ArticleLiterature Review

The early origins of asthma: Who is really at risk?

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Abstract

Asthma is largely a developmental disease in which the normal development of the respiratory and immune systems is altered by the impacts of environmental exposures acting on underlying genetic predispositions. This review will comment on the latest evidence in this field. There is increasing evidence that several potentially overlapping genetic predispositions may contribute to the development of asthma, including predisposition to abnormal lung growth, resulting in lower lung function; delayed immune maturation; predisposition to lower respiratory viral infections; early allergic sensitization; and predisposition to bronchial hyper-responsiveness. Networks of genes and environmental modification of gene expression via epigenetic mechanisms are also likely to be important. Antenatal exposures that increase the risk of asthma include tobacco smoke, ambient and indoor air pollution. Impacts of maternal nutrition and maternal diseases, such as asthma and diabetes, are also important. Early life environmental exposures may also increase the risk of asthma via impacts on lung growth and immune maturation. Synergistic interactions between viral lower respiratory infections and allergic sensitization in early life appear to be especially important in increasing the risk of subsequent asthma. The major risk factors for childhood asthma are a family history of asthma and allergies, early and persistent allergic sensitization to environmental allergens and viral lower respiratory illnesses in early life.

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... Some evidence suggests that infants who develop atopy and asthma have a particularly delayed maturation of immune responses, which might predispose to development of viral LRTIs and result in asthma. 15,[21][22][23][24]70,72 During infancy, dendritic cells are less capable of presenting antigen compared with later in childhood. 23 T cells, as part of the adaptive defence alliance, are less able to produce cytokines and form memory cells after birth, and instead might even undergo apoptosis upon antigen contact. ...
... 74 The combination of ineffi cacious immune response towards viral pathogens and a delay in the development of more focused and eff ective responses is related to an increased number of RTIs early in life, possibly because of increased viral spread to the lower airways. 21 ...
... Children and adults with asthma seem to be primarily colonised with gammaproteobacteria-ie, Haemophilus infl uenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. 3-6, 96 However, in individuals with asthma, whether this pattern of colonisation occurs secondary to airway epithelium damage, impaired barrier function, and infl ammatory changes in the airways 21,23,97 or is a primary cause of the disease remains to be elucidated. One birth cohort study 3 suggests that colonisation of the hypopharynx with H infl uenzae, M catarrhalis, and S pneumoniae very early in life precedes the onset of asthma. ...
Article
Bacterial and viral infections occur early and recurrently in life and thereby impose a substantial disease burden. Besides causing clinical symptoms, a potential role of infection in the development of the asthma syndrome later in life has also been suggested. However, whether bacterial and viral infections unmask host factors in children at risk of asthma or whether they directly cause asthma remains unclear; both viewpoints could be justified, but the underlying mechanisms are complex and poorly understood. Recently, the role of the bacterial microbiome has been emphasised. But data are still sparse and future studies are needed for definitive conclusions to be made. In this Review, we discuss present knowledge of viruses and bacteria that infect and colonise the respiratory tract and mucosal surfaces, including their timepoint of action, host factors related to infection, and their effect on childhood asthma. Childhood asthma could be the result of a combination of altered host susceptibility and infectious agents.
... We found notable differences between the Mbekweni (black African) and Newman (mixed-race) populations (table 1). More black African participants were in the lowest socioeconomic status quartile than mixed-race participants and the median household size was lower (four people [IQR 3-6] vs five people [4][5][6][7]) for mixed-race participants (table 1). A third of the 796 homes successfully assessed had fewer than two of the household dimensions; however, 94% of all homes had access to electricity (table 1). ...
... When correcting for both smoke exposure and IAP, a moderate-to-high socioeconomic status was associated with an increased risk of wheezing (IRR 1·53, 95% CI 1·17-2·00; p=0·002; appendix p 11). Neither postnatal self-reported maternal or household smoking nor PM 10 exposure was associated with an increased risk of LRTI or of LRTI-associated hospitalisation (appendix pp [4][5][6][7][8]. ...
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Article
Background Indoor air pollution (IAP) and environmental tobacco smoke (ETS) are associated with lower respiratory tract illness (LRTI) or wheezing in children. However, the effect of the timing of these exposures, specifically antenatal versus postnatal, and of alternate fuel sources such as the increasingly used volatile organic compounds have not been well studied. We longitudinally investigated the effect of antenatal or postnatal IAP and ETS on LRTI or wheezing prevalence and severity in African infants. Methods Mother and infant pairs enrolled over a 3-year period in a birth cohort study in two centres in Paarl, South Africa, were followed for the first year of life for LRTI or wheezing illness. We measured exposure to IAP (particulate matter, nitrogen dioxide, sulphur dioxide, carbon monoxide, and volatile organic compounds benzene and toluene) using devices placed in homes, antenatally and postnatally. We measured ETS longitudinally by maternal self-report and by urine cotinine measures. Study staff trained in recognition of LRTI or wheeze documented all episodes, which were categorised according to WHO case definition criteria. We used multivariate logistic and Poisson regressions to explore associations. Findings Between March 1, 2012, and March 31, 2015, we enrolled 1137 mothers with 1143 livebirths. Of 1065 infants who attended at least one study visit, 524 episodes of LRTI occurred after discharge with a wheezing prevalence of 0·23 (95% CI 0·21–0·26) episodes per child year. Exposures associated with LRTI were antenatal maternal smoking (incidence rate ratio 1·62, 95% CI 1·14–2·30; p=0·004) or particulate matter (1·43, 1·06–1·95; p=0·008). Subanalyses of LRTI requiring hospitalisation (n=137) and supplemental oxygen (n=69) found antenatal toluene significantly increased the risk of LRTI-associated hospitalisation (odds ratio 5·13, 95% CI 1·43–18·36; p=0·012) and need for supplemental oxygen (13·21, 1·96–89·16; p=0·008). Wheezing illness was associated with both antenatal (incidence rate ratio 2·09, 95% CI 1·54–2·84; p<0·0001) and postnatal (1·27, 95% CI 1·03–1·56; p=0·024) maternal smoking. Antenatally, wheezing was associated with maternal passive smoke exposure (1·70, 1·25–2·31; p=0·001) and, postnatally, with any household member smoking (1·55, 1·17 −2·06; p=0·002). Interpretation Antenatal exposures were the predominant risk factors associated with LRTI or wheezing illness. Toluene was a novel exposure associated with severe LRTI. Urgent and effective interventions focusing on antenatal environmental factors are required, including smoking cessation programmes targeting women of childbearing age pre-conception and pregnant women. Funding Bill & Melinda Gates Foundation, Discovery Foundation, South African Thoracic Society AstraZeneca Respiratory Fellowship, Medical Research Council South Africa, National Research Foundation South Africa, and CIDRI Clinical Fellowship.
... Family history of asthma and atopy are strong predisposing factors, but they are not sufficient causes of the condition. Childhood asthma likely originates early in life when the developing immune and respiratory systems are especially vulnerable to assault by environmental risk factors in genetically predisposed individuals [48]. Male sex and low birth weight have been identified as risk factors [49,50], and there is speculation that viral infections of the lower respiratory tract in early childhood may trigger the development of asthma, but the mechanism for this is unclear. ...
... Male sex and low birth weight have been identified as risk factors [49,50], and there is speculation that viral infections of the lower respiratory tract in early childhood may trigger the development of asthma, but the mechanism for this is unclear. It is uncertain whether viral infections cause asthma, or symptoms of viral infections are more apparent in asthma-susceptible children [48]. Conversely, some studies also suggest that upper respiratory tract infections in early life [49], day care attendance, breast feeding, and higher birth order may lower asthma risk [51][52][53]. ...
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Article
Numerous studies have reported a protective association between asthma and acute lymphoblastic leukemia (ALL), but the causal structure of this association remains unclear. We present a hybrid simulation to examine the compatibility of this association with uncontrolled confounding by infection or another unmeasured factor. We generated a synthetic cohort using inputs on the interrelations of asthma, ALL, infections, and other suggested risk factors from the literature and the Danish National Birth Cohort. We computed odds ratios (ORs) between asthma and ALL in the synthetic cohort with and without adjustment for infections and other (including unmeasured) confounders. Only if infection was an extremely strong risk factor for asthma (OR of 10) and an extremely strong protective factor against ALL (OR of 0.1) was the asthma-ALL association compatible with the literature (OR of 0.78). Similarly, strong uncontrolled confounding by an unmeasured factor could downwardly bias the asthma-ALL association, but not enough to replicate findings in the literature. This investigation illustrates that the reported protective association between asthma and ALL is unlikely to be entirely due to uncontrolled confounding by infections or an unmeasured confounder alone. Simulation can be used to advance our understanding of risk factors for rare outcomes as demonstrated by this study.
... Particulate and gaseous pollutants can act on both the upper and lower airways to initiate and exacerbate cellular inflammation through interactions with the innate immune system (Bonay and Aubier, 2007). In addition to air pollution, early and persistent allergic sensitization is known to be a risk factor for the development of asthma (Sly, 2011). Indoor allergens from dust mites, cockroaches and cats have been associated with asthma exacerbation in children (Sly, 2011). ...
... In addition to air pollution, early and persistent allergic sensitization is known to be a risk factor for the development of asthma (Sly, 2011). Indoor allergens from dust mites, cockroaches and cats have been associated with asthma exacerbation in children (Sly, 2011). It has also been reported that allergen sensitization is associated with allergic diseases and also with air pollutants . ...
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Article
Background: The synergistic effect of allergens and air pollutants on the risk of allergic diseases is unclear. Objective: To evaluate the joint effect of outdoor pollutants and indoor allergens on the risk of allergic diseases. Methods: We enrolled 2661 kindergarten children from the CEAS cohort. Data on allergic diseases and environmental exposure were collected. Skin prick tests were performed. Individual exposure to air pollution was estimated using a geographic information system with the mean concentration of air pollutants. Multiple logistic regression analysis was performed to estimate the association between air pollutants, allergen exposure and the risk of allergic diseases with adjustments for potential confounders. Results: Overall, 12.6% of the children had asthma, 30.0% had allergic rhinitis (AR), and 14.4% had atopic dermatitis (AD). Mite sensitization significantly increased the risk of AD, AR, and asthma (OR (95%CI) 2.15 (1.53-3.03), 1.94 (1.46-2.58), and 2.31 (1.63-3.29), respectively). Exposure to PM10, PM2.5, CO, and O3 was associated with asthma (OR (95% CI) 1.39 (1.03-1.87), 1.45 (1.07-1.97), 1.36 (1.01-1.83), and 0.68 (0.51-0.92), respectively). PM2.5 may have increased the risk of AR (OR (95% CI) 1.54 (1.03-2.32). Mite sensitization showed a synergistic effect with PM2.5 on the development of asthma (p<0.001). Moreover, mite allergens may modify the effect of air pollutants on allergic diseases. Conclusion: Dust mites and PM2.5 play an important role on the risk of asthma and AR. Exposure to PM2.5 and mite allergens had a synergistic effect on the development of asthma. Avoiding co-exposure to allergens and air pollutants is important.
... These varied findings highlight the complex relationships among host and environmental factors that are seldom examined concurrently. Because approximately 50% of children between the ages of 6 and 9 are sensitized (9) and early and persistent allergic sensitization is recognized as a risk factor for asthma development (10), the purpose of this study is to disentangle the relationships related to early childhood sensitization, gender, environmental exposure to SHS as measured by internal dose of hair cotinine, and the potential long-term consequences on pulmonary function. ...
... We feel that these findings are also generalizable to a nonhigh-risk cohort. Two of the major risk factors for childhood asthma are family history of asthma and allergies and early and persistent allergic sensitization to environmental allergens (10). It has been shown previously that nearly 50% of children between the ages of 6 and 9 are atopic (9). ...
Article
Contradictory findings on the differential effects of second-hand smoke (SHS) on lung function in girls and boys may result from masked relationships between host and environmental factors. Allergic sensitization may augment the relationship between SHS and decreased lung function, although its role in relation to the inconsistent gender differences in children has not been elucidated. We hypothesize that there will be differences between boys and girls related to early-life allergic sensitization and exposure to SHS on pulmonary function later in childhood. Participants in this study (n = 486) were drawn from the Cincinnati Childhood Allergy and Air Pollution (CCAAPS) birth cohort study consisting of 46% girls. Allergic sensitization was assessed by skin prick test (SPT) to 15 aeroallergens at ages 2, 4, and 7, while pulmonary function and asthma diagnosis occurred at age 7. SHS exposure was measured by hair cotinine at ages 2 and/or 4. Gender differences of SHS exposure on pulmonary function among children with positive SPTs at ages 2, 4, and 7 as well as first- and higher-order interactions were examined by multiple linear regression. Interactions significant in the multivariate models were also examined via stratification. Comparisons within and between stratified groups were assessed by examining the slope of the parameter estimates/beta coefficients and associated p-values and confidence intervals. Increased cotinine levels were significantly associated with decreases in FEV(1) (-0.03 l, p < 0.05), peak expiratory flow (-0.07 l/s, p < 0.05), and FEF (25-75%) (-0.06 l/s, p < 0.01). The interaction between cotinine and sensitization at age 2 was borderline significant (p = 0.10) in the FEF(25-75%) model and showed an exposure response effect according to the number of positive SPTs at age 2; zero (-0.06 l/s, p < 0.01), one (-0.09 l/s, p < 0.05), or two or more positive SPTs (-0.30 l/s, p < 0.01). Despite increased polysensitization among boys, the association between cotinine and FEF(25-75%) among girls, with two or more positive SPTs at age 2, showed the greatest deficits in FEF(25-75%) (-0.34 l/s vs. -0.05 l/s and -0.06 l/s for non-sensitized girls and boys, respectively. Girls with two or more positive SPTs showed a twofold greater decrease in FEF(25-5%) (-0.34 l/s; 95% CI: -0.55, -0.13) compared to boys with the same degree of allergic sensitization (-0.18 l/s; 95% CI: -0.41, 0.06), although this difference was not statistically significant. Reductions in lung function were observed among children exposed to SHS, and the number of aeroallergen-positive SPTs at age 2 modifies this relationship. Girls experiencing early childhood allergic sensitization and high SHS exposure are at greater risk of decreased lung function later in childhood compared to non-sensitized girls and boys and demonstrate greater deficits compared to boys with similar degrees of sensitization.
... Such studies provide powerful evidence for life experiences affecting health and disease across the life course and generations, and how "life circumstances, health and disease are linked at a molecular scale" [15]. Prenatal experiences influence health trajectories and contribute to adult health outcomes including obesity, cancer, cardiovascular and metabolic diseases, asthma and osteoporosis [16][17][18], while prenatal exposure to infectious agents is a risk factor for neurodevelopmental brain disorders, including schizophrenia [19,20], autism [21,22] and bipolar disorder [23,24]. ...
Article
Aims: To assess the epigenetic effects of in utero exposure to maternal Trypanosoma cruzi infection. Methods: We performed an epigenome-wide association study to compare the DNA methylation patterns of umbilical cord blood cells from uninfected babies from chagasic and uninfected mothers. DNA methylation was measured using Infinium EPIC arrays. Results: We identified a differential DNA methylation signature of fetal exposure to maternal T. cruzi infection, in the absence of parasite transmission, with 12 differentially methylated sites in B cells and CD4 ⁺ T cells, including eight protein-coding genes. Conclusion: These genes participate in hematopoietic cell differentiation and the immune response and may be involved in immune disorders. They also have been associated with several developmental disorders and syndromes.
... 而有关儿童出生前, 包括母体孕前 或孕期暴露的环境及儿童出生后早期的家居生活环 境却较少被人们关注 [6] . 目前, 国外有关出生前环境 暴露的研究, 如烟草燃烧 [7,8] 和室内霉菌 [9] 等; 早期 生活环境的暴露, 如使用人造板材的家具(如木屑板, 刨花板等) [10] , 花粉或孢子 [11] 及新型化学物质 [12,13] 等 已有报道, 均发现与儿童后期的呼吸道症状包括哮 喘和过敏性鼻炎等有相关性. ...
... L'asma e le malattie atopiche come la rinite allergica e l'eczema sono condizioni croniche comuni la cui prevalenza è ancora in aumento in molti paesi, e sono una significativa causa di morbilità in tutto il mondo (1,2). Il loro sviluppo ed espressione sono influenzati dall'interazione di diversi fattori genetici, biologici e ambientali, molti dei quali esercitano la loro azione nelle prime fasi della vita o addirittura durante la vita fetale (3). Negli ultimi 10 anni diversi studi condotti sia su adulti che su bambini hanno mostrato che l'esperienza di eventi stressanti è associata a un aumento del rischio di svilup-pare l'asma e le malattie atopiche (4)(5)(6). ...
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Background: La storia naturale dell'asma e delle malattie atopiche comin-cia in utero. Mancano studi che indagano l'influenza dell'esposizione fetale a eventi stressanti durante la gravidanza (SLEP) sulla comparsa di asma e di ma-lattie atopiche. Obiettivo: Esaminare se i bambini di madri che hanno speri-mentato SLEP presentano un rischio maggiore di asma, eczema atopico e rinite allergica. Metodi: L'associazione tra SLEP della madre (almeno un evento tra divorzio, lutto o perdita del lavoro) e la comparsa di asma e di malattie atopi-che nell'infanzia è stata studiata in una popolazione (n = 3854) di bambini di età 3-14 anni che vivono nell'Italia del Nord. I genitori hanno compilato un questionario standardizzato sulla salute dei figli e sugli eventi accaduti alle madri durante la gravidanza. Risultati: 333 (9%) madri hanno sperimentato SLEP. I figli di queste madri hanno nel corso della vita una prevalenza signi-ficativamente più alta di wheezing (31,6% vs. 23,1%), asma (8,9% vs. 5,6%), rinite allergica (10,9% vs. 7,3%) e eczema atopico (29,7% vs. 21,1%) rispetto ai bambini di madri che non hanno sperimentato SLEP. Dopo aggiustamento per potenziali confondenti, l'esposizione fetale a SLEP è risultata associata positivamente a wheezing (OR: 1,41, 95% CI: 1,03-1,94), asma (OR: 1,71, 95% CI: 1,02-2,89), rinite allergica (OR: 1,75, 95% CI: 1,08-2,84) e eczema atopico (OR: 1,53, 95% CI: 1,11-2,10). Conclusioni: I bambini di madri che hanno sperimentato SLEP hanno un rischio moderatamente più alto di avere wheezing, asma, eczema e rinite allergica durante la loro infanzia. Lo stress materno durante la gravidanza potrebbe incrementare l'espressione di asma e di fenotipi allergici nei bambini.
... Additional evidence was obtained when we compared the MN frequencies observed in cord blood lymphocytes from births that occurred during the rainy season with those obtained during the dry season, suggesting that increased air pollution is associated with the higher DNA damage observed. The impact of nonrepairable DNA damage represented by the presence of MN may include an increased risk for immune effects (Latzin et al., 2011;Sly, 2011), such as allergies (Kim and Bernstein, 2009), asthma, or cardiac and pulmonary (Proietti et al., 2013) diseases, leukemia (Carlos-Wallace et al., 2016;Janitz et al., 2016), and cancer (Lavigne et al., 2017) in later years. Although the government is taking measures to reduce air pollution, nevertheless newborns are still at risk. ...
Article
Studies associate particulate matter (PM) exposure with pulmonary, cardiovascular and neurologic diseases. Elevated levels of coarse (PM10) and fine (PM2.5) PM have been reported in the Mexico City metropolitan area (MCMA) during the last two decades. There is limited information if these conditions affect newborns. We associated maternal exposure to PM reported by the monitoring stations considering the place of residence of each participant with the presence of genotoxic damage (cytome analysis) in maternal and umbilical cord blood (UCB) lymphocytes. Eighty four healthy women in their last quarter of pregnancy met the inclusion criteria. Each volunteer exposure was estimated according to the average PM2.5 and PM10 levels during the last month of gestation. The micronuclei (MN) frequencies in UCB lymphocyte cultures ranged between 0‐9. They also showed lower cell proliferation indexes than their mothers. There was a strong correlation between the maternal and the UCB MN frequency (ρ=0.3767, p=0.0002). Multiple regression analysis including PM10 and PM2.5 levels, maternal age and occupation, showed a significant and positive association between UCB MN frequency and PM2.5. A statistically significant increase in the MN frequency in both maternal and UCB lymphocytes was observed in samples obtained during the dry season (higher PM levels) as compared with the MN frequency in blood samples obtained during the rainy season (lower PM levels). These results suggest that PM, mainly PM2.5, can cross the placenta causing DNA damage in fetal cells which may increase the potential for diseases during childhood or adult life. This article is protected by copyright. All rights reserved.
... [61][62][63] Other evidence supports the idea that short-and long-term effects of tobacco smoke exposure can influence the structure of the developing lung, as well as lung physiology, effects that can have lifelong consequences, [64][65][66][67] and there is evidence that the most common preventable early-life risk factor for asthma is exposure to tobacco smoke. 68 Long-term exposure of mice to THS can induce pulmonary toxicity by itself. 9 However, our study indicates that in mice exposure to a component of THS, even at doses too low to induce obvious histologic effects on the lungs, can significantly exacerbate multiple features of asthma pathology. ...
Article
Background: Thirdhand smoke (THS) represents the accumulation of secondhand smoke on indoor surfaces and in dust, which, over time, can become more toxic than secondhand smoke. Although it is well known that children of smokers are at increased risk for developing asthma and for exacerbation of that disease if they already have it, how exposure to THS may influence the development or exacerbation of asthma remains unknown. Objective: We investigated whether epicutaneous exposure to an important component of THS, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), can influence asthma pathology in a model elicited in mice by repeated intranasal challenge with cockroach antigen (CRA). Methods: Wild type mice, α7 nicotinic acetylcholine receptor (α7 nAChR)- or mast cell (MC)-deficient mice, and mice with MCs that lacked α7 nAChRs or that were the host's sole source of α7 nAChRs, were subjected to epicutaneous NNK exposure and/or intranasal CRA challenge, and the severity of features of asthma pathology, including airway hyperreactivity (AHR), airway inflammation and airway remodeling, were assessed. Results: We found that α7 nAChRs were required to observe adverse effects of epicutaneous NNK exposure on multiple features of CRA-induced asthma pathology. Moreover, MC expression of α7 nAChRs significantly contributed to the ability of epicutaneous NNK exposure to exacerbate AHR to methacholine, airway inflammation, and airway remodeling in this model. Conclusion: Our results show that skin exposure to NNK, a component of THS, can exacerbate multiple features of a cockroach antigen-induced model of asthma in mice and define MCs as key contributors to these adverse effects of NNK.
... These measurements could have been biased by time-specific conditions of pregnancy, such as morning sickness, that are likely to have altered the woman's exposure [15]. Third, the analysis lacked control for some potentially important confounding factors, such as respiratory infections and exposure to tobacco smoke, which are thought to be related to asthma [16][17][18]. Finally, the rationale behind the choice of MF metrics (average versus highest encountered) and cut-points (above 0.2 μT) used in the asthma study versus what was used by the same investigators in their miscarriage study (above 1.6 μT) is not given and is not clear. ...
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Background A study reported an increased risk of asthma in children whose mothers were exposed to magnetic field (MF) levels above 0.2 μT during pregnancy. We re-examined this association using data from mothers and children in the Danish National Birth Cohort (DNBC). Methods This study included 92,676 singleton-born children and their mothers from the DNBC. MF exposure from power lines was estimated for all residences where the mothers lived during pregnancy and for all children from birth until the end of follow up. Exposure was categorized into 0 μT, 0.1 μT, and ≥ 0.2 μT for analysis. Definitive and possible asthma cases were identified using data from three independent data sources: 1) mothers’ reports, 2) a national hospitalization register, 3) a national prescription drug register. We calculated hazard ratios (HR) and 95% confidence intervals (CI) for the association between the highest level of exposure during pregnancy and asthma in children, adjusting for several potential confounding factors. We also examined the sensitivity of the risk estimates to changes in exposure and outcome definitions. Results No differences or trends in the risk of asthma development were detected between children with different levels of MF exposure regardless of the asthma case definition or outcome data source. For definitive cases, the HR (95% CI) for those with any exposure was 0.72 (0.27–1.92), and it was 0.41 (0.06–2.92) for those exposed to ≥ 0.2 μT. Adjustments for confounding and variations in the exposure definition did not appreciably alter the results. Conclusion We did not find evidence that residential exposure to MF during pregnancy or early childhood increased the risk of childhood asthma. This interpretation is in line with the lack of an established biological mechanism directly linking MF exposure to asthma, but high exposure was very rare in this cohort.
... Another aspect that has to be taken into account when investigating the impact of prenatal air pollution on respiratory health is the role of the immune system early in life, as it is known to strongly influence later asthma development [48,49]. Immune maturation and immune responses can be influenced by environmental exposures in early life [50] and thus, exposure to air pollution may influence immune programming [51]. Several studies have shown that maternal smoke exposure during pregnancy has strong influences on the immune system of neonates [52][53][54], however, data on maternal exposure to outdoor air pollution and an altered neonatal immune system remain scarce. ...
Article
Air pollution exposure has increased extensively in recent years and there is considerable evidence that exposure to particulate matter can lead to adverse respiratory outcomes. The health impacts of exposure to air pollution during the prenatal period is especially concerning as it can impair organogenesis and organ development, which can lead to long-term complications. Exposure to air pollution during pregnancy affects respiratory health in different ways. Lung development might be impaired by air pollution indirectly by causing lower birth weight, premature birth or disturbed development of the immune system. Exposure to air pollution during pregnancy has also been linked to decreased lung function in infancy and childhood, increased respiratory symptoms, and the development of childhood asthma. In addition, impaired lung development contributes to infant mortality. The mechanisms of how prenatal air pollution affects the lungs are not fully understood, but likely involve interplay of environmental and epigenetic effects. The current epidemiological evidence on the effect of air pollution during pregnancy on lung function and children's respiratory health is summarized in this review. While evidence for the adverse effects of prenatal air pollution on lung development and health continue to mount, rigorous actions must be taken to reduce air pollution exposure and thus long-term respiratory morbidity and mortality.
... They noted that several loci, identified via candidate gene or genome-wide approaches, are associated with the disease phenotype and environmental exposures [3]. The research on environment-driven epidemic of RA has been fueled by the observation that early life events can have an impact on the prevalence of RA later in life [4][5][6]. Investigations making use of longitudinal cohorts are hampered because traditional blood sampling is an invasive approach-particularly in children and patient groups it is kept to a minimum for practical and ethical reasons. ...
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Article
The etiology of respiratory allergies (RA) can be partly explained by DNA methylation changes caused by adverse environmental and lifestyle factors experienced early in life. Longitudinal, prospective studies can aid in the unravelment of the epigenetic mechanisms involved in the disease development. High compliance rates can be expected in these studies when data is collected using non-invasive and convenient procedures. Saliva is an attractive biofluid to analyze changes in DNA methylation patterns. We investigated in a pilot study the differential methylation in saliva of RA (n = 5) compared to healthy controls (n = 5) using the Illumina Methylation 450K BeadChip platform. We evaluated the results against the results obtained in mononuclear blood cells from the same individuals. Differences in methylation patterns from saliva and mononuclear blood cells were clearly distinguishable (PAdj0.2), though the methylation status of about 96% of the cg-sites was comparable between peripheral blood mononuclear cells and saliva. When comparing RA cases with healthy controls, the number of differentially methylated sites (DMS) in saliva and blood were 485 and 437 (P0.1), respectively, of which 216 were in common. The methylation levels of these sites were significantly correlated between blood and saliva. The absolute levels of methylation in blood and saliva were confirmed for 3 selected DMS in the PM20D1, STK32C, and FGFR2 genes using pyrosequencing analysis. The differential methylation could only be confirmed for DMS in PM20D1 and STK32C genes in saliva. We show that saliva can be used for genome-wide methylation analysis and that it is possible to identify DMS when comparing RA cases and healthy controls. The results were replicated in blood cells of the same individuals and confirmed by pyrosequencing analysis. This study provides proof-of-concept for the applicability of saliva-based whole-genome methylation analysis in the field of respiratory allergy.
... The development of asthma involves a combination of host and environment factors occurring at critical moments in the maturation of the immune system (Sly, 2011). Two of the most important environmental factors in the onset and course of the disease are airborne allergens and viral respiratory infections. ...
Article
Objective: ADHD and asthma are prevalent conditions in childhood, with complex pathophysiology involving genetic-environmental interplay. The study objective is to examine the prevalence of asthma in our ADHD population and explore factors that may increase the risk of developing asthma in children with ADHD. Methods: We retrospectively analyzed the presence of maternal stress during pregnancy and history of asthma in 201 children diagnosed with ADHD. Results: Chi-square analysis indicated significant higher presence of asthma in our ADHD sample compared to Quebec children, χ(2)(1, N = 201) = 15.37, P<0.001. Only prematurity and stress during pregnancy significantly predicted asthma in a logistic regression model, χ(2)(2)=23.70, P<0.001, with odds ratios of 10.6 (95% CI: 2.8-39.5) and 3.2 (95% CI: 1.4-7.3), respectively. Conclusion: Children with ADHD have a higher prevalence of asthma than the general Quebec pediatric population. Children with ADHD born prematurely and/or those whose mothers experienced stress during pregnancy have a significantly increased risk of developing asthma. The study highlights the importance of potentially offering social and psychological support to mothers who experienced stress during pregnancy and/or are at risk of delivering prematurely.
... It is increasingly evident that lung function tracks into adult life [27], suggesting that environmental exposures (including maternal nutrition, environmental tobacco smoke, respiratory infections and allergen exposure) [28] in early life play a significant role in the development of chronic respiratory disease in adults. There is also emerging evidence that chronic obstructive pulmonary disease is linked to asthma in childhood [7,29], further highlighting the importance and necessity of a true life course approach to the investigation of chronic respiratory diseases, such as asthma. ...
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Young adulthood is a critical life period for health and health behaviours. Related measurements collected before and after birth, and during childhood and adolescence can provide a life-course analysis of important factors that contribute to health and behaviour in young adulthood. The Western Australian Pregnancy Cohort (Raine) Study has collected a large number of such measurements during the fetal, perinatal, infancy, childhood and adolescence periods and plans to relate them to common health issues and behaviours in young adults, including spinal pain, asthma, sleep disorders, physical activity and sedentary behaviour and, work absenteeism and presenteeism. The aim of this paper is to describe the rationale, design and methods of the 22 year follow-up of the Raine Study cohort. The Raine Study is a prospective cohort study. Participants still active in the cohort (n = 2,086) were contacted around the time of their 22nd birthday and invited to participate in the 22 year follow-up. Each was asked to complete a questionnaire, attend a research facility for physical assessment and an overnight sleep study, wear activity monitors for a week, and to maintain a sleep and activity diary over this week. The questionnaire was broad and included questions related to sociodemographics, medical history, quality of life, psychological factors, lifestyle factors, spinal pain, respiratory, sleep, activity and work factors. Physical assessments included anthropometry, blood pressure, back muscle endurance, tissue sensitivity, lung function, airway reactivity, allergic status, 3D facial photographs, cognitive function, and overnight polysomnography. Describing the prevalence of these health issues and behaviours in young adulthood will enable better recognition of the issues and planning of health care resources. Providing a detailed description of the phenotype of these issues will provide valuable information to help educate health professionals of the needs of young adults. Understanding the life-course risk factors of health issues and behaviours in young adulthood will have important health planning implications, supporting the development of targeted interventions to improve current health status and reduce the onset and development of further ill-health across adulthood.
... Most previous epidemiological studies on asthma have focused on preschool-or school-age children (3)(4)(5). However, as symptoms of atopic disease appear early in life (6), important risk factors may be missed when participants are preschool-age or older. Moreover, it may be difficult to eliminate the causal relationship between early environmental exposure and disease in case-control and cross-sectional studies. ...
Article
Symptoms of atopic disease start early in human life. Predicting risk for childhood asthma by early-life exposure would contribute to disease prevention. A birth cohort study was conducted to investigate early-life risk factors for childhood asthma and to develop a predictive model for the development of asthma. National representative samples of newborn babies were obtained by multistage stratified systematic sampling from the 2005 Taiwan Birth Registry. Information on potential risk factors and children's health was collected by home interview when babies were 6 months old and 5 years old, respectively. Backward stepwise regression analysis was used to identify the risk factors for childhood asthma for predictive models that were used to calculate the probability of childhood asthma. A total of 19,192 children completed the study satisfactorily. Physician diagnosed-asthma was reported in 6.6% of 5-year-old children. Pre-pregnancy factors (parental atopy and socioeconomic status), perinatal factors (place of residence, exposure to indoor mold and painting/renovations during pregnancy), and postnatal factors (maternal postpartum depression and presence of atopic dermatitis before 6 months of age) were chosen for the predictive models, and the highest predicted probability of asthma in 5-year-old children was 68.1% in boys and 78.1% in girls; the lowest probability in boys and girls was 4.1% and 3.2%, respectively. This investigation provides a technique for predicting risk of childhood asthma that can be used to developing a preventive strategy against asthma. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
... It has been proposed that prenatal and postnatal environmental insults during critical periods in early life have the potential to affect subsequent development of the respiratory system and, more specifically, susceptibility to asthma and poor lung function. 5,6 In this issue of The Journal, de Korte-de Boer et al relate postnatal growth rate to wheezing up to 3 years of age among 566 children participating in the LucKi population-based birth cohort. 7 SDS for weight, height, and body mass index (BMI) at each follow-up age were determined, and relative growth rate for each growth characteristic was calculated over 3 time periods: between 1 and 7 months, between 7 and 14 months, and between 2 and 3 years of age, using the difference between the SDS at 2 time points. ...
... Viral infections are well recognized as risk factors for asthma [39][40][41][42][43][44][45] and may cause up to 60% of asthma exacerbations [46], although it is not clear if the viruses are causal, impacting and modifying the growth and development of the immune system, or if viral infection agitates and initiates symptoms in a genetically susceptible individual with impaired lung function or a combination of the two [44,47]. The 'two-hit' hypothesis has been postulated, whereby viral infections promote asthma mainly in children already predisposed to getting asthma [44]. ...
Article
Purpose of review: Understanding the mechanisms involved in the development of asthma and allergic diseases is expanding, due in part to sequencing advances that have led to the identification of new viral strains such as human rhinovirus strain C (HRV-C) and the human microbiome project. Recent findings: Recent studies have identified new ways in which viral and microbial exposures in early life interact with host genetic background/variants to modify the risk for developing asthma and allergic diseases. Recent research suggests that HRV-C is the main pathogenic agent associated with infant wheeze, hospitalizations and likely the subsequent development of asthma. Pulmonary He MRI suggests that HRV infection in early childhood and subsequent immune responses initiate airway remodeling. Numerous studies of the microbiome indicate that intestinal and airway microbiome diversity and composition contribute to the cause of asthma and allergic diseases. Summary: Susceptibility to asthma and allergic diseases is complex and involves genetic variants and environmental exposures (bacteria, viruses, smoking, and pet ownership), alteration of our microbiome and potentially large-scale manipulation of the environment over the past century.
... HR: Hazard ratio ISAAC: International Study of Asthma and Allergies in Childhood MAS-90: Multicenter Allergy Study A family history of allergic disease as a surrogate for genetic predisposition, 4 indicative early symptoms, and sensitization patterns seem to be strong predictors of asthma in childhood and early school age. [5][6][7][8][9][10] Both their long-term effects and the role of the social family background on asthma in adolescence and early adulthood have rarely been examined in prospective studies. 11,12 Pregnancy and postnatal tobacco smoke exposure have been shown to trigger asthma-like symptom patterns (eg, wheezy bronchitis 13 ), but its harmful influence on asthma development and aeroallergen sensitization remains equivocal. ...
Article
The lack of longitudinal data analyses from birth to adulthood is hampering long-term asthma prevention strategies. We aimed to determine early-life predictors of asthma incidence up to age 20 years in a birth cohort study by applying time-to-event analysis. In 1990, the Multicenter Allergy Study included 1314 newborns in 5 German cities. Children were evaluated from birth to age 20 years at 19 time points. Using a Cox regression model, we examined the associations between 36 early-life factors and onset of asthma based on a doctor's diagnosis or asthma medication (primary outcome), typical asthma symptoms, or allergic asthma (including positive IgE measurements). Response at 20 years was 71.6%. Two hundred eighteen subjects met the primary outcome criteria within 16,257 person years observed. Asthma incidence was lower in participants who were vaccinated (measles, mumps, and rubella vaccine/tick-borne encephalitis vaccine/BCG vaccine: adjusted hazard ratio [HR], 0.66 [95% CI, 0.47-0.93]). Up to age 20 years, asthma incidence was higher in subjects who had parents with allergic rhinitis (adjusted HR, 2.24 [95% CI, 1.67-3.02]), started day care early or late (before 18 months: adjusted HR, 1.79 [95% CI, 1.03-3.10]; after 3 years: adjusted HR, 1.64 [95% CI, 0.96-2.79]), had mothers who smoked during pregnancy (adjusted HR, 1.79 [95% CI, 1.20-2.67]), had poor parents (adjusted HR, 1.55 [95% CI, 1.09-2.22]), and had parents with asthma (adjusted HR, 1.65 [95% CI, 1.17-2.31]). Not associated with asthma were aspects of diet and breast-feeding, pet ownership, presence of older siblings, and passive smoking. Parental asthma and nasal allergy increase asthma incidence in offspring up to adulthood. Avoiding tobacco smoke exposure during pregnancy, receiving vaccinations in early childhood, and starting day care between 1.5 and 3 years of age might prevent or delay the development of asthma.
... Thus, a direct activation of PPARs does not appear to be likely. Keep in mind though, that high weight phthalates like DiNP and DiDP are likely to partition to the particle phase rather than the gas phase (Schossler et al., 2011), suggesting uneven pulmonary deposition and higher concentrations of particles and thus phthalates in some regions than others (seeKim et al., 2010), with genetic predispositions and environmental exposures in early life as the major identified risk factors for asthma development (Sly, 2011). There are several phenotypes of asthma, including allergic, non-allergic and intrinsic asthma, and the cellular and molecular pathways involved in the development and pathogenesis of these different asthma phenotypes differs (Kim et al., 2010 ). ...
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Due to their extensive use as plasticisers in numerous consumer products, phthalates have become ubiquitous environmental contaminants. An increasing number of epidemiological studies suggest that exposure to phthalates may be associated with worsening or development of airway diseases. Peroxisome Proliferation Activated Receptors (PPAR)s, identified as important targets for phthalates in early studies in rodent liver, have been suggested as a possible mechanistic link. In this review we discuss the likelihood of an involvement of PPARs in asthma development and exacerbation due to pulmonary phthalate exposure. First, we go through the literature on indoor air levels of phthalates and pulmonary phthalate kinetics. These data are then used to estimate the pulmonary phthalate levels due to inhalation exposure. Secondly, the literature on phthalate-induced activation or modulation of PPARs is summarized. Based on these data, we discuss whether pulmonary phthalate exposure is likely to cause PPAR activation, and if this is a plausible mechanism for adverse effects of phthalates in the lung. It is concluded that the pulmonary concentrations of some phthalates may be sufficient to cause a direct activation of PPARs. Since PPARs mainly mediate anti-inflammatory effects in the lungs, a direct activation is not a likely molecular mechanism for adverse effects of phthalates. However, possible modulatory effects of phthalates on PPARs deserve further investigation, including partial antagonist effects and/or cross talk with other signalling pathways. Moreover other mechanisms, including interactions between phthalates and other receptors, could also contribute to possible adverse pulmonary effects of phthalates.
... The concept that lung events occurring early in life may have a permanent impact on adult health has drawn many efforts to better understand the mechanisms regulating early life responses to pulmonary insults. In particular, there is great interest in the interactions among genetic susceptibility, environmental exposures and infections that occur in early infancy and how these can affect adult health (Henderson and Warner, 2012;Sly, 2011;Svanes et al., 2010). ...
... The prevalence of asthma has increased constantly in recent decades [1][2][3] and different factors have been implicated in its aetiology. Although genetic factors are important determinants of asthma [4], exposures to certain environmental factors play an essential role in the phenotypic expression of this condition [5,6] thus contributing substantially to the risk of its development [7]. ...
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Background Studies have shown diverse strength of evidence for the associations between air pollutants and childhood asthma, but these associations have scarcely been documented in the early life. The purpose of this study was to evaluate the impacts of various air pollutants on the development of asthma phenotypes in the first year of life. Methods Adjusted odds ratios were estimated to assess the relationships between exposures to air pollutants and single and multi-dimensional asthma phenotypes in the first year of life in children of the EDEN mother-child cohort study (n = 1,765 mother-child pairs). The Generalized Estimating Equation (GEE) model was used to determine the associations between prenatal maternal smoking and in utero exposure to traffic-related air pollution and asthma phenotypes (data were collected when children were at birth, and at 4, 8 and 12 months of age). Adjusted Population Attributable Risk (aPAR) was estimated to measure the impacts of air pollutants on health outcomes. Results In the first year of life, both single and multi-dimensional asthma phenotypes were positively related to heavy parental smoking, traffic-related air pollution and dampness, but negatively associated with contact with cats and domestic wood heating. Adjusted odds ratios (aORs) for traffic-related air pollution were the highest [1.71 (95% Confidence Interval (CI): 1.08-2.72) for ever doctor-diagnosed asthma, 1.44 (95% CI: 1.05-1.99) for bronchiolitis with wheezing, 2.01 (95% CI: 1.23-3.30) for doctor-diagnosed asthma with a history of bronchiolitis]. The aPARs based on these aORs were 13.52%, 9.39%, and 17.78%, respectively. Results persisted for prenatal maternal smoking and in utero exposure to traffic-related air pollution, although statistically significant associations were observed only with the asthma phenotype of ever bronchiolitis. Conclusions After adjusting for potential confounders, traffic-related air pollution in utero life and in the first year of life, had a greater impact on the development of asthma phenotypes compared to other factors.
... In our study we found a trend toward an increased impact of air pollution on respiratory morbidity in infants with premorbid lung mechanics, reduced lung growth, and increased airway inflammation without statistically significant interaction tests. The independent involvement of several lung function parameters reflecting different aspects of lung development highlights the complex interaction between lung development, airway growth, and immune maturation on one side, and environmental triggers, respiratory viruses, and resulting symptoms on the other side (42). ...
Article
Rationale: There is increasing evidence that short-term exposure to air pollution has a detrimental effect on respiratory health, but data from healthy populations, particularly infants, are scarce. Objectives: To assess the association of air pollution with frequency and severity of respiratory symptoms and infections measured weekly in healthy infants. Methods: In a prospective birth cohort of 366 infants of unselected mothers, respiratory health was assessed weekly by telephone interviews during the first year of life (19,106 total observations). Daily mean levels of particulate matter (PM10), nitrogen dioxide (NO2), and ozone (O3) were obtained from local monitoring stations. We determined the association of the preceding week's pollutant levels with symptom scores and respiratory tract infections using a generalized additive mixed model with an autoregressive component. In addition, we assessed whether neonatal lung function influences this association and whether duration of infectious episodes differed between weeks with normal PM10 and weeks with elevated levels. Measurements and main results: We found a significant association between air pollution and respiratory symptoms, particularly in the week after respiratory tract infections (risk ratio, 1.13 [1.02-1.24] per 10 μg/m(3) PM10 levels) and in infants with premorbid lung function. During times of elevated PM10 (>33.3 μg/m(3)), duration of respiratory tract infections increased by 20% (95% confidence interval, 2-42%). Conclusions: Exposure to even moderate levels of air pollution was associated with increased respiratory symptoms in healthy infants. Particularly in infants with premorbid lung function and inflammation, air pollution contributed to longer duration of infectious episodes with a potentially large socioeconomic impact.
... Since PM affects the growth and development of the embryo/fetus, it is not surprising that infants represent a particularly susceptible population to the effects of PM as they take in more air per body weight, their lungs are still developing (i.e., at birth only 6.7-17.5% of the alveoli are formed [40]), and they have immature immune systems. One of the main risk factors for adult asthma is early life insults to the lung (both structurally and immunologically) brought upon by environmental exposures [41]. Because of this, there has been a surge in the number of studies attempting to understand the role of environmental factors (i.e., particulate pollution or respiratory tract viral infections) in determining risk to develop asthma/wheeze and other child respiratory health concerns ( Figure 2A). ...
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Article
The health impacts of airborne particulate matter (PM) are of global concern, and the direct implications to the development/exacerbation of lung disease are immediately obvious. Most studies to date have sought to understand mechanisms associated with PM exposure in adults/adult animal models; however, infants are also at significant risk for exposure. Infants are affected differently than adults due to drastic immaturities, both physiologically and immunologically, and it is becoming apparent that they represent a critically understudied population. Highlighting our work funded by the ONES award, in this review we argue the understated importance of utilizing infant models to truly understand the etiology of PM-induced predisposition to severe, persistent lung disease. We also touch upon various mechanisms of PM-mediated respiratory damage, with a focus on the emerging importance of environmentally persistent free radicals (EPFRs) ubiquitously present in combustion-derived PM. In conclusion, we briefly comment on strengths/challenges facing current PM research, while giving perspective on how we may address these challenges in the future.
... Viral infections are well recognized as an environmental risk factor for both the development of asthma and asthma exacerbations, [15][16][17][18][19][20][21] although it is not clear whether viruses are causal, affecting and modifying the growth and development of the immune system, or whether the relationship is indicative of a susceptible subject with impaired lung function and innate immune responses or a combination of the two. 20,22,23 The ''2-hit'' hypothesis has been postulated, whereby viral infections promote asthma mainly in predisposed children. ...
Article
Background: The innate immune system is essential for host survival because of its ability to recognize invading pathogens and mount defensive responses. Objectives: We sought to identify genetic associations of innate immunity genes with atopy and asthma and interactions with early viral infections (first 12 months of life) in a high-risk birth cohort. Methods: Three Canadian family-based studies and 1 Australian population-based case-control study (n = 5565) were used to investigate associations of 321 single nucleotide polymorphisms (SNPs) in 26 innate immunity genes with atopy, asthma, atopic asthma, and airway hyperresponsiveness. Interactions between innate immunity genes and early viral exposure to 3 common viruses (parainfluenza, respiratory syncytial virus, and picornavirus) were examined in the Canadian Asthma Primary Prevention Study by using both an affected-only family-based transmission disequilibrium test and case-control methods. Results: In a joint analysis of all 4 cohorts, IL-1 receptor 2 (IL1R2) and Toll-like receptor 1 (TLR1) SNPs were associated with atopy after correction for multiple comparisons. In addition, an NFKBIA SNP was associated with atopic asthma. Six SNPs (rs1519309 [TLR3], rs740044 [ILIR2], rs4543123 [TLR1], rs5741812 [LBP], rs917998 [IL18RAP], and rs3136641 [NFKBIB]) were significant (P < .05, confirmed with 30,000 permutations) in both the combined analysis of main genetic effects and SNP-virus interaction analyses in both case-control and family-based methods. The TLR1 variant (rs4543123) was associated with both multiple viruses (respiratory syncytial virus and parainfluenza virus) and multiple phenotypes. Conclusion: We have identified novel susceptibility genes for asthma and related traits and interactions between these genes and early-life viral infections.
... (42) Exposure to air pollution may influence immune programming and, together with a genetic predisposition, may cause immunological diseases such as asthma. (43) Although knowledge of changes in the immune system of neonates after maternal smoke exposure during pregnancy has existed for some time, (44)(45)(46) data on systemic inflammation in the mother and alteration in the neonatal immune system upon maternal exposure to outdoor air pollution have only recently been published. In one study from Pennsylvania, authors measured blood concentration of Creactive protein (CRP) in 1,696 women before the 22 nd week of gestation and estimated exposure during the previous 20 days to air pollution from maternal ZIP codes. ...
Article
Abstract There is increasing evidence of the adverse impact of prenatal exposure to air pollution. This is of particular interest, as exposure during pregnancy-a crucial time span of important biological development-may have long-term implications. The aims of this review are to show current epidemiological evidence of known effects of prenatal exposure to air pollution and present possible mechanisms behind this process. Harmful effects of exposure to air pollution during pregnancy have been shown for different birth outcomes: higher infant mortality, lower birth weight, impaired lung development, increased later respiratory morbidity, and early alterations in immune development. Although results on lower birth weight are somewhat controversial, evidence for higher infant mortality is consistent in studies published worldwide. Possible mechanisms include direct toxicity of particles due to particle translocation across tissue barriers or particle penetration across cellular membranes. The induction of specific processes or interaction with immune cells in either the pregnant mother or the fetus may be possible consequences. Indirect effects could be oxidative stress and inflammation with consequent hemodynamic alterations resulting in decreased placental blood flow and reduced transfer of nutrients to the fetus. The early developmental phase of pregnancy is thought to be very important in determining long-term growth and overall health. So-called "tracking" of somatic growth and lung function is believed to have a huge impact on long-term morbidity, especially from a public health perspective. This is particularly important in areas with high levels of outdoor pollution, where it is practically impossible for an individual to avoid exposure. Especially in these areas, good evidence for the association between prenatal exposure to air pollution and infant mortality exists, clearly indicating the need for more stringent measures to reduce exposure to air pollution.
... Strong evidence supports the concept that asthma in children has its origin within the first year of postnatal life [1]. Exposure to environmental contaminants, such as air pollutants and aeroallergens, during this period of rapid postnatal lung development, is thought to be a causative factor in the progression of asthma symptoms (from wheeze in infants to asthma in young children) [2][3][4][5][6][7]. ...
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Article
The risks for infants and young children receiving inhaled corticosteroid (ICS) therapy are largely unknown. Recent clinical studies indicate that ICS therapy in pre-school children with symptoms of asthma result in decreased symptoms without influencing the clinical disease course, but potentially affect postnatal growth and development. The current study employs a primate experimental model to identify the risks posed by ICS therapy. To (1) establish whether ICS therapy in developing primate lungs reverses pulmonary pathobiology associated with allergic airway disease (AAD) and (2) define the impact of ICS on postnatal lung growth and development in primates. Infant rhesus monkeys were exposed, from 1 through 6 months, to filtered air (FA) with house dust mite allergen and ozone using a protocol that produces AAD (AAD monkeys), or to FA alone (Control monkeys). From three through 6 months, the monkeys were treated daily with ICS (budesonide) or saline. Several AAD manifestations (airflow restrictions, lavage eosinophilia, basement membrane zone thickening, epithelial mucin composition) were reduced with ICS treatment, without adverse effects on body growth or adrenal function; however, airway branching abnormalities and intraepithelial innervation were not reduced. In addition, several indicators of postnatal lung growth and differentiation: vital capacity, inspiratory capacity, compliance, non-parenchymal lung volume and alveolarization, were increased in both AAD and Control monkeys that received ICS treatment. Incomplete prevention of pathobiological changes in the airways and disruption of postnatal growth and differentiation of airways and lung parenchyma in response to ICS pose risks for developing primate lungs. These responses also represent two mechanisms that could compromise ICS therapy's ability to alter clinical disease course in young children.
Chapter
Gestation and early life are highly susceptible to epigenetic alterations, as the fetal epigenome is undergoing large‐scale remodeling, including DNA demethylation and remethylation, which are followed by tissue‐specific methylation as cells undergo fate decisions. If these epigenetic changes are disrupted, the disruption may potentiate the development of disease later in life. This chapter introduces the use of epigenetic measurements as biomarkers of maternal exposure and their links to later health outcomes in the offspring. Further, it goes into the current state of the research across diverse environmental exposures such as to air pollution, metals, persistent organic pollutants, and nutrition. All in all, understanding the epigenetic effects of prenatal exposures may allow us to better assess the risk of adverse outcomes during pregnancy and later childhood diseases, as well as to inform strategies designed to prevent or reduce the impact of environmental exposure on women and children.
Article
Objective Some recent studies suggest that maternal prenatal stress (MPS) increases allergic diseases in the children. However, knowledge on this issue in Asian children are lacking. We investigated the association between MPS and the risks of wheeze and asthma in Japanese infants aged 16–24 months. Methods The present subjects were 763 Japanese mother–child pairs. The first, second, and third surveys based on self-administered questionnaires were performed during pregnancy, between 2 and 9 months postpartum, and from 16 to 24 months postpartum, respectively. Data on MPS was obtained in the first survey, using the Stress Inventory (SI), which constructs 12 specific behavioral patterns as response styles to stressors. Data on wheeze and asthma was obtained in the third survey, where wheeze was based on the International Study of Asthma and Allergies in Childhood criteria and asthma was based on doctors' diagnosis. Results There were 169 infants with wheeze (22.1%) and 33 infants with asthma (4.3%), at the time of the third survey. Multiple logistic regression analyses found that a maternal behavioral pattern characterized by chronic irritation and anger was associated with the risk of childhood asthma (adjusted odds ratio [OR] = 1.56, 95% confidence interval [CI]: 1.11 to 2.22), but not wheeze (adjusted OR = 1.02, 95%CI: 0.88 to 1.19), while there was no appreciable association between the other SI scales and the risk of childhood wheeze or asthma. Conclusions The results partly supported the hypothesis that MPS might increase the risk of asthma in their infants in Japanese.
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Introduction The first thousand days of life are a critical stage for the development of respiratory and immune systems. Many events in this period may be associated with wheezing in childhood. Objective: This study aimed to investigate the association between early life determinants and wheezing in children aged 6–7 years. Materials and Methods Population-based case-control study using early-life related questions. We used the International Study of Asthma and Allergies in Childhood questionnaire to assess wheezing symptoms. Multiple logistic regressions were performed according to a hierarchical framework, considering the complex dynamic of wheezing/asthma and potential interaction between different levels of determination. Results A total of 820 children were included, from which 162 reported wheezing symptoms (19.7%). Multivariable analysis identified socioeconomic conditions (OR 2.08, 95% CI 1.08–4.00), family history of asthma (OR 2.28, 95% CI 1.37–3.75), vaginal discharge that required treatment during pregnancy (OR 1.68, 95% CI 1.00–2.83), neonatal hyperbilirubinemia (OR 2.00, 95% CI 1.17–3.42), anemia and intestinal parasitosis in the first two years (OR 2.28, 95% CI 1.22–4.25; OR 1.72, 95% CI 1.02–2.92, respectively) independently associated to wheezing at 6–7 years. Intended pregnancy was associated with reduced wheezing (OR 0.47, 95% CI 0.28–0.77). Conclusions Several factors were associated with wheezing in childhood. Considering that intended pregnancy reduced wheezing and other associated exposures are considered modifiable, these findings may guide the planning of strategies to decrease the susceptibility to asthma symptoms in childhood.
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Introdução: Os primeiros 1000 dias de vida de uma criança, período desde a concepção até o final dosegundo ano, são considerados críticos para o desenvolvimento dos sistemas respiratório e imunológico. Muitos fatores ocorridos nesse período podem estar associados ao risco de asma na infância. Objetivo: Condensar evidências sobre fatores de risco e proteção para asma infantil e/ ou sibilância ocorridos nos primeiros 1000 dias de vida. Método: Foram revisadas as bases de dados MEDLINE, CINAHL e SCOPUS. Foram incluídas revisões sistemáticas com meta-análise, ou meta-análise de estudos observacionais e de intervenção sobre fatores de risco ou proteção para asma infantil/sibilância, enfatizando os primeiros 1000 dias de vida. A qualidade dos estudos foi avaliada pela ferramenta Assess Systematic Reviews. Odds ratio, intervalos de confiança e homogeneidade entre os estudos foram analisados. Resultados: Trinta e cinco estudos preencheram os critérios de inclusão, com boa qualidade metodológica. Foram identificados como fatores de risco para asma e/ou sibilância na infância: história parental de asma, ganho de peso materno durante a gestação, infecções urogenitais, estresse psicológico, tabagismo, parto cesárea, prematuridade, peso ao nascer e hiperbilirrubinemia neonatal. A ingestão de óleo de peixe, zinco e vitamina E durante a gestação aparecem como fatores de proteção, bem como amamentação, ingestão de peixe nos dois primeiros anos e vacinação BCG. Conclusão: Diversos comportamentos ou exposições modificáveis podem estar associados à asma e sibilância na infância. O conhecimento sobre estes comportamentos e exposições pode melhorar as estratégias de prevenção precoce, visando garantir um impacto benéfico na saúde respiratória.
Article
Objective The Developmental Origins of Disease hypothesis has spurred increased interest in how prenatal exposures affect lifelong health, while mechanisms such as epigenetics may explain the multigenerational influences on health. Such factors are not well captured within conventional epidemiologic study designs. We explored the feasibility of collecting information on the offspring and grand-offspring of participants in a long-running study. Design The Bogalusa Heart Study is a study, begun in 1973, of life-course cardiovascular health in a semirural population (65% white and 35% black). Main measures Female participants who had previously provided information on their pregnancies were contacted to obtain contact information for their daughters aged 12 and older. Daughters were then contacted to obtain reproductive histories, and invited for a clinic or lab visit to measure cardiovascular risk factors. Results Two hundred seventy-four daughters of 208 mothers were recruited; 81% (223) had a full clinic visit and 19% (51) a phone interview only. Forty-five percent of the daughters were black, and 55% white. Mean and median age at interview was 27, with 15% under the age of 18. The strongest predictors of participation were black race, recent maternal participation in the parent study, and living in or near Bogalusa. Simple correlations for cardiovascular risk factors across generations were between r = 0.19 (systolic blood pressure) and r = 0.39 (BMI, LDL). Conclusion It is feasible to contact the children of study participants even when participants are adults, and initial information on the grandchildren can also be determined in this manner.
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Air pollution is a global health threat and causes millions of human deaths annually. The late onset of respiratory diseases in children and adults due to prenatal or perinatal exposure to air pollutants is emerging as a critical concern in human health. Pregnancy and fetal development stages are highly susceptible to environmental exposure and tend to develop a long-term impact in later life. In this review, we briefly glance at the direct impact of outdoor and indoor air pollutants on lung diseases and pregnancy disorders. We further focus on lung complications in later life with early exposure to air pollutants. Epidemiological evidence is provided to show the association of prenatal or perinatal exposure to air pollutants with various adverse birth outcomes, such as preterm birth, lower birth weight, and lung developmental defects, which further associate with respiratory diseases and reduced lung function in children and adults. Mechanistic evidence is also discussed to support that air pollutants impact various cellular and molecular targets at early life, which link to the pathogenesis and altered immune responses related to abnormal respiratory functions and lung diseases in later life. Keywords: Air pollutants, Polycyclic aromatic hydrocarbon, Particulate matter, Early disease origin, Respiratory diseases
Article
Allergic diseases have been on the rise in many countries over the past few decades and indoor exposure may be a possible cause. An overall investigation of children’s health status and residential indoor air pollutants known or suspected to affect respiratory health was conducted in the homes of primary schoolchildren during winter in Porto, Portugal. In a case-control study (30 case children with asthma and 38 controls) and over a 1-wk monitoring period, air sample collection was conducted in children’s bedrooms for the analysis of 12 volatile organic compounds (VOC), aldehydes, particulate matter (PM)2.5, PM10, bacteria, and fungi. Home exposures to indoor pollutants are similar for children with and without asthma, except for d-limonene. For both groups, most VOC were present at low concentrations (median < 5 µg/m³) and below the respective World Health Organization (WHO) guidelines. Concentrations of PM2.5, PM10, and bacteria were frequently higher than WHO/reference values (80, 25, and 60% of all studied dwellings, respectively). Concentrations of carbon dioxide (CO2) exceeding 1000 ppm were encountered in 60% of the homes. Although this study does not provide evidence of causative factors for asthmatic status, the postulation that poor indoor air quality in homes heightens the risk of allergic symptoms development among children is conceivable. https://www.tandfonline.com/doi/abs/10.1080/15287394.2016.1210548?tab=permissions&scroll=top Copyright © 2018 Informa UK Limited Registered in England & Wales No. 3099067 5 Howick Place | London | SW1P 1WG
Article
Background Asthma is a common pediatric chronic inflammatory airway disease. Respiratory viral infections are frequent infectious triggers for exacerbations of asthma. Objective We sought to determine whether Enterovirus 71 (EV71), a ubiquitous virus that causes systemic inflammatory responses in children but is not a known respiratory pathogen, can also serve as an infectious trigger for asthma. Methods Specific EV71 IgE and IgM antibodies (Abs), total serum IgE, and IL-2 and IL-4 cytokine levels in serum of asthmatic and non-asthmatic children (N = 42, ages 5–19; N = 35, ages 1–20, respectively) were measured (ELISA). Results Asthmatic children had higher EV71 IgE Ab levels than non-asthmatic (P < 0.001). Non-asthmatic children had significantly higher EV71 IgM Ab levels than asthmatic (P < 0.001). Despite low serum IgE levels of non-asthmatic, compared with asthmatic (P < 0.001), the non-asthmatic children produced significantly more IL-2 and IL-4 than asthmatic (P < 0.001; P < 0.001). The ages of the asthmatics, but not the non-asthmatics had a significant effect on the levels of EV 71 IgE Abs (P = 0.02; P = 0.356). A test of difference between these two slopes was significant. However, the ages of the non-asthmatic, but not the asthmatic children had a significant effect on the levels of EV 71 IgM Abs; a test of difference between these two slopes was significant. Conclusions Increased specific EV71 IgE Ab responses may indicate that EV71 infection may also be an infectious trigger in asthma. However, the role of specific EV71 IgM Abs, Th2 cytokines, and age in non-asthmatic children should be further studied.
Article
BACKGROUND: Exposure to tobacco smoke in African infants has not been well studied, despite the high burden of childhood respiratory disease in these communities. OBJECTIVE: To investigate the prevalence of antenatal and early life tobacco smoke exposure and associations with infant birth outcomes in an African birth cohort, the Drakenstein Child Health Study. METHODS: Self-report questionnaires assessing maternal and household smoking were administered. Maternal and infant urine cotinine testing was conducted antenatally, at birth and at 6–10 weeks of life to measure tobacco smoke exposure. Multivariate regression models explored the associations between exposure to smoke and infant birth outcomes. RESULTS: Of 789 pregnant women included, 250 (32%) were active smokers on cotinine testing. At birth and at 6–10 weeks of life, respectively 135/241 (56%) and 154/291 (53%) infants had urine cotinine levels indicating tobacco smoke exposure. Household smoking was prevalent and was associated with positive infant cotinine test results. Antenatal maternal smoking was associated with decreased infant birthweight-for-age Z-score (0.3, 95%CI 0.1–0.5). CONCLUSION: Antenatal and early life tobacco smoke exposure is highly prevalent in this community, and may impact on birth outcomes and subsequent child health. Smoking cessation interventions are urgently needed to reduce tobacco smoke exposure in African communities.
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We investigated the prevalence of asthma and factors related to asthma development in schoolchildren aged 6 to 14, living in central and peripheral areas of the city of Montes Claros, Minas Gerais and who were registered with the Family Health Strategy program. Initially, a standard written questionnaire, based on ISAAC (International Study of Asthma and Allergies in Childhood), was administered to collect personal data, information regarding income, asthma prevalence, allergic rhinitis and eczema (N = 1,131). Secondly, a case-control study was performed by grouping the patients as either asthmatic (A; N = 172) or non-asthmatic (NA; N = 379). Potential factors associated with the occurrence of asthma were evaluated using the complementary questionnaire from ISAAC phase II. Skin tests for immediate hypersensitivity (STIH) and parasitological tests were also performed. The odds ratio, estimated by multivariate analysis, indicated that asthma cases were related to kindergarten attendance, household smoking, family history of asthma, rhinitis and positive STIH. It was concluded that, in the studied population, the prevalence of asthma was related to genetic predisposition, in addition to individual history, social demographics, exposure to pollutants such as tobacco smoke and a positive response to allergy testing.
Article
We studied the effects of exposure to multiple indoor air pollutants on allergic and respiratory health. The elements to consider for studying this phenomenon were, on one hand, the correlations between pollutants and, on the other hand, their potentially additive and synergistic effects. The analyses conducted in adults have shown that the prevalence of allergic and respiratory symptoms was higher in the dwellings highly polluted by many volatile organic compounds (VOCs). The observed health effects of VOCs were higher when the dwelling was also polluted by pet allergens. The analyses conducted in children have shown the difficulty to separate the effects of pollutants. However, we showed that poor air quality in schools was associated with an increased risk of respiratory symptoms. Some analyses on the total exposure to air pollution have implicated the combined effects of physico-chemical pollutants on respiratory function of children. The study of multi-pollution allowed to highlight the deleterious effect of some pollutants combined with other substances, although their individual effects were not detected. Our studies showed that associations were observed at concentrations lower than those observed in toxicological studies, involving the additive and synergistic effects between pollutants. Our results also provided some elements about the mechanism of action of indoor chemical pollutants on respiratory health, including their synergistic effects with allergens. In conclusion, our results showed combined effects between various pollutants on the respiratory health of adults and children.
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Even though bronchiolitis is a disease that has been recognized for many years, there are still few therapeutic strategies beyond supportive therapies. Bronchiolitis is the most frequent cause of hospital admission in children less than 1 year of age. The incidence is estimated to be about 150° million cases a year worldwide, and 2-3% of these cases require hospitalization. It is acknowledged that viruses cause bronchiolitis, but most of the studies focus on RSV. The RSV causes a more severe form of bronchiolitis in children with risk factors including prematurity, cardiovascular disease and immunodeficiency. Other viruses involved in causing bronchiolitis include RV, hMPV, hBoV and co-infections. The RV seems to be associated with a less severe acute disease, but there is a correlation between the early infection and subsequent wheezing bronchitis and asthma in later childhood and adulthood. The supportive therapies used are intravenous fluids and oxygen supplement administered by nasal cannula or CPAP in most complicated patients. Additional pharmacological therapies include epinephrine, 3% hypertonic saline and corticosteroids. The Epinephrine seems to have the greatest short-term benefits and reduces the need of hospital admission, whereas hypertonic saline and corticosteroids seem to reduce the length of hospital stay.As bronchiolitis is such a prevalent disease in children and RV seems to play an important role, perhaps more studies should center around the RV's contribution to the initial disease and following pathology.
Article
Interest in the contribution of changes in lung development during early life to subsequent respiratory morbidity is increasing. Most evidence of an association between adverse intrauterine factors and structural effects on the developing lung is from animal studies. Such evidence has been augmented by epidemiological studies showing associations between insults to the developing lung during prenatal and early postnatal life and adult respiratory morbidity or reduced lung function, and by physiological studies that have elucidated mechanisms underlying these associations. The true effect of early insults on subsequent respiratory morbidity can be understood only if the many prenatal and postnatal factors that can affect lung development are taken into account. Adverse factors affecting lung development during fetal life and early childhood reduce the attainment of maximum lung function and accelerate lung function decline in adulthood, initiating or worsening morbidity in susceptible individuals. In this Review, we focus on factors that adversely affect lung development in utero and during the first 5 years after birth, thereby predisposing individuals to reduced lung function and increased respiratory morbidity throughout life. We focus particularly on asthma and COPD.
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Elevated levels of combustion-derived particulate matter (CDPM) are a risk factor for the development of lung diseases such as asthma. Studies have shown that CDPM exacerbates asthma, inducing acute lung dysfunction and inflammation; however, the impact of CDPM exposure on early immunological responses to allergens remains unclear. To determine the effects of early-life CDPM exposure on allergic asthma development in infants, we exposed infant mice to CDPM and then induced a mouse model of asthma using house dust mite (HDM) allergen. Mice exposed to CDPM+HDM failed to develop a typical asthma phenotype including airway hyper-responsiveness, T-helper type 2 (Th2) inflammation, Muc5ac expression, eosinophilia, and HDM-specific immunoglobulin (Ig) compared with HDM-exposed mice. Although HDM-specific IgE was attenuated, total IgE was twofold higher in CDPM+HDM mice compared with HDM mice. We further demonstrate that CDPM exposure during early life induced an immunosuppressive environment in the lung, concurrent with increases in tolerogenic dendritic cells and regulatory T cells, resulting in the suppression of Th2 responses. Despite having early immunosuppression, these mice develop severe allergic inflammation when challenged with allergen as adults. These findings demonstrate a mechanism whereby CDPM exposure modulates adaptive immunity, inducing specific antigen tolerance while amplifying total IgE, and leading to a predisposition to develop asthma upon rechallenge later in life.Mucosal Immunology advance online publication, 30 October 2013; doi:10.1038/mi.2013.88.
Article
Parmi les principaux facteurs du macro-environnement (extérieur à l’organisme) qui influent pendant la vie intra-utérine sur la probabilité d’être atteint d’asthme et d’allergies plus tard dans la vie, on inclut le tabagisme passif, la nutrition maternelle, la prise de paracétamol, la vitamine D, l’exposition aux allergènes, les expositions aux autres irritants atmosphériques que la fumée de tabac tels que les polluants atmosphériques de l’extérieur et l’intérieur des locaux et plus récemment le stress.
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Prenatal and early life home environment might be related to children’s asthma or allergic diseases later in life. A cross-sectional epidemiological study was designed and a questionnaire survey was performed in 3700 preschool children in urban areas in Taiyuan, Shanxi Province, China. Questions on children’s asthma and allergic diseases from the International Study on Asthma and Allergies in Childhood (ISAAC) were integrated with questions on home environment from the Swedish Dampness in Buildings and Health (DBH) study, appropriately modified for Chinese life habits. By multivariate regression analyses controlling for age, gender, heredity, location in urban/suburban or rural areas, environmental tobacco smoke (ETS) and breastfeeding, we found that home new furniture (HNF) before birth (referring to 1 year before pregnancy and during pregnancy) was positively associated with wheezing ever (odds ratio(OR) 1.23 with 95%CI of 1.03–1.48) and wheezing last 12 months (1.24,1.00–1.54), allergic rhinitis (AR) (1.26,1.06–1.51), and eczema (1.42,1.01–1.99). HNF between 0–1 years old was also positively associated with wheezing last 12 months. Home new decoration (HND) during 0–1 years old was positively associated with AR symptoms and eczema symptoms, more in the last 12 months. Stronger positive associations were found for signs of home mold and dampness with almost all children’s asthmatic and allergic symptoms (OR ranging from 1.23–1.85, P<0.05). By mutual adjustment between HNF before children’s birth and home mold or dampness, all the significance remained unchanged. Prenatal HNF and home mold or dampness was independently associated with children’s asthmatic and allergic diseases later in life.
Article
Objective: Currently, in the United States there is a lack of a standardized method to effectively screen school children with undiagnosed or poorly controlled asthma. The purpose of this proof-of-concept study was to assess the use of the American College of Allergy, Asthma, and Immunology's (ACAAI) Asthma Screening Questionnaire to identify elementary school-age children at risk for asthma (undiagnosed) or poorly controlled asthma. Methods: Children in grades 3-5 from one urban and two suburban schools completed ACAAI's 14 question asthma screening questionnaire and had their peak expiratory flow (PEF) measured. Children were considered to have a positive asthma screen and be at risk for having undiagnosed or poorly controlled asthma if they answered 'yes' to more than three questions. Children were referred to a physician if they had a positive asthma screen, a previous history of asthma, or a low PEF. Results: Of the 86 participants, 52 were identified as being at risk for asthma. The number was higher among children attending an urban versus suburban school (p = 0.04). The sensitivity and specificity of the screening questionnaire for identifying asthma risk were 90% and 66%, respectively, when the number of 'yes' responses for a positive screen was increased from three to five of 14 questions. Conclusions: The ACAAI's Asthma Screening Questionnaire identified 52 children at risk for undiagnosed or poorly controlled asthma. Our findings support the need to validate this questionnaire to be used in conjunction with PEFR for identifying elementary school children at risk for asthma.
Article
Background: Respiratory tract viruses are a major environmental risk factor for both the inception and exacerbations of asthma. Genetic defects in Toll-like receptor (TLR) 7-mediated signaling, impaired type I interferon responses, or both have been reported in asthmatic patients, although their contribution to the onset and exacerbation of asthma remains poorly understood. Objective: We sought to determine whether Pneumovirus infection in the absence of TLR7 predisposes to bronchiolitis and the inception of asthma. Methods: Wild-type and TLR7-deficient (TLR7(-/-)) mice were inoculated with the rodent-specific pathogen pneumonia virus of mice at 1 (primary), 7 (secondary), and 13 (tertiary) weeks of age, and pathologic features of bronchiolitis or asthma were assessed. In some experiments infected mice were exposed to low-dose cockroach antigen. Results: TLR7 deficiency increased viral load in the airway epithelium, which became sloughed and necrotic, and promoted an IFN-α/β(low), IL-12p70(low), IL-1β(high), IL-25(high), and IL-33(high) cytokine microenvironment that was associated with the recruitment of type 2 innate lymphoid cells/nuocytes and increased TH2-type cytokine production. Viral challenge of TLR7(-/-) mice induced all of the cardinal pathophysiologic features of asthma, including tissue eosinophilia, mast cell hyperplasia, IgE production, airway smooth muscle alterations, and airways hyperreactivity in a memory CD4(+) T cell-dependent manner. Importantly, infections with pneumonia virus of mice promoted allergic sensitization to inhaled cockroach antigen in the absence but not the presence of TLR7. Conclusion: TLR7 gene defects and Pneumovirus infection interact to establish an aberrant adaptive response that might underlie virus-induced asthma exacerbations in later life.
Article
Components of the innate immune system such as macrophages and dendritic cells are instrumental in determining the fate of immune responses and are, also, among the most sensitive targets of early life environmental alterations including developmental immunotoxicity (DIT). DIT can impede innate immune cell maturation, disrupt tissue microenvironment, alter immune responses to infectious challenges, and disrupt regulatory responses. Dysregulation of inflammation, such as that observed with DIT, has been linked with an increased risk of chronic inflammatory diseases in both children and adults. In this review, we discuss the relationship between early-life risk factors for innate immune modulation and promotion of dysregulated inflammation associated with chronic inflammatory disease. The health risks from DIT-associated inflammation may extend beyond primary immune dysfunction to include an elevated risk of several later-life, inflammatory-mediated diseases that target a wide range of physiological systems and organs. For this reason, determination of innate immune status should be an integral part of drug and chemical safety evaluation.
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Asthma is a complex condition where genetic and environmental interactions occur at critical periods in development. The focus of this review was the role of environmental exposures on asthma causation. Selected studies published in 2010 and 2011 were reviewed to illustrate the challenge in relating environmental exposure(s) on asthma causation and also to focus on some exposures currently thought to be important to asthma pathogenesis. Challenges in understanding how environmental exposures may translate into asthma causation are summarised. Inhaled and ingested exposures are described, including microbial products, swimming pools, diet and antenatal tobacco exposure. A final synthesis summarises what is currently understood about childhood asthma causation and what advice might be given to parents and governments interested in reducing asthma risk.
Article
Background: The natural history of asthma and atopic diseases begins in utero. Studies investigating the influence of foetal exposure to maternal stressful life events during pregnancy (SLEP) on asthma and atopic diseases are lacking. Aim: To test whether the children of mothers who had experienced SLEP are at an increased risk for asthma, atopic eczema and allergic rhinitis. Methods: The association between maternal SLEP (at least one among: divorce, mourning or loss of the job) and the occurrence of asthma and atopic diseases in childhood was studied in a population (n = 3854) of children, aged 3-14 yrs, living in Northern Italy. The parents filled in a standardized questionnaire about the children's health and the events occurred to their mothers during pregnancy. Results: Three hundred and thirty-three (9%) of the mothers experienced SLEP. Their children had a statistically significantly higher lifetime prevalence of wheezing (31.6% vs. 23.1%), asthma (8.9% vs. 5.6%), allergic rhinitis (10.9% vs. 7.3%) and atopic eczema (29.7% vs. 21.1%) than those of mothers without SLEP. After adjusting for potential confounders, the foetal exposure to SLEP was positively associated with wheezing (OR: 1.41, 95% CI: 1.03-1.94), asthma (OR: 1.71, 95% CI: 1.02-2.89), allergic rhinitis (OR: 1.75, 95% CI: 1.08-2.84) and atopic eczema (OR: 1.53, 95% CI: 1.11-2.10). Conclusion: The children of mothers who had experienced SLEP were at a moderately increased risk of having wheezing, asthma, eczema and allergic rhinitis during their childhood. Maternal stress during pregnancy might enhance the expression of asthma and atopic phenotypes in children.
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Sex differences in the biology of different organ systems and the influence of sex hormones in modulating health and disease are increasingly relevant in clinical and research areas. Although work has focused on sex differences and sex hormones in cardiovascular, musculoskeletal, and neuronal systems, there is now increasing clinical evidence for sex differences in incidence, morbidity, and mortality of lung diseases including allergic diseases (such as asthma), chronic obstructive pulmonary disease, pulmonary fibrosis, lung cancer, as well as pulmonary hypertension. Whether such differences are inherent and/or whether sex steroids play a role in modulating these differences is currently under investigation. The purpose of this review is to define sex differences in lung structure/function under normal and specific disease states, with exploration of whether and how sex hormone signaling mechanisms may explain these clinical observations. Focusing on adult age groups, the review addresses the following: 1) inherent sex differences in lung anatomy and physiology; 2) the importance of certain time points in life such as puberty, pregnancy, menopause, and aging; 3) expression and signaling of sex steroid receptors under normal vs. disease states; 4) potential interplay between different sex steroids; 5) the question of whether sex steroids are beneficial or detrimental to the lung; and 6) the potential use of sex steroid signaling as biomarkers and therapeutic avenues in lung diseases. The importance of focusing on sex differences and sex steroids in the lung lies in the increasing incidence of lung diseases in women and the need to address lung diseases across the life span.
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Maternal exposure to tobacco smoke is known to have deleterious effects on the developing fetus, but it has only recently been shown that there may be life-long consequences due to genotoxic damage. Analysis of newborn cord bloods with the GPA somatic mutation assay demonstrates a significant effect of maternal active smoking and suggests that similar mutational induction occurs in mothers who experience only secondary exposure to environmental tobacco smoke (ETS). Moreover, in both cases, mutational induction occurs by the same molecular mechanism, likely chromosome missegregation, resulting in an effective loss of one parental chromosome 4 and duplication of the other. These data also suggest that quitting smoking during pregnancy without actively avoiding secondary ETS exposure is not effective at protecting the unborn child from the genotoxic effects of tobacco smoke.
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Events and exposures in pregnancy can have critical effects on fetal development with lasting implications for subsequent health and disease susceptibility. There is growing interest in how modern environmental changes influence fetal immune development and contribute to the recent epidemic of allergy and other immune disorders. Rising rates of allergic disease in early infancy, together with pre-symptomatic differences in immune function at birth, suggest that antenatal events play a predisposing role in the development of disease. A number of environmental exposures in pregnancy can modify neonatal immune function including diet, microbial exposure and maternal smoking, and there is emerging evidence from animal models that these factors may have epigenetic effects on immune gene expression and disease susceptibility. Furthermore, functional genetic polymorphisms also alter individual vulnerability to the effects of these environmental exposures, highlighting the complexity of gene-environmental interactions in this period. All these observations underscore the need for ongoing research to understand the pathogenesis and rising incidence of disease in the hope of better strategies to reverse this.
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Viral respiratory infections are the most common cause of an acute asthma exacerbation in both children and adults and represent a significant global health burden. An increasing body of evidence supports the hypothesis that these infections cause a greater degree of morbidity in asthmatic subjects than in the healthy population, emphasizing a discrepancy in the antiviral response of asthmatics. In this review we discuss why such a discrepancy might exist, examining the role of the bronchial epithelium as well as the main inflammatory cells, mediators, and molecular pathways that are involved in the immune response. In addition, the potential impact of virus-induced asthma exacerbations on airway remodelling is reviewed and we explore which therapeutic options might be of benefit in preventing the deterioration of asthma control seen following viral infection.
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Traffic-related air pollution has been associated with adverse cardiorespiratory effects, including increased asthma prevalence. However, there has been little study of effects of traffic exposure at school on new-onset asthma. We evaluated the relationship of new-onset asthma with traffic-related pollution near homes and schools. Parent-reported physician diagnosis of new-onset asthma (n = 120) was identified during 3 years of follow-up of a cohort of 2,497 kindergarten and first-grade children who were asthma- and wheezing-free at study entry into the Southern California Children's Health Study. We assessed traffic-related pollution exposure based on a line source dispersion model of traffic volume, distance from home and school, and local meteorology. Regional ambient ozone, nitrogen dioxide (NO(2)), and particulate matter were measured continuously at one central site monitor in each of 13 study communities. Hazard ratios (HRs) for new-onset asthma were scaled to the range of ambient central site pollutants and to the residential interquartile range for each traffic exposure metric. Asthma risk increased with modeled traffic-related pollution exposure from roadways near homes [HR 1.51; 95% confidence interval (CI), 1.25-1.82] and near schools (HR 1.45; 95% CI, 1.06-1.98). Ambient NO(2) measured at a central site in each community was also associated with increased risk (HR 2.18; 95% CI, 1.18-4.01). In models with both NO(2) and modeled traffic exposures, there were independent associations of asthma with traffic-related pollution at school and home, whereas the estimate for NO(2) was attenuated (HR 1.37; 95% CI, 0.69-2.71). Traffic-related pollution exposure at school and homes may both contribute to the development of asthma.
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There is increasing recognition of the importance of early environmental exposures in the development of childhood asthma. Outdoor air pollution is a recognized asthma trigger, but it is unclear whether exposure influences incident disease. We investigated the effect of exposure to ambient air pollution in utero and during the first year of life on risk of subsequent asthma diagnosis in a population-based nested case-control study. We assessed all children born in southwestern British Columbia in 1999 and 2000 (n = 37,401) for incidence of asthma diagnosis up to 34 years of age using outpatient and hospitalization records. Asthma cases were age- and sex-matched to five randomly chosen controls from the eligible cohort. We estimated each individual's exposure to ambient air pollution for the gestational period and first year of life using high-resolution pollution surfaces derived from regulatory monitoring data as well as land use regression models adjusted for temporal variation. We used logistic regression analyses to estimate effects of carbon monoxide, nitric oxide, nitrogen dioxide, particulate matter <or= 10 microm and <or= 2.5 microm in aerodynamic diameter (PM10 and PM2.5), ozone, sulfur dioxide, black carbon, woodsmoke, and proximity to roads and point sources on asthma diagnosis. A total of 3,482 children (9%) were classified as asthma cases. We observed a statistically significantly increased risk of asthma diagnosis with increased early life exposure to CO, NO, NO2, PM10, SO2, and black carbon and proximity to point sources. Traffic-related pollutants were associated with the highest risks: adjusted odds ratio = 1.08 (95% confidence interval, 1.041.12) for a 10-microg/m3 increase of NO, 1.12 (1.071.17) for a 10-microg/m3 increase in NO2, and 1.10 (1.061.13) for a 100-microg/m3 increase in CO. These data support the hypothesis that early childhood exposure to air pollutants plays a role in development of asthma.
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Single nucleotide polymorphisms (SNPs) at chromosome 17q21 confer an increased risk of early-onset asthma. The objective was to study whether 17q21 SNPs modify associations between early respiratory infections and asthma. Association analysis was conducted in 499 children (268 with asthma, median age 11 yrs) from the Epidemiological Study on the Genetics and Environment of Asthma (EGEA). The 12-yr follow-up data were used to assess persistent or remittent asthma in young adulthood. Respiratory infection before 2 yrs of age was assessed retrospectively. For the 12 17q21 SNPs studied, the odds ratios (OR) for association between infection and early-onset asthma (age at onset <or=4 yrs) were higher in carriers of risk genotypes (OR 3.42-6.36) than in noncarriers (OR 1.84-2.44; p-value for interaction 0.02-0.04 for five SNPs). Risk genotypes also increased the association between infection and childhood asthma that remits in adulthood (OR 4.84-7.16 in carriers and 1.74-2.25 in noncarriers; p-value for interaction 0.008-0.05 for 10 SNPs). In children with 17q21 risk genotypes and early-life environmental tobacco smoke (ETS) exposure, associations between infection and asthma were further enhanced. 17q21 genetic variants and early ETS exposure enhance the association between early respiratory infections and early-onset asthma and childhood asthma that remits in adulthood.
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Severe asthma exacerbations in children requiring hospitalization are typically associated with viral infection and occur almost exclusively among atopics, but the significance of these comorbidities is unknown. We hypothesized that underlying interactions between immunoinflammatory pathways related to responses to aeroallergen and virus are involved, and that evidence of these interactions is detectable in circulating cells during exacerbations. To address this hypothesis we used a genomics-based approach involving profiling of PBMC subpopulations collected during exacerbation vs convalescence by microarray and flow cytometry. We demonstrate that circulating T cells manifest the postactivated "exhausted" phenotype during exacerbations, whereas monocyte/dendritic cell populations display up-regulated CCR2 expression accompanied by phenotypic changes that have strong potential for enhancing local inflammation after their recruitment to the atopic lung. Notably, up-regulation of FcepsilonR1, which is known to markedly amplify capacity for allergen uptake/presentation to Th2 effector cells via IgE-mediated allergen capture, and secondarily programming of IL-4/IL-13-dependent IL-13R(+) alternatively activated macrophages that have been demonstrated in experimental settings to be a potent source of autocrine IL-13 production. We additionally show that this disease-associated activation profile can be reproduced in vitro by cytokine exposure of atopic monocytes, and furthermore that IFN-alpha can exert both positive and negative roles in the process. Our findings suggest that respiratory viral infection in atopic children may initiate an atopy-dependent cascade that amplifies and sustains airway inflammation initiated by innate antiviral immunity via harnessing underlying atopy-associated mechanisms. These interactions may account for the unique susceptibility of atopics to severe viral-induced asthma exacerbations.
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To investigate whether filaggrin gene defects, present in up to one in 10 western Europeans and North Americans, increase the risk of developing allergic sensitisation and allergic disorders. Systematic review and meta-analysis. Medline, Embase, ISI Science Citation Index, BIOSIS, ISI Web of Knowledge, UK National Research Register, clinical trials.gov, the Index to Theses and Digital dissertations, and grey literature using OpenSIGLE. Genetic epidemiological studies (family, case-control) of the association between filaggrin gene defects and allergic sensitisation or allergic disorders. Atopic eczema or dermatitis, food allergy, asthma, allergic rhinitis, and anaphylaxis, along with relevant immunological variables relating to the risk of allergic sensitisation as assessed by either positive skin prick testing or increased levels of allergen specific IgE. 24 studies were included. The odds of developing allergic sensitisation was 1.91 (95% confidence interval 1.44 to 2.54) in the family studies and 1.57 (1.20 to 2.07) in the case-control studies. The odds of developing atopic eczema was 1.99 (1.72 to 2.31) in the family studies and 4.78 (3.31 to 6.92) in the case-control studies. Three studies investigated the association between filaggrin gene mutations and allergic rhinitis in people without atopic eczema: overall odds ratio 1.78 (1.16 to 2.73). The four studies that investigated the association between filaggrin gene mutations and allergic rhinitis in people with atopic eczema reported a significant association: pooled odds ratio from case-control studies 2.84 (2.08 to 3.88). An overall odds ratio for the association between filaggrin gene mutations and asthma in people with atopic eczema was 2.79 (1.77 to 4.41) in case-control studies and 2.30 (1.66 to 3.18) in family studies. None of the studies that investigated filaggrin gene mutations and asthma in people without atopic eczema reported a significant association; overall odds ratio was 1.30 (0.7 to 2.30) in the case-control studies. The funnel plots suggested that publication bias was unlikely to be an explanation for these findings. No studies investigated the association between filaggrin gene mutations and food allergy or anaphylaxis. Filaggrin gene defects increase the risk of developing allergic sensitisation, atopic eczema, and allergic rhinitis. Evidence of the relation between filaggrin gene mutations and atopic eczema was strong, with people manifesting increased severity and persistence of disease. Filaggrin gene mutations also increased the risk of asthma in people with atopic eczema. Restoring skin barrier function in filaggrin deficient people in early life may help prevent the development of sensitisation and halt the development and progression of allergic disease.
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Complex cellular functions within immunoinflammatory cascades are conducted by networks of interacting genes. In this study, we employed a network modeling approach to dissect and interpret global gene expression patterns in allergen-induced Th cell responses that underpin human atopic disease. We demonstrate that a subnet of interconnected genes enriched for Th2 and regulatory T cell-associated signatures plus many novel genes is hardwired into the atopic response and is a hallmark of atopy at the systems level. We show that activation of this subnet is stabilized via hyperconnected "hub" genes, the selective disruption of which can collapse the entire network in a comprehensive fashion. Finally, we investigated gene expression in different Th cell subsets and show that regulatory T cell- and Th2-associated signatures partition at different stages of Th memory cell differentiation. Moreover, we demonstrate the parallel presence of a core element of the Th2-associated gene signature in bystander naive cells, which can be reproduced by rIL-4. These findings indicate that network analysis provides significant additional insight into atopic mechanisms beyond that achievable with conventional microarray analyses, predicting functional interactions between novel genes and previously recognized members of the allergic cascade. This approach provides novel opportunities for design of therapeutic strategies that target entire networks of genes rather than individual effector molecules.
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Many studies have found that the risk of childhood asthma varies by month of birth, but few have examined ambient aeroallergens as an explanatory factor. A study was undertaken to examine whether birth during seasons of elevated ambient fungal spore or pollen concentrations is associated with risk of early wheezing or blood levels of Th1 and Th2 type cells at 24 months of age. 514 children were enrolled before birth and followed to 24 months of age. Early wheezing was determined from medical records, and Th1 and Th2 type cells were measured in peripheral blood using flow cytometry. Ambient aeroallergen concentrations were measured throughout the study period and discrete seasons of high spore and pollen concentrations were defined. A seasonal pattern was observed, with birth in autumn to winter (the spore season) associated with increased odds of early wheezing (adjusted odds ratio 3.1; 95% confidence interval 1.3 to 7.4). Increasing mean daily concentrations of basidiospores and ascospores in the first 3 months of life were associated with increased odds of wheeze, as were increasing mean daily concentrations of total and specific pollen types. Levels of Th1 cells at age 24 months were positively associated with mean spore concentrations and negatively associated with mean pollen concentrations in the first 3 months of life. Children with higher exposure to spores and pollen in the first 3 months of life are at increased risk of early wheezing. This association is independent of other seasonal factors including ambient levels of particulate matter of aerodynamic diameter <or=2.5 microm and lower respiratory infections.
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Respiratory infections in early life are associated with risk for wheezing bronchiolitis, especially in children at high risk of atopy. The underlying mechanisms are unknown, but are suspected to involve imbalance(s) in host defense responses against pathogens stemming from functional immaturity of the immune system in this age group. To assess the contribution of eosinophil-trophic IL-5, and the potent antiinflammatory cytokine IL-10, to risk for infection in early life. We prospectively monitored a cohort of 198 high-risk children to age 5 years, recording every acute respiratory infection episode and classifying them by severity. We measured cord blood T-cell capacity to produce IL-10 and IL-5, and related these functions to subsequent infection history. IL-10 and IL-5 were associated, respectively, with resistance versus susceptibility to infections. The greatest contrasting effects of these two cytokines were seen when they were considered in combination by generating IL-10/IL-5 response ratios for each subject. The low IL-10/high IL-5 T-cell response phenotype was strongly associated with susceptibility to all grades of acute respiratory infection, relative to the more resistant high IL-10/low IL-5 phenotype. Excessive production of IL-5 by T cells at birth is associated with heightened risk for subsequent severe respiratory infections, and this risk is attenuated by concomitant IL-10 production. The underlying mechanisms may involve IL-10-mediated feedback inhibition of IL-5-dependent eosinophil-induced inflammation, which is a common feature of host antiviral responses in early life.
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The long-term solution to the asthma epidemic is thought to be prevention, and not treatment of established disease. Atopic asthma arises from gene-environment interactions, which mainly take place during a short period in prenatal and postnatal development. These interactions are not completely understood, and hence primary prevention remains an elusive goal. We argue that primary-care physicians, paediatricians, and specialists lack knowledge of the role of atopy in early life in the development of persistent asthma in children. In this review, we discuss how early identification of children at high risk is feasible on the basis of available technology and important for potential benefits to the children. Identification of an asthmatic child's atopic status in early life has practical clinical and prognostic implications, and sets the basis for future preventative strategies.
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Asthma is an inflammatory disorder principally involving the conducting airways and characterised by infiltration of the airway wall with a range of inflammatory cells driven in large part by activation of Th2-type lymphocytes, mast cells and eosinophils. However a key component of asthma is the structural change that involves all of the elements of the airway wall. Here evidence is presented to suggest that the airway epithelium in asthma is fundamentally abnormal with increased susceptibility to environmental injury and impaired repair associated with activation of the epithelial-mesenchymal trophic unit (EMTU). In addition to adopting an activated phenotype, the barrier function of the epithelium is impaired through defective tight junction formation thereby facilitating penetration of potentially toxic or damaging environmental insults. Activated and repairing epithelial cells generate a range of growth factors that are involved in the early life origins of this disease as well as its progression in the form of mucous metaplasia and airway wall remodeling. By placing the epithelium at the forefront of asthma pathogenesis, different approaches to treatment can be devised focused more on protecting vulnerable airways against environmental injury rather than focusing on suppressing airway inflammation or manipulating the immune response.
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Episodes of lower respiratory illnesses (LRIs) in the first years of life have been associated with recurrent wheeze in studies of high-risk and community-based cohorts. Respiratory syncytial virus (RSV) is an agent especially associated with severe cases of bronchiolitis affecting young infants in winter months and has a typical seasonal pattern. Data from the Children's Respiratory Study from Arizona and a hospital-based Swedish study have been interpreted as evidence that severe RSV bronchiolitis is associated with a 30-40% likelihood of subsequent asthma. Other respiratory viruses, especially Rhinovirus, have been identified to be importantly associated with recurrent wheeze in children at risk for asthma. A case-control study of palivizumab given in the first year of life to preterm infants has shown a 50% reduction in the occurrence of recurrent wheeze even after controlling for potential confounding variables. Prospective trials with anti-viral strategies, including potential new vaccines, should give us better understanding of the role of viral infections in early life in the causation of childhood asthma.
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Variation in the observed association between pet ownership and allergic disease may be attributable to selection bias and confounding. The aim of this study was to suggest a method to assess disease-related modification of exposure and second to examine how cat acquisition or dog ownership in early life affects atopy and asthma at 5 years. Information on sociodemographic factors and cat and dog ownership was collected longitudinally in an initially cat-free Australian birth cohort based on children with a family history of asthma. At age 5 years, 516 children were assessed for wheezing, and 488 for sensitisation. Data showed that by age 5 years, 82 children had acquired a cat. Early manifestations of allergic disease did not foreshadow a reduced rate of subsequent acquisition of a cat. Independent risk factors for acquiring a cat were exposure to tobacco smoke at home odds ratio (OR) 1.92 [95% confidence interval (CI) 1.13, 3.26], maternal education < or =12 years OR 1.95 [1.08, 3.51] and dog ownership OR 2.23 [1.23, 4.05]. Cat or dog exposure in the first 5 years was associated with a decreased risk of any allergen sensitisation, OR 0.50 [0.28, 0.88] but no association with wheeze OR 0.96 [0.57, 1.61]. This risk was not affected by age at which the cat was acquired or whether the pet was kept in- or outdoors. In conclusion, cat or dog ownership reduced the risk of subsequent atopy in this high-risk birth cohort. This cannot be explained by disease-related modification of exposure. Public health recommendations on the effect of cat and dog ownership should be based on birth cohort studies where possible selection bias has been taken into account.
Article
Exacerbations of childhood asthma and rhinovirus infections both peak during the spring and fall, suggesting that viral infections are major contributors to seasonal asthma morbidity. We sought to evaluate rhinovirus infections during peak seasons in children with asthma and to analyze relationships between viral infection and illness severity. Fifty-eight children aged 6 to 8 years with asthma provided 5 consecutive weekly nasal lavage samples during September and April; symptoms, medication use, and peak flow were recorded. Rhinoviruses were identified by using multiplex PCR and partial sequencing of viral genomes. Viruses were detected in 36% to 50% of the specimens, and 72% to 99% of the viruses were rhinoviruses. There were 52 different strains (including 16 human rhinovirus C) among the 169 rhinovirus isolates; no strains were found in more than 2 collection periods, and all but 2 children had a respiratory tract infection. Virus-positive weeks were associated with greater cold and asthma symptom severity (P < .0001 and P = .0002, respectively). Furthermore, virus-positive illnesses had increased duration and severity of cold and asthma symptoms and more frequent loss of asthma control (47% vs 22%, P = .008). Although allergen-sensitized versus nonsensitized children had the same number of viral infections, the former had 47% more symptomatic viral illnesses (1.19 vs 0.81 per month, P = .03). Rhinovirus infections are nearly universal in children with asthma during common cold seasons, likely because of a plethora of new strains appearing each season. Illnesses associated with viruses have greater duration and severity. Finally, atopic asthmatic children experienced more frequent and severe virus-induced illnesses.
Article
The role of early childhood infections and immunisation in the development of allergic diseases remains controversial. To examine these associations, six hundred and twenty infants with first-degree relatives with allergic diseases were recruited into the Melbourne Atopy Cohort Study. Information on risk factors and outcomes was collected by interviewer administered questionnaire and was based on parental report and/or a physician's diagnosis. Risk factors examined included early childhood infections (including gastroenteritis, otitis media and lower respiratory tract infections) and immunisations in the first 2 yr of life. Outcomes were current asthma, allergic rhinitis and eczema at 6 yr of age. Univariate and multivariate regression analysis were used to estimate relative risk (RR) and assess confounding. By 6 yr, 79% of the original cohort remained in the study. Those with at least three episodes of gastroenteritis showed an increased risk (crude RR 2.36, 95%CI 1.41 3.95; adjusted RR 2.03 95%CI 1.50 2.75) for the later development of asthma at age 6. Of the scheduled immunisations, Sabin immunisation in the second year had a reduced risk of asthma at 6 yr (crude RR 0.60, 95%CI 0.37 0.98; adjusted RR 0.63 95%CI 0.39 1.02). Combined diphtheria and tetanus (CDT) immunisation in the first year had an increased risk of asthma at 6 yr (RR 1.76, 95%CI 1.11 2.78; adjusted RR 1.88 95%CI 1.28 2.77). Recurrent gastroenteritis in early childhood is associated with a later risk of asthma. This may reflect a cause and effect relationship, or exposure to common risk factors. In contrast, Sabin immunisation in the second year is associated with a decreased risk of asthma in later childhood. CDT immunisation in the first year may be a risk factor for asthma, but the need for CDT immunisation may also be a marker of increased risk of asthma in later childhood.
Article
Epidemiologic associations between viral lower respiratory infections (LRIs) and asthma in later childhood are well known. However, the question of whether such infections cause asthma or unmask asthma in a susceptible host has still not been settled. Most early evidence centered on the role of the respiratory syncytial virus; however, recent studies highlight a potential role for human rhinovirus as a risk factor for asthma. The links between early-life viral LRI and subsequent asthma are generally via wheeze; however, the presence of wheeze does not give any information about why the child is wheezing. Wheeze in early life is, at best, a fuzzy phenotype and not specific for subsequent asthma. The risk of asthma after viral LRI is increased in the presence of allergic sensitization in early life and if the infection is more severe. Atopy-associated mechanisms also appear to be involved in viral-induced acute exacerbations of asthma, especially in prolonging symptomatology after the virus has been cleared from the lungs. Breaking the nexus between viral respiratory infections and asthma may be possible with interventions designed to inhibit atopy-related effectors mechanisms from participating in the host response to respiratory viral infections.
Article
Divergent results have been reported regarding early life exposure to indoor environmental agents and the risk of asthma and allergic sensitization later in life. To assess whether early exposure to indoor allergens, beta(1,3)-glucans and endotoxin modifies the risk of allergic diseases at 10 years of age. The concentrations of mite, cat and dog allergens, endotoxin and beta(1,3)-glucans were determined in dust from the homes of 260 two-year-old children with lung function measured at birth (tidal flow volume loops) in the Environment and Childhood Asthma study in Oslo. At 10 years, the health status was assessed in a follow-up study including a structured interview of the parents and an extended clinical examination. Cat and dog keeping at 2 years of age was reported in 6.5% and 5.5% of the families, respectively. Mite allergens were detected in only 4/260 dust samples. The adjusted odds ratio for asthma at age 10 was 1.20 (95% confidence interval: 1.01-1.43) and 1.22 (1.02-1.46) for bronchial hyperresponsiveness (BHR) per 10 microg/g dust increase in cat allergen exposure at 2 years of age. No association was seen with allergic sensitization. Moreover, endotoxin and beta(1,3)-glucan exposure did not modify the risk of asthma or allergic sensitization. None of the measured environmental factors were associated with lung function at 10 years of age or a relative change in lung function from birth. In a community with a low prevalence of pet keeping and low mite allergen levels, exposure to cat allergens early in life increased the risk of late childhood asthma and BHR, but not the risk of allergic sensitization. No risk modification was seen for dog allergens, endotoxin and beta(1,3)-glucans.
Article
Asthma increased dramatically in the last decades of the 20th century and is representative of chronic diseases that have been linked to altered microbial exposure and immune responses. Here we evaluate the effects of environmental exposures typically associated with asthma protection or risk on the microbial community structure of household dust (dogs, cats, and day care). PCR-denaturing gradient gel analysis (PCR-DGGE) demonstrated that the bacterial community structure in house dust is significantly impacted by the presence of dogs or cats in the home (P = 0.0190 and 0.0029, respectively) and by whether or not children attend day care (P = 0.0037). In addition, significant differences in the dust bacterial community were associated with asthma outcomes in young children, including wheezing (P = 0.0103) and specific IgE (P = 0.0184). Our findings suggest that specific bacterial populations within the community are associated with either risk or protection from asthma.
Article
Background. Asthma is a common childhood illness. The objective of this study is to determine the incidence of physician-diagnosed asthma in preschool years and its relationship to host, prenatal and postnatal factors, early childhood factors, parental factors, household factors and demographic factors. Methods. The study sample was comprised of 8,499 infants and toddlers (<2 years at baseline) enrolled in the Canadian Early Childhood Development Study. Incidence of asthma was determined when the children were in preschool age (2 to 5 years). Results. The 4-year cumulative incidence at preschool age was 13.7% for physician-diagnosed asthma. History of early childhood wheezing before 2 years of age was a significant risk factor for incidence of asthma in preschool years (hazard ratio (HR): 2.32; 95% confidence interval (CI): 2.04-2.65). Factors that were protective for the development of asthma were breastfeeding more than 3 months (HR: 0.82; 95% CI: 0.69-0.97); history of nose or throat infection often in childhood (HR: 0.79; 95% CI: 0.67-0.93); early daycare attendance (HR: 0.85; 95% CI: 0.74-0.98); presence of two or more siblings at birth, (HR: 0.79; 95% CI: 0.64-0.97); and dwelling in rural non- central metropolitan areas (HR: 0.81; 95% CI: 0.69-0.95). Male sex, low birth weight, childhood allergy, single parent, maternal smoking during pregnancy, maternal medication use, parental atopy, and low SES at baseline were significant risk factors for the incidence of physician-diagnosed asthma in preschool years. Conclusion. This study emphasizes the role of wheezing in infant and toddler age on early onset of asthma during preschool years. The results also provide additional importance of early exposures to environmental factors such as early infections, daycare attendance, and rural environment in the development of proper immune dynamics to prevent asthma.
Article
With the advent of the hygiene hypothesis, probiotics have provided an avenue of hope in curbing the allergic epidemic. The initial enthusiasm has been tempered by recognition of the inherent complexities of this approach. This review examines the current clinical evidence and practical issues in using probiotics and related products, for the prevention and treatment of allergic disease. So far, probiotics have shown more promise, albeit limited, in the primary prevention of allergic disease rather than in the treatment of established disease. These effects have largely been limited to the prevention of early childhood conditions such as eczema, with no consistent effects on other allergic outcomes. There is emerging evidence that clinical effects may be strain specific, but again these findings have been inconsistent. While there have been several meta-analyses to examine probiotics in both the prevention and the treatment of allergic disease, these have been hampered by significant heterogeneity between studies, including wide variations in the strains used, the methods and timing of administration and the age and assessment of allergic outcomes. In any case, these have also become outdated by a series of new studies published in the last year. Although it is not yet clear exactly how the growing number of new studies will modify the results of meta-analyses, it is likely that these will add yet further heterogeneity that will continue to make interpretation of pooled data difficult. At this stage, the effects of prebiotics, synbiotics and postbiotics are even less clear. Thus, while there is little doubt that microbiota modulate immune development and can prevent the allergic phenotype, the optimal way of achieving this is far from clear. Given the current level of evidence, it is not appropriate to recommend prebiotics/probiotics/synbiotics or postbiotics as a part of standard therapy or for the prevention of any allergic conditions. Further studies are needed to address the growing speculation that supplementation with a single probiotic strain may be oversimplistic and that approaches that have a more global effect on colonization may be warranted.
Article
Previous studies have suggested that environmental exposures may be related to the development of respiratory symptoms in early life. Intervention studies, however, have not produced consistent findings. The Peer Education in Pregnancy Study examined the effect of home environment intervention with pregnant women at risk for having children with asthma on the development of respiratory symptoms in their infants. A total of 383 pregnant women whose unborn child had a first-degree relative with an allergic history were randomized to 1 of 2 intervention groups, both of whom received general health education, smoking cessation advice, and encouragement to breastfeed. In addition, the intensive education group received 3 home visits focused on home environment modification. Home assessment was performed at baseline and after 1 year of follow-up. Respiratory symptoms were identified during the first year of life. Families in both intervention groups showed significant changes in several environmental factors, with significant differences between the 2 groups in insects other than cockroaches, use of mattress covers, and washing in hot water. Children in the intensive education group had slightly lower incidence rates of respiratory symptoms, but few differences were statistically significant. The results of this study do not provide strong support for a primary intervention focused on general modification of the home environment during pregnancy for high-risk children. It does not address the effects of more aggressive approaches or of interventions targeting individual environmental factors.
Article
Traditional farming represents a unique model situation to investigate the relationship of early-life farm-related exposure and allergy protection. To investigate associations between maternal farm exposures and cytokine production in cord blood (CB) mononuclear cells in a prospective multinational birth cohort of 299 farm and 326 nonfarm children and their families. Supernatants from phorbol 12-myristate 13-acetate/ionomycin-stimulated CB mononuclear cells were assessed for the production of IFN-gamma, TNF-alpha, IL-5, IL-10, and IL-12. Significantly higher levels of IFN-gamma and TNF-alpha in farm compared with nonfarm children were found, whereas IL-5, IL-10, and IL-12 levels did not differ between study groups. Maternal contact with different farm animal species and barns and consumption of farm-produced butter during pregnancy enhanced the production of proinflammatory CB cytokines, whereas maternal consumption of farm-produced yogurt resulted in significant lower levels of IFN-gamma and TNF-alpha in umbilical blood. Maternal exposure to farming activities and farm dairy products during pregnancy modulated cytokine production patterns of offspring at birth.
Article
Atopy is a highly prevalent condition and remains the single biggest risk factor for asthma. Although atopy has a heritable component, the time frame of the increase in the prevalence indicates that it is not due to genetic factors alone. The relationship between allergen exposure and sensitization is complex. Lipopolysaccharide (LPS) and its bioactive moiety endotoxin are common to all gram-negative bacteria, and have been used as a surrogate of microbial load. Endotoxin can be readily measured in dust collected from homes. Some studies have demonstrated a clear inverse dose–response relationship between exposure to endotoxin and the risk of atopy but this finding has not been reproduced in all studies. Our innate immune system recognizes LPS readily via the LPS signal transduction pathway, which has the trimolecular complex of CD14/TLR4/MD2 at the core. A common single-nucleotide polymorphism in the promoter region of CD14 rs2569190 C to T (CD14/−260 or CD14/−159) has been associated with elevated sCD14. Although early studies suggested that this variant was associated with more severe atopy, this finding was not uniformly replicated. It has now been demonstrated in four independent populations that high exposure to endotoxin in the domestic environment is protective against the development of atopy, but only among carriers of the C allele, that is, the environmental exposure is only relevant when taken in the context of the genotype. Furthermore, this interaction is biologically plausible. We propose that neither the environmental exposure nor the genotype in isolation is sufficient to cause complex diseases like asthma and atopy, but disease results from the one acting in the context of the other, of which CD14 and endotoxin is one example contributing to the risk for atopy. Cite this as: A. Simpson and F. D. Martinez, Clinical & Experimental Allergy, 2010 (40) 209–223.
Article
Low-level alloreactivity between mother and fetus may provide stimulation for fetal T helper type 1 (Th1) cell immune maturation. This study explored the effects of human leucocyte antigen (HLA) mismatch on materno-fetal interactions detected as cytokine responses and lymphoproliferation in mixed lymphocyte reactions, and whether this was altered in allergic women (n = 62) who have a Th2 propensity compared with non-allergic women (n = 65). HLA-DRbeta1 mismatch was associated with significantly increased Th1 interferon (IFN)-gamma, Th2 interleukin (IL)-13 and lymphoproliferative responses by both mothers and fetuses. Allergic women showed significantly lower IFN-gamma Th1 production in response to HLA-DRbeta1 mismatch. The infants of these women also showed significantly lower IL-10 and lower IFN-gamma production relative to IL-13. Both HLA-DRbeta1 mismatch and maternal allergy had significant independent effects on maternal IFN-gamma Th1 responses. Maternal allergy modifies HLA-mediated alloreactivity between the mother and the fetus, reducing Th1 activation. This may affect the cytokine milieu at the materno-fetal interface and could be implicated in the attenuated Th1 responses observed commonly in infants of atopic mothers.
Article
Breckler LA, Hale J, Jung W, Westcott L, Dunstan JA, Thornton CA, Prescott SL. Modulation of in vivo and in vitro cytokine production over the course of pregnancy in allergic and non-allergic mothers. Pediatr Allergy Immunol 2010: 21: 14–21. © 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard Cytokines secreted during pregnancy may influence immune development of the foetus. This study aimed to determine if maternal allergy alters patterns of systemic cytokine production throughout and after pregnancy. Maternal plasma cytokines and allergen-specific production of interleukin (IL)-10, IL-13 and interferon (IFN)-γ were measured in allergic (n = 63) and non-allergic (n = 70) pregnant women who had a full set of sequential peripheral blood samples collected at 20-, 30-, 36-wk gestation and 6-wk post-partum. Maternal allergy was strictly defined by both allergen sensitization and doctor-diagnosed asthma, eczema or rhinitis. IL-13 responses to allergen were higher for allergic mothers at all time-points (20 wk: p < 0.001; 30 wk: p = 0.001; 36 wk: p < 0.001; post-partum: p < 0.001). For the non-allergic group, IL-13 levels to house dust mite decreased from 20- to 36-wk gestation (Friedman anova p = 0.012) and were significantly lower at 36 wk compared with post-partum (p = 0.002). In contrast, IL-13 production by allergic mothers did not change from 20 wk through to post-partum. For both allergic and non-allergic mothers, in vitro IFN-γ production was lower at all pregnancy time-points compared with post-partum levels. Allergic women had an increased propensity for peripheral blood allergen-specific T helper-2 responses during pregnancy, and failed to downregulate these responses in comparison with non-allergic women. This may be a factor that contributes to the increased risk of atopy in infants born to allergic mothers.
Article
Asthma is a complex disease, and its incidence is determined by an intricate interplay of genetic and environmental factors. The identification of novel genes for asthma suggests that many genes with small effects rather than few genes with strong effects contribute to the development of asthma. These genetic effects may in part differ with respect to a subject's environmental exposures, although some genes may also exert their effect independently of the environment. Whereas the geneticist uses highly advanced, rapid, comprehensive technologies to assess even subtle changes in the human genome, the researcher interested in environmental exposures is often confronted with crude information obtained from questionnaires or interviews. There is thus substantial need to develop better tools for individual exposure assessment in all relevant environmental fields. Despite these limitations, a number of important gene-environment interactions have been identified. These interactions point to the biology of environmental exposures as the involved genetic variation is suggestive of certain underlying mechanisms. Furthermore, the identification of subjects who are particularly susceptible to environmental hazards through genetic analyses helps to estimate better the strength of effect of environmental exposures. Finally, the analysis of gene-environment interactions may result in a reconciliation of seemingly contradictory findings from studies not taking environmental exposures into account.
Article
Asthma risk has a clear hereditary component but, unexpectedly, the majority of reported associations between genetic variants and asthma have not been consistently replicated across studies. Methodological flaws have been indicated as a possible explanation for these inconsistencies. However, an alternative explanation is that the effects of genetic variants depend on other factors whose frequency and distribution vary, both across individuals and across populations. Within this framework, we review recent advances in asthma genetics and conclude that a paradigm shift is needed, because a static model in which the DNA sequence is associated with disease risk in a linear fashion fails to consider the interdependence of the diverse components of asthma risk. We propose an integrated approach, linking sequence variation to specific phenotypic manifestations of the disease by taking into account concurrent influences from biological systems and environmental factors that interact within specific developmental windows of opportunity.
The role of lipopolysaccharide in the development of atopy in humans
  • Simpson