Xiaomei Mai

Leptin and asthma in overweight children at 12 years of age

Obesity is suggested as a risk factor for asthma, but the mechanisms are unclear. The relationship between obesity and asthma has not been considered in children born with very low‐birth weight (VLBW). We hypothesized that overweight was a contributing factor for asthma in VLBW children, and that leptin and leptin‐associated cytokines might play roles in overweight‐related asthma. Seventy‐four VLBW and 64 normal birth weight (NBW) children participated in a 12‐yr follow up study assessing asthma and allergy. Twenty‐seven (12 VLBW) of the 138 children were overweight according to the proposed international definition. The diagnosis of current asthma was made by a pediatrician. Serum levels of leptin and interferon (IFN)‐γ were analyzed by enzyme‐linked immunosorbent assay (ELISA). Leptin levels were considerably higher in the overweight than in the non‐overweight children (median value: 18.1 vs. 2.8 ng/ml, p < 0.001). In the overweight children, current asthmatics had twice as high levels of leptin as children without current asthma (median value: 30.8 vs. 14.3 ng/ml, p = 0.14), but this was not the case in the non‐overweight children. IFN‐γ was more often detected in the overweight than in the non‐overweight children (61% vs. 12%, p < 0.001), and there was a positive correlation between the levels of leptin and the levels of IFN‐γ (Rho = 0.40, p < 0.001). In the VLBW group, the overweight children had a significantly increased risk for current asthma compared with the non‐overweight children after adjustment for the neonatal risk factors [adjusted odds ratio (OR) 5.8, 95% confidence interval (CI): 1.2–27]. Thus, overweight was associated with asthma in the VLBW children. Our hypothesis remained that leptin might be involved in the pathogenesis of asthma in the overweight children, and IFN‐γ might be a pathway in the process of leptin‐induced inflammation.

Asthma, lung function and allergy in 12-year-old children with very low birth weight: a prospective study.

We assessed the relationship between very low birth weight (VLBW) (≤1500 g) and the development of asthma, lung function and atopy. The study groups comprised 74 of all 86 (86%) VLBW and 64 of all 86 (74%) matched term children who were prospectively followed for 12 years. A questionnaire on asthmatic and allergic symptoms was completed and skin prick tests, spirometry and hypertonic saline provocation tests were performed at 12 years of age. Cytokine secretion was analysed in stimulated blood leukocyte cultures in 28 VLBW and 23 term children. A history of asthma was more frequent among the VLBW children, as compared with the term children at age 12 (22% vs. 9%, p = 0.046). Among the VLBW children, very preterm birth (gestational age: week 25 to 29) (RR 2.5, 95%CI 1.1–5.8), neonatal mechanical ventilation (RR 2.8, 95%CI 1.2–6.4) and neonatal oxygen supplementation (RR 4.3, 95%CI 1.3–14.0) were significantly associated with a history of asthma by the age of 12 years in univariate analyses. In multivariate logistic regression, neonatal oxygen supplementation ≥ 9 days was the only remaining significant risk factor for a history of asthma (adjusted OR 6.7, 95%CI 1.0–44). The VLBW children who required mechanical ventilation during the neonatal period were more likely to have bronchial hyperresponsiveness than those not requiring mechanical ventilation (60% vs. 28%, p = 0.050). The spirometric values were similar among the VLBW and the term children at 12 years. Very low birth weight was not significantly related to allergic rhinoconjunctivitis, eczema or positive skin prick tests. Furthermore, the levels of IL‐4, IL‐5 and IFN‐γ in stimulated cell cultures were similar in the VLBW and the term children. A history of asthma by 12 years of age was twice as common among the VLBW as the term children, and neonatal oxygen supplementation seemed to be associated with the increased risk. Furthermore, mechanical ventilation during the neonatal period was associated with bronchial hyperresponsiveness at age 12. Very low birth weight per se was not, however, related to atopy.

High body mass index, asthma and allergy in Swedish schoolchildren participating in the International Study of Asthma and Allergies in Childhood: Phase II

Aim: To assess the relationship between high body mass index (BMI) and asthma and atopic manifestations in 12‐y‐old children. Methods: The relationship between high BMI and asthma symptoms was studied in 457 sixth‐grade children, with (n= 161) and without (n= 296) current wheeze. High BMI was defined as ±75th percentile of gender‐specific BMI reference values for Swedish children at 12 y of age; overweight as a subgroup of high BMI was defined as ±95th percentile. Children with a BMI >75th percentile served as controls. Questionnaires were used to assess asthmatic and allergic symptoms, and bronchial hyperresponsiveness was assessed by hypertonic saline provocation tests. Results: Current wheeze was associated with high BMI after adjustment for confounding factors (adjusted OR 1.7, 95% CI 1.0–2.5) and overweight had an even more pronounced effect (adjusted OR 1.9, 95% CI 1.0–3.6). In addition, asthma severity was associated with high BMI, as evaluated by the number of wheezing episodes during the previous 12 mo among the wheezing children (adjusted OR 2.0, 95% CI 1.0–4.0). There was also an association between high BMI and the presence of eczema in wheezing children (adjusted OR 2.2, 95% CI 1.0–4.6). However, high BMI was not significantly associated with hay fever, positive skin prick tests or bronchial hyperresponsiveness.

Wheezing in relation to atopy and environmental factors in Estonian and Swedish schoolchildren.

Background The prevalence of asthma and allergic diseases is significantly lower in post socialist Eastern Europe than in Western industrialized countries. The reason for this difference is largely unknown. Different types of childhood wheezing could be related to different risk factors.

Early rapid weight gain and current overweight in relation to asthma in adolescents born with very low birth weight.

Early catch‐up growth and subsequent overweight are suggested to be associated with later cardiovascular diseases and later type II diabetes. However, the impact of early catch‐up growth and childhood overweight on the development of asthma has been less studied, particularly in children born with very low birth weight (VLBW). A birth cohort of 74 VLBW children (birth weight ≤ 1500 g) was followed from birth and investigated on asthma at 12 yr of age. Early rapid weight gain was in one way defined as an increase of weight ≥1 standard deviation score (SDS) at 6 months of corrected postnatal age. Current overweight was defined by body mass index (BMI) exceeding 21.2 and 21.7 kg/m2, respectively, for boys and girls at 12 yr of age. Current asthma was diagnosed by a pediatrician, according to asthma ever in combination with a positive response to hypertonic saline bronchial provocation test and/or wheeze at physical examination at 12 yr old. Being overweight at 12 yr of age was associated with an increased risk for current asthma in the VLBW children [crude odds ratio (OR): 5.5, 95% confidence interval (CI): 1.3–22.2]. After adjustment for early weight gain and neonatal risk, the OR of overweight increased nearly three times (adjusted OR: 15.3, 95% CI: 2.5–90.6). Early rapid weight gain seemed to be inversely associated with current asthma (adjusted OR: 0.49 for an increase of weight equal to 1 SDS, 95% CI: 0.23–1.02, p = 0.06). In addition, early rapid weight gain was inversely associated with the magnitude of bronchial responsiveness at 12 yr (coefficient −1.15, p < 0.01). There was a strong and positive association between overweight and asthma at 12 yr of age in the VLBW children. This strong association had been reduced by early rapid weight gain, possibly via the reduction of bronchial responsiveness.

Hypertonic saline challenge tests in the diagnosis of bronchial hyperresponsiveness and asthma in children

The hypertonic saline challenge test is the recommended method to assess bronchial hyperresponsiveness in the International Study of Asthma and Allergies in Childhood (ISAAC). The sensitivity of this procedure to assess asthma symptoms, however, has been reported to vary among study centers. The purpose of our study was to evaluate the value of this provocation test in an epidemiological survey in children, and to relate the degree of bronchial hyperresponsiveness to the severity of asthma symptoms. All 11–13‐year‐old children from 16 randomly selected schools in Linköping, Sweden received a questionnaire regarding respiratory symptoms and allergic disease. Skin prick tests with eight inhalant allergens were performed. In addition, all children with wheeze over the past 12 months (current wheeze) and a random sample of children without current wheeze were invited to perform hypertonic saline provocation tests. A complete data set was available for 170 children, including 50 with and 120 without current wheeze. Bronchial hyperresponsiveness (BHR) was defined as at least 15% decline in FEV1. The degree of BHR was represented by the response/dose ratio, i.e. the fall in FEV1 divided by total dose of inhaled saline. The severity of asthma symptoms was classified by the number of wheezing episodes over the past 12 months. ‘Asthma ever’ was defined by a combination of symptoms in the questionnaires. Children with ‘asthma ever’ and current wheeze were considered as having current asthma. Current atopic asthma was defined as current asthma with at least one positive skin prick test. The sensitivity of the procedure to detect ‘asthma ever’, current asthma and current atopic asthma was 62, 61 and 83%, and the specificity 83, 81 and 60%, respectively. The positive challenge rate was 52, 34, 13 and 7% among current wheezers, previous wheezers, non‐wheezers with a history of allergy and healthy children. The degree of bronchial hyperresponsiveness increased with the number of wheezing episodes. Thus, the median and range of the response/dose ratio were 4.8%/ml (2.1–14.8), 2.6%/ml (0.7–8.6) and 1.3%/ml (0.8–2.7), respectively, for children with ≥ 4 episodes, 1–3 episodes and no wheezing episodes over the past 12 months (p<0.001). In conclusion, hypertonic saline provocation test is useful as a tool to detect asthma in epidemiological studies in children. The degree of bronchial hyperresponsiveness, as represented by the response/dose ratio, reflects the severity of asthma symptoms.

Allergen‐induced cytokine secretion in atopic and non‐atopic asthmatic children

Atopic asthma is characterized by excessive T helper 2 (Th2)‐like immunity to allergens in the bronchial mucosa. The Th2‐cytokine interleukin (IL)‐4 induces IgE production, while the Th2‐cytokine IL‐5 promotes eosinophilic inflammation in the airways of asthmatics. Most asthmatics are atopic, but a subgroup is non‐atopic. We hypothesize that allergen‐induced Th2, particularly IL‐5, responses can be observed in peripheral blood in both atopic and non‐atopic asthmatic children but not in healthy control children. The aim of the present study was to determine IL‐4, IL‐5, IL‐9, IL‐10, IL‐13 and IFN‐γ secretion induced from peripheral blood mononuclear cells (PBMC) by a broad panel of inhalant allergens (timothy, cat, birch, dog and house dust mite) in asthmatic children with and without sensitization. The study included 13 atopic asthmatic, 5 non‐atopic asthmatic, and 12 non‐atopic non‐asthmatic children. PBMC were stimulated with allergens and cytokine production was measured with enzyme‐linked immunosorbent assay (ELISA). Higher levels of cat and dog antigen‐induced IL‐5 release were more commonly observed in both atopic and non‐atopic asthmatics than in controls. Children with atopic, but not non‐atopic, asthma produced higher levels of allergen‐induced IL‐4 and IL‐9 than controls. Non‐atopic asthmatics produced more IL‐10 than atopic asthmatics after cat stimulation. High levels of eosinophilia‐associated IL‐5 responses are induced by cat and dog allergen in both atopic and non‐atopic asthmatic children. The Th2 cytokines IL‐4 and IL‐9 were associated only with atopic asthma, probably due to their IgE‐inducing properties.

Birth anthropometric measures, body mass index and allergic diseases in a birth cohort study (BAMSE)

Objective: We aimed to assess increased birth weight or birth length in relation to allergic diseases at 4 years of age, taking body mass index (BMI) at age 4 as a covariate in the adjustment. Methods: The parents of a large prospective birth cohort answered questionnaires on environmental factors and allergic symptoms when their children were 2 months and 1, 2 and 4 years old. Perinatal data on weight and length at birth were received from the child care health centres. The children were clinically examined at 4 years of age and height and weight recorded. Blood was drawn for analysis of specific IgE antibodies to common inhalant allergens. Risk associations between birth anthropometric measures and wheeze, allergic diseases or sensitisation were estimated in multivariate logistic regression analyses (n = 2869). Results: There were no clear overall associations between birth weight and allergic diseases at 4 years of age. Birth length ⩾90th percentile was inversely associated with any wheeze at age 4 (adjusted OR 0.64, 95% CI 0.44 to 0.92) but was significantly associated only with late-onset wheeze (adjusted OR 0.40, 95% CI 0.21 to 0.77). No such associations were seen for persistent or transient wheeze, eczema, rhinitis or allergic sensitisation. Transient wheeze during the first 2 years of age tended to be associated with increased BMI at age 4. Conclusion: Increased birth weight was not associated with wheeze or allergic disease. Increased birth length may play a protective role in late-onset wheeze in early childhood.

Early Childhood Overweight and Asthma and Allergic Sensitization at 8 Years of Age

Objectives: Our aim was to examine the associations between high BMI and changes in BMI status during the first 7 years of life and asthma and allergic sensitization at age 8 years. Methods: A birth cohort of newborn infants was followed for 8 years. Repeated parental questionnaires provided information on environmental exposures and health outcomes. Information on height and weight during childhood was retrieved from preschool and school health care records. The analyses included the 2075 children for whom information was available on weight and height, as well as on asthma, at age 8 years. Results: A high BMI (≥85th percentile) at age 1, 4, and/or 7 years was associated with an increased risk of asthma at age 8 years. However, no significant association was observed among children with high BMI at age 12 and/or 18 months (early age) or at age 4 years who developed a normal BMI by age 7 years. The risk was increased among children with high BMI at age 7 years, regardless of their earlier weight. Moreover, we observed an increased risk of sensitization to inhalant allergens among children with high BMI at age 7 years. Conclusions: Our study indicates that high BMI during the first 4 years does not increase the risk of asthma at school age among children who have developed a normal weight by age 7 years. However, high BMI at age 7 years is associated with an increased risk of asthma and sensitization to inhalant allergens.

Urinary inflammatory mediators and inhalation of hypertonic saline in children

Background:  The inflammatory mechanisms of hypertonic saline‐induced bronchoconstriction are not well understood.