Workman LJ

The alpha-gal syndrome: Understanding the role of tick bites, and the delays in severe anaphylaxis.

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.

Reply to "Fatal reactions to alpha-gal might be due to comorbid mast cell diseases".

IgG to Galactose-Alpha-1,3-Galactose: Impact of Alpha-Gal IgE Sensitization, Blood Type, and Tick Bites.

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.

The Immunology of Alpha-Gal Syndrome: History, Tick Bites, IgE, and Delayed Anaphylaxis to Mammalian Meat.

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.

Implications of a fatal anaphylactic reaction occurring 4 hours after eating beef in a young man with IgE antibodies to galactose-α-1,3-galactose.

Mammalian Meat Allergy and IgE to Alpha-Gal in Central Virginia: Findings From a COVID-19 Vaccine and Patient Cohort.

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%.

Incidence of Alpha-Gal IgE Sensitization in 3000 Military Personnel, Assessing Sex, Race, Installation, and Occupational Impacts.

: 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.

Alpha-Gal IgE Prevalence Patterns in the United States: An Investigation of 3,000 Military Recruits.

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.

IgE to common food allergens is associated with cardiovascular mortality in the National Health and Examination Survey and the Multi-Ethnic Study of Atherosclerosis.

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.

Isotype diversity of antibodies specific for component allergens in the context of allergic diseases: eosinophilic esophagitis (EoE), asthma, and the alpha-gal syndrome (AGS).

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.