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Background: 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., Objective: 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., Methods: 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. IgG 4 to α-Gal and antibodies to regionally representative parasites were assessed in a subset of children., Results: 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 IgG 4 were not high in Ecuador, but were greater than in children from the United States., Conclusions: 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., (Copyright © 2021. Published by Elsevier Inc.)

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., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Allergen-specific IgG 4 (sIgG 4 ) antibodies are often associated with tolerance, but sIgG 4 antibodies to causally relevant foods have been reported recently in adults with eosinophilic esophagitis (EoE). Prevalence and levels of food sIgG 4 are not well established in the general pediatric population., Objective: We sought to investigate serum food sIgG 4 with component diagnostics in children with EoE and children from an unselected birth cohort and to explore the effects of sex, age, and milk consumption on sIgG 4 levels., Methods: Sera from 71 pediatric patients with EoE and 210 early adolescent children from an unselected birth cohort (Project Viva) were assayed for sIgG 4 and specific IgE (sIgE) to major cow's milk (CM) proteins (α-lactalbumin, β-lactoglobulin, and caseins) and to wheat, soy, egg, and peanut proteins., Results: In the EoE cohort high-titer sIgG 4 (≥10 μg/mL) to CM proteins was more common than in control sera and achieved odds ratios for EoE ranging from 5.5 to 8.4. sIgE levels to CM proteins were mostly 4 IU/mL or less in patients with EoE, such that sIgG 4 /sIgE ratios were often 10,000 or greater. When adjusted for age and milk consumption, high-titer sIgG 4 to CM proteins was strongly associated with EoE, with an odds ratio of greater than 20 to all 3 CM proteins in boys., Conclusions: sIgG 4 to CM proteins are common and high titer in children with EoE. Although it is not clear that this response is pathogenic, sIgG 4 levels imply that these antibodies are an important feature of the local immune response that gives rise to EoE., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The pathogenesis of severe asthma in childhood remains poorly understood., Objective: We sought to construct the immunologic landscape in the airways of children with severe asthma., Methods: Comprehensive analysis of multiple cell types and mediators was performed by using flow cytometry and a multiplex assay with bronchoalveolar lavage (BAL) specimens (n = 68) from 52 highly characterized allergic and nonallergic children (0.5-17 years) with severe treatment-refractory asthma. Multiple relationships were tested by using linear mixed-effects modeling., Results: Memory CCR5 + T H 1 cells were enriched in BAL fluid versus blood, and pathogenic respiratory viruses and bacteria were readily detected. IFN-γ + IL-17 + and IFN-γ - IL-17 + subsets constituted secondary T H types, and BAL fluid CD8 + T cells were almost exclusively IFN-γ + . The T H 17-associated mediators IL-23 and macrophage inflammatory protein 3α/CCL20 were highly expressed. Despite low T H 2 numbers, T H 2 cytokines were detected, and T H 2 skewing correlated with total IgE levels. Type 2 innate lymphoid cells and basophils were scarce in BAL fluid. Levels of IL-5, IL-33, and IL-28A/IFN-λ2 were increased in multisensitized children and correlated with IgE levels to dust mite, ryegrass, and fungi but not cat, ragweed, or food sources. Additionally, levels of IL-5, but no other cytokine, increased with age and correlated with eosinophil numbers in BAL fluid and blood. Both plasmacytoid and IgE + FcεRI + myeloid dendritic cells were present in BAL fluid., Conclusions: The lower airways of children with severe asthma display a dominant T H 1 signature and atypical cytokine profiles that link to allergic status. Our findings deviate from established paradigms and warrant further assessment of the pathogenicity of T H 1 cells in patients with severe asthma., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

We present results from clinical studies on plasma infusion done in the late 1970s in patients with hypogammaglobulinemia in which we documented the short half-life of both total and allergen-specific IgE in serum. The development of specific allergic sensitization in the skin of those patients followed by the gradual decrease in sensitization over 50 days was also documented. The data are included here along with a discussion of the existing literature about the half-life of IgE in both the circulation and skin. This rostrum reinterprets the earlier clinical studies in light of new insights and mechanisms that could explain the rapid removal of IgE from the circulation. These mechanisms have clinical implications that relate to the increasing use of anti-IgE mAbs for the treatment of allergic disease., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Although sensitization to indoor allergens is strongly associated with asthma, there are questions as to how this relates to asthma symptoms., Objective: We sought to study the relevance of IgE antibodies to cat and dog allergens in an area in which (1) the climate discourages cockroach, fungal, and mite growth and (2) dander allergens are known to be present in schools and houses without animals., Methods: IgE to 8 allergens was tested in 963 sera from a population-based study on 19-year-olds, and associations with asthma symptoms, diagnosis, and treatment were examined. In positive sera IgE to specific cat and dog allergens was also assayed., Results: IgE specific for animal dander had the highest prevalence and strongest relationship to asthma diagnosis. Furthermore, asthma severity, as judged by the frequency of symptoms and use of treatment, was directly associated with the titer of IgE antibodies to animal dander. Among the 103 subjects who had current asthma at age 19 years, 50 had asthma before age 12 years. Among those 50, the odds ratios for asthma related to any IgE antibodies to animal dander or high-titer IgE antibodies (≥17.5 IU/mL) were 9.2 (95% CI, 4.9-17) and 13 (95% CI, 6.9-25), respectively. In multivariable analysis IgE antibodies to Fel d 1 and Can f 5 were each associated with current asthma., Conclusion: High-titer IgE antibodies to cat and dog allergens were strongly associated with the diagnosis, severity, and persistence of asthma; however, a large proportion of patients with current asthma did not live in a house with a cat or dog., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

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 α-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 IgG4 to the same proteins. The recent finding is that patients with alpha-gal syndrome do not have detectable IgG4 to the oligosaccharide. Thus the serum results not only identify relevant antigens but also provide a guide to the nature of the immune response., (Copyright © 2016. Published by Elsevier Inc.)