Phenotype stability in asthma and atopy in childhood

The asthma phenotype can be described using a combination of the following: symptom type, pattern and severity; markers of atopy; and measurement of bronchial responsiveness. Because of the very nature of the disease, symptoms of asthma are variable in both the short- and the long-term, and the natural history of the disease is such that symptoms in an individual may evolve over time through different patterns. Although atopy appears to be a life-long attribute resulting from an early life switching to a TH₂ immune response, the surrogate markers of atopy each are subject to their own time-related determinants and patterns of change with age. Bronchial responsiveness in childhood is neither specific nor sensitive for asthma, and although showing good short-term repeatability, can vary widely when measured over a period of months or years. Stimuli for responsiveness testing should be chosen which can be inhaled safely in high doses so as to allow an end point to be reached by as many subjects within a population as possible, and individuals may have to be tested repeatedly over time so as to avoid misclassification.     

The complexities of defining atopy in severe childhood asthma

Background Defining atopy in children with severe, therapy‐resistant asthma is complex. There is currently no gold standard test; both skin prick testing (SPT) and allergen‐specific IgE (sIgE) are used. Furthermore, atopy is increasingly considered to be a spectrum, not an all‐or‐none phenomenon. Hypothesis SPTs and sIgE cannot be used interchangeably, and if both tests are not performed, opportunities for intervention will be missed. Furthermore, the severity of atopy will be defined differently by the two tests. Methods Cross‐sectional study of 47 children with severe, therapy‐resistant asthma, mean age 11.8 years, range 5.3–16.6 years, who underwent SPT, and measurement of total and sIgE as part of their clinical work‐up. Results Overall, 42/47 (89%) were atopic (defined as either one positive SPT or sIgE). There was 98% concordance between the two tests in classifying atopy. When each allergen was considered individually, in 40/200 (20%), the SPT and sIgE results were discordant, most commonly in 25/200 (12.5%), the SPT was negative and the sIgE was positive. House dust mite and cat sensitization were more likely detected by sIgE, but dog sensitization by SPT. When atopy was quantified, the sum of sIgEs compared with the sum of SPT weal diameter showed a moderate correlation (r²=0.44, P<0.001). Total IgE increased with an increasing number of positive sIgEs (P=0.028), but not significantly with increasing numbers of positive SPTs. Conclusion and Clinical Relevance SPT and sIgE identify group prevalence of atopy equally well; however, for individual allergens, concordance is poor, and when used to quantify atopy, SPTs and sIgE were only moderately correlated. In a clinical setting, if allergen avoidance is contemplated in children with severe, therapy‐resistant asthma, both tests should be performed in order to detect sensitization. Cite this as: J. Frith, L. Fleming, C. Bossley, N. Ullmann and A. Bush, Clinical & Experimental Allergy, 2011 (41) 948–953.     

Respiratory illnesses in early life and asthma and atopy in childhood

BACKGROUND: The relation between respiratory illnesses in early life and the development of asthma and atopy in childhood is incompletely understood. OBJECTIVE: We sought to examine the relationship between respiratory illnesses in early life and atopic diseases at school age. METHODS: We performed a prospective birth cohort study of the relationship between respiratory illnesses in the first year of life and asthma, atopy (sensitization to >or=1 allergen), and allergic rhinitis at school age in 440 children with a parental history of atopy. Logistic regression was used to examine the relationship between respiratory illnesses and asthma, atopy, and allergic rhinitis. The relationship between respiratory illnesses in early life and repeated measures of wheezing between the ages of 1 and 7 years was investigated by using a proportional hazards models. RESULTS: Physician-diagnosed croup (adjusted odds ratio [OR], 0.30; 95% CI, 0.12-0.72) and having 2 or more physician-diagnosed ear infections (adjusted OR, 0.58; 95% CI, 0.35-0.98) in the first year of life were inversely associated with atopy at school age. Physician-diagnosed bronchiolitis before age 1 year was significantly associated with asthma at age 7 years (adjusted OR, 2.77; 95% CI, 1.23-6.22). Recurrent nasal catarrh (>or=3 episodes of a runny nose) in the first year of life was associated with allergic rhinitis at age 7 years (adjusted OR, 2.99; 95% CI, 1.03-8.67). CONCLUSION: The relationship between early-life respiratory illnesses and asthma and atopy is complex and likely dependent on the type of infection and immune response it initiates. CLINICAL IMPLICATIONS: Certain respiratory illnesses in early life modify the risk of atopy and asthma at school age.     

Perinatal influences on the development of asthma and atopy in childhood

BackgroundIn most children with asthma and atopy, onset of disease occurs early in life, indicating a crucial role of in utero and early childhood environment. However, only a small part of this burden of disease established early in life has been explained.ObjectiveTo examine the effects of early environmental exposures on the development of asthma and atopy within the setting of an affluent urban population.MethodsThe authors followed 526 German children from birth to 5 years of age. Parental interviews in pregnancy and then yearly assessed the health of the child and environmental characteristics. Endotoxin and allergens in house dust were measured at 3 months. Atopic sensitization was assessed at 1 and 5 years.ResultsIn atopic mothers, acute atopic symptoms during pregnancy were associated with increased risk of early atopic dermatitis (adjusted odds ratio [aOR] 1.74, 95% confidence interval [CI] 1.00–3.02) and allergic rhinitis at 5 years (aOR 2.11, 95% CI 1.01–4.41). Further, maternal illnesses during pregnancy (ie, repeated common colds) increased the risk of asthma at 5 years (aOR 2.31, 95% CI 1.12–4.78). Endotoxin in the child's mattress was inversely associated with atopic sensitization (aOR 0.79, 95% CI 0.64–0.97) and asthma (aOR 0.71, 95% CI 0.55–0.93). A contrasting effect of early endotoxin and mite exposure was observed for mite sensitization: mite exposure increased the risk of mite sensitization at 5 years (aOR 1.30, 95% CI 1.11–1.53), whereas endotoxin exposure was inversely associated with mite sensitization (aOR 0.73, 95% CI 0.57–0.95).ConclusionFactors affecting the in utero environment, such as maternal atopy and infections, and bacterial exposure in pregnancy or early life may act as immunomodulators enhancing or inhibiting the development of asthma and atopy in childhood.     

Contributions of the early-life microbiome to childhood atopy and asthma development

The rapid rise in atopy and asthma in industrialized nations has led to the identification of early life environmental factors that promote these conditions and spurred research into how such exposures may mediate the trajectory to childhood disease development. Over the past decade, the human microbiome has emerged as a key determinant of human health. This is largely due to the increasing appreciation for the myriad of non-mutually exclusive mechanisms by which microbes tune and train host immunity. Microbiomes, particularly those in early life, are shaped by extrinsic and intrinsic factors, including many of the exposures known to influence allergy and asthma risk. This has led to the over-arching hypothesis that such exposures mediate their effect on childhood atopy and asthma by altering the functions and metabolic productivity of microbiomes that shape immune function during this critical developmental period. The capacity to study microbiomes at the genetic and molecular level in humans from the pre-natal period into childhood with well-defined clinical outcomes, offers an unprecedented opportunity to identify early-life and inter-generational determinants of atopy and asthma outcomes. Moreover, such studies provide an integrative microbiome research framework that can be applied to other chronic inflammatory conditions. This review attempts to capture key studies in the field that offer insights into the developmental origins of childhood atopy and asthma, providing novel insights into microbial mediators of maladaptive immunity and chronic inflammatory disease in childhood.     

Genetic variations in toll-like receptor pathway genes influence asthma and atopy

Innate immunity is a pivotal defence system of higher organisms. Based on a limited number of receptors, it is capable of recognizing pathogens and to initiate immune responses. Major components of these innate immunity pathogen recognition receptors are the toll-like receptors (TLRs), a family of 11 in humans. They are all membrane bound and through dimerization and complex downstream signaling, TLRs elicit a variety of specific and profound effects. In recent years, the role of TLRs signaling was not only investigated in infection and inflammation but also in allergy. Fuelled by the hygiene hypothesis, which suggests that allergies develop because of a change in microbial exposure and associated immune signals early in life, it had been speculated that alterations in TLRs signaling could influence allergy development. Thus, TLR genes, genetic variations of these genes, and their association with asthma and other atopic diseases were investigated in recent years. This review provides an overview of TLR genetics in allergic diseases.     

ADAM33 polymorphisms and phenotype associations in childhood asthma

BACKGROUND: A disintegrin and metalloproteinase (ADAM) 33 has been implicated as an asthma susceptibility gene by using a positional cloning approach. However, genetic linkage of asthma phenotypes to chromosome 20p13 (the location of ADAM33) has not been observed in most asthma genome scans, and it is unclear whether these associations with ADAM33 are broadly generalizable. OBJECTIVE: To examine whether ADAM33 is associated with asthma in a North American population of childhood asthmatic patients. METHODS: We performed a family-based association study by using 652 nuclear families ascertained through asthmatic subjects enrolled in a large randomized clinical trial. Seventeen ADAM33 single nucleotide polymorphisms (SNPs; including 9 associated with asthma in the initial report) were genotyped by mass spectrometry. Single-SNP and haplotype association analysis was performed. RESULTS: Among white and African American subjects, no single-SNP association with asthma was observed. However, a common 16-SNP haplotype (frequency, 14.6% in white subjects) was associated with asthma (P=.006). Two SNPs in strong linkage disequilibrium (T1 and T+1) were marginally associated with asthma in the Hispanic cohort (P=.04). These data provide marginal support for an asthma locus in the ADAM33 genomic region. However, the magnitudes of the observed associations are modest at best and are inconsistent with the original report. CONCLUSIONS: We conclude that either ADAM33 has only modest effects on asthma susceptibility, and the initial reports of association were a result of analysis in a selected population, or the initial findings were a result of chance. It is also possible that the true asthma susceptibility locus in this genomic region is near, but not at, ADAM33.     

Genetic polymorphisms and xenobiotic exposure in infantile asthma

Together with industrial development in Mexico has come a major increase in the generation of air pollutants. Some of these pollutants include compounds such as ozone, that like tobacco smoke, are related to the severity of certain respiratory diseases such as asthma. Although asthma affects people of all ages, it has been shown to primarily affect children and adolescents. Certain genetic polymorphisms have been found to be related to the symptoms or severity of the disease. The use of biomarker candidates has been proposed to study such genetic variations in several populations to detect and control this illness in its early stages. In addition, new research topics have been suggested that suggest a role for the metabolism of xenobiotics in the development of asthma. Furthermore, analysis of these polymorphisms in a Mexican population of children is being used as the first step in the development of strategies for detecting vulnerable groups. This paper reviews some genetic polymorphisms associated with allergic responses and their relationship with toxic exposure.     

Lack of association between genetic variation in G-protein-coupled receptor for asthma susceptibility and childhood asthma and atopy

G-protein-coupled receptor for asthma susceptibility (GPRA or GPR154) was identified as an asthma and atopy candidate gene by positional cloning. Some subsequent studies suggest associations of GPRA single nucleotide polymorphisms (SNPs) and haplotypes with asthma or atopy susceptibility. However, the associated SNPs or haplotypes vary among studies. The role of GPRA genetic variation in asthma and atopy remains unsolved. Published data on GRPA variants and asthma come exclusively from Caucasian and Asian populations. We examined whether GPRA SNPs and haplotypes are associated with asthma and atopy in a Mexican population. We genotyped and analyzed 27 GPRA SNPs in 589 nuclear families consisting of asthmatic children aged 4-17 years of age and their parents in Mexico City. Atopy was determined by skin prick tests to 25 aeroallergens. The 27 SNPs examined provided excellent coverage of the GPRA gene. GPRA SNPs and haplotypes were not associated with childhood asthma and the degree of atopy to aeroallergens in a Mexican population. Our review of studies of GPRA variants in relation to asthma phenotypes shows considerable heterogeneity. Accordingly, our results suggest that GPRA variants are not an important contributor to childhood asthma and atopy susceptibility in a Mexican population.     

The relationship between anthropometric measurements at birth: asthma and atopy in childhood

BACKGROUND: Recent studies have reported that a large head circumference at birth is associated with an increased risk of raised serum IgE in adult life, and asthma during childhood. OBJECTIVE: To examine the relationship between head circumference and other anthropometric measurements at birth and asthma and indices of atopy in childhood. METHODS: The presence of asthma and measures of atopic status (total serum IgE level and skin prick tests to common allergens) were assessed prospectively in offspring of families participating in a community-based genetic study in Southampton, UK. Measures of perinatal variables including birth weight, head circumference at birth, and gestational age were obtained from hospital records of 239 offspring aged 6-23 years. RESULTS: Children with a head circumference of 37 cm or more at birth had a relative risk of an elevated serum total IgE (> 150 IU) of 3.2 (95% CI 1.0-10.4). There were no consistent relationships between head circumference at birth and either skin prick positivity or the development of clinical asthma. There was no significant association between other perinatal markers and measures of atopic status or clinical asthma. CONCLUSION: The study has identified that a large head circumference at birth is associated with an increased risk of an elevated total serum IgE in childhood. The reasons for this association, and the lack of an association with asthma are unclear and will require further research.     

Genetic variants of IL-13 signalling and human asthma and atopy

Asthma and atopy show epidemiological association and are biologically linked by T-helper type 2 (T(h)2) cytokine-driven inflammatory mechanisms. IL-4 operates through the IL-4 receptor (IL-4R, a heterodimer of IL-4Ralpha and either gammac or IL-13Ralpha1) and IL-13 operates through IL-13R (a heterodimer of IL-4Ralpha and IL-13Ralpha1) to promote IgE synthesis and IgE-based mucosal inflammation which typify atopy. Recent animal model data suggest that IL-13 is a central cytokine in promoting asthma, through the stimulation of bronchial epithelial mucus secretion and smooth muscle hyper-reactivity. We investigated the role of common genetic variants of IL-13 and IL-13Ralpha1 in human asthma, considering IgE levels. A novel variant of human IL-13, Gln110Arg, on chromosome 5q31, associated with asthma rather than IgE levels in case-control populations from Britain and Japan [peak odds ratio (OR) = 2.31, 95% CI 1.33-4.00]; the variant also predicted asthma and higher serum IL-13 levels in a general, Japanese paediatric population. Immunohistochemistry demonstrated that both subunits of IL-13R are prominently expressed in bronchial epithelium and smooth muscle from asthmatic subjects. Detailed molecular modelling analyses indicate that residue 110 of IL-13, the site of the charge-modifying variants Arg and Gln, is important in the internal constitution of the ligand and crucial in ligand-receptor interaction. A non-coding variant of IL-13Ralpha1, A1398G, on chromosome Xq13, associated primarily with high IgE levels (OR = 3. 38 in males, 1.10 in females) rather than asthma. Thus, certain variants of IL-13 signalling are likely to be important promoters of human asthma; detailed functional analysis of their actions is needed.     

Mode of delivery is not associated with asthma or atopy in childhood

BACKGROUND: Caesarean-section delivery has been associated with the subsequent development of atopy and wheezing in childhood. OBJECTIVE: To examine the association between mode of delivery (vaginal vs. caesarean section) and development of atopy, asthma and wheezing disorders in a population-based cohort of children. METHODS: The Avon Longitudinal Study of Parents and Children is a longitudinal birth cohort of children born 1 April 1991 to 31 December 1992. Mode of delivery was categorized as vaginal (including forceps and ventouse extractions) or caesarean section (elective and emergency). Primary outcomes were parental report of asthma or wheezing between 69 and 81 months of age, physician-diagnosed asthma (PDA) at 91 months of age and atopy at 7 years by skin prick testing. Possible confounding factors were considered in a multivariable logistic regression model. RESULTS: Total livebirths were 14,062, from which were selected 12 367 born to mothers resident in a defined area and delivered in one of two major obstetric hospitals. Of these infants, 10,980 (88.8%) were delivered vaginally and 1387 (11.2%) by caesarean section. Outcome data were available for 7495 (61%) subjects (asthma 69-81 months); 7389 (60%) (wheeze 69-81 months); 7196 (58%) (PDA 91 months) and 5916 (48%) (atopy 7 years). Adjusted odds ratios [95%confidence interval] for caesarean section compared with vaginal delivery were not statistically significant for any outcome we considered: asthma 69-81 months 1.16 [0.9, 1.5]; wheeze 69-81 months 0.95 [0.7, 1.3]; PDA 1.14 [0.9, 1.4]; atopy 1.04 [0.8, 1.3]. CONCLUSION: Delivery by caesarean section was not associated with the subsequent development of asthma, wheezing or atopy in later childhood in this population.     

Association of prostaglandin-endoperoxide synthase 2 gene polymorphisms with asthma and atopy in Chinese children

BACKGROUND: Cyclooxygenase-2 (COX-2) plays essential roles in inflammation. Previous studies have suggested associations between prostaglandin-endoperoxide synthase 2 (PTGS2) polymorphisms and prostaglandins production in asthma. OBJECTIVE: We have investigated the effects of Chinese tagging single nucleotide polymorphisms (SNPs) of PTGS2 on asthma traits in 299 Chinese asthmatic children and 175 controls. METHODS: Plasma total and allergen-specific IgE were measured by enzyme immunoassay. PTGS2.8473T-->C in the 3'-untranslated region of exon 10 and three tag SNPs covering most of the variations in PTGS2 haplotypes in Chinese were genotyped by restriction fragment length polymorphism. RESULTS: Among the four SNPs, only PTGS2.8473 showed significant association with asthma (P = 0.034) and atopy (P = 0.005 when compared with non-atopic controls; P = 0.023 with all controls). Carriers of the C allele had a 1.5-fold (95% confidence interval: 1.01-2.30) risk of developing asthma than those homozygous for the T allele. Multivariate regression revealed significant correlations between PTGS2.8473 and forced expiratory volume in 1 s (FEV(1); P = 0.002) and peak expiratory flow rate (PEFR; P = 0.001) with age and gender adjusted. Patients with the C allele of PTGS2.8473 had significantly lower FEV(1) (median: 90.0%vs 98.0%; P = 0.0047) and PEFR (70.0%vs 73.5%; P = 0.0065) than those homozygous for the T allele. No significant association between plasma total and allergen-specific IgE and these SNPs or with their haplotypes was found. CONCLUSIONS: PTGS2.8473 polymorphism is associated with asthma, atopy and lung function but not plasma IgE in Chinese children. This may help to explore the pharmacogenetics of COX-2 inhibitors.     

Genetic analysis of atopy and asthma as quantitative traits and ordered polychotomies

Traits related to atopy and asthma were defined in a random cohort of 131 families with three or more children. Correlation analysis provides no evidence of imprinting, maternal effect, or a major role of environment shared by sibs. Commingling analysis favours more than one distribution, the upper one being common for asthma and very common for atopy. Segregation analysis of rank-transformed variables provides only equivocal evidence of major genes against a polygenic background but suggests that such genes (if present) are individually common and not of large effect. Segregation analysis under a two-locus model gives consistent results with minimal distributional assumptions. To enter combined segregation analysis we favour a restricted model in which the major locus is additive on the liability scale and the pseudopolygenic modifier locus accounts for at least half the genetic variance. Total IgE and bronchial reactivity are proposed for meta-analysis of atopy and asthma respectively. Genetic analysis of complex inheritance is discussed and it is shown that allelic association with random loci is not a feasible approach.     

Exposure to dust mite allergen and endotoxin in early life and asthma and atopy in childhood

BACKGROUND: There has been no longitudinal study of the relation between concurrent exposure to dust mite allergen and endotoxin in early life and asthma and atopy at school age. OBJECTIVES: To examine the relation between exposure to dust mite allergen and endotoxin at age 2 to 3 months and asthma, wheeze, and atopy in high-risk children. METHODS: Birth cohort study of 440 children with parental history of atopy in the Boston metropolitan area. RESULTS: In multivariate analyses, early exposure to high levels of dust mite allergen (> or =10 microg/g) was associated with increased risks of asthma at age 7 years (odds ratio [OR], 3.0; 95% CI, 1.1-7.9) and late-onset wheeze (OR, 5.0; 95% CI, 1.5-16.4). Exposure to endotoxin levels above the lowest quartile at age 2 to 3 months was associated with reduced odds of atopy at school age (OR, 0.5; 95% CI, 0.2-0.9). In contrast with its inverse association with atopy, endotoxin exposure in early life was associated with an increased risk of any wheeze between ages 1 and 7 years that did not change significantly with time (hazard ratio for each quartile increment in endotoxin levels, 1.23; 95% CI, 1.07-1.43). CONCLUSION: Among children at risk of atopy, early exposure to high levels of dust mite allergen is associated with increased risks of asthma and late-onset wheeze. In these children, endotoxin exposure is associated with a reduced risk of atopy but an increased risk of wheeze. CLINICAL IMPLICATIONS: Early endotoxin exposure may be a protective factor against atopy but a risk factor for wheeze in high-risk children.     

Deficient arginase II expression without alteration in arginase I expression attenuated experimental autoimmune encephalomyelitis in mice

In the past there have been a multitude of studies that ardently support the role of arginase II (Arg II) in vascular and endothelial disorders; however, the regulation and function of Arg II in autoimmune diseases has thus far remained unclear. Here we report that a global Arg II null mutation in mice suppressed experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. During EAE, both Arg I and Arg II were induced in spinal cords, but only Arg II was induced in spleens and splenic dendritic cells (DCs). DC activation by lipopolysaccharide (LPS), CD40L or TLR8 agonist significantly enhanced Arg II expression without affecting Arg I expression. Conversely, DC differentiating cytokines [IL‐4 and granulocyte macrophage‐colony‐stimulating factor (GM‐CSF)] yielded opposite effects. In addition, Arg I and Arg II were regulated differentially during Th1 and Th17 cell polarization. Arg II deficiency in mice delayed EAE onset, ameliorated clinical symptoms and reduced myelin loss, accompanied by a remarkable reduction in the EAE‐induced spinal cord expression of Th17 cell markers (IL‐17 and RORγt). The abundance of Th17 cells and IL‐23⁺ cells in relevant draining lymph nodes was significantly reduced in Arg II knockout mice. In activated DCs, Arg II deficiency significantly suppressed the expression of Th17‐differentiating cytokines IL‐23 and IL‐6. Interestingly, Arg II deficiency did not lead to any compensatory increase in Arg I expression in vivo and in vitro. In conclusion, Arg II was identified as a factor promoting EAE likely via an Arg I‐independent mechanism. Arg II may promote EAE by enhancing DC production of Th17‐differentiating cytokines. Specific inhibition of Arg II could be a potential therapy for multiple sclerosis.