John A. Burgess

Atopic dermatitis and the atopic march revisited

Atopic dermatitis (AD) has become a significant public health problem because of increasing prevalence, together with increasing evidence that it may progress to other allergic phenotypes. While it is now acknowledged that AD commonly precedes other allergic diseases, a link termed ‘the atopic march’, debate continues as to whether this represents a causal relationship. An alternative hypothesis is that this association may be related to confounding by familial factors or phenotypes that comanifest, such as early‐life wheeze and sensitization. However, there is increasing evidence from longitudinal studies suggesting that the association between AD and other allergies is independent of confounding by comanifest allergic phenotypes. The hypotheses on plausible biological mechanisms for the atopic march focus on defective skin barrier function and overexpression of inflammatory mediators released by the skin affected by AD (including thymic stromal lymphopoietin). Both human and animal studies have provided evidence supporting these potential biological mechanisms. Evidence from prevention trials is now critical to establishing a causal nature of the atopic march. An emerging area of research is investigation into environmental modifiers of the atopic march. Such information will assist in identifying secondary prevention strategies to arrest the atopic march. Despite much research into the aetiology of allergies, little progress has been made in identifying effective strategies to reduce the burden of allergic conditions. In this context, the atopic march remains a promising area of investigation.

The Interplay between the Effects of Lifetime Asthma, Smoking, and Atopy on Fixed Airflow Obstruction in Middle Age

RATIONALE The contribution by asthma to the development of fixed airflow obstruction (AO) and the nature of its effect combined with active smoking and atopy remain unclear. OBJECTIVES To investigate the prevalence and relative influence of lifetime asthma, active smoking, and atopy on fixed AO in middle age. METHODS The population-based Tasmanian Longitudinal Health Study cohort born in 1961 (n = 8,583) and studied with prebronchodilator spirometry in 1968 was retraced (n = 7,312) and resurveyed (n = 5,729 responses) from 2002 to 2005. A sample enriched for asthma and chronic bronchitis underwent a further questionnaire, pre- and post-bronchodilator spirometry (n = 1,389), skin prick testing, lung volumes, and diffusing capacity measurements. Prevalence estimates were reweighted for sampling fractions. Multiple linear and logistic regression were used to assess the relevant associations. MEASUREMENTS AND MAIN RESULTS Main effects and interactions between lifetime asthma, active smoking, and atopy as they relate to fixed AO were measured. The prevalence of fixed AO was 6.0% (95% confidence interval [CI], 4.5-7.5%). Its association with early-onset current clinical asthma was equivalent to a 33 pack-year history of smoking (odds ratio, 3.7; 95% CI, 1.5-9.3; P = 0.005), compared with a 24 pack-year history for late-onset current clinical asthma (odds ratio, 2.6; 95% CI, 1.03-6.5; P = 0.042). An interaction (multiplicative effect) was present between asthma and active smoking as it relates to the ratio of post-bronchodilator FEV(1)/FVC, but only among those with atopic sensitization. CONCLUSIONS Active smoking and current clinical asthma both contribute substantially to fixed AO in middle age, especially among those with atopy. The interaction between these factors provides another compelling reason for atopic individuals with current asthma who smoke to quit.

Childhood eczema and rhinitis predict atopic but not nonatopic adult asthma: A prospective cohort study over 4 decades

BACKGROUND The evidence on whether the atopic march observed in childhood (ie, the progression from eczema to allergic rhinitis and asthma) extends to adulthood is sparse, and there is no evidence on whether the progression leads to a specific phenotype of asthma. OBJECTIVE We sought to assess whether childhood eczema and rhinitis are risk factors for specific phenotypes of adult asthma. METHODS Participants of the Tasmanian Longitudinal Health Study recruited in 1968 (age range, 6.0-7.0 years) were followed up at age 44 years. The risk of current atopic or nonatopic asthma in middle age characterized by sensitization to aeroallergens given childhood eczema, rhinitis, or both was calculated by using multinomial logistic regression. RESULTS No association was found between childhood eczema or rhinitis and nonatopic adult asthma. In contrast, childhood eczema and rhinitis in combination predicted both new-onset atopic asthma by middle age (adjusted multinomial odds ratio [aMOR], 6.3; 95% CI, 1.7-23.2) and the persistence of childhood asthma to adult atopic asthma (aMOR, 11.7; 95% CI, 3.6-37.9). Participants with childhood eczema alone were at increased risk of new-onset atopic asthma (aMOR, 4.1; 95% CI, 1.9-8.8), whereas rhinitis alone predicted the persistence of childhood asthma to atopic asthma (aMOR, 2.7; 95% CI, 1.3-5.6). Of all asthma, 29.7% of persistent atopic asthma and 18.1% of new-onset atopic asthma could be attributed to having childhood eczema and rhinitis. CONCLUSION Childhood eczema and rhinitis are strongly associated with the incidence and persistence of adult atopic asthma.

Childhood eczema and asthma incidence and persistence: A cohort study from childhood to middle age

BACKGROUND The association between eczema and asthma is well documented, but the temporal sequence of this association has not been closely examined. OBJECTIVES To examine the association between childhood eczema and asthma incidence from preadolescence to middle age, and between childhood eczema and asthma persisting to middle age. A further aim was to examine any effect modification by nonallergic childhood exposures on the association between childhood eczema and both childhood asthma and later life incident asthma. METHODS Data were gathered from the 1968, 1974, and 2004 surveys of the Tasmanian Longitudinal Health Study. Multivariable logistic regression examined the association between childhood eczema and childhood asthma. Cox regression examined the association between childhood eczema and asthma incidence in preadolescence, adolescence, and adult life. Binomial regression examined the association between childhood eczema and childhood asthma persisting to age 44 years. RESULTS Childhood eczema was significantly associated with childhood asthma and with incident asthma in preadolescence (hazard ratio [HR], 1.70; 95% CI, 1.05-2.75), adolescence (HR, 2.14; 95% CI, 1.33-3.46), and adult life (HR, 1.63; 95% CI, 1.28-2.09). Although childhood eczema was significantly associated with asthma persisting from childhood to middle age (relative risk, 1.54; 95% CI, 1.17-2.04), this association was no longer evident when adjusted for allergic rhinitis. CONCLUSION Childhood eczema increased the likelihood of childhood asthma, of new-onset asthma in later life and of asthma persisting into middle age.

Factors influencing asthma remission: a longitudinal study from childhood to middle age

Objective To examine asthma remission from childhood to middle age. Methods This was a population-based cohort study. In 1968 the Tasmanian Longitudinal Health Study enrolled 8583 7-year-old Tasmanian schoolchildren who were re-surveyed in 2004. Those reporting ever having asthma when last surveyed completed another questionnaire in 2007 ascertaining age at last asthma attack and asthma medication use. The main outcome measure was asthma remission, defined as no asthma attack for 2 years and no current asthma medication use, or no self-reported asthma in adult life but with parent-reported childhood asthma. Results Of 5729 respondents to the 2004 survey, 1238 self-reported asthma. A further 573 denied asthma, but had parent-reported childhood asthma, giving a study sample of 1811. Asthma had remitted in 1177 (65.0%) of whom 649 (55.1%) were male. Childhood (OR 0.38, 95% CI 0.25 to 0.58) and later-onset allergic rhinitis (0.42, 0.29 to 0.63), childhood (0.66, 0.47 to 0.94) and later-onset eczema (0.66, 0.47 to 0.92), maternal asthma (0.66, 0.47 to 0.92) and childhood chronic bronchitis (0.56, 0.41 to 0.76) were negatively associated with remission. There was weaker evidence for a negative association between passive smoking (0.75, 0.54 to 1.04) and lower socio-economic status (p-trend 0.09) and remission. Childhood-onset asthma (3.76, 2.58 to 5.49) was more likely to remit than adult-onset asthma. Adult smoking was positively associated with remission in childhood-onset asthma (1.49, 1.06 to 2.09). Sex did not influence remission. Conclusion While inherited factors cannot be changed, the effect of allergic rhinitis or eczema on asthma remission might be altered by early, aggressive treatment. Every effort should be made to lessen passive exposure to tobacco smoke.

Does eczema lead to asthma

The nature of the relationship between eczema, asthma, and allergic rhinitis has been controversial. It has been commonly held that these disorders, while sharing genetic and environmental risk factors, are unrelated disorders that may develop sequentially along an atopic pathway. Conversely, the link between eczema and these later-onset respiratory disorders may be causal. This review examines the relationship between eczema, asthma, and allergic rhinitis in the context of the atopic march, the skin barrier, and recent developments in eczema genetics; and we propose that the relationship is causal. We describe a plausible biological pathway with eczema as the first step in a progressive atopic march that over time leads to asthma and/or allergic rhinitis. Such a pathway has implications for our understanding of these disorders and steps that might be made to prevent the development of asthma in particular. We propose that intervention studies in eczema should be conducted to confirm or refute this causal relationship. Such studies may materially improve the quality of life of eczema patients and will have important public health benefits if the interventions lead to a reduction in the burden of asthma.

Childhood adiposity predicts adult-onset current asthma in females: a 25-yr prospective study

Few data exist on associations between childhood adiposity and incident asthma in later life. The present authors examined the relationship between childhood body mass index (BMI) and incident asthma beginning in adolescence or in adult life. All subjects included in the study were participants in the Tasmanian Asthma Survey, a large population-based cohort study, and were asthma free at 7 yrs of age. Weight, height and lung function were measured at 7 yrs of age. Asthma status at 7 and 32 yrs of age was ascertained by questionnaire. Odds ratios were calculated for the association between childhood adiposity, expressed as “overweight” or as BMI z-score quartiles at 7 yrs of age, and asthma development after that age. In females, but not in males, there was a significant association between adiposity at 7 yrs of age and current asthma at 32 yrs of age that developed after the age of 21 yrs. The association was not explained by childhood lung function or age at menarche. There was no association between adiposity at 7 yrs of age and asthma that developed after that age and remitted at 32 yrs of age in either sex. Higher body mass index in nonasthmatic young females at 7 yrs of age predicts risk of current asthma developing in adult life.

Does eczema in infancy cause hay fever, asthma, or both in childhood? Insights from a novel regression model of sibling data

BACKGROUND The atopic march hypothesis proposes that eczema precedes the development of asthma and allergic rhinitis. OBJECTIVE We sought to assess the evidence for a causal effect of infantile eczema on childhood hay fever, asthma, or both. METHODS We used parental reports on infantile eczema and childhood asthma and hay fever for 3778 pairs of 7-year-olds matched to their sibling closest in age within 2 years from the Tasmanian Longitudinal Health Study. We analyzed paired sibling data using a logistic regression model that allowed inference about a causal effect of a familial predictor on a childs outcome by examining the change in association with their cosiblings predictor after adjusting for their own predictor status. RESULTS Siblings were concordant for infantile eczema (tetrachoric correlation, 0.40). For having both hay fever and asthma by age 7 years, the association with cosiblings eczema was an odds ratio (OR) of 1.98 (95% CI, 1.37-2.86), which reduced after adjusting for own eczema to an OR of 1.65 (95% CI, 1.17-2.34). For having hay fever only, the association with cosiblings eczema was an OR of 1.68 (95% CI, 1.22-2.31) before and an OR of 1.59 (95% CI, 1.19-2.14) after adjusting for own eczema. There was no association between having asthma only and cosiblings eczema (OR, 1.00; 95% CI, 0.77-1.30). CONCLUSIONS Eczema in infancy might have a causal effect on hay fever in children with and perhaps without asthma. The association of infantile eczema on asthma in children without hay fever, which might be early transient wheeze, is unlikely to be causal or familial. These findings have implications for hay fever prevention.

Introduction to causal diagrams for confounder selection

In respiratory health research, interest often lies in estimating the effect of an exposure on a health outcome. If randomization of the exposure of interest is not possible, estimating its effect is typically complicated by confounding bias. This can often be dealt with by controlling for the variables causing the confounding, if measured, in the statistical analysis. Common statistical methods used to achieve this include multivariable regression models adjusting for selected confounding variables or stratification on those variables. Therefore, a key question is which measured variables need to be controlled for in order to remove confounding. An approach to confounder‐selection based on the use of causal diagrams (often called directed acyclic graphs) is discussed. A causal diagram is a visual representation of the causal relationships believed to exist between the variables of interest, including the exposure, outcome and potential confounding variables. After creating a causal diagram for the research question, an intuitive and easy‐to‐use set of rules can be applied, based on a foundation of rigorous mathematics, to decide which measured variables must be controlled for in the statistical analysis in order to remove confounding, to the extent that is possible using the available data. This approach is illustrated by constructing a causal diagram for the research question: ‘Does personal smoking affect the risk of subsequent asthma?’. Using data taken from the Tasmanian Longitudinal Health Study, the statistical analysis suggested by the causal diagram approach was performed.

CD14 polymorphisms, microbial exposure and allergic diseases: a systematic review of gene-environment interactions.

Asthma and allergy may develop as a result of interactions between environmental factors and the genetic characteristics of an individual. This review aims to summarize the available evidence for, and potential effects of, an interaction between polymorphisms of the CD14 gene and exposure to microbes on the risk of asthma and allergic diseases. We searched PubMed, MEDLINE and Global Health databases, finding 12 articles which met inclusion criteria. Most studies reported a significant interaction between CD14 polymorphisms and microbial exposure. When stratified by age at microbial exposure (early life vs adult life), there was evidence of a protective effect of gene–environment interaction against atopy in children, but not adults. We also found different effects of interaction depending on the type of microbial exposures. There was no strong evidence for asthma and eczema. Future studies should consider a three‐way interaction between CD14 gene polymorphisms, microbial exposures and the age of exposure.