Acta Pñdiatr 92: 1144±1148. 2003 High body mass index, asthma and allergy in Swedish schoolchildren participating in the International Study of Asthma and Allergies in Childhood: Phase II X-M Mai1, L Nilsson1, O Axelson2, L Bråbäck3, A Sandin4, N-IM Kjellman1 and B Björkstén5 Department of Molecular and Clinical Medicine, Division of Paediatrics1, Division of Occupational and Environmental Medicine2, Linköping University, Sweden; Mid-Sweden Research and Development Centre3, Sundsvall Hospital, Sweden; Department of Paediatrics4, Östersund Hospital, Sweden; Centre for Allergy Research and Institute of Environmental Medicine5, Karolinska Institutet, Stockholm, Sweden Mai X-M, Nilsson L, Axelson O, Bråbäck L, Sandin A, Kjellman N-IM, Björkstén B. High body mass index, asthma and allergy in Swedish schoolchildren participating in the International Study of Asthma and Allergies in Childhood: Phase II. Acta Pædiatr 2003; 92: 1144–1148. Stockholm. ISSN 0803-5253 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. Conclusion: The study confirms and extends a previously observed relationship between BMI and the presence of wheezing and asthma. Key words: Asthma, body mass index, bronchial hyperreactivity, eczema, overweight Xiao-Mei Mai, Department of Molecular and Clinical Medicine, Division of Paediatrics, Faculty of Health Sciences, SE-581 85 Linköping, Sweden (Tel. ‡46 13 224 700, fax. ‡46 13 224 773, e-mail. xiama@imk.liu.se) The increasing prevalence of asthma in Western countries (1) has coincided with an increase in the number of people who are overweight, both children and adults (2, 3). An increased body mass index (BMI) has been reported to be associated with an increased prevalence of asthma (4–9). Furthermore, high BMI appears to be a risk factor for the development of asthma rather than a consequence, as indicated by several prospective studies (10–13). A gender-specific relationship has been shown consistently in female but not in male adults (4–6, 11–13), whereas the findings are inconsistent in children (7–10). The association of BMI with other allergic diseases and bronchial hyperresponsiveness has been less extensively studied, although a high prevalence of positive skin-prick tests was observed in teenage Taiwanese girls (14) and young Finnish adults (15) with high BMI. In another  2003 Taylor & Francis. ISSN 0803-5253 study, however, there was no relationship between BMI and skin-prick-test positivity, nor serum eosinophil counts (9). Exercise-induced bronchospasm, but not bronchial hyper-responsiveness to histamine (16), is more common in obese children than in children of normal weight (17). These contradictory reports prompted us to analyse the relationship between high BMI and asthma symptoms as well as other allergic diseases, skin-prick tests and bronchial hyperresponsiveness in 12-y-old children. Materials and Methods Data collection The study was part of the International Study of Asthma and Allergies in Childhood (ISAAC) Phase II (18) and DOI 10.1080/08035250310005666 High BMI, asthma and allergy in children ACTA PÆDIATR 92 (2003) 1145 included 2505 sixth-grade children (mean age 12 y, range 11 to 13 y) in two Swedish cities (Linköping and Östersund). Details about the study groups have been previously reported (19). Eighty-four percent of the parents completed ISAAC questionnaires regarding respiratory symptoms, eczema and environmental factors and 74% of the children participated in skin prick tests. All 195 children who reported wheeze over the previous 12 mo (current wheeze) and a random sample of 451 children without current wheeze were invited to participate in hypertonic saline provocation tests. From this group, 166 (85%) children with and 302 (67%) children without current wheeze underwent the tests. Gender distribution and the prevalence of a parental history of allergy, positive skin-prick tests and allergic disease were similar among those who participated and those who did not participate in the study. A research nurse measured body weight (subjects in underwear only) and height before the tests were started. This enabled us to perform a case-control study of BMI and wheezing symptoms. BMI was calculated as weight in kilograms, divided by the square of the height in metres. Gender-specific BMI reference values for Swedish children at 12 y of age (20) were used to identify groups of increased BMI. High BMI was defined as BMI 75th percentile (boys: BMI 19.3; girls: BMI 19.4), and overweight as a subgroup of high BMI was defined as BMI 95th percentile (boys: BMI 22.4; girls: BMI 23.2). Children with a BMI <75th percentile served as controls. Eleven children (5 with current wheeze) were excluded because of missing data on weight and height, thus leaving a data set of 457 children (161 with current wheeze). Current exerciseinduced wheeze, ever asthma, hay fever and eczema were defined as affirmative answers to the specific questions in the ISAAC questionnaire. Parental history of allergy was defined as at least one of the parents having or having had asthma and/or other allergic diseases. Environmental tobacco smoke was defined as at least one of the family members smoking more than one cigarette per day. Hypertonic saline provocation tests Hypertonic saline provocation tests were performed according to the ISAAC protocol (18). The method has been validated in a previous study (21). In brief, two reproducible measurements (within 5%) of FEV1 (forced expiratory volume in 1 s) were performed using a MasterScope spirometer (Jaeger), and the highest measurement was recorded as the baseline FEV1. Hypertonic saline (4.5%) was nebulized via a Devilbiss Ultraneb 2000 connected to a 60-cm tube (Devilbiss No. 8885) and a two-way valve (Laerdal valve No. 560 200/ 850 500, Devilbiss, manufactured by Dahlhausen, Cologne, Germany). The child was encouraged to maintain tidal breathing. The exposure time was progressively increased from 30 s to 1, 2, 4 and 8 min each and the maximum total inhalation period was 15.5 min. After each exposure, two reproducible measurements of FEV1 were made. The exposure time was doubled if the fall in FEV1 was less than 10%. The same dose was repeated if the fall was between 10 and 15%. The challenge test was stopped and considered to be positive when the decline in FEV1 was more than 15%. Skin-prick tests Ethical aspects The study was approved by the Human Research Ethics Committee of the Medical Faculty at Linköping University. Parents of the participating children gave their informed consent. Skin-prick tests were performed in duplicate on the forearms using extracts of birch pollen, grass pollen, dander of cat, dog and horse, D. pteronyssinus, D. farinae and Alternaria (ALK, Hørsholm, Denmark) according to the ISAAC module (18). Histamine 10 mg/ml and 50% glycerine were used as positive and negative controls, respectively. The size of a wheal was recorded as the mean of the greatest diameter and the diameter perpendicular to its mid-point. A mean diameter of 3 mm or more of the duplicate wheals was regarded as positive. Statistical analyses The Epi Info 2000 program (Centres for Disease Control and Prevention, Epidemiology Program Office and WHO) was used to calculate w2 for a trend of increased BMI for current wheeze. Since controls were random samples in this case-control study, unconditional logistic regression (22) was used with Stat View 5.0 for Macintosh (Abacus Concepts Inc., Berkeley, California, USA) to obtain crude and adjusted ORs (95% CI) of high BMI and overweight as a subgroup in relation to current wheeze. When the 95% CI excludes unity, the result is referred to as statistically significant. The possible association between high BMI and episodes of wheezing during the previous 12 mo, current exercise-induced wheeze, ever asthma, hay fever or eczema, positive skin-prick tests and bronchial hyperresponsiveness was analysed separately in children with current wheezing and children without current wheezing. Results Current wheeze was associated with increased BMI (Table 1). Furthermore, current wheeze was associated with high BMI after adjustment for potential confounding factors (parental history of allergy, maternal 1146 X-M Mai et al. ACTA PÆDIATR 92 (2003) Table 1. Increased body mass index in relation to current wheeze. Current wheeze (n = 161; Boys: 86) Total BMI <75th percentile 75th BMI <95th BMI 95th percentile Boys BMI <75th percentile 75th BMI <95th BMI 95th percentile Girls BMI <75th percentile 75th BMI <95th BMI 95th percentile No current wheeze (n = 296; Boys: 150) n % n % w2 for trend, p 84 50 27 52 31 17 188 77 31 64 26 10 0.01 44 27 15 51 31 17 100 35 15 67 23 10 0.02 40 23 12 53 31 16 88 42 16 60 29 11 0.23 BMI: Body mass index. Groups were classified according to BMI reference values for 12-y-old Swedish children, stratified for gender [20]. smoking during pregnancy, environmental tobacco smoke, gender, number of siblings and place of residence) (adjusted OR 1.7, 95% CI 1.0–2.5). This was even more pronounced in the subgroup of overweight children (BMI 95th percentile) (Table 2). There was a significant relationship between overweight and current wheeze among boys, but it was not significant among girls. However, the formal test of interaction did not show any significant difference in the association between boys and girls. Among children with current wheeze, children with high BMI were more likely to have four or more episodes of wheezing during the previous 12 mo compared with the controls (OR 1.9, 95% CI 1.0–3.8) (Table 3). The positive relationship remained after adjustment for confounding factors (adjusted OR 2.0, 95% CI 1.0–4.0). High BMI tended to be associated with ever eczema in children both with and without current wheeze (p = 0.06 and p = 0.09, respectively). However, the relationship between high BMI and eczema persisted only among children with current wheeze after adjustment for confounding factors (adjusted OR 2.2, 95% CI 1.0–4.6), and not among children without current wheeze (adjusted OR 1.6, 95% CI 0.9– 2.7). High BMI was not significantly associated with hay fever, positive skin-prick tests or bronchial hyperresponsiveness in either of the groups (Table 3). Discussion In this case-control analysis of 12-y-old children, current wheeze was associated with high BMI (BMI 75th percentile) and this was particularly obvious in the subgroup of overweight children (BMI 95th percentile). Furthermore, asthma severity was associated with high BMI, as evaluated by the number of wheezing episodes during the previous 12 mo among the wheezing children. There was also an association between high BMI and presence of eczema in wheezing children. A relationship between increased BMI and asthma has been shown consistently only in female adults (4–6, 11–13). However, gender differences have not been seen consistently in children (7–10), nor did we find a gender-specific association in the present study. The significant relationship between high BMI and wheezing in boys, but not in girls, could be a consequence of Table 2. Crude and adjusted odds ratios and 95% confidence intervals of high body mass index and overweight for current wheeze in multivariate logistic regression. Crude OR (95% CI) High BMI Overweight Adjusted OR (95% CI) Total Boys Girls Total Boys Girls 1.6 (1.0–2.4) 1.9 (1.0–3.5) 1.9 (1.1–3.3) 2.3 (1.0–5.1) 1.3 (0.7–2.4) 1.7 (0.7–3.9) 1.7 (1.0–2.5) 1.9 (1.0–3.6) 1.9 (1.0–3.4) 2.4 (1.0–5.7) 1.5 (0.8–2.8) 1.6 (0.6–4.0) OR: Odds ratio; CI: confidence interval; BMI: body mass index. High BMI: BMI 75th percentile of the reference value for Swedish children at 12 y of age, stratified for gender [20]. Overweight: BMI 95th percentile. Adjustment was made for parental history of allergy, maternal smoking during pregnancy, environmental tobacco smoke, gender, number of siblings and place of residence. 1147 High BMI, asthma and allergy in children ACTA PÆDIATR 92 (2003) Table 3. High body mass index in relation to asthmatic and allergic manifestations among children with or without current wheeze. Children with current wheeze Children without current wheeze High BMI N = 77 Controls N = 84 OR 95% CI 1.9 1.0–3.8 1.4 0.7–2.8 1.0 0.5–2.0 0.9 0.4–1.7 1.9 0.96–3.6 1.3 0.6–2.7 1.4 0.6–2.7 Episodes of wheeze (4 times during the past year) Current exercise-induced wheeze 35 26 52 51 Ever asthma 51 55 Ever hay fever 33 36/78 Ever eczema 53 46 Positive SPT 42/65 41/71 Bronchial hyperresponsiveness 35/65 31/67 High BMI N = 108 7 Controls N = 188 OR 95% CI 10 1.2 0.4–3.4 1.2 0.5–2.7 1.5 0.94–2.6 0.7 0.4–1.4 1.2 0.6–2.1 13/104 19/183 43 57 21/103 44/168 27/97 40/162 High BMI: BMI 75th percentile of the reference values for Swedish children at 12 y of age, stratified for gender [20]. Controls: BMI <75th percentile. BMI: Body mass index; OR: odds ratio; CI: confidence interval; positive SPT: positive skin-prick test, i.e. at least one positive skin reaction to tested allergens. N is indicated if it differs from the original number. higher degree of physical activity among boys and therefore a greater likelihood of discovering their symptoms. Underdiagnosis of asthma is more prevalent among girls and is associated with low physical activity and underreporting of symptoms (23). The association between high BMI and asthmatic symptoms could be due to a variety of factors, such as low physical activity, diet, hormonal influence, immune modification and/or mechanical factors. Low physical activity is clearly associated with being overweight (24), and the reduction in deep breathing associated with a sedentary lifestyle may lead to a latching state of airway smooth muscle, and in turn to airway obstruction and hyperreactivity (25). In their epidemiological study, Rasmussen et al. demonstrated that low physical activity in childhood was associated with the development of asthma in young adulthood (26). Whether being overweight causes asthma symptoms through low physical activity, or whether asthma symptoms result in avoidance of exercise, which then leads to weight gain, cannot be answered in a cross-sectionally based study. However, the results of prospective studies suggest that high BMI is a risk factor for asthma (10–13). In addition, airway obstruction and peak expiratory flow variability in obese asthmatics were improved after moderate weight loss, indicating a causal relationship (27). Beckett et al. found that gain in BMI predisposed young females to asthma, irrespective of physical activity (12). Therefore high BMI appears to be a risk factor for asthma, and low physical activity may not explain the relationship. There are several other possible explanations for the association between high BMI and asthma; for example dietary factors. A low intake of antioxidants may be associated with asthmatic symptoms in children (28), and a high intake of salt with bronchial hyperresponsiveness (29). It is conceivable that there are differences in the intake of nutrients between children with high BMI and those with normal BMI. Furthermore, overweight males and females have elevated oestrogen levels (30), which has been suggested to play a causal role in the development of asthma (31). Wheezing symptoms in children with a high BMI may also be induced by a low level of systemic inflammation, which is present in overweight and obese subjects (32). Finally, asthma symptoms in children with high BMI may simply be explained by mechanical factors, i.e. the deposition of adipose tissue in the chest wall and the airways, leading to narrow airways, and/or the presence of gastro-oesophageal reflux, which is associated with both overweight and asthma (25). In our study, bronchial hyperresponsiveness to hypertonic saline was not significantly associated with high BMI, nor was the positive histamine challenge test discussed in a report elsewhere (16). However, methacholine-induced bronchial hyperresponsiveness in adult men was recently found to be associated with high BMI (33), and exercise-induced bronchospasm is more common in obese children (17). Eczema, but not hay fever or positive skin-prick tests, was associated with high BMI in wheezing children. As yet, there is insufficient evidence to demonstrate a relationship between overweight and atopy (9), although two previous studies have shown an association between high BMI and positive skin-prick tests (14, 15). In conclusion, high BMI seems to be a risk factor for asthma. There are several possible underlying mechanisms for such an association, but these all remain speculative. 1148 X-M Mai et al. 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