Asthma is associated with carotid arterial injury in children: The Childhood Origins of Asthma (COAST) Cohort.

BACKGROUND: Asthma is associated with an increased cardiovascular disease (CVD) risk in adults, but the impact of asthma and atopic conditions on CVD risk in children is less well established. We hypothesized that children in the Childhood Origins of Asthma (COAST) Cohort with asthma and atopic conditions would have early carotid arterial injury. METHODS: The COAST study is a longitudinal birth cohort of children at increased risk of developing asthma. Children underwent ultrasonography measuring far wall right carotid bifurcation (RCB) and common carotid artery (RCCA) intima-media thickness (IMT; a measure of arterial injury). Multivariable linear regression models adjusted for age, gender, race, blood pressure, and body-mass index were used to assess associations of asthma and markers of arterial injury. RESULTS: The 89 participants were a mean (standard deviation) 15.3 (0.6) years old and 42% were female; 28 asthmatics had atopic disease, 34 asthmatics were without other atopic disease, and 15 non-asthmatics had atopic disease. This study population was compared to 12 controls (participants free of asthma or atopic disease). Compared to controls (589 µm), those with atopic disease (653 µm, p = 0.07), asthma (649 µm, p = 0.05), or both (677 µm, p = 0.005) had progressively higher RCB IMT values (ptrend = 0.011). In adjusted models, asthmatic and/or atopic participants had significantly higher RCB IMT than those without asthma or atopic disease (all p≤0.03). Similar relationships were found for RCCA IMT. CONCLUSION: Adolescents with asthma and other atopic diseases have an increased risk of subclinical arterial injury compared to children without asthma or other atopic disease.

Early childhood weight status in relation to asthma development in high-risk children.

BACKGROUND: Obesity has been proposed to be a risk factor for the development of childhood asthma. OBJECTIVE: We sought to examine weight status from birth to age 5 years in relation to the occurrence of asthma at ages 6 and 8 years. METHODS: Two hundred eighty-five full-term high-risk newborns with at least 1 asthmatic/atopic parent enrolled in the Childhood Origin of Asthma project were studied from birth to age 8 years. Overweight was defined by weight-for-length percentiles of greater than the 85th percentile before the age of 2 years and a body mass index percentile of greater than the 85th percentile at ages 2 to 5 years. RESULTS: No significant concurrent association was found between overweight status and wheezing/asthma occurrence at each year of age. In contrast, longitudinal analyses revealed complex relationships between being overweight and asthma. Being overweight at age 1 year was associated with a decreased risk of asthma at age 6 (odds ratio [OR], 0.32; P = .02) and 8 (OR, 0.35; P = .04) years, as well as better lung function. However, being overweight beyond infancy was not associated with asthma occurrence. In fact, only children who were overweight at age 5 years but not at age 1 year had an increased risk of asthma at age 6 years (OR, 5.78; P = .05). CONCLUSION: In children genetically at high risk of asthma, being overweight at age 1 year was associated with a decreased risk of asthma and better lung function at ages 6 and 8 years. However, being overweight beyond infancy did not have any protective effect and even could confer a higher risk for asthma.

The relationships among immunoglobulin levels, allergic sensitization, and viral respiratory illnesses in early childhood.

IgE plays an essential role in type I allergy, however, there is less information about the relationship between other immunoglobulins (IgA and IgG) and atopic phenotypes in early childhood. We hypothesized that levels of circulating IgA in early childhood would be inversely related to the number of respiratory infections and the risk of becoming sensitized to allergens. Immunoglobulin levels were analyzed (ELISA) in plasma samples (IgG, IgA), and in nasal secretions (IgA) from children participating in a high-risk birth cohort study. Samples were available from 264 children at age 2 yr and 257 children at age 4 yr, and results were compared to rates of respiratory illnesses, allergic sensitization, atopic dermatitis (AD), and asthma. Children who were sensitized to allergens had higher rather than lower levels of circulating IgA. A subgroup analysis showed that IgA levels were increased in relationship to foods sensitization (58 vs. 50 mg/dl, p = 0.003) but not aeroallergen sensitization (52 vs. 53 mg/dl, p = 0.11). IgA levels in the plasma correlated with levels of IgE levels (r(s) =0.19, p = 0.003). Levels of IgE, but not IgG or IgA, were positively correlated with rates of respiratory illnesses, AD, and the risk of developing asthma. Finally, there were no significant relationships between IgA in nasal secretions and infectious outcomes. In conclusion, low-normal concentrations of plasma IgA are associated with a reduced prevalence of allergic sensitization in infancy. Further, levels of IgA and IgG in plasma within the range of normal, and IgA in nasal secretions, do not appear to influence the risk of subsequent respiratory illnesses. Further studies to define relationships between IgA and allergic sensitization are likely to provide new insights into the pathogenesis of allergic diseases in infancy.

Fractional exhaled nitric oxide measurements are most closely associated with allergic sensitization in school-age children.

BACKGROUND: Factors affecting fractional exhaled nitric oxide (FeNO) in early childhood are incompletely understood. OBJECTIVE: To examine the relationships between FeNO and allergic sensitization, total IgE, atopic dermatitis, rhinitis, asthma, and lung function (spirometry) in children. METHODS: Children at high risk of asthma and other allergic diseases because of parental history were enrolled at birth and followed prospectively. FeNO was measured by an online technique at ages 6 and 8 years. Relationships among FeNO, various atopic characteristics, and asthma were evaluated. RESULTS: Reproducible FeNO measurements were obtained in 64% (135/210) of 6-year-old and 93% (180/194) of 8-year-old children. There was seasonal variability in FeNO. Children with aeroallergen sensitization at ages 6 and 8 years had increased levels of FeNO compared with those not sensitized (geometric mean; 6 years, 10.9 vs 6.7 parts per billion [ppb], P < .0001; 8 years, 14.6 vs 7.1 ppb, P < .0001). FeNO was higher in children with asthma than in those without asthma at 8 years but not 6 years of age (6 years, 9.2 vs 8.3 ppb, P = .48; 8 years, 11.5 vs 9.2 ppb, P = .03). At 8 years of age, this difference was no longer significant in a multivariate model that included aeroallergen sensitization (P = .33). There were no correlations between FeNO and spirometric indices at 6 or 8 years of age. CONCLUSION: These findings underscore the importance of evaluating allergen sensitization status when FeNO is used as a potential biomarker in the diagnosis and/or monitoring of atopic diseases, particularly asthma.

Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children.

RATIONALE: Virus-induced wheezing episodes in infancy often precede the development of asthma. Whether infections with specific viral pathogens confer differential future asthma risk is incompletely understood. OBJECTIVES: To define the relationship between specific viral illnesses and early childhood asthma development. METHODS: A total of 259 children were followed prospectively from birth to 6 years of age. The etiology and timing of specific viral wheezing respiratory illnesses during early childhood were assessed using nasal lavage, culture, and multiplex reverse transcriptase-polymerase chain reaction. The relationships of these virus-specific wheezing illnesses and other risk factors to the development of asthma were analyzed. MEASUREMENTS AND MAIN RESULTS: Viral etiologies were identified in 90% of wheezing illnesses. From birth to age 3 years, wheezing with respiratory syncytial virus (RSV) (odds ratio [OR], 2.6), rhinovirus (RV) (OR, 9.8), or both RV and RSV (OR , 10) was associated with increased asthma risk at age 6 years. In Year 1, both RV wheezing (OR, 2.8) and aeroallergen sensitization (OR, 3.6) independently increased asthma risk at age 6 years. By age 3 years, wheezing with RV (OR, 25.6) was more strongly associated with asthma at age 6 years than aeroallergen sensitization (OR, 3.4). Nearly 90% (26 of 30) of children who wheezed with RV in Year 3 had asthma at 6 years of age. CONCLUSIONS: Among outpatient viral wheezing illnesses in infancy and early childhood, those caused by RV infections are the most significant predictors of the subsequent development of asthma at age 6 years in a high-risk birth cohort.

Association between CD4(+)CD25(high) T cells and atopy in children.

BACKGROUND: There is evidence that CD4(+)CD25(high) T-regulatory cells are important for establishing tolerance to allergens, but information in children is limited. OBJECTIVE: To test the hypothesis that greater numbers and function of CD4(+)CD25(high) T cells are associated with a reduced risk of childhood allergies and wheezing. METHODS: A cohort of 151 six-year-old children from atopic families was analyzed for peripheral blood CD4(+)CD25(high) and CD4(+)CD25(int) T cells by flow cytometry and for clinical and immunologic correlates of atopy. The associations between these variables were assessed by regression analysis. RESULTS: Factors positively associated with % CD4(+)CD25(high)/CD4 T cells were male sex, number of positive allergen-specific IgE tests, total IgE, season, and 1-month average total pollen count preceding blood draw. The percentage of CD4(+)CD25(high)/total CD4 T cells did not correlate with induced cytokine production, and correlated negatively with suppressive capacity of CD4(+)CD25(+) T cells (r = -0.45; P = .034). The percentage of CD4(+)CD25(int)/CD4 T cells was 54% higher in pollen-sensitized children compared with nonsensitized children in spring (P = .023 for interaction), and correlated positively with IL-5, IL-10, and IL-13 (P < or = .001 for all). CONCLUSION: Our findings suggest that blood CD4(+)CD25(high) cells are a mixture of activated and regulatory T cells, and that these cells could be seasonally regulated by environmental factors such as pollen exposure. CLINICAL IMPLICATIONS: Seasonal increases in CD4CD25(high) expression in children with allergy may represent systemic immune activation caused by pollen exposures.

Viral infections, cytokine dysregulation and the origins of childhood asthma and allergic diseases.

BACKGROUND: The origins of asthma and allergic disease begin in early life for many individuals. It is vital to understand the factors and/or events leading to their development. METHODS: The Childhood Origins of Asthma project evaluated children at high risk for asthma to study the relationships among viral infections, environmental factors, immune dysregulation, genetic factors, and the development of atopic diseases. Consequently wheezing illnesses, viral respiratory pathogen identification, and in vitro cytokine response profiles were comprehensively evaluated from birth to 3 years of age, and associations of the observed phenotypes with genetic polymorphisms were investigated. RESULTS: For the entire cohort, cytokine responses did not develop according to a strict T helper cell 1 or T helper cell 2 polarization pattern during infancy. Increased cord blood mononuclear cell phytohemagglutin-induced interferon-gamma responses of mononuclear cells were associated with decreased numbers of moderate to severe viral infections during infancy, especially among subjects with the greatest exposure to other children. In support of the hygiene hypothesis, an increased frequency of viral infections in infancy resulted in increased mitogen-induced interferon-gamma responses at 1 year of age. First year wheezing illnesses caused by respiratory viral infection were the strongest predictor of subsequent third year wheezing. Also, genotypic variation interacting with environmental factors, including day care, was associated with clinical and immunologic phenotypes that may precede the development of asthma. CONCLUSIONS: Associations between clinical wheezing, viral identification, specific cytokine responses and genetic variation provide insight into the immunopathogenesis of childhood asthma and allergic diseases.

Rhinovirus illnesses during infancy predict subsequent childhood wheezing.

BACKGROUND: The contribution of viral respiratory infections during infancy to the development of subsequent wheezing and/or allergic diseases in early childhood is not established. OBJECTIVE: To evaluate these relationships prospectively from birth to 3 years of age in 285 children genetically at high risk for developing allergic respiratory diseases. METHODS: By using nasal lavage, the relationship of timing, severity, and etiology of viral respiratory infections during infancy to wheezing in the 3rd year of life was evaluated. In addition, genetic and environmental factors that could modify risk of infections and wheezing prevalence were analyzed. RESULTS: Risk factors for 3rd year wheezing were passive smoke exposure (odds ratio [OR]=2.1), older siblings (OR=2.5), allergic sensitization to foods at age 1 year (OR=2.0), any moderate to severe respiratory illness without wheezing during infancy (OR=3.6), and at least 1 wheezing illness with respiratory syncytial virus (RSV; OR=3.0), rhinovirus (OR=10) and/or non-rhinovirus/RSV pathogens (OR=3.9) during infancy. When viral etiology was considered, 1st-year wheezing illnesses caused by rhinovirus infection were the strongest predictor of subsequent 3rd year wheezing (OR=6.6; P < .0001). Moreover, 63% of infants who wheezed during rhinovirus seasons continued to wheeze in the 3rd year of life, compared with only 20% of all other infants (OR=6.6; P < .0001). CONCLUSION: In this population of children at increased risk of developing allergies and asthma, the most significant risk factor for the development of preschool childhood wheezing is the occurrence of symptomatic rhinovirus illnesses during infancy that are clinically and prognostically informative based on their seasonal nature.

Cytokine response patterns, exposure to viruses, and respiratory infections in the first year of life.

Daycare attendance and siblings are associated with viral-induced wheezing in children. Preexisting immunologic factors may influence the expression of viral infections in infancy, and in turn, recurrent infections may influence the development of immune responses. A total of 285 children were enrolled in the Childhood Origins of Asthma Project at birth and followed for at least 1 year. Cord blood and 1-year mononuclear cells were stimulated with phytohemagglutinin, and cytokine-response profiles were measured by enzyme-linked immunosorbent assay. Nasal lavage was performed for moderate to severe respiratory illnesses. Daycare attendance and/or siblings significantly increased the likelihood of contracting respiratory syncytial virus (1.5-1.6-fold increase) and rhinovirus (1.8-2.1-fold increase), and increased the risk of rhinovirus-induced wheezing (14-18% vs. 2%, p = 0.011). Cord blood IFN-gamma responses were inversely related to the frequency of viral respiratory infections (r(s) = -0.11, p = 0.05), and more significant for subjects with high exposure to other children (r(s) = -0.27, p = 0.028). The interval change in infantile IFN-gamma responses correlated positively with the frequency of viral infections in infancy (r(s) = 0.12, p = 0.047). These data suggest that neonatal IFN-gamma responses may influence antiviral activity, or may represent a marker of antiviral immunity maturation. Conversely, the frequency of viral infections in infancy can influence IFN-gamma responses.

Developmental cytokine response profiles and the clinical and immunologic expression of atopy during the first year of life.

BACKGROUND: Allergic diseases have been linked to abnormal patterns of immune development, and this has stimulated efforts to define the precise patterns of cytokine dysregulation that are associated with specific atopic phenotypes. OBJECTIVE: Cytokine-response profiles were prospectively analyzed over the first year of life and compared with the clinical and immunologic expressions of atopy. METHODS: Umbilical cord and 1-year PBMCs were obtained from 285 subjects from allergic families. PHA-stimulated cytokine-response profiles (IL-5, IL-10, IL-13, and IFN-gamma) were compared with blood eosinophil counts and total and specific IgE levels (dust mites, cat, egg, Alternaria species, peanut, milk, and dog) at age 1 year and at the development of atopic dermatitis and food allergy. RESULTS: For the cohort as a whole, cytokine responses did not evolve according to a strict TH1 or TH2 polarization pattern. PHA-stimulated cord blood cells secreted low levels of IL-5 (2.1 pg/mL), moderate levels of IFN-gamma (57.4 pg/mL), and greater amounts of IL-13 (281.8 pg/mL). From birth to 1 year, IL-5 responses dramatically increased, whereas IL-13 and IFN-gamma responses significantly decreased. Reduced cord blood secretion of IL-10 and IFN-gamma was associated with subsequent sensitization to egg. In addition, there was evidence of TH2 polarization (increased IL-5 and IL-13 levels) associated with blood eosinophilia and increased total IgE levels by age 1 year. CONCLUSION: These findings demonstrate that cytokine responses change markedly during the first year of life and provide further evidence of a close relationship between TH2 skewing of immune responses and the incidence of atopic manifestations in children.