Immunopathogenesis of eosinophilic esophagitis

Background: Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus associated with dysphagia in adults and refractory reflux syndromes in children. Methods: Immunological and genetic approaches have been used to better understand the pathophysiology of the underlying inflammation. Results and Conclusions: Evidence has accumulated that EoE represents a T-helper (Th) 2-type inflammatory disease, in which allergens play a role in triggering the disease. The majority of the patients suffer from concurrent allergic rhinitis, asthma, and eczema, and have a history of atopy. The chronic inflammatory response in EoE is associated with tissue damage and remodeling, both of which lead to esophageal dysfunction and bolus impaction. The new insights into the pathophysiology have resulted in the development of the first pharmacological therapies of EoE.

Atopic conditions and brain tumor risk in children and adolescents--an international case-control study (CEFALO)

BACKGROUND A number of epidemiological studies indicate an inverse association between atopy and brain tumors in adults, particularly gliomas. We investigated the association between atopic disorders and intracranial brain tumors in children and adolescents, using international collaborative CEFALO data. PATIENTS AND METHODS CEFALO is a population-based case-control study conducted in Denmark, Norway, Sweden, and Switzerland, including all children and adolescents in the age range 7-19 years diagnosed with a primary brain tumor between 2004 and 2008. Two controls per case were randomly selected from population registers matched on age, sex, and geographic region. Information about atopic conditions and potential confounders was collected through personal interviews. RESULTS In total, 352 cases (83%) and 646 controls (71%) participated in the study. For all brain tumors combined, there was no association between ever having had an atopic disorder and brain tumor risk [odds ratio 1.03; 95% confidence interval (CI) 0.70-1.34]. The OR was 0.76 (95% CI 0.53-1.11) for a current atopic condition (in the year before diagnosis) and 1.22 (95% CI 0.86-1.74) for an atopic condition in the past. Similar results were observed for glioma. CONCLUSIONS There was no association between atopic conditions and risk of all brain tumors combined or of glioma in particular. Stratification on current or past atopic conditions suggested the possibility of reverse causality, but may also the result of random variation because of small numbers in subgroups. In addition, an ongoing tumor treatment may affect the manifestation of atopic conditions, which could possibly affect recall when reporting about a history of atopic diseases. Only a few studies on atopic conditions and pediatric brain tumors are currently available, and the evidence is conflicting.

Genetics of recurrent airway obstruction (RAO)

Recurrent airway obstruction (RAO) is a multifactorial and polygenic disease. Affected horses are typically 7 years of age or older and show exercise intolerance, increased breathing effort, coughing, airway neutrophilia, mucus accumulation and hyperreactivity as well as cholinergic bronchospasm. The environmental factors responsible are predominantly allergens and irritants in haydust, but the immunological mechanisms underlying RAO are still unclear. Several studies have demonstrated a familiar predisposition for RAO and it is now proven that the disease has a genetic basis. In offspring, the risk of developing RAO is 3-fold increased when one parent is affected and increases to almost 5-fold when both parents have RAO. Segregation analysis in two high-prevalence families demonstrated a high heritability and a complex inheritance with several major genes. A whole genomescan showed chromosome-wide significant linkage of seven chromosomal regions with RAO. Of the microsatellites, which were located near atopy candidate genes, those in a region of chromosome 13 harboring the IL4R gene were strongly associated with the RAO phenotype in the offspring of one RAO-affected stallion. Furthermore, IgE-levels are influenced by hereditary factors in the horse, and we have evidence that RAO-affected offspring of the same stallion have increased levels of specific IgE against moldspore allergens. The identification of genetic markers and ultimately of the responsible genes will not only allow for an improved prophylaxis, i.e. early identification of susceptible individuals and avoidance of high-risk matings, but also improve our ability to find new therapeutic targets and to optimize existing treatments.

Effects of Breastfeeding on Respiratory Symptoms in Infancy.

OBJECTIVE To assess the impact of potential risk factors on the development of respiratory symptoms and their specific modification by breastfeeding in infants in the first year of life. STUDY DESIGN We prospectively studied 436 healthy term infants from the Bern-Basel Infant Lung Development cohort. The breastfeeding status, and incidence and severity of respiratory symptoms (score) were assessed weekly by telephone interview during the first year of life. Risk factors (eg, pre- and postnatal smoking exposure, mode of delivery, gestational age, maternal atopy, and number of older siblings) were obtained using standardized questionnaires. Weekly measurements of particulate matter <10 μg were provided by local monitoring stations. The associations were investigated using generalized additive mixed model with quasi Poisson distribution. RESULTS Breastfeeding reduced the incidence and severity of the respiratory symptom score mainly in the first 27 weeks of life (risk ratio 0.70; 95% CI 0.55-0.88). We found a protective effect of breastfeeding in girls but not in boys. During the first 27 weeks of life, breastfeeding attenuated the effects of maternal smoking during pregnancy, gestational age, and cesarean delivery on respiratory symptoms. There was no evidence for an interaction between breastfeeding and maternal atopy, number of older siblings, child care attendance, or particulate matter <10 μg. CONCLUSIONS This study shows the risk-specific effect of breastfeeding on respiratory symptoms in early life using the comprehensive time-series approach.

Rhinovirus Infections and Associated Respiratory Morbidity in Infants: A Prospective Cohort Study.

BACKGROUND Risk factors promoting rhinovirus (RV) infections are inadequately described in healthy populations, especially infants. OBJECTIVES To determine the frequency of symptomatic and asymptomatic RV infections and identify possible risk factors from host and environment among otherwise healthy infants. METHODS In a prospective birth cohort, respiratory health was assessed in 41 term-born infants by weekly telephone interviews during the first year of life, and weekly nasal swabs were collected to determine RV prevalence. In a multilevel logistic regression model, associations between prevalence and respiratory symptoms during RV infections and host/environmental factors were determined. RESULTS 27% of nasal swabs in 41 infants tested positive for RVs. Risk factors for RV prevalence were autumn months (OR=1.71, p=0.01, 95% CI 1.13-2.61), outdoor temperatures between 5-10 °C (OR=2.33, p=0.001, 95% CI 1.41-3.86), older siblings (OR=2.60, p=0.001, 95% CI 1.50-4.51) and childcare attendance (OR=1.53, p=0.07, 95% CI 0.96-2.44). 51% of RV-positive samples were asymptomatic. Respiratory symptoms during RV infections were less likely during the first three months of life (OR=0.34, p=0.003, 95% CI 0.17-0.69) and in infants with atopic mothers (OR=0.44, p=0.008, 95% CI 0.24-0.80). Increased tidal volume (OR=1.67, p=0.03, 95% CI 1.04-2.68) and outdoor temperatures between 2-5 °C (OR=2.79, p=0.02, 95% CI 1.17-6.61) were associated with more symptoms. CONCLUSIONS RVs are highly prevalent during the first year of life, and most infections are asymptomatic. Frequency of RV infections is associated with environmental factors, while respiratory symptoms during RV infections are linked to host determinants like infant age, maternal atopy, or premorbid lung function.

Interleukin 9: A candidate gene for asthma

Asthma is a complex heritable inflammatory disorder of the airways associated with clinical signs of atopy and bronchial hyperresponsiveness. Recent studies localized a major gene for asthma to chromosome 5q31-q33 in humans. Thus, this segment of the genome represents a candidate region for genes that determine susceptibility to bronchial hyperresponsiveness and atopy in animal models. Homologs of candidate genes on human chromosome 5q31-q33 are found in four regions in the mouse genome, two on chromosome 18, and one each on chromosomes 11 and 13. We assessed bronchial responsiveness as a quantitative trait in mice and found it linked to chromosome 13. Interleukin 9 (IL-9) is located in the linked region and was analyzed as a gene candidate. The expression of IL-9 was markedly reduced in bronchial hyporesponsive mice, and the level of expression was determined by sequences within the qualitative trait locus (QTL). These data suggest a role for IL-9 in the complex pathogenesis of bronchial hyperresponsiveness as a risk factor for asthma.

A first trial of retrospective collaboration for positional cloning in complex inheritance: Assay of the cytokine region on chromosome 5 by the Consortium on Asthma Genetics (COAG)

The central problem of complex inheritance is to map oligogenes for disease susceptibility, integrating linkage and association over samples that differ in several ways. Combination of evidence over multiple samples with 1,037 families supports loci contributing to asthma susceptibility in the cytokine region on 5q [maximum logarithm of odds (lod) = 2.61 near IL-4], but no evidence for atopy. The principal problems with retrospective collaboration on linkage appear to have been solved, providing far more information than a single study. A multipoint lod table evaluated at commonly agreed reference loci is required for both collaboration and metaanalysis, but variations in ascertainment, pedigree structure, phenotype definition, and marker selection are tolerated. These methods are invariant with statistical methods that increase the power of lods and are applicable to all diseases, motivating collaboration rather than competition. In contrast to linkage, positional cloning by allelic association has yet to be extended to multiple samples, a prerequisite for efficient combination with linkage and the greatest current challenge to genetic epidemiology.

Genetic mapping of a murine locus controlling development of T helper 1/T helper 2 type responses.

Genetic background of the T cell can influence T helper (Th) phenotype development, with some murine strains (e.g., B10.D2) favoring Th1 development and others (e.g., BALB/c) favoring Th2 development. Recently we found that B10.D2 exhibit an intrinsically greater capacity to maintain interleukin 12 (IL-12) responsiveness under neutral conditions in vitro compared with BALB/c T cells, allowing for prolonged capacity to undergo IL-12-induced Th1 development. To begin identification of the loci controlling this genetic effect, we used a T-cell antigen receptor-transgenic system for in vitro analysis of intercrosses between BALB/c and B10.D2 mice and have identified a locus on murine chromosome 11 that controls the maintenance of IL-12 responsiveness, and therefore the subsequent Th1/Th2 response. This chromosomal region is syntenic with a locus on human chromosome 5q31.1 shown to be associated with elevated serum IgE levels, suggesting that genetic control of Th1/Th2 differentiation in mouse, and of atopy development in humans, may be expressed through similar mechanisms.

Modelos de regressão para identificação de marcadores preditivos de asma na descendência de mulheres com atopia

Trabalho de projecto de mestrado, Bioestatística, Universidade de Lisboa, Faculdade de Ciências, 2016

Chronic rhinosinusitis and eosinophils: do macrolides have an effect?

Purpose of review: Long-term, low-dose macrolide therapy is effective in the treatment of chronic airway inflammation. It is believed that macrolide antibiotics produce this benefit through an antiinflammatory effect that is separate from their antibiotic effect. Eosinophils are key mediators in the inflammation seen in chronic rhinosinusitis. This review discusses the effect of macrolides on eosinophilic inflammation. Recent findings: In vitro studies recently have suggested that macrolides increase eosinophil apoptosis and reduce production of eosinophil chemotactic cytokines and adhesion molecules. In vivo studies have shown a reduction in eosinophil count and activity in asthma and chronic rhinosinusitis. Clinical response to macrolide treatment is thought to be less likely in patients with atopy. Summary: In contrast to the evidence supporting the effect of macrolides on neutrophilic inflammation, there are limited data to suggest an influence on eosinophilic inflammation. For this reason, patients with prominent eosinophilic inflammation may in the future be identified as being less likely to respond to treatment. Further in vitro and clinical studies are required to investigate this subject.

Variance components analyses of multiple asthma traits in a large sample of Australian families ascertained through a twin proband

Background: Intermediate phenotypes are often measured as a proxy for asthma. It is largely unclear to what extent the same set of environmental or genetic factors regulate these traits. Objective: Estimate the environmental and genetic correlations between self-reported and clinical asthma traits. Methods: A total of 3073 subjects from 802 families were ascertained through a twin proband. Traits measured included self-reported asthma, airway histamine responsiveness (AHR), skin prick response to common allergens including house dust mite (Dermatophagoides pteronyssinus [D. pter]), baseline lung function, total serum immunoglobulin E (IgE) and eosinophilia. Bivariate and multivariate analyses of eight traits were performed with adjustment for ascertainment and significant covariates. Results: Overall 2716 participants completed an asthma questionnaire and 2087 were clinically tested, including 1289 self-reported asthmatics (92% previously diagnosed by a doctor). Asthma, AHR, markers of allergic sensitization and eosinophilia had significant environmental correlations with each other (range: 0.23-0.89). Baseline forced expiratory volume in 1 s (FEV1) showed low environmental correlations with most traits. Fewer genetic correlations were significantly different from zero. Phenotypes with greatest genetic similarity were asthma and atopy (0.46), IgE and eosinophilia (0.44), AHR and D. pter (0.43) and AHR and airway obstruction (-0.43). Traits with greatest genetic dissimilarity were FEV1 and atopy (0.05), airway obstruction and IgE (0.07) and FEV1 and D. pter (0.11). Conclusion: These results suggest that the same set of environmental factors regulates the variation of many asthma traits. In addition, although most traits are regulated to great extent by specific genetic factors, there is still some degree of genetic overlap that could be exploited by multivariate linkage approaches.

Interleukin-4 receptor alpha gene variants and allergic disease

The interleukin-4 (IL-4) signalling cascade has been identified as a pathway potentially important in the development of asthma. Genetic variants within this signalling pathway might contribute to the risk of developing asthma in a given individual. A number of polymorphisms have been described within the IL-4 receptor alpha (IL-4Ralpha) gene. In addition polymorphism occurs in the promoter for the IL-4 gene itself. This commentary accompanies a paper by C Ober et al describing the contribution of IL-4Ralpha polymorphism to susceptibility to asthma and atopy in the Hutterite population and other outbred populations collected during the collaborative studies on the genetics of asthma (CSGA) programme

Caractérisation des maladies respiratoires en lien avec les problématiques d’humidité excessive ou de moisissures dans les logements des étudiants universitaires

Résumé : PROBLÉMATIQUE: L’exposition résidentielle à l’humidité excessive ou aux moisissures est maintenant reconnue comme un facteur important influençant la santé respiratoire. Cette problématique a été peu étudiée chez les étudiants universitaires, bien que vulnérables par leur faible revenu et leur statut de locataire. OBJECTIFS: Cette maîtrise vise à décrire la prévalence (a) de l’exposition résidentielle à l’humidité excessive ou aux moisissures et (b) des maladies respiratoires chez les étudiants universitaires, ainsi qu’à (c) examiner l’association entre l’exposition résidentielle à l’humidité excessive ou aux moisissures et ces maladies. MÉTHODES: En 2014, une enquête électronique a été réalisée auprès de 2097 étudiants enregistrés à l’Université de Sherbrooke (Québec, Canada). Lorsque possible, des questions et des scores validés ont été utilisés pour estimer les prévalences des maladies respiratoires (rhinite allergique, asthme et infections respiratoires), de l’exposition résidentielle à l’humidité excessive ou aux moisissures et des covariables (ex. : revenu annuel familial, statut tabagique, atopie familiale, caractéristiques de l’étudiant). Les associations entre cette exposition et ces maladies ont d’abord été examinées par des tests de chi-carré en utilisant un seuil alpha de 0,05. Des régressions logistiques multivariées ont ensuite été utilisées pour déterminer les associations brutes et ajustée entre cette exposition et les maladies respiratoires. Les analyses descriptives ont été pondérées pour le sexe, l’âge et le campus d’étude. RÉSULTATS: L’exposition à l’humidité excessive ou aux moisissures était fréquente parmi les participants (36,0%; Intervalle de confiance (IC)95% : 33,9-38,1). Ceux-ci ont également été nombreux à rapporter une rhinite allergique (23,9%; IC95% :22,0-25,8), de l’asthme (32,6%; IC95% : 30,5-34,7) et des infections respiratoires (19,4%; IC95% :17,7-21,2) au cours de la dernière année. Après ajustement, les associations demeuraient significatives entre l’exposition à l’humidité excessive ou aux moisissures et la rhinite allergique (Rapport de cote (RC) : 1,30; IC95% : 1.05-1.60), l’asthme RC : 1,75; IC95% : 1,42-2,16), mais pas les infections respiratoires (RC : 1,07; IC95% : 0,85-1.35). CONCLUSIONS: La prévalence élevée de l’exposition résidentielle des étudiants universitaires à l’humidité excessive ou aux moisissures, de même que son association avec l’asthme et la rhinite allergique, mettent en lumière sa contribution potentielle à la forte prévalence des maladies respiratoires ayant une composante allergique dans cette population. Cette étude fournit un nouveau levier pour les organisations de santé publique et leurs partenaires afin d’adapter les stratégies préventives ciblant les logements insalubres, particulièrement chez les populations vulnérables.

How epidemiology has challenged 3 prevailing concepts about atopic dermatitis

We challenge 3 prevailing concepts in understanding atopic dermatitis using data from epidemiologic studies. First, we show that although atopy is associated with atopic dermatitis to some degree, its importance is not likely to be a simple causeand- effect relationship, especially at a population level. Our epidemiologic data do not exclude a contributory role for IgEmediated immunologic processes, especially in those with existing and severe disease. Second, evidence is presented that does not support a straightforward inverse relationship between infections and atopic dermatitis risk. A link, if present, is likely to be more complex, depending critically on the timing and type of infectious exposure. Third, recent evidence suggests that the risk of subsequent childhood asthma is not increased in children with early atopic dermatitis who are not also early wheezers, suggesting a comanifestation of phenotypes rather than a progressive atopic march. Collectively, these observations underline the importance of epidemiologic studies conducted at a population level to gain a more balanced understanding of the enigma of atopic dermatitis.

Prevalencia de Atopia y determinación de los alérgenos inhalantes más comunes entre los adolescentes de Octavo y Noveno de Básica en Cuenca-Ecuador, durante el año lectivo 2013-2014

Las atopias constituyen un problema de salud que puede afectar a adolescentes y adultos, llegando incluso a ser mortal en ciertos casos. La investigación en este tema es escasa en nuestro medio, es por ello que este estudio tiene como objetivo determinar la prevalencia de atopias y los alérgenos inhalantes más comunes entre los adolescentes de octavo y noveno de básica de las áreas urbana y rural del cantón Cuenca, mediante la aplicación de un “skin prick test”. Para ello fueron evaluados los estudiantes de octavo y noveno de básica de los colegios del cantón Cuenca, incuyendo una muestra aleatoria representativa de 991 alumnos. Los resultados demostraron que más de la mitad de los participantes fueron atópicos para al menos uno de los alérgenos probados, situación que refleja un problema de salud pública que debe ser considerado. La prevalencia de atopia no fue diferente de acuerdo al sexo de los participantes; de los 20 alérgenos probados, los alérgenos intra-domiciliarios y las gramíneas estuvieron entre los más prevalentes, los cinco más comunes fueron los ácaros D. pteronyssinus y blomia tropicalis, epitelio de cucaracha, mezcla de pólenes de gramíneas y ecynodon. No se encontró una diferencia significativa en la prevalencia global de atopia según la ubicación geográfica de los colegios. Sin embrago, el análisis por alérgeno reveló que la atopia al epitelio de cucaracha fue mayor entre los alumnos que asisten a colegios rurales y la atopia al salix fue mayor entre los adolescentes de los colegios urbanos