against Fel d 5 (OD; median, 0.13; range, 0.103-1.285). Twenty-four of the parasite-infected patients were sensitized to CDE, and 21 of them had IgE antibodies to Fel d 5 and alpha-Gal. There was no correlation between IgE levels to CDE and rFel d 1 among the parasite-infected patients but a strong correlation between CDE and Fel d 5 and alpha-Gal (P < .001). Among the group with cat allergy, only 5 patients had IgE to alpha-Gal, and nearly 75% (n = 23) had IgE to rFel d 1 (median, 7.07 kU(A)/L; range, 0.51-148.5 kU(A)/L). In contrast, among the patients with cat allergy, there was a correlation between IgE levels to CDE and rFel d 1 (P < .05) but no correlation between CDE and Fel d 5 and alpha-Gal. CONCLUSION: IgE to alpha-Gal causes impaired allergy diagnostics in parasite-infected patients. Screening for IgE to rFel d 1 and other allergens without carbohydrates might identify patients with true cat sensitization/allergy in parasite-infested areas. 

Arnold, D. F. and S. A. Misbah (2008). “Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose.” N Engl J Med 358(25): 2735; author reply 2735-2736.

Cetuximab, a chimeric mouse-human IgG1 monoclonal antibody against the epidermal growth factor receptor, is approved for use in colorectal cancer and squamous-cell carcinoma of the head and neck. A high prevalence of hypersensitivity reactions to cetuximab has been reported in some areas of the United States.           

Arroyo, A. and L. Tourangeau (2015). “REGIONAL ANAPHYLAXIS: NOT SO REGIONAL? A CASE OF IGE ANTIBODIES TO ALPHA-GAL AFTER TICK BITE IN CALIFORNIA.” Annals of Allergy Asthma & Immunology 115(5): A71-A71.           

Arslan Lied, G. (2017). “Red meat allergy induced by tick bites: A Norwegian case report.” Eur Ann Allergy Clin Immunol 49(4): 186-188.

            Summary: Food allergies, especially delayed hypersensitivity reactions, are often challenging for both patients and clinicians. Here, we report the case of a 64-year-old man who had allergic reactions six hours after eating a meal containing red meat. He reported that he had several tick bites in months before the reaction. High serum specific IgE levels of alpha-gal confirmed the diagnosis of alpha-gal allergic reaction with delayed onset after red meat ingestion caused by tick bite. 

Atkinson, C. and R. Hatch (2018). “RESOLUTION OF GALACTOSE ALPHA 1-3 GALACTOSE (ALPHA-GAL) ANAPHYLAXIS AFTER TICK AND HOOVED MEAT AVOIDANCE.” Annals of Allergy Asthma & Immunology 121(5): S117-S117.

            Anaphylactic reactions to Alpha-Gal carbohydrate epitope commonly present in meat of hooved animals and are recognized as an important cause of delayed anaphylaxis. Tick bites appear to be a necessary cofactor in developing sensitization to Alpha-Gal. Case Description – Our patient is a 53-year-old female living in Oklahoma who presented to the clinic in 2011 with a two-year history of pruritis, hives, throat tightness, and facial swelling. Symptoms occurred at night after consuming corn or potato chips which had previously been tolerated. Prior to presentation, she had labs drawn which showed elevated counts to pork and beef. It was discovered that six hours after consuming meat she had these episodes and reported having tick bites from her dogs. Percutaneous tests with allergenic extracts showed minimal activity to fresh beef and lamb. Alpha-gal specific IgE was elevated at 65.8 kU/L and she was advised to avoid all meat products except poultry and fish. At four-month follow-up, she continued to avoid pork and beef without further events and had no new tick bites. She had her dogs and home treated for ticks and moved to a new house. At six years after presentation, she reintroduced small amounts of well cooked meat products without problems. Alpha-Gal specific IgE was 0.47 kU/L and continued to decline despite continued meat consumption. Discussion

This case implies that, at least in this patient, both tick bites and meat exposure are necessary to maintain sensitization. Reintroducing the meat alone without tick exposure did not result in re-sensitization.

Backer, E. and J. Carroll (2016). 1742: DELAYED ANAPHYLAXIS FOLLOWING MAMMALIAN MEAT CONSUMPTION: AN EVOLVING VECTOR-BORN PROCESS. Critical Care Medicine 44(12): 511.

 Methods: Our patient is a 69-year-old male who presented with an anaphylactic reaction. He has no known allergies or co-morbidities. A history revealed consumption of steak 6 hours before symptom onset of generalized urticaria, angioedema and dyspnea. 

Backer, E. and J. Carroll (2016). “A Case of Unexplained Shock Following Steak Consumption.” CHEST 150(4): 1139A.

INTRODUCTION: Delayed anaphylaxis following red meat consumption is a novel phenomenon in the Southwestern United States. This presentation will illustrate a case of IgE mediated activity against the galactose-a-1,3-galactose (alpha-gal) epitope.

This carbohydrate determinant is common in humans and isotope switching to alpha-gal IgE occurs following ectoparasite exposure. First described in 2009, early case reports led to identification of the Amblyomma americanum, or lone star tick, as the sensitizing exposure. We present the first reported case of anaphylaxis in New Hampshire from red meat consumption following alpha-gal sensitization. 

CASE PRESENTATION: Our patient is a 69-year-old male who presented with an anaphylactic reaction. He has no known allergies or co-morbidities. A history revealed consumption of steak 6 hours before symptom onset of generalized urticaria, angioedema and dyspnea. Treatment included anti-histamines, steroids, and epinephrine. It was later divulged he sustained a tick bite 5 weeks prior to this admission. Further work-up identified a total IgE of 129 kU/L and an elevated alpha-gal IgE of 10 kU/L (normal #0.34 kU/L). His history and serologic testing allowed us to confirm a diagnosis of delayed anaphylaxis due to a red meat allergy. He made a full recovery, and received follow-up in our Allergy clinic and counseling on red meat avoidance.

 DISCUSSION: IgE sensitization to the oligosaccharide alpha-gal following exposure to the lone star tick is described largely in the southeastern United States. After red meat ingestion, a delayed anaphylactic reaction may occur. The diagnosis should be suspected when caring for the patient with anaphylaxis of unclear etiology, and is confirmed using an IgE specific immunoassay. Treatment in the acute setting is supportive, and long-term care includes avoidance of mammalian meats and prevention of further tick exposure.

 CONCLUSIONS: This case demonstrates a vector-associated sensitivity leading to delayed anaphylaxis following consumption of mammalian meat. It is the first documented occurrence in our state, supporting the described geographic spread of the lone start tick. Practitioners should maintain this condition on their differential as it becomes increasingly recognized in non-endemic regions. 

Baker, M. G. and H. A. Sampson (2018). “Phenotypes and endotypes of food allergy: A path to better understanding the pathogenesis and prognosis of food allergy.” Ann Allergy Asthma Immunol 120(3): 245-253.

            Key Messages

  • Proper identification of phenotypes and endotypes of IgE-mediated food allergy may allow for more meaningful investigation of underlying pathobiologic mechanisms that can ultimately improve our approach to treatment.
  • Both phenotype and endotype are determined by genotype, inherited epigenetic factors and environmental factors.
  • Proposed phenotypes and respective endotypes include: Classic (persistent, transient, food-dependent exercise-induced, NSAIDdependent,

alcohol-dependent), Intermittent and Cross-Reactive, Aerosol Sensitization (local reactions to aerosolized cross reactant antigens, systemic reactions to aerosolized forms of food-specific antigens), α-Gal syndrome and Sensitized Nonreactive.

  • A formalized cluster analysis of patients with food allergy to refine phenotype and endotype identification remains an area of opportunity in our field. 

Bakhtiar, M., et al. (2017). “P66: ALLERGIC REACTION TO BOVINE GELATIN COLLOID: THE ROLE OF IMMUNOGLOBULIN E TOWARDS GALACTOSE-ALPHA-1,3-GALACTOSE: IMPLICATIONS BEYOND RED MEAT ALLERGIES.” Internal Medicine Journal 47(S5): 24-24.

 The bovine gelatin colloid is a recognized cause of adverse reactions, albeit uncommon. It is noteworthy that many patients with red‐meat‐derived gelatin allergy may have negative specific Immunoglobulin E (sIgE) antibody to the conventional red‐meat‐derived gelatin immunoassay. Bovine gelatin colloids have been shown to contain about 0.44 ± 0.2 mcg/g to 0.52 ± 0.1 mcg/g of galactose‐alpha‐1,3‐galactose (alpha‐gal). It has been demonstrated that sIgE towards the alpha‐gal moiety may cause life‐threatening anaphylactic reactions with wide ranging implications. We describe three patients with an allergic reaction to bovine gelatin colloid who had positive skin test to Gelofusine and sIgE to alpha‐gal but negative sIgE to bovine gelatin. 

Barbaud, A., et al. (2011). “How to manage hypersensitivity reactions to biological agents?Eur J Dermatol 21(5): 667-674.

Biological agents induce cutaneous adverse drug reactions (CADR) different from those observed with xenobiotics. Type alpha is the cytokine release syndrome, type beta are hypersensitivity reactions and type gamma is a cytokine imbalance syndrome. Infusion-reactions, anaphylactoid reactions occur with various biological agents administered intravenously. In non-severe cases the infusion rate has to be reduced, in severe reactions, the treatment must be stopped, and resuscitation carried out with corticosteroids and epinephrine. Reactions may be due to an alpha syndrome but a true allergy could be involved as demonstrated in some patients with IgE antibodies to the galactose-alpha-1,3-galactose portion of the cetuximab or anti infliximab-IgE. Some desensitisation protocols have been published. Non allergic itching and eczema-like lesions are frequent with epidermal growth factor receptor inhibitors. Rash or desquamation was observed in 40% of cases with antiangiogenic agents, 90% of patients treated with imatinib have rashes, oedema or pruritus and a non-allergic periorbital oedema. Severe CADR, such as Stevens-Johnson syndrome, can be provoked. Delayed readings of intradermal tests could be of value in managing patients with a maculopapular rash due to interferon. Anaphylaxis attributed to omalizumab seems to be rare (0.2%) and skin rashes occur in 7% of cases. Anaphylactoid reactions occur in 1% of patients treated with natalizumab. In the case of anti-natalizumab antibody-mediated reactions, treatment should be stopped. These allergic-like side effects of new biological agents must be known and reported to Pharmacovigilance agency networks. 

Baumgart, K. W., et al. (2019). “Sensitisation and sero-reversion to tick bite induced galactose-1,3-alpha-galactose, meat and dairy sensitisation in New South Wales, Australia.” Allergy (Oxford) 74(Suppl. 106, Sp. Iss. SI): 509.           

Beaman, M. H. (2018). “Non-infectious illness after tick bite.” Microbiology Australia 39(4): 212-215.

Tick bites are common and may have non-infectious complications. Reactions range from local reactions to systemic syndromes, tick paralysis, mammalian meat allergy and tick anaphylaxis. Management revolves around prevention with vector avoidance and immediate removal of the tick if bitten. Treatment of bite reactions is usually symptomatic only with antihistamines or corticosteroids. Adrenaline may be indicated for severe cases.

 Beaudouin, E., et al. (2015). “Allergy to galactose-alpha 1,3 galactose (alpha-Gal): Case report and literature review.” Revue Francaise D Allergologie 55(7): 492-497.

The authors report a singular case about mammalian meat anaphylaxis due to galactose-alpha 1,3 galactose (alpha-Gal) and review the current literature. 

Berends, M. A. and J. N. G. O. Elberink (2017). “The alpha-gal syndrome: an allergic reaction to mammalian meat secondary to a tick bite. / Het alfa-galsyndroom, allergische reacties op vlees: allergie voor zoogdierenvlees secundair aan een tekenbeet.” Ned Tijdschr Geneeskd 161(11): D1062-D1062. (lang: dut)

Here we present the case of a 68-year-old patient with alpha-gal syndrome. This is a delayed-onset allergic reaction, characteristically occurring 2-6 hours after ingestion of mammalian meat products. The reaction occurs because the patient has developed IgE antibodies to a mammalian oligosaccharide epitope, galactose-α-1,3-galactose (alpha-gal); tick bites induce this IgE antibody response. Presentation varies from chronic urticaria to life-threatening anaphylaxis. The alpha-gal syndrome is usually self-limiting as long as there are no new tick bites. Clinicians should be aware of this syndrome, which is often not recognized as such. 

Berg, E. A., et al. (2014). “Drug allergens and food-the cetuximab and galactose-alpha-1,3-galactose story.” Annals of Allergy Asthma & Immunology 112(2): 97-101.

Objective: A novel form of food allergy has been described that initially became apparent from IgE reactivity with the drug cetuximab. Ongoing work regarding the etiology, distribution, clinical management, and cellular mechanisms of the IgE response to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) is reviewed. Data Sources: Brief review of the relevant literature in peer-reviewed journals. Study Selection: Studies on the clinical and immunologic features, pathogenesis, epidemiology, laboratory evaluation, and management of IgE to alpha-gal are included in this review. Results: Recent work has identified a novel IgE antibody response to the mammalian oligosaccharide epitope, alpha-gal, that has been associated with 2 distinct forms of anaphylaxis: (1) immediate-onset anaphylaxis during first exposure to intravenous cetuximab and (2) delayed-onset anaphylaxis 3 to 6 hours after ingestion of mammalian food products (eg, beef and pork). Study results have suggested that tick bites are a cause of IgE antibody responses to alpha-gal in the United States. Patients with IgE antibody to alpha-gal continue to emerge, and, increasingly, these cases involve children. Nevertheless, this IgE antibody response does not appear to pose a risk for asthma but may impair diagnostic testing in some situations. Conclusion: The practicing physician should understand the symptoms, evaluation, and management when diagnosing delayed allergic reactions to mammalian meat from IgE to alpha-gal or when initiating treatment with cetuximab in patients who have developed an IgE antibody response to alpha-gal.

Bernth-Jensen, J. M., et al. (2011). “Biological variation of anti-alpha Gal-antibodies studied by a novel Time-Resolved ImmunoFluorometric Assay.J Immunol Methods 373(1-2): 26-35.

 As much as one percent of antibodies in human plasma are reported to be specific for the non-human disaccharide structure alphaGal. Various microbes express alphaGal. However, the implications of anti-alphaGal antibodies for the anti-microbial defenses are poorly established. With the perspective of studying the biological importance of the antibodies, we have established a sensitive Time-Resolved ImmunoFluorometric Assay (TRIFMA) for quantification of such antibodies. Two versions were developed, one for IgM antibodies and one for IgG antibodies. Samples were collected from plasma donations of healthy adults (n=120) of known gender (60+60), AB0-type (0: 15+15, A: 15+15, B: 15+15, and AB: 15+15) and age (19-64 yrs). We subsequently examined the potential association between antibody concentration and AB0-type, gender, age, and titers of antibodies to blood type antigens. We found that IgG and IgM anti-alphaGal concentrations are, 1) stable over time within the individual, 2) vary more than 400-fold between individuals, 3) negatively correlated with age for IgM but not for IgG antibodies, 4) IgM antibodies are 2-fold higher in females whereas no gender difference was observed for the IgG antibodies, 5) inter-mutual correlated, 6) lowest in individuals expressing B-antigen, and 7) AB0-type A individuals may constitute an intermediate group. Our established method and findings pave the way for further studies of the involvement of anti-alphaGal antibodies in immunity and may be a method to examine the potential of an individual to mount an anti-carbohydrate response. 

Biedermann, T., et al. (2015). “Mammalian meat allergy: a diagnostic challenge.” Allergo J Int 24(3): 81-83.

Introduction
The first national report in the lay press on galactose–1,3-galactose-mediated meat allergy (or red meat allergy) appeared in the German newspaper “Der Spiegel” in December 2012 [1]. Since then, awareness of this clinical picture has increased significantly, not least among affected patients, and it is not infrequent for affected individuals to take the initiative in terms of obtaining a diagnosis. The present report uses the case of an affected female patient as a basis to convey the fundamentals and procedures involved in a disease recognition and diagnosis that has become better understood and more readily diagnosed in recent years, as well as to emphasize the significance of skin tests. 

Biedermann, T. and M. Rocken (2012). “[Delayed appearance of symptoms in immediate hypersensitivity: type I sensitization to galactose-alpha-1,3-galactose].” Hautarzt 63 Suppl 1: 76-79.

Delayed immediate-type allergy to innards and red meat can be mediated by IgE antibodies to galactose-alpha-1, 3-galactose (alpha-Gal). Apart from humans and Old World apes, alpha-Gal is ubiquitously expressed in glycoproteins and glycolipids. Thus, as alpha-Gal is immunogenic for humans, they can be easily sensitized even through a tick bite. Anti-alpha-Gal IgG represents approximately 1% of total IgG; IgE antibodies to alpha-Gal are comparably rare. However, in these patients, consuming red meat and especially innards can lead to the development of immediate type reactions such as urticaria. Cetuximab is a humanized IgG1 antibody containing murine alpha-Gal. Therefore, allergic reactions may occur with its first administration. 

Bilo, M. B., et al. (2019). “Idiopathic anaphylaxis.” Clin Exp Allergy 49(7): 942-952.

Idiopathic anaphylaxis (IA) or spontaneous anaphylaxis is a diagnosis of exclusion when no cause can be identified. The exact incidence and prevalence of IA are not known. The clinical manifestations of IA are similar to other known causes of anaphylaxis. A typical attack is usually acute in onset and can worsen over minutes to a few hours. The pathophysiology of IA has not yet been fully elucidated, although an IgE-mediated pathway by hitherto unidentified trigger/s might be the main underlying mechanism. Elevated concentrations of urinary histamine and its metabolite, methylimidazole acetic acid, plasma histamine and serum tryptase have been reported, consistent with mast cell activation. There is some evidence that corticosteroids reduce the frequency and severity of episodes of IA, consistent with a steroid-responsive condition. Important differential diagnoses of IA include galactose alpha-1,3 galactose (a carbohydrate contained in red meat) allergy, pigeon tick bite (Argax reflexus), wheat-dependent exercise-induced anaphylaxis, Anisakis simplex allergy and mast cell disorders. Other differential diagnoses include “allergy-mimics” such as asthma masquerading as anaphylaxis, undifferentiated somatoform disorder, panic attacks, globus hystericus, vocal cord dysfunction, scombroid poisoning, vasoactive amine intolerance, carcinoid syndrome and phaeochromocytoma. Acute treatment of IA is the same as for other forms of anaphylaxis. Long-term management is individualized and dictated by frequency and severity of symptoms and involves treatment with H1 and H2 receptor blockers, leukotriene receptor antagonist and consideration for prolonged reducing courses of oral corticosteroids. Patients should possess an epinephrine autoinjector with an anaphylaxis self-management plan. There are anecdotal reports regarding the use of omalizumab. For reasons that remain unclear, the prognosis of IA is generally favourable with appropriate treatment and patient education. If remission cannot be achieved, the diagnosis should be reconsidered. 

Bircher, A. J., et al. (2017). “Food allergy to the carbohydrate galactose-alpha-1,3-galactose (alpha-gal): four case reports and a review.” Eur J Dermatol 27(1): 3-9.

Until recently, food allergies to mammalian meats have been considered to be very rare. The observation that patients not previously exposed to the monoclonal chimeric antibody cetuximab suffered from severe anaphylaxis upon first exposure, led to the identification of galactose-alpha-1,3-galactose as a new relevant carbohydrate allergen. These patients later often suffered from anaphylactic reactions to red meat. Epidemiological data indicated that bites by the tick Amblyomma americanum in the USA, later also by Ixodes species in other continents, resulted in sensitisation to alpha-gal. On the other hand, in African patients with parasitic disorders, a high prevalence of anti-alpha-gal IgE, without clinical relevance, has been reported. In our four cases, one patient with a late onset of meat allergy had a history of a tick bite. The other three patients had symptoms from childhood or at a juvenile age. This indicates that in some patients, other ways of sensitisation may also take place. However, in patients without atopy, tick bite-induced IgE to alpha-gal may be more relevant. Diagnosis is based on a history of delayed onset of anaphylaxis. Skin tests with commercially available meat test solutions are often equivocal or negative; skin tests with raw meat and particularly pork kidney are more sensitive. Determination of specific IgE to alpha-gal is commercially available. The highest sensitivity is observed with skin and basophil activation tests with cetuximab which is, however, limited by its high costs. 

Bircher, A. J. and K. Scherer (2009). “Hypersensitivity reactions due to agents that modify the biological response (biologicals).” Revue Francaise D Allergologie 49(3): 296-299.

Adverse reactions induced by biological agents which are being used increasingly in the therapy of inflammatory diseases, autoimmune disorders and tumors are being observed more and more frequently. This is a consequence of both the growing number of indications and the increasing number of these substances. They have an intrinsic immunologic effect, due to their structure, to their structural similarity to physiological proteins, as well as to their capacity to act directly on the immune system. In addition, they can induce the production of anti-allotype or anti-idiotype antibodies, especially when they have an extensive murine sequence, but also through their humanized or human antibody components. The adverse reactions which they induce also depend on the structure of their target, which they can activate, inhibit or modify by other mechanisms. The principal adverse reactions are of type alpha, with a “cytokine release syndrome”, or of type beta, with the production of IgG or IgE antibodies and subsequent immediate type reactions such as urticaria, anaphylaxis or serum sickness. Pre-existing antibodies directed against some of these agents may have been generated by ubiquitous crossreacting epitopes. Local reactions occur frequently at the subcutaneous injection site of these agents; these reactions can sometimes be avoided by modifying the injection technique. The means of diagnosing such reactions are currently limited and their value has not yet been established on a large number of subjects. Continuation of this therapy is generally contraindicated due to the risk of severe complications. 

Böer, U., et al. (2015). “The Immune Response to Crosslinked Tissue is Reduced in Decellularized Xenogeneic and Absent in Decellularized Allogeneic Heart Valves.” The International Journal of Artificial Organs 38(4): 199-209.

Background: The degeneration and failure of xenogeneic heart valves, such as the Matrix P Plus valve (MP-V) consisting of decellularized porcine valves (dec-pV) and equine glutaraldehyde-fixed conduits (ga-eC) have been linked to tissue immunogenicity accompanied by antibody formation. In contrast, decellularized allograft valves (dec-aV) are well-tolerated. Here, we determined tissue-specific antibody levels in patients after implantation of MP-V or dec-aV and related them to valve failure or time period after implantation. Methods and Results: Specific antibodies toward whole tissue-homogenates or alphaGal were determined retrospectively by ELISA analyses from patients who received MP-V with an uneventful course of 56.1 ± 5.1 months (n = 15), or with valve failure after 25.3 ± 14.6 months (n = 3), dec-aV for various times from 4 to 46 months (n = 14, uneventful) and from healthy controls (n = 4). All explanted valves were assessed histopathologically.MP-V induced antibodies toward both tissue components with significantly higher levels toward ga-eC than toward dec-pV (68.7 and 26.65 μg/ml IgG). In patients with valve failure, levels were not significantly higher and were related to inflammatory tissue infiltration. Anti-Gal antibodies in MP-V patients were significantly increased in both, the uneventful and the failure group. In contrast, in dec-aV patients only a slight tissue-specific antibody formation was observed after 4 months (6.24 μg/ml) that normalized to control levels after 1 year. Conclusions: The strong humoral immune response to glutaraldehyde-fixed tissues is reduced in decellularized xenogeneic valves and almost absent in decellularized allogeneic tissue up to 4.5 years after implantation. 

Bradfisch, F., et al. (2019). “Case series of anaphylactic reactions after rabies vaccinations with gelatin sensitization.” Allergo J Int 28(4): 103-106.

Side effects due to allergic reactions to vaccine antigen or to additives such as chicken protein or gelatin have been known for some time. Recent findings regarding reactions mediated via the carbohydrate epitope galactose-alpha-1,3-galactose (alpha-gal), a constituent of animal gelatin, broaden the spectrum of gelatin-related allergies. This case series presents four patients who developed anaphylactic reactions following rabies vaccination using the vaccine Rabipur®. After appropriate allergy testing by skin prick testing and the determination of specific IgE to allergens in the vaccine, triggering by alpha-gal could be excluded and an allergy to gelatin was detected. The absence of allergic symptoms following the consumption of gelatin could potentially be explained through intestinal hydrolysis resulting in a loss of allergenic potency. Further implications related to the use of gelatin-containing infusions in emergency medicine are discussed. 

Brady, S. P., et al. (2015). “Recurrent Anaphylaxis Due to Delayed Allergy to Mammalian Meat in a Patient with Mastocytosis.” Journal of Allergy and Clinical Immunology 135(2): AB206.

RATIONALE: Mastocytosis and delayed allergy to mammalian meat are under-recognized and potentially life-threatening conditions. We describe a patient with mastocytosis and delayed allergy to mammalian meat whose diagnoses came to light after several episodes of severe anaphylaxis. 

METHODS: Measurement of serum tryptase and IgE to galactose-alpha-1,3-galactose alpha-gal) were performed at Mayo Clinic, Rochester, MN. Bone Marrow biopsy was performed at Barnes-Jewish Hospital, St. Louis, MO. 

Brestoff, J. R., et al. (2018). “The B antigen protects against the development of red meat allergy.” Journal of Allergy and Clinical Immunology-in Practice 6(5): 1790-+.

Red meat allergy (RMA) is characterized by urticaria, angioedema, gastrointestinal symptoms, and/or anaphylaxis occurring approximately 3 to 6 hours after ingesting mammalian meats that contain the antigen galactose-a-1, 3-galactose (a-Gal). 

Brestoff, J. R., et al. (2017). “Diagnosis of red meat allergy with antigen-specific IgE tests in serum.” Journal of Allergy and Clinical Immunology 140(2): 608-+.

Red meat allergy is a tick-associated hypersensitivity reaction characterized by anaphylaxis, angioedema, urticaria, and/or gastrointestinal symptoms occurring 3 to 6 hours after ingesting red meat including beef, pork, or lamb.1 This disease is caused by IgE-mediated responses directed against galactose-a-1,3-galactose (a-gal), a carbohydrate produced by all mammals except humans and some nonhuman primates and that is also found in tick saliva.2 The unusually long delay in symptom onset, nonspecific symptoms, and uncertain prevalence of red meat allergy can make this diagnosis challenging. However, it is critical to identify patients with red meat allergy to prevent potentially life-threatening reactions. 

Burk, C. M., et al. (2016). “High rate of galactose-alpha-1,3-galactose sensitization in both eosinophilic esophagitis and patients undergoing upper endoscopy.” Dis Esophagus 29(6): 558-562.

Eosinophilic esophagitis (EoE) is an antigen/allergy-mediated chronic inflammatory condition. The rapid rise in the number of cases of EoE suggests an as-yet undiscovered environmental trigger. This study tested the hypothesis that immunoglobulin E (IgE) to galactose-alpha-1,3-galactose (alpha-gal), a newly recognized sensitization induced by a tick bite that causes mammalian meat allergy, is a risk factor for EoE. We conducted a case-control study using prospectively collected and stored samples in the University of North Carolina EoE Patient Registry and Biobank. Serum from 50 subjects with a new diagnosis of EoE and 50 non-EoE subjects (either with gastroesophageal reflux disease or dysphagia from non-EoE etiologies) was tested for alpha-gal-specific IgE using an ImmunoCAP-based method. Specific IgE > 0.35 kUA /L was considered a positive result. Subjects with EoE were a mean of 35 years old, 68% were male, and 94% were white. Non-EoE controls were a mean of 42 years, 50% were male, and 78% were white. A total of 22 (22%) subjects overall had alpha-gal-specific IgE > 0.35 kUA /L. Of the EoE cases, 12 (24%) were positive, and of the non-EoE controls, 10 (20%) were positive (p=0.63). Neither the proportion sensitized nor the absolute values differed between EoE and non-EoE subjects. We found a similar but high rate of alpha-gal sensitization in patients with EoE as found in non-EoE controls who were undergoing endoscopy. While our data do not support alpha-gal sensitization as a risk factor for EoE, the high rates of sensitization observed in patients undergoing upper endoscopy for symptoms of esophageal dysfunction is a new finding. 

Bylsma, L. C., et al. (2019). “The incidence of infusion reactions associated with monoclonal antibody drugs targeting the epidermal growth factor receptor in metastatic colorectal cancer patients: A systematic literature review and meta-analysis of patient and study characteristics.” Cancer Med 8(12): 5800-5809.

BACKGROUND: Systemic cancer therapies may induce infusion reactions (IRs) or hypersensitivities. Metastatic colorectal cancer (mCRC) patients treated with anti-EGFR therapies, including cetuximab and panitumumab, may be subject to these reactions. We conducted a meta-analysis to estimate the IR incidence in this population and identify variations in this incidence by patient or study characteristics. METHODS: A systematic review was conducted to identify observational studies or clinical trials of mCRC patients treated with anti-EGFR therapies that reported occurrences of IRs, hypersensitivity, or allergy/anaphylaxis. The objective of the study was to estimate the incidence of IRs. Random effects models were used to meta-analyze the incidence of IRs overall and stratified by therapy type, study design, geographic location, RAS or KRAS mutation status, grade of reaction severity, and terminology used to describe the reaction. RESULTS: The pooled estimate for IR incidence was 4.9% (95% confidence interval: 3.6%-6.5%). Lower-grade reactions were more common than higher-grade reactions overall and the incidence of reactions among cetuximab patients was nearly four times that of panitumumab patients (6.1% vs 1.6%). CONCLUSIONS: IRs occur in approximately 5% of mCRC patients treated with anti-EGFR therapies, and the incidence varies significantly by grade of severity and therapy type. Studies evaluating these outcomes should consider investigating survival outcomes by IR status to determine its prognostic relevance.

Cabezas-Cruz, A., et al. (2017). “Prevalence of type I sensitization to alpha-gal in forest service employees and hunters: Is the blood type an overlooked risk factor in epidemiological studies of the alpha-Gal syndrome?” Allergy 72(12): 2044-2047.

Correspondence. 

Cabezas-Cruz, A., et al. (2018). “Tick galactosyltransferases are involved in alpha-Gal synthesis and play a role during Anaplasma phagocytophilum infection and Ixodes scapularis tick vector development.” Sci Rep 8: 14224.

The carbohydrate Gal alpha 1-3Gal beta 1-(3)4GlcNAc-R (alpha-Gal) is produced in all mammals except for humans, apes and old world monkeys that lost the ability to synthetize this carbohydrate. Therefore, humans can produce high antibody titers against alpha-Gal. Anti-alpha-Gal IgE antibodies have been associated with tick-induced allergy (i.e. alpha-Gal syndrome) and anti-alpha-Gal IgG/IgM antibodies may be involved in protection against malaria, leishmaniasis and Chagas disease. The alpha-Gal on tick salivary proteins plays an important role in the etiology of the alpha-Gal syndrome. However, whether ticks are able to produce endogenous alpha-Gal remains currently unknown. In this study, the Ixodes scapularis genome was searched for galactosyltransferases and three genes were identified as potentially involved in the synthesis of alpha-Gal. Heterologous gene expression in alpha-Gal-negative cells and gene knockdown in ticks confirmed that these genes were involved in alpha-Gal synthesis and are essential for tick feeding. Furthermore, these genes were shown to play an important role in tick-pathogen interactions. Results suggested that tick cells increased alpha-Gal levels in response to Anaplasma phagocytophilum infection to control bacterial infection. These results provided the molecular basis of endogenous alpha-Gal production in ticks and suggested that tick galactosyltransferases are involved in vector development, tick-pathogen interactions and possibly the etiology of alpha-Gal syndrome in humans.

Cabezas-Cruz, A., et al. (2019). “Environmental and Molecular Drivers of the alpha-Gal Syndrome.” Front Immunol 10: 1210.

The alpha-Gal syndrome (AGS) is a type of allergy characterized by an IgE antibody (Ab) response against the carbohydrate Galalpha1-3Galbeta1-4GlcNAc-R (alpha-Gal), which is present in glycoproteins from tick saliva and tissues of non-catarrhine mammals. Recurrent tick bites induce high levels of anti-alpha-Gal IgE Abs that mediate delayed hypersensitivity to consumed red meat products in humans. This was the first evidence that tick glycoproteins play a major role in allergy development with the potential to cause fatal delayed anaphylaxis to alpha-Gal-containing foods and drugs and immediate anaphylaxis to tick bites. Initially, it was thought that the origin of tick-derived alpha-Gal was either residual blood meal mammalian glycoproteins containing alpha-Gal or tick gut bacteria producing this glycan. However, recently tick galactosyltransferases were shown to be involved in alpha-Gal synthesis with a role in tick and tick-borne pathogen life cycles. The tick-borne pathogen Anaplasma phagocytophilum increases the level of tick alpha-Gal, which potentially increases the risk of developing AGS after a bite by a pathogen-infected tick. Two mechanisms might explain the production of anti-alpha-Gal IgE Abs after tick bites. The first mechanism proposes that the alpha-Gal antigen on tick salivary proteins is presented to antigen-presenting cells and B-lymphocytes in the context of Th2 cell-mediated immunity induced by tick saliva. The second mechanism is based on the possibility that tick salivary prostaglandin E2 triggers Immunoglobulin class switching to anti-alpha-Gal IgE-producing B cells from preexisting mature B cells clones producing anti-alpha-Gal IgM and/or IgG. Importantly, blood group antigens influence the capacity of the immune system to produce anti-alpha-Gal Abs which in turn impacts individual susceptibility to AGS. The presence of blood type B reduces the capacity of the immune system to produce anti-alpha-Gal Abs, presumably due to tolerance to alpha-Gal, which is very similar in structure to blood group B antigen. Therefore, individuals with blood group B and reduced levels of anti-alpha-Gal Abs have lower risk to develop AGS. Specific immunity to tick alpha-Gal is linked to host immunity to tick bites. Basophil activation and release of histamine have been implicated in IgE-mediated acquired protective immunity to tick infestations and chronic itch. Basophil reactivity was also found to be higher in patients with AGS when compared to asymptomatic alpha-Gal sensitized individuals. In addition, host resistance to tick infestation is associated with resistance to tick-borne pathogen infection. Anti-alpha-Gal IgM and IgG Abs protect humans against vector-borne pathogens and blood group B individuals seem to be more susceptible to vector-borne diseases. The link between blood groups and anti-alpha-Gal immunity which in turn affects resistance to vector-borne pathogens and susceptibility to AGS, suggests a trade-off between susceptibility to AGS and protection to some infectious diseases. The understanding of the environmental and molecular drivers of the immune mechanisms involved in AGS is essential to developing tools for the diagnosis, control, and prevention of this growing health problem.

Cabezas-Cruz, A., et al. (2017). “Effect of blood type on anti-alpha-Gal immunity and the incidence of infectious diseases.” Experimental and Molecular Medicine 49.

The identification of factors affecting the susceptibility to infectious diseases is essential toward reducing their burden on the human population. The ABO blood type correlates with susceptibility to malaria and other infectious diseases. Due to the structural similarity between blood antigen B and Gal alpha 1-3Gal beta 1-(3)4GlcNAc-R (alpha-Gal), we hypothesized that self-tolerance to antigen B affects the immune response to alpha-Gal, which in turn affects the susceptibility to infectious diseases caused by pathogens carrying alpha-Gal on their surface. Here we found that the incidence of malaria and tuberculosis, caused by pathogens with alpha-Gal on their surface, positively correlates with the frequency of blood type B in endemic regions. However, the incidence of dengue fever, caused by a pathogen without alpha-Gal, was not related to the frequency of blood type B in these populations. Furthermore, the incidence of malaria and tuberculosis was negatively correlated with the anti-alpha-Gal antibody protective response. These results have implications for disease control and prevention.

Cabezas-Cruz, A. and J. de la Fuente (2017). “Immunity to α-Gal: The Opportunity for Malaria and Tuberculosis Control.” Frontiers in Immunology 8(1733).

Among all infectious diseases, malaria and tuberculosis constitute leading causes of morbidity and mortality of human populations in developed and undeveloped countries. In 2015, the WHO reported that 10.4 million people had tuberculosis and 1.8 million of them died from the disease. Despite a reduction of malaria cases between 2000 and 2015, the WHO reported 212 million cases and 429,000 deaths due to this disease in 2015 alone. Drug resistance to first-line antimalarial drugs (e.g., chloroquine, sulfadoxine–pyrimethamine, and artemisinin) is a major constrain of malaria control Sub-Saharan Africa. Likewise, multidrug-resistant tuberculosis is a growing problem worldwide. Thus, the control of these diseases is among the most challenging tasks of public health worldwide. Drug overuse and misuse are recognized as the main drivers of drug resistance in parasites and pathogenic bacteria. The identification of genetic factors affecting the susceptibility to these infectious diseases is essential toward reducing drug overuse and inappropriate treatment regimes. In this opinion, we propose that blood groups, a major driver of anti-α-Gal immunity and malaria and tuberculosis incidence, can be used to tailor anti-malaria and anti-tuberculosis vaccination. Blood group A and O individuals, that can potentially develop strong anti-α-Gal immunity, could be immunized with probiotic-based vaccines to enhance the natural levels of anti-α-Gal antibodies. This immunity could lead to protection against these diseases which in turn would reduce the use of anti-malaria and anti-tuberculosis drugs. 

Cabezas-Cruz, A., et al. (2017). “Salivary Prostaglandin E2: Role in Tick-Induced Allergy to Red Meat.” Trends Parasitol 33(7): 495-498.

Tick-induced allergy to red meat is associated with anti-alpha-Gal IgE antibody levels. We propose that tick salivary prostaglandin E2 triggers antibody class switching in mature B cells, increasing the levels of anti-alpha-Gal IgE antibodies. Immune tolerance to alpha-Gal in blood type B individuals might reduce the risk to this allergy.

Cabezas-Cruz, A., et al. (2015). “Regulation of the Immune Response to alpha-Gal and Vector-borne Diseases.” Trends Parasitol 31(10): 470-476.

Vector-borne diseases (VBD) challenge our understanding of emerging diseases. Recently, arthropod vectors have been involved in emerging anaphylactic diseases. In particular, the immunoglobulin E (IgE) antibody response to the carbohydrate Galalpha1-3Galbeta1-(3)4GlcNAc-R (alpha-gal) following a tick bite was associated with allergies to red meat, cetuximab, and gelatin. By contrast, an anti-alpha-gal IgM antibody response was shown to protect against mosquito-borne malaria. Herein, we highlight the interplay between the gut microbiota, vectors, transmitted pathogens, and the regulation of the immune response as a model to understand the protective or allergic effect of alpha-gal. Establishing the source of alpha-gal in arthropod vectors and the immune response to vector bites and transmitted pathogens will be essential for diagnosing, treating, and ultimately preventing these emerging anaphylactic and other vector-borne diseases.

Cabezas-Cruz, A., et al. (2014). “Cancer research meets tick vectors for infectious diseases.” Lancet Infect Dis 14(10): 916-917.

Continuous human exploitation of environmental resources and an increase in human outdoor activities have led to more contact with arthropod vectors, promoting an emergence and resurgence of tick-borne pathogens. Clinical trials of cetuximab, a monoclonal antibody that inhibits epidermal growth factor receptor used for treatment of metastatic colorectal cancer, have shown that the drug produces more hypersensitivity than expected, with some fatal cases.  Patients who developed these hypersensitivity reactions were deemed to have pre-existing IgE antibodies specific to the alpha-gal present in the variable portion of cetuximab.

Caglayan-Sozmen, S., et al. (2019). “Hazardous Medications in Children with Egg, Red Meat, Gelatin, Fish, and Cow’s Milk Allergy.” Medicina-Lithuania 55(8).

Childhood food allergies are a growing public health problem. Once the offending food allergens have been identified, a strict elimination diet is necessary in treatment or prevention of most of the allergic reactions. Accidental food ingestion can lead to severe anaphylaxis. Food- derived substances can be used in medications at various stages of the manufacturing process. In this review, the possible roles of medications which may contain egg, red meat, gelatin, and fish allergens on allergic reactions in children with food allergy were evaluated. 

Calamari, A. M., et al. (2015). “Alpha-gal anaphylaxis: the first case report in Italy.” Eur Ann Allergy Clin Immunol 47(5): 161-162.

We report the case of a 55-year-old man who went into anaphylactic shock six hours after eating a meal containing meat. He reported having had several tick bites in months before the reaction. The serum specific IgE showed strong positivity to alpha-gal. This is clearly alpha-gal anaphylaxis with delayed onset after meat ingestion caused by tick bite, confirmed by alpha-gal IgE positivity.

Caponetto, P., et al. (2013). “Gelatin-containing sweets can elicit anaphylaxis in a patient with sensitization to galactose-α-1,3-galactose.” The Journal of Allergy and Clinical Immunology: In Practice 1(3): 302-303.

Gelatin-containing sweets can elicit anaphylaxis in mammalian meat allergic patients. A warning regarding gelatin-containing foods and medical products should be included in recommendations for patients with IgE recognizing Galactose-α-1,3-Galactose.

Caponetto, P., et al. (2015). “Panitumumab: A safe option for oncologic patients sensitized to galactose-alpha-1,3-galactose.” Journal of Allergy and Clinical Immunology-in Practice 3(6): 982-983.

This case describes the treatment with panitumumab of a patient who is highly sensitized to galactose-α-1,3-galactose but also in need of a treatment with an anti–epidermal growth factor receptor mAb due to chemotherapy-refractory metastatic colorectal cancer. 

Carter, M. C., et al. (2018). “Identification of alpha-gal sensitivity in patients with a diagnosis of idiopathic anaphylaxis.” Allergy 73(5): 1131-1134.

Abstract IgE antibodies (Ab) specific to galactose-α-1,3-galactose (alpha-gal) are responsible for a delayed form of anaphylaxis that occurs 3-6 hours after red meat ingestion. In a unique prospective study of seventy participants referred with a diagnosis of idiopathic anaphylaxis (IA), six (9%) were found to have IgE to alpha-gal. Upon institution of a diet free of red meat, all patients had no further episodes of anaphylaxis. Two of these individuals had indolent systemic mastocytosis (ISM). Those with ISM had more severe clinical reactions but lower specific IgE to alpha-gal and higher serum tryptase levels, reflective of the mast cell burden. The identification of alpha-gal syndrome in patients with IA supports the need for routine screening for this sensitivity as a cause of anaphylaxis, where reactions to alpha-gal are delayed and thus may be overlooked.

Chandrasekhar, J. L., et al. (2019). “Cutaneous Exposure to Clinically Relevant Lone Star Ticks Promotes IgE Production and Hypersensitivity through CD4(+) T Cell- and MyD88-Dependent Pathways in Mice.” J Immunol 203(4): 813-824.

Tick-borne allergies are a growing public health concern and have been associated with the induction of IgE-mediated food allergy to red meat. However, despite the increasing prevalence of tick bite-induced allergies, the mechanisms by which cutaneous exposure to ticks leads to sensitization and the production of IgE Abs are poorly understood. To address this question, an in vivo approach was used to characterize the IgE response to lone star tick proteins administered through the skin of mice. The results demonstrated that tick sensitization and challenge induced a robust production of IgE Abs and supported a role for IgE-mediated hypersensitivity reactions in sensitized animals following oral administration of meat. The induction of IgE responses was dependent on cognate CD4(+) T cell help during both the sensitization phase and challenge phase with cutaneous tick exposure. In addition, IgE production was dependent on B cell-intrinsic MyD88 expression, suggesting an important role for TLR signaling in B cells to induce IgE responses to tick proteins. This model of tick-induced IgE responses could be used to study the factors within tick bites that cause allergies and to investigate how sensitization to food Ags occurs through the skin that leads to IgE production. 

Chandrasekhar, J., et al. (2018). “Development of a novel mouse model to study tick-borne onset of red meat allergy.” The Journal of Immunology 200(1 Supplement): 104.106.

Bites from Amblyomma americanum, also known as the lone star tick, cause a life-threatening food allergy that induces IgE-mediated allergic reactions in affected individuals after eating dietary ‘red’ meat such as beef, pork, and lamb. Currently, there is no treatment to prevent or cure red meat allergy. Thus, establishing how lone star ticks cause red meat allergy is important for protecting individuals against this allergy. Our lab has successfully developed a novel mouse model of hypersensitivity to tick exposure to better understand how bites from the lone star tick sensitize the host to produce and maintain allergic IgE. Using this model, we identified increased T follicular helper cell and germinal center B cell responses and elevated serum titers of tick-specific IgE and IgG1 in mice exposed to lone star ticks subcutaneously. Furthermore, these mice generate a hypersensitivity response after oral challenge with red meat, as measured by basophil activation. Finally, we found that both the formation of inflammatory skin lesions at the site of tick exposure and the production of IgE were dependent on CD4+ helper T cells. These findings suggest that contained within the tick are factors that markedly influence priming of CD4+ T cells leading to the production of allergic IgE. Based on these data, we propose that manipulation of the factors within lone star ticks that drive CD4+ helper T cell activity could be used locally in the skin at the tick bite site to prevent the onset of meat allergy and systemically to stop an allergic reaction from progressing to a state of severe hypersensitivity.

Chinuki Y, e. a. (2013). “Clinical and biochemical evaluation of twenty patients with red meat allergies.” Jpn J Dermatol.(123): 1807-1814. 

Chinuki, Y., et al. (2016). “Haemaphysalis longicornis tick bites are a possible cause of red meat allergy in Japan.” Allergy 71(3): 421-425.

Recent studies revealed that Amblyomma or Ixodes tick bites may cause red meat allergy, in which galactose-alpha-1,3-galactose (alpha-Gal) is a major IgE-binding epitope. The incidence of red meat allergy is high in Shimane Prefecture, as is tick-transmitted Japanese spotted fever. Therefore, we speculated that tick bites may cause these meat allergies. The carbohydrate alpha-Gal was detected in the salivary gland protein of Haemaphysalis longicornis (H. longicornis), the vector for Japanese spotted fever, by immunoblotting using anti-alpha-Gal antibody. H. longicornis salivary gland protein-specific IgE was detected in the sera of 24 of 30 patients with red meat allergies. Sensitization to tick salivary gland protein containing alpha-Gal is possibly a major etiology of red meat allergy; the carbohydrate plays a crucial role in its allergenicity. These results further indicate that the alpha-Gal epitope is present not only in Amblyomma or Ixodes, but also in Haemaphysalis.

Chinuki, Y., et al. (2019). “128 Measurement of galactose-alpha-1,3-galactose-related specific IgE before the first administration of cetuximab can reduce the incidence of cetuximab-induced anaphylactic shock.” Journal of Investigative Dermatology 139(9): S236.

It is known that the main causative antigenic epitope of cetuximab allergy is galactose-alpha-1,3-galactose (alpha-Gal). In 2013, 13 patients with head and neck cancer received the first administration of cetuximab at Matsue Red Cross Hospital in the western part of Japan, and four of them developed anaphylactic shock (Incidence rate was 31%). In the sera of these patients, both alpha-Gal specific IgE by CAP-FEIA and cetuximab specific IgE by western blotting were detected. Both sensitivity and specificity in 13 patients of these tests were 100%. We therefore aimed to prevent cetuximab-induced anaphylactic shock by performing these tests before the administration. We measured alpha-Gal specific IgE by CAP-FEIA and cetuximab specific IgE by western blotting before the first administration of cetuximab in 206 patients with head and neck cancer, and gave the first dose of cetuximab to the patients who showed either on these two tests. As a result, alpha-Gal-specific IgE was detected in 15 of 206, and cetuximab-specific IgE was detected in 12 of 206. Nine patients showed positive on both tests. Thirty nine of the 188 patients who showed negative either on these two tests have received cetuximab so far, and two of them developed anaphylactic shock (Incidence rate was 5%). Although the incidence rate did not reach to 0%, cetuximab-induced anaphylactic shock could be significantly reduced by prior measurement of alpha-Gal-related specific IgE. The reason why the incidence rate could not be 0% may be because the cutoff value (<0.35kUA/L) we decided was high.

Chinuki, Y. and E. Morita (2019). “Alpha-Gal-containing biologics and anaphylaxis.” Allergol Int 68(3): 296-300.

Cetuximab, the IgG1 subclass chimeric mouse-human monoclonal antibody biologic that targets the epidermal growth factor receptor (EGFR), is used worldwide for the treatment of EGFR-positive unresectable progressive/recurrent colorectal cancer and head and neck cancer. Research has shown that the principal cause of cetuximab-induced anaphylaxis is anti-oligosaccharide IgE antibodies specific for galactose-alpha-1,3-galactose (alpha-Gal) oligosaccharide present on the mouse-derived Fab portion of the cetuximab heavy chain. Furthermore, it has been revealed that patients who are allergic to cetuximab also develop an allergic reaction to mammalian meat containing the same alpha-Gal oligosaccharide owing to cross-reactivity, and the presumed cause of sensitization is tick bites: Amblyomma in the United States, Ixodes in Australia and Europe, and Haemaphysalis in Japan. The alpha-Gal-specific IgE test (bovine thyroglobulin-conjugated ImmunoCAP) or CD63-expression-based basophil activation test may be useful to identify patients with IgE to alpha-Gal in order to predict risk for cetuximab-induced anaphylactic shock. Investigations of cetuximab-related anaphylaxis have revealed three novel findings that improve our understanding of immediate-type allergy: 1) oligosaccharide can serve as the main IgE epitope of anaphylaxis; 2) because of the oligosaccharide epitope, a wide range of cross-reactivity with mammalian meats containing alpha-Gal similar to cetuximab occurs; and 3) tick bites are a crucial factor of sensitization to the oligosaccharide. Nonetheless, taking a medical history of tick bites and beef allergy may be insufficient to prevent cetuximab-induced anaphylaxis, and therefore blood testing with an alpha-Gal-specific IgE test, with high sensitivity and specificity, is necessary to detect sensitization to alpha-Gal.

Chitnavis, M., et al. (2017). “First-dose anaphylaxis to infliximab: a case of mammalian meat allergy.” J Allergy Clin Immunol Pract 5(5): 1425-1426.

Letter to the editor:

IgE antibodies to galactose-α-1,3-galactose, identified in patients with mammalian meat allergy, can cross-react with a glycosylated component of infliximab, resulting in anaphylaxis in patients who receive this therapy.

Choudhary, S. and S. P. Commins (2018). “Detection of antigen-specific IgE-expressing B cells in food allergy is feasible and inversely associated with dietary antigen exposure.” Journal of Allergy and Clinical Immunology 141(2): AB192.

RATIONALE: To understand the regulation of IgE production in the recently described alpha-gal mammalian meat food allergy, we have focused on IgE-expressing (IgE+) B cells. These cells typically circulate in low abundance and are generally difficult to detect. Recent improvements in technical methods have made their analysis more feasible. Once identified, we asked whether circulating alpha-gal-specific IgE+ B cell populations were affected by ongoing dairy consumption as others have shown that B cell receptor (BCR) signaling negatively regulates IgE responses.

METHODS: PBMCs were isolated from controls and subjects with alphagal allergy and stained for surface markers CD19, CD38, CD27, CD138, and membrane IgM, IgG, IgD and IgE as well as fluorochrome-labeled alpha-gal.

Choudhary, S., et al. (2019). “Tick Salivary Extract Induces Alpha-Gal Allergy in Alpha-Gal Deficient Mice.” Journal of Allergy and Clinical Immunology 143(2): AB252-AB252.

RATIONALE: Recent retrospective research associated early life acid suppressive medication with food allergies. We sought to prospectively evaluate the association between acid suppressive medication in infancy and development of IgE-mediated food allergy in early childhood.

METHODS: The Gastrointestinal Microbiome and Allergic Proctocolitis (GMAP) Study is an ongoing prospective observational cohort study of 1003 healthy newborn infants designed to evaluate the development of food allergies in their first 3 years of life. IgE-mediated food allergy was determined by independent agreement of two allergist reviewers based on clinical reactivity and documented IgE sensitivity.

Choudhary, S., et al. (2018). “Venom allergy is increased in alpha-gal allergy: shared environmental or immunologic factors?” Journal of Allergy and Clinical Immunology 141(2): AB199.

RATIONALE: Expansion of tick populations has been associated with environmental change. We now face a global increasing incidence of mammalian meat food allergy due to alpha-gal sIgE, which has been associated with tick bites. Since patients with alpha-gal allergy frequent the outdoor environment, we sought to determine whether rates of stinging insect venom allergy, another environmentally-influenced condition, are

increased in these patients.

Choudhary, S. K. and S. P. Commins (2017). “Association of Alpha-gal Red Meat Allergy Severity with Concentration of Antigen in Basophil Activation.” Journal of Allergy and Clinical Immunology 139(2): AB125.

RATIONALE: IgE to galactose-alpha-1,3,-galactose has been associated with delayed allergic reactions to red meat and appears to develop following bites from ectoparasitic ticks.

Chung, C. H., et al. (2008). “Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose.” N Engl J Med 358(11): 1109-1117.

BACKGROUND: Cetuximab, a chimeric mouse-human IgG1 monoclonal antibody against the epidermal growth factor receptor, is approved for use in colorectal cancer and squamous-cell carcinoma of the head and neck. A high prevalence of hypersensitivity reactions to cetuximab has been reported in some areas of the United States. METHODS: We analyzed serum samples from four groups of subjects for IgE antibodies against cetuximab: pretreatment samples from 76 case subjects who had been treated with cetuximab at multiple centers, predominantly in Tennessee, Arkansas, and North Carolina; samples from 72 control subjects in Tennessee; samples from 49 control subjects with cancer in northern California; and samples from 341 female control subjects in Boston. RESULTS: Among 76 cetuximab-treated subjects, 25 had a hypersensitivity reaction to the drug. IgE antibodies against cetuximab were found in pretreatment samples from 17 of these subjects; only 1 of 51 subjects who did not have a hypersensitivity reaction had such antibodies (P<0.001). IgE antibodies against cetuximab were found in 15 of 72 samples (20.8%) from control subjects in Tennessee, in 3 of 49 samples (6.1%) from northern California, and in 2 of 341 samples (0.6%) from Boston. The IgE antibodies were shown to be specific for an oligosaccharide, galactose-alpha-1,3-galactose, which is present on the Fab portion of the cetuximab heavy chain. CONCLUSIONS: In most subjects who had a hypersensitivity reaction to cetuximab, IgE antibodies against cetuximab were present in serum before therapy. The antibodies were specific for galactose-alpha-1,3-galactose. 

Commins, S. P. and T. A. Platts-Mills (2010). “Allergenicity of carbohydrates and their role in anaphylactic events.Curr Allergy Asthma Rep 10(1): 29-33.

The IgE response to pollen allergens often includes IgE antibodies specific for glycosylation motifs on the pollen proteins. These oligosaccharides are present on many different species and are known as cross-reactive carbohydrate determinants. However, IgE antibodies to plant-derived cross-reactive carbohydrate determinants seem to have only minor clinical significance and have not been related to anaphylaxis. Recently, two novel forms of anaphylaxis have become apparent in the southeastern United States: 1) reactions during the first infusion of the monoclonal antibody cetuximab and 2) adult-onset delayed anaphylaxis to red meat. Detailed investigation of serum antibodies established that in both cases, the patients had IgE antibodies specific for the mammalian oligosaccharide galactose alpha-1, 3-galactose. Identification of these cases is helpful in avoiding infusion reactions to cetuximab or recommending specific avoidance of meat derived from mammals. However, the current evidence does not fully resolve why these IgE antibodies are so common in the Southeast or why the anaphylactic or urticarial reactions to red meat are delayed. 

Commins, S., et al. (2008). “Anaphylaxis and IgE antibodies to galactose-alpha-1,3-galactose (alphaGal): Insight from the identification of novel IgE ab to carbohydrates on mammalian proteins.” Journal of Allergy and Clinical Immunology 121(2): S25-S25.

RATIONALE: Many cases of recurrent anaphylaxis or angioedema lack an obvious cause and are not explained by skin testing. The presence in serum of IgE ab to the xenoantigen galactose-alpha-1,3-galactose (alphaGal) may help in the understanding of these diseases. METHODS: Detailed histories were taken from patients (ages 18-75) presenting to the Allergy Clinic at the University of Virginia with recurrent anaphylaxis or angioedema. Prick tests, intradermal skin tests and serum IgE ab analysis were performed for common indoor, outdoor and food allergens.

 Commins, S. P. (2014). “Carbohydrates as Allergens.” Curr Allergy Asthma Rep 15(1): 492.

Complex carbohydrates are effective inducers of Th2 responses, and carbohydrate antigens can stimulate the production of glycan-specific antibodies. In instances where the antigen exposure occurs through the skin, the resulting antibody production can contain IgE class antibody. The glycan-stimulated IgE may be non-specific but may also be antigen specific. This review focuses on the production of cross-reactive carbohydrate determinants, the recently identified IgE antibody response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal), as well as discusses practical implications of carbohydrates in allergy. In addition, the biological effects of carbohydrate antigens are reviewed in setting of receptors and host recognition. 

Commins, S. P., et al. (2008). “Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose – Reply.” New England Journal of Medicine 358(25): 2735-2736. 

Commins, S. P. (2016). “Invited Commentary: Alpha-Gal Allergy: Tip of the Iceberg to a Pivotal Immune Response.” Curr Allergy Asthma Rep 16(9): 61.

The syndrome of delayed allergic reactions to the carbohydrate galactose-alpha-1,3-galactose (“alpha-gal”) has become increasingly recognized in allergy and immunology clinics regionally throughout the southeastern USA. Due to the increasing awareness of this unique food allergy, cases have been identified in the northeastern and central USA as well as in Central and South America, Europe, Asia, Scandinavia, and Australia. Clinically, alpha-gal allergy is characterized by reactions to non-primate mammalian meat (e.g., beef, pork, lamb) that occur 3-6 h following exposure. The IgE response to alpha-gal is thought to develop after tick bites and can result in the loss of tolerance to foods that have been safely consumed for years. Although the initial description of alpha-gal allergy in 2009 was limited to red meat, this epitope is now identified in an expanded number of products, medications and foods-both labeled and unlabeled. Moreover, we are beginning to recognize that alpha-gal food allergy is the tip of the iceberg for this immune response.

Commins, SP, Crispell, G, Karim, S,  Choudary, S, Iweala, OI, Addison, CT, Choudhary, S. (2019). “Red Meat Allergy May Develop Independent of Tick Blood Meal Status.” Journal of Allergy and Clinical Immunology 143(2, Suppl. S): AB35.

RATIONALE: Alpha-gal syndrome (AGS) is a paradigm-shifting food allergy characterized by delayed reactions to non-primate mammalian meat and derived products. Evidence continues to suggest that AGS develops following tick bites and multiple species have been implicated globally. Tick saliva may contain alpha-gal from prior blood meal or may act as an adjuvant to induce IgE. This study assessed whether tick salivary gland extract (TSGE) could activate alpha-gal-sensitized basophils directly and if IgE reactivity was present in tick saliva.

 

Commins, S. P., et al. (2011). “The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose.” Journal of Allergy and Clinical Immunology 127(5): 1286-1293.e1286.

Background – In 2009, we reported a novel form of delayed anaphylaxis to red meat that is related to serum IgE antibodies to the oligosaccharide galactose-α-1,3-galactose (alpha-gal). Most of these patients had tolerated meat for many years previously. The implication is that some exposure in adult life had stimulated the production of these IgE antibodies. Objectives – We sought to investigate possible causes of this IgE antibody response, focusing on evidence related to tick bites, which are common in the region where these reactions occur. Methods – Serum assays were carried out with biotinylated proteins and extracts bound to a streptavidin ImmunoCAP. Results – Prospective studies on IgE antibodies in 3 subjects after tick bites showed an increase in levels of IgE to alpha-gal of 20-fold or greater. Other evidence included (1) a strong correlation between histories of tick bites and levels of IgE to alpha-gal (χ2=26.8, P<.001), (2) evidence that these IgE antibodies are common in areas where the tick Amblyomma americanum is common, and (3) a significant correlation between IgE antibodies to alpha-gal and IgE antibodies to proteins derived from A. americanum (rs=0.75, P<.001). Conclusion – The results presented here provide evidence that tick bites are a cause, possibly the only cause, of IgE specific for alpha-gal in this area of the United States. Both the number of subjects becoming sensitized and the titer of IgE antibodies to alpha-gal are striking. Here we report the first example of a response to an ectoparasite giving rise to an important form of food allergy.

Commins, S. P., et al. (2010). “Testing for IgE Antibody to the Carbohydrate galactose-alpha-1,3-galactose (alpha-gal) in Patients with Recurrent, Idiopathic Anaphylaxis: How Many Cases Are We Missing?Journal of Allergy and Clinical Immunology 125(2): AB119-AB119.

RATIONALE: Patients with idiopathic anaphylaxis are at increased risk for recurrent episodes if the etiology of anaphylaxis is not established. The carbohydrate, galactose-a-1,3-galactose (alpha-gal), has recently been described as a novel food allergen and patients who have IgE to alpha-gal report delayed anaphylaxis or urticaria occurring 3-6 hours after eating mammalian meat. 

Commins, S. P., et al. (2016). “Delayed anaphylaxis to alpha-gal, an oligosaccharide in mammalian meat.” Allergol Int 65(1): 16-20.

IgE-mediated hypersensitivity refers to immune reactions that can be rapidly progressing and, in the case of anaphylaxis, are occasionally fatal. To that end, identification of the associated allergen is important for facilitating both education and allergen avoidance that are essential to long-term risk reduction. As the number of known exposures associated with anaphylaxis is limited, discovery of novel causative agents is crucial to evaluation and management of patients with idiopathic anaphylaxis. Within the last 10 years several apparently separate observations were recognized to be related, all of which resulted from the development of antibodies to a carbohydrate moiety on proteins. Interestingly, the exposure differed from airborne allergens but was nevertheless capable of producing anaphylactic and hypersensitivity reactions. Our recent work has identified these responses as being due to a novel IgE antibody directed against a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (“alpha-gal”). This review will present the historical summary of the identification of cetuximab hypersensitivity due to alpha-gal IgE and discuss the non-primate mammalian meat food allergy as well as current goals and directions of our research programs.

Commins, S. P., et al. (2014). “Delayed clinical and ex vivo response to mammalian meat in patients with IgE to galactose-alpha-1,3-galactose.” J Allergy Clin Immunol 134(1): 108-115.

BACKGROUND: In 2009, we reported a novel form of delayed anaphylaxis to red meat related to serum IgE antibodies to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal). Although patients were remarkably consistent in their description of a 3- to 6-hour delay between eating mammalian meat and the appearance of symptoms, this delay has not been demonstrated under observed studies. OBJECTIVES: We sought to formally document the time course of clinical symptoms after the ingestion of mammalian meat in subjects with IgE to alpha-gal and to monitor ex vivo for the appearance of markers of an allergic reaction. METHODS: Open food challenges were performed with mammalian meat in 12 subjects with a history of severe urticarial reactions 3 to 6 hours after eating beef, pork, or lamb, as well as in 13 control subjects. Blood samples were taken hourly during each challenge. RESULTS: Ten of 12 subjects with IgE to alpha-gal had clinical evidence of a reaction during the food challenge (vs none of the control subjects, P < .001). The reactions occurred 3 to 7 hours after the initial ingestion of mammalian meat and ranged from urticaria to anaphylaxis. Tryptase levels were positive in 3 challenges. Basophil activation, as measured by increased expression of CD63, correlated with the appearance of clinical symptoms. CONCLUSION: The results presented provide clear evidence of an IgE-mediated food allergy that occurs several hours after ingestion of the inciting allergen. Moreover, here we report that in vivo basophil activation during a food challenge occurs in the same time frame as clinical symptoms and likely reflects the appearance of the antigen in the bloodstream. 

Commins, S. P. and S. Karim (2017). “Development of a novel murine model of alpha-gal meat allergy.” Journal of Allergy and Clinical Immunology 139(2, Suppl. S): AB193.

RATIONALE: Specific IgE (sIgE) galactose-alpha-1,3-galactose (alphagal) has been associated with delayed reactions to beef, pork or lamb. Development of alpha-gal sIgE and red meat allergy appears to occur following tick bites and alpha-gal has been reported in the gastrointestinal tract of Ixodes ricinus ticks. In this study, we examined whether mice treated with tick salivary proteins would develop an alpha-gal IgE response and allergic reaction to red meat.

Commins, S. P., et al. (2012). “Galactose-alpha-1,3-galactose-specific IgE is associated with anaphylaxis but not asthma.” Am J Respir Crit Care Med 185(7): 723-730.

RATIONALE: IgE antibodies to the mammalian oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) are common in the southeastern United States. These antibodies, which are induced by ectoparasitic ticks, can give rise to positive skin tests or serum assays with cat extract. OBJECTIVES: To evaluate the relationship between IgE antibodies to alpha-gal and asthma, and compare this with the relationship between asthma and IgE antibodies to Fel d 1 and other protein allergens. METHODS: Patients being investigated for recurrent anaphylaxis, angioedema, or acute urticaria underwent spirometry, exhaled nitric oxide, questionnaires, and serum IgE antibody assays. The results were compared with control subjects and cohorts from the emergency department in Virginia (n = 130), northern Sweden (n = 963), and rural Kenya (n = 131). MEASUREMENTS AND MAIN RESULTS: Patients in Virginia with high-titer IgE antibodies to alpha-gal had normal lung function, low levels of exhaled nitric oxide, and low prevalence of asthma symptoms. Among patients in the emergency department and children in Kenya, there was no association between IgE antibodies to alpha-gal and asthma (odds ratios, 1.04 and 0.75, respectively). In Sweden, IgE antibodies to cat were closely correlated with IgE antibodies to Fel d 1 (r = 0.83) and to asthma (P < 0.001). CONCLUSIONS: These results provide a model of an ectoparasite-induced specific IgE response that can increase total serum IgE without creating a risk for asthma, and further evidence that the main allergens that are causally related to asthma are those that are inhaled.

Commins, S. P. and T. A. E. Platts-Mills (2009). “Anaphylaxis syndromes related to a new mammalian cross-reactive carbohydrate determinant.” Journal of Allergy and Clinical Immunology 124(4): 652-657.

Anaphylaxis is a severe allergic reaction that can rapidly progress and occasionally be fatal. In instances in which the triggering allergen is not obvious, establishing the cause of anaphylaxis is pivotal to long-term management. Assigning cause is limited, however, by the number of known exposures associated with anaphylaxis. Therefore, identification of novel causative agents can provide an important step forward in facilitating new, allergen-specific approaches to management. In contrast to the view that carbohydrate-directed IgE has minimal, if any, clinical significance, recent data suggest that IgE antibodies to carbohydrate epitopes can be an important factor in anaphylaxis that might otherwise appear to be idiopathic. Here we review the evidence relating to carbohydrates in food allergy and anaphylaxis and discuss the implications of a new mammalian cross-reactive carbohydrate determinant. (J Allergy Clin Immunol 2009;124:652-7.)

Commins, S. P. and T. A. E. Platts-Mills (2013). “Delayed Anaphylaxis to Red Meat in Patients with IgE Specific for Galactose alpha-1,3-Galactose (alpha-gal).” Curr Allergy Asthma Rep 13(1): 72-77.

Anaphylaxis is a severe allergic reaction that can be rapidly progressing and fatal. In instances where the triggering allergen is not known, establishing the etiology of anaphylaxis is pivotal to long-term risk management. Our recent work has identified a novel IgE antibody (Ab) response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal), that has been associated with two distinct forms of anaphylaxis: (1) immediate onset anaphylaxis during first exposure to intravenous cetuximab, and (2) delayed onset anaphylaxis 3-6 h after ingestion of mammalian food products (e.g., beef and pork). The results of our studies strongly suggest that tick bites are a cause, if not the only significant cause, of IgE Ab responses to alpha-gal in the southern, eastern and central United States. Patients with IgE Ab to alpha-gal continue to emerge and, increasingly, these cases involve children. This IgE Ab response cross-reacts with cat and dog but does not appear to pose a risk for asthma; however, it may impair diagnostic testing in some situations.

Commins, S. P., et al. (2016). “The glycan did it: how the α-gal story rescued carbohydrates for allergists — a US perspective.” Allergo Journal 25(2): 24-28.

IgE antibodies to carbohydrate epitopes on allergens are thought to be less common than IgE antibodies to protein epitopes and also of much less clinical significance. Our recent work, however, has identified a novel IgE antibody response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal). IgE to alpha-gal has been associated with two distinct forms of anaphylaxis including delayed allergic reactions after eating beef, pork or lamb. IgE antibody responses to alpha-gal have now been found globally. Therefore, establishing the mechanism of the specific IgE antibody response to alpha-gal will be an important aspect to address as this area of research continues. 

Commins, S. P. and T. A. E. Platts-Mills (2013). “Tick bites and red meat allergy.” Curr Opin Allergy Clin Immunol 13(4): 354-359.

Purpose of review A novel form of anaphylaxis has been described that is due to IgE antibody (Ab) directed against a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal). Ongoing work regarding the cause and distribution of this IgE response is reviewed. Recent findings: Our recent work has identified a novel IgE Ab response that has been associated with two distinct forms of anaphylaxis: immediate-onset anaphylaxis during first exposure to intravenous cetuximab and delayed-onset anaphylaxis 3-6h after ingestion of mammalian food products (e.g. beef and pork). Further studies strongly suggested that tick bites were a cause, if not the only significant cause, of IgE Ab responses to alpha-gal in the United States and internationally. Summary: Large numbers of patients with IgE Ab to alpha-gal continue to be identified in the USA and globally. Clinicians should be aware of this IgE response as the reactions often appear to be idiopathic because of the significant delay between eating mammalian meat and the appearance of symptoms.

Commins, S. P., et al. (2009). “Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-α-1,3-galactose.” Journal of Allergy and Clinical Immunology 123(2): 426-433.e422.

Background Carbohydrate moieties are frequently encountered in food and can elicit IgE responses, the clinical significance of which has been unclear. Recent work, however, has shown that IgE antibodies to galactose-α-1,3-galactose (α-gal), a carbohydrate commonly expressed on nonprimate mammalian proteins, are capable of eliciting serious, even fatal, reactions. Objective We sought to determine whether IgE antibodies to α-gal are present in sera from patients who report anaphylaxis or urticaria after eating beef, pork, or lamb. Methods Detailed histories were taken from patients presenting to the University of Virginia Allergy Clinic. Skin prick tests (SPTs), intradermal skin tests, and serum IgE antibody analysis were performed for common indoor, outdoor, and food allergens. Results Twenty-four patients with IgE antibodies to α-gal were identified. These patients described a similar history of anaphylaxis or urticaria 3 to 6 hours after the ingestion of meat and reported fewer or no episodes when following an avoidance diet. SPTs to mammalian meat produced wheals of usually less than 4 mm, whereas intradermal or fresh-food SPTs provided larger and more consistent wheal responses. CAP-RAST testing revealed specific IgE antibodies to beef, pork, lamb, cow’s milk, cat, and dog but not turkey, chicken, or fish. Absorption experiments indicated that this pattern of sensitivity was explained by an IgE antibody specific for α-gal. Conclusion We report a novel and severe food allergy related to IgE antibodies to the carbohydrate epitope α-gal. These patients experience delayed symptoms of anaphylaxis, angioedema, or urticaria associated with eating beef, pork, or lamb.

Commins, S. P., et al. (2015). “Delayed Urticarial and Anaphylactic Reactions to Red Meat: Age of Onset, Severity, and Immunology Among 353 Cases and 140 Controls.” Journal of Allergy and Clinical Immunology 135(2): AB205.

RATIONALE: Patients with IgE to galactose-alpha-1,3,-galactose report delayed reactions, which vary from itching or gastrointestinal distress to frank anaphylaxis. METHODS: Patients who presented to allergy clinics in Virginia with histories compatible with delayed reactions to red meat (n5353) or with recurrent urticarial or anaphylactic reactions of other types (n5140), many of which appeared to be idiopathic, completed a questionnaire. Sera were assayed for IgE antibodies, total IgE, and alpha-gal specific IgG.

Cox, K. M., et al. (2016). “Using mass cytometry to identify novel B cell subsets in red meat allergy.” The Journal of Immunology 196(1 Supplement): 191.125-191.125.

Previous studies have identified a novel food allergy driven by IgE antibodies specific for galactose-α-1,3-galactose (alpha-gal), an oligosaccharide found in red meat. While it is known that B cells play an important role in allergy as the producers of IgE antibodies that drive the allergic response, little is known about the phenotype of these B cells. The number of markers used to identify the major human B cell subsets by flow cytometry has been limited to common B cell proteins and thus precludes high dimensional immune phenotyping of B cell subsets, including unique phenotypes present in allergic individuals. We have addressed this problem by using mass cytometry (CyTOF), which enables the simultaneous analysis of up to 40 markers in a single staining panel. Here we analyzed the expression of 23 cell surface markers in PBMCs from 19 alpha-gal-allergic patients and 20 non-allergic controls by CyTOF. Additionally, we combined our CyTOF data with clinical endpoints to identify markers that may correlate with allergic disease. Our data reveals substantial heterogeneity within major B cells subsets on an individual level. Furthermore, our analysis identifies a number of markers that vary significantly in their expression in allergic versus non-allergic B cells and correlate with serum alpha-gal IgE titers. We hypothesize that B cells with this phenotype play an important role in mediating alpha-gal allergy. These findings demonstrate the power of using CyTOF and analytical tools to extract a hierarchy from high dimensional cytometry data in an unsupervised manner to identify known B cell subsets as well as to find novel B cell populations that differ between alpha-gal allergic and non-allergic individuals.

Cox, K. M., et al. (2019). “An integrated framework using high-dimensional mass cytometry and fluorescent flow cytometry identifies discrete B cell subsets in patients with red meat allergy.” Clinical & Experimental Allergy 49(5): 615-625.

Summary: Background B cells play a critical role in the development and maintenance of food allergy by producing allergen-specific IgE. Despite the importance of B cells in IgE-mediated food allergy, the identity of sIgE-producing human B cells and how IgE is regulated are poorly understood. Objective: To identify the immunophenotypes of circulating B cells associated with the production of galactose-alpha-1,3-galactose-specific IgE production in patients with red meat allergy. Methods: B cells in PBMC samples obtained from 19 adults with physician-diagnosed red meat allergy and 20 non-meat allergic healthy controls were assessed by mass cytometry along with a bioinformatics analysis pipeline to identify discrete B cell phenotypes that associated with serum sIgE. Fluorescent flow cytometry was then applied to sort purify discrete B cell subsets, and B cells were functionally evaluated on an individual cell level for the production of sIgE by ELISPOT. Results: Discrete B cell phenotypes abundant in meat allergic subjects compared to non-meat allergic controls were found in peripheral blood that do not share typical characteristics of classical isotype-switched memory B cells that express high levels of CD27. These B cell subsets shared higher IgD and lower IgM expression levels coupled with CXCR4, CCR6 and CD25 expression. In vitro polyclonal stimulation of purified B cell subsets from meat allergic subjects demonstrated that these subsets were enriched for cells induced to secrete sIgE. Conclusions and Clinical Relevance: Circulating B cells display increased abundance of discrete B cell subsets in meat allergic subjects. This observation, coupled with the capacity of individual B cell subsets to produce sIgE following activation, implicates these novel B cell phenotypes in promoting IgE in meat allergy. 

Cresce, N. D., et al. (2012). “Blood Type Does Not Predict the Development of an IgE Response to Galactose-alpha-1,3-Galactose.” Journal of Allergy and Clinical Immunology 129(2): AB80-AB80. 

Crispell, G., et al. (2019). “Discovery of Alpha-Gal-Containing Antigens in North American Tick Species Believed to Induce Red Meat Allergy.” Front Immunol 10: 1056.

Development of specific IgE antibodies to the oligosaccharide galactose-alpha-1, 3-galactose (alpha-gal) following tick bites has been shown to be the source of red meat allergy. In this study, we investigated the presence of alpha-gal in four tick species: the lone-star tick (Amblyomma americanum), the Gulf-Coast tick (Amblyomma maculatum), the American dog tick (Dermacentor variabilis), and the black-legged tick (Ixodes scapularis) by using a combination of immunoproteomic approach and, carbohydrate analysis. Anti-alpha-gal antibodies identified alpha-gal in the salivary glands of both Am. americanum and Ix. scapularis, while Am. maculatum and De. variabilis appeared to lack the carbohydrate. PNGase F treatment confirmed the deglycosylation of N-linked alpha-gal-containing proteins in tick salivary glands. Immunolocalization of alpha-gal moieties to the salivary secretory vesicles of the salivary acini also confirmed the secretory nature of alpha-gal-containing antigens in ticks. Am. americanum ticks were fed on human blood (lacks alpha-gal) using a silicone membrane system to determine the source of the alpha-gal. N-linked glycan analysis revealed that Am. americanum and Ix. scapularis have alpha-gal in their saliva and salivary glands, but Am. maculatum contains no detectable quantity. Consistent with the glycan analysis, salivary samples from Am. americanum and Ix. scapularis stimulated activation of basophils primed with plasma from alpha-gal allergic subjects. Together, these data support the idea that bites from certain tick species may specifically create a risk for the development of alpha-gal-specific IgE and hypersensitivity reactions in humans. Alpha-Gal syndrome challenges the current food allergy paradigm and broadens opportunities for future research.

Crow, H., et al. (2019). “Red Meat Allergy Associated with NSTEMI.” American Journal of Medical Case Reports 7(1): 13-15.

Alpha-gal syndrome, also known as mammalian meat allergy, is characterized by a hypersensitivity reaction to galactose-alpha-1,3-galactose. Reactions typically manifest hours after consumption of red meat products such as beef, pork, and lamb. We describe the case of a 64-year-old male resident of rural Oklahoma who presented with anaphylaxis and myocardial infarction. The patient suffered complications that were attributed to porcine-derived heparin in the setting of undiagnosed alpha-gal syndrome. We describe the clinical course of this patient that lead to the diagnosis of alpha-gal syndrome to raise awareness of this disease.

 

Dahlgren, F. S., et al. (2016). “Expanding Range of Amblyomma americanum and Simultaneous Changes in the Epidemiology of Spotted Fever Group Rickettsiosis in the United States.” The American Journal of Tropical Medicine and Hygiene 94(1): 35-42.

Abstract: Spotted fever group (SFG) Rickettsiaspecies are etiologic agents of a wide range of human infections from asymptomatic or mild infections to severe, life-threatening disease. In the United States, recent passive surveillance for SFG rickettsiosis shows an increased incidence and decreased severity of reported cases. The reasons for this are not well understood; however, we hypothesize that less pathogenic rickettsiae are causing more human infections, while the incidence of disease caused by more pathogenic rickettsiae, particularly Rickettsia, is relatively stable. During the same period, the range of Amblyomma americanumhas expanded. Amblyomma americanumis frequently infected with CandidatusRickettsia amblyommii”, a SFG Rickettsia of unknown pathogenicity. We tested our hypothesis by modeling incidence rates from 1993 to 2013, hospitalization rates from 1981 to 2013, and case fatality rates from 1981 to 2013 regressed against the presence of A. americanum, the decade of onset of symptoms, and the county of residence. Our results support the hypothesis, and we show that the expanding range of A. americanumis associated with changes in epidemiology reported through passive surveillance. We believe epidemiological and acarological data collected on individual cases from enhanced surveillance may further elucidate the reasons for the changing epidemiology of SFG rickettsiosis. 

de la Fuente, J. (2018). “Controlling ticks and tick-borne diseases…looking forward.” Ticks Tick Borne Dis 9(5): 1354-1357.

Tick-borne diseases (TBDs) represent a growing burden for human and animal health worldwide. Several approaches including the use of chemicals with repellency and parasiticidal activity, habitat management, genetic selection of hosts with higher resistance to ticks, and vaccines have been implemented for reducing the risk of TBDs. However, the application of latest gene editing technologies in combination with vaccines likely combining tick and pathogen derived antigens and other control measures should result in the development of effective, safe, and environmentally sound integrated control programs for the prevention and control of TBDs. This paper is not a review of current approaches for the control of ticks and TBDs, but an opinion about future directions in this area. 

de la Fuente, J., et al. (2017). “Targeting a global health problem: Vaccine design and challenges for the control of tick-borne diseases.” Vaccine 35(38): 5089-5094.

It has been over twenty years since the first vaccines for the control of tick infestations became commercially available. These vaccines proved their efficacy and the potential of this approach for the control of tick-borne diseases (TBDs), which represent a growing burden for human and animal health worldwide. In all these years, research in this area has produced new tick-derived and pathogen-derived candidate protective antigens. However, the potential of vaccines for the control of TBDs has been underestimated due to major challenges to reduce tick infestations, pathogen infection, multiplication and transmission, tick attachment and feeding time and/or host pathogen infection. Nevertheless, vaccines constitute the most safe and effective intervention for the control of TBDs in humans, domestic and wild animals. 

de la Fuente, J., et al. (2019). “The alpha-Gal syndrome: new insights into the tick-host conflict and cooperation.” Parasit Vectors 12(1): 154.

This primer focuses on a recently diagnosed tick-borne allergic disease known as the alpha-Gal syndrome (AGS). Tick bites induce in humans high levels of IgE antibodies against the carbohydrate Galalpha1-3Galbeta1-(3)4GlcNAc-R (alpha-Gal) present on tick salivary glycoproteins and tissues of non-catarrhine mammals, leading to the AGS in some individuals. This immune response evolved as a conflict and cooperation between ticks and human hosts including their gut microbiota. The conflict is characterized by the AGS that mediate delayed anaphylaxis to red meat consumption and certain drugs such as cetuximab, and immediate anaphylaxis to tick bites. The cooperation is supported by the capacity of anti-alpha-Gal IgM and IgG antibody response to protect against pathogens with alpha-Gal on their surface. Despite the growing diagnosis of AGS in all world continents, many questions remain to be elucidated on the tick proteins and immune mechanisms triggering this syndrome, and the protective response against pathogen infection elicited by anti-alpha-Gal antibodies. The answer to these questions will provide information for the evaluation of risks, diagnosis and prevention of the AGS, and the possibility of using the carbohydrate alpha-Gal to develop vaccines for the control of major infectious diseases. 

Deschamps Huvier, A., et al. (2018). “Recurring acute urticaria and abdominal pain: Consider a diagnosis of alpha-galactose anaphylaxis.” Ann Dermatol Venereol 145(11): 690-693.

BACKGROUND: Food urticaria is common and generally benign, and it may be of viral or idiopathic aetiology. A food origin of the allergy is frequently sought but rarely found. Mammalian meat anaphylaxis, or alpha-galactose (alpha-gal) anaphylaxis, is a rare and recently discovered entity. PATIENTS AND METHODS: Herein, we report a case of alpha-galactose (alpha-gal) anaphylaxis in a 60-year-old woman presenting four episodes of acute urticaria with signs of anaphylaxis occurring a few hours after meals containing mammalian meat (beef meat, pork meat and offal). The diagnosis was confirmed by a positive gelatine prick-test and the presence of alpha-gal IgE. DISCUSSION: In the event of acute urticaria associated with systemic symptoms, in particular gastrointestinal signs, allergy to alpha-galactose should be considered. 

Dewachter, P., et al. (2019). “Anesthetic management of patients with pre-existing allergic conditions: a narrative review.” Br J Anaesth 123(1): e65-e81.

This narrative review seeks to distinguish the clinical patterns of pre-existing allergic conditions from other confounding non-allergic clinical entities, and to identify the potential related risks and facilitate their perioperative management. Follow-up investigation should be performed after a perioperative immediate hypersensitivity to establish a diagnosis and provide advice for subsequent anaesthetics, the main risk factor for perioperative immunoglobulin E (IgE)-mediated anaphylaxis being a previous uninvestigated perioperative immediate hypersensitivity reaction. The concept of cross-reactivity between drugs used in the perioperative setting and food is often quoted, but usually not supported by evidence. There is no reason to avoid propofol in egg, soy, or peanut allergy. The allergenic determinants have been characterized for fish, shellfish, and povidone iodine, but remain unknown for iodinated contrast agents. Iodinated drugs may be used in seafood allergy. Evidence supporting the risk for protamine allergy in fish allergy and in neutral protamine Hagedorn insulin use is lacking. Conversely, cross-reactivity to gelatin-based colloid may occur in alpha-gal syndrome. Atopy and allergic asthma along with other non-allergic conditions, such as NSAID-exacerbated respiratory disease, chronic urticaria, mastocytosis, and hereditary or acquired angioedema, are not risk factors for IgE-mediated drug allergy, but there is a perioperative risk associated with the potential for exacerbation of the various conditions.

Donaldson, B. and M. N. Le (2019). “The clinical presentation of alpha-gal allergy among pediatric patients with food allergy in southwest Missouri.” Ann Allergy Asthma Immunol.

Alpha-gal allergy is associated with immunoglobulin E (IgE) antibodies to galactose-α-1,3-galactose (alpha-gal), a carbohydrate found in beef, pork, and lamb. First described in the adult population in 2009 by Commins et al, this syndrome is associated with delayed anaphylaxis, angioedema, and urticaria with symptom onset 3 to 6 hours after eating red meat.1-3 Bites from ticks, namely the Lone Star Tick (Amblyomma americanum) in the United States, are associated with production of IgE antibodies to alpha-gal, resulting in an immune system primed to react to foods containing the antigen in patients who previously tolerated meat without symptoms. 

Drouet, M., et al. (2016). “Characteristics of a group of 21 patients allergic to meat by sensitization to alpha-Gal allergens. / Caractéristiques d’un groupe de 21 patients allergiques aux viandes par sensibilisation aux allergènes alpha-Gal.” Revue Française d’Allergologie 56(7/8): 533-538.

Patients allergic to red meat with sensitization to alpha-Gal allergen typically have delayed allergic reactions after eating meats. We present a group of 21 patients allergic to meat with alpha-Gal sensitization and study various characteristics: the existence of tick bites or hymenoptera stings occurring before allergy, the existence of allergic reactions after ingestion of dairy products in particular cheese. Some patients present an associated allergy with dairy products that could lead to suspect an allergy to mammalian milk especially as the IgE sensitization to mammalian milk is common in this syndrome. However, we discuss another possibility: rennet, which is extracted from the stomach of the calf is used to manufacture cheese. This substance derived from offal contains alpha-Gal allergens and could most likely be involved in allergy induced by cheeses. 

Dunkman, W. J., et al. (2019). “What Does a Red Meat Allergy Have to Do With Anesthesia? Perioperative Management of Alpha-Gal Syndrome.Anesth Analg 129(5): 1242-1248.

Over the past decade, there has been a growing awareness of a new allergic syndrome known as alpha-gal allergy or alpha-gal syndrome, commonly recognized as a red meat allergy. We performed a review of the literature to identify articles that provide both background on this syndrome in general and any reports of reactions to medications or medical devices related to alpha-gal syndrome. Alpha-gal syndrome results from IgE to the oligosaccharide galactose-alpha-1,3-galactose, expressed in the meat and tissues of noncatarrhine mammals. It is triggered by the bite of the lone star tick and has been implicated in immediate-onset hypersensitivity to the monoclonal antibody cetuximab and delayed-onset hypersensitivity reactions after the consumption of red meat. There is growing recognition of allergic reactions in these patients to other drugs and medical devices that contain alpha-gal. Many of these reactions result from inactive substances that are part of the manufacturing or preparation process such as gelatin or stearic acid. This allergy may be documented in a variety of ways or informally reported by the patient, requiring vigilance on the part of the anesthesiologist to detect this syndrome, given its serious implications. This allergy presents a number of unique challenges to the anesthesiologist, including proper identification of a patient with alpha-gal syndrome and selection of anesthetic and adjunctive medications that will not trigger this allergy. 

Dupont, B., et al. (2014). “Case Report About Fatal or Near-Fatal Hypersensitivity Reactions to Cetuximab: Anticetuximab IgE as a Valuable Screening Test.” Clin Med Insights Oncol 8: 91-94.

Hypersensitivity reactions are a classic side effect of cetuximab. We report the cases of three patients who developed life-threatening hypersensitivity to cetuximab, which could have been predicted by assessing the concentration of serum anticetuximab immunoglobulin (Ig)E. The anticetuximab IgE concentration could be an interesting test to predict which patients are at risk of experiencing severe hypersensitivity reactions to cetuximab. 

Dupont, B., et al. (2014). “Risk factors associated with hypersensitivity reactions to cetuximab: anti-cetuximab IgE detection as screening test.” Future Oncol 10(14): 2133-2140.

AIM: To describe the factors associated with a high risk of a hypersensitivity reaction to cetuximab. PATIENTS & METHODS: We retrospectively studied a cohort of patients living in Normandy (France) treated with cetuximab. RESULTS: Among the 229 treated patients, 24 (10.5%) had a hypersensitivity reaction to cetuximab, including 11 grade 3-5 reactions. Detection of anti-cetuximab IgE could be performed in 108 patients. Anti-cetuximab IgE was found in 13 of 17 patients (76.5%) who had a hypersensitivity reaction to cetuximab compared with 17 of 91 control patients (18.7%; adjusted odds ratio: 14.99; 95% CI: 3.59-62.63). No clinical criteria predicted the risk of allergy to cetuximab. CONCLUSION: Anti-cetuximab IgE may help physicians identify patients at risk of a hypersensitivity reaction to cetuximab. 

Dupont, B., et al. (2017). “Utility of serum anti-cetuximab immunoglobulin E levels to identify patients at a high risk of severe hypersensitivity reaction to cetuximab.” British journal of clinical pharmacology 83(3): 623-631.

AIM: Cetuximab is an anti-epidermal growth factor receptor antibody used for the treatment of metastatic colorectal cancer and head and neck cancer. Hypersensitivity reactions (HSRs) are associated with cetuximab use. The aim of the study was to evaluate the utility of anti-cetuximab immunoglobulin E (IgE) detection in order to identify patients at risk of HSR to cetuximab. METHODS: We included patients ready to receive a first cetuximab infusion in a prospective cohort carried out at nine French centres. Pretreatment anti-cetuximab IgE levels were measured. We compared the proportion of severe HSRs in the low anti-cetuximab IgE levels (</=29 IgE arbitrary units) subgroup with that in a historical cohort of 213 patients extracted from a previous study. RESULTS: Of the 301 assessable patients (mean age: 60.9 +/- 9.3 years, head-and-neck cancer: 77%), 66 patients (22%) had high anti-cetuximab IgE levels, and 247 patients received cetuximab (including 38 with high anti-cetuximab levels). Severe HSRs occurred in eight patients (five grade 3 and three grade 4). The proportion of severe HSRs was lower in the low anti-cetuximab IgE levels subgroup vs. the historical cohort (3/209 [1.4%] vs. 11/213 [5.2%], odds ratio, 0.27, 95% confidence interval, 0.07-0.97), and higher in high vs. low anti-cetuximab IgE levels subgroup (5/38 [13.2%] vs. 3/209 [1.4%]; odds ratio, 10.4, 95% confidence interval, 2.4-45.6). Patients with severe HSRs had higher anti-cetuximab IgE levels than patients without reaction (median, 45 vs. 2 IgE arbitrary units, P = 0.006). CONCLUSIONS: Detection of pretreatment anti-cetuximab IgE is feasible and helpful to identify patients at risk of severe cetuximab-induced HSRs.

Ebo, D. G., et al. (2013). “Sensitization to the mammalian oligosaccharide galactose-alpha-1,3-galactose (alpha-gal): experience in a Flemish case series.Acta Clin Belg 68(3): 206-209.

BACKGROUND: Recent observations have disclosed that the galactose-alpha (1,3)-galactose (alpha-gal) moiety of non-primate glycoproteins can constitute a target for meat allergy. OBJECTIVE: To describe adults with allergic reactions to mammalian meat, dairy products and gelatin. To investigate whether patients could demonstrate sensitization to activated recombinant human coagulation factor VII ectapog alpha that is produced in baby hamster kidney cells. METHODS: Ten adults with mammalian meat, dairy products and gelatin allergies were examined using quantification of specific IgE and/or skin prick test for red meat, milk, milk components, gelatin, cetuximab and eptacog alpha. RESULTS: Most patients demonstrate quite typical clinical histories and serological profiles, with anti-alpha-gal titers varying from less than 1% to over 25% of total serum IgE. All patients demonstrate negative sIgE for gelatin, except the patient with a genuine gelatin allergy. All patients also demonstrated a negative sIgE to recombinant milk components casein, lactalbumin and lactoglobulin. Specific IgE to eptacog was positive in 5 out of the 9 patients sensitized to alpha-gal and none of the 10 control individuals. CONCLUSION: This series confirms the importance of the alpha-gal carbohydrate moiety as a potential target for allergy to mammalian meat, dairy products and gelatin (oral, topical or parenteral) in a Flemish population of meat allergic adults. It also confirms in vitro tests to mammalian meat generally to be more reliable than mammalian meat skin tests, but that diagnosis can benefit from skin testing with cetuximab. Specific IgE to gelatin is far too insensitive to diagnose alphaa-gal related gelatin allergy. IgE binding studies indicate a potential risk of alpha-gal-containing human recombinant proteins produced in mammalians. 

Erwin, E. A., et al. (2005). “Quantitative measurement of IgE antibodies to purified allergens using streptavidin linked to a high-capacity solid phase.J Allergy Clin Immunol 115(5): 1029-1035.

BACKGROUND: Commercially available assays for IgE antibody provide results in international units per milliliter for many allergen extracts, but this is not easily achieved with purified or novel allergens. OBJECTIVE: To develop assays for IgE antibody suitable for purified or novel allergens by using a commercially available immunosorbent. METHODS: Streptavidin coupled to a high-capacity immunosorbent (CAP) was used to bind biotinylated purified allergens from mite (Der p 1 and Der p 2), cat (Fel d 1), and dog (Can f 1). Assays for IgE antibody to these allergens were performed on sera from children (asthma and control) as well as adults with atopic dermatitis. RESULTS: The results were validated by serial dilution of sera with high and low levels of IgE antibody and were quantitated in international units per milliliter by using a standard curve. Values for IgE antibody to Der p 1, Der p 2, and Fel d 1 correlated with values obtained with the allergen extracts (r2 = 0.80, 0.84, and 0.95, respectively; P < .001 in each case). Furthermore, the values for IgE antibody in sera from children with high exposure to mite and cat allergens demonstrated 10-fold higher levels of IgE antibody to Der p 1 and Der p 2 than to Fel d 1 (P < .001). CONCLUSION: The streptavidin immunosorbent technique provides a new method for quantifying IgE antibody to purified proteins. The results provide evidence about the high quantities of IgE antibody to purified inhalant allergens in patients with atopic dermatitis. In addition, the results demonstrate major differences in IgE antibodies specific for mite and cat allergens among children with high exposure to both allergens. 

Ezhuthachan, I. and B. Kaplan (2018). “A CASE OF CHRONIC URTICARIA AND ANGIOEDEMA WITH FALSE-POSITIVE ALPHA-GAL IGE.” Annals of Allergy, Asthma & Immunology 121(5): S115.

Introduction: Sensitization to galactose-alpha-1,3-galactose (alpha-gal) has been linked with delayed urticaria, angioedema and anaphylaxis to mammalian meat. We report chronic urticaria and angioedema (CUA) in a patient with false-positive alpha-gal and mammalian meat IgE.

Farooque, S., et al. (2019). “Anaphylaxis to intravenous gelatin-based solutions: a case series examining clinical features and severity.” Anaesthesia 74(2): 174-179.

Summary: The proportion of patients receiving intravenous gelatin-based colloids has increased in the last decade due to safety concerns about starch-based products. Recent research suggests hypersensitivity reactions to intravenous gelatin-based solutions occur at similar rates per administration as non-depolarising neuromuscular blocking agents such as rocuronium (6.2/100,000 administrations). There are scant published data on clinical features, diagnosis and time course of these reactions. We undertook a review of cases reported and tested at one of the UK’s largest drug allergy clinics. All patients seen in the drug allergy clinic at Imperial College Healthcare NHS Trust (London, UK) with a confirmed diagnosis of anaphylaxis to gelatin-based solutions between May 2013 and May 2018 were included. We retrospectively reviewed clinical histories, skin test results and severity of reactions in this cohort of patients. Twelve patients with anaphylaxis to gelatin-based solutions were identified (eight women, mean (SD) age 58 (17) years). Eleven reactions were severe or life-threatening with three progressing to cardiac arrest. Presentation was commonly delayed; only three patients suffered reactions within 5 min of the solution being administered with a further six presenting 10–70 min later. Where measured, tryptase was elevated in all patients (median (IQR [range]) 14.7 (8.2–23.8 [6.5–83.4]) ng.ml−1). Reactions to gelatin-based solutions are usually severe and can present with latency uncommon with other intravenous anaesthetic triggers. The use of gelatin-based solutions in the peri-operative setting should be re-assessed given the risk of severe allergy. 

Fischer, J. and C. Hilger (2017). “Alpha-Gal Syndrome: Clinical Presentation, New Concepts, and Unmet Needs.Current Treatment Options in Allergy 4(3): 303-311.

For decades, carbohydrate determinants were seen as cross-reactive structures without clinical impact. The discovery of specific IgE to the carbohydrate galactose-α-1,3-galactose, called α-gal, changed our perspective on the allergenic potential of carbohydrate determinants. α-Gal is present in tissues of non-primate mammals and, upon ingestion, can provoke a delayed form of allergic reaction in sensitized patients. We are faced with a new and unique entity of allergy with high clinical relevance in food allergy and anaphylaxis to drugs derived from mammalian products. Tick bites are assumed to constitute the primary sensitization source to α-gal. To address the complexity of this disease, the term α-gal syndrome has been suggested. 

Fischer, J., et al. (2016). “Clinical spectrum of alpha-Gal syndrome: from immediate-type to delayed immediate-type reactions to mammalian innards and meat.” Allergo J Int 25: 55-62.

The term alpha-Gal syndrome describes a novel IgE-mediated immediate-type allergy to the disaccharide galactose-alpha-1,3-galactose (alpha-Gal). Its classification as a syndrome is proposed on the basis of its clinical relevance in three different fields of allergy: food, drugs, and tick bites. The main focus of the present article is on alpha-Gal as an eliciting allergen in food allergy. It was recently shown that immediate-type allergies to pork kidney and other mammalian innards belong to the spectrum of alpha-Gal syndrome. These allergic reactions manifest as classic immediate-type allergies with a typical latency of under 1 h. The phenomenon of a delayed-onset immediate-type allergy with a latency of 3-6 h following ingestion of mammalian meat is considered pathognomonic for alpha-Gal syndrome. This clinically distinct type of presentation can be explained using the concept of food-dependent exercise-induced anaphylaxis (FDEIA). However, clinical observations and challenge testing in this constellation reveal that individual sensitivity in alpha-Gal patients is highly variable and which broadens our basic understanding of alpha-Gal syndrome. 

Fischer, J. (2015). “Food Allergy through Tick Bites a new Health Risk?” Allergologie 38(4): 194-195.           

Fischer, J. and T. Biedermann (2016). “Delayed immediate-type hypersensitivity to red meat and innards: current insights into a novel disease entity.” Journal Der Deutschen Dermatologischen Gesellschaft 14(1): 38-43.

The development of component-resolved diagnostics instead of whole extracts has brought about major advances in recent years. Particularly remarkable has been the identification of new disease entities based on the detection of IgE antibodies against specific individual components. In this context, delayed immediate-type hypersensitivity to red meat and innards plays a key role. This disorder is more common in German-speaking countries and likely still underdiagnosed. Affected individuals exhibit delayed type I reactions following the consumption of red meat or innards (responses to the latter are more rapid). All patients have IgE antibodies against the oligosaccharide galactose-alpha-1,3-galactose – alpha-gal. Those affected also have to avoid-alpha-gal-containing drugs such as cetuximab or gelatin-containing colloidal solutions. Also referred to as alpha-gal syndrome, this condition is unique in that it is characterized by type I hypersensitivity to a sugar instead of a protein. Given that many patients have a history of recurrent episodes of acute urticaria or angioedema, dermatologists should be familiar with the alpha-gal syndrome.

Fischer, J., et al. (2017). “Alpha-gal is a possible target of IgE-mediated reactivity to antivenom.” Allergy 72(5): 764-771.

Background: Antivenoms are mammalian immunoglobulins with the ability to neutralize snake venom components and to mitigate the progression of toxic effects. Immediate hypersensitivity to antivenoms often occurs during the first administration of these heterologous antibodies. A comparable clinical situation occurred after introduction of cetuximab, a chimeric mouse-human antibody, for cancer treatment. The carbohydrate epitope galactose-alpha-1,3-galactose, located on the Fab region of cetuximab, was identified as the target responsible for IgE reactivity. Objective: To investigate whether serum IgE antibodies directed to the -gal epitope are associated with hypersensitivity to equine antivenoms. Methods: Antivenoms were screened for -gal epitopes via immunoblot and in comparison with cetuximab and pork kidney by IgE reactivity assays. Basophil activation tests were used to investigate reactivity to antivenoms in samples from 20 patients with specific IgE antibodies to -gal and 10 controls. Additional IgE detection, IgE inhibition, ImmunoCAP inhibition, and skin prick tests were performed using samples from selected patients. Results: Both antivenoms and cetuximab induced positive skin prick test results in patients with sIgE to -gal. Alpha-gal epitopes were detected by immunoblotting on antivenoms. Measurements of IgE reactivity and ImmunoCAP inhibition indicated that the antivenoms contained lower -gal contents than cetuximab. Deglycosylation assays and IgE inhibition tests confirmed that IgE-mediated reactivity to antivenom is associated with -gal. Antivenoms, pork kidney, and cetuximab activated basophils from patients with IgE to -gal. Conclusion: Alpha-gal is a potential target of IgE-mediated reactivity to equine antivenom and a possible cause of the high incidence of hypersensitivity reactions during the first application of equine antivenom. 

Fischer, J., et al. (2014). “Galactose-alpha-1,3-galactose sensitization is a prerequisite for pork-kidney allergy and cofactor-related mammalian meat anaphylaxis.” Journal of Allergy and Clinical Immunology 134(3): 755-759.e751. 

Fischer, J., et al. (2017). “Prevalence of type I sensitization to alpha-gal in forest service employees and hunters.” Allergy 72(10): 1540-1547.

BACKGROUND: The production of IgE molecules specific to the carbohydrate galactose-alpha-1,3-galactose (alpha-gal) is known to induce delayed anaphylaxis against mammalian meat. Tick bites constitute the primary sensitization source, as ticks transfer alpha-gal in their saliva to a host during a bite. The reported prevalence of alpha-gal-specific IgE (alpha-gal-sIgE) positivity varies between different populations from diverse geographic regions. OBJECTIVE: To investigate the prevalence of alpha-gal-sIgE positivity in a population of forest service employees who are highly exposed to ticks in comparison with a residential population and a historic sample. METHODS: A cross-sectional study evaluating 300 forest service employees and hunters from southwest Germany was performed. Alpha-gal-sIgE levels were assessed by ImmunoCAP assay. The prevalence of alpha-gal-sIgE-positive individuals was compared with a matched cohort composed of a residential population and blood samples from forest service employees collected 15 years ago. RESULTS: In the study population, the prevalence of alpha-gal-sIgE-positive (>/=0.10 kUA /L) individuals was 35.0%, whereas the prevalence of individuals with alpha-gal-sIgE levels >/=0.35 kUA /L was 19.3%. Alpha-gal-sIgE positivity was associated with total IgE levels and recent tick bites. Mammalian meat-induced delayed anaphylaxis was found in 8.6% of the participants with alpha-gal-sIgE levels >/=0.35 kUA /L. For forest service employees and hunters, the odds ratio for alpha-gal-sIgE positivity was 2.48 compared to the residential population. The prevalence of alpha-gal-sIgE positivity in the current and historic cohort was comparable. CONCLUSION: Forest service employees and hunters compose a population with a high prevalence of alpha-gal-sIgE positivity and carry a considerable risk of red meat allergy. 

Fischer, J., et al. (2016). “Clinical spectrum of alpha-Gal syndrome: from immediate-type to delayed immediate-type reactions to mammalian innards and meat.” Allergo J Int 25: 55-62.

The term alpha-Gal syndrome describes a novel IgE-mediated immediate-type allergy to the disaccharide galactose-alpha-1,3-galactose (alpha-Gal). Its classification as a syndrome is proposed on the basis of its clinical relevance in three different fields of allergy: food, drugs, and tick bites. The main focus of the present article is on alpha-Gal as an eliciting allergen in food allergy. It was recently shown that immediate-type allergies to pork kidney and other mammalian innards belong to the spectrum of alpha-Gal syndrome. These allergic reactions manifest as classic immediate-type allergies with a typical latency of under 1 h. The phenomenon of a delayed-onset immediate-type allergy with a latency of 3-6 h following ingestion of mammalian meat is considered pathognomonic for alpha-Gal syndrome. This clinically distinct type of presentation can be explained using the concept of food-dependent exercise-induced anaphylaxis (FDEIA). However, clinical observations and challenge testing in this constellation reveal that individual sensitivity in alpha-Gal patients is highly variable and which broadens our basic understanding of alpha-Gal syndrome. 

Fischer, J. and T. Biedermann (2016). “Verzögerte Soforttyp-Allergie gegen rotes Fleisch und Innereien: aktueller Wissensstand zu einem neuen Krankheitsbild.” JDDG: Journal der Deutschen Dermatologischen Gesellschaft 14(1): 38-44.

Zusammenfassung In der In-vitro-Allergiediagnostik hat die Entwicklung hin zu Einzelkomponenten statt die Verwendung von Gesamtextrakten in den letzten Jahren große Fortschritte gebracht. Besonders eindrücklich ist die Identifizierung von neuen Krankheitsentitäten, die mit dem Nachweis von IgE-Antikörpern gegen bestimmte Einzelkomponenten einhergehen. Eine besondere Bedeutung kommt der verzögerten Soforttypallergie gegen rotes Fleisch und Innereien zu. Dieses Krankheitsbild ist im deutschsprachigen Raum häufiger als zunächst angenommen und wird wahrscheinlich immer noch unterdiagnostiziert. Betroffene Patienten reagieren verzögert mit Typ-I-Reaktionen auf rotes Fleisch oder, etwas früher, nach Verzehr von Innereien. Bei allen Patienten können IgE-Antikörper gegen das Oligosaccharid Galaktose-α-1,3-Galaktose, kurz α-Gal, nachgewiesen werden. Betroffene müssen auch α-Gal-haltige Medikamente wie Cetuximab oder Gelatine-haltige Volumenersatzmittel meiden. Das Krankheitsbild, das auch α-Gal-Syndrom genannt wird, ist insofern neuartig als es sich um eine Soforttypallergie gegen einen Zucker und nicht gegen ein Protein handelt. Da viele Patienten eine Krankengeschichte mit wiederholten Schüben einer akuten Urtikaria oder von Angioödemen aufweisen, sollte das α-Gal-Syndrom Dermatologen geläufig sein. 

Flaherty, M. G., et al. (2017). “Diagnosis of Life-Threatening Alpha-Gal Food Allergy Appears to Be Patient Driven.” Journal of Primary Care & Community Health 8(4): 345-348.

Objective: Patients exhibiting life-threatening symptoms associated with the alpha-gal food allergy (delayed urticaria or anaphylaxis due to mammalian meat) are frequently undiagnosed, causing unnecessary emergency department (ED) and health care visits, and extensive pain and suffering. This study aimed to determine the path to diagnosis experienced by alpha-gal patients. Methods: Semistructured interviews were conducted from March to June 2016 with a chronological systematic sample of approximately 10% of patients diagnosed with alpha-gal and treated by the University of North Carolina Allergy and Immunology Clinic (n = 28). Main outcome measures included average length of time between first symptoms’ appearance and diagnosis, number and type of health care encounters en route to diagnosis, and typical symptom severity. Results: Six interviewees (21%) were diagnosed within a year of experiencing symptoms, of the remaining 22, mean time to diagnosis was 7.1 years. In over 100 medical encounters (including 28 ED visits and 2 urgent care) the correct diagnosis or effective diagnosing referral occurred less than 10% of the time. Seventy-one percent (20/28) described their first symptoms as severe. More patients found the allergist specializing in this condition on their own (n = 12; 43%) than those who were formally diagnosed or received referrals (n = 10; 36%) through the health care system. Conclusions: The medical community is challenged to stay abreast of emerging and newly uncovered illnesses through traditional medical literature communication channels. Presently, patients more often discover a diagnosis of alpha-gal allergy by using information resources on their own than by presenting to the ED with anaphylaxis. 

Flaherty, M. G., et al. “Patients’ Health Information Practices and Perceptions of Provider Knowledge in the Case of the Newly Discovered Alpha-gal Food Allergy.” Journal of Patient Experience 0(0): 2374373518808310.

Background:Alpha-gal food allergy is a life-threatening, newly discovered condition with limited presence in authoritative information sources. Sufferers seeking diagnosis are likely to encounter clinicians unfamiliar with the condition.Objective:To understand information practices of individuals diagnosed with alpha-gal allergy, how they obtained diagnosis, and their perceptions of health-care providers’ awareness of the condition.Methods:Semistructured interviews with open- and closed-ended questions were completed with a chronological systematic sample of 28 adults (11% of alpha-gal clinic patients at the time) diagnosed with alpha-gal allergy and treated at University of North Carolina Allergy and Immunology Clinic.Results:The majority of patients determined they had alpha-gal allergy through nontraditional health information channels. Three-quarters of patients rated their primary care provider as having little to no knowledge. In 25 specialists’ encounters, 23 were rated as having little to no knowledge.  Conclusion:With new conditions, information is often available through informal networks before appearing in the vetted medical literature. In this study, social connections were the primary pathway to successful diagnosis. Health practitioners need to develop mechanisms to understand that process. 

Flebbe-Rehwaldt, L., et al. (2011). “An Immunoassay to Measure IgE to Galactose alpha 1,3 Galactose Associated with Red Meat Allergies.” Journal of Allergy and Clinical Immunology 127(2): AB185.

RATIONALE: IgE antibodies specific for the galactose-a-1,3 galactose (Alpha-Gal) carbohydrate found on non-primate mammalian proteins have recently been linked to delayed hypersensitivity reactions following the consumption of these proteins. IgE-mediated hypersensitivity to Alpha-Gal typically develops in adults who have had no previous sensitivity to meat. 

Fong, A., et al. (2015). “Rapid Onset Anaphylaxis to Red Meat in Three Siblings from Uganda.” Journal of Allergy and Clinical Immunology 135(2): AB206.           

Francisco Lima-Barbero, J., et al. (2019). “Clinical gamasoidosis and antibody response in two patients infested with Ornithonyssus bursa (Acari: Gamasida: Macronyssidae).” Experimental and Applied Acarology 78(4): 555-564.

Blood-feeding ectoparasites constitute a growing burden for human and animal health, and animal production worldwide. In particular, mites (Acari: Gamasida) of the genera Dermanyssus (Dermanyssidae) and Ornithonyssus (Macronyssidae) infest birds and cause gamasoidosis in humans. The tropical fowl mite, Ornithonyssus bursa, is commonly found in tropical and subtropical countries but rarely reported in Europe. In this research we characterized the first two cases in Spain of clinical gamasoidosis diagnosed in patients infested with O. bursa, and investigated the IgE, IgM and IgG antibody response to mite proteins and the carbohydrate Gal alpha 1-3Gal beta 1-(3)4GlcNAc-R (alpha-Gal) involved in the tick-bite associated alpha-Gal syndrome (AGS). The results suggested that O. bursa is establishing across Mediterranean countries, and may increase the risk for gamasoidosis. The immune antibody response to mite proteins was higher for IgM and similar for IgE and IgG antibodies between patients and non-allergic control individuals exposed to mite or tick bites. The anti-alpha-Gal antibody levels were similar between patients and controls, a result supported by the absence of this carbohydrate in mites. These results suggested that mite bites do not correlate with antibody response to acarine proteins or alpha-Gal, and are not associated with the AGS.

Fujiwara, M. and T. Araki (2019). “Immediate anaphylaxis due to beef intestine following tick bites.” Allergol Int 68(1): 127-129.

Letter to the Editor:

Red meat allergy induces delayed anaphylaxis 3e6 h after ingestion of mammalian meat. Such delayed anaphylaxis is associated with immunoglobulin E (IgE) antibodies to galactose-alpha-1,3-galactose (a-Gal), a carbohydrate epitope contained in both

mammalian meat and tick saliva.

Galili, U. (2013). “Anti-Gal: an abundant human natural antibody of multiple pathogeneses and clinical benefits.” Immunology 140(1): 1-11.

Anti-Gal is the most abundant natural antibody in humans, constituting ~ 1% of immunoglobulins. Anti-Gal is naturally produced also in apes and Old World monkeys. The ligand of anti-Gal is a carbohydrate antigen called the ‘alpha-gal epitope’ with the structure Galalpha1-3Galbeta1-4GlcNAc-R. The alpha-gal epitope is present as a major carbohydrate antigen in non-primate mammals, prosimians and New World monkeys. Anti-Gal can contributes to several immunological pathogeneses. Anti-Gal IgE produced in some individuals causes allergies to meat and to the therapeutic monoclonal antibody cetuximab, all presenting alpha-gal epitopes. Aberrant expression of the alpha-gal epitope or of antigens mimicking it in humans may result in autoimmune processes, as in Graves’ disease. alpha-Gal epitopes produced by Trypanosoma cruzi interact with anti-Gal and induce ‘autoimmune like’ inflammatory reactions in Chagas’ disease. Anti-Gal IgM and IgG further mediate rejection of xenografts expressing alpha-gal epitopes. Because of its abundance, anti-Gal may be exploited for various clinical uses. It increases immunogenicity of microbial vaccines (e.g. influenza vaccine) presenting alpha-gal epitopes by targeting them for effective uptake by antigen-presenting cells. Tumour lesions are converted into vaccines against autologous tumour-associated antigens by intra-tumoral injection of alpha-gal glycolipids, which insert into tumour cell membranes. Anti-Gal binding to alpha-gal epitopes on tumour cells targets them for uptake by antigen-presenting cells. Accelerated wound healing is achieved by application of alpha-gal nanoparticles, which bind anti-Gal, activate complement, and recruit and activate macrophages that induce tissue regeneration. This therapy may be of further significance in regeneration of internally injured tissues such as ischaemic myocardium and injured nerves.

 Galili, U. (2018). Anti-Gal IgE Mediates Allergies to Red Meat.

Immunoglobulin class (isotype) switch to anti-Gal IgE was first observed in cancer patients receiving an immunotherapy treatment by infusion of the monoclonal antibody cetuximab (anti-epidermal growth factor receptor antibody). When produced in a hybridoma, this antibody carries the α-gal epitope, which binds anti-Gal IgE antibody in these patients, inducing allergic and anaphylactic reactions. Studies on the production of anti-Gal IgE indicated that it is rare in Northern regions of the United States (<1%) but is frequently found Southern regions (>20%). The production of anti-Gal IgE was further found to correlate with allergies to red meat (beef, pork, and lamb). One of the reasons for class switch from anti-Gal IgM or IgG1 to IgE was found to be “lone star” (Amblyomm americanum) tick bites. Bites of the ticks Ixodes ricinus in Europe, Haemaphysalis longicornis in Asia and Ixodes holocyclus in Australia were found to cause similar seroconversion to anti-Gal IgE and appearance of allergic reactions to red meat. Such allergies also are found with pork kidneys because they contain very large amounts of α-gal epitopes. The substances in tick saliva which stimulate the class switch in anti-Gal B cells into IgE producing cells have not been identified yet. Prevention of allergic reactions to α-gal epitopes may be achieved by identifying patients producing anti-Gal IgE, either by the use of a lab test or by a skin test with natural or synthetic α-gal epitopes linked to lipids or to other molecules. Use of therapeutic natural or recombinant glycoproteins and monoclonal antibodies lacking α-gal epitopes will also prevent anti-Gal IgE-mediated allergic reactions. This may be achieved by enzymatic destruction of α-gal epitopes with recombinant α-galactosidase or by using eukaryotic expression systems confirmed not to include the biosynthetic pathway for synthesis of α-gal epitopes. Because such biosynthetic pathways are also present in mammary glands of nonprimate mammals, recombinant therapeutic glycoproteins produced in mammary glands and secreted in milk of transgenic farm animals should be evaluated for presence of α-gal epitopes. If present, the α-gal epitopes may be destroyed enzymatically with α-galactosidase. Alternatively, the milk may be produced in knockout mammals for the α1,3GT gene, i.e., mammals that lack the ability to synthesize the α-gal epitope. Lastly, it would be of interest to determine whether red meat from cows, pigs, or lambs engineered to lack α-gal epitopes by disruption of the α1,3GT (GGTA1) gene, can be consumed by individuals producing anti-Gal IgE without having allergic reactions to this food. Copyright © 2018 Elsevier Inc. All rights reserved.

Galvao, V. R. and M. C. Castells (2015). “Hypersensitivity to biological agents-updated diagnosis, management, and treatment.J Allergy Clin Immunol Pract 3(2): 175-185; quiz 186.

Biological agents are used in the treatment of neoplastic, autoimmune, and inflammatory diseases and their clinical applications are becoming broader. Following their increased utilization, hypersensitivity reactions linked to these drugs have become more frequent, sometimes preventing the use of first-line therapies. The clinical presentation of hypersensitivity reactions to biological agents ranges from mild cutaneous manifestations to life-threatening reactions. In this scenario, rapid desensitization is a groundbreaking procedure that enables selected patients to receive the full treatment dose in a safe way, in spite of their immediate hypersensitivity reaction to the drug, and protects them against anaphylaxis. The aim of this review is to update and discuss some of the main biological agents used in clinical practice (rituximab, trastuzumab, cetuximab, ofatumumab, tocilizumab, brentuximab, omalizumab, and tumor necrosis factor alpha inhibitor agents) and their associated hypersensitivity reactions, including clinical presentations, diagnosis, and treatment in the acute setting. In addition, novel management options with rapid desensitization are presented.

 Garcia-Menaya, J. M., et al. (2016). “Successful Desensitization to Cetuximab in a Patient With a Positive Skin Test to Cetuximab and Specific IgE to Alpha-gal.” Journal of investigational allergology & clinical immunology 26(2): 132-134.

 Ghahramani, G. K. and J. Temprano (2015). “Tick bite-related meat allergy as a cause of chronic urticaria, angioedema, and anaphylaxis in endemic areas.” Int J Dermatol 54(2): e64-e65.

 Gronlund, H., et al. (2009). The carbohydrate galactose-alpha-1,3-galactose is a major IgE-binding epitope on cat IgA. J Allergy Clin Immunol. United States. 123: 1189-1191.

 Gonzalez-Quintela, A., et al. (2014). “IgE antibodies to alpha-gal in the general adult population: relationship with tick bites, atopy, and cat ownership.” Clinical and Experimental Allergy 44(8): 1061-1068.

Letter to the Editor. Background: The carbohydrate alpha-gal epitope is present in many animal proteins, including those of red meat and animal immunoglobulins, such as cat IgA. Systemic anaphylaxis to the alpha-gal epitope has recently been described. Objective: To investigate and compare the prevalence of alpha-gal-specific (s)IgE and its associated factors in the general adult population from two separated (Northern and Southern) European regions (Denmark and Spain, respectively). Methods: Cross-sectional study of 2297 and 444 randomly selected adults from 11 municipalities in Denmark and one in Spain. Alpha-gal sIgE was assessed by ImmunoCAP to bovine thyroglobulin. Additional assessments included a panel of skin prick test (SPT) to common aeroallergens and epidemiological factors, including the history of tick bites in the Danish series. Results The prevalence of positive (>= 0.1 kU(A)/L) sIgE to alpha-gal was 5.5% and 8.1% in the Danish and Spanish series, respectively. The prevalence of sIgE >= 0.35 kU(A)/L was 1.8% and 2.2% in Denmark and Spain, respectively. Alpha-gal sIgE positivity was associated with pet ownership in both series and, particularly, cat ownership (data available in the Danish series). Alpha-gal sIgE positivity was associated with atopy (SPT positivity) in both series, although it was not associated with SPT positivity to cat or dog dander. Alpha-gal sIgE positivity was strongly associated with a history of tick bites. Conclusions and Clinical Relevance: The prevalence of alpha-gal sIgE antibodies in these general adult European populations is similarly low. The presence of alpha-gal sIgE antibodies is associated with a history of tick bites, atopy, and cat ownership. 

Gray, C. L., et al. (2016). “Midnight anaphylaxis: to red meat in patients with alpha-gal sensitisation : a recent discovery in the food allergy world and a case report from South Africa : guest review.” Current Allergy; Clinical Immunology 29(2): 102-104.

A syndrome of delayed anaphylaxis to red meat, occurring in geographical clusters; initially identified in the United States, was first described in 2009. A few years later, this enigmatic anaphylactic reaction was ascribed to IgE antibodies to galactose-alpha-1,3-galactose (alphagal), an oligosaccharide, which is a major blood group substance in non-primate mammals. It appears that the predominant source of sensitisation to alpha-gal is bites from certain ticks. Since 2009, several hundreds to thousands of cases of delayed red-meat allergy have been described worldwide, but very few reports have come out of Africa. This case series describes 2 cases of an acquired form of delayed anaphylaxis to beef and mutton in patients who were subsequently found to be highly sensitised to alpha-gal, residing in the same region.

 Guillier, A., et al. (2015). “Allergic hypersensitivity to red meat induced by tick bites: a French case report.” Eur J Dermatol 25(3): 277.

An increasing number of cases of delayed anaphylactic reactions after the consumption of red meat have been reported in the United States but few similar cases have been reported in Europe. We report herein a French observation. A 54-year-old man first developed generalized urticaria, tachycardia, abdominal pain, nausea and vomiting 4 hours after eating beef kidneys. He subsequently had several similar episodes after eating beef, lamb and pork meat. He ate chicken and fish without problems. 

Gupta, M., et al. (2018). “GALACTOSE-A-1,3-GALACTOSE SENSITIZATION AND THE A-GAL SYNDROME: CHARACTERISTICS OF SUBJECTS SEEKING EMERGENCY CARE.” Annals of Allergy, Asthma & Immunology 121(5): S11.

Introduction Galactose -α-1,3- galactose (α-Gal) is an oligosaccharide of non-primate mammals and the culprit allergen in a syndrome of delayed anaphylaxis to mammalian meat (ie, α-Gal syndrome). We sought to describe the clinical presentations of a large cohort of subjects from Central Virginia, with or without IgE to α-Gal, who presented for emergent care for allergic reactions.

Gupta, M., et al. (2019). “Description of Subjects Reporting Reactions to Mammalian Meat Who Test Negative for IgE to Galactose-3b1;-1,3-galactose (x3b1;-Gal).” Journal of Allergy and Clinical Immunology 143(2): AB256.

RATIONALE: The oligosaccharide a-Gal has recently emerged as a regionally important cause of a syndrome of IgE-mediated delayed anaphylaxis to mammalian meat; however, other allergens can also contribute to meat allergy. We sought to describe subjects who were evaluated for suspicion of mammalian meat allergy but who tested negative for IgE to a-Gal.

Haji-Ghassemi, O., et al. (2014). “Groove-type recognition of chlamydiaceae-specific lipopolysaccharide antigen by a family of antibodies possessing an unusual variable heavy chain N-linked glycan.” J Biol Chem 289(24): 16644-16661.

The structure of the antigen binding fragment of mAb S25-26, determined to 1.95 A resolution in complex with the Chlamydiaceae family-specific trisaccharide antigen Kdo(2–>8)Kdo(2–>4)Kdo (Kdo = 3-deoxy-alpha-d-manno-oct-2-ulopyranosonic acid), displays a germ-line-coded paratope that differs significantly from previously characterized Chlamydiaceae-specific mAbs despite being raised against the identical immunogen. Unlike the terminal Kdo recognition pocket that promotes cross-reactivity in S25-2-type antibodies, S25-26 and the closely related S25-23 utilize a groove composed of germ-line residues to recognize the entire trisaccharide antigen and so confer strict specificity. Interest in S25-23 was sparked by its rare high mum affinity and strict specificity for the family-specific trisaccharide antigen; however, only the related antibody S25-26 proved amenable to crystallization. The structures of three unliganded forms of S25-26 have a labile complementary-determining region H3 adjacent to significant glycosylation of the variable heavy chain on asparagine 85 in Framework Region 3. Analysis of the glycan reveals a heterogeneous mixture with a common root structure that contains an unusually high number of terminal alphaGal-Gal moieties. One of the few reported structures of glycosylated mAbs containing these epitopes is the therapeutic antibody Cetuximab; however, unlike Cetuximab, one of the unliganded structures in S25-26 shows significant order in the glycan with appropriate electron density for nine residues. The elucidation of the three-dimensional structure of an alphaGal-containing N-linked glycan on a mAb variable heavy chain has potential clinical interest, as it has been implicated in allergic response in patients receiving therapeutic antibodies. 

Hamsten, C., et al. (2013). “Identification of galactose-alpha-1,3-galactose in the gastrointestinal tract of the tick Ixodes ricinus; possible relationship with red meat allergy.” Allergy 68(4): 549-552.

Patients with IgE antibodies against the carbohydrate epitope galactose-alpha-1,3-galactose (alpha-Gal) have reported severe allergic reactions after consumption of red meat. Investigations have revealed associations between IgE to alpha-Gal and tick bites. We provide the first direct evidence that alpha-Gal is present within ticks thus potentially explaining the relationship between tick exposure and sensitization to alpha-Gal, with development of red meat allergy as a secondary phenomena. Serum from Swedish patients with delayed severe reactions to red meat was included in the study. A dose-dependent inhibition of IgE responses to alpha-Gal by the tick Ixodes ricinus is demonstrated. Furthermore, using cryostat-cut sections of I. ricinus, we show that both a monoclonal and a polyclonal antibody against alpha-Gal stains the gastrointestinal tract of the tick. The same pattern is seen when staining with patient sera IgE positive to alpha-Gal. These results confirm that the alpha-Gal epitope is present in I. ricinus and imply host exposure to alpha-Gal during a tick bite. This provides further evidence that tick bites are associated with IgE responses to alpha-Gal and red meat allergy.

 Hamsten, C., et al. (2013). “Red meat allergy in Sweden: Association with tick sensitization and B-negative blood groups.” Journal of Allergy and Clinical Immunology 132(6): 1431-1434.e1436.

Letter to the Editor: Over the past few years, allergy to mammalian meat has been identified as a new syndrome of food allergy presenting as symptoms of delayed severe allergic reactions after consumption of red meat (beef, lamb, or pork). These allergic reactions are directed against the carbohydrate galactose-a-1,3-galactose (a-Gal). In the initial studies on red meat allergy, Commins et al observed that the geographic distribution of IgE antibodies to a-Gal in the United States overlapped the region where the tick Amblyomma americanum is common, suggesting that tick bites might be relevant to these reactions. Since then, several reports have confirmed a relationship between tick bites and red meat allergy. We have recently identified a-Gal in the gastrointestinal tract of the European tick Ixodes ricinus, which provides further evidence of the tick as an initiator of red meat allergy. 

Harper, V., et al. (2019). “Allergy in frequent travelers: the alpha-gal story and the first UK case series.” Ann Allergy Asthma Immunol.

Galactose-α-(1,3)-galactose(alpha-gal) is found in most non-primate mammalian cell membranes. Humans, apes and Old World monkeys lack alpha-1,3 galactosyltransferase required for the synthesis of this carbohydrate. It is therefore highly immunogenic to humans and implicated in alpha-gal syndrome/allergy – the first non-infectious tick-borne disease in humans. Alpha-gal moiety has been found in tick salivary proteins and primary IgE sensitisation to alpha-gal is thought to occur through inoculation of saliva during a tick bite. 

Hashizume, H., et al. (2018). “Repeated Amblyomma testudinarium tick bites are associated with increased galactose-α-1,3-galactose carbohydrate IgE antibody levels: a retrospective cohort study in a single institution.” J Am Acad Dermatol 78(6): 1135-1141.e1133.

Background: Alpha-gal syndrome is a hypersensitivity reaction to red meat mediated by IgE antibody specific to galactose-α-1,3-galactose carbohydrate (alpha-gal). Amblyomma tick bites are associated with this condition, but the pathophysiology is not understood. Objective: To clarify the mechanism of development of alpha-gal syndrome after tick bites. Methods: We compared alpha-gal antibody levels between patients with and without a history of tick bites and examined histologic stainings of tick bite lesions between patients with and without detectable alpha-gal IgE antibody. Results: Patients who had ≥2 tick bites had higher levels of alpha-gal IgE antibody compared with those with only 1 tick bite or healthy individuals. On histologic investigation, greater numbers of basophils and eosinophils, but not mast cells, were observed infiltrating lesions of patients with ≥2 tick bites compared with those with 1 tick bite. Type 2 cytokine-producing T-cell infiltration was predominantly observed in such patients. Limitations: The study was conducted at a single institution in Japan. Conclusion: In Amblyomma tick bite lesions, basophils; eosinophils; and type 2, cytokine-producing T cells infiltrate the skin and alpha-gal IgE antibodies are produced. These findings provide a potential mechanistic connection between Amblyomma bites and red meat hypersensitivity. 

Hawkins, R. B., et al. (2016). “Premature Bioprosthetic Aortic Valve Degeneration Associated with Allergy to Galactose-Alpha-1,3-Galactose.” Journal of cardiac surgery 31(7): 446-448.

We present the cases of two patients with bioprosthetic aortic valves who developed an allergy to alpha-gal. Each had premature degeneration of their bioprosthesis and demonstrated rapidly increasing transvalvular gradients after development of their allergy. Each underwent successful replacement with a mechanical aortic valve within 1-2 years of symptom onset.

Hawkins, R. B. and R. K. Ghanta (2017). “MAMMALIAN MEAT ALLERGY AND ADVANCES IN BIOPROSTHETIC VALVE TECHNOLOGY Reply.” Journal of Thoracic and Cardiovascular Surgery 154(4): 1327-+.

Letters to the Editor. We read with interest the letter to the editor by Ankersmit and colleagues. ‘‘When Meat Allergy Meets Cardiac Surgery: A Driver for Humanized Bioprosthesis.’’ The University of Virginia has led the epidemiologic characterization of the mammalian meat allergy to galactose-a-1,3-galactose (a-gal). 

Herman-Giddens, M. E. and D. M. Herman-Giddens (2017). “Retrospective Case Reports of Two Central North Carolina Residents: Frequency of Tick Bites and Associated Illnesses, 2001-2014.” North Carolina Medical Journal 78(3): 156-163.

BACKGROUND: Tick bites are a source of illness and disease agents that may lead to morbidity and occasional fatalities in North Carolina. Public health interest in tick-borne illness and disease has increased due to continuing discoveries of tick-borne diseases and their increasing geographic spread and disease incidence. There are no data published on lay individuals with cumulative tick bites and associated illnesses over a period of years. METHODS We learned of a married couple living on a central North Carolina property who had used reasonable bite prevention methods, kept attached ticks after removal, and recorded dates and related illness records from 2001–2014. We obtained permission to analyze their records. Ticks were identified by an entomologist. RESULTS The male subject had a total of 219 bites from identifiable ticks comprising 213 Amblyomma americanum, 4 Dermacentor variabilis, and 2 Ixodes scapularis. He was treated for possible Rocky Mountain spotted fever once and presumed Southern Tick Associated Rash Illness once. The female subject had 193 bites comprising 168 A. americanum, 23 D. variabilis, and 2 I. scapularis. She was treated for 4 episodes of presumed Southern Tick Associated Rash Illness and one possible case of a tick-borne infection. Several years of data were missing for both subjects. LIMITATIONS This retrospective report relied on the subjects’ own records for much of the data. The experience of these individuals cannot be generalized. Diagnoses of these tick-related illnesses are inexact due to lack of tests for the Southern Tick Associated Rash Illness and cross-reactivity in tests for spotted fever rickettsiosis. CONCLUSIONS This report demonstrates that tick-associated illnesses, including episodes fitting the Center for Disease Control and Prevention’s definition of the Southern Tick Associated Rash Illness, may be more common than realized. Use of personal tick protection measures for tick bite illness and disease prevention may not be sufficiently protective. Further subject-based research on tick and disease burden on selected populations would be informative, and could aid in planning appropriate actions to mitigate the effects of tick-borne disease in North Carolina. 

Hilger, C., et al. (2018). “Alpha-Gal beyond meat.” Revue Francaise D Allergologie 58(3): 222-223.

Hilger, C., et al. (2016). “Two galactose-alpha-1,3-galactose carrying peptidases from pork kidney mediate anaphylactogenic responses in delayed meat allergy.” Allergy 71(5): 711-719.

Background: Serum IgE antibodies directed at galactose-alpha-1,3-galactose (alpha-Gal) are associated with a novel form of delayed anaphylaxis occurring upon consumption of red meat or innards. Pork kidney is known as the most potent trigger of this syndrome, but the culprit allergens have not yet been identified. The aim of this study was the identification and characterization of pork kidney proteins mediating delayed anaphylactic reactions through specific IgE to alpha-Gal. Methods: A cohort of 59 patients with specific IgE to alpha-Gal was screened by immunoblot for IgE-reactive proteins in pork kidney. Proteins were identified by peptide mass fingerprinting. Isolated proteins were assayed in ELISA and ELISA inhibition, basophil activation and skin prick test. Results: Several IgE-binding proteins of high molecular weight (100- >200 kDa) were detected in pork kidney extracts by immunoblot using patient sera and an anti-alpha-Gal antibody. Two major IgE-binding proteins were identified as porcine angiotensin-I-converting enzyme (ACE I) and aminopeptidase N (AP-N). Reactivity of patient sera and anti-alpha Gal antibody to both proteins was abolished by carbohydrate oxidation. The alpha-Gal IgE epitopes were resistant to heat denaturation. Pork kidney extract, isolated ACE I, and AP-N were able to activate patient basophils and elicit positive responses in skin prick tests. Conclusion: Two cell-membrane proteins carrying alpha-Gal epitopes were identified in pork kidney. For the first time, isolated meat proteins were shown to induce basophil activation in patients with delayed anaphylaxis to red meat providing further confirmation for the clinical relevance of these alpha-Gal-carrying proteins.

Hilger, C., et al. (2019). “Role and mechanism of galactose-alpha-1,3-galactose in the elicitation of delayed anaphylactic reactions to red meat.” Curr Allergy Asthma Rep 19(1): Article 3-Article 3.

Purpose of Review: The alpha-Gal (α-Gal) syndrome is characterized by the presence of IgE antibodies directed at the carbohydrate galactose-alpha-1,3-galactose (α-Gal). In this article, we review the presence of α-Gal in food and non-food sources; we discuss the evolutionary context of the antibody response to α-Gal and highlight immune responses to α-Gal and other carbohydrates. Recent findings: IgE antibodies have been associated with delayed allergy to red meat. In addition to food, drugs, and other products of animal origin are increasingly perceived as a risk for patients sensitized to α-Gal. The link between tick bites and anti-α-Gal IgE-antibody production that has been established first by epidemiological studies has now been confirmed in mouse models. Summary: The anti-α-Gal immune response is complex and characterized by a unique feature. IgM and IgG antibodies have been found to confer protection against pathogens whereas the IgE-response to α-Gal is detrimental and causes severe reactions upon exposure to mammalian meat and other products. 

Hodzic, A., et al. (2019). “Delayed hypersensitivity reaction to mammalian galactose-alpha-1,3-galactose (alpha-Gal) after repeated tick bites in a patient from France.” Ticks Tick Borne Dis 10(5): 1057-1059.

The alpha-Gal syndrome is a tick-associated and emerging IgE-mediated hypersensitivity reaction directed against the carbohydrate Galalpha1-3Galbeta1-(3)4GlcNAc-R (alpha-Gal) epitope after red meat intake. Herein, we describe a clinical case of a 44-year-old French patient who suffered from recurrent anaphylactic reactions after mammalian meat consumption for five years before the final diagnosis of the alpha-Gal syndrome was established in 2018. The patient also reported multiple tick bites prior to symptom onset. This unique type of allergy has increasingly been reported across the world, but it is still unknown in many European countries. Therefore, the present clinical case should increase awareness among primary care practitioners and further improve the early diagnosis of the alpha-Gal syndrome in affected individuals. 

Hodzic, A., et al. (2019). “Tick Bites Induce Anti-alpha-Gal Antibodies in Dogs.” Vaccines (Basel) 7(3).

Due to the functional inactivation of the gene encoding for the enzyme that is involved in the oligosaccharide galactose-alpha-1,3-galactose (alpha-Gal) synthesis, humans and Old-World primates are able to produce a large amount of antibodies against the glycan epitope. Apart from being involved in the hyperacute organ rejection in humans, anti-alpha-Gal antibodies have shown a protective effect against some pathogenic agents and an implication in the recently recognized tick-induced mammalian meat allergy. Conversely, non-primate mammals, including dogs, have the ability to synthetize alpha-Gal and, thus, their immune system is not expected to naturally generate the antibodies toward this self-antigen molecule. However, in the current study, we detected specific IgG, IgM, and IgE antibodies to alpha-Gal in sera of clinically healthy dogs by an indirect enzyme-linked immunosorbent assay (ELISA) for the first time. Furthermore, in a tick infestation experiment, we showed that bites of Ixodes ricinus induce the immune response to alpha-Gal in dogs and that the resulting antibodies (IgM) might be protective against Anaplasma phagocytophilum. These findings may help lead to a better understanding of the underlying mechanisms involved in mammalian meat allergy and tick-host-pathogen interactions, but they also open up the question about the possibility that dogs could develop an allergy to mammalian meat after tick bites, similar to that in humans.

 Hollander, D. H. (1995). “Beef allergy and the persian gulf syndrome.” Medical Hypotheses 45(3): 221-222.

It is suggested that the Persian Gulf Syndrome (PGS) is caused by beef allergy. In the first symptomless phase, as a result of an energetic US Army immunizing program, using sera with adjuvants to produce detectable antibody levels, the subjects not only developed immunity to the targeted substances, but also became sensitized to one or more of the other substances in the immunizing sera, and specifically to beef protein. The subjects remained healthy while in the war zone on a restricted diet essentially free from beef, but developed PGS after they came home, and were again able to obtain steaks and hamburgers.

 Homann, A., et al. (2017). “Glycans and glycan-specific IgE in clinical and molecular allergology: Sensitization, diagnostics, and clinical symptoms.” J Allergy Clin Immunol 140(2): 356-368.

Glycan-specific IgE antibodies cross-react with highly similar or even identical carbohydrate structures on a variety of different natural allergens, the so-called cross-reactive carbohydrate determinants (CCDs). In clinical practice CCDs often interfere with the specificity of in vitro allergy diagnostics, thus impairing allergy therapy decisions for individual patients. Strikingly, these IgE antibodies directed against CCDs often do not cause clinically relevant allergy symptoms. On the other hand, the IgE-binding glycan allergen galactose-alpha-(1,3)-galactose (alpha-Gal) is associated with IgE-mediated delayed anaphylaxis in meat allergy. The reason for this discrepancy is not known. The discovery of alpha-Gal stimulated new discussions and investigations regarding the relevance of anti-glycan IgE for allergic diseases. In this review the effect of glycans and glycan-specific IgE on sensitization to allergens and allergy diagnosis is described. Because parasite infections elicit a similar immunologic environment as allergic diseases, the association of glycan-specific antibodies against parasite glycoproteins with glycan structures on allergens is discussed. 

Honda, Y., et al. (2015). “Delayed Anaphylaxis after Eating Beef Likely Due to IgE Antibody Specific for Galactose-α-1, 3-galactose.” Nishi Nihon Hifuka 77: 453-455.

A 67-year-old Japanese man experienced 4 episodes of delayed anaphylaxis between March, 2012 and October, 2013. Delayed anaphylactic attacks occurred several hours after eating egg-bearing flatfish or beef. The skin prick allergen test was positive for beef, pork, and cow&apos;s milk. Moreover, CAP-RAST testing revealed the presence of IgE antibodies specific to beef, pork, cow&apos;s milk, and dandruff of cat and dog. Western blotting analysis using the patient&apos;s sera showed a putative IgE with high affinity for the 50-kDa protein of the mouse chimeric antibody, cetuximab, which contains the oligosaccharide galactose-α-1, 3-galactose (α-gal), a common epitope for the delayed anaphylaxis response to beef meat. Since the patient lived in an area where Japanese spotted fever, for which a tick bites are a cause, is endemic, he might have a history of unnoticed tick bites that sensitized him to α-gal. Furthermore, we speculate that some medicines including aspirin might lower the threshold for exposure to this allergen above which anaphylactic symptoms occur. 

Hong, D. I., et al. (2012). “Allergy to monoclonal antibodies: cutting-edge desensitization methods for cutting-edge therapies.” Expert Rev Clin Immunol 8(1): 43-52; quiz 53-44.

Monoclonal antibodies are important therapeutic tools, but their usefulness is limited in patients who experience acute infusion reactions, most of which are consistent with type I hypersensitivity reactions including anaphylaxis. Patients who experience acute infusion reactions face the prospect of stopping treatment or switching to an alternative, and potentially more toxic or inferior treatment. Another option that overcomes the treatment hurdle of these reactions is rapid desensitization, a procedure in which the offending agent is re-administered in a step-wise, highly controlled fashion. While the risk of reactions is not completely eliminated, desensitization has proven to be a highly effective re-administration strategy for most patients who otherwise would not be able to tolerate their monoclonal antibody therapy owing to drug-induced anaphylaxis. This article reviews the current literature on desensitization and other readministration protocols to monoclonal antibodies with an emphasis on four agents: rituximab, infliximab, cetuximab and trastuzumab. 

Hopps, S., et al. (2013). “Cetuximab hypersensitivity infusion reactions: Incidence and risk factors.” J Oncol Pharm Pract 19(3): 222-227.

INTRODUCTION: Cetuximab is a chimeric mouse-human (30:70) IgG1 monoclonal antibody that competitively inhibits the binding of epidermal growth factor. Cetuximab is generally well tolerated; however, hypersensitivity infusion reactions have been reported. The incidence at the University of Oklahoma was currently unknown, though anecdotally high. The purpose of this study was to determine the incidence of severe HIRs and secondarily to determine risk factors for cetuximab-induced hypersensitivity infusion reactions. METHODS AND RESULTS: A retrospective chart review was conducted and included all patients that received cetuximab from 2005 to 2010 at the outpatient clinics of the Oklahoma University Health Sciences Center. A total of 153 patients were included in the analysis. The overall incidence proportion of severe hypersensitivity infusion reactions was 12.4%. Male patients had an increased incidence of severe hypersensitivity infusion reactions compared to female patients (20.6% vs. 5%, p = 0.0036). Current smokers had an increased incidence of severe hypersensitivity infusion reactions of 23.6% when compared to never smokers or former smokers, p = 0.0012. Cervical cancer had a significantly decreased risk of severe hypersensitivity infusion reactions when compared to other tumor types (5.3% vs. 16.7%, p = 0.0387). Multivariate analysis identified risk factors associated with severe HIRs to be: male gender, RR = 3.9, p = 0.01 and current smokers, RR = 3.98, p = 0.0048. CONCLUSION: Patients at the University of Oklahoma had an increased incidence of severe hypersensitivity infusion reactions when compared to the national average. Male patients and current smokers were found to be at increased risk for severe hypersensitivity infusion reactions in our study. Further investigation is warranted. 

Hosen, J., et al. (2008). “IgE antibodies to helminths and the cross-reactive oligosaccharide galactose-alpha-1,3-galactose (alphaGal) among children in a village in Africa.” Journal of Allergy and Clinical Immunology 121(2): S140-S140.

Recent reports have identified IgE antibodies to alphaGal as a cause of anaphylactic reactions to the mAb cetuximab. These IgE antibodies cross-react with proteins from cat, dog, beef and pork. Previous reports showed that children in Africa had IgE ab to cat allergens despite negative skin tests and no exposure to cats. We report here the connection between IgE ab to alphaGal, cat proteins and helminth parasites. 

Huai, G., et al. (2016). “Characteristics of α-Gal epitope, anti-Gal antibody, α1,3 galactosyltransferase and its clinical exploitation (Review).” International journal of molecular medicine 37(1): 11-20.

The α-Gal epitope (Galα1,3Galα1,4GlcNAc‑R) is ubiquitously presented in non-primate mammals, marsupials and New World Monkeys, but it is absent in humans, apes and Old World monkeys. However, the anti-Gal antibody (~1% of immunoglobulins) is naturally generated in human, and is found as the immunoglobulin G (IgG), IgM and IgA isotypes. Owing to the specific binding of the anti‑Gal antibody with the α‑Gal epitope, humans have a distinct anti‑α‑gal reactivity, which is responsible for hyperacute rejection of organs transplanted from α‑gal donors. In addition, the α1,3 galactosyltransferases (α1,3GT) can catalyze the synthesis of the α‑Gal epitope. Therefore, the α1,3GT gene, which encodes the α1,3GT, is developed profoundly. The distributions of the α‑Gal epitope and anti‑Gal antibody, and the activation of α1,3GT, reveal that the enzyme of α1,3GT in ancestral primates is ineffective. Comparison of the nucleotide sequence of the human α1,3‑GT pseudogene to the corresponding different species sequence, and according to the evolutionary tree of different species, the results of evolutionary inactivation of the α1,3GT gene in ancestral primates attribute to the mutations under a stronger selective pressure. However, on the basis of the structure, the mechanism and the specificity of the α‑Gal epitope and anti‑Gal antibody, they can be applied to clinical exploitation. Knocking out the α1,3GT gene will eliminate the xenoantigen, Gal(α1,3)Gal, so that the transplantation of α1,3GT gene knockout pig organ into human becomes a potential clinically acceptable treatment for solving the problem of organ shortage. By contrast, the α‑Gal epitope expressed through the application of chemical, biochemical and genetic engineering can be exploited for the clinical use. Targeting anti‑Gal‑mediated autologous tumor vaccines, which express α‑Gal epitope to antigen‑presenting cells, would increase their immunogenicity and elicit an immune response, which will be potent enough to eradicate the residual tumor cells. For tumor vaccines, the way of increasing immunogenicity of certain viral vaccines, including flu vaccines and human immunodeficiency virus vaccines, can also be used in the elderly. Recently, α‑Gal epitope nanoparticles have been applied to accelerate wound healing and further directions on regeneration of internally injured tissues. 

Huvier, A. D., et al. (2018). “Recurring acute urticaria and abdominal pain: Consider a diagnosis of alpha-galactose anaphylaxis.” Ann Dermatol Venereol 145(11): 690-693.

Background. – Food urticaria is common and generally benign, and it may be of viral or idiopathic aetiology. A food origin of the allergy is frequently sought but rarely found. Mammalian meat anaphylaxis, or alpha-galactose (alpha-gal) anaphylaxis, is a rare and recently discovered entity. Patients and methods. – Herein, we report a case of alpha-galactose (alpha-gal) anaphylaxis in a 60-year-old woman presenting four episodes of acute urticaria with signs of anaphylaxis occurring a few hours after meals containing mammalian meat (beef meat, pork meat and offal). The diagnosis was confirmed by a positive gelatine prick-test and the presence of alpha-gal IgE. Discussion. – In the event of acute urticaria associated with systemic symptoms, in particular gastrointestinal signs, allergy to alpha-galactose should be considered. (C) 2018 Elsevier Masson SAS. All rights reserved.

Iglesia, E. G. A., et al. (2019). “Regional and Temporal Patterns of Alpha-Gal Allergy Using Google Trends.” Journal of Allergy and Clinical Immunology 143(2): AB161.

RATIONALE: An increasing number of cases of alpha-gal allergy (AGA) have been reported in the U.S. and in several parts of the world over the past decade. In the U.S., cases of AGA are most often reported in the southeastern region, overlapping with the distribution of the Lone Star tick. However, epidemiological and time trend studies onAGAare lacking. METHODS: Using Google Trends (GT), a web-based surveillance tool that captures data on search engine terms, time and geographic trends were explored from January 2004 – August 2018. 

Inam, M., et al. (2016). “Prevalence of sensitization to food allergens and challenge proven food allergy in patients visiting allergy centers in Rawalpindi and Islamabad, Pakistan.” SpringerPlus 5(1): 1330.

In this study, we estimated the prevalence of food allergy in the adult allergic patients of Rawalpindi and Islamabad , Pakistan, based on self-report, skin prick test (SPT) and oral food challenge test (OFC). SPT was used for the estimation of sensitization to wheat, egg, milk, beef, chicken, mutton, fish, corn, lentils, rice, soya, peanut and banana. Among 689 patients, 39.19 % showed sensitivity to one or more foods, where, sensitization to wheat (156; 22.6 %) was highest, followed by egg (148; 21.48 %) and milk (138; 20.03 %). Sensitization to various proteins ranged between 15.53–15.97 %, while lentils, corn, rice, soya and peanut sensitization was 15.4, 16, 12.5, 12 and 11.5 % respectively. Only 7.1 % patients were SPT positive for banana allergen. SPT was performed in patients with self-reported food allergy (341/689) and also with no self-reported history of food allergy (348/689). SPT results were positive in 69.8 % of the self-report group, whereas, in the patients with no self-reported food allergy 9.2 % were found sensitized to one or more tested food allergens. 101 patients were recruited for OFC, 61 % of these were confirmed of food allergy. The prevalence of food allergy in the study population was 9 %. Food specific OFC results show that wheat allergy is affecting 1.6 % (95 % CI 0.9–2.84 %) of the total allergy patients, followed by egg allergy 1.31 % (95 % CI 0.70–2.47 %). Furthermore, corn allergy, rice allergy and peanut allergy were 1.02, 0.87 and 0.73 %, respectively. In conclusion, wheat allergy is the most prevalent, followed by egg, chicken, beef and fish allergy, respectively. 

Iwamoto, T., et al. (2016). “A novel approach to predict cetuximab-induced hypersensitivity reaction: detection of drug-specific IgE on basophils.” Cancer Med 5(6): 1004-1012.

Cetuximab is remarkable for the relatively high rate and severity of hypersensitivity reactions (HR) being reported in the literature. Screening for cetuximab-specific IgE in serum via immunoassay has been found to be useful in preventing HR; however, these tests are known to have a low positive predictive rate. In an attempt to remedy this, we evaluated the interaction between cetuximab and IgE on basophils for predicting severe cetuximab-induced HR. Twelve head and neck cancer patients were enrolled in this single-institution study: four with a history of cetuximab-induced HR and eight with no such history. Cetuximab-specific and galactose-alpha-1,3-galactose (alpha-gal) specific IgEs in serum were measured in vitro using an enzyme-linked immunosorbent assay (ELISA). IgE-cetuximab binding on basophils was also analyzed to evaluate the decrease in cetuximab molecules on basophils after dissociation of IgE from FcepsilonRI. The positive predictive value associated with the presence of cetuximab- or alpha-gal-specific IgE in serum was found to be only 0.67, whereas the negative predictive value was 1.00. On the other hand, in all four patients who developed HR, the cetuximab molecules on basophils were decreased significantly due to the dissociation of IgE from basophils (P < 0.05). However, this was not the case in patients who did not develop HR. In conclusion, our results strongly imply that the IgE-cetuximab interaction on basophils may be key to developing improved methods for predicting severe cetuximab-induced HR. 

Iweala, O. I., et al. (2019). “Epigenetic Dysfunction in T cells is Associated with Enhanced Type-2 and Blunted Regulatory Immunity.” Journal of Allergy and Clinical Immunology 143(2): AB205.

Epigenetic alterations partly mediated by histone H3 lysine 27 (H3K27) demethylase UTX are critical for humoral and cellular immunity against chronic viral infections. Whether UTX-modulated epigenetic changes impact type 2 immunity in allergic sensitization and type 2/regulatory immunity associated with chronic helminth infection is unclear.          

Iweala, O., et al. (2017). “Serum IgE Specific for Alpha-Gal Sugar Moiety Can Bind Glycolipid.” Journal of Allergy and Clinical Immunology 139(2): AB88.

RATIONALE: Alpha-gal meat allergy, characterized by anaphylaxis to mammalian meats like beef, pork or lamb three or more hours after consumption, has been associated with specific IgE (sIgE) antibodies against the sugar moiety galactose-alpha-1,3-galactose (alpha-gal) lining the surface of non-primate mammalian tissues. Meat fat content appears to impact reaction severity in alpha-gal-allergic patients. 

Iweala, O. I. and A. W. Burks (2016). “Food Allergy: Our Evolving Understanding of Its Pathogenesis, Prevention, and Treatment.” Curr Allergy Asthma Rep 16(5).

Food allergy is defined as an IgE-mediated hypersensitivity response to ingested food with allergic symptoms ranging from urticaria to life-threatening anaphylaxis. Food allergy is thought to develop because of (1) failed induction of tolerance upon initial exposure to food antigen or (2) breakdown of established tolerance to food antigen. We review current understanding of the pathogenesis, epidemiology, and natural history of food allergy, including the unconventional IgE-mediated food allergy to mammalian meat known as alpha-gal food allergy. We highlight emerging data on food allergy treatment and prevention, emphasizing the growing appeal of manipulating the gut microenvironment using probiotics and helminth products to blunt systemic allergic responses to food. 

Iweala, O. I., et al. (2018). “A Role for CD1d-restricted Invariant Natural Killer T Cells and Glycolipids in Alpha-Gal Allergy.” Journal of Allergy and Clinical Immunology 141(2): AB288.

RATIONALE: Alpha-gal meat allergy is associated with IgE-mediated sensitization to galactose-alpha-1,3-galactose (alpha-gal), a carbohydrate moiety found in non-primate mammals. Lipid content of consumed meat drives reaction severity, suggesting that mammalian meat-derived glycolipids containing alpha-gal may act as immunogens. Immunogenic lipids complexed to CD1d antigen-presenting molecules activate iNKT cells. We have shown that alpha-gal-specific IgE binds mammalian glycosphingolipids complexed with CD1d.

Jackson, W. L. (2018). “Mammalian meat allergy following a tick bite: a case report.” Oxf Med Case Reports 2018(2): omx098.

The alpha-gal allergy is an emerging IgE-mediated reaction against the galactose-alpha-1,3-galactose carbohydrate found in mammalian meats. Patients with this condition will develop anaphylactic symptoms 3-6 h after the ingestion of mammalian meat food products such as beef, pork or lamb. The prevalence of this allergy is drastically increasing and severe reactions including anaphylactic shock have been reported, yet many patients experience symptoms for years before a diagnosis is made. We describe the presentation, diagnosis and management of a patient with the alpha-gal allergy in attempt to improve early recognition and management of patients with this condition. 

Jacquenet, S. (2016). “Alpha-gal, from invertebrate to vertebrate.Revue Francaise D Allergologie 56(3): 257-259.           

Jacquenet, S., et al. (2009). “Mammalian meat-induced anaphylaxis: clinical relevance of anti-galactose-alpha-1,3-galactose IgE confirmed by means of skin tests to cetuximab.J Allergy Clin Immunol 124(3): 603-605.

Letter to the Editor.

 James, H., et al. (2013). “Pediatric Alpha-Gal: IgE Antibodies to Galactose-Alpha-1,3-Galactose in Children Presenting with Delayed Urticaria or Anaphylaxis.” Journal of Allergy and Clinical Immunology 131(2): AB217.           

James, H. R., et al. (2011). “Further Evidence For Tick Bites As A Cause Of The IgE Responses To Alpha-gal That Underlie A Major Increased In Delayed Anaphylaxis To Meat.” Journal of Allergy and Clinical Immunology 127(2): AB243-AB243.

RATIONALE: Delayed onset of urticaria or anaphylaxis after eating meat in patients who have IgE to alpha-gal is now a common presenting cause of food allergy in Virginia. The evidence that ticks are related to this IgE response comes from histories of bites, absence of this ab in areas where tick bites are rare, and from following IgE responses after tick bites. METHODS: Detailed histories and assays for IgE were compared in a population of anaphylaxis, asthma, and clinic controls. 

James, H. R., et al. (2012). “Parasite-related IgE Antibodies, Including IgE to Galactose-alpha-1,3-galactose, in Sera from Virginia and Ecuador.” Journal of Allergy and Clinical Immunology 129(2): AB82-AB82.

IgE antibodies to galactose-alpha-1,3-galactose (alpha-gal) have become increasingly prevalent in the southeastern United States. These antibodies have recently been linked to bites from the tick Amblyomma americanum, but the possibility of a role for other parasites remains. 

James, H., et al. (2010). “Tick Bites From Amblyomma Americanum As A Major Cause Of Ige Antibodies Specific To Galactose-alpha-1,3-galactose.” Journal of Allergy and Clinical Immunology 125(2): AB28-AB28.

The high prevalence of IgE to galactose-a-1,3-galactose (alpha-gal) in Virginia, North Carolina, Tennessee, Arkansas, Oklahoma, and Missouri correlates with an area where tick bites are common. Using a modified ImmunoCAP assay, we measured IgE to biotinylated proteins from two tick species, A. americanum and D. variabilis. Sera were obtained from three subjects who had experienced extensive tick bites, 100 subjects who presented with delayed anaphylaxis to red meat and were found to have IgE to alpha-gal, and from 60 children living in rural Ecuador. Ticks for extracts were obtained from OSU Tick Rearing Facility. 

Jappe, U. (2012). “Update on meat allergy. alpha-Gal: a new epitope, a new entity?” Hautarzt 63(4): 299-306.

The association between the carbohydrate galactose-[alpha]-1,3-galactose (alpha-Gal) and anaphylaxis was first documented after severe hypersensitivity reactions to cetuximab, a chimeric mouse-human IgG1 monoclonal antibody approved for targeted therapy of carcinomas of colon, as well as of the head and neck region. alpha-Gal is a ubiquitous glycan moiety expressed on cells and tissue of non-primate mammals. Since this epitope is not expressed in humans, it is very immunogenic for them. alpha-Gal is located on the Fab portion of cetuximab and thus on the murine part of the chimera. The anaphylactic reactions to the antibody were mediated by IgE specific for alpha-Gal. Anti-alpha-Gal-IgE were first detected in sera of patients from the southeastern U.S. and reacted with a wide range of mammalian allergens. The geographic distribution prompted investigations of sensitization routes apart from the ingestion of red meat, such as tick bites und parasitic infections. Anti-alpha-Gal-IgE seems to be of clinical relevance for allergy to red meat and for the pork-cat syndrome. It is also associated with a novel form of delayed anaphylaxis, which appears more than 3 hours following the ingestion of red meat (beef, pork and lamb), a phenomenon which is still to be elucidated. For most of these patients conventional skin prick tests with commercial reagents proved insufficient for diagnosis. 

Jappe, U. (2014). “Anaphylaxis caused by hidden food allergens: the alpha-Gal syndrome.” Allergologie 37(7): 265-274.

Hidden allergens may be defined as allergen deliberately added to food but unlabeled in the ingredient list or present due to unintentional cross contact during food manufacturing itself and, therefore, not recognizable for the consumer. An allergen present in food may also be considered as “hidden” if causing reactions in a patient because of so far unknown cross-reactivity. A novel food allergen is one that has been introduced to human diet for the first time, e.g., kiwi at the beginning of the 1980s, and to which patients develop sensitivity after exposure. A new allergen also can be an IgE-binding molecule that has never been described and identified before in a particular species as allergen source, a-Gal is an ubiquitous glycan moiety expressed on cells and tissue of nonprimate mammals, but not in humans, which is the reason for its strong immunogenicity for the latter. a-Gal is located on the Fab portion of the monoclonal treatment antibody Cetuximab. In 2008, it has been identified as being responsible for severe, sometimes fatal anaphylactic reactions to Cetuximab. Anti-alpha-Gal-IgE also seem to be responsible for severe allergy to red meat, innards and to gelatine, however, fatal reactions have not been reported so far. Anti-a-Gal-IgE are associated with a novel food allergy, a delayed anaphylaxis (more than 3 hours) following the ingestion of red meat and innards, a phenomenon which is still to be elucidated. An additional characteristic feature is that for most of these patients conventional skin prick tests with commercial reagents proved insufficient for diagnosis. Anti-a-Gal-IgE were first detected in sera from patients in an area of the southeastern U.S. and bound to a wide range of mammalian allergens. The [GRAPHICS] geographic distribution prompted investigations of sensitization routes apart from the ingestion of red meat, like tick bites und parasitic infections. 

Jappe, U. and A. Kuehn (2016). “Diagnostically relevant single allergens from plant and animal source foods – an update.” Allergologie 39(9): 425-438.

Over the past years, considerable progress has been made in the field of molecular allergology. Some new single allergens have been isolated from various sources of food allergens, and some of these single allergens are already available for routine allergy diagnosis, which results in a higher sensitivity and specificity of IgE determination. Furthermore, the underlying cause of a new disease entity delayed-type anaphylaxis has been found: galactose alpha-1,3-galactose, a disaccharide of mammalian meat. Now, meat allergy can be confirmed more frequently and does not have to be classified as idiopathic anaphylaxis so often. In addition, completely new allergens could be isolated: hydrophobic and lipophilic peanut allergens, the defensins and oleosins. With this, it might be possible to close a diagnostic gap, i.e., the allergens of the lipid fractions of oilseeds. 

Jappe, U., et al. (2018). “Meat allergy associated with galactosyl–(1,3)-galactose (-Gal)Closing diagnostic gaps by anti–Gal IgE immune profiling.” Allergy 73(1): 93-105.

Background: Glycoproteins and glycolipids of some mammalian species contain the disaccharide galactosyl–(1,3)-galactose (-Gal). It is known that -Gal is immunogenic in humans and causes glycan-specific IgG and also IgE responses with clinical relevance. -Gal is part of the IgE-reactive monoclonal therapeutic antibody cetuximab (CTX) and is associated with delayed anaphylaxis to red meat. In this study, different -Gal-containing analytes are examined in singleplex and multiplex assays to resolve individual sensitization patterns with IgE against -Gal. Methods: Three serum groups, -Gal-associated meat allergy (MA) patients, idiopathic anaphylaxis (IA) patients with suspected MA, and non-meat-allergic healthy control individuals (HC), were analyzed via singleplex allergy diagnostics and a newly established immunoblot diagnostic system. The new dot blot detection system resolved individual IgE sensitization profiles for -Gal-containing analytes CTX, bovine thyroglobulin (Bos d TG), and human serum albumin (HSA)-conjugated -Gal. Results: Singleplex allergy diagnostics using the -Gal analytes CTX and Bos d TG confirms the history of MA patients in 91% and 88% of the cases, respectively. A novel dot blot-based assay system for the detection of IgE against -Gal reveals individual IgE sensitization profiles for -Gal-containing analytes. An -Gal-associated IgE cross-reactivity profile (IgE against CTX, Bos d TG, and HSA–Gal) was identified, which is associated with MA. Conclusions: Detection of individual sensitization patterns with different -Gal-containing analytes provides the basis for an individual allergy diagnosis for -Gal-sensitized patients. Higher amounts of -Gal in pork and beef innards compared to muscle meat as indicated by a higher staining intensity are a plausible explanation for the difference in allergic symptom severity. 

Johansen, K. L. and K. Rasmussen (2014). “[IgE-induced anaphylactic reaction after eating lamb meat].” Ugeskr Laeger 176(35).

This article presents the case of a 54-year-old male, who was admitted to hospital after suffering a severe anaphylactic reaction after tasting a spoonful of chili con carne and four months later after eating lamb meat. Galactose-alpha-1,3-galactose allergy was suspected and the subsequent blood test showed highly elevated specific IgE levels. Delayed allergy to meat is a relatively new type of allergy and the delayed onset of allergic symptoms poses a diagnostic challenge to the physician. This type of allergy should be considered when there has been no obvious allergen exposition prior to the allergic reaction. 

Josko, D. (2014). “Anaphylactic Reaction After Beef Consumption Due to the Development of IgE Antibodies Against the Carbohydrate Galactose-Alpha-1,3-Galactos.” American Journal of Clinical Pathology 142(suppl_1): A027-A027.

A 52-year old female was seen in the emergency department with symptoms of anaphylaxis. History revealed that shortly after eating dinner she developed hives, which quickly evolved into wheezing, throat tightness, and difficulty breathing. Her symptoms intensified even after taking Benadryl. Once in the emergency department she was treated with epinephrine as well as 125 mg of Solu-Medrol. She was later admitted for observation. The patient stated she had several visits to the emergency department in the past few years with hives possibly due to food allergies but not this severe. Subsequent laboratory testing revealed elevated levels of IgE specific antibodies to the beef allergen. An alpha-gal panel was performed for beef, lamb/mutton, and pork IgE levels which were all elevated. The patient was advised to avoid eating these types of meats in the future. Individuals with IgE antibodies to galactose-alpha-1,3galactose (alpha-gal) are at risk for delayed anaphylaxis, angioedema, or urticaria following consumption of these products. The patient lives in a rural area in New Jersey and has been bitten numerous times by ticks. Recently, several cases in Virginia have been reported of hives and difficulty breathing in 45 children aged 4–17 after ingesting red meat. All described being bitten by a tick within the past year. It is believed the Lone Star tick, which is endemic in the southern and eastern United States, carries the carbohydrate alpha-gal in its saliva and once bitten, the patient develops antibodies against this sugar, which can result in life-threatening anaphylaxis. Although there is currently no treatment, individuals who experience symptoms such as hives and difficulty breathing after ingesting meat should be tested for alpha-gal sensitivity and if positive, should avoid consumption of mammalian meat in the future.

Kageyama, R., et al. (2019). “The contribution made by skin-infiltrating basophils to the development of alpha-gal syndrome.” Allergy 74(9): 1805-1807.

Kaloga, M., et al. (2016). “Allergy to Red Meat: A Diagnosis Made by the Patient and Confirmed by an Assay for IgE Antibodies Specific for Alpha-1,3-Galactose.” Case Reports in Dermatology 8(1): 10-13.

We report the first case of allergy to red meat observed in Ivory Coast. A 49-year-old male presented with pruritus. The diagnosis of allergy to red meat was confirmed by an assay for IgE antibodies specific for alpha-1,3 galactose. Interestingly, the disease was considered a spell to the patient who was suspected of being a sorcerer by the community. 

Kaman, K. and D. Robertson (2018). “ALPHA-GAL ALLERGY; MORE THAN MEAT?” Annals of Allergy, Asthma & Immunology 121(5): S115.

Introduction: Galactose-alpha-1,3-galactose (alpha-gal) is a carbohydrate moiety found on non-primate mammalian cell membranes. Over the last 10 years, delayed allergic reactions caused by IgE to alpha-gal has drastically changed the way we think about food allergy. Patients with alpha gal allergy classically present with delayed allergic reactions, including anaphylaxis, hours after consuming mammalian meats. Alpha-gal has also been found to be present in other mammalian products via immunoblot, primarily in dairy that contains higher fat content, but the vast majority of patients tolerate other mammalian byproducts (e.g. milk) with no issue. We present a case of delayed urticaria in a patient with known alpha-gal allergy associated with whey consumption. 

Kaplan, A. C. and M. P. Carson (2018). “Diagnosing Meat Allergy After Tick Bite Without Delay.” J Am Board Fam Med 31(4): 650-652.

Galactose-alpha-1, 3 galactose (alpha-gal) is a carbohydrate found in mammalian meat. In 2007, it was implicated as a cause of severe hypersensitivity reactions when a study found elevated levels of antibodies directed against this oligosaccharide among patients treated with cetuximab, a monoclonal antibody that contained an alpha -gal epitope. The majority of these cases were reported in the Southeast United States in a distribution similar to that of Rocky Mountain spotted fever and ehrlichiosis, and that geographic association led researchers to the conclusion that a bite from the Lone Star tick can induce this antibody. Here, we present a case of delayed urticarial angioedema due to a mammalian meat allergy caused by alpha-gal immunoglobulin E acquired after tick exposures, and the knowledge and patient education required to prevent recurrences. It is estimated that approximately 0.5% to 1.0% of the general population will experience an episode of angioedema in their lifetime, and this case demonstrates why clinicians in areas that are inhabited by ticks, particularly the Lone Star species, should include this cause in their differential. 

Keating, K., et al. (2014). “Incidence of cetuximab-related infusion reactions in oncology patients treated at the University of North Carolina Cancer Hospital.” Journal of Oncology Pharmacy Practice 20(6): 409-416.

Purpose: The primary purpose of this study was to determine the rate of infusion reactions to cetuximab in oncology patients treated at the University of North Carolina Cancer Hospital. Secondarily, we sought to evaluate predictors of grade 3–4 hypersensitivity, including geography.MethodsData were collected by retrospective chart review for patients treated with cetuximab at the University of North Carolina Cancer Hospital between 15 November 2006 and 31 December 2010. Data were analyzed for occurrence of hypersensitivity reaction in 125 patients with various cancer types.ResultsOf the 125 subjects, 31 (24.8%) experienced an infusion reaction of any grade. Of 125, 18 (14.4%) experienced a grade 3 or 4 reaction. The odds ratio for patients with an allergy history having a grade 3 or 4 reaction was 2.57 (95% CI 0.93 to 7.09, p = 0.07). Pretreatment with steroids was associated with absence of grade 3 or 4 reaction with an odds ratio of 0.21 (95% CI 0.05 to 0.83, p = 0.04). Mapping of reaction rates by county revealed higher rates in some of the more rural counties of North Carolina, however, statistical power was lacking.ConclusionsRates of hypersensitivity reaction at UNC are similar to rates seen in other areas of the southeastern United States and higher than in other regions of the United States and Europe. Rates of both hypersensitivity reactions and grade 3 to 4 hypersensitivity reactions have not substantially changed over time. Geography, allergy history, and perhaps smoking or cancer type may help predict who will react to cetuximab. Steroids should be strongly considered as premedication in addition to diphenhydramine. 

Kelly, E. A., et al. (2011). “IgE Antibodies To The Oligosaccharide Galactose-Alpha-1,3-Galactose (Alpha-Gal) Cross-React With Cat Allergens But Are Not Associated With Asthma.” American Journal of Respiratory and Critical Care Medicine 183. 

Kelly, L. A., et al. (2011). “Delayed Anaphylactic Reactions to Mammalian Meat are not Associated with an Increased Prevalence of Asthma.” Journal of Allergy and Clinical Immunology 127(2): AB4.

In contrast to most food allergic patients, relatively few patients with delayed anaphylaxis after ingestion of mammalian meat and IgE specific for galactose-alpha-1,3-galactose (a-gal) suffer from atopic diseases. While these individuals frequently have IgE to cat, only a minority report symptoms of asthma. 

Kelly, L. A., et al. (2012). “Ectoparasite Induced Elevations of alpha-gal Specific IgE are Associated with Increased Total Serum IgE and Cat Sensitization but not with Asthma.” Journal of Allergy and Clinical Immunology 129(2): AB7. 

Kelly, L. A., et al. (2012). “The indoor air and asthma: the role of cat allergens.” Curr Opin Pulm Med 18(1): 29-34.

PURPOSE OF REVIEW: The objective is to discuss recent progress in our understanding of the role of the indoor environment in asthma, focusing on the special role of cat allergens. RECENT FINDINGS: Sensitization to Fel d 1 is the dominant event in inhalant responses to cat; however, there are also IgE responses to the lipocalin (Fel d 4), to cat albumin (Fel d 2), and to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) on cat IgA (Fel d 5w) and other molecules. The dose response and routes of sensitization for these allergens are now thought to be diverse. It is important to remember that exposure outside a house with a cat is sufficient to cause sensitization. Furthermore, the only solid evidence about a role in asthma relates to Fel d 1. Recently, it has been shown that tolerance associated with early exposure to cats can persist to age 18 and that IgE to alpha-gal (on cat IgA) is not related to asthma. In addition, a recent study of anti-IgE reinforces the evidence that IgE antibodies to indoor allergens make a major contribution to asthma severity. SUMMARY: Exposure to Fel d 1 in a home with a cat is far higher than the levels necessary to induce an allergic (IgE antibody) response. In keeping with that, children may develop tolerance, which can be long-lived. In addition, there is increasing evidence that IgE antibodies to an inhalant allergen, such as Fel d 1, dust mite, or cockroach, are causally related to lung inflammation and asthma. 

Kennedy, J. L., et al. (2013). “Galactose-alpha-1,3-galactose and Delayed Anaphylaxis, Angioedema, and Urticaria in Children.” Pediatrics 131(5): E1545-E1552.

BACKGROUND AND OBJECTIVE: Despite a thorough history and comprehensive testing, many children who present with recurrent symptoms consistent with allergic reactions elude diagnosis. Recent research has identified a novel cause for “idiopathic” allergic reactions; immunoglobulin E (IgE) antibody specific for the carbohydrate galactose-alpha-1,3-galactose (alpha-Gal) has been associated with delayed urticaria and anaphylaxis that occurs 3 to 6 hours after eating beef, pork, or lamb. We sought to determine whether IgE antibody to alpha-Gal was present in sera of pediatric patients who reported idiopathic anaphylaxis or urticaria. METHODS: Patients aged 4 to 17 were enrolled in an institutional review board-approved protocol at the University of Virginia and private practice allergy offices in Lynchburg, VA. Sera was obtained and analyzed by ImmunoCAP for total IgE and specific IgE to alpha-Gal, beef, pork, cat epithelium and dander, Fel d 1, dog dander, and milk. RESULTS: Forty-five pediatric patients were identified who had both clinical histories supporting delayed anaphylaxis or urticaria to mammalian meat and IgE antibody specific for alpha-Gal. In addition, most of these cases had a history of tick bites within the past year, which itched and persisted. CONCLUSIONS: A novel form of anaphylaxis and urticaria that occurs 3 to 6 hours after eating mammalian meat is not uncommon among children in our area. Identification of these cases may not be straightforward and diagnosis is best confirmed by specific testing, which should certainly be considered for children living in the area where the Lone Star tick is common. 

Khoury, J. K., et al. (2018). “A tick-acquired red meat allergy.” Am J Emerg Med 36(2): 341.e341-341.e343.

Allergic reaction is a common clinical picture in the Emergency Department (ED). Most allergic reactions are from food or drugs. A detailed history is an integral aspect of determining the causative agent of an allergy. Galactose-alpha-1,3-galactose (alpha-gal) allergy is a tick-acquired red meat allergy that causes delayed-onset allergic reaction or anaphylaxis due to molecular mimicry. Alpha-gal allergy may not be widely known as a cause of allergic reactions. Lack of universal awareness of this phenomenon in the ED and Urgent Care setting could lead to misdiagnosis, or delayed diagnosis. Subsequently, lack of proper instruction to avoid red meat could put patients at risk for future attacks with morbidity or mortality. We report three cases of allergic reaction presumed from red meat consumption secondary to alpha-gal allergy. 

Kiewiet, M. B. G., et al. (2019). “Clinical and serological characterization of a large cohort of red meat allergic patients from Sweden.” Allergy (Oxford) 74(Suppl. 106, Sp. Iss. SI): 877.           

Kim, M. S., et al. (2019). “IgE to galactose-alpha-1,3-galactose wanes over time in patients who avoid tick bites.” J Allergy Clin Immunol Pract.

Galactose-a-1,3-galactose (a-Gal) is an oligosaccharide of nonprimate mammals and the target of IgE antibodies in the syndrome of delayed anaphylaxis to mammalian meat. The connection between IgE sensitization to a-Gal and tick bites is now well established, and in North America, the a-Gal syndrome has consistently been associated with Amblyomma americanum. Case reports and clinical experience suggest that levels of IgE to a-Gal can decrease over time in some patients, particularly those who avoid additional tick exposures, but the natural history of IgE to a-Gal has not been systematically examined. Here we report results of a retrospective investigation into the trend and rate of changes in a-Gal specific IgE (sIgE) and total IgE in relation to tick exposure in subjects with established a-Gal syndrome 

Kimpel, D., et al. (2019). “SERO-REACTIVITY TO GALACTOSE-ALPHA-1,3-GALACTOSE AND CLINICAL PRESENTATIONS OF PATIENTS SEEN IN A RHEUMATOLOGY OUTPATIENT PRACTICE.” Annals of the Rheumatic Diseases 78(Suppl. 2): 1317-1318.

Anaphylactic reactions to cetuximab, a monoclonal antibody used in cancer therapy, were recognized in 2007 as a regional complication related to recognition of a protein epitope by IgE. This protein epitope was defined as galactose-alpha-1,3-galactose (alpha-gal), which is found in non-primate mammalian tissue. Reactivity to this epitope was also found to occur after meat consumption with manifestations including anaphylaxis, urticaria, or angioedema. Further study showed that reactivity was induced by tick bites from the Lone Star tick. Similar cases of reaction to red meat have been described in Australia in 2006, and more recently in Japan and various European countries. In our Rheumatology practices where patients often raise concerns about possible tick-borne illnesses, we have observed patients presenting with symptoms related to consumption of mammalian meat, but generally less severe, and with IgE reactivity to alpha-gal. 

Kleiman, A. M., et al. (2017). “Delayed Anaphylaxis to Mammalian Meat Following Tick Exposure and Its Impact on Anesthetic Management for Cardiac Surgery: A Case Report.” A & a Case Reports 8(7): 175-177.

Hypersensitivity reactions to mammalian meat following tick exposure are increasing in prevalence and provide a unique challenge to anesthesiologists. The reactions, including anaphylaxis, are delayed and therefore may not be easily recognized and treated. The risk is especially high in cardiac surgery, where several potential triggers, including biological valves as well as heparin, are used frequently. In the presence of such hypersensitivity, prophylactic measures including preoperative testing and pharmacologic prophylaxis may be useful in modulating the immune response such that triggering agents may be used relatively safely. We present 3 patients with previous sensitization to meat protein following a tick bite with known allergic reactions to mammalian meat who presented for cardiac surgery involving exposure to potential allergens and discuss the perioperative management including possible prevention. 

Knight, M. E., et al. (2015). “Exercise-induced anaphylaxis after consumption of red meat in a patient with IgE antibodies specific for galactose-alpha-1,3-galactose.” J Allergy Clin Immunol Pract 3(5): 801-802.

Testing for alpha-gal antibodies in patients with exercise-induced anaphylaxis should be considered even if the patient has not exhibited symptoms at times not associated with exercise. 

Kollmann, D., et al. (2017). “The quantity and quality of alpha-gal-specific antibodies differ in individuals with and without delayed red meat allergy.” Allergy 72(2): 266-273.

Background: IgG to galactose-alpha-1,3-galactose (alpha-gal) are highly abundant natural antibodies (Ab) in humans. alpha-Gal-specific IgE Ab cause a special form of meat allergy characterized by severe systemic reactions 3-7 h after consumption of red meat. We investigated 20 patients who experienced such reactions and characterized their alpha-gal-specific IgE and IgG responses in more detail. Methods: alpha-Gal-specific IgE was determined by ImmunoCAP. IgE reactivity to meat extract and bovine gamma globulin (BGG) was assessed by immunoblotting and ELISA, respectively. In some experiments, sera were pre-incubated with alpha-gal or protein G to deplete IgG Ab. alpha-Gal-specific IgG(1-4) Ab in individuals with and without meat allergy were assessed by ELISA. Results: In immunoblots, BGG was the most frequently recognized meat protein. Binding of IgE and IgG to BGG was confirmed by ELISA and completely abolished after pre-incubation with alpha-gal. Neither the depletion of autologous alpha-gal-specific IgG Ab nor the addition of alpha-gal-specific IgG Ab from nonallergic individuals changed the IgE recognition of BGG of meat-allergic patients. Meat-allergic patients showed significantly higher alpha-gal-specific IgG1 and IgG3 Ab than nonallergic individuals, whereas the latter showed significantly higher levels of alpha-gal-specific IgG4 Ab. Conclusion: Patients with delayed meat allergy display IgE and IgG Ab that selectively recognize the alpha-gal epitope on BGG. Their enhanced alpha-gal-specific IgE levels are accompanied by high levels of alpha-gal-specific IgG1 devoid of IgE-blocking activity. This subclass distribution is atypical for food allergies and distinct from natural alpha-gal IgG responses in nonallergic individuals.

Kondo, M., et al. (2017). “Case with acute urticaria by red meat after Haemaphysalis longicornis bite.J Dermatol 44(7): e168-e169.

Kondo, M., et al. (2017). “Rapid changes in the red meat and alpha-Gal specific IgE-RAST level profile in the clinical course of a case with red meat allergy and Haemaphysalis longicornis bite.” Journal of Investigative Dermatology 137(5, Suppl. 1): S99.

A case with stroke was referred to our hospital with two ticks attached on her right arm. Five days after admission, she started slurry food including red meat, and developed generalized urticarial rash. Then, she was diagnosed having urticarial allergic reaction to red meat, and red meat was eliminated from her hospital diet. The eruption disappeared within 3 days without systemic corticosteroid therapy. Her rash didn’t recur during 4 months hospitalization. High prevalence of urticarial type red meat allergy was reported in the endemic area of Japanese spotted fever, which is mediated by Haemaphysalis longicornis (H. longicornis). Then, we investigated immunological background of the present case. 

Krishna, N., et al. (2017). “P112 Correlation between clinical findings and laboratory tests for alpha gal sensitivity.” Annals of Allergy, Asthma & Immunology 119(5): S37.           

Kuhlen, J. L. and Y. V. Virkud (2015). “Pathogenesis, newly recognized etiologies, and management of idiopathic anaphylaxis.” Discov Med 19(103): 137-144.

Idiopathic anaphylaxis (IA) is a life-threatening allergic disease and the most common diagnosis given to patients following an anaphylactic event. The inability of the healthcare provider and the patient to identify the trigger for anaphylaxis makes standard allergen avoidance measures ineffectual. IA is diagnosed after other causes of anaphylaxis have been excluded. Mast cell activation syndromes (MCAS), mastocytosis, IgE to galactose-alpha-1,3-galactose (alpha-gal), and certain medications have recently been recognized as causes of anaphylaxis that were previously labeled idiopathic. This review will describe the epidemiology and proposed theories of pathogenesis for IA, its diagnostic approach, its clinical management, and examine newly recognized disorders that were previously labeled as idiopathic anaphylaxis. 

Kugler, C. and T. Biedermann (2016). “Delayed anaphylaxis to mammalian meat (Alpha-Gal) – oral challenge. / Orale Provokationstestung bei verzögerter Soforttypallergie auf Sägetierfleisch (Alpha-Gal).” Allergologie 39(11): 497-501.

Carbohydrate moieties are frequently encountered in food and can evoke IgE responses – the clinical significance of which, has been unclear, until recently. However, recent work has shown that IgE antibodies to galactose-alpha-1,3-galactose (Alpha-Gal), a carbohydrate commonly expressed on non-primate mammalian proteins, are capable of eliciting serious – even fatal – reactions. Sensitization may occur through tick bites. Upon exposure of sensitized subjects to mammalian red meat containing alpha-gal on glycoproteins, delayed anaphylaxis may ensue, often 3-6 hours after ingestion, in some cases in combination with trigger factors. In the following, the diagnostic work-up for alpha-gal allergy is reviewed and discussed. 

Kusuma, A. and A. C. Knulst (2009). “A rare case of meat allergy.” Nederlands Tijdschrift voor Dermatologie en Venereologie 19: 233-234.

A 48-year-old man developed three hours after eating pigs kidney an anaphylactic reaction consisting of general itching, malaise, urticaria, angioedema and hypotension. Later he also developed similar symptoms after eating organ as well as non-organ meat. Skin prick tests and specific IgE values were positive, as well as oral provocation tests. Remarkably the reaction occurred after one to four hours. Very recently such an allergy has been reported in American patients, in which IgE antibodies against galactose-α-1,3-galactose, a carbohydrate group in animal proteins appeared to be the explanation. This is the first case of such an allergy in Europe. 

Kwak, M., et al. (2018). “A novel Australian tick Ixodes (Endopalpiger) australiensis inducing mammalian meat allergy after tick bite.” Asia Pac Allergy 8(3): e31.

Tick-induced mammalian meat allergy has become an emergent allergy world-wide after van Nunen et al. first described the association between tick bites and the development of mammalian meat allergy in 2007. Cases of mammalian meat allergy have now been reported on all 6 continents where humans are bitten by ticks, in 17 countries – Australia, United States of America (USA), Europe (France, Spain, Germany, Belgium, Switzerland, Sweden, United Kingdom, Italy, and Norway), Asia (Korea and Japan), Central America (Panama), South America (Brazil), and Africa (South Africa and Ivory Coast). To date, in each of these countries, bites from only a single tick species have been linked to the development of mammalian meat allergy: Ixodes holocyclus (Australia), Amblyomma americanum (USA), Ixodes ricinus (Europe), and Ixodes cajennense (Panama) are confirmed as culprits, and Ixodes nipponensis (Japan and Korea), Amblyomma sculptum (Brazil), Amblyomma variegatum (Ivory Coast), and Haemaphysalis longicornis (Japan) suspected of provoking mammalian meat allergy after tick bite. Other tick species remain to be formally identified (South Africa). Identification of tick species associated with development of mammalian meat allergy is crucial to the uptake of public health measures to prevent tick bites from culprit tick species, for both individuals living in these tick-endemic areas and those who choose to visit these regions. We report a tick associated with the enhancement of mammalian meat anaphylaxis after tick bite which is novel for both Australia and the world and establishes Ixodes (Endopalpiger) australiensis as a second tick species associated with mammalian meat allergy in Australia.

Lammerts van Bueren, J. J., et al. (2011). “Anti-galactose-alpha-1,3-galactose IgE from allergic patients does not bind alpha-galactosylated glycans on intact therapeutic antibody Fc domains.Nat Biotechnol 29(7): 574-576.

Letter to the Editor 

Langerak, A., et al. (2009). “Panitumumab Monotherapy in Patients with Metastatic Colorectal Cancer and Cetuximab Infusion Reactions: A Series of Four Case Reports.” Clinical Colorectal Cancer 8(1): 49-54.

Purpose Monoclonal antibodies against the epidermal growth factor receptor approved for treating metastatic colorectal cancer (mCRC) include cetuximab (a chimeric antibody) and panitumumab (a fully human antibody). Because these antibodies have differences in protein sequence, patients intolerant to one antibody might still tolerate the other. Four cases are presented from a US panitumumab compassionate-use program in which patients with mCRC who were intolerant to cetuximab received panitumumab. Patients and Methods Eligible patients had failed previous fluoropyrimidine therapy with oxaliplatin- and irinotecan-containing chemotherapy, had cetuximab intolerance (ie, experienced an infusion reaction), and were unable to participate in a panitumumab clinical trial. For each patient, individual Federal Drug Administration-approved single-patient treatment use Investigational New Drug– and Institutional Review Board–approved protocols were used, informed consent was obtained, and data were collected independently by the investigator. Results All 4 patients (2 men, 2 women) had received previous bevacizumab and premedications before cetuximab administration. In response to cetuximab, all 4 patients experienced Common Terminology Criteria for Adverse Events grade 3 or grade 4 infusion-reaction symptoms, which required acute therapy. Time from cetuximab discontinuation to panitumumab administration ranged from 8 days to 5 months. Panitumumab monotherapy was administered at approximately 6 mg/kg every 2 weeks. Two patients received premedications before panitumumab use. No physician reported any infusion reaction to panitumumab. One patient had stable disease, and 3 patients had disease progression. Conclusion Though this small case series provides evidence that patients with mCRC intolerant to cetuximab can receive subsequent panitumumab monotherapy without experiencing infusion reactions, additional clinical testing is needed to definitively examine this finding. 

Lee, J. H., et al. (2013). “Delayed mammalian meat-induced anaphylaxis confirmed by skin test to cetuximab.” The Journal of Dermatology 40(7): 577-578. 

Lee, S. C., et al. (2019). “Clinical Features and Culprit Food Allergens of Korean Adult Food Allergy Patients: A Cross-Sectional Single-Institute Study.” Allergy Asthma & Immunology Research 11(5): 723-735.

Purpose: To investigate the causative allergens and clinical characteristics of Korean adult patients with food allergy (FA). Methods: This retrospective, cross-sectional single-institutional study enrolled Korean adult patients (n = 812) suspected of having FA. For diagnosis, causality assessment history taking, ImmunoCAP specific immunoglobulin E measurement and/or skin prick test were performed. Results: Among 812 patients, 415 were diagnosed as having FA. The most common causative allergen was fruit, with a diagnosis of pollen food allergy syndrome (PFAS: 155, 37.3%), followed by crustaceans (111, 26.7%), wheat (63, 15.1%), fruits in patients without PFAS(43, 10.3%), buckwheat (31, 7.4%), peanut (31, 7.4%), walnut (25, 6.0%), red meat due to reaction to galactose-alpha-1,3-galactose (alpha-Gal) (8, 1.9%), and silkworm pupa (13, 3.1%). Allergy to egg, milk, fish, or shellfish was rare in Korean adults. One-third of patients with FA exhibited multiple FAs (238/415, 57.3%); the average number of causative allergens was 2.39. About 129 patients (31.0%) were diagnosed as having anaphylaxis; in these patients, wheat was the most frequent causative food. Twenty patients were further diagnosed with food-dependent exercise-induced anaphylaxis (FDEIA); all were due to wheat. In particular, crustaceans, wheat, PFAS, buckwheat, and red meat (alpha-Gal) were also frequent causes of anaphylaxis. Conclusions: Wheat, fruits with or without PFAS, and crustaceans are important and frequent causative allergens in Korean adult FA; these allergens differ from those found in childhood FA. It is notable that non-classic allergies, such as PFAS, FDEIA, and a-Gal allergy, are the important causes of anaphylaxis in Korean adult FA. 

Levin, M., et al. (2019). “Galactose alpha-1,3-galactose phenotypes: Lessons from various patient populations.” Ann Allergy Asthma Immunol 122(6): 598-602.

OBJECTIVE: To review published studies on galactose alpha-1,3-galactose (alpha-gal), a carbohydrate epitope found on proteins and lipids in nonprimate mammals and present in foods (particularly organ or fat-rich red meat) and medications, where it causes delayed-onset and immediate-onset anaphylaxis. DATA SOURCES: A literature search for the terms galactose alpha-1,3-galactose and alpha-gal using PubMed and Embase was performed. STUDY SELECTIONS: Studies on alpha-gal were included in this review. RESULTS: Several species of ticks contain alpha-gal epitopes and possibly salivary adjuvants that promote high titer sensitization and clinical reactivity. Risk factors for alpha-gal syndrome include exposure to ticks of particular species. Age and sex differences seen in various cohorts possibly reflect the prevalence of these exposures that vary according to setting. CONCLUSION: The reason and mechanisms for delayed onset of food-related anaphylaxis and the preponderance of abdominal reactions are not clear but may involve the kinetics of allergen digestion and processing or immunologic presentation via a different mechanism from usual immediate-type food allergy. 

Li, J., et al. (2017). “P44: SPECIFIC IGE TO GALACTOSE-ALPHA-1,3-GALACTOSE (ALPHA-GAL) DOES NOT ADD TO THE DIAGNOSIS OF MAMMALIAN MEAT ALLERGY IN A TICK-ENDEMIC POPULATION.” Internal Medicine Journal 47(S5): 18-18.

The clinical manifestations of mammalian meat allergy (MMA) are varied, encompassing urticaria, angioedema, gastrointestinal symptoms and anaphylaxis. Diagnosis is difficult based on clinical history alone as there are many differential diagnoses to exclude. Specific IgE (sIgE) to alpha‐gal is considered a useful diagnostic test. Sensitisation to alpha‐gal is considered a prerequisite to MMA. In Australia, one major mechanism is through tick bites from Ixodes holocyclus. 

Li, J., et al. (2018). “Specific-IgE to galactose-alpha-1,3-galactose (alpha-gal) has limited utility in diagnosing meat allergy in a tick-endemic population.” Ann Allergy Asthma Immunol 121(4): 509-511.

Sensitization to galactose-α-1,3-galactose (alpha-gal) is considered a prerequisite to mammalian meat allergy (MMA) and can occur through tick bites, which is due to the paralysis tick, Ixodes holocyclus, in Australia.1 The onset of symptoms is typically 3 to 6hours after ingestion of mammalian meat, but immediate reactions have been described.

Li, R. C., et al. (2019). “Investigation into specific IgE and IgG4 to the oligosaccharide galactose-alpha-1,3-galactose (alpha-Gal) in children with eosinophilic esophagitis.” Journal of Allergy and Clinical Immunology 143(2): AB139-AB139.

Serum specific IgE (sIgE) to food allergens are common in children with eosinophilic esophagitis (EoE), albeit usually at low titers, and we have recently reported that high-titer specific IgG4 (sIgG4) to milk proteins are also a feature of the disease. Foods, including dairy, are recognized as important triggers of EoE. The oligosaccharidegalactose-a1,3-galactose (a-Gal) is present in mammalian meat and dairy, is recognized in man as a foreign epitope and is the causal epitope in a syndrome of IgE-mediated delayed anaphylaxis. It is possible that a-Gal could be a relevant allergen that contributes to EoE pathogenesis. We sought to determine the prevalence and levels of IgE and IgG4 to a-Gal in children with EoE. 

Lieberman, P. L. (2014). “Idiopathic anaphylaxis.” Allergy Asthma Proc 35(1): 17-23.

Idiopathic anaphylaxis is not uncommon and can be found in as many as 60% of patients referred to an allergist for anaphylactic events. It is an extremely frustrating condition for patients because they have no means of avoiding a known allergen and events occur spontaneously and unprovoked. The objective of this study was to synthesize and review the medical literature on idiopathic anaphylaxis and present a strategy for diagnosis, prevention, and treatment of episodes. A literature review was performed after a search of PubMed using the key words of idiopathic anaphylaxis. Idiopathic anaphylaxis is more common in adults than in children and in women than in men. The symptoms and signs are identical to those found in other causes of anaphylaxis. Perhaps the most common entities to be considered in the differential diagnosis are somatoform reactions. The two most recent advances in our ability to detect the cause are the discovery that episodes can be caused by mast cell-activating syndromes, systemic mastocytosis, and IgE to galactose-alpha-1,3-galactose. Patients experiencing idiopathic anaphylactic episodes should, if possible, avoid taking drugs that may complicate therapy or worsen a reaction. Fortunately, the vast majority of cases follow a benign course. Although many recurrent episodes of anaphylaxis remain idiopathic, recent advances in our knowledge, especially the description of mast cell-activating disorders and the discovery of anaphylactic reactions to galactose-alpha-1,3-galactose have allowed us to find causes in events that previously would have been classified as idiopathic. In addition, the majority of such patients exhibit a diminishing frequency of reactions over time and can be managed in a way that prevents mortality and a severe effect on their quality of life. 

Lied, G. A. (2017). “Red meat allergy induced by tick bites: A Norwegian case report.” Eur Ann Allergy Clin Immunol 49(4): 186-188.

Food allergies, especially delayed hypersensitivity reactions, are often challenging for both patients and clinicians. Here, we report the case of a 64-year-old man who had allergic reactions six hours after eating a meal containing red meat. He reported that he had several tick bites in months before the reaction. High serum specific IgE levels of alpha-gal confirmed the diagnosis of alpha-gal allergic reaction with delayed onset after red meat ingestion caused by tick bite. 

Lied, G. A., et al. (2019). “Intraoperative anaphylaxis to gelatin-based hemostatic agents: a case report.” J Asthma Allergy 12: 163-167.

Surgiflo Haemostatic Matrix is an absorbable gelatin matrix hemostatic material that has been widely used in various surgical operations to assist hemostasis. Nonetheless, as biologically active agents (contains porcine gelatin), there is potential for allergic reactions to these products. Here, we report the case of a 71-year-old man who had intraoperative anaphylaxis with cardiovascular events to gelatin associated with the use of a topical hemostatic agent (Surgiflo). The patient reported a history of red meat allergy and tick bites during his allergological examination after anaphylaxis. He also had high levels of specific IgE antibodies towards alpha-gal. Special consideration should be given before administering bovine- or porcine-derived gelatin products during surgery to patients with animal-related allergies, such as alpha-gal or gelatin allergy and an atopic background. 

Lima-Barbero, J. F., et al. (2019). “Clinical gamasoidosis and antibody response in two patients infested with Ornithonyssus bursa (Acari: Gamasida: Macronyssidae).” Experimental and Applied Acarology 78(4): 555-564.

Blood-feeding ectoparasites constitute a growing burden for human and animal health, and animal production worldwide. In particular, mites (Acari: Gamasida) of the genera Dermanyssus (Dermanyssidae) and Ornithonyssus (Macronyssidae) infest birds and cause gamasoidosis in humans. The tropical fowl mite, Ornithonyssus bursa, is commonly found in tropical and subtropical countries but rarely reported in Europe. In this research we characterized the first two cases in Spain of clinical gamasoidosis diagnosed in patients infested with O. bursa, and investigated the IgE, IgM and IgG antibody response to mite proteins and the carbohydrate Galα1-3 Galβ1-(3)4 GlcNAc-R (α-Gal) involved in the tick-bite associated alpha-Gal syndrome (AGS). The results suggested that O. bursa is establishing across Mediterranean countries, and may increase the risk for gamasoidosis. The immune antibody response to mite proteins was higher for IgM and similar for IgE and IgG antibodies between patients and non-allergic control individuals exposed to mite or tick bites. The anti-α-Gal antibody levels were similar between patients and controls, a result supported by the absence of this carbohydrate in mites. These results suggested that mite bites do not correlate with antibody response to acarine proteins or α-Gal, and are not associated with the AGS. 

Luker, A. J., et al. (2019). “A new look at IgE beyond allergies.” F1000Res 8.

Immunoglobulin E (IgE), though constitutively present at low levels, is most commonly studied in atopic disease where it plays a vital role in mast cell degranulation and in initiating a T helper 2 (Th2) response. With the advent of better detection assays, however, researchers are discovering the importance of IgE in actively contributing to many disease states and pathologies. This review will discuss the latest findings in IgE beyond its role in allergies and recently discovered roles for IgE in its cell-bound form on FcepsilonRI-expressing effector cells like monocytes and dendritic cells. In terms of parasites, we will discuss helminth-induced IgE that appears to protect the worms from immune recognition and a tick-borne illness that elicits an IgE response against red meat. Next, we describe recent findings of how auto-reactive IgE can contribute to the progression of lupus and induce organ damage. Finally, we summarize the emerging roles of IgE in tumor surveillance and antibody-dependent cytotoxicity. We additionally discuss recent or ongoing clinical trials that either target harmful IgE or use the unique characteristics of the isotype.

Mabelane, T., et al. (2018). “Predictive values of alpha-gal IgE levels and alpha-gal IgE: Total IgE ratio and oral food challenge-proven meat allergy in a population with a high prevalence of reported red meat allergy.” Pediatr Allergy Immunol 29(8): 841-849.

BACKGROUND: Severe meat allergy with anaphylaxis may be caused by sensitization to alpha-gal. Levels of alpha-gal sensitization that correlate with high risk of meat allergy are currently unknown. We have identified an area with a high prevalence of reported red meat allergy which offered the opportunity to evaluate the diagnostic value of IgE antibody tests.

METHODS: To determine levels of alpha-gal IgE and alpha-gal:total IgE ratio in a large cohort of subjects with challenge-proven meat allergy compared with control subjects from the same environment, we conducted fieldwork assessing 131 participants who reported adverse reactions to meat, and 26 control subjects, by questionnaires, IgE sensitization to alpha-gal and oral food challenge to beef sausage.

RESULTS: Eighty-four participants were diagnosed with alpha-gal allergy. Alpha-gal IgE ranged between 0.7 and 344.5 kU/L. Alpha-gal:total IgE ratio ranged from 0.1% to 67.6%. Logistic regression analysis showed both alpha-gal IgE and alpha-gal:total IgE ratio strongly correlated with meat allergy, with AUC of 0.95. The values giving the best correct classification were IgE of 2.00 kU/L and ratio of 0.75%. The value above which there is a 95% probability of meat allergy is IgE>5.5 kU/L and ratio of 2.12%.

CONCLUSION: Alpha-gal allergy in a population with a high prevalence of reported red meat allergy showed a more rapid onset of symptoms than previously described and a high prevalence of isolated subjective gastrointestinal manifestations. Cutoff values are described for levels of sensitization to alpha-gal IgE and alpha-gal:total IgE ratio that are highly likely to result in clinically significant meat allergy.

Mabelane, T., et al. (2018). “Alpha Gal Allergy in rural black African subjects associated with a high prevalence of abdominal manifestations and a more rapid onset of symptoms.” Journal of Allergy and Clinical Immunology 141(2): AB200.

RATIONALE: Reports were received of high prevalence of meat allergy in black African subjects in the rural Eastern Cape Province of South Africa. METHODS: 85 subjects were diagnosed with alpha-gal allergy during fieldwork conducted in the 1 month period of June 2017. Questionnaires assessed symptoms to meat ingestion. Sensitisation was confirmed with ImmunoCAP_ to alpha-gal. 83 were diagnosed by a positive Oral Food Challenge (OFC) to beef sausage.

Mabelane, T. and G. A. Ogunbanjo (2019). “Ingestion of mammalian meat and alpha-gal allergy: Clinical relevance in primary care.” Afr J Prim Health Care Fam Med 11(1): e1-e5.

BACKGROUND: An allergic reaction to mammalian meat has recently been reported in rural parts of South Africa and throughout other parts of the world. The cause of this allergic reaction is because of an oligosaccharide antigen known as galactose-alpha-1, 3-galactose (alpha-gal) found in mammalian meat. Hard ticks in various parts of the world have been identified as a cause of sensitisation to the alpha-gal antigen. However, mechanisms of sensitisation in Africa are poorly understood. AIM: The aim of this article is to review current literature on the alpha-gal allergy and mammalian meat ingestion and the family physician’s role in diagnosing and managing this condition. METHOD: Indexes were searched using the keywords in the following electronic databases: Elsevier Science Direct, Google Scholar, Medline and PubMed. RESULTS: Clinical presentation of the alpha-gal allergy occurs typically as a delayed anaphylaxis occurring within 3-6 hours after the ingestion of mammalian meat. A subset of patients described in South Africa presented with a rapid onset of symptoms occurring within 45 minutes. Furthermore, some of these patients present with abdominal symptoms only, which may be mistaken as food poisoning. Diagnosis is based on a history of reaction to mammalian meats (especially to fatty portions or organs) and serum specific alpha-gal antibodies. The main management of the alpha-gal allergy is avoidance of red meat and in mild reactions treatment with oral H1 receptor antihistamines. CONCLUSION: Sensitisation to the alpha-gal allergy results in adverse reactions to red meat, with tolerance to turkey, chicken and fish. A family physician can safely manage this condition.

Macher, B. A. and U. Galili (2008). “The Galα1,3Galβ1,4GlcNAc-R (α-Gal) epitope: A carbohydrate of unique evolution and clinical relevance.” Biochimica et Biophysica Acta (BBA) – General Subjects 1780(2): 75-88.

In 1985, we reported that a naturally occurring human antibody (anti-Gal), produced as the most abundant antibody (1% of immunoglobulins) throughout the life of all individuals, recognizes a carbohydrate epitope Galα1–3Galβ1–4GlcNAc-R (the α-gal epitope). Since that time, an extensive literature has developed on discoveries related to the α-gal epitope and the anti-Gal antibody, including the barrier they form in xenotransplantation and their reciprocity in mammalian evolution. This review covers these topics and new avenues of clinical importance related to this unique antigen/antibody system (α-gal epitope/anti-Gal) in improving the efficacy of viral vaccines and in immunotherapy against cancer.

Mackenzie, K. J. (2015). “Implications of xenoglycan sensitivity for increased cancer risk.” Proceedings of the National Academy of Sciences of the United States of America 112(12): E1404.

The excellent study by Samraj et al. shows that dietary intake of the nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc) promotes the production of anti-Neu5Gc antibodies. The resulting “xenosialitis” and associated chronic inflammation was shown to contribute to carcinogenesis.

Maldonado-Ruiz, L. P., et al. (2019). “Differential Tick Salivary Protein Profiles and Human Immune Responses to Lone Star Ticks (Amblyomma americanum) From the Wild vs. a Laboratory Colony.” Front Immunol 10: 1996.

Ticks are a growing concern to human and animal health worldwide and they are leading vectors of arthropod-borne pathogens in the United States. Ticks are pool blood feeders that can attach to the host skin for days to weeks using their saliva to counteract the host defenses. Tick saliva, as in other hematophagous arthropods, contains pharmacological and immunological active compounds, which modulate local and systemic immune responses and induce antibody production. In the present study, we explore differences in the salivary gland extract (SGE) protein content of Amblyomma americanum ticks raised in a laboratory colony (CT) vs. those collected in the field (FT). First, we measured the IgG antibody levels against SGE in healthy volunteers residing in Kansas. ELISA test showed higher IgG antibody levels when using the SGE from CT as antigen. Interestingly, antibody levels against both, CT-SGE and FT-SGE, were high in the warm months (May-June) and decreased in the cold months (September-November). Immunoblot testing revealed a set of different immunogenic bands for each group of ticks and mass spectrometry data revealed differences in at 19 proteins specifically identified in the CT-SGE group and 20 from the FT-SGE group. Our results suggest that differences in the salivary proteins between CT-SGE and FT-SGE may explain the differential immune responses observed in this study. 

Malisiewicz, B., et al. (2017). “Delayed anaphylaxis after the ingestion of kidney skewer – a link between alpha-Gal and mastocytosis.” Allergologie 40(12): 517-521.

IgE-mediated delayed-type anaphylactic reactions after the ingestion of red meat represent a young entity. Specific IgE antibodies against the carbohydrate alpha-Gal are responsible for the clinical occurrence of anaphylactic reactions after consumption of red meat. Known trigger factors are physical activity, alcohol, infections, or taking nonsteroidal anti-inflammatory drugs. We report a 46-year-old patient who experienced an intensive care-dependent anaphylactic reaction grade III a few hours after the consumption of a kidney skewer. A type-I sensitization against pork, beef, and alpha-Gal could be proven. Further serological analysis detected an elevated basal tryptase. A subsequent hema-to-oncological evaluation revealed, alongside a known cutaneous mastocytosis, an indolent systemic mastocytosis. This case is highlighting the relevance of this specific allergy type. In unclear anaphylaxis, this entity should be taken into account as a differential diagnosis. Furthermore an indolent systemic mastocytosis should be evaluated alongside the known trigger factors. 

Mangold, A., et al. (2009). “Alpha-Gal Specific IgG Immune Response after Implantation of Bioprostheses.” Thorac cardiovasc Surg 57(04): 191-195.

Background: We have previously shown that the α‐Gal (Galα1.3-Galβ1–4GlcNAc-R) epitope is a relevant xenoantigen present on bioprostheses utilized in cardiac surgery and elicits an α‐Gal specific IgM immune response. We sought to investigate whether that immune response continues after valve implantation. Materials and Methods: We collected plasma samples from patients who underwent bioprosthesis implantation (n = 19) or mechanical valve replacement (n = 8), respectively, prior to, at 10 days and at 3 months after cardiac surgery. ELISA was utilized to quantify α‐Gal specific IgG and IgG subclasses. 3 bioprosthetic tissue samples were obtained from patients who had to undergo re-operation within 1 week (n = 1) or at 12–15 months (n = 2) after the initial operation. We utilized confocal laser scanning microscopy (CLSM) to detect the presence of α‐Gal epitopes (IB4) and cell nuclei (DAPI). Results: α‐Gal specific IgG was significantly increased 3 months after implantation of bioprostheses compared to preoperative values (p < 0.001) and was significantly higher than α‐Gal specific IgG levels of the control group (p < 0.05). IgG3 was the major subclass directed against α‐Gal (p < 0.05, pre- vs. postoperative values). In CLSM analysis we demonstrated that bioprostheses explanted 1 week after implantation contained IB4/DAPI positive cells within the collagen matrix. In contrast, in patients who underwent reoperation after 12 months, porcine tissue showed a complete lack of IB4/DAPI. Conclusion: Our results indicate that the implantation of bioprostheses elicits a specific humoral immune response against α‐Gal bearing cells compared to controls within 3 months after cardiac surgery. The complete absence of IB4/DAPI positive structures 12 months after implantation indicates a specific degradation of α‐Gal bearing cells through previous exposure to the human blood circuit. 

Mariotte, D., et al. (2011). “Anti-cetuximab IgE ELISA for identification of patients at a high risk of cetuximab-induced anaphylaxis.” Mabs 3(4): 396-401.

Cetuximab, a chimeric mouse-human IgG1 monoclonal antibody against the epidermal growth factor receptor, has proven effective in the treatment of metastatic colorectal cancer and squamous cell carcinoma of the head and neck. However, a high incidence of immediate hypersensitivity reactions (HSR) to cetuximab after the first infusion has been observed. We have developed a test for identification of patients likely to show treatment-related HSR to cetuximab. An enzyme-linked immunosorbent assay (ELISA) for detecting anti-cetuximab IgEs was developed and tested on serum samples collected from cancer patients before start of cetuximab treatment, and from healthy blood donors. Similar levels of anti-cetuximab IgE were detected in pre-treatment patient sera (24/92, 26.1%) and sera from healthy blood donors (33/117, 28.2%). HSR were observed in 14 out of the 92 patients (15.2%), and 8 of these (57.1%) were grade 3-4. Anti-cetuximab IgEs were detected in 7/8 of the patients (87.5%) with severe HSRs as compared with 14/78 patients (17.9%) with no HSR (p=0.0002). Predictive value of the anti-cetuximab IgE test for HSR events of grades 3-4 was calculated using Receiver Operating Characteristics analysis. With a cut-off value of 29 arbitrary units for the anti-cetuximab IgE, the ELISA test showed a sensitivity of 87.5%, specificity of 82.1%, positive predictive value of 33.3% and negative predictive value of 98.5%. Anti-cetuximab IgE ELISA detection could be a valuable tool to help the physician anticipate an anaphylaxis episode following cetuximab infusion and opt for a suitable alternative treatment.

 

Martin-Lazaro, J., et al. (2019). “Galactose-alpha-1,3-galactose (alpha-gal) allergy: first pediatric case in a series of patients in Spain.” Allergol Immunopathol (Madr).

INTRODUCTION AND OBJECTIVES: Allergy to galactose-alpha-1,3-galactose (alpha-gal) is a peculiar form of food allergy generally manifesting as an anaphylactic reaction hours after mammalian meat consumption, due to the presence of specific IgE against this oligosaccharide. In addition, immediate anaphylaxis may develop after exposure to other sources of alpha-gal, such as monoclonal antibody cetuximab, vaccines, plasma expanders or anti-snake venoms. Sensitization to alpha-gal has also been implicated in the rapid degeneration of biological valve implants, and recognized as a cause of occupational disease in cattle raisers. The implication of tick bites in this type of sensitization has been accepted by all the research groups dedicated to this disease. PATIENTS AND METHOD: The present study describes the clinical and sensitization characteristics of 39 patients diagnosed with alpha-gal allergy in the hospitals of our province (Lugo, Monforte de Lemos and Burela, Spain). RESULTS: Most patients were middle-age males. Of note, is the fact that the series includes the first pediatric patient reported in Spain to date. The predominant clinical manifestations were urticaria or delayed anaphylaxis after consumption of mammalian meat. Seventy-four percent of the patients reported having suffered a previous tick bite, and the clinical presentation of anaphylaxis was significantly more prevalent in those with a persistent local reaction following the bite than in those with no such reaction (p=0.032). CONCLUSIONS: A review is also made of the disorder which, due to its variable clinical expression, is referred to as alpha-gal syndrome. The study concludes that a diagnosis of alpha-gal allergy should be considered in patients with urticaria-anaphylaxis of uncertain origin or manifesting after the administration of vaccines or products of bovine/porcine origin. 

Mateo-Borrega, M. B., et al. (2019). “IgE-mediated sensitization to galactose-alpha-1,3-galactose (alpha-gal) in urticaria and anaphylaxis in Spain: geographical variations and risk factors.” J Investig Allergol Clin Immunol: 0.

BACKGROUND: The aims of this study were to investigate the prevalence of sIgE to galactose-alpha-1,3-galactose (alpha-gal) in individuals with acute urticaria or anaphylaxis from different geographical areas of Spain and to evaluate the relevance of demographics and lifestyle as risk factors for this immune response. METHODS: Participants were recruited from allergy departments at 14 Spanish hospitals. Patients aged 18 years or older presenting with urticaria or anaphylaxis were enrolled into one of two arms: cases and controls. An interviewer-administered questionnaire collecting demographic data, lifestyle habits, and the presence of cofactors was obtained from each participant. sIgE to alpha-gal and total IgE were determined using ImmunoCAP(R). sIgE levels >/=0.35 kU/l were considered a positive result. RESULTS: The study population comprised 160 cases and 126 controls. The median age was 44 years. The overall prevalence of a positive result of sIgE to alpha-gal was 15.7%; this was higher in cases (26.3%) than in controls (2.4%). The sIgE anti alpha-gal positivity rate ranged from 37.68% (rural) to 15.38% (semi-urban) and 7.85% (urban). The rates of positivity were 46.32%, (Northern), 0.72% (Center), and 0% (Mediterranean). A positive result of sIgE to alpha-gal associated with history of tick bites, participation in outdoor activities, pet ownership, and ingestion of mammalian meats or innards before the onset of symptoms. Only alcohol consumption could be implicated as a cofactor. CONCLUSIONS: Sensitization to alpha-gal in patients with urticaria or anaphylaxis differs considerably between the three geographical areas studied and is related to tick bites.

Mateos-Hernandez, L., et al. (2017). “Tick-host conflict: immunoglobulin E antibodies to tick proteins in patients with anaphylaxis to tick bite.” Oncotarget 8(13): 20630-20644.

Tick-borne infectious diseases and allergies are a growing problem worldwide. Tick bite allergy has been associated with the direct effect of immunoglobulin E (IgE) response to tick salivary antigens, or secondary to the induction of allergy to red meat consumption through IgE antibodies against the carbohydrate alpha-Gal (Gal alpha 1-3Gal beta 1-(3)4GlcNAc-R). However, despite the growing burden of this pathology, the proteins associated with anaphylaxis to tick bite have not been characterized. To address this question, a comparative proteomics approach was used to characterize tick proteins producing an IgE antibody response in a healthy individual with record of tick bites, which had not resulted in any allergic reactions, and two patients with anaphylactic reactions to Rhipicephalus bursa or Hyalomma marginatum tick bites. Both patients and the healthy individual were red meat tolerant. The results supported a patient-specific IgE antibody response to tick species responsible for the anaphylaxis to tick bite. Both patients and the healthy individual serologically recognized tick proteins with and without alpha-Gal modifications, with proteins differentially recognized by patients but not control sera. These proteins could be used as potential antigens for diagnostics, treatment and prevention of tick bite-induced allergies.

Maurer, M., et al. (2015). “Galactose-alpha-1,3-Galactose Allergy Is Not a Hitherto Unrecognized Cause of Chronic Spontaneous Urticaria.” Int Arch Allergy Immunol 167(4): 250-252.

BACKGROUND: Tick bite-induced galactose-alpha-1,3-galactose (alpha-Gal) IgE and subsequent ingestion of red meat may cause delayed severe allergic reactions including urticaria, gastrointestinal symptoms or anaphylaxis. We tested the hypothesis that increased levels of IgE to alpha-Gal due to tick bites and the subsequent ingestion of red meat or meat products may possibly be an un(der)recognized cause of chronic spontaneous urticaria (CSU). METHODS: Levels of IgE to alpha-Gal and total IgE were measured (ImmunoCAP, Phadia AB/Thermo Fisher Scientific) in 83 patients (61 female and 22 male, median age 43 years, range 18-82) from the Department of Dermatology and Allergy, Charite – Universitatsmedizin, Berlin, Germany. All had been clinically diagnosed with moderate-to-severe CSU of a median duration of 2.9 years (range 0.1-50). RESULTS: Eighty of the 83 patients (96%) had undetectable (<0.1 kUA/l) serum levels of IgE against alpha-Gal. The levels in the remaining 3 were all low (0.25, 0.4 and 3.1 kUA/l). In no patient, including those with measurable serum levels of IgE against alpha-Gal, was eating red meat associated with the development of symptoms of urticaria. CONCLUSION: Our results indicate that an allergic response to alpha-Gal is highly unlikely to be a hitherto unrecognized common cause of CSU.

Mawhirt, S. L. and E. Banta (2019). “Successful intravenous heparin administration during coronary revascularization surgery in a patient with alpha-gal anaphylaxis history.” Ann Allergy Asthma Immunol.

Mehlich, J., et al. (2019). “The basophil activation test differentiates between patients with alpha-gal syndrome and asymptomatic alpha-gal sensitization.” Journal of Allergy and Clinical Immunology 143(1): 182-189.

Background: Galactose-alpha-1,3-galactose (alpha-gal) syndrome is characterized by the presence of serum specific IgE antibodies to alpha-gal and delayed type I allergic reactions to the carbohydrate alpha-gal after consumption of mammalian (red) meat products and drugs of mammalian origin. Diagnostics currently rely on patient history, skin tests, determination of serum specific IgE antibodies, and oral food or drug challenges. Objective: We sought to assess the utility of different basophil parameters (basophil reactivity and sensitivity, the ratio of the percentage of CD63(+) basophils induced by the alpha-gal-containing allergen to the percentage of CD63(+) basophils after stimulation with anti-Fc epsilon RI antibody [%CD63(+)/anti-Fc epsilon RI], and area under the dose-response curve [AUC]) as biomarkers for the clinical outcome of patients with alpha-gal syndrome compared with subjects with asymptomatic alpha-gal sensitization. Methods: In addition to routine diagnostics, a basophil activation test (Flow CAST) with different concentrations of alpha-gal-containing allergens (eg, commercially available alpha-gal-carrying proteins and pork kidney extracts) was performed in 21 patients with alpha-gal syndrome, 12 alphagal-sensitized subjects, and 18 control subjects. Results: Alpha-gal-containing allergens induced strong basophil activation in a dose-dependent manner in patients. Basophil reactivity at distinct allergen concentrations, the % CD63(+)/anti-FceRI ratio across most allergen concentrations, the AUC of dose-response curves, and basophil allergen threshold sensitivity (CD-sens) with pork kidney extract were significantly higher in patients with alpha-gal syndrome compared with those in sensitized subjects. All parameters were negative in control subjects. Conclusion: The basophil activation test should be considered as an additional diagnostic test before performing time-consuming and potentially risky oral provocation tests. The % CD63(+)/anti-Fc epsilon RI ratio for all allergens and AUCs for pork kidney were the best parameters for distinguishing patients with alpha-gal syndrome from subjects with asymptomatic alpha-gal sensitization.

Michel, S., et al. (2014). “Skin prick test and basophil reactivity to cetuximab in patients with IgE to alpha-gal and allergy to red meat.Allergy 69(3): 403-405.

Severe hypersensitivity reactions to red meat with delay of several hours in patients with IgE to alpha-gal (galactose-alpha-1,3-galactose) have been reported. The diagnosis of meat allergy is difficult, because of the limited sensitivity of skin prick tests and specific IgE tests to meat extracts. These circumstances have been explained by the delayed expression of alpha-gal due to digestive processes. Because of the low sensitivity of skin prick tests to meat, we studied the possibility to perform skin prick tests with cetuximab, which carries the alpha-gal epitope. Skin prick and intradermal tests with cetuximab were clearly positive in 2 of 2 patients. As a further diagnostic step, we performed basophil activation tests with cetuximab. Skin prick tests and basophil activation test using cetuximab may be a more sensitive alternative in patients with an assumed allergy to meat.

Mirakhur, B., et al. (2008). “Anaphylactic reactions to cetuximab in patients with IgE antibodies to the xenoantigen galactose-alpha-1,3-galactose.” Journal of Allergy and Clinical Immunology 121(2): S67-S67. 

Monzón, J. D., et al. (2016). “Population and Evolutionary Genomics of Amblyomma americanum, an Expanding Arthropod Disease Vector.” Genome Biology and Evolution 8(5): 1351-1360.

The lone star tick, Amblyomma americanum, is an important disease vector and the most frequent tick found attached to humans in the eastern United States. The lone star tick has recently experienced a rapid range expansion into the Northeast and Midwest, but despite this emerging infectious threat to wildlife, livestock, and human health, little is known about the genetic causes and consequences of the geographic expansion. In the first population genomic analysis of any tick species, we characterize the genetic diversity and population structure of A. americanum across its current geographic range, which has recently expanded. Using a high-throughput genotyping-by-sequencing approach, we discovered more than 8,000 single nucleotide polymorphisms in 90 ticks from five locations. Surprisingly, newly established populations in New York (NY) and Oklahoma (OK) are as diverse as historic range populations in North and South Carolina. However, substantial population structure occurs among regions, such that new populations in NY and OK are genetically distinct from historic range populations and from one another. Ticks from a laboratory colony are genetically distinct from wild populations, underscoring the need to account for natural variation when conducting transmission or immunological studies, many of which utilize laboratory-reared ticks. An FST-outlier analysis comparing a recently established population to a long-standing population detected numerous outlier sites, compatible with positive and balancing selection, highlighting the potential for adaptation during the range expansion. This study provides a framework for applying high-throughput DNA sequencing technologies for future investigations of ticks, which are common vectors of diseases.

Morisset, M., et al. (2010). “Anaphylaxis to beef or pork kidney due to IgE antibodies specific for galactose-alpha-1,3-galactose.” Allergy 65: 587-588.

Carbohydrate‐specific IgE antibodies present on nonprimate mammalian proteins were incriminated recently in delayed meat anaphylaxis. The aim of this study was to explore whether anaphylaxis to mammalian kidney is also associated with galactose‐α‐1,3‐galactose (αGal)‐specific IgE. 

Morisset, M., et al. (2012). “Anaphylaxis to pork kidney is related to IgE antibodies specific for galactose-alpha-1,3-galactose.” Allergy 67(5): 699-704.

BACKGROUND: Carbohydrate-specific IgE antibodies present on nonprimate mammalian proteins were incriminated recently in delayed meat anaphylaxis. The aim of this study was to explore whether anaphylaxis to mammalian kidney is also associated with galactose-alpha-1,3-galactose (alphaGal)-specific IgE. METHODS: Fourteen patients with anaphylaxis to pork or beef kidney underwent prick tests to meat and kidney. Some patients also underwent skin tests to Erbitux((R)) (cetuximab). IgE antibodies to alphaGal, swine urine proteins, beef and pork meat, serum albumin proteins, cat, and rFel d 1 were measured by ImmunoCAP((R)). The alphaGal levels were estimated in meats and kidney by ELISA inhibition assay. Cross-reactivity between alphaGal and pork kidney was studied with the ImmunoCAP((R)) inhibition assay. RESULTS: Among the 14 patients, 12 presented with anaphylactic shock. Reactions occurred within 2 h from exposure in 67% of patients. Associated risk factors were observed in 10 cases, and alcohol was the main cofactor. Three patients underwent an oral challenge to pork kidney, and anaphylaxis occurred after ingestion of small quantities (1-2 g). Prick tests to kidney were positive in 54% of patients. All tested patients showed positive skin tests to Erbitux((R)). All patients tested positive for IgE to alphaGal, with levels ranging from 0.4 to 294 kU/l. IgE binding to alphaGal was inhibited by raw pork kidney extract (mean, 77%; range, 55-87%), which showed a high amount of alphaGal determinants. CONCLUSIONS: Pork or beef kidney anaphylaxis is related to alphaGal IgE. Its peculiar severity could be due to an elevated content of alphaGal epitopes in kidney.

Mozzicato, S., et al. (2012). “Delayed Food Challenge Reactions Correspond Temporally to the Appearance of CD63+ Basophils in Subjects with IgE to alpha-Gal.” Journal of Allergy and Clinical Immunology 129(2): AB1. 

Mozzicato, S. M., et al. (2014). “Porcine or bovine valve replacement in 3 patients with IgE antibodies to the mammalian oligosaccharide galactose-alpha-1,3-galactose.” J Allergy Clin Immunol Pract 2(5): 637-638.

Patients who develop IgE to the oligosaccharide galactose-alpha-1, 3-galactose (alpha-gal) report delayed allergic reactions after eating beef, pork or lamb. To date, there have been no published reports indicating whether IgE to alpha-gal is associated with a risk of anaphylaxis at the time of engraftment of a bovine or porcine valve. This case series documents the clinical courses of three patients with elevated IgE to alpha-gal who required porcine or bovine valve replacement. Two patients experienced perioperative or postoperative hypersensitivity reactions, but all three are tolerating valve replacement.

Muglia, C., et al. (2015). “Anaphylaxis to medications containing meat byproducts in an alpha-gal sensitized individual.” Journal of Allergy and Clinical Immunology-in Practice 3(5): 796-797.

We present a case of alpha-gal allergy in conjunction with allergic reactions to medications that contain magnesium stearate, which may be of bovine origin. Physicians should be aware of the possible cross-reactivity between alpha-gal and medications that contain meat byproducts because inadequate avoidance can result in anaphylaxis.

Mullins, R. J., et al. (2012). “Relationship between red meat allergy and sensitization to gelatin and galactose-alpha-1,3-galactose.” Journal of Allergy and Clinical Immunology 129(5): 1334-U1217.

Background: We have observed patients clinically allergic to red meat and meat-derived gelatin. Objective: We describe a prospective evaluation of the clinical significance of gelatin sensitization, the predictive value of a positive test result, and an examination of the relationship between allergic reactions to red meat and sensitization to gelatin and galactose-alpha-1,3-galactose (alpha-Gal). Methods: Adult patients evaluated in the 1997-2011 period for suspected allergy/anaphylaxis to medication, insect venom, or food were skin tested with gelatin colloid. In vitro (ImmunoCAP) testing was undertaken where possible. Results: Positive gelatin test results were observed in 40 of 1335 subjects: 30 of 40 patients with red meat allergy (12 also clinically allergic to gelatin), 2 of 2 patients with gelatin colloid-induced anaphylaxis, 4 of 172 patients with idiopathic anaphylaxis (all responded to intravenous gelatin challenge of 0.02-0.4 g), and 4 of 368 patients with drug allergy. Test results were negative in all patients with venom allergy (n = 241), nonmeat food allergy (n = 222), and miscellaneous disorders (n = 290). ImmunoCAP results were positive to a-Gal in 20 of 24 patients with meat allergy and in 20 of 22 patients with positive gelatin skin test results. The results of gelatin skin testing and anti-alpha-Gal IgE measurements were strongly correlated (r = 0.46, P < .01). alpha-Gal was detected in bovine gelatin colloids at concentrations of approximately 0.44 to 0.52 mu g/g gelatin by means of inhibition RIA. Conclusion: Most patients allergic to red meat were sensitized to gelatin, and a subset was clinically allergic to both. The detection of a-Gal in gelatin and correlation between the results of a-Gal and gelatin testing raise the possibility that a-Gal IgE might be the target of reactivity to gelatin. The pathogenic relationship between tick bites and sensitization to red meat, alpha-Gal, and gelatin (with or without clinical reactivity) remains uncertain.

Mullins, R. J. A. (2008). “Clinical Significance Of Sensitisation To Gelatine Colloids In 800 Patients.” Journal of Allergy and Clinical Immunology 121(2): S26.

Mur Gimeno, P., et al. (2015). “Red meat allergy and gelatine sensitization.” Allergy (Oxford) 70(Suppl. 101, Sp. Iss. SI): 488.

Nakagawa, Y., et al. (2019). “175 Prevalence and regional differences of sensitization to galactose-a-1,3-galactose and/or cetuximab in Japan.” Journal of Investigative Dermatology 139(9): S244.

Research has shown that the principal cause of cetuximab-induced anaphylaxis is antioligosaccharide IgE antibodies specific for galactose-a-1,3-galactose (a-Gal) present on the mouse-derived Fab portion of the cetuximab heavy chain. Furthermore, it has been revealed that patients who are allergic to cetuximab also develop an allergic reaction to mammalian meat containing the a-Gal owing to cross-reactivity, and the presumed cause of sensitization is tick bites. The prevalence of red meat allergy is high in Shimane Prefecture located at the western mountainous area of Japan, as is tick-transmitted Japanese spotted fever. On the other hand, Tokyo Medical and Dental University (TMDU) is located in an urban area, so there are few mountains and forests and the occasion of tick bites are limited. In this study, we aimed to clarify the difference of a-Gal and/or cetuximab specific IgE retention rate in Japan. We enrolled 100 subjects from Shimane University and 50 subjects from TMDU, who had consulted with complaining anything except food allergy. 

Naso, F., et al. (2012). “Alpha-Gal detectors in xenotransplantation research: a word of caution.Xenotransplantation 19(4): 215-220.

Xenogeneic tissues are currently employed in clinical practice to create biological substitutes (bioprosthetic heart valves) and in the repair of various damaged tissues (pericardium, gastric-mucosa, nerves, cartilage). Many studies have shown that xenogeneic tissues express superficial epitopes as alpha-Gal, capable of triggering hyperacute and acute vascular rejection phenomena. Currently, no tissue treatment has proven able to completely mask or inactivate such epitopes. In fact, neither glutaraldehyde fixation nor decellularisation procedures ensure a definitive solution because of the persistence of reactive xenoantigen residues. The ability to ascertain alpha-Gal epitope removal from a xenogeneic tissue is closely related to the possibility of its quantitative determination. In the past, detection of the alpha-Gal epitope relied on the use of alpha-Gal reactive isolectin molecules and was limited to isolated cells. Recently, the quantitative evaluation of this antigen has been carried out in whole connective tissue through the use of the monoclonal antibody M86. This article provides an overview of the implications of the alpha-Gal epitope in the current clinical scenario and a definitive comparison between the reliability and specificity of isolectines vs. M86 in alpha-Gal determination. 

Naso, F., et al. (2013). “First quantification of alpha-Gal epitope in current glutaraldehyde-fixed heart valve bioprostheses.” Xenotransplantation 20(4): 252-261.

Abstract
Background: Glutaraldehyde fixation does not guarantee complete tissue biocompatibility in current clinical bioprosthetic heart valves (BHVs). Particularly, circulating anti-αGal human antibodies increase significantly from just 10 days after a BHV implantation. The inactivation of such epitope should be mandatory to meet the requirements for a perspectively safe clinical application; nevertheless, its quantitative assessment in commercially available BHVs has never been carried out.

Methods: In this investigation, seven different models of BHVs were tested. The number of epitopes was determined with reference to a standard αGal source by an ELISA test. The presence of xenoantigen was subsequently confirmed by immunofluorescence analysis. Porcine tissue, knockout for the αGal epitopes, was used as negative control.

Results: Epic™ valve was the only model among those tested, in which the αGal antigen appeared to be completely shielded. Composite Trifecta™ valve exhibited conflicting results: cusps of bovine pericardial tissue were devoid of reactive αGal epitopes, while the stent cover strip of porcine pericardium still maintained 30% of active antigens originally present in native tissue. All other tested BHVs express an αGal amount not significantly different from that exhibited by porcine Mosaic® valve (5.2 ± 0.6 × 1010 each 10 mg of tissue).

Conclusions: For the first time, the quantitative evaluation of the αGal epitope in heart valve bioprostheses, already in clinical practice for about 40 yrs, was finally determined. Such quantification might provide indications of biocompatibility relevant for the selection of bioprosthetic devices and an increase in the confidence of the patient. It might become a major quality control tool in the production and redirection of future investigation in the quest for αGal-free long-lasting substitutes. 

Nunez, R., et al. (2011). “Delayed mammalian meat-induced anaphylaxis due to galactose-alpha-1,3-galactose in 5 European patients.” Journal of Allergy and Clinical Immunology 128(5): 1122-1124.

In 2008, severe anaphylactic reactions after first infusion of cetuximab were reported for the first time.1 These episodes went against the idea that an allergic reaction needs previous contact with the allergen to develop sensitization. The authors demonstrated that preexisting specific IgE (sIgE) antibodies to galactose-a-1,3-galactose (a-gal) were responsible for the reactions. The a-gal epitope is a well-known antigen widely expressed on tissues of nonprimate mammals and capable of inducing specific IgG and IgM antibodies in those species that do not express it, humans among them. After the identification of a-gal-sIgE, a few cases of anaphylaxis, angioedema, and urticaria related to this oligosaccharide moiety have been described. 

Nunez-Orjales, R., et al. (2017). “Bovine Amniotic Fluid: A New and Occupational Source of Galactose-alpha-1,3-Galactose.” J Investig Allergol Clin Immunol 27(5): 313-314.

In 2009, Commins et al reported a series of patients with delayed anaphylaxis, angioedema, and urticaria after consumption of red meat or dairy products. In 2011, the first cases showing the same features were reported in Spain. Since then, several additional sources of galactose-α-1,3galactose (α-gal) have been reported, namely, mammalian innards [3], gelatin-containing foods and drugs, and bioprosthetic aortic valves [7]. Here, we report the cases of 3 cattle workers who presented with allergic symptoms after assisting the veterinarian during calving.

Ohshita, N., et al. (2017). “Management of infusion reactions associated with cetuximab treatment: A case report.” Mol Clin Oncol 6(6): 853-855.

Cetuximab is a drug targeting the epidermal growth factor receptor, which is indicated for the treatment of unresectable advanced or recurrent head and neck or colorectal cancer. Cetuximab also enhances the cytotoxic effects of radiation in squamous cell carcinoma. The severity of infusion reactions (IR) is categorized from grade 1 to 5; grades 3 and 4 are associated with life-threatening reactions (anaphylaxis), whereas grade 5 indicates death. The incidence of grade 3-4 IR with premedication is reported to be 1.1%. We herein describe a case of a 77-year-old man who developed IR during intravenous administration of cetuximab. The patient developed grade 3-4 anaphylaxis with pruritus, rash and urticaria, followed by hypotension and bradycardia. The timely diagnosis and treatment with intravenous infusion of a vasopressor drug and Ringer’s acetate solution proved to be effective. The case presented herein demonstrated an unfeatured aspect of cetuximab-related IR as dermatological reactions over the entire body followed by circulatory collapse. 

Ohta, T., et al. (2017). “Skin CD4+ Memory T Cells Play an Essential Role in Acquired Anti-Tick Immunity through Interleukin-3-Mediated Basophil Recruitment to Tick-Feeding Sites.Frontiers in Immunology 8(1348).

Ticks, blood-sucking arthropods, serve as vectors for transmission of infectious diseases including Lyme borreliosis. After tick infestation, several animal species can develop resistance to subsequent infestations, reducing the risk of transmission. In a mouse model, basophils reportedly infiltrate tick-feeding sites during the second but not first infestation and play a crucial role in the expression of acquired tick resistance. However, the mechanism underlying basophil recruitment to the second tick-feeding site remains ill-defined. Here, we investigated cells and their products responsible for the basophil recruitment. 

Olafson, P. (2014). Ticks and the Mammalian Meat Allergy Topic Brief:  Beef Safety. Washington Dc, USDA.

Warmer temperatures and longer days signal the start to spring and summer chores on most cattle ranches. While the time spent outdoors is refreshing after the winter months, it brings with it an increased risk for not only heat exhaustion and dehydration but also for exposure to disease‐transmitting insects and ticks. Within the past three years, the novel Heartland and Bourbon viruses were discovered, both of which are transmitted via tick bites and resulted in human illnesses in Missouri, Tennessee and Kansas. Tick‐borne diseases of humans and livestock are well documented, as are immediate allergic skin reactions that can occur upon being bitten. But what if a tick bite could also cause a food allergy to red meat? It may sound like something straight out of the Twilight Zone, but tick bites and specific sugar modifications on red meat are actually the major players in the intriguing, highly publicized mammalian meat allergy. 

O’Neil, B. H., et al. (2007). “High Incidence of Cetuximab-Related Infusion Reactions in Tennessee and North Carolina and the Association With Atopic History.” Journal of Clinical Oncology 25(24): 3644-3648.

Purpose: To confirm the anecdotal observation that patients in North Carolina (NC) and Tennessee (TN) treated with cetuximab experience hypersensitivity reactions (HSR) at a much higher rate than are reported nationally and internationally (≤ 3%). Patients and Methods Data from patients treated with cetuximab on clinical trials (n = 88) at three research sites were analyzed for grade 3 or 4 HSR. Additional information was obtained from medical records for patients treated with cetuximab at the University of North Carolina (Chapel Hill, NC) to determine whether history of other significant allergy was a risk factor for HSR to cetuximab. Results Data for 88 patients on clinical trials and an additional 55 patients treated outside of trials were included in this analysis. Patients had a variety of tumor types. For the clinical trial group (n = 88), the overall rate of grade 3 to 4 HSR was 22%, significantly higher than the rate noted in any large published trial. All HSRs occurred during the first dose. There was a strong relationship between prior allergy history and chance of HSR. Conclusion At the sites in neighboring NC and TN studied, HSR was far more common than reported in national studies. History of prior allergy is a strong predictor of HSR. Further investigation of more specific predictors of HSR in the US middle south region is warranted, and patients being treated with cetuximab in this area should be observed particularly closely during their first infusion.

Pattanaik, D., et al. (2018). “The changing face of anaphylaxis in adults and adolescents.” Annals of Allergy, Asthma & Immunology 121(5): 594-597.

Background Our institution has published serial studies of adults and adolescents with anaphylactic events. The first series was published in 1993 and the last was published in 2006. It was our perception that the nature of anaphylactic episodes had changed over the 2 decades since the last review. Objective To determine whether the etiologies and presentations of anaphylaxis have changed during the past decade in our population. Methods Patient charts were identified based on International Classification of Diseases, Ninth Revision codes for anaphylactic shock. Charts identified were analyzed for clinical symptoms reported, comorbidities, etiology, investigative testing, and subsequent treatment. These cases were categorized as definitive, probable, or idiopathic based on history and results from testing, similar to our prior reports. Results We identified 281 possible cases, of which 218 met criteria for anaphylaxis. Of these cases, median age was 42 years (range 9–78) and 64% were female. In the review of cases, 85 (39%) were determined to have a definitive etiology, 57 were determined to have a probable etiology (26%), and 76 (35%) were idiopathic. Interestingly, of those with a definitive cause, the most common etiology identified was galactose-α-1,3-galactose, accounting for 28 cases (33%). Foods were the second leading cause, accounting for 24 cases (28%). Conclusion In this follow-up report on anaphylaxis etiology from a single center, the most common etiology was galactose-α-1,3-galactose. This differs greatly from prior reports from our center. Interestingly, the percentage of cases attributed to idiopathic anaphylaxis decreased from 59% in our previous report to 35% in the present report, which could largely be explained by the number of galactose-α-1,3-galactose cases.

Pek, C. H., et al. (2016). “Rare Cause of Facial Palsy: Case Report of Tick Paralysis by Ixodes Holocyclus Imported by a Patient Travelling into Singapore from Australia.” The Journal of Emergency Medicine 51(5): e109-e114.

Background Ticks are blood-sucking arachnids that feed on all classes of vertebrates, including humans. Ixodes holocyclus, also known as the Australian Paralysis Tick, is capable of causing a myriad of clinical issues in humans and companion animals, including the transmission of infectious agents, toxin-mediated paralysis, allergic and inflammatory reactions, and mammalian meat allergies in humans. The Australian Paralysis Tick is endemic to Australia, and only two other exported cases have been reported in the literature. Case Report We report the third exported case of tick paralysis caused by I. holocyclus, which was imported on a patient into Singapore. We also discuss the clinical course of the patient, the salient points of management, and the proper removal of this tick species. Why Should An Emergency Physician Be Aware of This? With increasing air travel, emergency physicians need to be aware of and to identify imported cases of tick paralysis to institute proper management and advice to the patient. We also describe the tick identification features and proper method of removal of this tick species.

Pelletier, T., et al. (2018). “Meat reintroduction in a patient with alpha-gal allergy.” Annals of Allergy Asthma & Immunology 121(1): 123-124.

A 56-year-old woman presented to a drug allergy clinic for evaluation of a possible allergic reaction to acetaminophen. Two months before presentation, the patient took 1,000 mg acetaminophen for pain relief and 5 hours later awoke with pruritic hives that resolved with diphenhydramine. Two weeks later, she took acetaminophen and developed pruritic hives 4 hours later, this time with vomiting, cramping, pruritic mouth, and sensation of throat closure. These symptoms resolved with diphenhydramine. 

Perota, A., et al. (2019). “Generation of cattle knockout for galactose-α1,3-galactose and N-glycolylneuraminic acid antigens.” Xenotransplantation 26(5): e12524.

Abstract Two well-characterized carbohydrate epitopes are absent in humans but present in other mammals. These are galactose-α1,3-galactose (αGal) and N-glycolylneuraminic acid (Neu5Gc) which are introduced by the activities of two enzymes including α(1,3) galactosyltransferase (encoded by the GGTA1 gene) and CMP-Neu5Gc hydroxylase (encoded by the CMAH gene) that are inactive in humans but present in cattle. Hence, bovine-derived products are antigenic in humans who receive bioprosthetic heart valves (BHVs) or those that suffer from red meat syndrome. Using programmable nucleases, we disrupted (knockout, KO) GGTA1 and CMAH genes encoding for the enzymes that catalyse the synthesis of αGal and Neu5Gc, respectively, in both male and female bovine fibroblasts. The KO in clonally selected fibroblasts was detected by polymerase chain reaction (PCR) and confirmed by Sanger sequencing. Selected fibroblasts colonies were used for somatic cell nuclear transfer (SCNT) to produce cloned embryos that were implanted in surrogate recipient heifers. Fifty-three embryos were implanted in 33 recipients’ heifers; 3 pregnancies were carried to term and delivered 3 live calves. Primary cell cultures were established from the 3 calves and following molecular analyses confirmed the genetic deletions. FACS analysis showed the double-KO phenotype for both antigens confirming the mutated genotypes. Availability of such cattle double-KO model lacking both αGal and Neu5Gc offers a unique opportunity to study the functionality of BHV manufactured with tissues of potentially lower immunogenicity, as well as a possible new clinical approach to help patients with red meat allergy syndrome due to the presence of these xenoantigens in the diet. 

Peters, C., et al. (2016). Anaphylaxie peranesthésique à la gélatine associée à une allergie alimentaire à l’alpha-gal.” Anesthésie & Réanimation 2(2): 123-125.

Résumé Récemment, le galactose-α-1,3-galactose, également connu sous alpha-gal, un sucre présent chez la plupart des mammifères à l’exception des primates, a été identifié comme allergène responsable d’anaphylaxies immédiates lors de l’administration de cetuximab et d’anaphylaxies retardées après consommation de viandes de mammifères. Certaines personnes allergiques à la viande de mammifère montrent également une sensibilisation à la gélatine. Nous décrivons le cas d’un patient présentant à la fois une allergie aux abats de mammifères reposant sur une hypersensibilité IgE-dépendante à l’alpha-gal et une anaphylaxie à un substitut plasmatique à base de gélatine fluide modifiée (Geloplasma®). Summary Recently, galactose-α-1,3-galactose, also known as alpha-gal, an oligosaccharide found in all mammals except primates, has been identified as an allergen responsible of immediate anaphylaxis during cetuximab perfusion or late-onset anaphylaxis after consumption of mammal meat. Some subjects with mammal meat allergy also present gelatin sensitization. We describe the observation of a patient with an allergy to mammal kidneys due to an IgE-mediated alpha-gal allergy and an anaphylactic reaction to gelatin-based plasma substitute (Geloplasma®). 

Pfutzner, W. and K. Brockow (2018). “Perioperative drug reactions – practical recommendations for allergy testing and patient management.” Allergo J Int 27(4): 126-129.

Background: Allergy testing for perioperative drug reactions poses a particular diagnostic challenge. Neuromuscular blocking agents (NMBA) and antibiotics are among the most common triggers. In principle, however, any drug administered perioperatively is capable of causing a hypersensitivity reaction. Methods: This article is an overview of selected scientific articles and is based on research in PubMed, specialist databases, and guidelines. Results: Besides patient’s history and laboratory tests (the latter being feasible to only a limited extent), skin tests play a particularly important role. To obtain clinical relevant results, profound knowledge on the best point in time for testing, the drug concentrations to be used, how to perform tests correctly, and the assessment criteria is of special importance. Conclusion: Final outcomes of the diagnostic procedures should be providing thorough information of the patient about the findings, drugs that should be avoided in the future as well as alternative preparations, and, if necessary, preventive measures to be taken in the event of further surgical interventions.

 Pinion, A. K. and S. A. Gierer (2015). “A Novel Description of Polyarthralgia with Alpha-Gal Allergy.” Journal of Allergy and Clinical Immunology 135(2, Suppl. S): AB253.

RATIONALE: Southern tick-associated rash illness (STARI) is a disease characterized by erythema migrans and flu-like symptoms that is temporally associated with a bite from Amblyomma americanum (Lone Star tick). Preliminary polymerase chain reaction studies have suggested that STARI is caused by Borrelia lonestari, a spirochete closely related to Borrelia burgdorferi. Delayed anaphylaxis to red meat with an elevated serum IgE to galactose-alpha-1,3-galactose occurring with STARI has not been reported. 

Pinson, M. L. and K. H. Waibel (2015). “Safe administration of a gelatin-containing vaccine in an adult with galactose-α-1,3-galactose allergy.” Vaccine 33(10): 1231-1232.

Immunoglobulin (Ig) E antibodies to galactose-α-1,3-galactose (α-Gal) are associated with delayed anaphylaxis to mammalian food products and gelatin-based foods (Commins et al., J Allergy Clin Immunol 2009;123:426; Caponetto et al., J Allergy Clin Immunol Pract 2013;1:302). We describe a patient with α-Gal allergy who successfully tolerated the live zoster vaccine and we review anaphylactic reactions reported to this vaccine. Our patient, who tolerated a vaccine containing the highest gelatin content, is reassuring but continued safety assessment of gelatin-containing vaccines for this patient cohort is recommended as there are multiple factors for this patient cohort that influence the reaction risk. 

Pisazka, V., et al. (2019). “Alpha-gal allergy after a tick bite in Austria.” Wien Klin Wochenschr 131(15-16): 385-388.

Tick bites can cause the alpha-gal syndrome, which is characterized by delayed anaphylactic reactions mainly to red meat and offal due to IgE antibodies against mammalian galactose-alpha-1.3-galactose carbohydrate (alpha-gal). Ixodes ricinus bites are considered the primary cause of IgE antibody responses specific for alpha-gal in Europe. This article reports on a 51-year-old Austrian male who acquired a tick bite in Austria in spring 2017, which, within 48h, resulted in prolonged inflammation of the skin area around the bite. The patient experienced an allergic reaction 3 months later approximately 8h after eating a medium rare steak for dinner. The symptoms included an itchy rash on both sides of the torso and on both arms which persisted for several hours. In spring 2018, the patient suffered another tick bite. The patient’s skin reaction was similar to that of the previous year. In the following months, the patient experienced five episodes of severe allergic reactions, each during the night after having eaten beef for dinner. The symptoms included pruritic urticarial rash involving the entire body along with swollen hands, diarrhea, vomiting and in some episodes even shortness of breath. At the request of the patient, specific IgE antibodies against alpha-gal were determined, revealing a highly positive result (>100kU/l). This brief report aims to raise awareness that recurrent delayed anaphylactic reactions to food can develop after tick bites. 

Pita, J., et al. (2018). “Alergia a galactose-±-1,3-galactose.” Revista Portuguesa de Imunoalergologia 26: 11-19.

The aim of this article is to review allergy to galactose-α-1,3-galactose. The authors performed a search in Pubmed and selected 24 articles in the last 5 years. Galactose-alpha-1,3-galactose (α-gal) is an oligosaccharide present in mammals, except in humans and higher primates. α-gal hypersensitivity differs from other IgE-mediated reactions, particularly on the late-onset of symptoms and is characterized by the association between a confirmed episode of tick bite and the posterior development of urticaria, anaphylaxis or gastrointestinal symptoms, two to six hours after red meat ingestion. Reactions to cetuximab, a monoclonal antibody against EGFR (epidermal growth factor receptor) occur immediately after the first administration, due to the presence of the epitope α-gal. Skin prick tests utility is limited, as they are not highly specific, and dosing the serum specific IgE to α-gal is an essential analysis for diagnosis and monitoring of the disease. 

Platts-Mills, T. A., et al. (2019). “Diagnosis and management of patients with the alpha-gal syndrome.” J Allergy Clin Immunol Pract.

The alpha-Gal syndrome has many novel features that are relevant to diagnosis and management. In most cases the diagnosis can be made on a history of delayed allergic reactions to red meat and the blood test for IgE to the oligosaccharide galactose-alpha-1,3-galactose (alpha-Gal). In general, the diagnosis also dictates the primary treatment, i.e. – avoiding mammalian meat and also dairy in some cases. In the USA the lone star tick is the primary cause of this disease but different ticks are responsible in other countries. Blood levels of IgE to alpha-Gal often drop in patients who avoid recurrent tick bites, but the rate of decline is variable. Similarly, the delay before reactions is variable and the severity of the allergic reactions is not predicted by the delay or the titer of specific IgE. Some mammalian-derived products are only relevant to select patient groups, such as heart valves, gelatin-based plasma expanders, and pancreatic enzymes. A minority of cases may benefit from avoiding a wide range of products that are prepared with mammalian-derived constituents, such as gelatin. This review focuses on the nature of the syndrome, common challenges in diagnosis and management, and also gaps in our current knowledge that would benefit from additional investigation. 

Platts-Mills, T. A. E. and S. P. Commins (2013). “Emerging antigens involved in allergic responses.” Current Opinion in Immunology 25(6): 769-774.

New allergic diseases can ’emerge’ because of exposure to a novel antigen, because the immune responsiveness of the subject changes, or because of a change in the behavior of the population. Novel antigens have entered the environment as new pests in the home (e.g., Asian lady beetle or stink bugs), in the diet (e.g., prebiotics or wheat isolates), or because of the spread of a biting arthropod (e.g., ticks). Over the last few years, a significant new disease has been identified, which has changed the paradigm for food allergy. Bites of the tick, Amblyomma americanum, are capable of inducing IgE antibodies to galactose-alpha-1,3-galactose, which is associated with two novel forms of anaphylaxis. In a large area of the southeastern United States, the disease of delayed anaphylaxis to mammalian meat is now common. This disease challenges many previous rules about food allergy and provides a striking model of an emerging allergic disease. 

Platts-Mills, T. A. E. and S. P. Commins (2013). “Tick bite induced IgE antibodies to alpha-gal and delayed anaphylactic reactions to mammalian derived foods.” Allergo Journal 22(8): 559-561.

Cross reactive carbohydrate determinants (CCD) on plant proteins are recognized as a target for IgE (immunoglobulin E) responses. However, in most cases IgE specific for these CCD are not associated with symptoms. In 2006, several oncology groups in the USA became aware that cetuximab was causing severe hypersensitivity reactions in a surprising number of patients. Investigating these reactions, we showed that the patients who reacted had IgE specific for an oligosaccharide on the Fab (fragment, antigen binding) portion of the heavy chain. In collaboration with ImClone, it became clear that this epitope was galactose alpha-1, 3-galactose (alpha-gal). This sugar is a well-known blood group substance of the non-primate mammals. Using the assay for IgE to alpha-gal we screened sera from the clinic and identified a group of patients who had repeated episodes of urticaria or anaphylaxis and who also had IgE to alpha-gal. 

Platts-Mills, T. A. E., et al. (2019). “A consistent ”shortage” of cases of the alpha-gal syndrome (AS) on the Gulf coast: possible relevance of fire ants as a predator of lone star ticks.” Journal of Allergy and Clinical Immunology 143(2): AB278-AB278.

RATIONALE: Allergic reactions to red meat in patients with IgE to alpha-gal are common in the southeastern U.S., but appear less common on the Gulf coast and into much of Texas. This contrasts with the reported distribution of A americanum (lone star tick). In addition, it has been known for many years that fire ants can kill ticks. METHODS: We carried out a survey of the prevalence of AS in allergy practices in areas where the fire ant has been present since 1974 (n510), compared to areas of the Southeast without fire ants in 2000 (n523). In a subset of clinics we additionally assessed reports of fire ant anaphylaxis (FAA). 

Platts-Mills, T. A. E., et al. (2018). “Characterizing the Geographic Distribution of the Alpha-gal Syndrome: Relevance to Lone Star Ticks (Amblyomma americanum) and Rickettsia.” Journal of Allergy and Clinical Immunology 141(2): AB147-AB147.

Methods Using a modified snowball design, we interviewed∼ 100 allergists starting in areas with high prevalence of AS. The questionnaire related to the number of confirmed cases, the response to an avoidance diet and the relationship to tick bites. The incidence of AS was compared to recent publications from the CDC describing the geographic distribution of A. americanum and tick-borne infections. Results Large numbers of cases, ie 50-200, were reported by many allergists in the southeast, but also in Long Island, NY. 

Platts-Mills, T. A. E., et al. (2016). “IgE in the diagnosis and treatment of allergic disease.” Journal of Allergy and Clinical Immunology 137(6): 1662-1670.

Traditionally, the concept of allergy implied an abnormal response to an otherwise benign agent (eg, pollen or food), with an easily identifiable relationship between exposure and disease. However, there are syndromes in which the relationship between exposure to the relevant allergen and the “allergic” disease is not clear. In these cases, the presence of specific IgE antibodies can play an important role in identifying the relevant allergen and provide a guide to therapy. Good examples include chronic asthma and exposure to perennial indoor allergens and asthma related to fungal infection. Finally, we are increasingly aware of forms of food allergy in which the relationship between exposure and the disease is delayed by 3 to 6 hours or longer. Three forms of food allergy with distinct clinical features are now well recognized. These are (1) anaphylactic sensitivity to peanut, (2) eosinophilic esophagitis related to cow’s milk, and (3) delayed anaphylaxis to red meat. In these syndromes the immunology of the response is dramatically different. Peanut and galactose alpha-1,3-galactose (alpha-gal) are characterized by high- or very high- titer IgE antibodies for Ara h 2 and alpha-gal, respectively. By contrast, eosinophilic esophagitis is characterized by low levels of IgE specific for milk proteins with high- or very high- titer IgG(4) to the same proteins. The recent finding is that patients with alpha-gal syndrome do not have detectable IgG(4) to the oligosaccharide. Thus the serum results not only identify relevant antigens but also provide a guide to the nature of the immune response. 

Platts-Mills, T. A. E., et al. (2015). “Delayed Anaphylaxis Involving IgE to Galactose-alpha-1,3-galactose.” Curr Allergy Asthma Rep 15(4).

Hypersensitivity in the allergic setting refers to immune reactions, stimulated by soluble antigens that can be rapidly progressing and, in the case of anaphylaxis, are occasionally fatal. As the number of known exposures associated with anaphylaxis is limited, identification of novel causative agents is important in facilitating both education and other allergen-specific approaches that are crucial to long-term risk management. Within the last 10 years, several seemingly separate observations were recognized to be related, all of which resulted from the development of antibodies to a carbohydrate moiety on proteins where exposure differed from airborne allergens but which were nevertheless capable of producing anaphylactic and hypersensitivity reactions. Our recent work has identified these responses as being due to a novel IgE antibody directed against a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal). This review will present the history and biology of alpha-gal and discuss our current approach to management of the mammalian meat allergy and delayed anaphylaxis. 

Platts-Mills, T. A. E., et al. (2015). “Anaphylaxis to the Carbohydrate Side Chain Alpha-gal.” Immunol Allergy Clin North Am 35(2): 247-+.

In 2007, the monoclonal antibody cetuximab caused severe hypersensitivity reactions during the first infusion in a region of the southeastern United States. Investigation of pretreatment sera established that they contained immunoglobulin (Ig) E against the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal), which is present on the Fab of cetuximab. Alpha-gal is a blood group substance of nonprimate mammals. These IgE antibodies are also associated with delayed anaphylaxis to red meat (ie, to meat or organs of animals that carry this oligosaccharide). Evidence shows that the primary cause of these IgE antibodies is bites from the tick Amblyomma americanum or its larvae. 

Pointreau, Y., et al. (2012). “Fatal Infusion Reactions to Cetuximab: Role of Immunoglobulin E–Mediated Anaphylaxis.” Journal of Clinical Oncology 30(3): 334-334.

In Journal of Clinical Oncology, Tronconi et al report a fatal hypersensitivity reaction to cetuximab in a 63-year-old patient with metastatic colon cancer and outlined a 0.1% incidence of death in the literature. We greatly acknowledge the authors’ desire to communicate the risk of fatal anaphylactic reaction with cetuximab. Over the past 2 years in our center in Tours, France, four instances of grade 4 anaphylactic reactions occurred in patients treated for head and neck cancer (locally advanced or metastatic), with one immediately fatal; another patient died within 5 days (unpublished data). Seven lethal anaphylactic reactions were registered in a pharmacovigilance survey in France, based on spontaneous declarations (Grandvuillemin et al, manuscript in preparation). Anaphylaxis to cetuximab is a problem that merits serious clinical attention. 

Pollack, K., et al. (2019). “α-Gal Syndrome vs Chronic Urticaria.” JAMA Dermatology 155(1): 115-116.

Galactose-α-1,3-galactose (α-gal) is an oligosaccharide expressed on glycoproteins and glycolipids of nonprimate mammals and is the causal epitope of an IgE-mediated allergy to mammalian meat. First reported in 2009, the α-gal syndrome is an increasingly appreciated problem across the southeastern United States and other parts of the world. It is clear that tick bites, specifically relating to Amblyomma americanum (lone star tick), are causal in many, if not most, cases of α-gal sensitization in the United States. Following sensitization, many individuals will experience allergic symptoms on ingestion of meat or other products (eg, dairy) derived from nonprimate mammals. In contrast to typical IgE-mediated reactions, which occur within minutes of exposure, the α-gal allergy typically has a delayed onset of 2 to 6 hours. The severity of the reaction varies from general urticaria to anaphylaxis, and individuals may not react to every exposure. Because of these atypical features, proper diagnosis can prove challenging. An epidemiological investigation of a pediatric population reported that α-gal may be misdiagnosed as recurrent urticaria or idiopathic anaphylaxis. While a recent report postulated that α-gal syndrome might represent a novel cause of chronic urticaria, further research failed to find such an association. Nevertheless, in areas where α-gal sensitization is prevalent, the potential for misdiagnosing cases of α-gal syndrome as chronic urticaria still exists. Here, we report cases labeled as chronic urticaria or chronic idiopathic urticaria within a cohort of patients in central Virginia being evaluated for α-gal syndrome. 

Popescu, F. D., et al. (2019). “DRUG ALLERGIES DUE TO IgE SENSITIZATION TO alpha-GAL.” Farmacia 67(1): 43-49.

Serum specific IgE antibodies for non-primate mammalian carbohydrate galactose-alpha-1,3-galactose (alpha-Gal) are associated to alpha-Gal syndrome: delayed allergy to red meat manifested as anaphylaxis, angioedema or urticaria after ingestion of beef, pig or lamb meat, immediate-onset anaphylaxis at first parenteral exposure to drugs significantly containing alpha-Gal. IgE-mediated drug allergy in the alpha-Gal syndrome was reported for some therapeutic monoclonal antibodies, such as cetuximab, snake antivenom, and varicella-zoster vaccine, but there are risks also for colloid plasma volume substitutes, vaccines containing gelatin of porcine/bovine animal origin as an excipient, and drugs with porcine pancreatin or bovine-origin magnesium stearate. 

Posthumus, J., et al. (2010). “Correlation of Blood Type with the Presence of IgE Antibodies to Galactose-alpha-1,3-galactose (Alpha-gal): Is there a Protective Effect of Blood Group Substance B?” Journal of Allergy and Clinical Immunology 125(2): AB203-AB203. 

Posthumus, J., et al. (2012). “In the Pork-Cat Syndrome, Allergic Reactions to Pork Reflect IgE Antibodies to Cat Albumin that Cross-reacts with Other Albumins.” Journal of Allergy and Clinical Immunology 129(2): AB177. 

Posthumus, J., et al. (2013). “Initial description of pork-cat syndrome in the United States.” Journal of Allergy and Clinical Immunology 131(3): 923-925.

Despite meat being an important source of protein in Western diets, development of meat allergy is uncommon.javascript:void(0); For mammalian meat, the extensive homology of proteins across mammalian species decreases the likelihood of creating a specific IgE (sIgE) response. In fact, when clinically relevant reactivity to meats has been demonstrated, the results point to cross-reactivity (eg, serum albumin [SA] and actin) and not to a sensitization with meat-specific epitopes. In keeping with this cross-reactivity, reports of IgE antibodies that bind various mammalian albumins do exist, notably pork-cat syndrome. In this uncommon syndrome patients have an IgE antibody response specific for cat SA that cross-reacts with porcine albumin and can lead to severe or even fatal allergic reactions on occasions when pork is consumed.  Interestingly, the reported cases of pork-cat syndrome are largely European.

Raghavan, R. K., et al. (2019). “Current and Future Distribution of the Lone Star Tick, Amblyomma americanum (L.) (Acari: Ixodidae) in North America.” PLOS ONE 14(1): e0209082.

Acarological surveys in areas outside the currently believed leading edge of the distribution of lone star ticks (Amblyomma americanum), coupled with recent reports of their identification in previously uninvaded areas in the public health literature, suggest that this species is more broadly distributed in North America than currently understood. Therefore, we evaluated the potential geographic extent under present and future conditions using ecological niche modeling approach based on museum records available for this species at the Walter Reed Biosystematics Unit (WRBU). The median prediction of a best-fitting model indicated that lone star ticks are currently likely to be present in broader regions across the Eastern Seaboard as well as in the Upper Midwest, where this species could be expanding its range. Further northward and westward expansion of these ticks can be expected as a result of ongoing climate change, under both low- and high-emissions scenarios. 

Ramey, K. and P. H. Stewart (2016). “Top Ten Facts You Should Know about “Alpha-gal, the Newly Described Delayed Red Meat Allergy.J Miss State Med Assoc 57(9): 279-281. 

Rauschenberg, R., et al. (2014). “Intraoperative anaphylactic reaction IV° to gelatin.” JDDG: Journal der Deutschen Dermatologischen Gesellschaft 12(7): 617-618. 

Renaudin, J., et al. (2012). “Interest Of Specific Ige Measurement For Galactose-alpha-1,3-galactose In Unexplained Recurrent Urticaria With Angioedema, Predominantly Nocturnal: About 6 Cases.” Journal of Allergy and Clinical Immunology 129(2): AB177-AB177. 

Retterer, M. K. C., et al. (2018). “Specific IgE to gelatin as a cause of anaphylaxis to zoster vaccine.” Journal of Allergy and Clinical Immunology 141(5): 1956-1957.

Reading the recent letter from Stone et al reminded us of a subject from our previous galactose-a-1,3-galactose (alpha-gal) study. Indeed, she may well be the same 76-year-old lady found in the letter (Table E1) who was reported as negative to alpha-gal. Her first reaction to meat started 45 minutes after eating barbecue, only a few months following her recovery from Lyme disease. Since then she has had multiple reactions of varying severity, some of which started less than 1 hour after ingestion of red meat. Although not the average time for the onset of an alpha-gal allergic reaction, which is approximately 3 to 5 hours, her reactions to meat were not immediate either. In 2007, 20 minutes after receiving zoster vaccine, she went into cardiovascular collapse, requiring emergency treatment and an overnight hospital stay. 

Retterer, M. K. C., et al. (2019). “Tick bites and IgE sensitization to the oligosaccharide galactose-alpha-1,3-galactose (alpha-Gal): a Bacterial Hypothesis.” Journal of Allergy and Clinical Immunology 143(2): AB155-AB155.

RATIONALE: IgE to a-Gal is causal in delayed anaphylaxis to mammalian meat and relates to bites from hard ticks. Though it is unclear whether ticks intrinsically express a-gal, these glycans have been shown to be present in tick saliva. Because gram-negative enteric bacteria are known to express a-Gal, we considered the possibility that the source of a-Gal relates to symbionts in lone star ticks

Ribeiro, F., et al. (2013). “Mammal’s meat and cow’s milk allergy – case report.” Clinical and Translational Allergy 3(3): P152.

Background The mammalian meat allergy is not very common. When it happens in adults, it may be related to respiratory allergy to mammalian epithelia (e.g. pork-cat syndrome) or to sensitization to the recently discovered IgE antibody to a mammalian oligosaccharide epitope galactose-alpha-1,3-galactose (a-gal). 

Richards, S. L., et al. (2017). “Do Tick Attachment Times Vary between Different Tick-Pathogen Systems?” Environments 4(2).

Improvements to risk assessments are needed to enhance our understanding of tick-borne disease epidemiology. We review tick vectors and duration of tick attachment required for pathogen transmission for the following pathogens/toxins and diseases: (1) Anaplasma phagocytophilum (anaplasmosis); (2) Babesia microti (babesiosis); (3) Borrelia burgdorferi (Lyme disease); (4) Southern tick-associated rash illness; (5) Borrelia hermsii (tick-borne relapsing fever); (6) Borrelia parkeri (tick-borne relapsing fever); (7) Borrelia turicatae (tick-borne relapsing fever); (8) Borrelia mayonii; (9) Borrelia miyamotoi; (10) Coxiella burnetii (Query fever); (11) Ehrlichia chaffeensis (ehrlichiosis); (12) Ehrlichia ewingii (ehrlichiosis); (13) Ehrlichia muris; (14) Francisella tularensis (tularemia); (15) Rickettsia 364D; (16) Rickettsia montanensis; (17) Rickettsia parkeri (American boutonneuse fever, American tick bite fever); (18) Rickettsia ricketsii (Rocky Mountain spotted fever); (19) Colorado tick fever virus (Colorado tick fever); (20) Heartland virus; (21) Powassan virus (Powassan disease); (22) tick paralysis neurotoxin; and (23) Galactose-alpha-1,3-galactose (Mammalian Meat Allergy-alpha-gal syndrome). Published studies for 12 of the 23 pathogens/diseases showed tick attachment times. Reported tick attachment times varied (<1 h to seven days) between pathogen/toxin type and tick vector. Not all studies were designed to detect the duration of attachment required for transmission. Knowledge of this important aspect of vector competence is lacking and impairs risk assessment for some tick-borne pathogens. 

Rispens, T. (2014). “IgE antibodies specific to alpha-gal: an example of clinically relevant cross-reactive anti-carbohydrate antibodies.” Clinical & Experimental Allergy 44(8): 1008-1011.

Red meat allergy is an unusual, novel form of allergy with delayed onset of reactions (anaphylaxis, angioedema or urticaria) several hours after meat consumption and is thought to be primarily mediated by IgE antibodies to gal-o-1, 3-gal-b-1, 4-GlcNAc (o-gal)[1–4]. The o-gal epitope is a carbohydrate structure that is abundantly expressed on many proteins and cellular structures of many mammalian species. Notable exceptions are humans as well as several other primates that lost the ability to express o-gal. 

Rispens, T., et al. (2013). “IgE Production to α-Gal Is Accompanied by Elevated Levels of Specific IgG1 Antibodies and Low Amounts of IgE to Blood Group B.” PLoS One 8(2): e55566.

IgE antibodies to gal-α-1,3-gal-β-1,4-GlcNAc (α-gal) can mediate a novel form of delayed anaphylaxis to red meat. Although IgG antibodies to α-gal (anti-α-gal or anti-Gal) are widely expressed in humans, IgE anti-α-gal is not. We explored the relationship between the IgG and IgE responses to both α-gal and the related blood group B antigen. Contradicting previous reports, antibodies to α-gal were found to be significantly less abundant in individuals with blood group B or AB. Importantly, we established a connection between IgE and IgG responses to α-gal: elevated titers of IgG anti-α-gal were found in IgE-positive subjects. In particular, proportionally more IgG1 anti-α-gal was found in IgE-positive subjects against a background of IgG2 production specific for α-gal. Thus, two types of immune response to α-gal epitopes can be distinguished: a ‘typical’ IgG2 response, presumably in response to gut bacteria, and an ‘atypical’, Th2-like response leading to IgG1 and IgE in addition to IgG2. These results suggest that IgE to a carbohydrate antigen can be formed (probably as part of a glycoprotein or glycolipid) even against a background of bacterial immune stimulation with essentially the same antigen. 

Ristivojevic, M. K., et al. (2018). “alpha-Gal on the protein surface affects uptake and degradation in immature monocyte derived dendritic cells.” Sci Rep 8.

Red meat allergy is characterized by an IgE response against the carbohydrate galactose-alpha-1,3-galactose (alpha-Gal), which is abundantly expressed on glycoproteins from non-primate mammals. The mechanisms of how alpha-Gal is processed and presented to the immune system to initiate an allergic reaction are still unknown. The aim of this study was to reveal whether the presence of alpha-Gal epitopes on the protein surface influence antigen uptake and processing in immature monocyte-derived dendritic cells (iMDDCs). Immature MDDCs were prepared from healthy blood donors and red meat allergic patients. We found an increased internalization of alpha-Gal carrying proteins over time in iMDDCs by flow cytometric analysis, which was independent of the donor allergic status. The uptake of alpha-Gal carrying proteins was significantly higher than the uptake of non-alpha-Gal carrying proteins. Confocal microscopy revealed alpha-Gal carrying proteins scattered around the cytoplasm in most iMDDCs while detection of proteins not carrying alpha-Gal was negligible. Fluorescent detection of protein on SDS-PAGE showed that degradation of alpha-Gal carrying proteins was slower than degradation of non-alpha-Gal carrying proteins. Thus, the presence of alpha-Gal on the protein surface affects both uptake and degradation of the protein, and the results add new knowledge of alpha-Gal as a clinically relevant food allergen.

 Rizer, J., et al. (2017). “Acute hypersensitivity reaction to Crotalidae polyvalent immune Fab (CroFab) as initial presentation of galactose–1,3-galactose (-gal) allergy.” Clinical Toxicology 55(7): 668-669.

Crotalidae polyvalent immune Fab antivenom (CroFab), commonly used for the treatment of clinically significant North American crotalinae envenomation, is generally well-tolerated. A novel form of anaphylaxis due to an IgE antibody response to the mammalian oligosaccharide galactose–1,3-galactose (-gal) has been established following red-meat consumption as well as IV administration of cetuximab, which contain the -gal epitope. We present a case of -gal allergy discovered after acute hypersensitivity reaction to FabAV. A 61-year-old healthy female was bitten on her left ankle by Agkistrodon contortrix. Given the patient’s rapid progression of pain and swelling, she was given FabAV. During infusion of FabAV, she developed diffuse hives over her entire body and itching, but denied respiratory or gastrointestinal symptoms and her vital signs remained stable. The FabAV was immediately discontinued and she received intravenous diphenhydramine and famotidine with gradual resolution of symptoms. On further discussion, she denied a history of -gal or papaya allergy but rarely ate red meat and endorsed sustaining frequent tick bites. Subsequent antibody testing was significant for an -1,3-galactose IgE concentration of 45,000U/L (normal <3500U/L), confirming -gal allergy. To our knowledge, this is the first report of FabAV hypersensitivity associated with an underlying -gal allergy.

 Robison, S. W. (2017). “Tick Bites And Delayed Anaphylaxis To Red Meat: Rare Alpha-Gal Allergy In Florida.” Am J Respir Crit Care Med 195.

Accurate identification of a dietary trigger for anaphylaxis can have a dramatic, lifesaving impact for a patient. Galactose alpha-1,3-galactose is an oligosaccharide found in non-primate mammals, so an allergy to this antigen causes an allergic reaction to mammalian meat and milk products. Diagnosis can be difficult because the allergic reaction is delayed, occurring 3-6 hours after the meal. A 65-year-old gentleman presented to the allergy and immunology clinic for an evaluation of episodes of “spontaneous” anaphylaxis. Per the patient’s report, the episodes began about 10 years ago. They vary in severity: sometimes he only develops urticaria, but other times he develops severe hypotension and is taken to the emergency department. The episodes occur more frequently at night, and he has them a few times per week. They do not occur while eating or directly after eating. He lives in a rural, wooded area in central Florida and has sustained many tick bites, mosquito bites, and bee stings over his life and has not had a reaction associated with insect bites. Allergy skin prick testing to common food allergens done in the office was negative. He had an elevated serum IgE level. Based on the history of tick bites and the possibility of delayed anaphylaxis after meals, he was tested for alpha gal allergy. He was positive for IgE alpha galactose 1,3. He was advised to avoid all mammalian meat products including beef, pork, lamb, and milk.

 Rodenas, M., et al. (2019). “Increased Alpha-Gal Allergy In The Northern Florida Region: A Descriptive Cohort.” Journal of Allergy and Clinical Immunology 143(2, Suppl. S): AB158.

RATIONALE: Prevalence of alpha-gal allergy due to meat allergy is unknown. Tick borne diseases have been reported to be on the rise in Florida. Despite presence of the Amblyomma americanum tick in the region, there is only one case report of alpha-gal allergy in Florida.We provide the clinical profile of a cohort of patients with alpha-gal allergy seen at our tertiary center. METHODS: We performed a retrospective chart review of adult patients with both, meat specific IgE, and detectable alpha-gal IgE evaluated from May 2016 to August 2018. Age, sex, total IgE, alpha-gal IgE as well as available specific IgE against meats or skin test results were collected. Presenting symptoms and presence of atopic disorders were noted.

 Roenneberg, S., et al. (2016). “alpha-Gal-a new clue for anaphylaxis in mastocytosis.” Journal of Allergy and Clinical Immunology-in Practice 4(3): 531-532.

Anaphylactic reactions based on food allergy in patients with systemic mastocytosis have been rarely described. Here, we present the first case of galactose-α-1,3-galactose-associated anaphylaxis in a patient with co-occurring indolent systemic mastocytosis.

 Roman-Carrasco, P., et al. (2019). “Only alpha-Gal bound to lipids, but not to proteins, is transported across enterocytes as an IgE-reactive molecule that can induce effector cell activation.” Allergy.

BACKGROUND: The oligosaccharide galactose-alpha-1,3-galactose (alpha-Gal), present in mammalian proteins and lipids, causes an unusual delayed allergic reaction 3 to 6 hours after ingestion of mammalian meat in individuals with IgE antibodies against alpha-Gal. To better understand the delayed onset of allergic symptoms and investigate whether protein-bound or lipid-bound alpha-Gal causes these symptoms, we analyzed the capacity of alpha-Gal conjugated proteins and lipids to cross a monolayer of intestinal cells. METHODS: Extracts of proteins and lipids from beef were prepared, subjected to in vitro digestions, and added to Caco-2 cells grown on permeable supports. The presence of alpha-Gal in the basolateral medium was investigated by immunoblotting, thin-layer chromatography with immunostaining and ELISA, and its allergenic activity was analyzed in a basophil activation test. RESULTS: After addition of beef proteins to the apical side of Caco-2 cells, alpha-Gal containing peptides were not detected in the basolateral medium. Those peptides that crossed the Caco-2 monolayer did not activate basophils from an alpha-Gal allergic patient. Instead, when Caco-2 cells were incubated with lipids extracted from beef, alpha-Gal was detected in the basolateral medium. Furthermore, these alpha-Gal lipids were able to activate the basophils of an alpha-Gal allergic patient in a dose-dependent manner. CONCLUSION: Only Alpha-Gal bound to lipids, but not to proteins, is able to cross the intestinal monolayer and trigger an allergic reaction. This suggests that the slower digestion and absorption of lipids might be responsible for the unusual delayed allergic reactions in alpha-Gal allergic patients and identifies glycolipids as potential allergenic molecules.

Saleh, H., et al. (2012). “Anaphylactic reactions to oligosaccharides in red meat: a syndrome in evolution.” Clin Mol Allergy 10(1): 5.

OBJECTIVE: While most allergic responses to food are directed against protein epitopes and occur within 30 minutes of ingesting the allergen, recent studies suggest that delayed reactions may occur, sometimes mediated by IgE antibodies directed against carbohydrate moieties. The objective of this review is to summarize the clinical features and management of delayed hypersensitivity reactions to mammalian meat mediated by IgE antibodies to galactose-alpha 1,3-galactose (alpha-gal), an oligosaccharide. METHODS: A PubMed search was conducted with MeSH terms: galactosyl-(1,3) galactose, oligosaccharides, cetuximab, allergy/hypersensitivity, and anaphylaxis. Reported cases with alpha-gal-mediated reactions were reviewed. This research study was approved by the Institutional Review Board of East Tennessee State University. RESULTS: Thirty-two cases of adults presenting with red-meat induced allergy thought to be related to oligosaccharides have been reported in the literature so far, making this a rare and evolving syndrome. Most of these patients demonstrated delayed reactions to beef, as was seen in the case reported by us in this manuscript. IgE specific to alpha-gal was identified in most patients with variable response to skin testing with beef and pork. Inhibition studies in some cases showed that the IgE antibodies to beef were directed towards alpha-gal in the meat rather than the protein. The patients often reported history of tick bites, the significance of which is unclear at present. Reactions to cetuximab, a monoclonal antibody, are mediated by a similar mechanism, with IgE antibodies directed against an alpha-gal moiety incorporated in the drug structure. CONCLUSION: Alpha-gal is an oligosaccharide recently incriminated in delayed anaphylactic reactions to mammalian meats such as to beef, pork, and lamb. It appears that anaphylactic reactions to the anti-cancer biological agent, cetuximab, may be linked mechanistically to the same process. More studies are required to understand the underlying molecular basis for these delayed reactions in specific, and their broader implications for host defense in general.

Schmidle, P., et al. (2018). “Recall-Urticaria in two patients with Tick-bite Alpha-gal Syndrome.” Journal Der Deutschen Dermatologischen Gesellschaft 16: 2-2.

Schmidle, P., et al. (2019). “Recall urticaria-A new clinical sign in the diagnosis of alpha-gal syndrome.” Journal of Allergy and Clinical Immunology-in Practice 7(2): 685-686.

Diagnosis of alpha-gal syndrome remains difficult. Thus, clinical signs such as recall urticaria at the location of previous tick bites may be helpful diagnostic tools, not only as symptoms in clinical history but also for evaluating the results of oral provocation tests. 

Schroeder, N., et al. (2014). “Cellular Infiltrate Induced By Bites From The Tick Amblyomma Americanum In Subjects With Or Without IgE To Galactose-Alpha-1,3-Galactose (Alpha-gal).” Journal of Allergy and Clinical Immunology 133(2): AB226-AB226.

RATIONALE: Bites from A. americanum can cause severe pruritis and are considered to be the main cause of sensitization to alpha-gal. We hypothesized that local inflammation at the tick bite site plays a significant role in stimulation of the IgE response. METHODS: Naturally occurring bites of larval or adult ticks were biopsied 1 day (n52), 2 days (n51), or 4 days (n51) post-bite. Two subjects had previous positive IgE to alpha-gal and one was negative. The samples were either frozen and sectioned, or formalin-fixed and paraffin-embedded. H&E staining and immunohistochemistry for evaluation of eosinophils, basophils, dendritic cells, T cells, and TSLP was compared between alpha-gal positive and negative subjects and to normal skin.

Schuyler, A. J., et al. (2015). “Quantitative Binding Assay for Measuring Specific IgG Antibodies to Alpha-Gal Using the Neoglycoprotein Gal-alpha-1,3-Gal-beta-1,4-Glcnac-Human Serum Albumin.” Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI), Houston, TX, February 20-24, 2015 135(2): AB188-AB188.

Tick bites are known to induce IgE production to alpha-gal. Elevated alpha-gal IgG1 compared to natural alpha-gal IgG2 production has been reported in alpha-gal IgE+ subjects. We here report further investigation of the relationship between alpha-gal IgG and both reactions to red meat and exposure to ticks. Methods: IgG from serum was absorbed onto recombinant Protein G-Sepharose and incubated with radiolabeled allergen. The radioactivity of bound allergen was measured using a gamma counter. A control curve was generated in parallel to assign unit age. Additional testing of serum immunoglobulins was performed via ImmunoCAP and nephelometry. Results: Alpha-gal IgG was measured in a Northern Sweden cohort and in subjects presenting to allergy clinics in Virginia with delayed reactions to red meat. Alpha-gal IgG was significantly higher in alpha-gal IgE+ subjects versus alpha-gal IgE- subjects, and longitudinal serology in several alpha-gal IgE+ subjects demonstrates parallel alpha-gal IgE and IgG response trends. Among the alpha-gal IgE+ subjects, alpha-gal IgG was higher in those with alpha-gal IgE: total IgE ratios &gt;25%, but was not related to reported severity to red meat. Compared to the alpha-gal IgE- subjects in Virginia, alpha-gal IgG was lower in the group from Northern Sweden, where alpha-gal IgE-mediated hypersensitivity is absent and ticks are rare. Conclusions: Alpha-gal IgG is strongly related to alpha-gal IgE and is significantly lower in prevalence and titer in subjects without tick exposure. The absence of a relationship between alpha-gal IgG and severity of reactions to red meat suggests that the alpha-gal syndrome may not be a suitable candidate for conventional immunotherapy.

Sekiya, K., et al. (2012). “Delayed anaphylactic reaction to mammalian meat.” Journal of investigational allergology & clinical immunology 22(6): 446-447. 

Sell-Dottin, K., Sola, Michael and Caransos, Thomas G. (2017). “Impact of Newly Emerging Alpha-Gal Allergies on Cardiac Surgery: A Case Series.” Clinics in Surgery 2: 1477.

The influence of alpha-gal allergies on cardiothoracic surgery is largely unknown. Allergic responses to galactose-alpha-1, 3-galactose, or “alpha-gal”, are due to antibodies against non-primate mammalian proteins and are mediated by IgE. This allergy has only recently been discovered and is increasingly prevalent, upwards of 20%-25% of the general population in the southeast United States is sensitized to alpha-gal. Due to the exposure of patients to significant amounts of alpha-gal containing heparin during the course of cardiopulmonary bypass, this allergy may have significant implications for patients undergoing cardiac surgery. We provide a four case series from a single institution detailing successful cardiac surgery in four patients with known alpha gal allergies. These cases demonstrate that pre-treatment with diphenhydramine and steroids may help attenuate serious allergic reactions and allow cardiac surgery to be performed more safely. 

Shan, Y., et al. (2015). “[Assessment Method of Remnant alpha-1, 3-galactosyle Epitopes in Animal Tissue-derived Biomaterials].Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 32(3): 662-668, 679.

The aim of this study was to establish an assessment method for determining alpha-Gal (alpha-1, 3-galactosyle) epitopes contained in animal tissue or animal tissue-derived biological materials with ELISA inhibition assay. Firstly, a 96 well plate was coated with Gal alpha-1, 3-Gal/bovine serum albumin (BSA) as a solid phase antigen and meanwhile, the anti-alpha-Gal M86 was used to react with alpha-Gal antigens which contained in the test materials. Then, the residual antibodies (M86) in the supernatant of M86-Gal reaction mixture were measured using ELISA inhibition assay by the alpha-Gal coating plate. The inhibition curve of the ELISA inhibition assay, the R2 = 0.999, was well established. Checking using both alpha-Gal positive materials (rat liver tissues) and alpha-Gal negative materials (human placenta tissues) showed a good sensitivity and specificity. Based on the presently established method, the alpha-Gal expression profile of rat tissues, decellular animal tissue-derived biological materials and porcine dermal before and after decellular treatment were determined. The M86 ELISA inhibition assay method, which can quantitatively determine the alpha-Gal antigens contained in animal tissues or animal tissue-derived biomaterials, was refined. This M86 specific antibody based-ELISA inhibition assay established in the present study has good sensitivity and specificity and could be a useful method for determining remnant alpha-1, 3Gal antigens in animal tissue-derived biomaterials. 

Shroba, J., et al. (2018). “Possible Role of Environmental Factors in the Development of Food Allergies.” Clin Rev Allergy Immunol.

The development of food allergies is thought to involve multiple factors, and it is unclear which conveys the most risk regarding this process. Since food allergy is a chronic disease without a cure at this time, understanding its development could provide an avenue for preventive practices and development of a curative treatment. Both historical and current data implicate maternal factors, genetics, and environmental exposures as major risk factors in the development of food allergy. An immature gut of the infant has been hypothesized as a possible route of sensitization. Breastfeeding until at least 6 months of age has been shown to have protective factors for the newborn and may possibly improve gut permeability. Newer studies such as the LEAP and EAT investigations also looked at early exposure and prevention of food allergies; their long-term results are critical in understanding early introduction and tolerance. Cutaneous exposure, oral exposure, and food protein exposure in house dust with their relation to the food allergy course are also a path of interest. Current research has shown sensitization can occur through impaired skin such as those with eczema and a filaggrin mutation. Tropomyosin and alpha-gal also are related to the complicated immunomodulatory factors involved in food allergy and allergic response. Cross-reactivity with plant allergens, sensitization to house dust mite and cockroach, and lone star tick bites can also induce food allergens in children and adults. Together, these factors provide a cohesive beginning to understanding how food allergies can occur and can influence further investigation into prevention, treatment, and eventual cure of food allergies.

Sicherer, S. H. and H. A. Sampson (2014). “Food allergy: Epidemiology, pathogenesis, diagnosis, and treatment.” J Allergy Clin Immunol 133(2): 291-307; quiz 308.

This review focuses on advances and updates in the epidemiology, pathogenesis, diagnosis, and treatment of food allergy over the past 3 years since our last comprehensive review. On the basis of numerous studies, food allergy likely affects nearly 5% of adults and 8% of children, with growing evidence of an increase in prevalence. Potentially rectifiable risk factors include vitamin D insufficiency, unhealthful dietary fat, obesity, increased hygiene, and the timing of exposure to foods, but genetics and other lifestyle issues play a role as well. Interesting clinical insights into pathogenesis include discoveries regarding gene-environment interactions and an increasing understanding of the role of nonoral sensitizing exposures causing food allergy, such as delayed allergic reactions to carbohydrate moieties in mammalian meats caused by sensitization from homologous substances transferred during tick bites. Component-resolved diagnosis is being rapidly incorporated into clinical use, and sophisticated diagnostic tests that indicate severity and prognosis are on the horizon. Current management relies heavily on avoidance and emergency preparedness, and recent studies, guidelines, and resources provide insight into improving the safety and well-being of patients and their families. Incorporation of extensively heated (heat-denatured) forms of milk and egg into the diets of children who tolerate these foods, rather than strict avoidance, represents a significant shift in clinical approach. Recommendations about the prevention of food allergy and atopic disease through diet have changed radically, with rescinding of many recommendations about extensive and prolonged allergen avoidance. Numerous therapies have reached clinical trials, with some showing promise to dramatically alter treatment. Ongoing studies will elucidate improved prevention, diagnosis, and treatment.

Sim, D. W., et al. (2017). “Accurate assessment of alpha-gal syndrome using cetuximab and bovine thyroglobulin-specific IgE.” Molecular Nutrition & Food Research 61(10).

Scope: IgE against galactose-alpha-1,3-galactose (alpha-Gal) causes alpha-gal syndrome. Bovine thyroglobulin (BTG) and cetuximab share this epitope. We aimed to determine the utility of specific IgE (sIgE) against cetuximab as compared to BTG for diagnosing alpha-gal syndrome. Methods and results: Twelve patients with alpha-gal syndrome, 11 patients with immediate beef or pork allergy, 18 asymptomatic individuals with meat sensitization, and 10 non-atopic subjects were enrolled. We checked the levels of sIgE against BTG and cetuximab using the streptavidin CAP assay. Additionally, IgE reactivity to BTG and cetuximab was assessed by immunoblotting. All alpha-gal syndrome patients had a high concentration of sIgE against BTG, and cetuximab. In contrast to alpha-gal syndrome, patients with immediate allergic reactions to meat consumption and those with asymptomatic sensitization had significantly lower concentration of BTG and cetuximab sIgE, and a high prevalence of sIgE against bovine or porcine serum albumin. Although the concentration of sIgE against alpha-gal was lower in individuals with asymptomatic sensitization, IgE immunoblotting showed the presence of sIgE against alpha-Gal in this group. Conclusion: Differentiation of alpha-gal syndrome from patients with immediate allergy to meat consumption or asymptomatic sensitization requires quantification of cetuximab- or BTG-induced sIgE via detection of IgE for alpha-gal.

Sodhi, N. (2016). “Mammalian meat allergy: a tick-ing time bomb?” Australian Veterinary Journal 94(11): N8-N8.

Soemantri, S. P., et al. (2015). “[Delayed anaphylaxis after ingestion of meat. Carbohydrate epitope galactose-alpha-1,3-galactose as cause of severe anaphylactic reactions].” Hautarzt 66(2): 117-120.

The correlation between anaphylaxis after consumption of meat and the carbohydrate epitope galactose-alpha-1,3-galactose (alpha-Gal) was first described in oncologic patients treated with cetuximab. An association with tick bites and parasitosis is suspected. We report on a healthy patient who developed sudden anaphylactic reactions after the ingestion of meat. Serologic and skin tests confirmed sensitization to alpha-Gal. Avoiding the consumption of mammalian meat led to a complete absence of symptoms.

Soh, J. Y., et al. (2015). “Carbohydrates as food allergens.” Asia Pac Allergy 5(1): 17-24.

The literature supports the notion that carbohydrate epitopes, on their own, do not contribute significantly to the induction of allergic reactions. They bind weakly to IgE antibodies and have been termed as cross-reactive carbohydrate determinants. These epitopes cause confusion in in vitro IgE testing through nonspecific cross-reactivity. Coincident with the rising trends in food allergy prevalence, there has recently been reports of anaphylaxis induced by carbohydrate epitopes. There are two distinct groups, each with unique characteristics and geographical distribution. Anaphylaxis and acute allergic reactions related to the carbohydrate galactose-alpha-1,3-galactose (alpha-Gal) epitope that are present in the monoclonal antibody, cetuximab and red meat have been described in the United States and Europe populations where tick bites have been found to be the primary sensitizer. Another carbohydrate inducing anaphylaxis is galacto-oligosaccharides in commercial milk formula which has been described in the several Asian populations including Singapore. The latter is unique in that the allergen is a pure carbohydrate. We summarize the current literature on carbohydrate-induced food allergy, and evaluate the two new groups of carbohydrate allergy that have defied previous findings on carbohydrates and their role.

Sonenshine, D. E. (2018). “Range Expansion of Tick Disease Vectors in North America: Implications for Spread of Tick-Borne Disease.” International Journal of Environmental Research and Public Health 15(3): 478.

Ticks are the major vectors of most disease-causing agents to humans, companion animals and wildlife. Moreover, ticks transmit a greater variety of pathogenic agents than any other blood-feeding arthropod. Ticks have been expanding their geographic ranges in recent decades largely due to climate change. Furthermore, tick populations in many areas of their past and even newly established localities have increased in abundance. These dynamic changes present new and increasing severe public health threats to humans, livestock and companion animals in areas where they were previously unknown or were considered to be of minor importance. Here in this review, the geographic status of four representative tick species are discussed in relation to these public health concerns, namely, the American dog tick, Dermacentor variabilis, the lone star tick, Amblyomma americanum, the Gulf Coast Tick, Amblyomma maculatum and the black-legged tick, Ixodes scapularis. Both biotic and abiotic factors that may influence future range expansion and successful colony formation in new habitats are discussed.

Stankus, T. (2019). “Reviews of Science for Science Librarians: Alpha-Gal: The Curious Case of Ticks Whose Bite Induces Red Meat Allergies in Humans.” Science & Technology Libraries: 1-11.

ABSTRACTA growing number of tick species have now been demonstrated to induce red meat allergies through biting humans. During the course of the bite, Galactose alpha-1,3-Galactose, commonly abbreviated as alpha-Gal, a carbohydrate not found in humans, but common in four-legged mammals, makes its way through to the bloodstream, triggering antibody production. Subsequent consumption of red meat by bite victims sets off a peculiarly delayed immunological reaction that may range from hives through to anaphylaxis. This paper documents the discovery of its linkage with tick bites. The spread of this syndrome worldwide warrants the attention of scientific and clinical librarians serving allergists, immunologists, dieticians, and entomologists.

Stein, D., et al. (2016). “P-002 YI First Dose IgE-Mediated Allergy to Infliximab Due to Galactose-α-1,3-Galactose Allergy.” Inflammatory Bowel Diseases 22(suppl_1): S9-S10.

Mammalian meat allergy is an IgE antibody-mediated response to a mammalian oligosaccharide epitope galactose-α-1,3-galactose (alpha-gal). Anaphylaxis may occur after patients bitten by a lone star tick develop IgE antibodies to alpha-gal and are re-exposed to the same epitope following ingestion of mammalian products such as beef, pork, and lamb. Severe anaphylaxis to monoclonal antibodies glycosylated with alpha-gal (i.e., cetuximab) has been reported in this patient population. We present a case of first dose IgE-mediated allergic reaction to infliximab in a woman with mammalian meat allergy. A 53-year-old woman with a history of Crohn’s disease was initiated on infliximab. She developed diffuse urticaria and wheezing during the first infusion, indicative of a pre-formed IgE response. She was pre-treated with corticosteroids and diphenhydramine for a second treatment, but developed a similar reaction and therapy was discontinued. Subsequent therapy with vedolizumab was initiated without recurrence of symptoms. Separately, she was confirmed to have mammalian meat allergy mediated by IgE antibody to galactose-α-1,3-galactose. Patient serum was collected and compared to serum from 3 other individuals with known mammalian meat allergy (mediated by IgE to galactose-α-1,3-galactose) and 2 controls. Total and specific IgE antibodies to monoclonal antibodies derived from cell lines that glycosylate with galactose-α-1,3-galactose (cetuximab, infliximab, and natalizumab) as well as non-glycosylated monoclonal antibodies (rituximab and vedolizumab) were measured with the use of either ImmunoCAP (Phadia U.S.) or a modified assay with streptavidin-coated ImmunoCAP. Each monoclonal Ab was biotinylated, and approximately 5 μg was added to each streptavidin-coated ImmunoCAP before serum was added. The assays were performed with the ImmunoCAP250 instrument. The threshold value for a positive reaction was 0.35 IU per milliliter. Positive reactions were seen with monoclonal antibodies from cell lines that glycosylate with galactose-α-1,3-galactose (infliximab, natalizumab, and cetuximab) in our patient and the 3 individuals with known galactose-α-1,3-galactose allergy, but not in the 2 controls. No reaction was seen to the non-glycosylated monoclonal antibodies (rituximab or vedolizumab) in any of the samples. First-dose allergic reactions to infliximab are rare. We describe evidence for a potential allergic mechanism through IgE-mediated reaction to galactose-α-1,3-galactose. Immediate anaphylaxis has previously been described in patients with first exposure to intravenous cetuximab, in which galactose-α-1,3-galactose is present on the FAb portion of the heavy chain, but similar reactions to infliximab have not previously been described to our knowledge. Care should be taken in patients with known mammalian meat allergy prior to use of infliximab.

Steinke, J. W., et al. (2015). “The alpha-gal story: Lessons learned from connecting the dots.” Journal of Allergy and Clinical Immunology 135(3): 589-596.

Anaphylaxis is a severe allergic reaction that can be rapidly progressing and fatal, and therefore establishing its cause is pivotal to long-term risk management. Our recent work has identified a novel IgE antibody response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal). IgE to alpha-gal has been associated with 2 distinct forms of anaphylaxis: (1) immediate-onset anaphylaxis during first exposure to intravenous cetuximab and (2) delayed-onset anaphylaxis 3 to 6 hours after ingestion of mammalian food products (eg, beef and pork). Results of our studies and those of others strongly suggest that tick bites are a cause, if not the only significant cause, of IgE antibody responses to alpha-gal in the southern, eastern, and central United States; Europe; Australia; and parts of Asia. Typical immune responses to carbohydrates are considered to be T-cell independent, whereas IgE antibody production is thought to involve sequential class-switching that requires input from T cells. Therefore, establishing the mechanism of the specific IgE antibody response to alpha-gal will be an important aspect to address as this area of research continues.

Steinke, J. W., et al. (2016). “Altered metabolic profile in patients with IgE to galactose-alpha-1, 3-galactose following in vivo food challenge.” Journal of Allergy and Clinical Immunology 138(5): 1465-1467.

Over the past few years, a large number of patients have been identified who experience delayed anaphylaxis or urticaria following eating red meat and who have IgE antibodies to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal).1Patients with this alpha-gal syndrome had tolerated mammalian products before onset of the disease and in many cases recall tick bites before sensitization. Many anecdotal reports suggest that glycolipids may be as important as glycoproteins in the clinical episodes. Furthermore, delayed absorption and processing of glycolipids could provide a rational explanation for the delay in onset of symptoms.

 Stewart, P. H., et al. (2015). “Delayed red meat allergy: clinical ramifications of galactose-alpha-1,3-galactose sensitization.” Ann Allergy Asthma Immunol 115(4): 260-264.

A 42-year-old man with hypertension, allergic rhinitis, and anaphylaxis to penicillin presents after 2 episodes of worsening pruritic rash, with the most recent episode progressing to anaphylaxis.

Stoltz, L. P., et al. (2019). “Could chiggers be contributing to the prevalence of galactose-alpha-1,3-galactose sensitization and mammalian meat allergy?” J Allergy Clin Immunol Pract 7(2): 664-666.

It is now well recognized that IgE antibodies to galactose-alpha-1,3-galactose (alpha-gal) result in delayed anaphylaxis to mammalian meats, including beef, pork, and lamb, among others. Alpha-gal is an oligosaccharide that was originally described as a “B-like” blood group substance in nonprimate mammals. Cases of alpha-gal allergy have been reported around the world including in the United States, Europe, Australia, Asia, and Central America. In general, patients have reported symptoms of generalized urticaria, angioedema, or anaphylaxis anywhere from 3 to 6 hours after ingestion of mammalian meat, which was previously tolerated. A well-established mechanism of alpha-gal sensitization is tick bites. Multiple species of ticks including Amblyomma americanum (the lone star tick), Ixodes ricinus, Ixodes holocyclus, Amblyomma cajennense, Amblyomma sculptum, and Haemaphysalis longicornis have all been implicated in alpha-gal sensitization. Ticks are parasitic arthropods in the order Ixodida that live by sucking the blood of the host mammal (Figure 1). Alpha-gal has been demonstrated to be present in the gastrointestinal tract of the I. ricinus and the saliva of A. sculptum, which supports the theory that tick bites can cause the production of IgE to alpha-gal and subsequently mammalian meat allergy. This suggests that alpha-gal might be present in numerous species of ticks, either intrinsically within tick glycoproteins or as part of microbes within ticks, and raises the possibility of its presence in other mite species known to feed parasitically on mammals, including the Trombiculidae, whose larvae are commonly known as chiggers. This larval stage is the only point in the mites’ life cycle when they can bite host animals. Once they latch onto skin, they inject digestive enzymes and can transmit diseases to human hosts, such as scrub typhus. They also travel extensively along the epidermis and remain attached for several days. They most commonly affect the legs and waistline and are often drawn to areas of thin epidermis and high humidity. Their bites are not painful, but they do cause groupings of papular and papulovesicular lesions that are very erythematous and pruritic. The pruritus usually begins within hours of the bite and resolves within 72 hours. 

Stone, C. A., Jr., et al. (2019). “Anaphylaxis after vaccination in a pediatric patient: further implicating alpha-gal allergy.” The Journal of Allergy and Clinical Immunology: In Practice 7(1): 322-324.e322.

It is increasingly well known that specific IgE antibodies to galactose-a-1,3-galactose (alpha-gal) are associated with delayed anaphylaxis to mammalian meat and gelatin-based products.

Stone, C. A., Jr., et al. (2017). “Anaphylaxis after zoster vaccine: Implicating alpha-gal allergy as a possible mechanism.” Journal of Allergy and Clinical Immunology 139(5): 1710-1713.e1712.

In the Southeastern United States galactose-a-1,3-galactose (alpha-gal) sensitivity has emerged as a cause of red meat allergy that is causally linked to bites from the lone star tick.1 Alpha-gal sensitivity often presents with delayed anaphylaxis after consumption

of red meat, with lesser degrees of reactivity to milk and gelatin.

Strickler, J. (2017). “Mammalian meat allergy: Unexpected danger.” Nursing 47(8): 48-51.

IT’S EARLY MORNING when Mr. M, 40, presents to the ED via ambulance after experiencing a possible allergic reaction at home. Treated immediately in the ED, he responded well to I.M. epinephrine, I.V. diphenhydramine, and I.V. methylprednisolone.1

He’s now awake, alert, and oriented and in no obvious distress. His vital signs are stable and his signs and symptoms have resolved. He denies any known allergies, prescribed or over-the-counter medications, nutritional or herbal supplement use, or pertinent health history. Mr. M states that he was awakened at about 0400 because of severe back “itching” and his wife stated his back “was covered in hives.” When he became short of breath and dizzy, she called the ambulance. On further questioning, the patient denies exposure to any obvious agents that could trigger an allergic reaction. However, when asked about recent meals, he says that he’d eaten a hamburger for dinner at about 1900. Given the absence of other likely allergens, the ED physician begins to suspect mammalian meat allergy. The patient is referred to an allergist who, based on this presentation, also suspects mammalian meat allergy, formally called galactose-alpha-1,3-galactose (alpha-gal) sensitization.2 Skin testing is done to rule out other more common allergens. After serum confirmation testing, the patient is ultimately diagnosed with this unique allergy.

This article discusses how to assess patients who may be experiencing this disorder and how they’re managed.

Swiontek, K., et al. (2019). “Drugs of porcine origin—A risk for patients with α-gal syndrome?” The Journal of Allergy and Clinical Immunology: In Practice 7(5): 1687-1690.e1683.

The a-gal syndrome is characterized by a delayed allergic reaction to mammalian meat associated with the presence of specific IgE antibodies to galactose-a-1,3-galactose.1 Sensitized patients are at risk upon ingestion of red meat, in particular pork kidney and innards.2 However, diverse other products of mammalian origin have been shown to carry the a-gal epitope and to trigger allergic symptoms, for example, therapeutic mAbs of rodent origin, bovine-derived gelatin colloids, as well as gelatin contained in drugs and sweets.3 Polyclonal antibody preparations such as antivenoms derived from horses have been shown to carry the a-gal epitope,4 and a case of hypersensitivity has been reported recently in an a-galesensitized patient.5 The high gelatin content of some vaccines has been attributed to anaphylaxis upon vaccination in 2 a-galeallergic patients,6,7 and the premature degradation of bioprosthetic heart valves has been associated with the presence of specific IgE in 2 patients.8

 

Takahashi, H., et al. (2014). “Laminin gamma-1 and collagen alpha-1 (VI) chain are galactose-alpha-1,3-galactose-bound allergens in beef.Allergy 69(2): 199-207.

BACKGROUND: Sensitization to the carbohydrate galactose-alpha-1,3-galactose (alpha-Gal) has been reported in patients with beef allergy. However, the proteins responsible for this allergy have not yet been identified. This study aimed to identify beef proteins that predominantly react with serum IgE in Japanese patients with beef allergy.

METHODS: Sera were collected from 29 patients with beef allergy who had allergic reaction(s) such as urticaria, abdominal pain, vomiting, and anaphylactic shock after ingestion of beef and pork; the sera tested positive for IgE against beef and pork. IgE-binding proteins were detected by immunoblotting sera from the patients and identified using a combination of two-dimensional gel electrophoresis and peptide mass fingerprinting techniques. The involvement of carbohydrate in the binding of IgE to allergens was examined by periodate treatment and an inhibition assay with cetuximab by immunoblotting. Specific IgE binding to cetuximab was measured using the CAP-fluorescent enzyme immunoassay.

RESULTS: Two IgE-binding proteins (240 kDa and 140 kDa) were detected in beef extract and identified as laminin gamma-1 and the collagen alpha-1 (VI) chain from Bos taurus, respectively. Periodate treatment or the inhibition assay resulted in the loss of IgE binding to these proteins. Immunoblotting with anti-alpha-Gal antibody revealed the presence of alpha-Gal on the 240- and 140-kDa beef proteins. The amount of IgE bound to cetuximab was significantly correlated with that to beef in the patients with beef allergy.

CONCLUSION: The carbohydrate moiety (alpha-Gal) on laminin gamma-1 and collagen alpha-1 (VI) chain are possibly common IgE-reactive proteins in the Japanese patients with beef allergy.

 Tankersley, M., et al. (2016). “Alpha-Gal Hypersensitivity: A Case Series from Good Ol’ Rocky Top Tennessee.” Journal of Allergy and Clinical Immunology 137(2): AB55.

RATIONALE: Galactose-alpha-1,3-galactose hypersensitivity (alpha gal) is a recently reported condition associated with the production of specific IgE to this oligosaccharide found in mammalian meat. A registry was maintained of alpha-gal patients to more fully understand this condition in our patient population. METHODS: A retrospective chart review of a single-site Allergy practice in Tennessee was conducted of the clinic’s alpha-gal registry of patients seen from 2010-2015.

 Thomas, H., et al. (2017). “Mammals food anaphylaxis’s cases from the French allergy vigilance network.” Revue Francaise D Allergologie 57(8): 533-538.

Since 2009, cases of food-related anaphylaxis caused by mammalian meat and stemming from IgE antibodies specific to alpha-galactose have been identified, first in the United States then in Australia and several European states. However, there is little epidemiological data enabling these reactions to be classified as food allergies. The aim of this study is to determine the frequency of anaphylaxis caused by reaction to alpha-gal residue within the sphere of food allergy (FA) in France, to identify the symptoms, to analyze the results of diagnostic tests, and to check for the presence of cofactors. We studied 19 adult cases of anaphylaxis stemming from mammalian meat consumption and confirmed by the presence of IgE to alpha-Gal and reported in a questionnaire to identify food-related anaphylaxis by members of the Allergy Vigilance Network covering France and French-speaking Belgium from September 2008 to December 2015. The diagnostic assessment comprised assay of specific anti-alpha-Gal IgE, skin tests, and tests for IgE antibodies specific to meat. The presence of cofactors such as alcohol, physical exertion and medication, as well as exposure to tick bites, was also checked. Mammalian meat anaphylaxis stemming from alpha-galactose constituted 2.8% of FA in this period and occurred 2-12 hours after ingestion of the offending food, which in most cases was offal. In 47% of the cases studied, the reaction was preceded by a tick bite. In 12 (63.2%) of cases, cofactors were present, with alcohol consumption in 26.3% of subjects and physical exertion in 21.0%. 

Tjernberg, I., et al. (2017). “IgE reactivity to alpha-Gal in relation to Lyme borreliosis.” PLoS One 12(9): e0185723.

BACKGROUND: An association between tick bites, the development of immunoglobulin E (IgE) antibodies to galactose-alpha-1, 3-galactose (alpha-Gal) and red meat allergy has recently been reported. Here we wanted to elucidate the relation between tick exposure, IgE antibodies to alpha-Gal and Lyme borreliosis (LB). METHODS: In the highly LB endemic area of Kalmar County, Sweden, serum samples and health inquiries from 518 blood donors were included. All sera were investigated for multiple IgG anti-Borrelia antibodies using a multiplex assay (recomBead, Mikrogen). In addition, three serially collected sera over a six-month period from 148 patients with clinically defined erythema migrans (EM) were included. IgE antibodies against alpha-Gal were determined using ImmunoCAP (Thermo Fisher Scientific). RESULTS: In blood donors reporting previous LB (n = 124) IgE to alpha-Gal was found in 16%, while in donors denying previous LB but with multiple anti-Borrelia antibodies (n = 94; interpreted as asymptomatic LB) 10% were IgE alpha-Gal-positive. Finally, in donors without Borrelia antibodies denying previous LB (n = 300) 14% showed IgE to alpha-Gal. No significant difference in proportions among the groups were found. In EM patients, IgE to alpha-Gal was found in 32/148 (22%) at diagnosis, 31/148 (21%) after two-three months and 23/148 (16%) after six months. A significant reduction of proportion and level of IgE to alpha-Gal was found between the second and third sample (p<0.01). A positive IgE anti alpha-Gal was more common among men compared with women both in blood donors and in EM patients (p</=0.01). CONCLUSIONS: IgE to alpha-Gal reactivity was common in a tick endemic area but showed no significant relation to previous LB. IgE anti-alpha-Gal reactivity in EM patients peaked within three months of diagnosis of EM, after which it waned indicating that recent tick exposure is of importance in alpha-Gal sensitization. Furthermore, IgE anti alpha-Gal was more common in men compared with women.

Tobacman, J. K. (2015). “The common food additive carrageenan and the alpha-gal epitope.” Journal of Allergy and Clinical Immunology 136(6): 1708-1709.

Antibodies to the oligosaccharide epitope galactose-a-1,3-galactose (alpha-gal) are of considerable interest because they are so prevalent, include all isotypes, and are specific to humans and Old World apes. Alpha-gal–mediated responses, including immediate and delayed anaphylaxis, appear to be increasing. In the recent review ‘‘The alpha-gal story: lessons learned from connecting the dots,’’ sources of exposure to the alpha-gal epitope were presented, with particular attention to cetuximab, mammalian meat products, and tick bites.

 Tripathi, A., et al. (2014). “Delayed Anaphylaxis to Red Meat Masquerading as Idiopathic Anaphylaxis.” Journal of Allergy and Clinical Immunology-in Practice 2(3): 259-265.

Anaphylaxis is traditionally recognized as a rapidly developing combination of symptoms that often includes hives and hypotension or respiratory symptoms. Furthermore, when a specific cause is identified, exposure to this cause is usually noted to have occurred within minutes to 2 hours before the onset of symptoms. This case is of a 79-year-old woman who developed a severe episode of anaphylaxis 3 hours after eating pork. Before 2012, she had not experienced any symptoms after ingestion of meat products. Delayed anaphylaxis to mammalian meat has many contrasting features to immediate food-induced anaphylaxis. The relevant IgE antibody is specific for the oligosaccharide galactose-alpha-1,3-galactose, a blood group substance of nonprimate mammals. There is evidence from Australia, Sweden, and the United States that the primary cause of this IgE antibody response is tick bites. These bites characteristically itch for 10 days or more. Diagnosis can be made by the presence of specific IgE to beef, pork, lamb, and milk, and the lack of IgE to chicken, turkey, and fish. Skin prick tests (but not intradermal tests) generally are negative. Management of these cases, now common across the southeastern United States, consists of education combined with avoidance of both ingestion of red meat and further tick bites. 

Tripathi, A., et al. (2015). “Analysis of IgE Antibodies in Several Food Allergy Syndromes By Serial Dilutions of Serum on Immunocap with Whole and Component Allergens.” Journal of Allergy and Clinical Immunology 135(2, Suppl. S): AB249.

RATIONALE: IgE ImmunoCAP levels are often above detection limit (>100 IU/mL). Actual IgE levels are determined by re-assay with diluted sera. For most allergens including those specific to food-induced immediate anaphylaxis, consistent, calculated results are obtained across the range of dilutions. By contrast, diluted sera of patients with certain food allergy (FA) syndromes, when assayed, do not yield the predicted results. 

Turner, P. J., et al. (2019). “Global Trends in Anaphylaxis Epidemiology and Clinical Implications.” J Allergy Clin Immunol Pract.

The true global scale of anaphylaxis remains elusive, because many episodes occur in the community without presentation to healthcare facilities, and most regions have not yet developed reliable systems with which to monitor severe allergic events. The most robust datasets currently available are based largely on hospital admissions, which are limited by inherent issues of misdiagnosis, misclassification and generalizability. Despite this, there is convincing evidence of a global increase in rates of all cause-anaphylaxis, driven largely by medication and food-related anaphylaxis. There is no evidence of parallel increases in global all-cause anaphylaxis mortality, with surprisingly similar estimates for case fatality rates at approximately 0.5-1% rate of fatal outcomes for hospitalizations due to anaphylaxis across several regions. Studying regional patterns of anaphylaxis to certain triggers have provided valuable insights into susceptibility and sensitizing events: for example, the link between the monoclonal antibody cetuximab and allergy to mammalian meat. Likewise, data from published fatality registers can identify potentially modifiable risk factors which can be used to inform clinical practice, such as prevention of delayed epinephrine administration, correct posturing during anaphylaxis, special attention to populations at risk (such as the elderly on multiple medications) and use of venom immunotherapy in individuals at risk of insect-related anaphylaxis.

Uasuf, C. G., et al. (2018). “An unusual case of positive sIgE to Galactose-alpha-1,3-galactose from South Italy.” Eur Ann Allergy Clin Immunol 50(1): 45-47.

Summary: We report the case of a 38-year-old man who was bitten several times during his life by a tick. He didn’t report any previous history of anaphylaxis after the ingestion of red meat. The serum specific IgE showed positivity to alpha-Gal. The proximity of the bits didn’t increase the titer of IgE antibodies to alpha-gal. We could hypothesize that the frequency of the exposure to the tick Corresponding author bites and the amount of tick bites during his lifetime induced a sort of tolerance in this patient. 

Uyttebroek, A., et al. (2014). “Anaphylaxis to succinylated gelatin in a patient with a meat allergy: galactose-alpha(1, 3)-galactose (alpha-gal) as antigenic determinant.J Clin Anesth 26(7): 574-576.

Specific immunoglobulin E (sIgE) antibodies towards the galactose-alpha(1,3)-galactose (alpha-gal) moieties may elicit life-threatening and fatal anaphylactic reactions. Patients sensitized to alpha-gal moieties from mammalian meat may also react towards mammalian gelatins and gelatin-containing drugs such as bovine gelatin-based colloid plasma substitute. The case of a 56-year-old woman with a meat allergy who suffered anaphylaxis to succinylated gelatin is reported.

Van Nunen, S. (2007). “The Association Between Ixodes Holocyclus Tick Bite Reactions and Red Meat Allergy” ASCIA 2007 ALLERGIC DISEASE POSTERS.” Internal Medicine Journal 37(s5): A128-A135.           

Van Nunen, S. (2011). “ASCIA 2011 Poster Abstract.” Internal Medicine Journal 41(s4): 1-22.           

van Nunen, S. (2014). “Galactose-Alpha-1,3-Galactose, Mammalian Meat and Anaphylaxis: A World-Wide Phenomenon?” Current Treatment Options in Allergy 1(3): 262-277.

Mammalian meat allergy following tick bites is known to occur in Australia, North America, Europe, Asia, Africa and Central America. Over the last decade, the condition has become increasingly prevalent in tick-endemic areas of Australia and the USA. In mammalian meat-allergic individuals, gelatine allergy and/or cow’s milk allergy may co-exist. Awareness of tick-induced allergies in health professionals and the general community is key to both a timely diagnosis and the prevention of mammalian meat allergy. Treatment of mammalian meat allergy is limited currently to avoidance of all mammalian meat, whilst gelatine allergy similarly mandates avoidance of mammalian-derived gelatine, especially intravenously administered gelatine-containing solutions. Adults with anaphylaxis to mammalian meat should have a convalescent tryptase estimation and investigations for mastocytosis should then be undertaken if the tryptase is significantly elevated. Before initiating treatment with certain therapeutic agents (e.g. cetuximab, gelatine-containing substances, bovine artificial blood), a careful assessment of the risk of anaphylaxis, including serological analysis for galactose-alpha-1,3-galactose-specific immunoglobulin E, should be undertaken in any individual who works, lives, volunteers or participates in leisure activities in a tick-endemic area, particularly where a history is obtained of a tick bite prior, or of mammalian meat or gelatine allergy. Strategies aimed at the prevention of tick bites are paramount for primary prevention and amelioration of mammalian meat allergy. 

van Nunen, S., et al. (2013). “Clinical significance of detectable alphagal-specific IgE in individuals with undetectable specific IgE for mammalian meats in mammalian meat allergy following tick bites.” Allergy 68: 40-40.           

van Nunen, S. (2015). “Tick-induced allergies: mammalian meat allergy, tick anaphylaxis and their significance.” Asia Pac Allergy 5(1): 3-16.

Serious tick-induced allergies comprise mammalian meat allergy following tick bites and tick anaphylaxis. Mammalian meat allergy is an emergent allergy, increasingly prevalent in tick-endemic areas of Australia and the United States, occurring worldwide where ticks are endemic. Sensitisation to galactose-alpha-1,3-galactose (alpha-Gal) has been shown to be the mechanism of allergic reaction in mammalian meat allergy following tick bite. Whilst other carbohydrate allergens have been identified, this allergen is unique amongst carbohydrate food allergens in provoking anaphylaxis. Treatment of mammalian meat anaphylaxis involves avoidance of mammalian meat and mammalian derived products in those who also react to gelatine and mammalian milks. Before initiating treatment with certain therapeutic agents (e.g., cetuximab, gelatine-containing substances), a careful assessment of the risk of anaphylaxis, including serological analysis for alpha-Gal specific-IgE, should be undertaken in any individual who works, lives, volunteers or recreates in a tick endemic area. Prevention of tick bites may ameliorate mammalian meat allergy. Tick anaphylaxis is rare in countries other than Australia. Tick anaphylaxis is secondarily preventable by prevention and appropriate management of tick bites. Analysis of tick removal techniques in tick anaphylaxis sufferers offers insights into primary prevention of both tick and mammalian meat anaphylaxis. Recognition of the association between mammalian meat allergy and tick bites has established a novel cause and effect relationship between an environmental exposure and subsequent development of a food allergy, directing us towards examining environmental exposures as provoking factors pivotal to the development of other food allergies and refocusing our attention upon causation of allergy in general. 

van Nunen, S. A. (2018). “Tick-induced allergies: mammalian meat allergy and tick anaphylaxis.” Med J Aust 208(7): 316-321.

Mammalian meat allergy after tick bites and tick anaphylaxis are the most serious tick-induced allergies. They are often severe, should be largely avoidable and offer fascinating insights into the development and prevention of allergies. Australian clinicians reported the first cases of tick anaphylaxis and discovered the association between tick bites and the development of mammalian meat allergy. The subsequent finding of the allergen epitope within the meat responsible for the allergic reaction, alpha-gal (galactose-alpha-1,3-galactose), stimulated further interest in this emergent allergy. Reports of mammalian meat allergy associated with bites from several tick species have now come from every continent where humans are bitten by ticks. The number of diagnosed patients has continued to rise. Clinically, mammalian meat allergy and tick anaphylaxis present quite differently. The prominent role of cofactors in triggering episodes of mammalian meat allergy can make its diagnosis difficult. Management of mammalian meat allergy is complicated by the manifold potential therapeutic implications due to the widespread distribution of the mammalian meat allergen, alpha-gal. Exposures to alpha-gal-containing medications have proved lethal in a minority of people, and fatal tick anaphylaxis has been reported in Australia. Prevention of tick bites is prudent and practicable; killing the tick in situ is crucial to both primary and secondary prevention of allergic reactions. Mechanisms in the development of mammalian meat allergy constitute a paradigm for how allergies might arise. 

Van Nunen, S. A., et al. (2009). “An association between tick bite reactions and red meat allergy in humans.” Med J Aust 190(9): 510-511.

Twenty-five patients living in a tick-endemic region of Sydney, New South Wales developed red meat allergy after experiencing large local reactions to tick bites. This represents a potentially novel cross-reaction between an arthropod and a food protein. 

van Nunen, S. A., et al. (2013). “Use of expanded search criteria in diagnosing mammalian meat allergy provoked by previous tick bites in individuals who do not live in areas where ticks are endemic.” Allergy 68: 701-701.           

Venturini, M., et al. (2018). “IgE to alpha-Gal in Foresters and Forest Workers From La Rioja, North of Spain.” J Investig Allergol Clin Immunol 28(2): 106-112.

OBJECTIVE: To investigate the prevalence of and factors associated with the presence of alpha-gal-specific IgE in a risk group of foresters and forest workers from La Rioja, Spain and in a control group. METHODS: The study population comprised 169 workers and 100 individuals who did not recall having had tick bites. A questionnaire including demographic data and number of tick bites per year was completed by a physician. alpha-Gal sIgE was assessed using ImmunoCAP with serum samples that had been taken in 2010. In 2015, second serum specimens were taken from all but 1 of the workers, who had positive specific IgE to alpha-gal in 2010. These new samples were tested for IgE to the alpha-gal epitope and to mammalian meat. RESULTS: The prevalence of positive sIgE to alpha-gal was 15% in the risk population and 4% in the control population. alpha-Gal sIgE positivity was associated with the number of tick bites per year and with seniority. Thirteen out of 21 patients sensitized to alpha-gal in 2010 showed positive specific IgE to alpha-gal in serum samples from 2015. Eleven had specific IgE to mammalian meat, but none reported symptoms of meat allergy. CONCLUSIONS: The prevalence of alpha-gal sIgE antibodies in this risk population was higher than in the control group and was associated with the number of tick bites per year and with seniority. None of the workers sensitized to mammalian meat developed meat allergy, possibly owing to the low levels of sIgE to alpha-gal. 

Vidal, C., et al. (2016). “Vaginal Capsules: An Unsuspected Probable Source of Exposure to alpha-Gal.” Journal of Investigational Allergology and Clinical Immunology 26(6): 388-389.

Severe anaphylactic reactions after a first infusion of cetuximab due to pre-existing specific IgE (sIgE) antibodies to the oligosaccharide moiety galactose-α-1,3-galactose (α-gal) were first reported in 2008. Since the identification of sIgE to α-gal, several cases of delayed anaphylaxis, angioedema, and urticaria have been reported. In 2011, our group reported the first 5 cases of mammal meat–induced anaphylaxis due to α-gal in Spain. The α-gal epitope is abundantly expressed on glycoconjugates of nonprimates (including allergenic proteins in beef, pork, lamb, and cat dander), prosimians, and New World monkeys. Moreover, sIgE to α-gal was demonstrated to underlie some cases of anaphylaxis after infusion of bovine-derived gelatin colloids (Gelofusine and Haemaccel) , and 2 patients were recently reported to have experienced bioprosthetic aortic valve degeneration due to α-gal allergy. Finally, the possibility of successful desensitization with cetuximab in patients with sIgE to α-gal was demonstrated by García-Menaya et al . Here, we report the case of a patient diagnosed with α-gal allergy who developed a systemic reaction after application of an intravaginal capsule of fenticonazole. Note: PDF of the article can be found on page 15 of the supplied link. 

Villalta, D., et al. (2017). “Galactose-alpha-1,3-galactose syndrome: an Italian survey.” Eur Ann Allergy Clin Immunol 49(6): 263-269.

Summary: Background. The term of alpha-Gal syndrome, which includes the delayed allergy to red meat and the allergic reactions following the administration of cetuximab, is associated to the presence of specific IgE to alpha-Gal. In Italy, only anecdotal cases were reported so far. The Association of Italian Allergists (AAITO) carried out a survey with the aim of evaluating presence, characteristics, clinical features, and distribution of the syndrome in Italy. Methods. A web structured questionnaire was made available on the website of AAIITO from July 2016 to January 2017. It included 31 multiple-choice questions concerning different items, including the site of physicians, the number of patients diagnosed as having cetuximab allergy and/or delayed red meat allergy, recall of tick bites, symptoms, time to reactions, elicitor foods, reactions with foods other than meat, and in-vivo and in-vitro tests used for the diagnosis. Results. Seventy-nine physicians completed the questionnaire. Nine cases of allergy to cetuximab and 40 cases of delayed red meat allergy were recorded across Italy. 22.5% of patients with cetuximab allergy and 62.5% of those with delayed red meat allergy recalled a tick bite. 75% of patients with delayed red meat allergy experienced symptoms after eating beef (butcher’s cut in 72.5%). Urticaria was the most frequent clinical manifestation (65% of cases). In 60.6% of cases symptoms appeared 2 – 4 hours after meat ingestion, while in 7.9% symptoms appeared after > 4 hours. The most used diagnostic methods were the intradermal test for cetuximab allergy (88.9%) and the detection of IgE to alpha-Gal (55.5%) for red meat allergy. Most case reports came from Northern Italy. Conclusions. alpha-Gal syndrome is present in Italy and beef is the most frequent offending food. In most cases symptoms were not severe. 

Villalta, D., et al. (2016). “High prevalence of sIgE to Galactose-α-1,3-galactose in rural pre-Alps area: a cross-sectional study.” Clinical & Experimental Allergy 46(2): 377-380.

Wagner, K. D., et al. (2015). “Fifty-six-year-old man with anaphylaxis: A novel delayed food hypersensitivity reaction.” The Journal of the Arkansas Medical Society 112(7): 110-112.

Anaphylaxis and urticaria are commonly seen in both primary care and allergy clinics. Foods, drugs, and insects are frequent culprits for immediate reactions; however, the trigger for recurring and/or chronic episodes is often unclear. We present a 56-year-old male with recurrent symptoms of urticaria, angioedema, and anaphylaxis found to be triggered by sensitization to galactose-alpha 1, 3-galactose (alpha-gal), a novel food allergen.

Wagner, N., et al. (2012). “Anaphylaxis to red meat: galactose-alpha-1,3-galactose (alpha-Gal) – an interesting allergen.” Allergologie 35(11): 559-562.

Wang, X., et al. (2018). “Inactivation of Gene α-1,3-Galactosyltransferase in Bovine Aortic Smooth Muscle Cells Using CRISPR-Cas9.” The FASEB Journal 32(1_supplement): 649.647-649.647.

People who get bites from Amblyomma americanum usually develop a severe allergic reaction to red meat. The main reason caused this allergy is because of the presence of α-1,3-galactosyl epitopes on the membranes of most mammalian cells. Since human beings do not create galactose-alpha-1,3-galactose (alpha-gal), the patients’ immune system is free to start attacking alpha-gal when they eat red meat. The epitope transferase coded geneα-1,3-galactosyltransferase (GGTA1) was already identified, and it can be knocked out to solve the allergy of eating red meat. GGTA1 gene has successfully knocked out in pigs. However, there is no evidence to show the GGTA1 gene has been knocked out in beef. In this study, we utilized bovine aortic smooth muscle cells (BAOSMC) as the module for the research of GGTA1 gene knockout. The clustered regularly interspaced short palindromic repeats (CRISPR) systems are widely used in performing targeted genome editing in cultured cells. The use of CRISPR-associated (Cas) systems as an RNA-programmable DNA targeting and editing platform is followed by a synthetic single-guide RNA (sgRNA), which can simply edit genome sequences like other tools such as transcription activator-like effector nucleases (TALENs) and zinc-finger nucleases (ZFNs). We used the gRNA design tool and selected 5′-GGCCTGACGGTTTTCGCCGT-3′ as the target gRNA sequence from the coding DNA sequence of Bos taurus alpha-galactosyltransferase 1 (glycoprotein). The gRNA was constructed in the pSpCas9 BB-2A-GFP (PX458) vector provided by GenScript USA Inc. Vectors were amplified and transfected into BAOSMC by GenePORTER2 transfection reagent when the cells were 80% confluency. Green fluorescent can be viewed after 24 hours transfection (Fig. 1). The transfection efficiency can reach about 70% to 80%. Cells were collected in PBS at pH7.4 after 24 hours transfection. Total protein was extracted then the enzyme-linked immunosorbent assay was used to examine the GGTA1 production. By normalized with the total protein concentration, the GGTA1 protein level in the transfected cells was 17.9 ± 7.25% lower (P< 0.05) than in the control cells, showing a significant inhibition of GGTA1 gene expression in the cells by CRISPR-Cas9 gene edition method (Fig. 2). Our data show that the gRNA sequence that we chose was suitable for the GGTA1 gene knockout in BAOSMC. Moreover, the CRISPR-Cas9 system was proved can be applied in the genome editing of bovine cells. Support or Funding Information This study is funded by Arkansas Beef Council. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal. 

Weins, A. B., et al. (2019). “[Diagnostics of alpha-gal syndrome : Current standards, pitfalls and perspectives].” Hautarzt 70(1): 36-43.

Alpha-Gal syndrome results from sensitization to the carbohydrate epitope galactose-alpha-1,3-galactose (alphagal). The allergen occurs in mammalian meat and innards, but also in other foods and medical products of animal origin. Allergic reactions generally occur delayed after allergen intake with a latency period, depending on the individual tolerance threshold and the influence of cofactors. Details in the patient’s medical history can help to establish the suspected diagnosis of alphagal syndrome. Confirmation of the diagnosis requires the expertise of specialists, experienced with the implementation and interpretation of in vitro and in vivo diagnostic tests. Whereas skin prick testing with commercial whole-meat extracts often does not provide reliable results, allergen-specific IgE (alpha-gal) is generally detectable in affected patients. Cell-based tests such as the basophil activation test are currently only employed in an experimental setting. To evaluate, whether a sensitization is clinically relevant, an in-patient oral food challenge should be performed, using for example cooked pork or porcine kidney in addition to suspected cofactors.

Weiss, J., et al. (2016). “Using the galactose-alpha-1,3-galactose enzyme-linked immunosorbent assay to predict anaphylaxis in response to cetuximab.” Cancer 122(11): 1697-1701.

BACKGROUND: Cetuximab is a monoclonal antibody against epidermal growth factor receptor with activity against head and neck cancer and colorectal cancer. Anaphylaxis in response to cetuximab is a significant clinical problem in the Southeastern United States with a grade 3/4 infusion reaction rate of 14%. Previous retrospective data have suggested that the presence of preformed immunoglobulin E antibodies against galactose-alpha-1,3-galactose in serum can predict anaphylaxis in response to cetuximab.

METHODS: Sixty patients were prospectively screened as part of the entry criteria for a phase 2 study of neoadjuvant carboplatin, nab-paclitaxel, and cetuximab. Patients were recruited at 2 academic medical centers known to have high anaphylaxis rates: the University of North Carolina and Vanderbilt. Only patients with a negative laboratory result were treated on the clinical protocol.

RESULTS: No patient experienced anaphylaxis; the negative predictive value was thus 100%. Other than smoking history, the demographics were similar for assay-positive subjects and assay-negative subjects.

CONCLUSIONS: Subjects with a negative test result can be safely treated with cetuximab. Further research is required regarding the optimal cutoff for positivity and the positive predictive value. Cancer 2016;122:1697-701. (c) 2016 American Cancer Society. 

Wen, L. P., et al. (2015). “Delayed Anaphylaxis to Red Meat Associated With Specific IgE Antibodies to Galactose.” Allergy Asthma & Immunology Research 7(1): 92-94.

A novel delayed anaphylactic reaction to red meat, associated with tick bites and IgE antibodies against galactose-alpha-1, 3-galactose (alpha-gal), was reported in 2009 in the US, Australia and Europe. In this case, serum specific IgE to galactose-alpha-1, 3-galactose (>100 kU/L) and IgE to multiple non-primate mammalian proteins were positive. However, the pathogenesis of this disease remains unclear. We report the first case in Asia of delayed anaphylactic reaction to red meat, which was induced by bites from the hard tick. Hematophagous ixodidae. We confirmed the increased concentration of IgE reactive epitopes in non-primate mammalian organs, which may be rich in alpha-gal proteins in lymphatic and endothelial tissues. All confirmed ticks associated with this disorder in the literature and in our case belonged to the hard tick family. We hypothesize that hard tick saliva is enriched with blood-type substances, such as oligosaccharides, from the non-primate mammal victim’s blood after days to weeks of blood sucking, which sensitizes humans through the injection route while blood sucking.

Wickner, P. G. and S. P. Commins (2014). “The First 4 Central American Cases Of Delayed Meat Allergy With Galactose-Alpha-1,3-Galactose Positivity Clustered Among Field Biologists In Panama.” Journal of Allergy and Clinical Immunology 133(2, Suppl. S): AB212.

RATIONALE: Serological positivity to galactose-alpha-1,3-galactose has been associated with delayed meat anaphylaxis and tick bite exposure. This entity has been reported in Australia, North America and Europe. Here we report the first 4 Central American cases of delayed meat anaphylaxis clustered among field biologists in Panama.

METHODS: Subjects describing a history of urticaria, food allergy, or anaphylaxis were enrolled in IRB HSR#13298. Total and sIgE antibody analyses were performed on the sera of these patients. Alpha-gal sIgE antibodies were measured using our modification of the ImmunoCAP assay with streptavidin on the solid phase.

Wilson, J., et al. (2017). “OR074 Comparison of galactose-a-1,3-galactose specific IgE responses in children from rural Kenya and central Virginia.” Annals of Allergy, Asthma & Immunology 119(5): S10.

Wilson, J. M., et al. (2016). “IgG4 Component Allergens Are Preferentially Increased in Eosinophilic Esophagitis As Compared to Patients with Milk Anaphylaxis or Galactose-Alpha-1,3-Galactose Allergy.” Journal of Allergy and Clinical Immunology 137(2): AB199.

Wilson, J. M., et al. (2019). “IgE, alpha-Gal and atherosclerosis.” Aging (Albany NY) 11(7): 1900-1902.

Emerging evidence suggests a link between allergic disease and cardiovascular disease. The idea that there could be a connection between ‘allergies’ and heart disease is not readily apparent. Nonetheless, over the past 20 years research in mice and humans has linked hematopoietic cells and soluble factors that mediate allergic disease with coronary artery disease (CAD). Specifically, mast cells and elevated levels of the Immunoglobulin E (IgE) isotype [4] have been associated with the presence and/or severity of CAD. However, despite these associations, no specific allergens or IgE responses to specific allergens, have been implicated in CAD. It was on this backdrop that a team of allergists and cardiologists collaborated to investigate the hypothesis that specific IgE to a novel oligosaccharide allergen present in mammalian meat could be a risk factor for CAD.

Wilson, J. M., et al. (2018). “IgE Sensitization to the Food Allergen Galactose-a-1,3-Galactose is Associated with Coronary Atherosclerosis.” Journal of Allergy and Clinical Immunology 141(2): AB146.

RATIONALE: The oligosaccharide galactose-a-1,3-galactose (a-Gal) is the target of IgE in cases of delayed anaphylaxis to red meat. Sensitization to a-Gal is more prevalent in the community than cases of delayed anaphylaxis and is particularly common in the southeastern United States, a region with high incidence of cardiovascular disease. Additionally, recent reports have linked mast cells and elevated total IgE with coronary artery disease. We sought to test the hypothesis that sensitization to a-Gal represents an independent risk factor for coronary atherosclerosis.

Wilson, J. M. and T. A. E. Platts-Mills (2019). “IgE to galactose-alpha-1,3-galactose and the alpha-Gal syndrome: Insights from basophil activation testing.” J Allergy Clin Immunol 143(1): 101-103.

Since the earliest reports describing a connection between the galactose-a-1,3-galactose (a-Gal) syndrome and tick bites, it has been clear that the prevalence of IgE sensitization to a-Gal in some regions and select populations is 10% or greater, with population estimates of approximately 20% in studies from Virginia, North Carolina, and Tennessee. On the other hand, the question of the prevalence of cases of bona fide a-Gal syndrome (ie, subjects who manifest allergic symptoms on ingestion of mammalian meat or innards) is less clear and has not been investigated in the United States. 

Wilson, J. M., et al. (2018). “IgE to the Mammalian Oligosaccharide Galactose–1,3-Galactose Is Associated With Increased Atheroma Volume and Plaques With Unstable Characteristics: Brief Report.” Arteriosclerosis Thrombosis and Vascular Biology 38(7): 1665-1669.

Objective Emerging evidence suggests a link between coronary artery disease and type 2 immunity. We sought to test the hypothesis that IgE sensitization to the mammalian oligosaccharide galactose–1,3-galactose (-Gal) the target allergen of delayed anaphylaxis to red meat is associated with coronary artery disease. Approach and Results Total IgE and specific IgE to -Gal were assayed on sera from 118 subjects who presented for cardiac catheterization and underwent intravascular ultrasound. IgE to -Gal was detected in 26%, and atheroma burden was higher in sensitized subjects (P=0.02). Because -Gal sensitization relates to an environmental exposure that could be a risk factor for early-onset coronary artery disease (ie, tick bites), we age stratified the cohort. In subjects 65 years of age, the strength of the association with atheroma burden was stronger (P<0.001), and plaques in the sensitized group had less stable features based on intravascular ultrasound. To address the specificity of the association with IgE to -Gal, IgE to inhalants and peanut were assayed and were not associated with coronary artery disease. Total IgE and -Gal-specific IgE were strongly associated with each other, but the strength of the relationship with atheroma burden was stronger for -Gal-specific IgE. This association was significant when adjusted for sex, diabetes mellitus, hypertension, statin use, and total IgE (regression coefficient, 12.2; SE, 5.2; P=0.02). Conclusions Increased atheroma burden and plaques with more unstable features were associated with IgE to -Galan effect most pronounced in subjects 65 years of age. IgE sensitization to -Gal may represent a novel, and potentially modifiable, risk factor for coronary atherosclerosis. 

Wilson, J. M., et al. (2019). “Investigation of increased prevalence of IgE specific for galactose alpha-1,3-galactose in patients with coronary artery disease.” Allergy 74: 595-595. 

Wilson, J. M. and T. A. E. Platts-Mills (2018). “Meat allergy and allergens.” Molecular Immunology 100: 107-112.

IgE-mediated hypersensitivity to ingested animal products, including both mammalian and avian sources, is increasingly appreciated as an important form of food allergy. Traditionally described largely in children, it is now clear that allergy to meat (and animal viscera) impacts both children and adults and represents a heterogeneous group of allergic disorders with multiple distinct syndromes. The recognition of entities such as pork-cat syndrome and delayed anaphylaxis to red meat, i.e- the a-Gal syndrome, have shed light on fundamental, and in some cases newly appreciated, features of allergic disease. These include insights into routes of exposure and mechanisms of sensitization, as well as the realization that IgE-mediated reactions can be delayed by several hours. Here we review mammalian and avian meat allergy with an emphasis on the molecular allergens and pathways that contribute to disease, as well as the role of in vitro IgE testing in diagnosis and management. 

Wilson, J. M. and T. A. E. Platts-Mills (2019). “Red meat allergy in children and adults.” Curr Opin Allergy Clin Immunol 19(3): 229-235.

Purpose of review To highlight recent advances in our understanding of the clinical features, prevalence, and pathophysiology of red meat allergy. Recent findings Allergic reactions to red (i. e. mammalian) meat have historically been considered rare and described primarily in young atopic children. It is now clear that red meat allergy is not uncommon in some parts of the world in other age groups. Strikingly, the majority of these cases relate to specific IgE to galactose-a1,3- galactose, an oligosaccharide of nonprimate mammals. The mechanism of sensitization in this syndrome relates to bites of certain hard ticks and the clinical reactions often have a delay of 3 to 6 h. An additional form of red meat allergy relates to inhalant sensitization to mammalian proteins. The best characterized example involves cat-sensitized patients with specific IgE to cat serum albumin who can react to ingested pork because of cross-sensitization to pork serum albumin. Summary Red meat allergy is more common than previously appreciated and relates to at least three different forms that are distinguished by mechanisms of sensitization and have characteristic clinical and immunologic features. 

Wilson, J. M., et al. (2017). “Galactose-α-1,3-galactose: atypical food allergen or model IgE hypersensitivity?” Curr Allergy Asthma Rep 17(1): 8-8.

Purpose of Review: Galactose-α-1,3-galactose (α-gal) is a carbohydrate allergen with several unique characteristics. In this article, we discuss some recent advances in our understanding of the ‘alpha-gal syndrome,’ highlight data supporting the role of ticks in pathogenesis, and speculate on immune mechanisms that lead to sensitization. Recent Findings: First described as the target of IgE in individuals suffering immediate hypersensitivity reactions to the novel anti-EGF monoclonal antibody cetuximab, it is now clear that α-gal sensitization is associated with mammalian meat allergy as well as reactions to other mammalian products. Unlike traditional IgE-mediated food allergies, reactions to α-gal often do not manifest until several hours following an exposure, although co-factors can influence the presentation. Multiple pieces of evidence, including recent work with a mouse model, point to the fact that sensitization is mediated by exposure to certain hard ticks and increasingly we are aware of its globally widespread impact. Summary: The oligosaccharide α-gal represents a novel allergen with several unusual clinical features. It has been recognized now on multiple continents and its clinical presentation can be quite variable. Moreover, efforts to delineate the mechanisms leading to α-gal sensitization may have ramifications for our broader understanding of type 2 immunity. 

Wilson, J. M., et al. (2016). “IgG4 Component Allergens Are Preferentially Increased in Eosinophilic Esophagitis As Compared to Patients with Milk Anaphylaxis or Galactose-Alpha-1,3-Galactose Allergy.” Journal of Allergy and Clinical Immunology 137(2): AB199.

RATIONALE: Incidence of food allergy is increasing, including diseases with apparently unique pathophysiologic pathways such as eosinophilic esophagitis (EoE), milk anaphylaxis and galactose-alpha-1,3-galactose (alpha-gal) allergy. The role of IgE in these diseases has been well studied, though the contribution of other antibody subtypes, including IgG4, is less clear. 

Wilson, J. M., et al. (2019). “Investigation into the alpha-Gal Syndrome: Characteristics of 261 Children and Adults Reporting Red Meat Allergy.” J Allergy Clin Immunol Pract 7(7): 2348-2358.e2344.

BACKGROUND: Red meat allergy has historically been understood as a rare disease of atopic children, but the discovery of the “alpha-Gal syndrome,” which relates to IgE to the oligosaccharide galactose-alpha-1,3-galactose (alpha-Gal), has challenged that notion. OBJECTIVE: To describe the clinical and immunologic characteristics of a large group of subjects with self-reported allergy to mammalian meat. METHODS: This was an observational study of 261 children and adults (range, 5-82 years) who presented for evaluation for allergic reactions to mammalian meat. Results were based on serum assays and a detailed questionnaire. RESULTS: alpha-Gal specific IgE >/= 0.35 IU/mL was detected in 245 subjects and symptom onset occurred >/=2 hours after eating mammalian meat in 211 (81%). Component testing supported a diagnosis of alpha-Gal syndrome in 95%, pork-cat syndrome in 1.9%, and primary beef allergy in 1.1%. Urticaria was reported by 93%, anaphylaxis by 60%, and gastrointestinal symptoms by 64%. Levels of IgE and IgG specific to alpha-Gal were similar in subjects who reported early- or delayed-onset symptoms, and in those with and without anaphylaxis. Levels of alpha-Gal specific IgE and severity of reactions were similar among those with and without traditional atopy, and among children (n = 35) and adults (n = 226). Blood group B trended toward being under-represented among alpha-Gal-sensitized subjects; however, alpha-Gal specific IgE titers were high in symptomatic cases with B-antigen. CONCLUSIONS: The alpha-Gal syndrome is a regionally common form of food allergy that has a characteristic but not universal delay in symptom onset, includes gastrointestinal symptoms, can develop at any time in life, and is equally common in otherwise nonatopic individuals. 

Wolver, S. E., et al. (2013). “A Peculiar Cause of Anaphylaxis: No More steak?” J Gen Intern Med 28(2): 322-325.

In recent years, a newly recognized allergic disease has been uncovered, and seemingly idiopathic causes of anaphylaxis now have an explanation. Individuals bitten by the lone star tick may develop IgE antibodies to the carbohydrate galactose-alpha-1,3-galactose (alpha-gal). Upon exposure of sensitized subjects to mammalian meat containing alpha-gal on glycoproteins or glycolipids, delayed anaphylaxis may ensue, often three to six hours after ingestion.1 Many of these individuals have negative allergy skin prick tests to meat, further obscuring the diagnosis. With the recent development of IgE alpha-gal tests, the clinical diagnosis can be confirmed in the laboratory. 

Wong, X. L. and D. F. Sebaratnam (2018). “Mammalian meat allergy.” Int J Dermatol 57(12): 1433-1436.

Mammalian meat allergy is an allergic reaction mediated by IgE antibodies directed against the mammalian oligosaccharide epitope galactose-alpha-1,3-galactose. Clinically, it is characterized by a range of symptoms including urticaria, angioedema, gastroenteritis, and anaphylaxis hours following ingestion of red meat. It is an emergent allergy in tick endemic areas across the world. As a recently described disease with a cutaneous presentation, dermatologists should be familiar with this entity and recognize it as a differential diagnosis for urticarial and anaphylaxis reactions. 

Wuerdeman, M. F. and J. M. Harrison (2014). “A Case of Tick-Bite-Induced Red Meat Allergy.” Military Medicine 179(4): e473-e475.

Delayed hypersensitivity disorders and food allergies are often challenging for the clinician and patient alike. A recent discovery of an IgE antibody specific to galactose-α-1,3-galactose, which is a carbohydrate abundantly expressed on cells and tissues of beef, pork, and lamb, adds one more tool to aid the clinician in making the appropriate diagnosis. A link has been discovered between the bite of the Lone Star Tick (Amblyomma americanum) and the development of sensitivity to galactose-α-1,3-galactose. With a high prevalence of Lone Star Tick populations inhabiting major U.S. Army Installations, and the type of duty required by our Service members, it could potentially affect susceptible individuals. We describe a case of an active duty soldier who went 4 years searching for this elusive diagnosis and connection and discuss why it should remain in the differential diagnosis when treating military health care beneficiaries.

Yi, C. H., et al. (2014). “Function characterization of a glyco-engineered anti-EGFR monoclonal antibody cetuximab in vitro.” Acta Pharmacol Sin 35(11): 1439-1446.

AIM: To evaluate the biochemical features and activities of a glyco-engineered form of the anti-human epidermal growth factor receptor monoclonal antibody (EGFR mAb) cetuximab in vitro. METHODS: The genes encoding the Chinese hamster bisecting glycosylation enzyme (GnTIII) and anti-human EGFR mAb were cloned and coexpressed in CHO DG44 cells. The bisecting-glycosylated recombinant EGFR mAb (bisec-EGFR mAb) produced by these cells was characterized with regard to its glycan profile, antiproliferative activity, Fc receptor binding affinity and cell lysis capability. The content of galactose-alpha-1,3-galactose (alpha-Gal) in the bisec-EGFR mAb was measured using HPAEC-PAD. RESULTS: The bisec-EGFR mAb had a higher content of bisecting N-acetylglucosamine residues. Compared to the wild type EGFR mAb, the bisec-EGFR mAb exhibited 3-fold higher cell lysis capability in the antibody-dependent cellular cytotoxicity assay, and 1.36-fold higher antiproliferative activity against the human epidermoid carcinoma line A431. Furthermore, the bisec-EGFR mAb had a higher binding affinity for human FcgammaRIa and FcgammaRIIIa-158F than the wild type EGFR mAb. Moreover, alpha-Gal, which was responsible for cetuximab-induced hypersensitivity reactions, was not detected in the bisec-EGFR mAb. CONCLUSION: The glyco-engineered EGFR mAb with more bisecting modifications and lower alpha-Gal content than the approved therapeutic antibody Erbitux shows improved functionality in vitro, and requires in vivo validations. 

Yucel, E., et al. “Red meat desensitization in a child with delayed anaphylaxis due to alpha-Gal allergy.” Pediatric Allergy and Immunology 0(0).