Indian J Pediatr (March 2011) 78:291–295 DOI 10.1007/s12098-010-0281-0
ORIGINAL ARTICLE
Association Between Clinical Severity of Childhood Asthma and Serum Leptin Levels Asya Tanju & Ferhat Cekmez & Secil Aydinoz & Ferhan Karademir & Selami Suleymanoglu & Ismail Gocmen
Received: 27 March 2010 / Accepted: 13 October 2010 / Published online: 27 October 2010 # Dr. K C Chaudhuri Foundation 2010
Abstract Objective To investigate the association between the clinical severity of childhood asthma and serum leptin levels, to define whether the severity of asthma correlates with body mass index (BMI) or serum leptin levels and to examine the sensitivity of leptin levels in predicting asthma severity. Methods This study was conducted in 65 patients, aged 2 to 14 yrs with newly diagnosed asthma without any chronic co-morbidity. The subjects were distributed into three groups according to the severity of asthma. Results Intra-group serum leptin levels before and after treatment did not show significant difference (p>0.05). Inter-group pre-treatment leptin levels were different significantly (p<0.01) and the difference originated from Group I and III as well as Group II and III. No correlation existed between leptin levels and BMI (p>0.05). Conclusions Leptin levels correlated with the clinical severity of asthma and this was suggested to be associated with the severity of inflammation in asthma. More studies are required to evaluate leptin levels in predicting asthma severity. Keywords Asthma . Leptin . Obesity
A. Tanju : F. Cekmez : S. Aydinoz : F. Karademir : S. Suleymanoglu : I. Gocmen Department of Pediatrics, GATA Haydarpasa Teaching Hospital, Istanbul, Turkey F. Cekmez (*) GATA Medical Faculty, Istanbul, Turkey e-mail:
[email protected]
Introduction Bronchial asthma is a chronic lung disease characterized with increased responsiveness of respiratory tract to various stimulants and with airway obstruction and inflammation improving spontaneously or with treatment. In fact, asthma should be evaluated as a clinical syndrome and it is a group of diseases with common symptoms, based on different etiological and pathogenic mechanisms. Recent studies have demonstrated the co-existence of asthma and obesity and discussions have started on the association of asthma and obesity [1–6]. Leptin, a hormone affecting appetite and energy consumption, which is related to body fat mass, is also a subject of this discussion. Some studies have demonstrated that leptin is not only involved in energy metabolism and its concomitance with asthma has been questioned [7–9]. In these patients, leptin and obesity relationship was investigated. Then, discussions led to the question whether hyperleptinemia accompanying obesity had a role in the etiology of asthma or it was a result of hyperinflammatory state in asthma and obesity [1–3, 6]. In the present study, the authors evaluated the relationship between the severity of asthma and serum leptin levels, changes in leptin levels during treatment, the relation of leptin levels, besides asthma severity, with BMI, and the sensitivity of serum leptin levels in repdicting the severity of asthma
Material and Methods This study, conducted from September 2004 through May 2006 in GATA Haydarpasa Teaching Hospital Department of Pediatrics, included children aged 2 to 14 years, with a recent asthma diagnosis and followed up for the disease,
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and without any other chronic comorbidity. The total number of subjects were 65 (29 girls, 36 boys). Asthma diagnosis was based on history, physical examination and reversibility of test results (>12% increase in FEV1, 10 min after the administration of 200 μg salbutamol). The subjects were evaluated according to NHLBI (National Asthma Education and Prevention Program) clinical classification. They were divided into three groups as mild intermittent, mild persistent and moderate persistent, according to their symptom scores. Group 1: 20 patients (9 girls, 11 boys) aged 2 to 14 years (mean age 5.93 ± 3.0), with a diagnosis of intermittent asthma, who use neither inhaled or oral steroids nor leukotriene receptor antagonists. Group 2: 29 patients (12 girls, 17 boys) aged 2 to 14 years (mean age 5.17±2.82), with a diagnosis of persistent mild asthma, who use inhaled steroids, and during attacks, salbutamol and a leukotriene receptor antagonists when needed. Group 3: 16 patients (8 girls, 8 boys) aged 2 to 14 years (mean age 6.13± 3.1), with a diagnosis of persistent moderate asthma who use inhaled steroids, formoterol, montelukast, and salbutamol during attacks and leukotriene receptor antagonists when needed. Patients who had been initiated a treatment earlier and who had received chronic treatment, were excluded from the study. Before getting blood samples, all patients’ parents were informed and their consent was obtained. All subjects were followed with a daily symptom diary kept by their family which contained information on daily respiratory quality, cough, wheezing, night time sleep, drugs that they received and peak flow meter (PEF) values, in those who were able to perform. Changes in the administered drug doses were decided upon this symptom scoring. In each control visit, disease history, compliance to drugs and the appropriateness of the techniques used during the interval, starting with the last visit were questioned and physical examination findings was recorded and a pulmonary function tests was performed if needed. Table 1 Demographics of groups
Figures in parenthesis indicate%
Age (year) Gender Girl Boy Body weight (kg) Height (cm) BMI (kg/m2)
Laboratory Analysis Serum leptin levels were assessed before the treatment initiation in blood samples (2 to 6 ml) of all the subjects obtained between 1 and 4 p.m. All the subjects with symptoms were followed. Also, in subjects whose symptoms were controlled according to this follow-up, serum leptin levels were assessed 6 to 8 weeks after the treatment initiation with blood samples (2 to 6 ml) obtained between 1 and 4 p.m. Blood samples were put into polypropylene tubes. They were centrifuged at room temperature for 10 min at 5,000 × g cycles and serum samples were separated and kept at −70°C until the analysis. Leptin levels were measured in the biochemistry laboratory with ELISA, using Leptin (Sandwich) Elisa (DRG Instruments GmbH, Germany Division of DRG İnternational, Inc Frauenbergstr) kit and Microplate Reader RT–2100 C instrument. Statistical Analysis The study data were analyzed using SPSS (Statistical Package for Social Sciences) for Windows version 11.5. In the descriptive statistical analysis of BMI, age, sex, initial and control leptin levels, Tukey’s weighted means test and standard deviations were used. The normality analysis of the data was performed with KolmogorovSmirnov. Differences between groups were evaluated with Kruskal-Wallis test and Mann-Whitney-U test. The statistical significance of the difference between initial and control values for intra-group data was analyzed with Wilcoxon test. For the evaluation of the sensitivity of serum leptin levels in predicting asthma severity, intergroup logistic regression analysis was performed.
Results The mean ages in Group I, II and III were 5.93±3, 5.17± 2.82 and 6.13±3.01, respectively. There were 29 girls (44.6%) and 36 boys (%55.3) in total. Sex distribution in study groups were as follows: Group I, 9 (45%) girls and 11 (55%) boys; Group II, 12 (41.4%) girls, 17 (48.6%) boys;
Group I
Group II
Group III
p value
5.93±3
5.17±2.82
6.13±3.01
p>0.05
9 (45) 11 (55) 21.3±7.41 114.46±17.8 16.02±2,8
12 (41.4) 17 (48.6) 21.4±8.54 113.3±20.58 16.85±2.48
8(50) 8(50) 23.5±7.08 119.17±17.78 16.2±2.11
p>0.05 p>0.05 p>0.05 p>0.05
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Table 2 Mean values being analyzed with Tukey’s test Group I Group II Group III
Before treatment
After treatment
Normality analysis
1.70±1.10 2.33±0.68 7.75±1.55
1.51±0.97 1.79±0.59 4.45±1.25
p<0.05 p<0.05 p<0.05
Leptin Leptin Leptin
and Group III, 8 (50%) girls and 8 (50%) boys. In Group I, II and III, mean body weights were 21.3±7.41 kg, 21.4± 8.54 kg and 23.5±7.08 kg, respectively; mean heights were 114.46±17.8 cm, 113.3±20.58 cm and 119.17±17.78 cm, respectively. Mean BMI values, on the other hand, were 16.02±2.8 kg/m2 in Group I, 16.85±2.48 kg/m2 in Group II, and 16.2±2.11 kg/m2 in Group III. There were no significant differences between the groups regarding age, sex, weight, height, BMI (p>0,05) (Table 1). Leptin levels were evaluated before and after treatment, mean values being analyzed with Tukey’s test (Table 2). Mean leptin levels before and after treatment were 1.70±1.10 and 1.51± 0.97 in Group I, 2.33±0.68 and 1.79±0.59 in Group II, and 7.75±1.55 and 4.45±1.25 in Group III. Intra-group leptin levels did not differed significantly before and after treatment (p>0.05). In the normality analysis, Kolmogorov-Smirnov test was used. Leptin levels and BMI values were not distributed normally in the groups (p<0.05). Leptin levels showed significant difference between the mild intermittent, mild persistent and moderate persistent asthma groups (KruskalWallis test, p<0.01). The statistically significant difference between groups were due to the difference between Group I and III, and between Group II and III (Mann Whitney-U test, p<0.01). The existence of a correlation between leptin levels and BMI was also evaluated. The study groups did not differed significantly according to BMI (p>0.05). There were no correlation between leptin levels and BMI (Pearson correlation analysis, p>0.05). The sensitivity of serum leptin level in predicting asthma severity was evaluated using logistic regression analyses (Table 3). No significant difference was found for pretreatment leptin level between Group I and II (p>0.05). On the other hand, there were significant relations between increases in pretreatment leptin levels and asthma severity, between Group I and III and between Group II and III. The sensitivity of serum leptin level in predicting asthma
severity before treatment was 72% between Group I and II, and 66.7% between Group II and III (p<0.1).
Discussion The authors thought that leptin levels might predict asthma severity. Bronchial asthma is a chronic inflammatory disease accompanied by increased airways sensitivity, and eosinophils and mast cells play a prominent role. Asthma is one of the most widely encountered chronic diseases in childhood and its prevalence has been increasing gradually worldwide, although its etiology not wholly clear. Asthma prevalence in childhood increased from 3.11% to 4.3% and this is especially prominent in Caucasians and in both sexes [10]. Follow-ups and treatment is difficult for the patient and her/his family due to the chronic nature of the disease and frequent exacerbation periods. When these are considered, asthma has become a worldwide health problem, being a heavy burden for the society [11]. Studies in recent years showed the concomitance of asthma and obesity and a discussion about this association ensued. It was suggested that obesity was the result of asthma related sedentary lifestyle and use of inhaled steroids [1]. Also, obesity is part of an inflammatory process per se [1, 3–7]. The relationship between obesity, leptin and asthma become a subject of research when leptin, whose association with obesity is already known was demonstrated to be involved also in the inflammatory process. But when asthma’s clinical presentation is controlled with long term steroid use, pretreatment leptin levels regressed, unrelated to BMI. The discussions progressed from that on, whether hyperleptinemia accompanying obesity played a role in asthma etiology alone or is a result of asthma and hyperinflammatory state due to obesity [1, 3–7].
Table 3 Logistic regression analyses of groups Group I–II pretreatment Leptin level Group I–III pretreatment leptin level Group II–III pretreatment leptin level
Meaningfulness
Rise
Validity percentage
0.383 (p>0.1) 0.049 (p<0.1) 0.073 (p<0.1)
1.001
59%
1.002
72%
1.002
66.7%
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Leptin is a molecule which is mainly effective in the regulation of body fat mass, but also has a major role in the proinflammatory response. Increases in the leptin levels in allergic inflammatory response may be related to the clinical severity of asthma [9]. When leptin levels were compared in intermittent, mild persistent and moderate persistent asthma groups, increase in leptin levels correlated with the increase in the clinic severity of asthma, suggesting that serum leptin levels may reflect clinic severity of asthma. In previous studies, the relationship between leptin and IgE, also its association with exhaled nitric oxide (eNO)—an indicator of inflammatory response- shows leptin may be effective in the regulation of allergic inflammation in the airways [12]. Winter-de Groot et al. demonstrated that leptin and eNO values increased in asthma patients without a relation with BMI. Increase in leptin is one of the results of inflammatory processes in asthma [12]. Shore et al. showed in an animal study that leptin infusion alone causes bronchial hyperreactivity and indicated that leptin causes inflammatory changes per se, rather than involving in allergic events [9]. In the present study, increase in serum leptin levels and severity of asthma correlated. This suggests that high leptin levels in asthma patients is the result of the inflammatory process intensified with the severity of asthma rather than being a function of body fat mass. Guler et al., in their study, demonstrated that leptin is a predictive factor for asthma [7]. In the present study, the authors found that while leptin could be used in asthma as a predictor, also it had a predictive value for determining clinical severity of asthma and may be used for this purpose. There are several studies showing the relationship between asthma and BMI [1, 13]. In the pathogenesis of asthma, whether activity restriction causes obesity or obesity by itself causes the development of asthma has been questioned. Leptin is a hormone related with the amount of body fat tissue and affects appetite and energy consumption. Serum leptin levels show positive correlation with BMI and reflect body fat mass [14]. The coexistence of asthma and obesity may be a result of hyperleptinemia.In their study, Guler et al. demonstrated that BMI might be a determining factor for leptin, but did not have a predictive value for asthma [7]. On the other hand, Mai et al., in their study, grouped low birth weight infants as obese and nonobese, and then grouped once more according to the development of asthma. During follow-ups, serum leptin levels in obese patients who developed asthma was found two times higher than that of obese patients without asthma [15]. The present study group included only asthma patients and the authors found that high serum leptin levels and the severity of asthma were not associated with BMI. The authors think that hyperleptinemia in asthma patients is not a function of BMI, thus body fat mass and mainly, it may be evaluated as an indicator of an increased inflam-
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matory process in asthma. Leptin levels increase when systemic steroids are administered. The effect of glucocorticoids on serum leptin levels are due to peripheral effects on fat tissue and central effects of neuropeptide Y, which is a neurosecretory agent secreted from hypothalamus [8]. Moreover, one other reason for increased leptin secretion may be that leptin is secreted as a counter-regulatory answer to glucocorticoid induced hyperphagia and weight gain [16]. Serum leptin levels are unaffected by inhaled steroids because of very low bioavailability and there is no relationship between inhaled steroid use and weight gain [7, 17]. In the present study, no inter- or intra-group differences were found for serum leptin levels after the use of inhaled steroids in patients followed up due to asthma. Yet, the author were expecting that leptin level, which is an indicator of inflammatory process, would decrease after asthma was controlled and would be correlated with BMI. The authors attributed this result to the shortness of treatment duration and also getting serum control leptin samples after a short time interval. The authors have obtained their control blood samples in 6 to 8 weeks in average. They concluded that this duration was not enough to suppress the inflammatory process with the use of inhaled steroids and that those drugs had low systemic effects. Determination of serum leptin levels may be an insufficient method in predicting the control of inflammatory process in asthma. Additional studies are required on this subject.
Conclusions The severity of the clinical presentation of asthma correlates with serum leptin level. Increased leptin level in asthma patients is predictive for asthma and may also be used as a predictive value in determining clinical severity of asthma, independent of BMI. But further studies are needed to evaluate the value of serum leptin level in the treatment of asthma patients.
Conflict of Interest None.
Role of Funding Source None.
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