The atopic march: the pattern of allergic disease development in childhood

The sequential development of allergic disease manifestations during early childhood is often referred to as the atopic march. Various epidemiologic and birth-cohort studies have begun to elucidate the evolution of allergic disease manifestations and to identify populations at risk for disease. These studies, along with intervention studies, emphasize the effects of environmental factors and genetic predisposition on the atopic march. This article discusses the populations at risk for the development of atopic conditions and the interventions that have been explored in attempts to modify the progression of allergic disease.     

Development of atopic disease during childhood and its prediction by Phadiatop Paediatric

Background Evaluating in vivo and/or in vitro tests for ‘early’ prediction of childhood allergy is of interest in paediatric allergology. Objective To determine whether the measurement of Phadiatop Paediatric (PP) during early childhood could be used to predict the development of atopic disease during the first 5 years of life among infants with a family history of atopic disease. Methods Phadiatop Paediatric was evaluated in 134 infants. The analysis was performed at 6 months, at 18 months and at 5 years of age and the numbers of available serum samples were 61, 85 and 134, respectively. The potential capacity of the test to predict the development of atopic disease was studied by relating the result of the test, a positive or a negative score, to the cumulated incidence of atopic diseases from birth to 18 months of age and from birth to 5 years of age. Results Three of four children with a positive PP at 6 months of age developed clinical signs/symptoms of atopic disease before 18 months and all four before 5 years of age. The predictive value of a positive test at 18 months for symptoms before 5 years of age was 80% (12/15). If the diagnostic criterion, instead of clinical signs/symptoms of atopic disease, was at least one positive skin-prick test to major food or inhalant allergens, the predictive value of a positive PP-test at 18 months decreased to 53% (8/ 15). Conclusion Although the presence of circulating IgE antibodies, as detected by Phadiatop Paediatric, can predict the development of atopic diseases during childhood, the usefulness of the test is limited by its low sensitivity (22-47%).     

Exposure to birch pollen in infancy and development of atopic disease in childhood

BACKGROUND: The relationship between early allergen exposure, sensitization, and development of atopic disease remains controversial. In 1993, extremely high levels of birch pollen were recorded in Stockholm, Sweden, creating the unique opportunity to study children with different exposures during infancy. OBJECTIVE: We sought to assess the influence of early high-dose exposure to an inhalant allergen (birch pollen) on sensitization and development of atopic disease in children. METHODS: A total of 583 children with atopic heredity born in Stockholm in February through April 1992, 1993, or 1994 were investigated at age 4.5 to 5 years. The children were examined and underwent skin prick testing with inhalant and food allergens. IgE antibodies (RAST) against birch pollen and recombinant birch pollen allergen (rBet v 1) were analyzed in serum. RESULTS: The children born in 1993 (high-dose exposure at 0-3 months) were more often sensitized (ie, positive skin prick test response) to birch pollen than the children born in 1994 (low-dose exposure; 17.8% and 8.8%, respectively; odds ratio [OR], 2.4; 95% CI, 1.2-4.6). A tendency in the same direction was seen for children born in 1992 (high-dose exposure at 12-15 months; OR, 1.7; 95% CI, 0.9-3.2). The results were supported by the RAST analyses. The prevalence of bronchial asthma, allergic rhinoconjunctivitis, and atopic dermatitis did not differ between the birth-year groups. However, the prevalence of pollen- and animal dander-induced allergic asthma was increased in the children born in 1993 (OR, 2.6; 95% CI, 1.2-5.6). An interaction between early high-dose exposure to birch pollen and cat in the household was suggested for sensitization to cat (P =.06). CONCLUSION: Exposure to high levels of birch pollen in infancy increases the risk of sensitization to the same allergen, as well as the risk of allergic asthma.     

Perinatal factors and atopic disease in childhood

Background Recent work has suggested possible linkages between perinatal factors and notably, head circumference and risks of subsequent atopic illness. Objective To examine the linkages between perinatal factors and risks of atopic conditions in a birth cohort of New Zealand children studied to the age of 16. Methods Measures of atopic illness including asthma, eczema, and other allergies were assessed prospectively during the course of a 16 year longitudinal study of a birth cohort of 1265 New Zealand children. In the initial stage of this research, measures of perinatal variables including birthweight, gestational age, head circumference and length at birth were obtained from hospital record data. Results Children with head circumference at birth of 37 cm or greater had (unadjusted) odds of asthma that were 1.8 (P < 0.01) to 3.0 (P < 0.0001) times higher than the odds for children of lesser head circumference. However, risks of asthma were not related to other perinatal measures including birthweight, gestational age or length or ratios of these measures. There were no consistent associations between perinatal measures and other measures of childhood atopy including eczema, allergic rhinitis and other allergies. The associations between head circumference and asthma risks persisted when due allowance was made for potentially confounding social and perinatal factors. Conclusions It is concluded that large head circumference at birth may be associated with increased risks for the development of asthma. Possible explanations for the linkages between head circumference and asthma risks are considered.     

Defining childhood atopic phenotypes to investigate the association of atopic sensitization with allergic disease

AIMS: Although atopic sensitization is common in childhood, its relationship to clinical allergic disease remains incompletely understood. We therefore sought to explore this relationship by defining sensitization based atopic phenotypes. METHODS: Children were recruited at birth (n = 1456) and reviewed at 1, 2, 4 and 10 years. Skin prick testing (SPT) to common allergens was done at 4 (n = 980) and 10 years (n = 1036) with lung function (n = 981), bronchial challenge (n = 784) and serum IgE (n = 953) testing at 10. Atopic phenotypes were defined, by sensitization pattern, for children with SPT at both 4 and 10 years (n = 823). RESULTS: Of phenotyped children, 68.0% were never atopic, 4.3% early childhood atopic (only atopic at age 4), 16.5% chronic childhood atopics (at 4 and 10 years) and 11.2% delayed childhood atopics (only at 10). Never atopics showed small but identifiable prevalence of allergic diseases such as asthma, eczema and rhinitis. Amongst allergen-sensitized subjects, aeroallergen predominated over food sensitization throughout childhood. Chronic childhood atopics showed highest prevalence of lifetime plus persistent wheeze, eczema and rhinitis, increased prevalence of aeroallergen sensitization, some evidence of persistent food sensitization, significantly greater cord IgE than never atopics (P = 0.006), plus higher total IgE (P < 0.001) and bronchial hyper-responsiveness (P < 0.001) at 10 years than other phenotypes. CONCLUSION: A proportion of childhood eczema, rhinitis and asthma is nonatopic. The commonest childhood pattern of atopy is chronic sensitization, associated with early, persisting and clinically significant allergic disease. The currently accepted childhood 'Allergic March' may oversimplify the natural history of childhood atopy and allergic disease.     

Levels of soluble CD30 in cord blood and peripheral blood during childhood are not correlated with the development of atopic disease or a family history of atopy

BACKGROUND: The CD30 molecule has been linked to Th2 responses. Furthermore, elevated levels of the soluble form of CD30 (sCD30) in blood as well as of the expression of CD30 on the plasma membrane of T cells are associated with atopic disease. OBJECTIVE: To assess the potential usefulness of sCD30 levels as a prognostic indicator of and/or diagnostic marker for the development of atopic disease in children. METHODS: sCD30 levels in cord blood and peripheral blood from 36 2-year-old (10 atopic and 26 non-atopic) and 74 7-year-old (35 atopic and 39 non-atopic) children were determined employing an ELISA procedure. Atopy was diagnosed on the basis of clinical evaluation in combination with a positive skin prick test. RESULTS: No significant correlation between sCD30 levels in cord blood and the development of atopic disease at 2 or 7 years of age was observed. At 7 years of age, the circulating sCD30 levels in children with atopic disease (median 41 U/mL, range 6-503 U/mL) did not differ from the corresponding values for non-atopic subjects (median 41 U/mL, range 8-402 U/mL). The same was true for children at 2 years of age. Furthermore, the sCD30 levels of children who had developed atopic eczema/dermatitis syndrome by the age of 7 years (median 49 U/mL, range 14-503 U/mL) were not significantly elevated in comparison with those of the non-atopic children. Finally, neither sCD30 levels in cord blood nor peripheral blood at 2 or 7 years of age could be linked to a family history of atopy. CONCLUSION: These findings indicate that the sCD30 concentration in cord blood is not a reliable prognostic indicator of, nor a useful diagnostic marker for, atopic disease in children up to 7 years of age. If such correlations do exist, they might be masked by age-dependent variations in the circulating levels of sCD30, which may reflect individual differences in the maturation of children's immunological responses.     

Effects of dog ownership in early childhood on immune development and atopic diseases

Background Exposure to pets in childhood has been associated with a reduced risk of wheezing and atopy. Objective Our objective was to determine whether the effects of pet exposure on immune development and atopy in early childhood can be explained by alterations in exposure to innate immune stimuli in settled dust. Methods Two hundred and seventy‐five children at increased risk of developing allergic diseases were evaluated to age 3 years for pet ownership, blood cell cytokine responses, and atopy. Can f 1, Fel d 1, endotoxin, ergosterol, and muramic acid were measured in settled dust from 101 homes. Results Dog exposure at birth was associated with decreased atopic dermatitis (AD) (12% vs. 27%; P=0.004) and wheezing (19% vs. 36%; P=0.005) in year 3. The rates of AD (23%) and wheezing (42%) in year 3 were relatively high in children who acquired dogs after birth. The prevalence of dog sensitization (10–12%) did not vary according to dog exposure. Can f 1 levels in bedroom dust were positively associated with IL‐10 (r=0.26; P=0.01), IL‐5 (r=0.34, P<0.001), and IL‐13 (r=0.28; P=0.004) responses at age 1, and IL‐5 (r=0.24; P=0.022) and IL‐13 (r=0.25; P=0.015) responses at age 3. In contrast, endotoxin was associated with IFN‐γ (r=0.31; P=0.002) and IL‐13 (r=0.27; P=0.01) responses at age 3 but not at age 1, and similar relationships were present for muramic acid. Adjustment for levels of innate immune stimuli in house dust did not significantly affect the relationships between Can f 1 and cytokine responses. Conclusions Exposure to dogs in infancy, and especially around the time of birth, is associated with changes in immune development and reductions in wheezing and atopy. These findings are not explained by exposure to endotoxin, ergosterol, or muramic acid.     

Features of childhood atopic dermatitis

Eczema or atopic dermatitis (AD) is the most common skin disease in children, and recent data derived from several studies showed that the prevalence of AD is still increasing in most Asian countries. The role of allergic reactions in AD is still a matter of debate. In some children allergy is not involved, while in others allergic reactions can trigger and maintain the skin lesions. Therefore, AD is now considered as a group of skin diseases with as a common feature the existence of a chronic skin inflammation. The underlying mechanisms of AD are not uniform, but differ from patient to patient, and also differ in one patient in time, suggesting the existence of different subtypes of AD, in a complex interplay. From different studies it is now suggested that at least 4 different players are involved in AD. These 4 players are: congenital skin barrier defects, allergy, autoimmunity (i.e. the production of autoantibodies against skin cells), and microbial agent colonization, especially colonization with bacteria, mainly Staphylococcus aureus. Much more needs to be discovered on the mechanisms of AD and other "players" might be discovered soon, as the current "4-player-model" cannot explain all features of AD. Treatment of AD might change in the near future. Today's cornerstones of treatment are still moisturizers (from a young age to prevent further skin barrier dysfunctions and allergic sensitization), local corticosteroids, and antiseptics, but new future therapeutic approaches become very likely.     

Breastfeeding duration is a risk factor for atopic eczema

BACKGROUND: The results of numerous studies on the influence of breastfeeding in the prevention of atopic disorders are often contradictory. One of the most important problems is confounding by other lifestyle factors. OBJECTIVE: The aim of the present study was to analyse the effect of any breastfeeding duration on the prevalence of atopic eczema in the first seven years of life taking into account other risk factors. METHODS: In an observational birth cohort study 1314 infants born in 1990 were followed-up for seven years. At 3, 6, 12, 18, 24 months and every year thereafter, parents were interviewed and filled in questionnaires, children were examined and blood was taken for in vitro allergy tests. Generalized Estimation Equations (GEE)-models were used to model risk factors for the prevalence of atopic eczema and for confounder adjustment RESULTS: Breastfeeding was carried out for longer if at least one parent had eczema, the mother was older, did not smoke in pregnancy, and the family had a high social status. The prevalence of atopic eczema in the first seven years increased with each year of age (OR 1.05; 95% CI 1.01-1.09 for each year), with each additional month of breastfeeding (1.03; 1.00-1.06 for each additional month), with a history of parental atopic eczema (2.06; 1.38-3.08), and if other atopic signs and symptoms appeared, especially specific sensitization (1.53; 1.25-1.88), and asthma (1.41; 1.07-1.85). Although breastfeeding should be recommended for all infants, it does not prevent eczema in children with a genetic risk. CONCLUSION: Parental eczema is the major risk factor for eczema. But in this study, each month of breastfeeding also increased the risk.     

Antibiotic use in the first year of life and risk of atopic disease in early childhood

Background Reduced post‐natal microbial stimulation resulting from improvements in public health measures, smaller family size, and through increased antibiotic use has been postulated to account for the increasing prevalence of atopic diseases seen predominantly in developed countries. Objective To investigate use of antibiotics in the first year of life and subsequent development of atopic disease in early childhood. Methods A prospective birth cohort of 198 children at high atopic risk was recruited prenatally and followed for 5 years. Illnesses and antibiotic use were ascertained through daily diaries, and diagnoses of asthma and hayfever were collected by questionnaire interviews. The children were examined regularly for eczema, and atopic status was defined by skin prick tests and serum total IgE. The effect of antibiotic use on subsequent atopic disease was examined using logistic regression with propensity score adjustment. Results 54.0% (107/198) of children received at least one course of antibiotics, mainly for acute respiratory illnesses (ARI). Thirty‐three percent (329/984) of the ARI involved the lower respiratory tract (LRI). Twenty‐three percent (222/984) of ARI were treated with antibiotics, with LRI significantly more likely to receive antibiotics. Antibiotic use was associated with asthma (unadjusted odds ratio 2.3; 95% confidence interval 1.2–4.5; P=0.01) but this association was reduced after propensity score adjustment. No associations were found between antibiotic use and eczema, current wheeze, current asthma, atopic asthma, allergic rhinoconjunctivitis or atopy. Conclusion Although this was a small study, systematic and careful monitoring of ARI, antibiotic use, and asthma and atopic diseases did not indicate that receipt of antibiotics early in life led to subsequent asthma or atopy at 5 years.     

The pattern of atopic sensitization is associated with the development of asthma in childhood.

BACKGROUND: Even though atopic sensitization has been shown to be strongly associated with childhood asthma, asthma eventually develops in only one third of atopic children. OBJECTIVE: The aim of this study was to prospectively investigate the pattern of atopic sensitization typically associated with the development of asthma in childhood. METHODS: The German Multicenter Allergy Study followed 1314 children from birth to the age of 7 years. Parental questionnaires on asthma and asthmatic symptoms were completed 6 times up to the age of 2 years and from then on yearly. Determination of specific IgE to 9 food and inhalant allergens was performed yearly, and at the age of 7 years, a bronchial histamine challenge was conducted. RESULTS: Onset of atopic sensitization in atopic children with current asthma at the age of 7 years was significantly earlier than in atopic children without current asthma (39.4% before age 1 year vs 21.0%, P =.015). Early atopic sensitization without any sensitization to inhalant allergens at the age of 7 years conferred no increased risk for asthma at this age. Only those children sensitized to any allergen early in life and sensitized to inhalant allergens by the age of 7 years were at a significantly increased risk of being asthmatic at this age (odds ratio, 10.12; 95% CI, 3.81-26.88). However, even in this group of persistently sensitized children, the risk of being asthmatic at the age of 7 years was only increased if a positive parental history of asthma or atopy was present (odds ratio, 15.56; 95% CI, 5.78-41.83), with the effect being strongest for maternal asthma. CONCLUSION: Our results indicate that an underlying factor pertaining to asthma and maternal transmission may determine both a certain pattern of sensitization and the expression of asthma.     

Early childhood environment related to microbial exposure and the occurrence of atopic disease at school age

BACKGROUND: There is a growing body of evidence that the early childhood environment with respect to day care attendance, older siblings, pet ownership, and early life airway infections may protect from developing atopic disease. Few studies have distinguished between atopic sensitization and symptoms, and none have evaluated independent contributions for all of these different environmental conditions. OBJECTIVE: Examine independent effects on atopic sensitization and symptoms of day care attendance, older siblings, pet ownership, and early infancy's airway disease. METHODS: A cross-sectional survey among 8-13-year-old school children with complete data for 1555 children. RESULTS: After adjustment for confounders, atopic sensitization occurred less frequently in children that had attended a day care centre (OR: 0.73, 95% CI: 0.55-0.98) or had a cat or dog before 2 years of age (OR: 0.78, 95% CI: 0.61-0.99). Having older siblings yielded a nonsignificant trend towards protection (OR: 0.88, 95% CI: 0.70-1.11). For symptoms, there was no relation with having older sibs, day care attendance and pet ownership, although there was a trend towards protection for the combination of atopy and symptoms. In contrast, children with doctors' treated airway disease before age 2, more frequently reported recent symptoms of wheeze, asthma, rhinitis, or dermatitis (all P < 0.05). CONCLUSION: Early life environmental exposure to day care, or pets may protect against atopic sensitization. Protection against symptoms only occurred if atopic sensitization was present as well.