Alpha-gal syndrome is an allergic condition resulting from the bite of the Lonestar tick in the southeastern US that leads to sensitization to mammalian products containing the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal). Cetuximab is a chimeric monoclonal antibody that contains alpha-gal and can lead to allergic reactions in individuals with alpha-gal syndrome. A 66-year-old with metastatic squamous cell carcinoma of the right tonsil with involvement of the lung and liver was planned to receive palliative therapy with cetuximab. He was screened for alpha-gal sensitization and found to have elevated specific IgE to alpha-gal but had not had adverse reactions to mammalian products previously. He was referred to our allergy clinic for further recommendations to minimize the risk of a hypersensitivity reaction. He received his first dose as a graded challenge with cetuximab. Shortly after increasing the rate of his infusion to the second step of his challenge, the patient developed flushing, disseminated urticaria, and labored breathing. The remainder of his first dose and subsequent treatments were administered via a one-bag desensitization protocol. This case suggests caution with the use of cetuximab in those with asymptomatic alpha-gal sensitization, along with the potential utility of graded challenge in a closely monitored setting, such as the ICU, to diagnose and desensitize to manage such patients in the future.
Foster M, Brown M, Mueller A, Tahiri T, Atchison K, et al.
Transfusion •
Transfusion-related alpha-gal syndrome (TRAGS) has recently been proposed as a cause of allergic transfusion reactions (ATRs) in which alpha-gal-specific IgE in sensitized group O (or potentially group A) recipients reacts with epitopes on group B or AB plasma-containing components. Fewer than 10 cases have been reported, all from the Northeast and mid-Atlantic United States, and alpha-gal-specific ATR evaluation practices are unstudied. Two patients with ATRs consistent with TRAGS at a large academic medical center in Nashville, Tennessee are reported alongside a 5-year retrospective cohort analysis of group O and A recipients experiencing ATRs following transfusion of group B or AB plasma-containing products. Alpha-gal IgE testing, AGS diagnosis documentation, and documented consideration of IgA deficiency were assessed for each qualifying reaction. Both index patients had pre-existing AGS diagnoses unrecognized at component selection; one was a 42-year-old female and the second an 83-year-old male. Among 50 qualifying ATRs in 44 patients, including 13 severe or anaphylactic reactions, alpha-gal IgE testing was not performed for any event, and no patient had a documented AGS diagnosis. IgA deficiency was considered in eight patients (18%), yielding no diagnoses. TRAGS occurs in the tick-endemic southeastern United States across a broader demographic range than previously recognized. IgA deficiency, present in <0.3% of the population, was considered in 18% of qualifying patients while alpha-gal sensitization, affecting 20%-30% in this region, was investigated in none. Integration of AGS history into pre-transfusion risk assessment and ATR evaluation protocols is warranted.
Jacobs JW, Kaufman RM, Schwartz JY, Hall E, Tahiri T, et al.
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons •
Alpha-gal syndrome (AGS) is an IgE-mediated hypersensitivity to the oligosaccharide galactose-α-1,3-galactose, acquired through tick bites and increasingly recognized as a cause of allergic reactions to mammalian-derived medical products. Every major transplant modality creates distinct conditions under which sensitized patients may encounter alpha-gal, yet AGS knowledge has developed almost entirely outside the transplant literature. In conventional solid organ transplantation, risk arises primarily from perioperative exposures to porcine-derived heparin, gelatin-based hemostatic agents, and other mammalian-derived materials. In xenotransplantation, the well-characterized role of alpha-gal as the principal xenoantigen has driven development of glycoprotein alpha-galactosyltransferase 1-knockout swine, but the distinct IgE-mediated pathway that defines AGS has received little attention. Hematopoietic stem cell transplantation introduces questions about conditioning-related immune remodeling of preexisting IgE sensitization, rabbit antithymocyte globulin as an underrecognized alpha-gal exposure, and transfusion-related alpha-gal syndrome when group B or AB plasma-containing blood products are transfused to susceptible patients. Cellular therapy manufacturing workflows that use animal-derived ancillary materials represent a further theoretical exposure pathway. Importantly, detectable anti-alpha-gal IgE does not invariably predict clinical reactivity, and the most appropriate clinical approach is risk stratification rather than reflexive exclusion. Generating the evidence base to support such stratification will require collaboration across allergy, transplant, and transfusion medicine.
Wang Y, Zhang Y, Dudley C, Fitzgerald K, Carson AS, et al.
The Journal of allergy and clinical immunology •
In alpha-gal syndrome (AGS), IgE antibodies form against the glycan galactose-α-1,3-galactose (alpha-gal) in mammal products rather than food proteins. Alpha-gal glycolipids and glycoproteins activate human basophils sensitized with AGS plasma in an IgE-dependent fashion. However, it is unknown whether alpha-gal specific IgE (sIgE), independent of other blood proteins, is sufficient for mediating basophil and mast cell activation. We sought to determine whether alpha-gal antigens could activate passively sensitized rat basophilic leukemia (RBL) SX-38 cells, which express human IgE receptors and are commonly used to model allergen/IgE-mediated mast cell activation in food protein allergy. Using the clustered regularly interspaced short palindromic repeats technology, we created a novel, alpha-gal-deficient RBL cell line, alpha-gal knockout RBL SX-38, passively sensitizing cells with sera from AGS donors or with novel alpha-gal sIgE clones, and then stimulated with alpha-gal glycoproteins. To assess effector cell activation, we measured cell surface expression of activation marker CD63 by flow cytometry and mediator release through β-hexosaminidase release assays. After alpha-gal antigen stimulation, the percentage of CD63 alpha-gal knockout RBL SX-38 cells sensitized with AGS sera increased 3-fold compared with cells sensitized with control serum. Select human AGS IgE clones facilitated alpha-gal antigen-dependent and antigen-independent CD63 upregulation. Cells sensitized with pooled AGS sera released β-hexosaminidase in an alpha-gal-independent fashion. We saw no β-hexosaminidase release above background in cells sensitized with alpha-gal sIgE clones. Certain alpha-gal-specific human IgE clones may partially activate allergic effector cells independent of antigen, potentially lowering thresholds for subsequent alpha-gal-induced or antigen-independent allergic effector cell degranulation. This may affect duration and severity of allergic symptoms in patients with AGS.
An estimated 7.6% of children and 10.8% of adults have IgE-mediated food-protein allergies in the US. IgE-mediated food allergies may cause anaphylaxis and death. A delayed, IgE-mediated allergic response to the food-carbohydrate galactose-α-1,3-galactose (alpha-gal) in mammalian meat affects an estimated 96 000 to 450 000 individuals in the US and is currently a leading cause of food-related anaphylaxis in adults. In the US, 9 foods account for more than 90% of IgE-mediated food allergies-crustacean shellfish, dairy, peanut, tree nuts, fin fish, egg, wheat, soy, and sesame. Peanut is the leading food-related cause of fatal and near-fatal anaphylaxis in the US, followed by tree nuts and shellfish. The fatality rate from anaphylaxis due to food in the US is estimated to be 0.04 per million per year. Alpha-gal syndrome, which is associated with tick bites, is a rising cause of IgE-mediated food anaphylaxis. The seroprevalence of sensitization to alpha-gal ranges from 20% to 31% in the southeastern US. Self-injectable epinephrine is the first-line treatment for food-related anaphylaxis. The cornerstone of IgE-food allergy management is avoidance of the culprit food allergen. There are emerging immunotherapies to desensitize to one or more foods, with one current US Food and Drug Administration-approved oral immunotherapy product for treatment of peanut allergy. IgE-mediated food allergies, including delayed IgE-mediated allergic responses to red meat in alpha-gal syndrome, are common in the US, and may cause anaphylaxis and rarely, death. IgE-mediated anaphylaxis to food requires prompt treatment with epinephrine injection. Both food-protein allergy and alpha-gal syndrome management require avoiding allergenic foods, whereas alpha-gal syndrome also requires avoiding tick bites.
Li Z, Ma A, Miller I, Starnes R, Talkington A, et al.
Journal of controlled release : official journal of the Controlled Release Society •
Polyethylene glycol (PEG) is frequently used in various protein and nanomedicine therapeutics. However, various studies have shown that select PEGylated therapeutics can induce production of anti-PEG antibodies (APA), potentially culminating in rapid clearance from the systemic circulation, loss of efficacy and possibly increased risks of allergic reactions. Although IgE is a frequent cause of immediate hypersensitivity reactions (IHR), the role of IgE APA in PEG-related IHR is not well understood, due in part to a lack of standardized assays for measuring IgE APA. Here, we developed a rigorous competitive ELISA method to measure the concentrations of various APA isotypes, including IgE, with picomolar sensitivities. In a small number of serum samples from patients with known PEG allergy, the assay allowed us to detect a strong correlation between IgG and IgE APA in individuals with history of allergic reactions to PEG or PEGylated drugs, but not between IgM and IgE APA. We detected appreciable levels of IgG and IgM APA in individuals with history of alpha-gal allergy, however, they were not elevated relative to those detected in other healthy controls, and we found no pre-existing IgE APA. While preliminary and should be further investigated, these results suggest that differences in the route and mechanism of PEG exposure may drive variability in APA response.
Alpha Gal Syndrome (AGS) is an emerging immune response to mammalian products (MP) containing the oligosaccharide galactose-α-1,3 galactose (α-Gal) which includes meats and inactive ingredients in certain medications. This becomes clinically important in the perioperative realm as MPs are commonly found in the operating room, and pre- and post-operative settings, and can trigger responses as severe as anaphylaxis. In this review, authors discuss the epidemiology, diagnosis and treatment of AGS reactions. Additionally, strategies are explored in order to screen and prevent exposure to MP with a multidisciplinary approach. While this emerging allergy is still not fully understood, it is of paramount importance that all anesthesia providers recognize the implications of MP exposure in AGS patients and ultimately prevent harm in this highly vulnerable population.
Alpha-gal syndrome is an immunoglobulin E (IgE)-mediated delayed hypersensitivity reaction to nonprimate mammalian products, which has a newly established gastrointestinal (GI) phenotype in adults. We assessed the GI presentation and treatment response in children. This is a retrospective study of patients presenting in a pediatric gastroenterology clinic tested for alpha-gal IgE. Forty of 199 patients (20%) tested had a positive alpha-gal-specific IgE, with 77.5% reporting GI symptoms in isolation. Of the 30 that attempted dietary elimination, 8 (27%) experienced full resolution of symptoms. Alpha-gal syndrome can present with isolated GI symptoms in children.
Smith BRE, Reid Black K, Bermingham M, Agah S, Glesner J, et al.
Frontiers in allergy •
Allergic reactions are mediated by human IgE antibodies that bind to and cross-link allergen molecules. The sites on allergens that are recognized by IgE antibodies have been difficult to investigate because of the paucity of IgE antibodies in a human serum. Here, we report the production of unique human IgE monoclonal antibodies to major inhaled allergens and food allergens that can be produced at scale in perpetuity. The IgE antibodies were derived from peripheral blood mononuclear cells of symptomatic allergic patients, mostly children aged 3-18 years, using hybridoma fusion technology. Total IgE and allergen-specific IgE was measured by ImmunoCAP. Their specificity was confirmed through ELISA and immunoblotting. Allergenic potency measurements were determined by ImmunoCAP inhibition. Biological activity was determined by comparing -hexosaminidase release from a humanized rat basophilic cell line. Human IgE monoclonal antibodies ( = 33) were derived from 17 allergic patients with symptoms of allergic rhinitis, asthma, atopic dermatitis, food allergy, eosinophilic esophagitis, or red meat allergy. The antibodies were specific for five inhaled allergens, nine food allergens, and alpha-gal and had high levels of IgE (53,450-1,702,500 kU/L) with ratios of specific IgE to total IgE ranging from <0.01 to 1.39. Sigmoidal allergen binding curves were obtained through ELISA, with low limits of detection (<1 kU/L). Allergen specificity was confirmed through immunoblotting. Pairs of IgE monoclonal antibodies to Ara h 6 were identified that cross-linked after allergen stimulation and induced release of significant levels of -hexosaminidase (35%-80%) from a humanized rat basophilic cell line. Human IgE monoclonal antibodies are unique antibody molecules with potential applications in allergy diagnosis, allergen standardization, and identification of allergenic epitopes for the development of allergy therapeutics. The IgE antibody probes will enable the unequivocal localization and validation of allergenic epitopes.
This case report describes the implementation of a heparin desensitisation strategy for a patient with confirmed galactose-alpha-1,3-galactose (alpha-gal) allergy, prior to cardiac surgery. We describe the pre-, intra- and postoperative management. We believe this report can enhance the limited data currently in existence on alternative strategies for heparin utilisation in cardiopulmonary bypass in a previously intolerant patient population.
Caballero ML, Krantz MS, Quirce S, Phillips EJ, Stone CA
The journal of allergy and clinical immunology. In practice •
Excipients are necessary as a support to the active ingredients in drugs, vaccines, and other products, and they contribute to their stability, preservation, pharmacokinetics, bioavailability, appearance, and acceptability. For both drugs and vaccines, these are rare reactions; however, for vaccines, they are the primary cause of immediate hypersensitivity. Suspicion for these "hidden dangers" should be high, in particular, when anaphylaxis has occurred in association with multiple chemically distinct drugs. Common excipients implicated include gelatin, carboxymethylcellulose, polyethylene glycols, and products related to polyethylene glycols in immediate hypersensitivity reactions and propylene glycol in delayed hypersensitivity reactions. Complete evaluation of a suspected excipient reaction requires detailed information from the product monograph and package insert to identify all ingredients that are present and to understand the function and structure for these chemicals. This knowledge helps develop a management plan that may include allergy testing to identify the implicated component and to give patients detailed information for future avoidance of relevant foods, drugs, and vaccines. Excipient reactions should be particularly considered for specific classes of drugs where they have been commonly found to be the culprit (eg, corticosteroids, injectable hormones, immunotherapies, monoclonal antibodies, and vaccines). We provide a review of the evidence-based literature outlining epidemiology and mechanisms of excipient reactions and provide strategies for heightened recognition and allergy testing.
Stone CA, Hemler JA, Commins SP, Schuyler AJ, Phillips EJ, et al.
The Journal of allergy and clinical immunology •
A patient with alpha-gal allergy presented with anaphylaxis after receiving zoster vaccine. Subsequent testing of selected vaccines revealed the presence of alpha-gal allergen in MMR and zoster vaccines, which have in common a higher content of gelatin and content of bovine calf serum.
Hussain M, Daignault S, Agarwal N, Grivas PD, Siefker-Radtke AO, et al.
Cancer •
Epidermal growth factor receptor overexpression is associated with poor outcomes in urothelial carcinoma (UC). Cetuximab (CTX) exhibited an antitumor effect in in vivo UC models. The efficacy of gemcitabine/cisplatin (GC) with or without CTX in patients with advanced UC was evaluated. Patients with advanced UC, measurable disease, and adequate organ function were randomized 1:2 to cisplatin (70 mg/m(2) ) on day 1 plus gemcitabine (1000 mg/m(2) ) on days 1, 8, and 15 (arm A) or GC plus CTX (500 mg/m(2) ) on days 1 and 15 (arm B). The primary endpoint was the overall response rate. The secondary endpoints were the response duration, safety, progression-free survival, overall survival, determination of whether or not CTX sensitized nonresponders to GC, and exploratory biomarker analysis. The accrual targets were 27 and 54 patients for the 2 arms, respectively. The overall response rate was reported by arm with binomial confidence intervals (CIs). Kaplan-Meier methods were used for time-to-event endpoints. Eighty-eight eligible patients were randomized; 87 were toxicity-evaluable, and 85 were response-evaluable. The overall response rates were 57.1% for arm A (95% CI = 37%-76%) and 61.4% for arm B (95% CI = 48%-74%). The median progression-free survival times were 8.5 months for arm A (95% CI = 5.7-10.4 months) and 7.6 months for arm B (95% CI = 6.1-8.7 months). The median overall survival times were 17.4 months for arm A (95% CI = 12.8 months to unreached) and 14.3 months for arm B (95% CI = 11.6-22.2 months). The most common grade 3/grade 4 adverse events in both arms were myelosuppression and nausea. Thromboembolism, acneiform rash, fatigue, pain, hypersensitivity reactions, elevated transaminases, hyponatremia, and hypomagnesemia were more common in arm B; 3 grade 5 adverse events occurred in arm B. The presence of primary disease significantly correlated with thromboembolism. An increased soluble E-cadherin level after cycle 2 correlated with a higher risk of death. GC plus CTX was feasible but was associated with more adverse events and no improvements in outcomes.
