Several prospective longitudinal studies have provided evidence for the atopic march from eczema to the development of allergic rhinitis and asthma (111
). A systematic review of the risk of asthma development in children with eczema during the first four years of life reported a pooled odds ratio of 2.14 (95%CI 1.67–2.75) for asthma (114
), which is lower than originally estimated, but still supports the hypothesis of the atopic march from eczema to asthma.
Given the natural history of eczema, birth cohorts provide an optimum study design to evaluate eczema development and progression in early life. Many birth cohort studies designed to examine asthma and allergic diseases have been implemented in both European countries and the US. Although almost all of these studies aim to evaluate environmental contributions to asthma and allergic diseases, only a few of these cohorts are designed to evaluate both environment and genetics concurrently, which is important given the well-documented genetic contributions to these complex diseases. The birth cohorts discussed in this review are summarized in the .
Select birth cohort studies evaluating atopic diseases.
One of the first birth cohort studies to evaluate eczema began in Denmark in 1985 (115
). The children (n=276) were followed up at 6, 12 and 18 months and at 5, 10, and 15 years of age to investigate the natural course of sensitization and development of atopic diseases in childhood (115
). Their results mirrored the progression of the atopic march. Since then, many other larger birth cohort studies have been implemented.
The largest of these is the Avon Longitudinal Study of Parents and Children (ALSPAC) study (15
). ALSPAC is an ongoing birth cohort study that initially enrolled 14,541 mothers in their eighth week of pregnancy in the county of Avon, UK, between 1991 and 1992. The study collected parental and child completed questionnaires, biological samples including cord blood, a piece of the umbilical cord and placenta, hair and toe nail samples, teeth, blood, urine and saliva, as well as clinical assessments on a myriad of health outcomes including asthma, eczema, atopy and allergies (116
). The study has also collected measurements from environmental monitors placed in the home regarding air pollutants and radiation (116
). This birth cohort was designed to evaluate the genetic influences on disease as well; the ALSPAC DNA bank is comprised of 10,232 child samples, 10,364 mothers and 700 validated trios (117
). Parental lifetime histories of eczema, asthma and hay fever as well as the child’s eczema symptoms at 6, 18, 30 and 42 months were collected (15
). Children whose mothers reported itchy rash in the joints or creases or oozy crusty rashes on the face, forearms or shins at least two times in the follow-up questionnaires were defined as having eczema (15
). The authors found a strong association between parental and childhood eczema, regardless of which parent had eczema. There was no association of childhood eczema with parental asthma and hay fever (15
). Their findings support the hypothesis that eczema has a polygenic etiology and suggests genes associated with parental eczema are more strongly associated with child eczema than genes related to asthma and hay fever (15
). The ALSPAC group has also confirmed the importance of filaggrin mutations in the development of eczema and ‘eczema plus asthma’ phenotypes in children (38
) and observed an association of the Il4R gene with eczema in children without infections requiring antibiotics, supporting the hygiene hypothesis (58
). In the future, this study is well poised to contribute greatly to the literature in the area of genetics and allergic diseases.
Another large birth cohort evaluating allergic diseases is the BAMSE (B=barn (children), A=allergy, M=milieu (environment), S=Stockholm, E=epidemiology) (118
) project with a sample size of 4089 children. BAMSE aims to evaluate the role of genetics, socio-economics, environment, diet and infections on the development of asthma, eczema and allergic diseases in children (120
). The authors of the BAMSE cohort have published a protective effect for eczema with breast feeding (121
) an increased risk with symptoms to pollen and fruit exposure in early life (119
), and no relationship between eczema and anthropometric measures (122
Other large birth cohorts (n > 1000) evaluating allergic diseases in children include the Isle of Wight Study (N=1456) (123
), the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study in the Netherlands (n=3291) (124
), the Environment and Childhood Asthma (ECA) study in Norway (n=3754) (125
), the German Infant Nutritional Intervention Study (GINI) (n=3739) (126
), the Lifestyle-related Factors in the Immune System/Development of Allergies in Children (LISA) study in Germany (n=3097) (127
) and the Study of Eczema/Asthma to Observe Influence on Nutrition (SEATON) study in the UK (n=1924) (128
). In the Isle of Wight study, atopy, rhinitis, food allergy and maternal asthma have all been identified as independent risk factors for eczema at age 10 (129
). Infants participating in the PIAMA study were at an increased risk of eczema if they had a higher birth weight or attended daycare, and exclusive breastfeeding for at least three months was protective (130
). The GINI study has reported an increase in eczema risk in 6 year olds with early sensitization foods and aeroallergens (131
), as well as an increase in eczema risk at age four with avoidance of eggs in the first year of life (132
). In contrast, children who avoided soybeans and nuts in the first year of life had a decreased risk of eczema at age four (132
). In 2008, Morgenstern et al. evaluated air pollution exposures and allergic disease development in children aged four and six participating in either the GINI or LISA cohorts. The authors found strong positive associations between distance to the nearest main road and asthmatic bronchitis, hay fever, eczema and sensitization, with the highest odds ratios observed for those living within 50 meters of a busy street (133
). An association was also observed between eczema and nitrogen dioxide levels at the residential address, assessed by regression models of air pollution measurements (133
). An increase in eczema development has also been reported with margarine consumption (134
) and early life stressors such as parental divorce (135
) in children participating in the LISA study. In the SEATON cohort, children born to atopic mothers that consume higher amounts of vitamin E during pregnancy were less likely to develop eczema and wheeze without a cold in the first two years of life (136
), consistent with the hypothesis that antioxidant intake during pregnancy may modulate susceptibility to allergic diseases (137
Some birth cohort studies have selected high-risk populations, which enrich allergy-associated alleles, thereby increasing power to detect genetic and gene-environment interactions (120
). The German Multicenter Allergy Study (GMAS) was developed in 1990 and includes 1314 children, 499 of which are considered high risk due to having two atopic first-degree relatives and/or cold blood IgE ≥ 0.9kU/l, as discussed above (138
). The children are followed-up several times until age two, and annually thereafter until the age of ten. GMAS participants also undergo pulmonary function testing and bronchial challenges at age seven, and DNA samples, cord blood and IgE measurements are collected. Questionnaires results provide data regarding atopic symptoms, nutrition, environmental factors, housing conditions, psychological problems and demographics. This study aims to assess the impact of immunizations, allergen exposures, early sensitization and upper airway infections on development of allergy and atopy in children (138
). The GMAS investigators have evaluated the natural course of eczema and how it relates to asthma development in the participating children at age seven. They observed that the association of atopic sensitization and early eczema (onset in the first two years) was strongest when the onset of sensitization was before age one (140
). The authors also found early eczema development to be significantly associated with wheeze and bronchial hyper-reactivity at age seven (140
). Food sensitization was a strong predictor of asthma development and airway hyperresponsiveness until school age, regardless of inhalant sensitization (140
). Interestingly, food allergen sensitivity usually develops in the first few months of life until age 2 years, and inhalant allergen sensitization develops later (141
) another indicator that early life atopic status may be more predictive of asthma development than childhood allergy.
The Childhood Origins of Asthma (COAST) study is a birth cohort studying wheezing and subsequent asthma development in high risk children enrolled in 1998–2000 (142
). Eligible participants in COAST (n=287) had at least one parent with a positive SPT and/or a physician diagnosis of asthma (142
). The children are examined annually and undergo pulmonary function tests including eNO, post-bronchodilator reversibility, impulse oscillometry and spirometry, SPT testing, DNA and nasal mucus collection, sputum induction and plethysmography. The aims of the COAST study are to evaluate associations of cytokine dysregulation response at birth as well as lower respiratory tract viral infection, specifically respiratory syncytial virus, with development of persistent wheezing in children. With regards to the atopic march, COAST has evaluated risk factors for the expression and persistence of eczema. Of the 65 high-risk infants that developed eczema during infancy, 46% had persistence of the disease to age five (144
). The persistent expression of eczema into early childhood was associated with differences in immunological profiles, measured from cord and peripheral blood, and the presence of wheezing (144
). As in the GMAS study, there was a strong association between food allergen sensitization, specifically egg, and asthma development by age six (145
), however, this group also found a associations with aeroallergen sensitization and asthma (146
) and persistent wheezing (147
). As this cohort ages and additional objective measures of asthma are collected annually, this study is well designed to evaluate not only the atopic march in high-risk children, but also the early life predictors of persistent asthma and severity of disease in children and adolescents.
The Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) is a high-risk birth cohort (n=762) uniquely poised to evaluate environmental and genetic associations with the development and progression of allergic disease and asthma. Newborns identified from birth records were enrolled if at least one parent had an allergy symptom and a positive skin prick test (SPT) (148
). This study was designed in 2001 to determine the effects of environmental exposures, specifically diesel exhaust, on asthma and allergy development in children, and how these associations are modified by genotype and other factors. At annual visits starting at age one, children are examined for clinical symptoms of asthma and allergic disease, parents report detailed information on allergy and asthma symptoms, medical history, environmental exposures, diet and demographics, skin prick testing is performed and DNA, nasal swabs for eosinophils and hair samples for nicotine and cotinine analysis are taken (149
). Dust samples are taken from the children’s primary activity room and bedroom to determine home allergen levels and endotoxin exposures. The children are currently being evaluated for definitive asthma at age seven and pulmonary function tests including spirometry, exhaled nitric oxide (eNO) measurements, post-bronchodilator reversibility and methacholine challenge tests are being performed. The CCAAPS investigators have reported significant associations between SPT results and eczema. Children that were SPT+ by the age of three were significantly more likely to have eczema at age three or at both ages two and three (76
). Further, those children that had a SPT+ to milk or egg allergen were at the highest risk for eczema development at ages one, two and three (76
). This same study also reported that children with exposure to dog(s) were significantly less likely to develop eczema at age one or at both ages two and three, and this finding was most significant among children carrying the CC genotype of the CD14 −159C/T SNP. Even though the children in this study are still being examined for definitive diagnosis of asthma, this study is well-suited to dissect the associations of allergic sensitization, eczema, allergic rhinitis and asthma as they pertain to the atopic march in the future.
The Urban Environment and Childhood Asthma (URECA) birth cohort study was implemented in 2004 and enrolled 560 inner-city children who have at least one parent with allergic disease or asthma during the prenatal period (150
). The overall aim of this study is to determine how specific urban exposures, including immune response (genetics), allergens, pollution, infection, microbes, stress, diet, altered innate and adaptive immune responses and lower respiratory infection affect childhood persistent wheeze and asthma. The participants will be followed-up until the age of seven. This study proposes the most inclusive environmental and genetic factors currently studied by CCAAPS, COAST and GMAS, and expands to include unique measures of urban life during pregnancy and throughout the study such as anxiety, depression, life circumstances, neighborhood conditions, and support networks, as well as measurements of bioelectrical impedance analysis and airborne nicotine and NO2
in the home. This study is also unique in that they enrolled a concurrent non-allergic control group (n=49). Although this cohort is still in the early stages, it is poised to analyze the natural course of allergic diseases up to age seven, specifically in high-risk, urban, low-income children, a population which had not been specifically targeted by previous asthma cohorts.
These unique resources have and will continue to allow researchers to better understand the environmental and genetic factors that lead to allergic disease development. Further, these studies also serve to generate new hypotheses exploring the underlying mechanisms of all allergic diseases, including eczema, as well as the atopic march.