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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.

Supplement: SMeeting Abstract: 574

BACKGROUND: Childhood asthma is a global problem affecting the respiratory health of children. Physical activity (PA) plays a role in the relationship between asthma and respiratory health. We hypothesized that a low level of PA would be associated with asthma in children and adolescents. The objectives of our study were to (1) summarize the evidence available on associations between PA and asthma prevalence in children and adolescents and (2) assess the role of PA in new-onset or incident asthma among children and adolescents.METHODS: We searched Medline, the Cochrane Library, and Embase and extracted data from original articles that met the inclusion criteria. Summary odds ratios (ORs) and confidence intervals (CIs) were used to express the results of the meta-analysis (forest plot). We explored heterogeneity using funnel plots and the Graphic Appraisal Tool for Epidemiology (GATE).RESULTS: We retrieved 1,571 titles and selected 11 articles describing three cohort and eight cross-sectional studies for inclusion. A meta-analysis of the cohort studies revealed a risk of new-onset asthma in children with low PA (OR [95 % CI] 1.32 [0.95; 1.84] [random effects] and 1.35 [1.13; 1.62] [fixed effects]). Three cross-sectional studies identified significant positive associations between childhood asthma or asthma symptoms and low PA.CONCLUSIONS: Children and adolescents with low PA levels had an increased risk of new-onset asthma, and some had a higher risk of current asthma/or wheezing; however, there was some heterogeneity among the studies. This review reveals a critical need for future longitudinal assessments of low PA, its mechanisms, and its implications for incident asthma in children. The systematic review was prospectively registered at PROSPERO (registration number: CRD42014013761; available at: http://www.crd.york.ac.uk/PROSPERO [accessed: 24 March 2016]).

IgE to mammalian allergens can contribute significantly to asthma risk. Studying the details of the relationship between animal sensitization and asthma is simpler in an environment where mite, fungal, and cockroach allergens make little or no contribution to asthma risk. Methods: Quantitative assays for IgE to eight allergens were carried out on 963 sera from 19-year-olds in a population-based cohort in northern Sweden, and associations with questionnaire data from ages 7, 12, and 19 on asthma symptoms, diagnosis, and treatment were tested. Results: Overall, 79 (53%) of the students with a physician diagnosis of asthma were positive to one or more of the mammalian allergens (cat, dog, or horse danders) tested. Of the allergens assessed, only mammalian allergens, birch, and timothy grass pollen showed a significant relationship with asthma diagnosis. Multivariate analysis showed that high titer (>17.5 IU/ml) IgE to any mammalian allergen had the strongest relationship with asthma at age 19 (odds ratio 5.1 [3.0-8.6]). Furthermore, IgE to mammalian allergens gave an odds ratio of 8.5 [4.9-15] for asthma that started before age 12 and was still present at age 19. Sensitization to Fel d 1 and Fel d 4 was strongly associated with asthma and significantly reduced in cat owners. Conclusions: Sensitization to cat and dog related allergens, and specifically to the components Fel d 1 and Fel d 4, is a major risk factor for the persistence and severity of asthma in an area where these are the only significant perennial allergens.

Common variable immunodeficiency (CVID) is characterized by antibody deficiency and recurrent infections as well as autoimmunity, lymphoproliferation, and hematologic malignancy. The current diagnostic criteria for CVID include reduction in serum immunoglobulin (Ig)G and either IgA or IgM and failure of antibody production. Serum IgE level is not currently considered in establishing the diagnosis of CVID. Methods: A cohort of 123 subjects from the University of Virginia Health Systems, Medical College of Wisconsin and Mount Sinai School of Medicine were diagnosed with CVID by an experienced immunologist on the basis of currently accepted diagnostic criteria, including clinical history, serum IgG, IgA and IgM, and antibody response to vaccinations. Serum IgE was measured in all of these subjects using the Phadia ImmunoCap system. Serum IgE was also measured in an unbiased control cohort of 963 healthy 17-18 year olds from northern Sweden. Results: The prevalence of undetectable (<2 IU/ml) total serum IgE in our cohort of 123 subjects with CVID was 84.6% and the prevalence of IgE <10 IU/ml was 97.6%. In comparison, IgE <2 IU/ml was found in only 3.8% of controls, in agreement with other published population estimates. Conclusions: The finding of an undetectable (<2 IU/ml) serum IgE has both a high sensitivity of 84.6% and a high specificity of 96.2% for the diagnosis of CVID. Based on this observation, measurement of serum IgE should be included as a part of the routine laboratory work-up for CVID, and an undetectable serum IgE included as a component of the diagnostic criteria.

Tick bites are known to induce IgE production to alpha-gal. Elevated alpha-gal IgG1 compared to natural alpha-gal IgG2 production has been reported in alpha-gal IgE+ subjects. We here report further investigation of the relationship between alpha-gal IgG and both reactions to red meat and exposure to ticks. Methods: IgG from serum was absorbed onto recombinant Protein G-Sepharose and incubated with radiolabeled allergen. The radioactivity of bound allergen was measured using a gamma counter. A control curve was generated in parallel to assign unitage. Additional testing of serum immunoglobulins was performed via ImmunoCAP and nephelometry. Results: Alpha-gal IgG was measured in a Northern Sweden cohort and in subjects presenting to allergy clinics in Virginia with delayed reactions to red meat. Alpha-gal IgG was significantly higher in alpha-gal IgE+ subjects versus alpha-gal IgE- subjects, and longitudinal serology in several alpha-gal IgE+ subjects demonstrates parallel alpha-gal IgE and IgG response trends. Among the alpha-gal IgE+ subjects, alpha-gal IgG was higher in those with alpha-gal IgE:total IgE ratios >25%, but was not related to reported severity to red meat. Compared to the alpha-gal IgE- subjects in Virginia, alpha-gal IgG was lower in the group from Northern Sweden, where alpha-gal IgE-mediated hypersensitivity is absent and ticks are rare. Conclusions: Alpha-gal IgG is strongly related to alpha-gal IgE and is significantly lower in prevalence and titer in subjects without tick exposure. The absence of a relationship between alpha-gal IgG and severity of reactions to red meat suggests that the alpha-gal syndrome may not be a suitable candidate for conventional immunotherapy.

Rationale: IgE antibodies to the mammalian oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) are common in the southeastern United States. These antibodies, which are induced by ectoparasitic ticks, can give rise to positive skin tests or serum assays with cat extract. Objectives: To evaluate the relationship between IgE antibodies to alpha-gal and asthma, and compare this with the relationship between asthma and IgE antibodies to Fel d 1 and other protein allergens. Methods: Patients being investigated for recurrent anaphylaxis, angioedema, or acute urticaria underwent spirometry, exhaled nitric oxide, questionnaires, and serum IgE antibody assays. The results were compared with control subjects and cohorts from the emergency department in Virginia (n = 130), northern Sweden (n = 963), and rural Kenya (n = 131). Measurements and Main Results: Patients in Virginia with high-titer IgE antibodies to a-gal had normal lung function, low levels of exhaled nitric oxide, and low prevalence of asthma symptoms. Among patients in the emergency department and children in Kenya, there was no association between IgE antibodies to a-gal and asthma (odds ratios, 1.04 and 0.75, respectively). In Sweden, IgE antibodies to cat were closely correlated with IgE antibodies to Fel d 1 (r = 0.83) and to asthma (P < 0.001). Conclusions: These results provide a model of an ectoparasite-induced specific IgE response that can increase total serum IgE without creating a risk for asthma, and further evidence that the main allergens that are causally related to asthma are those that are inhaled.

Background: In 2009, we reported a novel form of delayed anaphylaxis to red meat that is related to serum IgE antibodies to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal). Most of these patients had tolerated meat for many years previously. The implication is that some exposure in adult life had stimulated the production of these IgE antibodies. Objectives: We sought to investigate possible causes of this IgE antibody response, focusing on evidence related to tick bites, which are common in the region where these reactions occur. Methods: Serum assays were carried out with biotinylated proteins and extracts bound to a streptavidin ImmunoCAP. Results: Prospective studies on IgE antibodies in 3 subjects after tick bites showed an increase in levels of IgE to alpha-gal of 20fold or greater. Other evidence included (1) a strong correlation between histories of tick bites and levels of IgE to alpha-gal (chi(2) = 26.8, P < .001), (2) evidence that these IgE antibodies are common in areas where the tick Amblyomma americanum is common, and (3) a significant correlation between IgE antibodies to alpha-gal and IgE antibodies to proteins derived from A americanum (r(s) = 0.75, P < .001). Conclusion: The results presented here provide evidence that tick bites are a cause, possibly the only cause, of IgE specific for alpha-gal in this area of the United States. Both the number of subjects becoming sensitized and the titer of IgE antibodies to alpha-gal are striking. Here we report the first example of a response to an ectoparasite giving rise to an important form of food allergy.