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Body mass index, respiratory function and bronchial hyperreactivity in allergic rhinitis and asthma
Respiratory Medicine (2009) 103, 289e295
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Body mass index, respiratory function and bronchial hyperreactivity in allergic rhinitis and asthma Giorgio Ciprandi a,b,*, Angela Pistorio c, Mariangela Tosca d, Maria Rosaria Ferraro e, Ignazio Cirillo e a
Department of Internal Medicine, University of Genoa, Genoa, Italy Azienda Ospedaliera Universitaria San Martino, University of Genoa, Genoa, Italy c Epidemiology and Statistics Unit, IRCCS G. Gaslini, Genoa, Italy d Allergic Diseases Center, IRCCS G. Gaslini, Genoa, Italy e Navy Medical Service, La Spezia, Italy b
Received 23 April 2008; accepted 12 August 2008 Available online 24 September 2008
KEYWORDS Body mass index; Allergic rhinitis; Asthma; Bronchial hyperreactivity
Summary Background: Several studies have outlined a possible relationship between an increased body mass index (BMI) and respiratory allergic diseases, such as asthma and rhinitis. The aim of the study was to analyse the relationship between BMI and allergic diseases, including allergic rhinitis and asthma, and functional parameters, such as nasal airflow, FEV1, and non-specific BHR to methacholine, in a cohort of navy army subjects. Methods: The study included 100 patients with moderateesevere persistent allergic rhinitis alone, 100 with intermittent allergic asthma alone, and 100 healthy controls. All subjects were evaluated performing skin prick test, spirometry, and bronchostimulation test with methacholine. Rhinomanometry was performed in patients with rhinitis. Results: BMI values were significantly lower in control subjects with respect to patients with rhinitis (P Z 0.0002) and with respect to patients with asthma (P < 0.0001). BMI was also significantly higher in males with respect to females (P Z 0.005). A significant relationship has been observed between some categories of BHR and BMI either in patients with rhinitis (P < 0.01) or in patients with asthma (P < 0.01), whereas there was no association between BMI and functional parameters. Conclusion: This study provides the first evidence of a significant relationship between BMI and allergic rhinitis and between BMI and BHR in both allergic disorders. ª 2008 Elsevier Ltd. All rights reserved.
* Corresponding author. Semeiotica e Metodologia Medica I, Padiglione 3, A.O.U. San Martino, Largo R. Benzi 10, 16132 Genoa, Italy. Tel.: þ39 10 3533 8120; fax: þ39 10 353 7573. E-mail address: [email protected] (G. Ciprandi).
Introduction The incidence of obesity and associated co-morbidities is dramatically increasing worldwide in both children and
0954-6111/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2008.08.008
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adults.1 Obesity is characterized by a low grade systemic inflammation. In fact, inflammatory markers, such as Creactive protein (CRP) and interleukin (IL)-6, are increased in obese subjects.1 Several studies have also hypothesized a possible relationship between an increased body mass index (BMI) and respiratory allergic diseases such as asthma and rhinitis.2e4 Moreover, a stronger association in women has been reported.4e6 Nevertheless, the mechanism for the association between respiratory allergic diseases and obesity and the reasons for the apparent difference between men and women remain yet unclear.2 Because both respiratory allergic diseases and obesity are characterized by inflammation, a common inflammatory pathway has been proposed as a plausible explanation for the association between respiratory allergic diseases and obesity.7 The current view of adipose tissue is that of an active secretory organ, sending out and responding to signals that modulate appetite, energy expenditure, insulin sensitivity, endocrine and reproductive systems, bone metabolism, inflammation and immunity.1,8 Moreover, adipose tissue produces adipokines such as leptin and adiponectin that might concur to maintaining, and/or amplifying inflammation.1,9 We hypothesized that body mass index (BMI), which is considered a universal indicator of adiposity in according to World Health Organization (WHO) criteria, could be associated with allergic asthma and rhinitis. To this aim, a cohort of navy army subjects containing 100 rhinitis patients, 100 asthmatic patients, and 100 healthy controls was enrolled. Therefore, we analysed the relationship between BMI and allergic diseases, including allergic rhinitis and asthma, and functional parameters, such as nasal airflow, FEV1, and non-specific BHR to methacholine.
Methods Study design The study included patients with moderateesevere persistent allergic rhinitis alone or with intermittent allergic
Table 1
asthma alone. It is to consider that persistent asthma is unfitting with military service. All subjects were consecutively enrolled from April to June 2007 until the previously calculated needed sample of 100 subjects per arm was reached. All subjects were evaluated performing skin prick test, spirometry, and bronchostimulation test with methacholine. Rhinomanometry was performed in patients with rhinitis.
Subjects Three hundred subjects were included in the study: 257 males and 43 females. The mean age was 25 years (SD: 6.5 years). One hundred subjects had moderateesevere persistent allergic rhinitis without asthma and with mean disease duration of 5 years (SD: 3.3 years); one hundred subjects had intermittent allergic asthma without rhinitis and with mean disease duration of 7.1 years (SD: 4.5 years); one hundred subjects were healthy subjects. Demographic characteristics, including gender, age, smoking, BMI, overweight and obesity, BHR, and type of are reported in Table 1. All of them were Navy soldiers who had to refer to Navy Hospital for mandatory periodic visit for maintaining the qualification. An informed consent was obtained from each patient. A detailed clinical history was taken and a complete physical examination was performed. The patients were included in the study on the basis of a clinical history of: (i) persistent allergic rhinitis and presence of moderatee severe nasal symptoms according to validated criteria10; or (ii) intermittent allergic asthma on the basis of validated diagnostic criteria.11 Exclusion criteria were: acute or chronic upper respiratory infections, anatomical nasal disorders (i.e. nasal polyps, septum deviation, etc.), previous or current specific immunotherapy, use of nasal steroids in the current pollen season, and use of inhaled short acting beta agonists and antihistamines during the previous week. All patients assumed only short acting beta agonists or oral antihistamines on demand. The diagnosis of persistent allergic rhinitis and intermittent allergic asthma were made on the basis of a history
Demographic and clinical parameters of the study subjects. Healthy subjects N Z 100
Allergic rhinitis N Z 100
Gender: males e N (%) Age at study visit e mean [SD] Smokers e N (%)
90 28.5 [8.1] 24
76 24.6 [4.9] 9
Body mass index e mean [SD]
24.0 [2.4]
25.5 [2.6]
Normal body weight e N (%) Overweight e N (%) Obese e N (%) BHR positive e N (%) Indoor allergens sensitization e N (%) Outdoor allergens sensitization e N (%) Ineoutdoor allergens sensitization e N (%) a
Fisher’s Exact test.
Allergic asthma N Z 100
P
Total N Z 300
91 22.0 [4.0] 3
0.003 <0.0001 <0.0001
257 (85.7) 25.0 [6.5] 36 (12.0)
26.0 [2.8]
<0.0001
70 30 0
41 57 2
35 60 5
<0.0001
0
64
100
<0.0001
e e e
11 24 65
21 10 69
0.011
25.2 [2.7] a
146 (48.7) 147 (49.0) 7 (2.3) 164 (54.7) 32 (16) 34 (17) 134 (67)
BMI and respiratory allergic diseases of upper or lower respiratory symptoms and positive skin prick test according to validated criteria.10,11
Skin prick test It was performed as stated by the European Academy of Allergy and Clinical Immunology.12 The panel of employed allergens consisted of: house dust mites (Dermatophagoides farinae and pteronyssinus), cat, dog, grasses mix, Compositae mix, Parietaria officinalis, birch, hazel, olive tree, Alternaria tenuis, Cladosporium, Aspergilli mix (Stallergenes, Milan, Italy).
Spirometry It was performed with a computer-assisted spirometer (Pulmolab 435-spiro 235, Morgan, England) and according to international guidelines.13,14 Briefly, three blows (every 5 min) were performed and the best result was considered. All subjects met the criteria for reproducibility and acceptability.
Methacholine bronchial challenge It was performed to evaluate BHR when basal FEV1 was equal or more than 80% of predicted values. Aerosol is delivered using a dosimetric computerized supply (MEFAR MB3, Marcos, Italy). Subjects inhaled increasing doses of methacholine, starting from 30 mg. The scheduled doses consisted of the following: 30, 30, 30, 60, 90, 150, 150, 300, 300, 300, 150 mg as previously reported.15 The test was interrupted and considered positive when FEV1 value diminished by more or equal than 20% of control or a maximal cumulative methacholine dose of 1590 mg was achieved. The threshold dose causing a 20% fall of FEV1 (PD20) was calculated.
Degree of BHR Four arbitrary categories of BHR were considered on the basis of PD20: very severe PD20 <100 mg; severe PD20 between 100 and 349 mg; moderate PD20 ranging from 350 to 649 mg, and mild PD20 between 650 and 1590 mg as previously reported.15 Subjects without response to the cumulative dose of 1590 mg were considered without BHR.
Statistical analysis and data definitions Descriptive statistics were firstly performed and quantitative parameters were reported as means and standard deviations (SD), or as medians with first and third quartiles [1ste3rd quartiles] in case of skewed distribution. Qualitative data were reported as absolute frequencies and percentages. Comparison of qualitative variables among groups of subjects was made by the chi-square test; posthoc comparison of percentages has been made by means of Bonferroni’s correction (PB). Comparison of quantitative variables between two groups of subjects (males vs females) was made by means of the non-parametric Manne Whitney U-test due to the skewed distributions of the variables or to the absence of homoscedasticity.
291 Comparison of quantitative variables among different groups of subjects (ex.: patients with rhinitis vs patients with asthma vs control subject long-lasting rhinitis) was made by means of the parametric analysis of variance (ANOVA) in case of normally distributed data or by means of the non-parametric KruskaleWallis test in case of skewed distributions; Sheffe ´ test was chosen as the parametric post-hoc test, and the Dunn’s test was used as the nonparametric post-hoc test. A two-way analysis of variance has been performed in order to simultaneously evaluate the effect of gender and of different groups of patients on BMI values. Correlation between quantitative variables was evaluated by means of the Pearson’s correlation coefficient (r). Finally, a multivariate logistic regression analysis was used to evaluate the role of different independent explanatory variables for the condition of being an overweight/obese subject. The three explanatory variables were: gender, BHR positivity, and diagnosis. Odd ratios with 95% confidence intervals (95% CI) were calculated using a backward procedure. Statistical significance of the variables included in the models was tested by means of the likelihood ratio test (LR test). All tests were two sided and a P value less than 0.05 was considered statistically significant. The statistical package Statistica (StatSoft Corp., Tulsa, OK) was used for univariate analyses and the Stata release 7 (Stata Corporation, TX) for multivariate analyses.
Results Three hundred patients, 257 males and 43 females, were included in the study. A complete description of the three groups of subjects is reported in Table 1. As also shown in Figure 1A, BMI values were significantly lower in control subjects (mean: 24.0; SD: 2.4) with respect to patients with rhinitis (mean: 25.5; SD: 2.6; P Z 0.0002) and with respect to patients with asthma (mean: 26.0; SD: 2.8; P < 0.0001). In addition, Table 1 shows that the number of smokers is significantly higher in normal subjects (24) than in both patients with rhinitis (9) and asthma (3) (P < 0.0001). All asthmatics have BHR, and 64 rhinitics have BHR. Indoor allergens sensitization is more frequent in patients with asthma, whereas outdoor allergens sensitization is more frequent in patients with allergic rhinitis (P Z 0.011). Table 2 reports demographic and clinical parameters of the three groups of subjects by gender: BMI is significantly higher in healthy males with respect to healthy females (P Z 0.02), in rhinitics males with respect to rhinitics females (P Z 0.0004), whereas there is no difference in asthmatics. Figure 1B confirms these results, using the twoways ANOVA analyzing the effect of gender (P Z 0.005). Analogously the percentage of overweight/obese subjects is significantly higher in patients with asthma (65%) and rhinitis (59%) with respect to control subjects (30%) (PB < 0.0001 and PB Z 0.0001, respectively). No correlation is observed between BMI values and nasal airflow values (ml/s) (r Z 0.19) in patients with rhinitis and no correlation is observed between BMI values and FEV1 (% of predicted) (r Z 0.08) in patients with asthma. A clear relationship is observed between categories of BHR and BMI either in patients with rhinitis (Figure 2A) or in
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A 27.0 0.0002
26.5
variables for the condition of being an overweight/obese subject; the only variable that turned out to be associated with the condition of overweight/obesity is the BHR positivity (OR: 4.5; 95%CI: 2.8e7.4) (LR-test; P < 0.0001); the other two variables (diagnosis and gender) are not confirmed as important predictors of overweight/obesity when analyzed in the multivariate model (P Z 0.29 and P Z 0.06, respectively).
< 0.0001
Body Mass Index
26.0 25.5 25.0 24.5 A N OVA P<0.0001
24.0
Mean ±SE ±1.96*SE
23.5 23.0
B
Controls
Rhinitis
Asthma
29 28
Body Mass Index
27 26 25 24 23 22 21 Males Females
20 19
Controls
Rhinitis
Asthma
Figure 1 BMI mean values in different groups of subjects: control subjects, patients with rhinitis, and with asthma (panel A); P values over the boxes refer to the Scheffe ´ test; BMI mean values in different groups of subjects and by gender (panel B).
patients with asthma (Figure 2B); in particular, in patients with rhinitis (Figure 2A), BMI is significantly higher in patients with PD20 values <100 (mean BMI: 28.1; SD: 0.5) and in patients with PD20 values between 100 and 350 (mean BMI: 26.9; SD: 2.7) with respect to patients without BHR values (mean BMI: 24.3; SD: 2.1) (both P values <0.01). Moreover, in patients with asthma (Figure 2B), BMI is significantly higher in patients with PD20 values <100 (mean BMI: 27.9; SD: 2.7) with respect to patients with PD20 values between 100 and 350 (mean BMI: 25.3; SD: 2.6) (P < 0.01). Among patients with rhinitis or asthma, the percentage of overweight/obese subjects is not associated to mono- or poly-sensitizations: in fact the percentage of overweight/ obese subjects is 65.3% (32/49) among mono-sensitized patients and 69.3% (92/151) among poly-sensitized patients (P Z 0.58). Analogously there is no association between type of sensitization (indoor, outdoor or ine outdoor allergens) and percentage of overweight/obese subjects; in fact the percentage of overweight/obese subjects is 60.4% (81/134) among patients sensitized to indoor allergens, 64.7% (22/34) among patients sensitized to outdoor allergens, and 65.6% (21/32) among patients sensitized to ineoutdoor allergens (P Z 0.84). A multivariate logistic regression model was used to evaluate the role of different independent explanatory
Discussion There is evidence that the prevalence of allergic disorders, such as rhinitis and asthma, has worldwidely increased in developed countries.16 Even though several environmental factors have been hypothesized to be involved in the development of allergic diseases, none could fully explain the rapid increase of the prevalence. However, some lifestyle factors, including dietary factors, alcohol consumption, physical inactivity, and obesity, have recently obtained distinctive regard. Indeed, the increase in affluence, typical of western society, may result in increased availability of foods and decreased physical activities, both of them may contribute to promote the prevalence of obesity and overweight. In addition, there is evidence that obesity and overweight are linked with allergic diseases probably because of the immunogical effects of adipose tissue on the development of allergies. Obesity has been associated with an increased risk of asthma both in children and adults.17,18 However, the real association between obesity and allergic disorders is unclear. Many crosssectional surveys pointed out that obesity is a risk factor for asthma. Moreover, a gender-dependant influence was observed and a significant association between body fat and asthma in women but not in men was found.2 A recent meta-analysis of prospective epidemiological studies concerning the relationship between obesity and asthma has been recently published.19 Most of them evidenced that obesity was a risk factor for the development of asthma (OR ranging between 1.1 and 3.0) and that obesity preceded the development of asthma.3 However, the studies including lung function assessment showed conflicting results. One study evidenced an increased risk of bronchial hyperreactivity in obese patients.20 In contrast, another study provided evidence of lower risk of BHR21 and another survey reported less airflow obstruction in obese patients,22 even though obese patients reported more respiratory complaints and used more bronchodilator drugs than normal-weight patients. Other relevant issue is the relationship between BMI and allergic disorders: some studies reported a positive association even if not consistent, mainly concerning the gender relevance.23e27 BMI would seem to be an independent risk factor for allergy in females, but not in males. However, it is to note that not all studies found a greater association between BMI and asthma in women than in men. In addition, most of these studies have been relied on selfreported height and weight. Moreover, only two studies investigated the effects of obesity on allergic rhinitis. The first study, conducted on a large cohort of 1,247,038 Swedish military conscripts, reported that obesity was not associated with allergic rhinitis in patients with nasal symptoms only.4 The second
BMI and respiratory allergic diseases Table 2
293
Demographic and clinical parameters of the three groups of subjects by gender. Males
Females
P
Healthy subjects Age at study visit e median [1ste3rd quartiles] Smokers e N (%) Body mass index e median [1ste3rd quartiles] Overweight e N (%)
(N Z 90) 27 [24e29] 23 (25.6) 23.7 [22.9e25.5] 28 (31.1)
(N Z 10) 28.5 [24e42] 1 (10.0) 22.4 [19.6e24.0] 2 (20.0)
0.50a 0.44c 0.02a 0.72c
Allergic rhinitis Age at study visit e median [1ste3rd quartiles] Smokers e N (%) Body mass index e median [1ste3rd quartiles] Overweight or obese e N (%) BHR positive e N (%) Indoor allergens sensitization e N (%) Outdoor allergens sensitization e N (%) Ineoutdoor allergens sensitization e N (%)
(N Z 76) 24 [21.5e26.0] 7 (9.2) 26.6 [24.3e27.7] 49 (64.5) 46 (60.5) 11 (14.5) 20 (26.3) 45 (59.2)
(N Z 24) 23 [21.0e24.5] 2 (8.3) 23.3 [22.2e25.8] 10 (41.7) 18 (75.0) 0 (0.0) 4 (16.7) 20 (83.3)
Allergic asthma Age at study visit e median [1ste3rd quartiles] Smokers e N (%) Body mass index e median [1ste3rd quartiles] Overweight or obese e N (%) Indoor allergens sensitization e N (%) Outdoor allergens sensitization e N (%) Ineoutdoor allergens sensitization e N (%)
(N Z 91) 21 [19e24] 3 (3.3) 25.6 [24.1e28.1] 59 (64.8) 21 (23.1) 9 (9.9) 61 (67.0)
(N Z 9) 23 [22e25] 0 (0.0) 25.5 [23.3e28.0] 6 (66.7) 0 (0.0) 1 (11.1) 8 (88.9)
a b c
0.05a 1.00c 0.0004a 0.05b 0.20b 0.05c
0.06a 1.00c 0.89a 1.00c 0.26c
ManneWhitney U-test. Chi-square test. Fisher’s Exact test.
study evidenced that the risk of allergic rhinitis increased with increasing BMI among women but not among men.28 On the other hand, the association between obesity and respiratory allergy may, at least partially, depend on decreased immunological tolerance to allergen as a consequence of immunological changes induced by adipokines, such as adiponectin and leptin, and some pro-inflammatory cytokines, including IL-6 and TNF-a, secreted by WAT. However, two recent studies demonstrated the absence of a significant association between body fat and airway inflammation in both sexes.2,29 On the basis of these data, the present study was designed to analyse the relationship among BMI, nasal airflow, FEV1, and non-specific bronchial hyperreactivity to methacholine in patients with allergic asthma or rhinitis. This study was conducted on a well selected and evaluated group of subjects: all subjects were processed to skin prick test, spirometry, broncostimulation test with methacholine, and rhinomanometry (rhinitics alone). In addition, all patients were allergic. Firstly, this study provides evidence of a global significant association between BMI and both allergic rhinitis and asthma. Considering the gender, a different association pattern was evident: allergic rhinitis was associated with increased BMI only in males, whereas allergic asthma was associated with increased BMI in both genders. This finding confirms the positive studies reported in literature about the association between asthma and obesity in females, and provides the first evidence of a significant association between increased BMI and allergic rhinitis in males. This
finding is conflicting with previous studies.27,28 However, both studies were conducted considering a diagnosis made by questionnaires without performing clinical visit and functional tests. Thus, there was less accuracy of data in those surveys in comparison with the present study. Moreover, the mean BMI is relatively increased, it may depend on the particular case study represented by trained, substantially healthy, and continuously checked people as Navy soldiers. The second relevant outcome is the absence of a relationship between BMI and both nasal airflow and bronchial function. This finding underlines the fact that the possible mechanisms of association between obesity and respiratory allergy should not depend on mechanical consequences linked with fat build up, but might be likely related to immunological changes induced by adipokines and cytokines secreted by adipose tissue. The third interesting result is the significant association between BMI and BHR in both allergic rhinitis and asthma. Even though a different behavior exists in the two disorders, the relationship is more evident in patients with most severe BHR. First of all, this finding is the first evidence of a relationship between BMI and BHR in allergic rhinitis, which is also related with the severity of BHR. In addition, overweight-obesity represents a relevant risk factor for BHR (OR Z 4.5). On the other hand, the possible limitations of this study may be: the mild severity of asthma, the restricted number of patients, and the disproportion between genders. Persistent asthma is unsuited with active duty. About the adequacy of the number of patients, it was
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A 29
Conflict of interest statement Rhinitis
None of the authors have a conflict of interest to declare in relation to this work.
28
BMI
27
References
26
25
24
23
P < 0.01 P < 0.01
< 100 N=4
100-349 350-649 >= 650 Negative N=25 N=14 N=21 N=36
B 30
Asthma
29 28
BMI
27 26 25
P < 0.01
24 23 22
< 100 N=28
100-349 N=61
350-649 N=7
>= 650 N=4
Figure 2 BMI mean values in different groups of subjects according to MCH-PD20 values in patients with rhinitis (panel A) and in patients with asthma (panel B). P values inside the figure refer to the non-parametric Dunn’s test.
previously calculated the consistency of the sample: this cohort assures the statistical significance of the findings. However, the difference between males and females is too big to allow any definitive conclusion on the gender effect and it constitutes a limitation of this study. In fact, this study failed to find any association between allergic rhinitis and BMI in women because of the low number of females. In addition, this was a group of well-trained navy soldiers; this may mean that muscle part is more represented than in normal population. However, a control group of healthy sailors has been considered in the study design to partially avoid this bias. Moreover, it is important to underline the fact that allergic rhinitis is to consider as a risk factor for both BHR and asthma as it may precede asthma30 and hence it may account for the relationship between allergic rhinitis and BMI. In conclusion, this study provides the first evidence of a significant relationship between BMI and allergic rhinitis and between BMI and BHR in both allergic disorders. Further studies should be addressed to investigate the role of the adipokines in the pathogenesis of these relationships.
1. Fantuzzi G. Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol 2005;115:911e9. 2. McLachlan CR, Poulton R, Car G, Cowan J, Filsell S, Greene J, et al. Adiposity, asthma, and airway inflammation. J Allergy Clin Immunol 2007;119:634e9. 3. Ford ES. The epidemiology of obesity and asthma. J Allergy Clin Immunol 2005;115:897e909. 4. Bra ˚ba ¨ck L, Hjern A, Rasmussen F. Body mass index, asthma and allergic rhinoconjunctivitis in Swedish conscripts-a national cohort study over three decades. Respir Med 2005;99:1010e4. 5. Beckett WS, Jacobs Jr DR, Yu X, Iribarren C, Williams OD. Asthma is associated with weight gain in females but not males, independent of physical activity. Am J Respir Crit Care Med 2001;164:2045e50. 6. Chen Y, Rennie D, Cormier Y, Dosman J. Sex specificity of asthma associated with objectively measured body mass index and waist circumference. Chest 2005;128:3048e54. 7. Weiss S. Obesity: insight into the origins of asthma. Nat Immunol 2005;6:537e9. 8. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003;112:1796e808. 9. Cottam DR, Mattar SG, Barinas-Mitchell E, Eid G, Kuller L, Kelley DE, et al. The chronic inflammatory hypothesis for the morbidity associated with morbid obesity: implications and effects of weight loss. Obes Surg 2004;14:589e600. 10. Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001;108(5 Suppl.):S147e334. 11. Global Initiative for Asthma. Pocket Guide for Asthma Management and Prevention. Bethesda, MD: National Hearth, Lung and Blood Institute, National Institute of Health; 1997. NIH Publication no. 96-3659B. 12. Dreborg S, editor. EAACI subcommittee on skin tests. Skin tests used in type I allergy testing. Position Paper. Allergy 1989;44 (Suppl. 10):22e31. 13. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung function tests. Eur Respir J 2005;26:948e68. 14. Miller MR, Hankinson J, Brusasco V, Burgos R, Casaburi R, Coates R, et al. Standardisation of spirometry. Eur Respir J 2005;26:319e38. 15. Cirillo I, Klersy C, Marseglia GL, Vizzaccaro A, Pallestrini E, Tosca MA, et al. Role of FEF25e75 as predictor of bronchial hyperreactivity in allergic patients. Ann Allergy Asthma Immunol 2006;96:692e700. 16. Asher I. ISAAC International Study of Asthma and Allergies in Childhood. Pediatr Pulmonol 2007;42:100. 17. Hersoug LG, Linneberg A. The link between the epidemics of obesity and allergic diseases: does obesity induce decreased immune tolerance? Allergy 2007;62:1205e13. 18. Matricardi PM, Gruber C, Wahna U, Lau S. The asthma-obesity link in childhood: open questions, complex evidence, a few answers only. Clin Exp Allergy 2007;37:476e84. 19. Beuther DA, Weiss ST, Sutherland ER. Obesity and asthma. Am J Resp Crit Care Med 2006;174:112e9. 20. Chinn S, Jarvis D, Burney P. Relation of bronchial responsiveness to body mass index in the ECRHS. European Community Respiratory Health Survey. Thorax 2002;57:1028e33.
BMI and respiratory allergic diseases 21. Schachter LM, Salome CM, Peat JK, Woolcock AJ. Obesity is a risk for asthma and wheeze but not for airway hyperresponsiveness. Thorax 2001;56:4e8. 22. Sin D, Jones RL, Man SF. Obesity is a risk factor for dyspnea but not for airflow obstruction. Arch Intern Med 2002;162: 1477e81. 23. Huang SL, Shiao G, Chou P. Association between body mass index and allergy in teenage girls in Taiwan. Clin Exp Allergy 1999;29:323e9. 24. Xu B, Jarvelin MR, Pekkanen J. Body build and atopy. J Allergy Clin Immunol 2000;105:393e4. 25. Linneberg A, Nielsen NH, Madsen F, Frolund L, Dirksen A, Jorgensen T. Factors related to allergic sensitisation to aeroallergens in a cross-sectional study in adults: The Copenhagen Allergy Study. Clin Exp Allergy 2001;31:1409e17.
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Body mass index, respiratory function and bronchial hyperreactivity in allergic rhinitis and asthma Giorgio Ciprandi a,b,*, Angela Pistorio c, Mariangela Tosca d, Maria Rosaria Ferraro e, Ignazio Cirillo e a
Department of Internal Medicine, University of Genoa, Genoa, Italy Azienda Ospedaliera Universitaria San Martino, University of Genoa, Genoa, Italy c Epidemiology and Statistics Unit, IRCCS G. Gaslini, Genoa, Italy d Allergic Diseases Center, IRCCS G. Gaslini, Genoa, Italy e Navy Medical Service, La Spezia, Italy b
Received 23 April 2008; accepted 12 August 2008 Available online 24 September 2008
KEYWORDS Body mass index; Allergic rhinitis; Asthma; Bronchial hyperreactivity
Summary Background: Several studies have outlined a possible relationship between an increased body mass index (BMI) and respiratory allergic diseases, such as asthma and rhinitis. The aim of the study was to analyse the relationship between BMI and allergic diseases, including allergic rhinitis and asthma, and functional parameters, such as nasal airflow, FEV1, and non-specific BHR to methacholine, in a cohort of navy army subjects. Methods: The study included 100 patients with moderateesevere persistent allergic rhinitis alone, 100 with intermittent allergic asthma alone, and 100 healthy controls. All subjects were evaluated performing skin prick test, spirometry, and bronchostimulation test with methacholine. Rhinomanometry was performed in patients with rhinitis. Results: BMI values were significantly lower in control subjects with respect to patients with rhinitis (P Z 0.0002) and with respect to patients with asthma (P < 0.0001). BMI was also significantly higher in males with respect to females (P Z 0.005). A significant relationship has been observed between some categories of BHR and BMI either in patients with rhinitis (P < 0.01) or in patients with asthma (P < 0.01), whereas there was no association between BMI and functional parameters. Conclusion: This study provides the first evidence of a significant relationship between BMI and allergic rhinitis and between BMI and BHR in both allergic disorders. ª 2008 Elsevier Ltd. All rights reserved.
* Corresponding author. Semeiotica e Metodologia Medica I, Padiglione 3, A.O.U. San Martino, Largo R. Benzi 10, 16132 Genoa, Italy. Tel.: þ39 10 3533 8120; fax: þ39 10 353 7573. E-mail address: [email protected] (G. Ciprandi).
Introduction The incidence of obesity and associated co-morbidities is dramatically increasing worldwide in both children and
0954-6111/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2008.08.008
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adults.1 Obesity is characterized by a low grade systemic inflammation. In fact, inflammatory markers, such as Creactive protein (CRP) and interleukin (IL)-6, are increased in obese subjects.1 Several studies have also hypothesized a possible relationship between an increased body mass index (BMI) and respiratory allergic diseases such as asthma and rhinitis.2e4 Moreover, a stronger association in women has been reported.4e6 Nevertheless, the mechanism for the association between respiratory allergic diseases and obesity and the reasons for the apparent difference between men and women remain yet unclear.2 Because both respiratory allergic diseases and obesity are characterized by inflammation, a common inflammatory pathway has been proposed as a plausible explanation for the association between respiratory allergic diseases and obesity.7 The current view of adipose tissue is that of an active secretory organ, sending out and responding to signals that modulate appetite, energy expenditure, insulin sensitivity, endocrine and reproductive systems, bone metabolism, inflammation and immunity.1,8 Moreover, adipose tissue produces adipokines such as leptin and adiponectin that might concur to maintaining, and/or amplifying inflammation.1,9 We hypothesized that body mass index (BMI), which is considered a universal indicator of adiposity in according to World Health Organization (WHO) criteria, could be associated with allergic asthma and rhinitis. To this aim, a cohort of navy army subjects containing 100 rhinitis patients, 100 asthmatic patients, and 100 healthy controls was enrolled. Therefore, we analysed the relationship between BMI and allergic diseases, including allergic rhinitis and asthma, and functional parameters, such as nasal airflow, FEV1, and non-specific BHR to methacholine.
Methods Study design The study included patients with moderateesevere persistent allergic rhinitis alone or with intermittent allergic
Table 1
asthma alone. It is to consider that persistent asthma is unfitting with military service. All subjects were consecutively enrolled from April to June 2007 until the previously calculated needed sample of 100 subjects per arm was reached. All subjects were evaluated performing skin prick test, spirometry, and bronchostimulation test with methacholine. Rhinomanometry was performed in patients with rhinitis.
Subjects Three hundred subjects were included in the study: 257 males and 43 females. The mean age was 25 years (SD: 6.5 years). One hundred subjects had moderateesevere persistent allergic rhinitis without asthma and with mean disease duration of 5 years (SD: 3.3 years); one hundred subjects had intermittent allergic asthma without rhinitis and with mean disease duration of 7.1 years (SD: 4.5 years); one hundred subjects were healthy subjects. Demographic characteristics, including gender, age, smoking, BMI, overweight and obesity, BHR, and type of are reported in Table 1. All of them were Navy soldiers who had to refer to Navy Hospital for mandatory periodic visit for maintaining the qualification. An informed consent was obtained from each patient. A detailed clinical history was taken and a complete physical examination was performed. The patients were included in the study on the basis of a clinical history of: (i) persistent allergic rhinitis and presence of moderatee severe nasal symptoms according to validated criteria10; or (ii) intermittent allergic asthma on the basis of validated diagnostic criteria.11 Exclusion criteria were: acute or chronic upper respiratory infections, anatomical nasal disorders (i.e. nasal polyps, septum deviation, etc.), previous or current specific immunotherapy, use of nasal steroids in the current pollen season, and use of inhaled short acting beta agonists and antihistamines during the previous week. All patients assumed only short acting beta agonists or oral antihistamines on demand. The diagnosis of persistent allergic rhinitis and intermittent allergic asthma were made on the basis of a history
Demographic and clinical parameters of the study subjects. Healthy subjects N Z 100
Allergic rhinitis N Z 100
Gender: males e N (%) Age at study visit e mean [SD] Smokers e N (%)
90 28.5 [8.1] 24
76 24.6 [4.9] 9
Body mass index e mean [SD]
24.0 [2.4]
25.5 [2.6]
Normal body weight e N (%) Overweight e N (%) Obese e N (%) BHR positive e N (%) Indoor allergens sensitization e N (%) Outdoor allergens sensitization e N (%) Ineoutdoor allergens sensitization e N (%) a
Fisher’s Exact test.
Allergic asthma N Z 100
P
Total N Z 300
91 22.0 [4.0] 3
0.003 <0.0001 <0.0001
257 (85.7) 25.0 [6.5] 36 (12.0)
26.0 [2.8]
<0.0001
70 30 0
41 57 2
35 60 5
<0.0001
0
64
100
<0.0001
e e e
11 24 65
21 10 69
0.011
25.2 [2.7] a
146 (48.7) 147 (49.0) 7 (2.3) 164 (54.7) 32 (16) 34 (17) 134 (67)
BMI and respiratory allergic diseases of upper or lower respiratory symptoms and positive skin prick test according to validated criteria.10,11
Skin prick test It was performed as stated by the European Academy of Allergy and Clinical Immunology.12 The panel of employed allergens consisted of: house dust mites (Dermatophagoides farinae and pteronyssinus), cat, dog, grasses mix, Compositae mix, Parietaria officinalis, birch, hazel, olive tree, Alternaria tenuis, Cladosporium, Aspergilli mix (Stallergenes, Milan, Italy).
Spirometry It was performed with a computer-assisted spirometer (Pulmolab 435-spiro 235, Morgan, England) and according to international guidelines.13,14 Briefly, three blows (every 5 min) were performed and the best result was considered. All subjects met the criteria for reproducibility and acceptability.
Methacholine bronchial challenge It was performed to evaluate BHR when basal FEV1 was equal or more than 80% of predicted values. Aerosol is delivered using a dosimetric computerized supply (MEFAR MB3, Marcos, Italy). Subjects inhaled increasing doses of methacholine, starting from 30 mg. The scheduled doses consisted of the following: 30, 30, 30, 60, 90, 150, 150, 300, 300, 300, 150 mg as previously reported.15 The test was interrupted and considered positive when FEV1 value diminished by more or equal than 20% of control or a maximal cumulative methacholine dose of 1590 mg was achieved. The threshold dose causing a 20% fall of FEV1 (PD20) was calculated.
Degree of BHR Four arbitrary categories of BHR were considered on the basis of PD20: very severe PD20 <100 mg; severe PD20 between 100 and 349 mg; moderate PD20 ranging from 350 to 649 mg, and mild PD20 between 650 and 1590 mg as previously reported.15 Subjects without response to the cumulative dose of 1590 mg were considered without BHR.
Statistical analysis and data definitions Descriptive statistics were firstly performed and quantitative parameters were reported as means and standard deviations (SD), or as medians with first and third quartiles [1ste3rd quartiles] in case of skewed distribution. Qualitative data were reported as absolute frequencies and percentages. Comparison of qualitative variables among groups of subjects was made by the chi-square test; posthoc comparison of percentages has been made by means of Bonferroni’s correction (PB). Comparison of quantitative variables between two groups of subjects (males vs females) was made by means of the non-parametric Manne Whitney U-test due to the skewed distributions of the variables or to the absence of homoscedasticity.
291 Comparison of quantitative variables among different groups of subjects (ex.: patients with rhinitis vs patients with asthma vs control subject long-lasting rhinitis) was made by means of the parametric analysis of variance (ANOVA) in case of normally distributed data or by means of the non-parametric KruskaleWallis test in case of skewed distributions; Sheffe ´ test was chosen as the parametric post-hoc test, and the Dunn’s test was used as the nonparametric post-hoc test. A two-way analysis of variance has been performed in order to simultaneously evaluate the effect of gender and of different groups of patients on BMI values. Correlation between quantitative variables was evaluated by means of the Pearson’s correlation coefficient (r). Finally, a multivariate logistic regression analysis was used to evaluate the role of different independent explanatory variables for the condition of being an overweight/obese subject. The three explanatory variables were: gender, BHR positivity, and diagnosis. Odd ratios with 95% confidence intervals (95% CI) were calculated using a backward procedure. Statistical significance of the variables included in the models was tested by means of the likelihood ratio test (LR test). All tests were two sided and a P value less than 0.05 was considered statistically significant. The statistical package Statistica (StatSoft Corp., Tulsa, OK) was used for univariate analyses and the Stata release 7 (Stata Corporation, TX) for multivariate analyses.
Results Three hundred patients, 257 males and 43 females, were included in the study. A complete description of the three groups of subjects is reported in Table 1. As also shown in Figure 1A, BMI values were significantly lower in control subjects (mean: 24.0; SD: 2.4) with respect to patients with rhinitis (mean: 25.5; SD: 2.6; P Z 0.0002) and with respect to patients with asthma (mean: 26.0; SD: 2.8; P < 0.0001). In addition, Table 1 shows that the number of smokers is significantly higher in normal subjects (24) than in both patients with rhinitis (9) and asthma (3) (P < 0.0001). All asthmatics have BHR, and 64 rhinitics have BHR. Indoor allergens sensitization is more frequent in patients with asthma, whereas outdoor allergens sensitization is more frequent in patients with allergic rhinitis (P Z 0.011). Table 2 reports demographic and clinical parameters of the three groups of subjects by gender: BMI is significantly higher in healthy males with respect to healthy females (P Z 0.02), in rhinitics males with respect to rhinitics females (P Z 0.0004), whereas there is no difference in asthmatics. Figure 1B confirms these results, using the twoways ANOVA analyzing the effect of gender (P Z 0.005). Analogously the percentage of overweight/obese subjects is significantly higher in patients with asthma (65%) and rhinitis (59%) with respect to control subjects (30%) (PB < 0.0001 and PB Z 0.0001, respectively). No correlation is observed between BMI values and nasal airflow values (ml/s) (r Z 0.19) in patients with rhinitis and no correlation is observed between BMI values and FEV1 (% of predicted) (r Z 0.08) in patients with asthma. A clear relationship is observed between categories of BHR and BMI either in patients with rhinitis (Figure 2A) or in
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A 27.0 0.0002
26.5
variables for the condition of being an overweight/obese subject; the only variable that turned out to be associated with the condition of overweight/obesity is the BHR positivity (OR: 4.5; 95%CI: 2.8e7.4) (LR-test; P < 0.0001); the other two variables (diagnosis and gender) are not confirmed as important predictors of overweight/obesity when analyzed in the multivariate model (P Z 0.29 and P Z 0.06, respectively).
< 0.0001
Body Mass Index
26.0 25.5 25.0 24.5 A N OVA P<0.0001
24.0
Mean ±SE ±1.96*SE
23.5 23.0
B
Controls
Rhinitis
Asthma
29 28
Body Mass Index
27 26 25 24 23 22 21 Males Females
20 19
Controls
Rhinitis
Asthma
Figure 1 BMI mean values in different groups of subjects: control subjects, patients with rhinitis, and with asthma (panel A); P values over the boxes refer to the Scheffe ´ test; BMI mean values in different groups of subjects and by gender (panel B).
patients with asthma (Figure 2B); in particular, in patients with rhinitis (Figure 2A), BMI is significantly higher in patients with PD20 values <100 (mean BMI: 28.1; SD: 0.5) and in patients with PD20 values between 100 and 350 (mean BMI: 26.9; SD: 2.7) with respect to patients without BHR values (mean BMI: 24.3; SD: 2.1) (both P values <0.01). Moreover, in patients with asthma (Figure 2B), BMI is significantly higher in patients with PD20 values <100 (mean BMI: 27.9; SD: 2.7) with respect to patients with PD20 values between 100 and 350 (mean BMI: 25.3; SD: 2.6) (P < 0.01). Among patients with rhinitis or asthma, the percentage of overweight/obese subjects is not associated to mono- or poly-sensitizations: in fact the percentage of overweight/ obese subjects is 65.3% (32/49) among mono-sensitized patients and 69.3% (92/151) among poly-sensitized patients (P Z 0.58). Analogously there is no association between type of sensitization (indoor, outdoor or ine outdoor allergens) and percentage of overweight/obese subjects; in fact the percentage of overweight/obese subjects is 60.4% (81/134) among patients sensitized to indoor allergens, 64.7% (22/34) among patients sensitized to outdoor allergens, and 65.6% (21/32) among patients sensitized to ineoutdoor allergens (P Z 0.84). A multivariate logistic regression model was used to evaluate the role of different independent explanatory
Discussion There is evidence that the prevalence of allergic disorders, such as rhinitis and asthma, has worldwidely increased in developed countries.16 Even though several environmental factors have been hypothesized to be involved in the development of allergic diseases, none could fully explain the rapid increase of the prevalence. However, some lifestyle factors, including dietary factors, alcohol consumption, physical inactivity, and obesity, have recently obtained distinctive regard. Indeed, the increase in affluence, typical of western society, may result in increased availability of foods and decreased physical activities, both of them may contribute to promote the prevalence of obesity and overweight. In addition, there is evidence that obesity and overweight are linked with allergic diseases probably because of the immunogical effects of adipose tissue on the development of allergies. Obesity has been associated with an increased risk of asthma both in children and adults.17,18 However, the real association between obesity and allergic disorders is unclear. Many crosssectional surveys pointed out that obesity is a risk factor for asthma. Moreover, a gender-dependant influence was observed and a significant association between body fat and asthma in women but not in men was found.2 A recent meta-analysis of prospective epidemiological studies concerning the relationship between obesity and asthma has been recently published.19 Most of them evidenced that obesity was a risk factor for the development of asthma (OR ranging between 1.1 and 3.0) and that obesity preceded the development of asthma.3 However, the studies including lung function assessment showed conflicting results. One study evidenced an increased risk of bronchial hyperreactivity in obese patients.20 In contrast, another study provided evidence of lower risk of BHR21 and another survey reported less airflow obstruction in obese patients,22 even though obese patients reported more respiratory complaints and used more bronchodilator drugs than normal-weight patients. Other relevant issue is the relationship between BMI and allergic disorders: some studies reported a positive association even if not consistent, mainly concerning the gender relevance.23e27 BMI would seem to be an independent risk factor for allergy in females, but not in males. However, it is to note that not all studies found a greater association between BMI and asthma in women than in men. In addition, most of these studies have been relied on selfreported height and weight. Moreover, only two studies investigated the effects of obesity on allergic rhinitis. The first study, conducted on a large cohort of 1,247,038 Swedish military conscripts, reported that obesity was not associated with allergic rhinitis in patients with nasal symptoms only.4 The second
BMI and respiratory allergic diseases Table 2
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Demographic and clinical parameters of the three groups of subjects by gender. Males
Females
P
Healthy subjects Age at study visit e median [1ste3rd quartiles] Smokers e N (%) Body mass index e median [1ste3rd quartiles] Overweight e N (%)
(N Z 90) 27 [24e29] 23 (25.6) 23.7 [22.9e25.5] 28 (31.1)
(N Z 10) 28.5 [24e42] 1 (10.0) 22.4 [19.6e24.0] 2 (20.0)
0.50a 0.44c 0.02a 0.72c
Allergic rhinitis Age at study visit e median [1ste3rd quartiles] Smokers e N (%) Body mass index e median [1ste3rd quartiles] Overweight or obese e N (%) BHR positive e N (%) Indoor allergens sensitization e N (%) Outdoor allergens sensitization e N (%) Ineoutdoor allergens sensitization e N (%)
(N Z 76) 24 [21.5e26.0] 7 (9.2) 26.6 [24.3e27.7] 49 (64.5) 46 (60.5) 11 (14.5) 20 (26.3) 45 (59.2)
(N Z 24) 23 [21.0e24.5] 2 (8.3) 23.3 [22.2e25.8] 10 (41.7) 18 (75.0) 0 (0.0) 4 (16.7) 20 (83.3)
Allergic asthma Age at study visit e median [1ste3rd quartiles] Smokers e N (%) Body mass index e median [1ste3rd quartiles] Overweight or obese e N (%) Indoor allergens sensitization e N (%) Outdoor allergens sensitization e N (%) Ineoutdoor allergens sensitization e N (%)
(N Z 91) 21 [19e24] 3 (3.3) 25.6 [24.1e28.1] 59 (64.8) 21 (23.1) 9 (9.9) 61 (67.0)
(N Z 9) 23 [22e25] 0 (0.0) 25.5 [23.3e28.0] 6 (66.7) 0 (0.0) 1 (11.1) 8 (88.9)
a b c
0.05a 1.00c 0.0004a 0.05b 0.20b 0.05c
0.06a 1.00c 0.89a 1.00c 0.26c
ManneWhitney U-test. Chi-square test. Fisher’s Exact test.
study evidenced that the risk of allergic rhinitis increased with increasing BMI among women but not among men.28 On the other hand, the association between obesity and respiratory allergy may, at least partially, depend on decreased immunological tolerance to allergen as a consequence of immunological changes induced by adipokines, such as adiponectin and leptin, and some pro-inflammatory cytokines, including IL-6 and TNF-a, secreted by WAT. However, two recent studies demonstrated the absence of a significant association between body fat and airway inflammation in both sexes.2,29 On the basis of these data, the present study was designed to analyse the relationship among BMI, nasal airflow, FEV1, and non-specific bronchial hyperreactivity to methacholine in patients with allergic asthma or rhinitis. This study was conducted on a well selected and evaluated group of subjects: all subjects were processed to skin prick test, spirometry, broncostimulation test with methacholine, and rhinomanometry (rhinitics alone). In addition, all patients were allergic. Firstly, this study provides evidence of a global significant association between BMI and both allergic rhinitis and asthma. Considering the gender, a different association pattern was evident: allergic rhinitis was associated with increased BMI only in males, whereas allergic asthma was associated with increased BMI in both genders. This finding confirms the positive studies reported in literature about the association between asthma and obesity in females, and provides the first evidence of a significant association between increased BMI and allergic rhinitis in males. This
finding is conflicting with previous studies.27,28 However, both studies were conducted considering a diagnosis made by questionnaires without performing clinical visit and functional tests. Thus, there was less accuracy of data in those surveys in comparison with the present study. Moreover, the mean BMI is relatively increased, it may depend on the particular case study represented by trained, substantially healthy, and continuously checked people as Navy soldiers. The second relevant outcome is the absence of a relationship between BMI and both nasal airflow and bronchial function. This finding underlines the fact that the possible mechanisms of association between obesity and respiratory allergy should not depend on mechanical consequences linked with fat build up, but might be likely related to immunological changes induced by adipokines and cytokines secreted by adipose tissue. The third interesting result is the significant association between BMI and BHR in both allergic rhinitis and asthma. Even though a different behavior exists in the two disorders, the relationship is more evident in patients with most severe BHR. First of all, this finding is the first evidence of a relationship between BMI and BHR in allergic rhinitis, which is also related with the severity of BHR. In addition, overweight-obesity represents a relevant risk factor for BHR (OR Z 4.5). On the other hand, the possible limitations of this study may be: the mild severity of asthma, the restricted number of patients, and the disproportion between genders. Persistent asthma is unsuited with active duty. About the adequacy of the number of patients, it was
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A 29
Conflict of interest statement Rhinitis
None of the authors have a conflict of interest to declare in relation to this work.
28
BMI
27
References
26
25
24
23
P < 0.01 P < 0.01
< 100 N=4
100-349 350-649 >= 650 Negative N=25 N=14 N=21 N=36
B 30
Asthma
29 28
BMI
27 26 25
P < 0.01
24 23 22
< 100 N=28
100-349 N=61
350-649 N=7
>= 650 N=4
Figure 2 BMI mean values in different groups of subjects according to MCH-PD20 values in patients with rhinitis (panel A) and in patients with asthma (panel B). P values inside the figure refer to the non-parametric Dunn’s test.
previously calculated the consistency of the sample: this cohort assures the statistical significance of the findings. However, the difference between males and females is too big to allow any definitive conclusion on the gender effect and it constitutes a limitation of this study. In fact, this study failed to find any association between allergic rhinitis and BMI in women because of the low number of females. In addition, this was a group of well-trained navy soldiers; this may mean that muscle part is more represented than in normal population. However, a control group of healthy sailors has been considered in the study design to partially avoid this bias. Moreover, it is important to underline the fact that allergic rhinitis is to consider as a risk factor for both BHR and asthma as it may precede asthma30 and hence it may account for the relationship between allergic rhinitis and BMI. In conclusion, this study provides the first evidence of a significant relationship between BMI and allergic rhinitis and between BMI and BHR in both allergic disorders. Further studies should be addressed to investigate the role of the adipokines in the pathogenesis of these relationships.
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BMI and respiratory allergic diseases 21. Schachter LM, Salome CM, Peat JK, Woolcock AJ. Obesity is a risk for asthma and wheeze but not for airway hyperresponsiveness. Thorax 2001;56:4e8. 22. Sin D, Jones RL, Man SF. Obesity is a risk factor for dyspnea but not for airflow obstruction. Arch Intern Med 2002;162: 1477e81. 23. Huang SL, Shiao G, Chou P. Association between body mass index and allergy in teenage girls in Taiwan. Clin Exp Allergy 1999;29:323e9. 24. Xu B, Jarvelin MR, Pekkanen J. Body build and atopy. J Allergy Clin Immunol 2000;105:393e4. 25. Linneberg A, Nielsen NH, Madsen F, Frolund L, Dirksen A, Jorgensen T. Factors related to allergic sensitisation to aeroallergens in a cross-sectional study in adults: The Copenhagen Allergy Study. Clin Exp Allergy 2001;31:1409e17.
295 26. Castro-Rodriguez JA, Holberg CJ, Morgan WJ, Wright AL, Martinez FD. Increased incidence of asthmalike symptoms in girls who become overweight or obese during the school years. Am J Respir Crit Care Med 2001;163:1344e9. 27. Vieira VJ, Ronan AM, Windt MR, Taglaiferro AR. Elevated atopy in health obese women. Am J Clin Nutr 2005;82:504e9. 28. Kilpelainen M, Terbo EO, Helenius H, Koskenvuo M. Body mass index and physical activity in relation to asthma and atopic diseases in young adults. Respir Med 2006;100:1518e25. 29. Santamaria F, Montella S, De Stefano S, Sperlı` F, Barbarano F, Spadaro R, et al. Asthma, atopy, and airway inflammation in obese children. J Allergy Clin Immunol 2007;120:965e7. 30. Shaaban R, Zureik M, Soussan D, Anto ´ JM, Heinrich J, Janson C, et al. Allergic rhinitis and onset of bronchial hyperresponsiveness. Am J Resp Crit Care Med 2007;176:659e66.