Obesity and asthma

Associate editor:J.S.FedanObesity and asthmaStephanie A.Shore *,Richard A.JohnstonPhysiology Program,Harvard School of Public Health,665Huntington Avenue,Boston,MA 02115,United StatesAbstractObesity is an important public health problem.An increasing body of data supports the hypothesis that obesity is a risk factor for asthma.These data include numerous large cross-sectional and prospective studies performed in adults,adolescents,and children throughout the world.With few exceptions,these studies indicate an increased relative risk of asthma in the obese and overweight and demonstrate that obesity antedates asthma.Obesity appears to be a particularly important issue for severe asthma.Studies showing improvements in asthma in subjects who lose weight,as well as studies showing that obese mice have innate airway hyperresponsiveness (AHR)as well as increased responses to certain asthma triggers also suggest a causal relationship between obesity and asthma.The mechanistic basis for this relationship has not been established.It may be that obesity and asthma share some common etiology,such as a common genetic predisposition,common effects of in utero conditions,or that obesity and asthma are both the result of some other predisposing factor such as physical activity or diet.However,there are also plausible biological mechanisms whereby obesity could be expected to either cause or worsen asthma.These include co-morbidities such as gastroesophageal reflux,complications from sleep-disordered breathing (SDB),breathing at low lung volume,chronic systemic inflammation,and endocrine factors,including adipokines and reproductive hormones.Understanding the mechanistic basis for the relationship between obesity and asthma may lead to new therapeutic strategies for treatment of this susceptible population.D 2005Elsevier Inc.All rights reserved.Keywords:Atopy;Airway responsiveness;Inflammation;Leptin;AdiponectinAbbreviations:h 2-AR,h 2-adrenoceptor;AHR,airway hyperresponsiveness;ASM,airway smooth muscle;BALF,bronchoalveolar lavage fluid;BMI,body mass index;CDC,Centers for Disease Control and Prevention;COPD,chronic obstructive pulmonary disease;Cpe,carboxypeptidase E;DIO,diet-induced obesity;ECM,extracellular matrix;eNO,exhaled nitric oxide;ERV ,expiratory reserve volume;FEF 25–75,mid-expiratory flow;FEV 1.0,forced expiratory volume in 1s;FRC,functional residual capacity;FVC,forced vital capacity;Gaw,airway conductance;GERD,gastroesophageal reflux disease;IC,inspiratory capacity;IL,interleukin;LPS,lipopolysaccharide;MCh,methacholine;MCP-1,monocyte chemotactic protein-1;MIP-2,macrophage inflammatory protein;O 3,ozone;Ob-R b ,long isoform of the leptin receptor;OV A,ovalbumin;PAI-1,plasminogen activator inhibitor-1;PEF,peak expiratory flow;R L ,pulmonary resistance;RV ,residual volume;SDB,sleep-disordered breathing;SNP,single nucleotide polymorphism;TNF a ,tumor necrosis factor-a ;TNFR,TNF receptor;TLC,total lung capacity;V E ,minute ventilation.Contents 1.Introduction ...........................................842.Epidemiology of obesity and asthma ..............................842.1.Cross-sectional studies ..................................842.2.Prospective studies ....................................852.3.Weight change studies ..................................862.4.Gender differences ....................................872.5.Asthma severity .....................................882.6.Other asthma phenotypes.................................882.6.1.Airway hyperresponsiveness ..........................882.6.2.Atopy ......................................880163-7258/$-see front matter D 2005Elsevier Inc.All rights reserved.doi:10.1016/j.pharmthera.2005.10.002*Corresponding author.Tel.:+16174320199;fax:+16174323468.E-mail address:sshore@ (S.A.Shore).Pharmacology &Therapeutics 110(2006)83–102/locate/pharmthera2.6.3.Airway obstruction (88)2.6.4.Airway inflammation (89)2.7.Is obesity the cause of the asthma epidemic? (89)3.Animal studies (90)4.Mechanistic basis for the relationship between obesity and asthma (91)4.1.Co-morbidities (92)4.2.Fetal programming: (92)4.3.Genetics (93)4.4.Effects on lung volume (93)4.5.Chronic systemic inflammation (94)4.5.1.Tumor necrosis factor-a (94)4.6.Other adipokines (95)4.6.1.Leptin (95)4.6.2.Adiponectin (96)4.6.3.Plasminogen activator inhibitor (96)5.Summary (96)Acknowledgements (97)References (97)1.IntroductionObesity is an important public health problem.Current estimates from the U.S.Centers for Disease Control and Prevention(CDC)are that¨30%of the U.S.population is obese.An additional35%is overweight.Moreover,the prevalence of obesity is rising steadily.CDC statistics indicate that in adults obesity has doubled in the last20years from ¨15%in the period between1976and1980,to23%in the period between1988and1994,to30%in the period from1999 to2002.The prevalence of obesity is currently lower in children and adolescents(about16%as of2002)but has approximately tripled in adolescents in the last2decades (/nccdphp/dnpa/obesity/trend/index.htm).The problem is not restricted to the United States.Obesity prevalence is rising worldwide in both developed and developing nations(Monteiro et al.,2004;Popkin and Gordon-Larsen,2004).Obesity is a known risk factor for cardiovascular disease, type II diabetes,and some forms of cancer(Field et al.,2001). An ever-increasing body of epidemiological data supports the hypothesis that obesity is also a risk factor for asthma.These data include numerous cross-sectional studies performed throughout the world,several large prospective studies,as well as several studies of the effects of weight loss or weight gain.As elegantly discussed in a recent review by Ford(2005), there are confounding issues with many of these studies,not the least of which are the use of self-reports of doctor-diagnosed asthma as the measure of asthma and the use of body mass index(BMI)as the measure of obesity.However,in aggregate,the data indicate that a relationship between obesity and asthma exists.Moreover,obesity appears to be a particularly important issue for severe asthma.The causality relating obesity and asthma has not been established,but the data do not support the hypothesis that asthma causes obesity.It may be that obesity and asthma share some common etiology,such as a common genetic predispo-sition,common effects of in utero conditions,or that obesity and asthma are both the result of some other predisposing factor such as physical activity or diet.However,there are also plausible biological mechanisms whereby obesity could be expected to either cause or worsen asthma.These include co-morbidities such as gastroesophageal reflux and complications from sleep-disordered breathing(SDB),breathing at low lung volume,altered pattern of breathing,chronic systemic inflam-mation,and endocrine factors,including adipokines and reproductive hormones.Studies using obese animals also support the hypothesis that obesity may either cause or worsen asthma.Here we review the epidemiological data describing the relationship between obesity and asthma,as well as the data from animal models.We also discuss what is known about the mechanistic basis for this relationship.2.Epidemiology of obesity and asthma2.1.Cross-sectional studiesOne of the first reports of an association between obesity and asthma was a report from a Dutch cohort studied in the 1980s and reported in1986that examined the impact of being overweight or obese on the prevalence of some chronic diseases(Seidell et al.,1986).Another study of obesity and chronic diseases in1988also found an association with asthma (Negri et al.,1988).However,it was not until the late1990s that the surge of interest in the relationship between obesity and asthma occurred.Since1999,over30cross-sectional and case–control studies on this topic have been reported.Except for3(Brenner et al.,2001;Schachter et al.,2003;To et al., 2004),each of these studies reported an increased prevalence of asthma in the obese and/or overweight(Unger et al.,1990; Gold et al.,1993;Chen et al.,1999;Huang et al.,1999; Shaheen et al.,1999;Belamarich et al.,2000;Celedon et al., 2001;Figueroa-Munoz et al.,2001;Schachter et al.,2001;vonS.A.Shore,R.A.Johnston/Pharmacology&Therapeutics110(2006)83–102 84Kries et al.,2001;von Mutius et al.,2001;Young et al.,2001; Jarvis et al.,2002;Rodriguez et al.,2002;Arif et al.,2003; Del-Rio-Navarro et al.,2003;Mokdad et al.,2003;Perez-Perdomo et al.,2003;Santillan and Camargo,2003;Bibi et al., 2004;Gidding et al.,2004;Gunnbjornsdottir et al.,2004; Kronander et al.,2004;Luder et al.,2004;Mishra,2004; Rizwan et al.,2004;Tutor and Campbell,2004;Braback et al., 2005;Hancox et al.,2005;Ronmark et al.,2005;Wickens et al.,2005).These studies include data from children,adoles-cents,and adults of multiple nationalities and ethnic groups throughout the world.Of the three studies that failed to show an association between obesity and an increased risk of asthma, one,a study in children,did find a relationship with wheeze and cough(Schachter et al.,2003).Another involved a very small sample size(Brenner et al.,2001).The third compared children in the lowest and highest quintiles of BMI(To et al., 2004).Such a design would be flawed if the relationship between BMI and asthma risk was J or U shaped,as suggested by some investigators(see below).Several studies have also reported that obesity is more prevalent in asthmatics than in non-asthmatics(Gennuso et al.,1998;Luder et al.,1998; Epstein et al.,2000;Ford and Mannino,2005).A major limitation of these cross-sectional studies is their inability to address the direction of causality.Indeed,these studies were originally interpreted as indicating that because of respiratory symptoms during exercise,asthmatics adopt a more sedentary lifestyle leading to more obesity in this population. Results from prospective studies now very clearly indicate that this is not the case.Rather,obesity antedates asthma.The hypothesis that taking asthma medication might lead to obesity has also been largely discounted(Hedberg and Rossner,2000).2.2.Prospective studiesThirteen prospective studies examining the relationship between obesity and new-onset asthma have now been published.Eight were conducted in adults(Camargo et al., 1999;Beckett et al.,2001;Chen et al.,2002;Guerra et al., 2002;Huovinen et al.,2003;Ford et al.,2004;Nystad et al., 2004;Stanley et al.,2005)and five were conducted in children and adolescents(Castro-Rodriguez et al.,2001;Chinn and Rona,2001;Gilliland et al.,2003;Gold et al.,2003;Guerra et al.,2004).Each one involved several thousand individuals with follow-up periods varying from2to21years.All but one (Stanley et al.,2005)of these studies indicate a greater incidence of asthma in the overweight and/or obese.Impor-tantly,each indicates that obesity antedates asthma.Some studies have indicated a greater effect of obesity in females than in males,although the results have not been consistent. Many of these studies controlled for physical activity.The first prospective analysis of the relationship between obesity and asthma came from the Nurses Health Study (Camargo et al.,1999)and examined the relationship between BMI and the risk of new-onset asthma in adult women. Subjects who had asthma at the start of the study in1991were excluded.Subjects were then followed for4years.Of almost 86,000subjects,1596reported receiving a physician’s diag-nosis of asthma during this period.Incident asthma was confirmed with a second questionnaire that also required that the subject reported using asthma medication since diagnosis. Subjects’reports of exacerbation triggers were typical for asthma and included respiratory infections and environmental allergens.Very few of the subjects were current smokers(11% at baseline).Subjects were then grouped according to BMI calculated from self-reported height and weight in1991.BMI in1991had a strong,positive association with the risk of new asthma,with a relative risk of2.6for obese subjects(those with a BMI!30)after adjustment for age,race,U.S.region, smoking,physical activity,total energy intake,hysterectomy status,birth weight,and duration of breastfeeding.For these obese women,¨60%of their increased risk could be accounted for by their excess weight.When increasingly strict criteria were used in the diagnosis of asthma,the relative risk of incident asthma increased for the obese group.There was also a clear dose–response relationship between BMI and risk of new-onset asthma.Controlling for diet,menopause,use of oral contraceptives,or use of hormones did not substantially change this relationship.The largest prospective study examined over135,000 Norwegian men and women(Nystad et al.,2004).Participants were followed for an average of21years.Asthma was self-reported and height and weight were measured before the development of asthma.In men,beginning at a BMI of20,the incidence of asthma increased steadily at a rate of10%per unit increase in BMI.In women,there was a7%increase in the incidence of asthma per unit increase in BMI,beginning at a BMI of22.While in this study the relationship between obesity and asthma was at least as strong in men as in women,gender differences in the relationship between obesity and asthma have been reported by others,but the results have not been consistent(Chen et al.,1999;Huang et al.,1999;Shaheen et al.,1999;Beckett et al.,2001;von Kries et al.,2001;Chen et al.,2002;Guerra et al.,2002;Gilliland et al.,2003;Gold et al., 2003;Huovinen et al.,2003;Ford et al.,2004;Hancox et al., 2005)(see gender differences below).While both the Nurses Health Study and the Norwegian study found a linear relationship between the relative risk for incident asthma and BMI,several studies have described either a J-or U-shaped relationship(Negri et al.,1988;Beckett et al., 2001;Celedon et al.,2001;Guerra et al.,2002;Gold et al., 2003;Huovinen et al.,2003;Luder et al.,2004).Thus,being too thin can also increase the risk of asthma.The mechanistic basis for the effect of low BMI is not known.It may be that a very low BMI is an indicator of defects in nutrients that impact asthma.For example,consumption of antioxidants has been shown to protect against asthma(Fogarty and Britton,2000).It is also possible that low BMI is indicative of overall nutritional defects that impact somatic growth.Small lung size would be expected to result from such defects and has been shown to be a risk factor for asthma(Gold et al.,2003).One of the major criticisms of these studies is that in most, asthma was ascertained by self-reports of a doctor’s diagnosis of asthma,even though this is a commonly used method for large epidemiological studies such as these and has been shownS.A.Shore,R.A.Johnston/Pharmacology&Therapeutics110(2006)83–10285to be valid and reliable(Harlow and Linet,1989;Toren et al., 1993).One concern is that asthma is diagnosed more frequently in the obese because they are more likely to seek physicians’care for other co-morbidities.Based on data regarding the frequency of undiagnosed asthma in the general population and some reasonable assumptions about the magnitude of obesity-related differences in asthma diagnosis, Ford(2005)concluded that increases in diagnosis cannot explain the magnitude of the increased relative risk of incident asthma attributed to obesity.Concerns about detection bias were also addressed in the Nurses Health Study.In that study, the authors used history of a recent health screening examination and the use of nutritional supplements as indices of health-oriented behavior.A strong positive relationship between BMI and relative risk of adult-onset asthma was observed whether subjects took supplements or not,and whether subjects had had a recent health screening examination or not.A second concern is that asthma in the obese is misdiagnosed and actually reflects dyspnea upon exertion resulting from poor conditioning or increased work of breathing,although Gilliland et al.(2003)have argued the opposite,that is,that in fact doctors may fail to diagnose asthma in the obese because they assume that it is merely shortness of breath brought on by exercise.The strongest argument against the likelihood that misdiagnosed dyspnea accounts for the apparent increase in incident asthma in the obese comes from the Tuscon Childhood Asthma Study (Castro-Rodriguez et al.,2001)because asthma cases were confirmed by peak flow variability and response to a bronchodilator.Data from the Nurses Health Study have also addressed this concern(Camargo et al.,1999).When increas-ingly stringent criteria were used to ascertain cases of incident asthma,including use of bronchodilators,and use of anti-inflammatory medication,the obesity-related relative risk of asthma increased.Investigators in the Children’s Health Study found that including recent bronchodilator use in addition to physician-diagnosed asthma did not change the risk estimate (Gilliland et al.,2003).The CARDIA study included questions about bronchodilator use and in most cases verified their use by examining medication containers(Beckett et al.,2001).The Finnish Twin Study compared questionnaire data with national records for reimbursements for asthma medication and for asthma hospitalizations and found fairly good concordance (Huovinen et al.,2003).In several studies,asthma was verified by the presence of airway hyperresponsiveness(AHR) (Celedon et al.,2001;Ronmark et al.,2005).The likelihood that asthma diagnosed in the obese reflects true asthma is also supported by some studies showing that AHR is associated with increased BMI(Celedon et al.,2001;Chinn et al.,2002; Litonjua et al.,2002),and by the study of Thomson et al. (2003),which showed that obese asthmatics seeking emergen-cy room care for their asthma had marked airway obstruction and responded to a regimen of bronchodilators and corticoster-oids with improvements in pulmonary function similar to those of non-obese asthmatics.The observations that BMI is associated with airway obstruction(see below)and that obese mice exhibit innate AHR and increased responses to certain asthma triggers(see below)also supports the likelihood that what is being assessed is truly asthma.It is possible that what is diagnosed as new-onset adult asthma in the obese actually reflects worsening symptoms of asthma in individuals who had childhood asthma that waned at puberty.The observation that prospective studies begun in school-age children also demonstrate an increased risk of asthma in the obese(Castro-Rodriguez et al.,2001;Gilliland et al.,2003;Gold et al.,2003)argues against this possibility.Misclassification of chronic obstructive pulmonary disease (COPD)as asthma is also a possible concern in these studies, especially as smoking can be a risk factor for asthma(Beckett et al.,2001;Chen et al.,2002;Guerra et al.,2002).However, the data from both longitudinal and cross-sectional studies indicate that potential co-variation between smoking and obesity cannot explain the relationship between obesity and asthma.In the Norwegian prospective study(Nystad et al., 2004),the relationship between obesity and asthma was observed regardless of smoking status and did not change when analyses were performed only on persons40years old or younger to reduce the possibility that the subjects had COPD. In the Nurses Health Study,an increase in asthma incidence with increasing BMI was observed even after controlling for smoking status.Others have also observed an increased incidence of asthma with obesity in both smokers and non-smokers(Guerra et al.,2002).2.3.Weight change studiesStudies showing that weight change alters disease status in asthma provide additional critical evidence of a causal relationship between obesity and asthma.Both weight loss and weight gain have been shown to impact asthma.The impact of weight gain was initially examined in the Nurses Health Study(Camargo et al.,1999).Subjects who gained weight since age18had an increased risk of incident asthma. The effect of weight gain was substantial:subjects who gained more than25kg since age18had a relative risk of 4.7 compared to subjects whose weight remained stable.Similarly, in the Tuscon Children’s Respiratory Health Study,girls who gained weight between the ages of6and11had an increased risk of developing new asthma symptoms(Castro-Rodriguez et al.,2001).Again,the effect was marked with a relative risk of 4.8for symptoms of persistent wheeze at age13.An increase in asthma incidence with weight gain was also reported in the CARDIA study and in children in the U.S.6cities’study (Beckett et al.,2001;Gold et al.,2003).Several studies of the impact of surgically induced weight loss on asthma have been reported(Murr et al.,1995;Dixon et al.,1999;Dhabuwala et al.,2000;Dixon and O’Brien, 2002;O’Brien et al.,2002;He and Stubbs,2004;Simard et al.,2004;Ahroni et al.,2005;Spivak et al.,2005).In many of these,the effects on asthma were anecdotal or were not central to the goals of the study.However,in those where asthma was a focus,these studies report significant improve-ments in all asthma outcomes,including prevalence,severity, use of asthma medications,and hospitalizations for asthmaS.A.Shore,R.A.Johnston/Pharmacology&Therapeutics110(2006)83–102 86(Dixon et al.,1999;Simard et al.,2004;Spivak et al.,2005). Caveats in interpreting these studies include concerns that in addition to reductions in energy intake there may have been changes in dietary composition.In addition,because surgery is usually restricted to massively obese individuals,it is not certain that the results can be generalized to the entire obese population.The likelihood that weight loss will have a generally beneficial effect for asthmatics is supported by studies of diet-induced weight loss that also show improvements in asthma outcomes.For example,Hakala et al.(2000)reported reductions in airway obstruction in obese asthmatics who underwent an8-week very low calorie diet that resulted in an ¨14%reduction in body weight(from101to87kg).In a randomized controlled study of obese asthmatics in which the treatment group took part in a weight reduction program that also involved a very low calorie diet,a14.5%reduction in body weight in the treatment group versus no change in the control group was associated with increases in peak expiratory flow(PEF),forced expiratory volume in1s(FEV1.0),and forced vital capacity(FVC),and reductions in dyspnea score and use of rescue medications(Stenius-Aarniala et al.,2000). Aaron et al.(2004)also reported increases in FEV1.0and FVC, but no improvement in AHR in a group of obese women after diet-induced weight reduction.They suggested that benefits of weight loss were due to reductions in mass loading of the respiratory system rather than improvements in asthma per se. However,caution should be used in interpreting the results of such studies because the number of subjects is still quite small.2.4.Gender differencesSeveral cross-sectional studies of obesity and asthma found a relationship between obesity and asthma only in females (Seidell et al.,1986;Chen et al.,1999;Huang et al.,1999; Figueroa-Munoz et al.,2001;von Kries et al.,2001;Del-Rio-Navarro et al.,2003;Hancox et al.,2005).Many of the prospective studies also found either no effect in men or a greater effect in females than in males(Beckett et al.,2001; Castro-Rodriguez et al.,2001;Chen et al.,2002;Guerra et al., 2002).Only3of these studies have found a stronger relationship in males than in females(Gilliland et al.,2003; Huovinen et al.,2003;Ford et al.,2004).Chinn has argued that it is not sufficient to establish a relationship in one gender and not the other,but that a significant gender interaction must also exist(Chinn,2003).Varraso et al.(2005)did report such an interaction but others have not.The reason(s)for apparent gender-based differences in the relationship between obesity and asthma reported in some studies have not been established.It is possible that these differences are the result of methodological defects in the design of the studies.For example,Santillan and Camargo (2003)compared the relative risk for asthma as a function of BMI in men using self-reports of weight and height versus investigator measured weight and height.When BMI was self-assessed,they found no relationship between BMI and asthma, but when BMI was investigator-assessed,they did.This is an unlikely explanation for the gender-based differences in risk overall because many of the reports where an impact of obesity was observed in females only used height and weight measured by the investigators,and not self-reports(Beckett et al.,2001; Castro-Rodriguez et al.,2001).It is also possible that the lack of a relationship between obesity and asthma in males in some studies may result from the use of BMI as an index of obesity. Overall,males tend to be more muscular than females and increased weight in males may reflect increased muscle mass rather than increased adiposity.Population stratification might also play a role because Kim and Camargo(2003)observed that the obesity–asthma association was present among males from minority groups,but not among Caucasian males.Gender differences in airway caliber might also result in an apparent difference in the relationship between obesity and asthma.For example,AHR is more prevalent in women than in men,but this difference is the result of smaller airway caliber in women (Kanner et al.,1994).Although the epidemiological data are still mixed regarding the existence of a gender bias in the relationship between obesity and asthma,it is interesting to consider the implications of such a bias.Gold et al.(2003)have suggested that their detection of a relationship between obesity and asthma in girls but not boys may have been related to the age of their subjects (6–14years).They argued that if the impact of obesity on the development of asthma stems in part from effects on lung and/ or airway growth,then the effects of obesity might be expected to be most profound at the age when peak lung growth occurs. This occurs earlier for girls than for boys.If that is the case, then it may be very important to consider the life history of obesity rather than the just the existence of obesity at the time when asthma is diagnosed.If there is a stronger relationship between obesity and asthma in females than in males,obesity may be acting through effects on female hormones.This hypothesis is supported by data from Castro-Rodriguez et al.(2001),who observed the strongest impact of obesity on asthma in girls who had undergone early puberty,and by the data of Varraso et al.(2005),who found that asthma severity increased with BMI among women with early menarche,but to a much lesser extent in women without early menarche.Obesity advances the onset of puberty in females,likely through effects on estrogen(Mandel et al.,2004),and postmenopausal estrogen use has been associated with asthma incidence (Troisi et al.,1995).Obesity also decreases progesterone levels(Hernandez Garcia et al.,1999)and progesterone potentiates airway smooth muscle(ASM)relaxation(Foster et al.,1983).Alternatively,female hormones may impact the function of adipose tissue(Mayes and Watson,2004).For example,the satiety hormone,leptin,is produced by adipose tissue and may promote asthma via effects on lung growth or via effects on immune and inflammatory cells(see below). Leptin concentrations are4–6times greater in severely obese compared to lean human subjects(Maffei et al.,1995; Rosenbaum et al.,1996).Importantly,for equivalent BMI, leptin levels are higher in women than in men(Rosenbaum et al.,1996).S.A.Shore,R.A.Johnston/Pharmacology&Therapeutics110(2006)83–10287。