Filip AB, Mahmood L, Tilly C, Foster HR, Jackson F, et al.
Annals of emergency medicine •
North American pit viper antivenoms, CroFab® and ANAVIP®, contain galactose-α-1,3-galactose (α-GAL) oligosaccharide. We compared adverse drug reactions, including presumed anaphylaxis, following administration of these antivenoms and investigated biological plausibility of these antivenoms leading to anaphylaxis in α-GAL-immunoglobulin (Ig) E-sensitized individuals. We performed 2 studies. A retrospective chart review from the Arkansas Poison Center (May 2021 to July 2023) identified adverse drug reactions and presumed anaphylaxis in patients treated with crotaline antivenom. Two allergists (JK, LM), blinded to the antivenom used, adjudicated presumed anaphylaxis cases. To assess whether antivenoms could activate basophils from α-GAL-IgE-sensitized individuals, basophil activation tests were performed on blood from 5 α-GAL-IgE-sensitized participants with a history of mammalian meat allergy. Basophil activation was assessed by %CD63 upregulation. Adverse drug reactions without presumed anaphylaxis occurred in 7 out of 171 (4.1%) Fab recipients versus 8 out of 37 (21.6%) F(ab') recipients (Δ=17.5%, 95% confidence interval [CI] [4.0 to 31.0]). Presumed anaphylaxis was observed in 3 out of 171 (1.8%) for Fab and 6/37 (16.2%) for F(ab') (Δ=14.3%, 95% CI 2.5 to 26.2). In the basophil activation tests, the mean EC for basophil CD63 activation was 144-fold higher for Fab (mean, [standard deviation]; 647 μg/mL of antivenom [627]) compared to F(ab') (4.48 μg/mL of antivenom [2.75]). We demonstrate a substantial incidence of adverse drug reactions and presumed anaphylaxis to crotaline antivenoms in an α-GAL endemic region, with F(ab') antivenom associated with more reactions than F(ab). Clinicians in α-GAL endemic regions should be cautious in the use of antivenoms, especially for patients with α-GAL allergy.
Platts-Mills TAE, Dunaway CA, Gangwar RS, Workman LJ, Wilson JM
Allergy and asthma proceedings •
The presence of serum immunoglobulin E (IgE) antibodies to the oligosaccharide galactose-alpha-1,3-galactose (α-gal) was first recognized during the investigation of allergic reactions to the monoclonal antibody cetuximab. The availability of an assay for IgE to α-gal made it possible to show that the patients who reported delayed allergic reactions to meat also had IgE to α-gal. This syndrome of delayed reactions to meat in patients with IgE to an oligosaccharide that was present in nonprimate mammals represented a complete contrast to the other forms of food allergy. However, the realization that the sensitization resulted from bites of the lone star tick, Ambloymma americanum, provided an explanation for the increase in cases in an area of the United States where there had been a major increase in the deer population, which is the primary breeding host of this tick. In contrast to almost all other IgE-mediated reactions, there is no relationship between the delay after eating red meat and the severity of allergic reactions. There is also increasing evidence that serum tryptase in the range of 20-90 ng/mL can occur after severe reactions related to α-gal. In addition, a recently reported fatal anaphylaxis, which started 4 hours after the individual ate a hamburger, included a postmortem tryptase of >2000 ng/mL. A working hypothesis to explain the delay in reactions relates to the time taken to process glycolipids in food derived from mammals, first into chylomicrons and, finally, to low-density lipoproteins. However, the quantitative presence of α-gal that remains on these particles may have major individual differences. In contrast to the patients who have symptoms related to eating meat, there are many individuals who are sensitized and who are not aware of any symptoms. In addition, individuals who are sensitized to alpha-gal can react rapidly to intravenous injections to the monoclonal antibody cetuximab, or polyclonal antibodies to venom, or the newer antivenom digested to Fab or Fab'2.
Venkat PG, Nehrbas JF, Bortz PS, Platts-Mills TA, Behm BW, et al.
JGH open : an open access journal of gastroenterology and hepatology •
Ustekinumab, a monoclonal antibody (mAb) used to treat inflammatory bowel disease, has been associated with immediate hypersensitivity reactions during first intravenous infusion. While rare, the mechanism for these reactions is unclear. IgE to the oligosaccharide galactose-α-1,3-galactose (α-gal) is a cause of allergy to mammalian meat and other mammalian products that express α-gal. Given that ustekinumab (Stelara) is produced in murine SP2/0 cells, a cell line known to introduce α-gal during post-translational modification, we hypothesized that α-gal could explain some of these reactions. We describe six patients with Crohn's disease who experienced acute reactions during ustekinumab infusion and were found to have IgE specific to α-gal. Serum or cells from a separate group of α-gal IgE-sensitized patients with red meat allergy were used for in vitro experiments to investigate ustekinumab allergenicity. ImmunoCAP binding assays confirmed that IgE from four red meat allergic patients, but not controls, bound to ustekinumab on the solid phase. This binding was inhibited by the α-gal-containing glycoprotein beef thyroglobulin. Basophil activation tests (BAT), carried out to assess functional activity, revealed dose-dependent activation with ustekinumab from four α-gal-sensitized individuals, but not controls. Two other mAbs produced in SP2/0 cells (cetuximab and infliximab) as well as a representative mAb produced in Chinese Hamster Ovary (CHO) cells (vedolizumab) were evaluated as comparators, with the mAbs from SP2/0 but not CHO cells eliciting BAT activity. Pre-existing IgE to α-gal may account for some first-dose infusion reactions to ustekinumab. Screening for α-gal sensitization in patients with alpha-gal syndrome should be considered prior to ustekinumab infusion.
Ailsworth SM, MacCallum M, Richards NE, Workman LJ, Schoppee Bortz P, et al.
Antibodies (Basel, Switzerland) •
Antibodies to galactose-alpha-1,3-galactose (alpha-gal), particularly the IgM and IgG isotypes, are abundant in human sera. These antibodies are known to be an important xenotransplantation barrier, but the full implications of these antibodies to health and disease remain incompletely understood. By contrast, IgE to alpha-gal is uncommon in the population but has been associated with tick bites and causally linked with mammalian meat allergy, often now known as alpha-gal syndrome (AGS). To date, there have been few population-based studies that have investigated alpha-gal IgG levels in relation to demographic factors, diet, tick bites, and mammalian meat allergy. Adults, predominantly healthcare workers, were recruited for a COVID-19 vaccine study. At least one serum sample was collected, and subjects completed questionnaires to provide demographic, diet, and tick exposure data. Alpha-gal IgG, IgE, and total IgG were measured using the ImmunoCAP platform, and blood group was assessed via reverse typing using stored serum. We also assessed alpha-gal IgG levels among subjects with AGS, recruited from an allergy clinic. The median age of the 267 subjects in the vaccine cohort was 42 years, and median alpha-gal IgG levels were 3.0 μg/mL. Alpha-gal IgG levels were higher among the 43 (16.1%) subjects who had alpha-gal IgE sensitization (≥0.1 IU/mL) and among subjects lacking the B blood group antigen (blood groups A and O). Alpha-gal IgG levels did not differ between the subjects who had asymptomatic alpha-gal IgE sensitization and those who had meat allergy. However, both groups had higher alpha-gal IgG levels than subjects who lacked alpha-gal IgE sensitization. Subjects who reported prior tick or chigger bites had higher alpha-gal IgG levels than those without a bite history, regardless of alpha-gal IgE sensitization status. In a population-based cohort, alpha-gal IgG antibodies were found to be prevalent, and levels were increased in subjects with blood groups A and O, subjects who were alpha-gal IgE sensitized, and those who reported a history of tick bites.
Platts-Mills TAE, Gangwar RS, Workman L, Wilson JM
Immunological reviews •
The primary features of the alpha-gal syndrome (AGS) are (i) The IgE ab that are causally related to anaphylaxis with infusions of Cetuximab are specific for galactose alpha-1,3-galactose. (ii) In the USA, this IgE ab is induced by bites of the tick Amblyomma americanum. (iii) The anaphylactic reactions to food derived from non-primate mammals are delayed in onset by three to five hours. A further important fact is that all humans make a "natural" response to alpha-gal which includes IgM, IgG, and IgA, but not IgE. The clinical features of AGS are recognized in many parts of the world, but different species of ticks are involved. The immune response to tick bites includes T cells specific for tick protein, while IgE producing B cells appear to be derived from B cells specific for IgM or IgG. With repeated tick bites, the T cells develop a strong Th2 signal with IL-4 and IL-13 This obviously relates to IgE production, but may also be relevant to itching after tick bites which can last for weeks. The current hypothesis about the cause of the delayed reactions is based on the time that it takes to digest glycolipids from meat to LDL. The management of AGS symptoms is based on the avoidance of food derived from mammals; however, the only thing that can allow IgE to decrease is avoidance of tick bites.
Allergology international : official journal of the Japanese Society of Allergology •
Alpha-gal syndrome (AGS) is a unique allergic condition triggered by IgE antibody production against the mammalian oligosaccharide galactose-α-1,3-galactose (α-gal). The syndrome, acquired by bites from multiple tick species, leads to delayed allergic reactions after consuming mammalian-derived products containing α-gal, including red meat, dairy, and select medications. AGS is especially prevalent in regions with high tick exposure and has become a global public health concern, with rising cases across continents. Despite growing research, including recent findings suggesting that asymptomatic α-gal sensitization may contribute to coronary artery disease, the precise immune mechanisms-particularly B cell-mediated IgE production following tick bites-remain poorly understood. Additionally, the tick saliva components that trigger sensitization and the role of the skin-gut axis in food allergy development are knowledge gaps. AGS research has benefited from animal models like mice, zebrafish, and pigs, which replicate key syndrome features, though have limitations. Humanized mouse models and human organoid systems now offer promising tools for investigating AGS pathogenesis and testing potential therapies. This review explores current pre-clinical methodologies, challenges, and the future of AGS research, emphasizing innovative models that may bridge knowledge gaps and advance therapeutic development.
The journal of allergy and clinical immunology. In practice •
IgE to galactose-alpha-1,3-galactose (alpha-gal) is linked to tick bites and an important cause of anaphylaxis and urticarial reactions to mammalian meat. The alpha-gal syndrome (AGS) is recognized as being common in the southeastern United States. However, prevalence studies are lacking and open questions remain about risk factors and clinical presentation of alpha-gal sensitization. Here we characterized the prevalence as well as the presentation and risk factors of AGS and alpha-gal IgE sensitization in adults in central Virginia recruited without regard to the history of allergic disease. Adults in central Virginia, primarily University of Virginia Health employees, were recruited as part of a COVID-19 vaccine study. Subjects provided at least one blood sample and answered questionnaires about medical and dietary history. We used ImmunoCAP for IgE assays and assessed the ABO blood group by reverse typing using stored serum. We also investigated biobanked serum from COVID-19 patients. Median age of the 267 enrollees was 42 years, 76% were female, and 43 (16%) were sensitized to alpha-gal (cutoff of 0.1 IU/mL), of which mammalian meat allergy was reported by seven (2.6%). Sensitized subjects (1) were older, (2) had higher total IgE levels but a similar frequency of IgE to common respiratory allergens, and (3) were more likely to report tick bites than were nonsensitized subjects. Among those who were sensitized, alpha-gal IgE levels were higher among meat-allergic than nonallergic subjects (geometric mean, 9.0 vs 0.5 IU/mL; P < .001). Mammalian meat and dairy consumption was common in individuals with low-level sensitization. In central Virginia, AGS is a dominant cause of adult food allergy with a prevalence approaching or exceeding 2%.
Ching SJ, Susi A, Ailsworth SM, Workman LJ, Platts-Mills TAE, et al.
Journal of clinical medicine •
: IgE to galactose-alpha-1,3-galactose (alpha-gal) is associated with (lone star tick) bites, accounting for the regional distribution of the alpha-gal syndrome (AGS). Longitudinal studies describing risk factors for incident alpha-gal sensitization are lacking. The objective of this project was to assess the incidence of alpha-gal IgE seroconversion and identify associated demographic, occupational, and geographical risk factors among US military personnel. : Samples from the Department of Defense Serum Repository were evaluated at two time points at least 3 years apart. In total, 3000 service members stationed at 10 military installations within the tick range were included. Installation, sex, race and ethnicity, rank, military occupation, and branch of service were evaluated. Alpha-gal IgE seroconversion was defined as a change from <0.1 kU/L) to ≥0.1 kU/L. : Among the 2821 personnel who were alpha-gal IgE-negative at baseline, 138 (4.9%) seroconverted over a mean interval of 3.4 years. Seroconversion was more frequent in males (5.5% vs. 1.9%), White individuals (6.6% vs. 1.0% in Black people and 1.5% in Hispanics), and individuals in occupations with higher presumed outdoor exposure (e.g., infantry/law enforcement: 12.7% vs. administrative: 1.2%). Differences were not significant between sexes when accounting for military installation/occupation, but differences in race and ethnicity remained significant. : This study demonstrates that alpha-gal IgE seroconversion is occurring within the tick range and is associated with White race and ethnicity, and occupations with higher outdoor exposure. Further research is needed to elucidate the influence of race and ethnicity on alpha-gal sensitization and develop effective prevention and treatment strategies for AGS.
Zvara J, Smith AL, Mazzeffi MA, Kleiman AM, Tanaka K, et al.
Journal of cardiothoracic and vascular anesthesia •
Galactose-alpha-1,3-galactose (alpha-gal) is a carbohydrate expressed by all mammals except for humans and certain old-world primates. It can be found in a plethora of products derived from mammals, including milk, organs, skeletal muscle and gelatin, in addition to products prepared with mammalian cells or constituents. In the late 2000s, an association between tick bites and the development of immunoglobulin E antibodies to the alpha-gal carbohydrate was discovered. The term "alpha-gal syndrome" (AGS) was then coined to describe allergic reactions to mammalian meat or other alpha-gal-containing products derived from mammals. Symptoms are often delayed several hours from consumption and can be urticarial and/or gastrointestinal. Medications and bioprosthetic inserts derived from mammals were also noted to cause allergic reactions in affected patients. Cardiac surgery, in particular, is considered high risk, given that unfractionated heparin has a bovine or porcine origin and is administered in large doses for cardiopulmonary bypass. Bioprosthetic valves have similar origins and risks. Awareness of AGS in cardiac surgery patients can lead to decreased risk preoperatively and inform management perioperatively and postoperatively. In this narrative review, we have reviewed the published literature relevant to AGS in patients undergoing cardiac surgery and shared our treatment approach.
Wilson JM, Erickson L, Levin M, Ailsworth SM, Commins SP, et al.
Allergy •
The recent recognition of a syndrome of tick-acquired mammalian meat allergy has transformed the previously held view that mammalian meat is an uncommon allergen. The syndrome, mediated by IgE antibodies against the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal), can also involve reactions to visceral organs, dairy, gelatin and other products, including medications sourced from non-primate mammals. Thus, fittingly, this allergic disorder is now called the alpha-gal syndrome (AGS). The syndrome is strikingly regional, reflecting the important role of tick bites in sensitization, and is more common in demographic groups at risk of tick exposure. Reactions in AGS are delayed, often by 2-6 h after ingestion of mammalian meat. In addition to classic allergic symptomatology such as urticaria and anaphylaxis, AGS is increasingly recognized as a cause of isolated gastrointestinal morbidity and alpha-gal sensitization has also been linked with cardiovascular disease. The unusual link with tick bites may be explained by the fact that allergic cells and mediators are mobilized to the site of tick bites and play a role in resistance against ticks and tick-borne infections. IgE directed to alpha-gal is likely an incidental consequence of what is otherwise an adaptive immune strategy for host defense against endo- and ectoparasites, including ticks.
Ailsworth SM, Susi A, Workman LJ, Ji YS, Patel J, et al.
The journal of allergy and clinical immunology. In practice •
IgE to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) is an important cause of allergic reactions to mammalian meat. The "alpha-gal syndrome" is strongly associated with a preceding history of tick bites and in the United States is most commonly reported in parts of the southeast, but there has been limited investigation into national alpha-gal sensitization patterns and the relevance of other risk factors. To systematically investigate alpha-gal IgE prevalence, regional patterns, and risk factors. Alpha-gal IgE was measured by ImmunoCAP in biobanked serum samples collected from 3000 service members who presented for intake to 1 of 10 military bases in the central/eastern United States. Alpha-gal IgE sensitization (cutoff 0.1 international units/mL) was related to home of record at enlistment. Of the cohort, 2456 (81.9%) subjects were male, median age was 19 years (interquartile range: 18-22 years), and alpha-gal IgE was detected in 179 (6.0%). Home of record spanned all 50 states, with a median of 36 recruits per state (range: 3-261). The highest prevalence rates were in Arkansas (39%), Oklahoma (35%), and Missouri (29%), with several other southeastern states >10%. Granular mapping revealed sensitization patterns that closely mimicked county-level Amblyomma americanum reports and Ehrlichia chaffeensis infections. Sensitization was associated with male sex, rural residence, and White race in univariate and multivariable models. In this systematic survey, the prevalence of alpha-gal IgE among incoming military personnel was 6.0%. There were significant regional differences, with an overall pattern consistent with the known range of the lone star tick (A. americanum) and highest frequency in an area including Arkansas, Oklahoma, and Missouri.
Keet C, McGowan EC, Jacobs D, Post WS, Richards NE, et al.
The Journal of allergy and clinical immunology •
In individuals without symptomatic food allergy, food-specific IgE is considered clinically irrelevant. However, recent studies have suggested that galactose-α-1,3-galactose (alpha-gal) IgE is associated with cardiovascular (CV) disease. We sought to determine whether sensitization to common food allergens is associated with CV mortality. The association between IgE sensitization to foods and CV mortality ascertained to 2019 was examined in the National Health and Examination Survey (NHANES) 2005-2006 and the Wake Forest site of the Multi-Ethnic Study of Atherosclerosis (MESA) cohort; MESA enrolled adults without baseline clinical CV diseases between 2000 and 2002. Total and specific IgE was measured to cow's milk, egg, peanut, shrimp, and a panel of aeroallergens (NHANES), and to cow's milk, alpha-gal, peanut, dust mite, and timothy grass (MESA). Cox proportional hazard models were constructed, adjusting for sex, age, race/ethnicity, smoking, education, and asthma. A total of 4414 adults from NHANES (229 CV deaths) and 960 from MESA (56 CV deaths) were included. In NHANES, sensitization to at least 1 food was associated with higher CV mortality (hazard ratio [HR], 1.7 [95% confidence interval (CI), 1.2-2.4], P = .005). Milk sensitization was particularly associated (HR, 2.0 [95% CI, 1.1-3.8], P = .026), a finding replicated in MESA (HR, 3.8 [95% CI, 1.6-9.1], P = .003). Restricting analyses in NHANES to consumers of the relevant allergen strengthened food sensitization relationships, unmasking shrimp and peanut sensitization as additional risk factors for CV mortality. The finding that food sensitization is associated with increased risk of CV mortality challenges the current paradigm that sensitization without overt allergy is benign. Further research is needed to clarify mechanisms of this association.
Platts-Mills TAE, MacCallum MH, Wilson JM, Workman LJ, Erwin EA
Frontiers in allergy •
From the earliest days of studying the reagins in allergic sera that give rise to the Prausnitz-Kuestner reaction, there was evidence that there were other types of antibodies (Ab) specific for allergens, particularly those induced by immunotherapy. By 1980, not only was IgE recognized and could be measured, but the presence of other isotypes including IgG and IgA in patients with IgE was well established. From that time onwards the development of monoclonal antibodies made it possible to distinguish and measure antibodies of other isotypes such as IgG4, IgG2, and IgG3. Over the past 40 years two things have dominated the field- firstly, the techniques for measuring isotype specific antibodies to allergens have improved steadily. Secondly, several different allergic diseases or phenomena have been identified in which isotype diversity of the antibodies has become a major issue. Prior to 1990 only occasional cases of eosinophilic esophagitis (EoE) had been identified, but since then they have become common. Most of the cases have positive skin tests and/or IgE Ab to cow's milk or wheat, but it became obvious that most cases of EoE are not primarily related to IgE. Today it is clear that IgG4 Ab to these allergens play a significant role in cases of EoE. In 2000 the first reports of children developing tolerance to cat allergen appeared. Today it is clear that this tolerance depends on high levels of IgG4 antibodies and there is increasing evidence that the IgG4 response is primarily against . The most recent novel allergic disease is the alpha-gal syndrome (AGS). This condition is based on IgE antibodies specific for the oligosaccharide galactose alpha,1-3-galactose, which are primarily induced by tick bites. However, in this case it was already well known that all immunocompetent primates have made IgG and IgM antibodies to this oligosaccharide. Furthermore, it is not clear whether the IgG isotypes, particularly IgG1 and IgG3, play a role in the inflammatory response to the oligosaccharide. Overall, it is clear that current and future investigation of allergic diseases requires careful assessment of allergen specific antibodies of diverse isotypes in addition to IgE.
Reddy S, Yi L, Shields B, Platts-Mills T, Wilson J, et al.
Journal of the American Academy of Dermatology •
Alpha-gal syndrome (AGS) is an allergy to "red meat" and other mammalian products due to immunoglobulin E (IgE) antibodies against the sugar moiety galactose-alpha-1,3-galactose (alpha-gal), which is acquired following tick bites. Clinically, AGS presents with urticaria, abdominal pain, nausea, and occasionally anaphylaxis, and has wide inter- and intra-personal variability. Because symptom onset is generally delayed by 2 to 6 hours after meat consumption, AGS can be easily confused with other causes of urticaria and anaphylaxis, such as chronic spontaneous urticaria (CSU) and mast cell activation syndrome (MCAS). Diagnosis relies on a combination of clinical history, positive alpha-gal IgE blood testing and improvement on a mammalian-restricted diet. Management of the syndrome centers primarily on avoidance of mammalian meats (and occasionally dairy and other products) as well as acute management of allergic symptoms. Counseling about tick avoidance measures is also important as AGS will wane over time in many patients.
Richards NE, Wilson JM, Platts-Mills TAE, Richards RD
Frontiers in gastroenterology (Lausanne, Switzerland) •
The galactose-α-1,3-galactose (α-gal) mammalian meat allergy, α-gal syndrome, often includes diarrhea, abdominal pain, and other gastrointestinal (GI) symptoms. Pancreatic exocrine insufficiency causes similar symptoms. The pancreatic replacement enzymes, referred to here as pancreatic enzymes, used to treat pancreatic insufficiency are porcine products and contain α-gal. Patients with pancreatic insufficiency who also have α-gal syndrome may be intolerant of mammalian products in their diet and of α-gal in pancreatic enzymes. In this article, we describe 40 patients from one GI clinic in central Virginia with suspected pancreatic insufficiency and increased α-gal immunoglobulin E (IgE) levels. Over 50% of these patients had some clinical improvement when mammalian products were removed from the diet. Most patients could tolerate pancreatic enzymes; 10% could not tolerate them due to suspected allergy symptoms, but none developed anaphylaxis. Understanding that α-gal syndrome can be superimposed on pancreatic exocrine insufficiency and exacerbate symptoms, and that treatment with pancreatic enzymes may increase GI and/or allergy symptoms in this group, will lead to improved medical management of this complex patient population.
Richards NE, Makin TA, Smith AR, Platts-Mills TAE, Richards RD, et al.
Frontiers in gastroenterology (Lausanne, Switzerland) •
The α-Gal mammalian meat allergy classically presents with urticaria, with or without gastrointestinal (GI) symptoms or anaphylaxis, but increasingly we are aware of patients with only GI symptoms. Here we describe patients presenting with isolated GI symptoms who had detectable IgE antibodies to α-Gal and reported symptom improvement on a mammal-restricted diet. Forty patients in the practice of a single gastroenterologist, and 35 patients in one allergy clinic were identified, with abdominal pain, diarrhea, and nausea the most common symptoms. Alpha-Gal IgE levels were lower than in a previously described cohort of patients who exhibited classic allergic reactions. This large case series suggests that α-Gal IgE is an important contributor to GI morbidity in areas where lone star tick bites are common. Symptom presentations in GI-AGS can be easily confused with other common GI conditions, and α-Gal IgE levels are often lower than those in patients with classic AGS.