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Asthma, bronchial hyperresponsiveness and body weight in children
Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: In the past few years, the relationship between overweight and asthma has been shown in countries with a Western life-style, but the mechanisms of this relation are only partially understood. Also, very low birth weight (VLBW) babies have immature lung and immune systems, which can conceivably affect the development of asthma and allergy later in life. Bronchial hyperresponsiveness (BHR) is a cardinal feature of asthma. A good and validated method is therefore needed to assess BHR in epidemiological studies in children.

Aims: To assess the sensitivity and specificity of hypertonic saline bronchial provocation test as a tool to identify asthma in epidemiological studies and to elucidate the inflammatory mechanisms. To assess whether overweight and VLBW increase the risk for asthma, BHR and atopy. To assess the role of the adipose-derived hormone leptin and leptin-associated pro-inflammatory cytokines in asthma in overweight children.

Material and Methods: Three groups of children were included. Allergic diseases were defined according to standardized and validated questionnaires. The hypertonic saline provocation test with a standardized methodology was applied to assess BHR. Cytokines were analyzed by ELISA in stimulated cells and in serum. The serum levels of leptin were also analyzed by ELISA. Urinary LTE4, 11ß-PGF and histamine were determined by EIA, and EPX by RIA.

Results: The sensitivity of the hypertonic saline provocation test for identifying asthma was over 60% and the specificity was over 80%. Recurrent wheeze was associated with a high magnitude of BHR. The levels of urinary LTE4 increased after the challenge tests, both in the asthmatics (p = 0.05) and in the healthy controls (p < 0.01). The levels of histamine also increased in the latter (p = 0.03). However, the levels of 11ß-PGF and EPX were similar in the asthmatics and in the healthy controls. Current wheeze was independently associated with high body mass index (BMI) (≥ 75th percentile of sex-specific reference values for Swedish children at 12-year-old). Overweight (≥ 90th percentile) had an even more pronounced effect (adjusted OR 1.9, 95 % CI 1.0-3.6). Leptin levels were considerably higher in children with than without overweight (p < 0.001). Among the overweight children, children with current asthma had higher levels of leptin than children without current asthma (30.8 vs. 14.3 ng/ml), although not significant. Interferon-y was more often detected in children with than without overweight (61% vs. 12%, p < 0.001), and there was a weak positive correlation between leptin and IFN-γ. A history of asthma up to 12 years of age was more frequent in the VLBW than in the term children (p < 0.05). In the VLBW children, neonatal oxygen supplementation seemed to be the only independent risk factor for a history of asthma (adjusted OR 4.2). The VLBW children who required neonatal mechanical ventilation were more likely to have BHR at age 12 than those who did not (60% vs. 28%, p = 0.05). However, very low birth weight was not associated with allergic rhinoconjunctivitis, eczema or positive skin prick tests, and the levels of IL-4, IL-5 and IFN-γ in stimulated cell cultures were similar in the VLBW and the term children.

Conclusions: Hypertonic saline provocation tests are useful for identifying asthma in population-based studies in children. Inhalation of hypertonic saline induces the secretion of leukotrienes and histamine even in healthy individuals with no clinical consequences, but the bronchoconstriction does not seem to be induced by the analyzed inflammatory mediators. High BMI and overweight are associated with asthma symptoms. Leptin and leptin-associated pro-inflammatory cytokines, such as IFN-γ, may be involved in overweight-related asthma. Very low birth weight is associated with asthma in adolescence, and neonatal oxygen supplementation seems to be the risk factor. Neonatal mechanical ventilation is related to BHR. However, very low birth weight is not associated with atopy. Thus, very low birth weight may lead to non-atopic, rather than atopic asthma.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2003. , p. 72
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 806
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-26663Local ID: 11229ISBN: 91-7373-498-5 (print)OAI: oai:DiVA.org:liu-26663DiVA, id: diva2:247212
Public defence
2003-10-03, Elsa Brändströmssalen, Hälsouniversitet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-10-15Bibliographically approved
List of papers
1. Hypertonic saline challenge tests in the diagnosis of bronchial hyperresponsiveness and asthma in children
Open this publication in new window or tab >>Hypertonic saline challenge tests in the diagnosis of bronchial hyperresponsiveness and asthma in children
2002 (English)In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 13, no 5, p. 361-367Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26544 (URN)10.1034/j.1399-3038.2002.01011.x (DOI)11106 (Local ID)11106 (Archive number)11106 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
2. High body mass index, asthma and allergy in Swedish schoolchildren participating in the International Study of Asthma and Allergies in Childhood: phase II
Open this publication in new window or tab >>High body mass index, asthma and allergy in Swedish schoolchildren participating in the International Study of Asthma and Allergies in Childhood: phase II
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2003 (English)In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 92, no 10, p. 1144-1148Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26373 (URN)10.1080/08035250310005666 (DOI)10907 (Local ID)10907 (Archive number)10907 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
3. Asthma, lung function and allergy in 12-year-old children with very low birth weight: a prospective study
Open this publication in new window or tab >>Asthma, lung function and allergy in 12-year-old children with very low birth weight: a prospective study
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2003 (English)In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 14, no 3, p. 184-192Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26442 (URN)10.1034/j.1399-3038.2003.00045.x (DOI)10985 (Local ID)10985 (Archive number)10985 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
4. Overweight as a contribution factor for asthma in adolescents born with very low birth weight, and the increased level of leptin in overweight-related asthma
Open this publication in new window or tab >>Overweight as a contribution factor for asthma in adolescents born with very low birth weight, and the increased level of leptin in overweight-related asthma
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Obesity is a risk factor for asthma, but the mechanisms are unclear. Childhood-obesity is suggested to be the link between very low birth weight (VLBW) and chronic diseases in adults. Thus, we hypothesized that overweight was a contributing factor for asthma in adolescents born with VLBW, and that leptin and leptinassociated cytokines might play roles in overweight-related asthma. Seventy-four VLBW and 64 normal birth weight (NBW) children participated in a 12-year follow-up study assessing asthma and allergy. Twelve of the 74 VLBW and 15 of the 64 NBW children were overweight. The diagnosis of current asthma was made by pediatricians, and serum levels of leptin, IFN-γ, IL-4, IL-6 and TNF-α were analyzcd by ELISA. Overweight was an independent contributing factor for current asthma in children born with VLBW (OR 5.8, 95% CI 1.2-27). Leptin levels were higher in children with than without overweight (18.1 vs. 2.8 ng/mL, p < 0.001). In children with overweight, current asthmatics had somewhat higher levels of leptin than children without current asthma (30.8 vs. 14.3 ng/mL, p = 0.14), but this was not the case in children without overweight. lnterferon-y was more often detectable in children with than without overweight (60.9% vs. 12.4%, p < 0.001). There was a weak correlation between leptin and IFN-γ. However, the levels of IFN-γ, IL-4, IL-6 and TNF-a were similar in children with and without current asthma irrespective of overweight. Thus, overweight was a contributing factor for asthma in the VLBW children. Leptin and IFN-γ might be involved in asthma in the overweight children.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84613 (URN)
Available from: 2012-10-15 Created: 2012-10-15 Last updated: 2012-10-15Bibliographically approved
5. Inflammatory mediators monitored in urine in asthmatic children with hypertonic saline-induced bronchoconstriction and in healthy controls
Open this publication in new window or tab >>Inflammatory mediators monitored in urine in asthmatic children with hypertonic saline-induced bronchoconstriction and in healthy controls
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Hypertonic saline provocation tests have been validated to be useful in the International Study of Asthma and Allergies in Childhood, but the inflammatory mechanisms of hypertonic saline-induced bronchial hyperresponsiveness (BHR) have not been well understood in asthmatic children. Of the 127 children who participated in hypertonic saline provocation tests, all asthmatics with (n = 13) and without BHR (n = 7) as well as all healthy controls without BHR (n = 37) were evaluated with urine samples collected before and one hour after the provocation test. Paired samples were analyzed in 11 asthmatics with and 6 asthmatics without BHR and 18 healthy controls. Urinary histamine, 11ß-PGF and LTE4 were analyzed by EIA and urinary EPX by RIA. The levels of LTE4 increased after the challenge tests, both in the asthmatics (median value: 354.2 pg/mg pre-challenge vs. 628.3 pg/mg post-challenge, p = 0.05) and in the healthy controls (median value: 294.4 pg/mg pre-challenge vs. 460.0 pg/mg post-challenge, p = 0.008). The levels of histamine also increased in the latter (median value: 299.3 µmol/rug pro-challenge vs. 568.8 µmol/mg post-challenge, p = 0.03). However, the levels of 11ß-PGF and EPX were similar before and after the challenge tests both in the asthmatics and in the healthy controls. The inhalation of hypertonic saline induced the secretion of LTE4 and histamine even in healthy children, but the bronchoconstriction did not seem to be induced by the analyzed inflammatory mediators, such as LTE4, 11ß-PGF, histamine and EPX.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84614 (URN)
Available from: 2012-10-15 Created: 2012-10-15 Last updated: 2012-10-15Bibliographically approved

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