Rhinitis associated with asthma is distinct from rhinitis alone: The ARIA-MeDALL hypothesis.

Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one-airway-one-disease," coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the "Epithelial Barrier Hypothesis." This review determined that the "one-airway-one-disease" concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme "allergic" (asthma) phenotype combining asthma, rhinitis, and conjunctivitis. Rhinitis alone and rhinitis and asthma multimorbidity represent two distinct diseases with the following differences: (i) genomic and transcriptomic background (Toll-Like Receptors and IL-17 for rhinitis alone as a local disease; IL-33 and IL-5 for allergic and non-allergic multimorbidity as a systemic disease), (ii) allergen sensitization patterns (mono- or pauci-sensitization versus polysensitization), (iii) severity of symptoms, and (iv) treatment response. In conclusion, rhinitis alone (local disease) and rhinitis with asthma multimorbidity (systemic disease) should be considered as two distinct diseases, possibly modulated by the microbiome, and may be a model for understanding the epidemics of chronic and autoimmune diseases.

Asthma Exacerbations: The Genes Behind the Scenes.

The clinical and socioeconomic burden of asthma exacerbations (AEs) constitutes a major public health problem. In the last 4 years, there has been an increase in ethnic diversity in candidate-gene and genome-wide association studies of AEs, which in the latter case led to the identification of novel genes and underlying pathobiological processes. Pharmacogenomics, admixture mapping analyses, and the combination of multiple "omics" layers have helped to prioritize genomic regions of interest and/or facilitated our understanding of the functional consequences of genetic variation. Nevertheless, the field still lags behind the genomics of asthma, where a vast compendium of genetic approaches has been used (eg, gene-environment nteractions, next-generation sequencing, and polygenic risk scores). Furthermore, the roles of the DNA methylome and histone modifications in AEs have received little attention, and microRNA findings remain to be validated in independent studies. Likewise, the most recent transcriptomic studies highlight the importance of the host-airway microbiome interaction in the modulation of risk of AEs. Leveraging -omics and deep-phenotyping data from subtypes or homogenous subgroups of patients will be crucial if we are to overcome the inherent heterogeneity of AEs, boost the identification of potential therapeutic targets, and implement precision medicine approaches to AEs in clinical practice.

Asthma Exacerbations: The Genes Behind the Scenes

The clinical and socioeconomic burden of asthma exacerbations (AEs) constitutes a major public health problem. In the last 4 years, there has been an increase in ethnic diversity in candidate-gene and genome-wide association studies of AEs, which in the latter case led to the identification of novel genes and underlying pathobiological processes. Pharmacogenomics, admixture mapping analyses, and the combination of multiple “omics” layers have helped to prioritize genomic regions of interest and/or facilitated our understanding of the functional consequences of genetic variation. Nevertheless, the field still lags behind the genomics of asthma, where a vast compendium of genetic approaches has been used (eg, gene–environment interactions, next-generation sequencing, and polygenic risk scores). Furthermore, the roles of the DNA methylome and histone modifications in AEs have received little attention, and microRNA findings remain to be validated in independent studies. Likewise, the most recent transcriptomic studies highlight the importance of the host–airway microbiome interaction in the modulation of risk of AEs. Leveraging -omics and deep-phenotyping data from subtypes or homogenous subgroups of patients will be crucial if we are to overcome the inherent heterogeneity of AEs, boost the identification of potential therapeutic targets, and implement precision medicine approaches to AEs in clinical practice (AU)

La carga clínica y socioeconómica de las exacerbaciones asmáticas (EA) representa un importante problema de salud pública. En los últimos cuatro años, ha aumentado la diversidad étnica en los estudios de asociación de genes candidatos y del genoma completo (GWAS) de las EA, lo que, en este último caso, ha llevado a la identificación de nuevos genes y procesos fisiopatológicos subyacentes. La farmacogenómica, los análisis de mapeo por mezcla y la combinación de múltiples capas "ómicas" han contribuido a priorizar regiones genómicas de interés y/o comprender las consecuencias funcionales de la variación genética. A pesar de esto, el campo todavía está en desarrollo en comparación con la genómica del asma, donde se ha utilizado un amplio compendio de enfoques genéticos (por ejemplo: interacciones gen-ambiente, secuenciación de nueva generación o puntuaciones de riesgo poligénico). Además, el papel de la metilación del ADN y las modificaciones de las histonas en las EA se ha explorado escasamente, y los hallazgos relacionados con los microARNs aún no se han validado en estudios independientes. Asimismo, los estudios transcriptómicos más recientes destacan la importancia de la interacción entre el microbioma de las vías respiratorias y el huésped en la modulación del riesgo de las EA. La integración de datos ómicos y de fenotipado profundo de subtipos o subgrupos homogéneos de pacientes será crucial para superar la heterogeneidad inherente de las EA e impulsar la identificación de dianas terapéuticas potenciales y la implementación de la medicina de precisión para las EA en la práctica clínica (AU)

Circulating 25-hydroxyvitamin D, nasopharyngeal airway metabolome, and bronchiolitis severity.

Low circulating 25-hydroxyvitamin D (25OHD) levels are a risk factor for acute respiratory infection (eg, bronchiolitis) in children. However, little is known about the relation of circulating 25OHD with the many downstream functional molecules in target organs-such as the airway-and with clinical outcomes. In this prospective multicenter study of infants (age <1 year) hospitalized with bronchiolitis, we measured serum 25OHD levels and profiled the metabolome of 144 nasopharyngeal airway samples. Among 254 metabolites identified, we defined a set of 20 metabolites that are related to lower serum 25OHD and higher vitamin D-binding protein levels. Of these metabolites, 9 metabolites were associated with a significantly higher risk of positive pressure ventilation use. These metabolites were glycerophosphocholines esterified with proinflammatory fatty acids (palmitate, arachidonate, linoleate, and stearate), sphingomyelins, alpha-hydroxyisovalerate, 2-hydroxybutyrate, and 3-(4-hydroxyphenyl)lactate (all FDR<0.05). Based on the multicenter data, vitamin D-related airway metabolites were associated with risks of bronchiolitis severity.

Maternal nutrition during pregnancy and risk of asthma, wheeze, and atopic diseases during childhood: a systematic review and meta-analysis.

BACKGROUND: Epidemiologic studies suggest a relationship between maternal nutrition during pregnancy and the occurrence of asthma and atopic conditions during childhood. However, individual study results are conflicting. The objective of this meta-analysis was to critically examine the current evidence for an association between nutrition (dietary patterns, food groups, vitamins, or oligo-elements) ingestion during pregnancy and asthma, wheeze, or atopic conditions in childhood. METHODS: The inclusion criteria were as follows: (i) systematic recording of diet during the gestational period and (ii) documentation of asthma, wheezing, eczema, or other atopic disease in the offspring. The primary outcomes were prevalence of asthma or wheeze among the offspring during childhood; and secondary outcomes were prevalence of eczema, allergic rhinitis, or other atopic conditions. RESULTS: We found 120 titles, abstracts, and citations, and 32 studies (29 cohorts) were included in this analysis. Data on vitamins, oligo-elements, food groups, and dietary patterns during pregnancy were collected. A meta-analysis revealed that higher maternal intake of vitamin D [odds ratio (OR) = 0.58, 95% confidence interval (CI) = 0.38-0.88], vitamin E (OR = 0.6, 95% CI = 0.46-0.78), and zinc (OR = 0.62, 95% CI = 0.40-0.97) was associated with lower odds of wheeze during childhood. However, none of these or other nutrients was consistently associated with asthma per se or other atopic conditions. CONCLUSIONS: Current evidence suggests a protective effect of maternal intake of each of three vitamins or nutrients (vitamin D, vitamin E, and zinc) against childhood wheeze but is inconclusive for an effect on asthma or other atopic conditions.

A genome-wide association study of bronchodilator response in asthmatics.

Reversibility of airway obstruction in response to ß2-agonists is highly variable among asthmatics, which is partially attributed to genetic factors. In a genome-wide association study of acute bronchodilator response (BDR) to inhaled albuterol, 534 290 single-nucleotide polymorphisms (SNPs) were tested in 403 white trios from the Childhood Asthma Management Program using five statistical models to determine the most robust genetic associations. The primary replication phase included 1397 polymorphisms in three asthma trials (pooled n=764). The second replication phase tested 13 SNPs in three additional asthma populations (n=241, n=215 and n=592). An intergenic SNP on chromosome 10, rs11252394, proximal to several excellent biological candidates, significantly replicated (P=1.98 × 10(-7)) in the primary replication trials. An intronic SNP (rs6988229) in the collagen (COL22A1) locus also provided strong replication signals (P=8.51 × 10(-6)). This study applied a robust approach for testing the genetic basis of BDR and identified novel loci associated with this drug response in asthmatics.

Genome-wide association study of body mass index in 23 000 individuals with and without asthma.

BACKGROUND: Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions. OBJECTIVE: To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. METHODS: In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. RESULTS: We report associations between several DENND1B variants (P = 2.2 × 10(-7) for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms(SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P < 0.05) in two of the seven studies and of borderline significance in one (P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m(2) (P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1BSNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. CONCLUSIONS AND CLINICAL RELEVANCE: DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.

HLA-DQ strikes again: genome-wide association study further confirms HLA-DQ in the diagnosis of asthma among adults.

BACKGROUND: Asthma is a common chronic respiratory disease in children and adults. An important genetic component to asthma susceptibility has long been recognized, most recently through the identification of several genes (e.g., ORMDL3, PDE4D, HLA-DQ, and TLE4) via genome-wide association studies. OBJECTIVE: To identify genetic variants associated with asthma affection status using genome-wide association data. METHODS: We describe results from a genome-wide association study on asthma performed in 3855 subjects using a panel of 455 089 single nucleotide polymorphisms (SNPs). RESULT: The genome-wide association study resulted in the prioritization of 33 variants for immediate follow-up in a multi-staged replication effort. Of these, a common polymorphism (rs9272346) localizing to within 1 Kb of HLA-DQA1 (chromosome 6p21.3) was associated with asthma in adults (P-value = 2.2E-08) with consistent evidence in the more heterogeneous group of adults and children (P-value = 1.0E-04). Moreover, some genes identified in prior asthma GWAS were nominally associated with asthma in our populations. CONCLUSION: Overall, our findings further replicate the HLA-DQ region in the pathogenesis of asthma. HLA-DQA1 is the fourth member of the HLA family found to be associated with asthma, in addition to the previously identified HLA-DRA, HLA-DQB1 and HLA-DQA2.

Maternal intestinal flora and wheeze in early childhood.

BACKGROUND: Increasing evidence links altered intestinal flora in infancy to eczema and asthma. No studies have investigated the influence of maternal intestinal flora on wheezing and eczema in early childhood. OBJECTIVE: To investigate the link between maternal intestinal flora during pregnancy and development of wheeze and eczema in infancy. METHODS: A total of 60 pregnant women from the Boston area gave stool samples during the third trimester of their pregnancy and answered questions during pregnancy about their own health, and about their children's health when the child was 2 and 6 months of age. Quantitative culture was performed on stool samples and measured in log(10)colony-forming units (CFU)/gram stool. Primary outcomes included infant wheeze and eczema in the first 6 months of life. Atopic wheeze, defined as wheeze and eczema, was analysed as a secondary outcome. RESULTS: In multivariate models adjusted for breastfeeding, day care attendance and maternal atopy, higher counts of maternal total aerobes (TA) and enterococci (E) were associated with increased risk of infant wheeze (TA: OR 2.32 for 1 log increase in CFU/g stool [95% CI 1.22, 4.42]; E: OR 1.57 [95% CI 1.06, 2.31]). No organisms were associated with either eczema or atopic wheeze. CONCLUSIONS AND CLINICAL RELEVANCE: In our cohort, higher maternal total aerobes and enterococci were related to increased risk of infant wheeze. Maternal intestinal flora may be an important environmental exposure in early immune system development.

TSLP polymorphisms are associated with asthma in a sex-specific fashion.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in thymic stromal lymphopoietin (TSLP) have been associated with IgE (in girls) and asthma (in general). We sought to determine whether TSLP SNPs are associated with asthma in a sex-specific fashion. METHODS: We conducted regular and sex-stratified analyses of association between SNPs in TSLP and asthma in families of children with asthma in Costa Rica. Significant findings were replicated in whites and African-American participants in the Childhood Asthma Management Program, in African-Americans in the Genomic Research on Asthma in the African Diaspora study, in whites and Hispanics in the Children's Health Study, and in whites in the Framingham Heart Study (FHS). MAIN RESULTS: Two SNPs in TSLP (rs1837253 and rs2289276) were significantly associated with a reduced risk of asthma in combined analyses of all cohorts (P values of 2 × 10(-5) and 1 × 10(-5) , respectively). In a sex-stratified analysis, the T allele of rs1837253 was significantly associated with a reduced risk of asthma in males only (P = 3 × 10(-6) ). Alternately, the T allele of rs2289276 was significantly associated with a reduced risk of asthma in females only (P = 2 × 10(-4) ). Findings for rs2289276 were consistent in all cohorts except the FHS. CONCLUSIONS: TSLP variants are associated with asthma in a sex-specific fashion.

Multiple microbial exposures in the home may protect against asthma or allergy in childhood.

BACKGROUND: Experimental animal data on the gram-negative bacterial (GNB) biomarker endotoxin suggest that persistence, dose, and timing of exposure are likely to influence its effects on allergy and wheeze. In epidemiologic studies, endotoxin may be a sentinel marker for a microbial milieu, including gram-positive bacteria (GPB) as well as GNB, that may influence allergy and asthma through components (pathogen-associated molecular patterns) that signal through innate Toll-like receptor pathways. OBJECTIVE: To determine the influence of current GNB and GPB exposures on asthma and allergic sensitization in school-aged children. METHODS: We examined the relationship between bacterial biomarkers and current asthma and allergic sensitization in 377 school-aged children in a birth cohort study. We then evaluated the effects of school-aged endotoxin, after controlling for exposure in early life. RESULTS: Exposure to GNB was inversely associated with asthma and allergic sensitization at school age [for >median endotoxin: prevalence odds ratio (POR)=0.34, 95% CI=0.2-0.7, for current asthma and prevalence ratio=0.77, 95% CI=0.6-0.97, for allergic sensitization]. In contrast, elevated GPB in the bed was inversely associated with current asthma (POR=0.41, 95% CI=0.2-0.9) but not with allergic sensitization (POR=1.07, 95% CI=0.8-1.4). School-aged endotoxin exposure remained protective in models for allergic disease adjusted for early-life endotoxin. CONCLUSION: Both GNB and GPB exposures are associated with decreased asthma symptoms, but may act through different mechanisms to confer protection. Endotoxin exposure in later childhood is not simply a surrogate of early-life exposure; it has independent protective effects on allergic disease.

Risk factors for allergic rhinitis in Costa Rican children with asthma.

BACKGROUND: Risk factors for allergic rhinitis (AR) in asthmatics are likely distinct from those for AR or asthma alone. We sought to identify clinical and environmental risk factors for AR in children with asthma. METHODS: We performed a cross-sectional study of 616 Costa Rican children aged 6-14 years with asthma. Candidate risk factors were drawn from questionnaire data, spirometry, methacholine challenge testing, skin testing, and serology. Two outcome measures, skin test reaction (STR)-positive AR and physician-diagnosed AR, were examined by logistic regression. RESULTS: STR-positive AR had high prevalence (80%) in Costa Rican children with asthma, and its independent risk factors were nasal symptoms after exposure to dust or mold, parental history of AR, older age at asthma onset, oral steroid use in the past year, eosinophilia, and positive IgEs to dust mite and cockroach. Physician-diagnosed AR had lower prevalence (27%), and its independent risk factors were nasal symptoms after pollen exposure, STR to tree pollens, a parental history of AR, inhaled steroid and short-acting beta2 agonist use in the past year, household mold/mildew, and fewer older siblings. A physician's diagnosis was only 29.5% sensitive for STR-positive AR. CONCLUSIONS: Risk factors for AR in children with asthma depend on the definition of AR. Indoor allergens drive risk for STR-positive AR. Outdoor allergens and home environmental conditions are risk factors for physician-diagnosed AR. We propose that children with asthma in Costa Rica and other Latin American nations undergo limited skin testing or specific IgE measurements to reduce the current under-diagnosis of AR.

Association of VEGF polymorphisms with childhood asthma, lung function and airway responsiveness.

Vascular endothelial growth factor (VEGF) is an angiogenic factor implicated in asthma severity. The objective of the present study was to determine whether VEGF single nucleotide polymorphisms (SNPs) are associated with asthma, lung function and airway responsiveness. The present authors analysed 10 SNPs in 458 white families in the Childhood Asthma Management Program (CAMP). Tests of association with asthma, lung function and airway responsiveness were performed using PBAT software (Golden Helix, Inc. Bozeman, MT, USA; available at www.goldenhelix.com). Family and population-based, revpeated measures analysis of airflow obstruction were conducted. Replication studies were performed in 412 asthmatic children and their parents from Costa Rica. Associations with asthma, lung function and airway responsiveness were observed in both cohorts. SNP rs833058 was associated with asthma in both cohorts. This SNP was also associated with increased airway responsiveness in both populations. An association of rs4711750 and its haplotype with forced expiratory volume in 1 s (FEV(1))/forced vital capacity (FVC) ratio in both cohorts was observed. Longitudinal analysis in CAMP confirmed an association of rs4711750 with FEV(1)/FVC decline over approximately 4.5 yrs of observation. VEGF polymorphisms are associated with childhood asthma, lung function and airway responsiveness in two populations, suggesting that VEGF polymorphisms influence asthma susceptibility, airflow obstruction and airways responsiveness.

Mouse allergen exposure, wheeze and atopy in the first seven years of life.

BACKGROUND: Little is known about mouse allergen exposure in home environments and the development of wheezing, asthma and atopy in childhood. OBJECTIVE: To examine the relation between mouse allergen exposure and wheezing, atopy, and asthma in the first 7 years of life. METHODS: Prospective study of 498 children with parental history of allergy or asthma followed from birth to age 7 years, with longitudinal questionnaire ascertainment of reported mouse exposure and dust sample mouse urinary protein allergen levels measured at age 2-3 months. RESULTS: Parental report of mouse exposure in the first year of life was associated with increased risk of transient wheeze and wheezing in early life. Current report of mouse exposure was also significantly associated with current wheeze throughout the first 7 years of life in the longitudinal analysis (P = 0.03 for overall relation of current mouse to current wheeze). However, early life mouse exposure did not predict asthma, eczema or allergic rhinitis at age 7 years. Exposure to detectable levels of mouse urinary protein in house dust samples collected at age 2-3 months was associated with a twofold increase in the odds of atopy (sensitization to >=1 allergen) at school age (95% confidence interval for odds ratio = 1.1-3.7; P = 0.03 in a multivariate analysis. CONCLUSIONS: Among children with parental history of asthma or allergies, current mouse exposure is associated with increased risk of wheeze during the first 7 years of life. Early mouse exposure was associated with early wheeze and atopy later in life.

Predictors of indoor exposure to mouse allergen in urban and suburban homes in Boston.

BACKGROUND: Mouse allergen exposure is prevalent among urban children with asthma. Little is known about mouse allergen exposure in children at risk for the development of allergic diseases. AIMS OF THE STUDY: To assess indoor mouse allergen exposure in early life among children with parental history of asthma or allergies. METHODS: Prospective birth cohort study of 498 children with a history of allergy or asthma in at least one parent living in metropolitan Boston. RESULTS: Of the 498 participating children, 357 (71.7%) resided outside the city of Boston and 439 (90.7%) lived in households with incomes > 30,000 dollars. Mouse allergen was detected in 42% of the homes of study participants. In a multivariate analysis adjusting for sex, income, and endotoxin, black race [odds ratio (OR) = 3.0; 95% confidence interval (CI) = 1.3-6.6, P = 0.009], signs of mice in the home at age 2-3 months (OR = 3.0; 95% CI = 1.6-5.6, P = 0.0006), and kitchen cockroach allergen levels > or = 0.05 to < 2 U/g (OR = 1.8; 95% CI = 1.1-3.2, P = 0.02) were associated with detectable mouse allergen in the kitchen. In this model, living in a single detached house was inversely associated with detectable kitchen mouse allergen levels (OR = 0.4; 95% CI = 0.2-0.6, P = 0.0001). CONCLUSION: Infants with a parental history of asthma or allergies are commonly exposed to mouse allergen in their homes. Among infants at high risk for atopy, predictors of increased mouse allergen levels included black race, reported mice exposure, and moderate levels of cockroach allergen.

Polymorphisms in the interleukin 17F gene (IL17F) and asthma.

Interleukin17F (IL17F) is a regulatory cytokine for T-cell-mediated immune responses. The gene coding for IL17F (IL17F) is located on chromosome 6p, a genomic region linked to asthma and asthma-related phenotypes in multiple genome scans. IL17F is expressed in lung tissue, in bronchoalveolar lavage fluid from asthmatic subjects, and in activated CD4+ cells. We were thus interested in testing for association between single-nucleotide polymorphisms (SNPs) and haplotypes in IL17F and asthma. To characterize polymorphisms in IL17F, we sequenced this gene in a group of African Americans and a group of European Americans. A total of 50 SNPs (30 not previously reported in a public database (dbSNP build 118)) and two insertions/deletions were detected in IL17F; five of these polymorphisms were genotyped in participants of the Nurses' Health Study. We then tested for association between SNPs and haplotypes in IL17F and physician-diagnosed asthma in subjects with (cases) and without (control subjects) physician-diagnosed asthma. None of the SNPs or haplotypes tested in IL17F were associated with asthma. The polymorphisms identified in this study may be used in future studies of association between IL17F and phenotypes related to immune responses.