A dynamic relationship between two regional causes of IgE-mediated anaphylaxis: α-Gal syndrome and imported fire ant

doi:10.1016/j.jaci.2020.05.034

Journal of Allergy and Clinical Immunology

Volume 147, Issue 2, February 2021, Pages 643-652.e7

https://doi.org/10.1016/j.jaci.2020.05.034 Get rights and content

Background

A syndrome of mammalian meat allergy relating to IgE specific for galactose-α–1,3-galactose (α-Gal) was first reported 10 years ago in the southeastern United States and has been related to bites of the lone star tick (Amblyomma americanum).

Objective

Here we investigated the epidemiology of the “α-Gal syndrome” in the United States and sought additional evidence for the connection to tick bites.

Methods

A survey of allergists was conducted by using a snowball approach. A second tier of the survey included questions about anaphylaxis to imported fire ants (IFAs). History of tick bites and tick-related febrile illness were assessed as part of a case-control study in Virginia. Antibody assays were conducted on sera from subjects reporting allergic reactions to mammalian meat or IFA.

Results

In North America the α-Gal syndrome is recognized across the Southeast, Midwest, and Atlantic Coast, with many providers in this area managing more than 100 patients each. The distribution of cases generally conformed to the reported range of A americanum, although within this range there was an inverse relationship between α-Gal cases and cases of IFA anaphylaxis that were closely related to the territory of IFA. The connection between tick bites and α-Gal sensitization was further supported by patients' responses to a questionnaire and the results of serologic tests.

Conclusions

The α-Gal syndrome is commonly acquired in adulthood as a consequence of tick bites and has a regional distribution that largely conforms to the territory of the lone star tick. The epidemiology of the syndrome is expected to be dynamic and shifting north because of climate change and ecologic competition from IFA.

Section snippets

Survey of patients with α-Gal syndrome in the United States

The study was carried out by surveying allergists in practice starting in 2016 in an area of the Southeast with a high number of established α-Gal cases. Most surveys were conducted by telephone; however, some provider questionnaires were completed in person at local or national allergy meetings or by e-mail communications. The initial sampling included many allergists in practice known to the authors; however, the participating allergists were asked about other providers in their region who

The epidemiology of α-Gal syndrome in the United States

The first phase of the survey was carried out beginning in 2016. On the basis of prior reports, we initially focused on the Southeast and confirmed that most of the clinics surveyed in this area had diagnosed 5 or more cases of delayed anaphylaxis to mammalian meat in the past 3 years. The survey was then extended outward, and in total we collected information from 152 clinics in 44 states and 1 Canadian province. More than 90% of allergists who were approached agreed to participate in the

Discussion

There are several major issues that we have addressed in the current report: (1) information about the epidemiology of the α-Gal syndrome in the United States, including additional evidence that the immunologic features of the syndrome are similar in geographically distinct areas; (2) further evidence for a connection with the lone star tick; (3) a novel explanation for the apparent “shortage” of α-Gal cases in the Deep South; and (4) increasing evidence that fire ants represent another

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Cited by (20)

Alpha-Gal IgE Prevalence Patterns in the United States: An Investigation of 3,000 Military Recruits
2024, 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.
Allergies to food and airborne allergens in children and adolescents: role of epigenetics in a changing environment
2022, The Lancet Child and Adolescent Health
Citation Excerpt :
Apart from repeated tick bites, polysensitisation (to other allergens) during childhood, and male sex, appear to be individual risk factors for later α-gal sensitisation.19 Detailed studies of tick populations are scarce; however, climate change is thought to be contributing to changes in the distribution and ecology of these ticks, which, in turn, is altering the areas where human populations are susceptible to developing α-gal-mediated meat allergy.20 Concerns about the environmental and climate effects of animal agriculture have led some families to adopt vegetarian and vegan diets.
Allergic diseases affect millions of children and adolescents worldwide. In this Review, we focus on allergies to food and airborne allergens and provide examples of prevalence trends during a time when climate change is of increasing concern. Profound environmental changes have affected natural systems in terms of biodiversity loss, air pollution, and climate. We discuss the potential links between these changes and allergic diseases in children, and the clinical implications. Several exposures of relevance for allergic disease also correlate with epigenetic changes such as DNA methylation. We propose that epigenetics could be a promising tool by which exposures and hazards related to a changing environment can be captured. Epigenetics might also provide promising biomarkers and help to elucidate the mechanisms related to allergic disease initiation and progress.
Tick exposures and alpha-gal syndrome: A systematic review of the evidence
2021, Ticks and Tick-borne Diseases
Citation Excerpt :
Further research is required to examine the possible influence of blood type, and other risk factors, on AGS development. Given the role of tick bites as the primary exposure leading to AGS (Fischer et al., 2020a; Mateo-Borrega et al., 2019; Wilson et al., 2020), prevention and awareness efforts with the public should focus on the importance of avoiding tick exposures in tick-endemic areas. Research on Lyme disease prevention suggests that increasing public awareness of tick-borne diseases is an important predictive factor affecting people’s likelihood to engage in tick prevention behaviours, such as tick checks and applying insect repellant (Aenishaenslin et al., 2017; Niesobecki et al., 2019).
Alpha-gal syndrome (AGS) refers to a delayed allergic reaction to galactose-α-1,3-galactose (α-Gal) that occurs following the consumption of mammalian meat or exposure to other animal-based foods and products. Increasing evidence suggests that bites from certain tick species can lead to AGS through sensitization of a person’s α-Gal specific IgE levels. This systematic review aimed to summarize the published evidence on this topic to understand post-tick exposure AGS epidemiology and health outcomes. A structured search for literature in eight bibliographic databases was conducted in January, 2020. Grey literature and verification searches were also performed. The exposure of interest was tick bites, and the outcome of interest was AGS. All primary research study designs were eligible for inclusion. References were screened for relevance, and data extraction and risk-of-bias assessment were conducted on relevant studies by two independent reviewers. Data were descriptively and narratively summarized. Of 1390 references screened, 102 relevant articles (103 unique studies) were identified (published from 2009 to 2020). Most studies (76.7 %) were case report or series. These 79 studies reported on 236 post-tick exposure AGS cases from 20 different countries, mostly the United States (33.5 %), Spain (19.5 %), Sweden (18.6 %), and France (12.7 %). The mean case age was 51.3 (SD = 16.7, range 5–85, n = 229), while 68.1 % were male (n = 226). The most commonly reported symptom was urticaria (71.2 %); 51.7 % of cases reported anaphylaxis. Twenty-one observational studies were reported, mostly (95.2 %) among clinical allergy patients. The proportion of AGS cases that recalled tick bites was highly variable across these studies. Three challenge studies evaluating tick exposures and α-Gal levels in α-Gal deficient mice were identified. The existing evidence suggests tick bites lead to α-Gal-specific IgE sensitization, which can cause AGS, but further research is needed to clarify if AGS is only attributable to certain tick species and whether other vectors may trigger AGS. Additional research is needed on risk factors for AGS development, evaluation of diagnostic immunoassays, and the epidemiology and distribution of AGS in different populations. Climate change will likely lead to future cases of AGS in new regions worldwide due to the predicted alteration of suitable tick habitats.
Prevalence of alpha-gal sensitization among Kentucky timber harvesters and forestry and wildlife practitioners
2021, Journal of Allergy and Clinical Immunology: In Practice
α-Gal specific-IgE prevalence and levels in Ecuador and Kenya: Relation to diet, parasites, and IgG<inf>4</inf>
2021, Journal of Allergy and Clinical Immunology
Citation Excerpt :
Similar findings, including the higher rates in males than females, have also been reported in North America.22 In the United States, these variables lose significance when accounting for tick exposure,22 which is consistent with a large body of evidence that supports the connection between tick bites and α-Gal sensitization in North America, Europe, Australia, and Japan.1 Unfortunately, tick history was not available in the current studies and there are no validated serologic assays to determine previous tick exposure.
IgE to α-Gal is a cause of mammalian meat allergy and has been linked to tick bites in North America, Australia, and Eurasia. Reports from the developing world indicate that α-Gal sensitization is prevalent but has been little investigated.
We sought evidence for the cause(s) of α-Gal sensitization and lack of reported meat allergy among children in less developed settings in Ecuador and Kenya.
IgE to α-Gal and total IgE were assessed in children from Ecuador (n = 599) and Kenya (n = 254) and compared with children with (n = 42) and without known (n = 63) mammalian meat allergy from the southeastern United States. Information on diet, potential risk factors, and helminth infections was available for children from Ecuador. IgG₄ to α-Gal and antibodies to regionally representative parasites were assessed in a subset of children.
In Ecuador (32%) and Kenya (54%), α-Gal specific IgE was prevalent, but levels were lower than in children with meat allergy from the United States. Sensitization was associated with rural living, antibody markers of Ascaris exposure, and total IgE, but not active infections with Ascaris or Trichuris species. In Ecuador, 87.5% reported consuming beef at least once per week, including 83.9% of those who had α-Gal specific IgE. Levels of α-Gal specific IgG₄ were not high in Ecuador, but were greater than in children from the United States.
These results suggest that in areas of the developing world with endemic parasitism, α-Gal sensitization is (1) common, (2) associated with Ascaris exposure, and (3) distinguished by a low percentage of specific/total IgE compared with individuals with meat allergy in the United States.
α-Gal on Crotalidae-polyvalent Fab antivenom (CroFab): Investigating the relevance to immediate hypersensitivity reactions
2021, Journal of Allergy and Clinical Immunology: In Practice

View all citing articles on Scopus

: Supported by the National Institutes of Health (grant NIH R37 AI-20565 [to T.P.M.]).

: Disclosure of potential conflict of interest: T.A.E. Platts-Mills and T. Merritt have a patent on an IgE assay to α-Gal, and T. Platts-Mills has received assay support from Thermo Fisher/Phadia. J. Wilson has received research support from Thermo Fisher/Phadia. S. Commins has been on the speaker’s bureau for Genentech. The rest of the authors declare that they have no relevant conflicts of interest.

^∗: These authors contributed equally to this article.

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Anaphylaxis, drug allergy, urticaria, and angioedemaA dynamic relationship between two regional causes of IgE-mediated anaphylaxis: α-Gal syndrome and imported fire ant

Background

Objective

Methods

Results

Conclusions

Section snippets

Survey of patients with α-Gal syndrome in the United States

The epidemiology of α-Gal syndrome in the United States

Discussion

High incidence of cetuximab-related infusion reactions in Tennessee and North Carolina and the association with atopic history

J Clin Oncol

Structural characterization of N-linked oligosaccharides on monoclonal antibody cetuximab by the combination of orthogonal matrix-assisted laser desorption/ionization hybrid quadrupole-quadrupole time-of-flight tandem mass spectrometry and sequential enzymatic digestion

Anal Biochem

Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose

N Engl J Med

Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-alpha-1,3-galactose

J Allergy Clin Immunol

The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-alpha-1,3-galactose

J Allergy Clin Immunol

On the cause and consequences of IgE to galactose-alpha-1,3-galactose: a report from the National Institute of Allergy and Infectious Disease workshop on understanding IgE-mediated mammalian meat allergy

J Allergy Clin Immunol

Galactose-alpha-1,3-galactose: atypical food allergen or model IgE hypersensitivity?

Curr Allergy Asthma Rep

An association between tick bite reactions and red meat allergy in humans

Med J Aust

Red meat allergy in Sweden: association with tick sensitization and B-negative blood groups

J Allergy Clin Immunol

Repeated Amblyomma testudinarium tick bites are associated with increased galactose-alpha-1,3-galactose carbohydrate IgE antibody levels: a retrospective cohort study in a single institution

J Am Acad Dermatol

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

Tick-induced allergies: mammalian meat allergy and tick anaphylaxis

Med J Aust

Effect of imported fire ant (Hymenoptera: Formicidae) invasion on lone star tick (Acarina: Ixodidae) populations

J Med Entomol

Predation on the lone star tick by the imported fire ant

Environmental Ent

Metastriate ixodid life stages protected from predatory ants in Texas

Environ Entomol

Decreased small mammal and on-host tick abundance in association with invasive red imported fire ants (Solenopsis invicta)

Biol Lett

Snowball versus respondent-driven sampling

Sociol Methodol

Enhancing the sample diversity of snowball samples: recommendations from a research project on anti-dam movements in Southeast Asia

PLoS One

Investigation into the alpha-Gal syndrome: characteristics of 261 children and adults reporting red meat allergy

J Allergy Clin Immunol Pract

Relevance of specific IgE antibody titer to the prevalence, severity, and persistence of asthma among 19-year-olds in northern Sweden

J Allergy Clin Immunol

The second international reference preparation for human serum immunoglobulin E and the first British standard for human serum immunoglobulin E

J Biol Stand

Quantitative measurement of IgE antibodies to purified allergens using streptavidin linked to a high-capacity solid phase

J Allergy Clin Immunol

Meat allergy and allergens

Mol Immunol

Modeling the present and future geographic distribution of the lone star tick, Amblyomma americanum (Ixodida: Ixodidae), in the continental United States

Am J Trop Med Hyg

Current and future distribution of the lone star tick, Amblyomma americanum (L.) (Acari: Ixodidae) in North America

PLoS One

Using citizen science to describe the prevalence and distribution of tick bite and exposure to tick-borne diseases in the United States

PLoS One

Anaphylaxis, drug allergy, urticaria, and angioedema
A dynamic relationship between two regional causes of IgE-mediated anaphylaxis: α-Gal syndrome and imported fire ant