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1 American Thoracic Society Documents An Official American Thoracic Society Workshop Report: Obesity an Asthma Anne E. Dixon, Fernano Holguin, Akshay Soo, Cheryl M. Salome, Richar E. Pratley, Davi A. Beuther, Juan C. Celeón, an Stephanie A. Shore, on behalf of the American Thoracic Society A Hoc Subcommittee on Obesity an Lung Disease THIS OFFICIAL WORKSHOP REPORT WAS APPROVED BY THE AMERICAN THORACIC SOCIETY BOARD OF DIRECTORS, MAY 2010 Executive Summary Backgroun Methoology Epiemiology Cross-Sectional Epiemiologic Stuies of Asthma an Obesity Prospective Epiemiologic Stuies of Asthma an Obesity Epiemiology of Asthma an Airway Hyperreactivity Limitations of the Epiemiologic Literature on Asthma an Obesity Animal Moels Support a Relationship between Obesity an Asthma Pathogenesis of Asthma in the Obese Genetic Basis for the Obesity Asthma Association Obesity an Lung Function Obesity an Inflammation Role of Aipokines Human Stuies of Aipokines an Asthma Role of Monocyte/Macrophage in Obesity-associate Inflammation Macronutrient Intake in Asthma Obese Asthma: A New Phenotype Obesity an Asthma Control Obesity an Airway Inflammation Treatment of Asthma in the Obese Conclusions an Future Directions Rationale: The evelope worl is currently facing an epiemic of obesity. With the increase prevalence of obesity has come the recognition that obesity is a risk factor for asthma. Objectives: The purpose of this workshop was to bring together experts in the fiel of asthma, with experts in the fiel of obesity to review the current state-of-the-art knowlege regaring obesity an asthma, with the goal of furthering our unerstaning of the link between these two isease entities to help efine important future irections for research. Methos: Speakers were invite to give presentations highlighting recent evelopments in their area of expertise that were relate to obesity an lung isease. These presentations were followe by interactive iscussion. A writing committee from among the participants prouce a ocument summarizing the proceeings. Measurements an Main Results: The participants foun that obesity was a risk factor for asthma in all emographic groups stuie. Asthma in the obese may represent a unique phenotype of asthma, with more severe isease that oes not respon as well to conventional therapy. Factors that coul contribute to the pathogenesis of asthma in the obese inclue both mechanical factors an Supporte by an unrestricte eucational grant from Merck. Proc Am Thorac Soc Vol 7. pp , 2010 DOI: /pats ST Internet aress: altere inflammation an immune responses relate to the obese state. Conclusions: There is an urgent nee for research to better unerstan the mechanisms of asthma in the obese, an to evelop new therapies specifically targete to this unique patient population. Keywors: asthma; obesity; epiemiology; lung function EXECUTIVE SUMMARY Obesity has recently been ientifie as a major risk factor for the evelopment of asthma. Asthma in obese iniviuals tens to be more severe, oes not respon as well to treatment, an is becoming a major public health issue in many countries. Research in this fiel is complicate by the nee to bring together expertise from two fiels that traitionally have little interaction: obesity/metabolism an asthma. The American Thoracic Society convene a symposium in May 2008, bringing together experts in the fiels of both asthma an obesity to review our unerstaning of the relationship between these two synromes, with the goals of ientifying future research irections an ultimately to evelop new strategies to intervene in obese iniviuals with asthma. The first part of the conference reviewe the current stateof-the-art knowlege linking obesity an asthma: this inclue a review of the epiemiology linking asthma an obesity, ata from animal moels linking asthma an obesity, an our current unerstaning of the pathogenesis of asthma in the obese from genetic stuies, physiology, an human stuies. A number of inflammatory meiators relevant to the innate an aaptive immune system are affecte in obesity, an the relevance of these to asthma was reviewe in etail. Other factors, such as iet an macronutrient intake that are present in the Western iet, were also consiere for the role they may have in contributing to inflammation in asthma an the pathogenesis of asthma in the obese. Participants conclue that obesity was a major risk factor for asthma in all emographic groups stuie. It likely represents a new phenotype of asthma. The mechanisms relating obesity an asthma are likely to inclue mechanical factors, inflammatory meiators, an immune responses that are all altere in the obese state. There is an urgent nee to better unerstan the pathogenesis of asthma in the obese to evelop new therapies to target this patient population. Backgroun The worl is in the mist of an unpreceente obesity epiemic. With this epiemic has come a major shift in the type of iseases commonly encountere in meical practice, for example type 2

2 326 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL iabetes (once a isease of the overweight elerly patient) is now a isease that may present in chilhoo. We are only just beginning to unerstan the impact obesity has on pulmonary health. This workshop was convene to review the current stateof-the-art unerstaning of the impact of obesity on pulmonary health, particularly as it relates to asthma. The goal was to ientify current gaps in our knowlege, an potential important areas for future research. Methoology A group of researchers with expertise in the mechanisms of inflammation in obesity, an a group of researchers an clinicians with expertise in lung isease an obesity were invite to a workshop on obesity an asthma in May Participants were aske to present the current state of science in their particular fiel of expertise. The literature was assesse by electronic an manual searches, but no specific instructions on how to search the literature or regaring inclusion an exclusion criteria were given or use. Consensus on the current state of knowlege, an irections for future research, were reache by active iscussion at the workshop. A writing committee summarize the finings of the workshop, an all invite participants were given the opportunity to view an comment on the report, which was then revise to ensure that it reflecte the proceeings of the workshop. EPIDEMIOLOGY OF ASTHMA AND OBESITY Cross-Sectional Epiemiologic Stuies of Asthma an Obesity There is an increase prevalence of asthma in the obese population. The majority of the forty cross-sectional stuies publishe to ate report a moest positive association between obesity an asthma, with os ratios of 1.5 to 3.5 (1). Most of these stuies are large, population-base investigations that use measure or reporte boy mass inex (BMI) to quantify obesity, an self-reporte physician iagnosis of asthma. It is important to note that some of these stuies group unerweight subjects (BMI, 18.5 kg/m 2 ) an subjects of normal weight (BMI kg/m 2 ) together, but the prevalence of asthma increases at both extremes of BMI, giving the asthma BMI curve a J shape (Figure 1) (2). If the increase prevalence of asthma in unerweight populations is not accounte for, the magnitue of the obesity asthma relationship may be unerestimate. Though many of these stuies are base on preominantly white populations (3 6), similar finings have been reporte in Chinese (2) an Inian populations (7). Kim an Camargo specifically looke at the effect of race on the relationship between asthma an obesity in a U.S. population, an foun that there was a positive relationship in both black an Hispanic men (8), suggesting that the relationship between asthma an obesity is consistent among iverse patient populations Prospective Epiemiologic Stuies of Asthma an Obesity There have been a number of stuies of obesity an the risk of incient asthma, an all but one have shown a significant positive association between increasing obesity (usually BMI) an a new iagnosis of asthma, with moest risk ratios in the range of 1.1 to 3.5. However, among these stuies there is heterogeneity in effect size an in the influence of sex on this relationship. These stuies consistently show that obesity is a risk factor for obesity among women (9 13), though some report that obesity is not a risk factor among men (14 17). This may be relate to ifferences in the number of males that are obese, giving limite power to some of these stuies (15, 17), an ifferent levels of obesity use in the obese category (14, Figure 1. U-Shape relationship between boy mass inex (kg/m 2 ) an risk of asthma an symptomatic airway hyperresponsiveness in 3,386 men in Anqing, ajusting for age, intensity of cigarette smoking, skin test reactivity to one or more allergens, an familial correlations. Aapte with permission from Reference 2. 16). It may also reflect some iagnostic bias; Chinn an coworkers reporte that obesity was a risk factor for asthma in women, whereas it was only a risk factor for wheeze (in the absence of col symptoms) in men (18), suggesting that women with respiratory symptoms were more likely to be given a iagnosis of asthma than men. A recent meta-analysis of ault prospective stuies reporte that the os of a new iagnosis of asthma at 1 year in overweight or obese versus normal-bmi iniviuals were significantly elevate at 1.51 (95% confience interval [CI], ), that there was a ose response effect of increasing BMI leaing to increasing os of incient asthma, an that the effect of sex on this relationship was not significant (19). The authors estimate that 250,000 new ault cases of asthma each year in the Unites States may be attributable to overweight an obesity. Epiemiological Stuies of Airway Hyperreactivity an Obesity It is still unclear whether obesity increases the prevalence or incience of airway hyperresponsiveness (AHR). Many crosssectional stuies have foun no association between AHR an obesity in either chilren (20) (Table 1) or young aults (17, 21, 22). Other cross-sectional stuies have foun significant associations that are specific to sex. In 1,459 Taiwanese junior high school stuents, Huang an colleagues (23) foun that girls in the lowest quintile of BMI ha the lowest prevalence of AHR. However, there were no ifferences between the upper four quintiles, suggesting that this association was not riven by overweight an obesity, an there was no association between BMI an AHR in boys. In contrast, Chinn an coworkers, in a report of 11,277 aults from the European Community Respiratory Health Survey (age yr) (24) foun an association between BMI an airway responsiveness that was significant in men, but not in women. The effect was small, in that a 10-unit increase in BMI woul be neee to ecrease PD 20 FEV 1 of one thir of a oubling ose. There are few longituinal stuies to etermine the effect of obesity on the incience of AHR. In a case-control stuy of 61 men who evelope AHR uring a 4-year follow-up, an 244 control subjects, in the Greater Boston area (mean age 62 yr), Litonjua an colleagues (25) foun that both low an high BMI at baseline were risk factors for the evelopment of AHR.

3 American Thoracic Society Documents 327 However, Hancox an coworkers (17) foun no association, in either men or women, between BMI an AHR in 1,000 subjects followe from age 9 to age 26 years. The reasons for these iffering finings is unclear, but it is possible that the effect is small, an therefore only etectable in large stuies, or is relate to variation in emographics incluing age an egree of obesity, which may also be interrelate. The combination of AHR an symptoms is use as a stanar for efining asthma in epiemiologic stuies (26), an several stuies have shown that obesity is associate with the prevalence or incience of asthma efine this way (2, 17, 27). Interestingly, in their longituinal stuy, Hancox an colleagues (17) foun that while obesity i not increase the risk of eveloping AHR, women were at increase risk of eveloping asthma symptoms, an at greater risk for the combination of symptoms an AHR. Similarly, Celeon an coworkers foun that increasing BMI was associate with an increase risk of symptomatic AHR in a cross-sectional stuy of 7,109 Chinese aults (2). So, while increasing BMI may have a very small effect on the risk of AHR, increasing obesity is also likely to be associate with increasing symptoms, an the combination of increase symptoms an increase AHR woul significantly increase the risk of an asthma iagnosis. In stuies of subjects with asthma, however, there is consistent evience for a lack of association between BMI an AHR, inicating that the severity of AHR is not increase in obese iniviuals with asthma (28 32). This suggests that any effect of obesity on airway responsiveness has no further effect once the asthma phenotype is establishe. Inee, Soo an colleagues came to just this conclusion following a stuy of 1,725 subjects referre for assessment of respiratory symptoms (33). They foun that increasing BMI was associate with increasing airway responsiveness among subjects without AHR (without asthma), but was not associate with the severity of AHR in subjects with asthma. Limitations of the Epiemiologic Literature Boy mass inex is a convenient an wiely accepte measure of aiposity, but obesity is a heterogeneous isease, an BMI may not be the best measure of the effect of obesity on the lung. The mechanical effect of obesity on lung function is more strongly associate with central boy fat istribution (34), an a subset of obese iniviuals emonstrate a phenotype of enhance systemic inflammation an insulin resistance (35) that may be more relevant in an inflammatory moel of obesity asthma pathogenesis. Most large epiemiologic stuies rely on self-reporte weight an height, an self-reporte physician s iagnosis of asthma. Concerns about misclassification of weight category an valiity of asthma iagnosis have been raise. However, self-reporte weight correlates strongly with measure weight in this population (36), an many of these stuies use several efinitions of asthma, with no change in results using ifferent asthma efinitions (10). In aition, a recent stuy suggests that the rate of false asthma iagnosis in those carrying a physician iagnosis of asthma is the same in the obese an nonobese: 32% of obese an 30% of nonobese subjects reporting asthma faile to meet more rigorous criteria for an asthma iagnosis (37). Thus, there is strong, consistent, an vali epiemiologic ata to support a relationship between obesity an the evelopment of asthma. ANIMALS MODELS SUPPORT A RELATIONSHIP BETWEEN OBESITY AND ASTHMA Obese mice exhibit innate AHR. AHR is observe using both serotonin or methacholine as the bronchoconstricting agonist, similar to the nonspecific AHR that characterizes human asthma. This innate AHR has been observe regarless of the moality of obesity. For example, mice obese because of a genetic eficiency in the satiety hormone, leptin, or its receptor (ob/ob an b/b mice), because of a genetic eficiency in carboxypeptiase E, an enzyme involve in processing neuropepties associate with satiety (Cpe fat mice), an mice renere obese as the result of a high fat iet, each exhibit AHR compare with age- an sex-matche controls (38 41). The magnitue of this AHR appears to vary with the magnitue of the obesity. For example, ob/ob an b/b mice are the most obese of the moels stuie an also have the greatest egree of AHR (42). However, the uration of obesity may also play a role, since mice raise on high fat iets for 30 or more weeks exhibit AHR, whereas mice raise on this iet for only 16 weeks o not, even though the extent of their obesity is similar (41). Compare with lean mice, obese mice also have greater allergen-inuce increases in airway responsiveness (43). Obese mice also have augmente pulmonary responses to acute ozone exposure, another asthma trigger. In particular, obese mice ex- TABLE 1. STUDIES ON THE RELATIONSHIP BETWEEN AHR AND BMI Stuy Country n Approx. Age Type of Stuy Fining Huang, 1999 Taiwan 1,459 Junior High Cross-sectional Relationship between AHR an BMI, girls only Celeon, China 7,109 Mean 5 37 Cross-sectional Relationship between symptomatic AHR an BMI 2001 Schachter, Australia 1,971 Mean 5 35 Cross-sectional, poole No relationship AHR an BMI 2001 Chinn, 2002 Europe, Australia, New Zealan, 11, Cross-sectional Relationship between AHR an BMI, significant in men only Unite States Litonjua, 2002 Unite States 61 with new-onset Mean 5 62 Case control New-onset AHR relate to BMI AHR 244 matche Mean 5 61 control subjects Schachter, Australia 5, Cross-sectional, poole No relationship AHR an BMI 2003 Bustos, 2005 Chile 1,232 early Cross-sectional No relationship AHR an BMI Hancox, 2005 New Zealan z 1, poole ata from birth cohort No relationship AHR an BMI Relationship between AHR, asthma, an BMI Soo, 2006 Unite States 1,725 Aults Cross-sectional, clinic referral population Definition of abbreviations: AHR, airway hyperresponsiveness; BMI, boy mass inex. Relationship between AHR an BMI, only subjects without asthma

4 328 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL hibit greater ozone-inuce increases in pulmonary resistance, airway responsiveness, an airway inflammation (38 41). It is unlikely that these changes are the result of obesity-relate ifferences in the inhale ose of ozone. Compare with lean iniviuals, obese humans also respon to ozone with greater increases in airway responsiveness an greater ecrements in lung function (44, 45). PATHOGENESIS OF ASTHMA IN THE OBESE Genetic Basis for the Obesity Asthma Association Little is known about a potential genetic basis for the observe association between obesity an asthma. Hallstran an colleagues reporte an analysis of 1,001 monozygotic an 383 izygotic same-sex American twin pairs, an foun that 8% of the genetic component of obesity is share with asthma, thus explaining the greatest amount of covariation in the association between the two iseases (46). In a subsequent large stuy of 29,183 Danish twin subjects, the age-ajuste genetic liabilities to obesity an asthma were significantly correlate only in women, with an r value of 0.28 (47). These results an the observe overlap in caniate genes an/or caniate genomic regions for obesity an asthma suggest that certain genetic variants may have pleiotropic effects on both obesity an asthma an/or influence pathways that are common to both iseases (e.g., growth). Stuies will be require to investigate whether specific genetic variants influence both obesity an asthma within the same population. Future genetic association stuies will also have to account for potential epigenetic mechanisms, gene-bygene interactions, an gene-by-environment interactions on obesity an asthma. Obesity an Lung Function The most consistently reporte effect of obesity on lung function is a ecrease in the functional resiual capacity (FRC) an expiratory reserve volume (ERV) (48, 49). The FRC is etermine by the balance between inflationary an eflationary pressures on the lung. In the obese, increase eflationary pressures, ue to increases in intra-abominal pressure on the iaphragm an in fat mass on the chest wall (49), mean that the FRC occurs at a lower lung volume than in the nonobese iniviual (Figure 2). There are smaller effects on total lung capacity (TLC) that become more prominent in severe obesity (48, 49), but resiual volume (RV) is usually well preserve (48, 50) or even elevate (51). Airflow obstruction, as measure by the FEV 1 /FVC ratio, is not usually associate with obesity (52). Inee, the FEV 1 /FVC ratio may be increase in obese iniviuals if airway closure an gas trapping reuces the FVC. As a consequence of breathing at lower FRC, airway caliber is ecrease throughout the tial breathing cycle, resulting in an increase in airway resistance (53). Some stuies have suggeste that the increase in airflow resistance may not be ue entirely to the reuce lung volume (48, 54), but the cause of the aitional resistance remains unknown. It has been suggeste that the mechanical effects of obesity on the lungs coul alter airway smooth muscle (ASM) contractility an increase airway responsiveness (55). Breathing voluntarily at low lung volumes increases airway responsiveness to methacholine in lean subjects without asthma (56), an effect that is presume to be a consequence of unloaing of the airways ue to the reuction in lung elastic recoil at low lung volumes. However, lung elastic recoil is increase in the obese (57), an may therefore offset the effects of low lung volumes. Tial volumes may be reuce in the obese (50), but this is not a consistent fining in obese subjects at rest (58, 59). Inee, Boulet an coworkers (58) foun that breathing patterns in obese an nonobese subjects were similar in the volume an frequency of both regular tial breaths an occasional eep inspirations. However, in obese subjects breathing at low lung volumes, the airways remain at smaller caliber an the ASM is at shorter length throughout the breathing cycle. It is possible that this woul change the contractile properties of the ASM, either by plastic aaptation to a shorter length (60) or alterations in cross-brige cycling (61), resulting in an increase in ASM contractility an an increase in airway responsiveness. The effects of bronchoconstriction in obese iniviuals can be compoune by other mechanical changes that increase the sensation of yspnea. Compare with nonobese iniviuals, bronchoconstriction in obese iniviuals causes greater hyperinflation (32, 59), possibly as a consequence of increase expiratory flow limitation (62, 63) an greater airway closure (64). Both expiratory flow limitation (65) an airway closure (66) contribute to changes in respiratory system reactance. In a recent stuy, obese an nonobese subjects without asthma ha similar changes in FEV 1 following methacholine-inuce airway narrowing, but the severity of yspnea was greater in the obese group (59). This ifference in symptoms was attribute to a greater change in respiratory system reactance in the obese, reflecting increase elastic loas. The occurrence of aitional elastic loas in the obese uring bronchoconstriction, which are not well reflecte by spirometry, may explain why some obese iniviuals with asthma have more severe symptoms than their lean counterparts espite similar spirometry (67). Obesity an Inflammation Obesity is associate with a state of chronic, low-grae inflammation that has been linke to conitions such as insulin resistance, type 2 iabetes, nonalcoholic fatty liver isease, an atherosclerosis. Both cellular meiators of immunity an proinflammatory signaling molecules are perturbe in obesity. The total leukocyte count correlates with the egree of obesity in otherwise healthy subjects (68), an the monocyte/macrophage an lymphocyte lineages, in particular, are altere in the obese state (69). In the obese, the number of aipose tissue resient macrophages is increase (Figure 3), an these macrophages secrete a large variety of inflammatory molecules such as tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), macrophage chemotactic protein- 1 (MCP-1), an complement, an circulating plasma levels of these factors are increase in obesity (69). Aipocytes also prouce a number of hormones, incluing leptin an aiponectin. Factors prouce by aipose tissue an release into the circulation (aipokines) may affect the airway irectly, or may act through cells of the immune system (Figure 4), as has been most clearly shown for leptin an aiponectin (70, 71). We will first aress ata linking aipokines to asthma an then consier the potential role that cells of the monocyte/macrophage lineage may play in obesity-associate asthma. Role of Aipokines Leptin is a small, 16-kD protein secrete from aipocytes. Leptin was originally ientifie as a meiator of appetite an energy expeniture (72). Circulating plasma leptin levels are increase in proportion to obesity (73). Leptin s structure is similar to that of the IL-6 cytokine family, consisting of a four a-helix bunle (74), an not surprisingly, leptin also has significant immunomoulatory functions. The action of leptin is meiate through a specific membrane receptor that has

5 American Thoracic Society Documents 329 Figure 2. Pressure volume curves for the chest wall (Ccw), lung (CL), an respiratory system (Crs) in normalweight an obese iniviuals. In the obese iniviual there is a rightwar shift in the chest wall curve, consistent with mass loaing of the thorax, an a reuction the compliance of the lung an the respiratory system, resulting in a reuction in functional resiual capacity (FRC). homology to the IL-6 family of class 1 cytokine receptors (75). Several isoforms of this receptor have been ientifie that arise from alternative splicing an that iffer in their signal transuction ability. The leptin receptor is expresse in the hypothalamus (where it regulates foo intake an energy expeniture) (76), an also on all cell types of the innate an aaptive immune system (77 82). Leptin has multiple effects on cells of the innate immune system, such as promoting phagocytosis, proinflammatory cytokine prouction, chemotaxis, an surface markers of activation (80, 83 90). Leptin also affects cells of the aaptive immune response in humans, leptin can inuce proliferation of naïve T cells an moulate cytokine prouction towar prouction of Th1 cytokines (91). The importance of these effects of leptin on asthma are not known, though in roent moels of inflammatory bowel isease leptin appears to be a pivotal meiator: intestinal inflammation is ecrease in leptin-eficient ob/ob mice (92), an T cells from leptin receptor eficient (b/b) mice isplay reuce capacity to inuce colitis (93). The role of leptin in pulmonary inflammation is not well efine, although leptin infusion increases allergen-inuce airway hyperreactivity in normal-weight mice (70). Interestingly, this hyperresponsiveness occurs espite similar levels of airway inflammatory Th2 cytokine levels in leptininfuse versus saline-infuse mice, suggesting that leptin may be proucing effects on cells other than the Th2 lymphocyte population. Another factor prouce by aipose tissue that has been implicate in asthma is aiponectin (71). In contrast to leptin, aiponectin levels are ecrease in obesity, iabetes, an atherosclerosis, an serum levels increase with weight loss (94, 95). In aition to important effects on fatty aci metabolism an insulin sensitivity, aiponectin also appears to have anti-inflammatory properties. Aiponectin infusion ecreases allergen-inuce airway hyperreactivity, but the mechanisms relating aiponectin to pulmonary isease are yet to be efine. Three species of aiponectin are recognize in serum: high molecular weight, hexameric, an trimeric (96, 97). T caherin, which bins particularly to high-molecular-weight aiponectin, may be important for the actions of aiponectin in the lung as levels of aiponectin are markely ecrease in the BAL of T caherin eficient mice (whereas serum levels are increase) (98). Two other aiponectin receptors, Aipo R1 an R2, have also been ientifie (99). AipoR1 is expresse in multiple cell types, incluing bronchial epithelium, but the role of Aipo R1 an R2 in the lung are not known. Human Stuies of Aipokines an Asthma A number of human stuies have examine the relationship between leptin an/or aiponectin an asthma. Although the obesity asthma association oes not appear to be explaine by either serum leptin or aiponectin alone (100, 101), both serum leptin an aiponectin concentrations o appear to be inepenently associate with asthma in population subgroups, even after ajusting for obesity ( ). Most stuies show a positive relationship between serum leptin an a negative association between serum aiponectin an the risk of asthma ( ). These stuies usually inclue asthma iagnose on the basis of self report, parental report, or physician report ( ). The only stuy that use a physiological phenotype of asthma (methacholine reactivity), in chilren i not show significant associations between serum leptin or aiponectin an asthma (104). The strength of the associations escribe is usually moest. For leptin, the strength varies from os ratios of about 2 4 for asthma (100, 102, 103), although os ratios of about 6 13 have been escribe in a subgroup analyses in some stuies (100, 102, 103). For aiponectin, os ratio of about 0.5 for asthma have been escribe in the highest tertile of serum aiponectin concentration in premenopausal women (101). The aipokine asthma associations appear to be sex an age epenent. Associations are note in prepubertal boys, peripubertal girls, an premenopausal women for leptin an peripubertal girls an premenopausal women for aiponectin ( ). One longituinal stuy reporte that aiponectin (but not leptin) in term infants was associate with asthma (105). It is therefore possible that serum aipokines have ifferent inflammatory effects in the perinatal perio, as compare with later in life. Sex- an age-relate factors may therefore moify the aipokine asthma association. Stuies o not show a consistent relationship of aipokines with either atopic or nonatopic variants of asthma (100, 102, 103). One stuy showe a positive association between serum leptin an serum immunoglobulin E (103) an another showe a negative association between serum aiponectin an atopic ermatitis an eczema in chilren (102). These cross-sectional stuies are unable to etermine causation or irection of the association between aipokines an asthma. In mice these relationships are biirectional, with aipokines affecting allergen-inuce airway hyperreactivity an asthma (allergen challenge) affecting aipokine prouction (70, 71). However, a small stuy of human subjects with mil asthma oes not support the hypothesis establishe in mice that allergen inhalation affects serum leptin an aiponectin concentrations (106).

6 330 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL Figure 3. Aipose tissue is a complex tissue containing aipocytes (a, light green), vascular cells (a, bright green, arrows), an macrophages (b, re) among other stromal an immune cell populations. Local changes in aipokine prouction by aipocytes can affect leukocyte cytokine secretion an may influence both local an systemic inflammation. (c) DAPI counterstaine nuclei. () Merge image. Scale bar mm. The human stuies suggest that aipokines such as leptin an aiponectin may affect human asthma, though other factors such as age an sex may moify this affect. One cross-sectional stuy suggests that another aipokine, resistin, may reuce asthma risk in chilren (104). The role an mechanism of action of aipokines in asthma requires further stuy. Role of Monocyte/Macrophage in Obesity-associate Inflammation Cells of the monocyte/macrophage lineage are clearly altere in obesity. Stuies in mice an humans show that over 800 genes associate with obesity are involve in inflammatory responses an macrophage activation, creating a macrophage enhance metabolic network (107). Aipose tissue resient macrophages are increase in obesity (108) (Figure 3), an are an important source of proinflammatory cytokines in the obese. An active area of investigation is the stuy of macrophage populations in nonaipose tissues. For example, altere Kupfer cell function in the liver of obese iniviuals are involve in the pathogenesis of steatohepatitis (109). Alveolar macrophage function is likely also to be affecte by obesity, as leptin (which is increase in obesity) can affect alveolar macrophage function. Leptin eficiency impairs alveolar macrophage function, an exogenous leptin can increase alveolar macrophage activation (110, 111). One of the important ways it may o this is through enhancing leukotriene prouction, as shown in vitro (112). This may be important clinically, as obese patients with asthma are relatively resistant to inhale corticosterois, but respon in a similar manner to antileukotrienes as o lean asthmatics (113). Macronutrient Intake an Asthma Another factor that may affect asthma in obese people is macronutrient intake. Both acute foo ingestion an chronic overnutrition may exacerbate inflammation in the obese. Glucose loaing causes an acute leukocytosis an evience of increase reactive oxygen species in monocytes an neutrophils in the circulation (114). Similarly, a high-fat, high-carbohyrate Figure 4. Factors that may be involve in the pathogenesis of asthma in the obese. meal leas to increase markers of oxiative stress in mononuclear cells isolate from peripheral bloo (115). This effect is exaggerate in obese compare with lean iniviuals. Conversely, fasting leas to a ecrease in reactive oxygen species prouction from circulating neutrophils (116). The relevance of acute an chronic macronutrient intake in the pathophysiology of asthma is not known, but may represent a significant cause of oxiative stress in obese people. The role of macronutrients may be a useful area of future investigation, as oxiative stress is implicate in the pathophysiology of asthma (117). One stuy has alreay shown that alternate-ay caloric restriction leas to ecrease levels of reactive oxiant species in subjects with asthma, which is associate with significant improvements in peak flow an ecrease asthma symptoms, although whether this was relate to the caloric restriction or the weight loss is not known (118). OBESE ASTHMA: A NEW PHENOTYPE Recent literature suggests that asthma is ifferent in the obese than in the nonobese patient. Obesity not only affects lung mechanics, but has significant effects on asthma control an response to meication, an these changes appear to be inepenent of airway cellular inflammation. These ifferences may justify aing a new phenotype, obesity-associate asthma, to the existing list that inclues allergic, occupational, exercise-inuce, nocturnal, aspirin-sensitive, an severe asthma. Obesity an Asthma Control Obesity has a significant averse effect on asthma control. Using ata from the National Asthma Survey, a populationbase stuy of asthma in four U.S. states, Taylor an colleagues showe that obese iniviuals with asthma ha more severe symptoms an increase meication use in multivariate regression ajuste for age, sex, race, income, an eucation status (119). Vortmann an Eisner also foun that obese subjects with asthma who were recruite following hospital ischarge in Northern California ha increase symptoms an ecrease asthma-specific quality of life when controlling for age, sex, race, income, an eucational status, but i not fin

7 American Thoracic Society Documents 331 increase emergency health care utilization (120). In a crosssectional survey stuy of health care plan participants in Colorao an the Northwestern Unite States, Mosen an coworkers showe that obesity has significant averse effects on symptoms, meication use, an quality of life, an that, in aition, obese iniviuals with asthma have a 4.6-fol increase risk of hospitalization for asthma compare with nonobese iniviuals with asthma in multivariate analysis (121). The fining of increase hospitalizations in the obese by Mosen an colleagues contrasts with the fining of similar emergency health care utilization by Vortmann an Eisner. This may be relate to the ifferent patient populations; all participants in the stuy by Vortmann an Eisner ha severe asthma an were recruite following a hospitalization for asthma, whereas Mosen an coworkers inclue iniviuals with asthma of all isease severities. Therefore, ientifying strategies to improve asthma control in the obese shoul be a research priority in this fiel. Obesity an Airway Inflammation Although obese iniviuals with asthma appear to have worse asthma control, the airways o not exhibit increase eosinophilic or neutrophilic inflammation (122, 123). In fact, two stuies showe a negative correlation between either waist circumference or BMI, an sputum eosinophil count (28, 31). In aition, weight loss in obese iniviuals with asthma oes not alter airway cellular inflammation, espite significant improvements in clinical measures of asthma (124). There is also no obvious cellular inflammation in the airways of unchallenge obese mice, an obese mice that are allergen sensitize an challenge also have reuce airway eosinophils compare with lean mice (43). The absence of cellular inflammation oes not necessarily imply a lack of inflammation. Komakula an colleagues have reporte that 8-isoprostane, a marker of oxiative stress, increases with increasing BMI in iniviuals with asthma (125), an oxiative stress is known to play a role in the pathophysiology of asthma. Future stuies are require to ientify the pathways that are responsible for asthma in the obese, so as to guie therapeutic intervention. Treatment of Asthma in the Obese Obesity alters responses to asthma meications. Obese patients o not respon as well as normal-weight iniviuals to inhale corticosterois or inhale corticosteroi/long-acting bronchoilator combination meications (113, 126), an have worsene asthma control with theophylline (127). A retrospective analysis using poole ata from participants in stuies of asthma treatment (fune by Merck) foun that obese iniviuals with asthma have attenuate response to inhale corticiosterois, but obese an nonobese participants respon in a similar manner to leukotriene moifiers (113). Prospective stuies are require to investigate these altere responses to meication. The explanation for this altere response to asthma controller therapy is likely to be more complicate than a ifficulty with inhale rug elivery or ifferences in airway mechanics, as illustrate by a recent stuy. Sutherlan an coworkers reporte that elevate BMI was associate with attenuate in vitro response to glucocorticois in a well-characterize ault group of iniviuals with moerate to severe asthma (128). A better unerstaning of the pathogenesis of asthma in the obese is neee to improve therapies for this population. An obvious therapeutic intervention that shoul be evaluate is weight loss. Many stuies of surgical an iet-inuce weight loss have shown that weight loss in the obese iniviual with asthma leas to significant improvements in asthma control an lung function (as measure by FEV 1, FVC, an peak flow) (118, ), but this oes not appear to correlate with any changes in airway eosinophilic or neutrophilic inflammation, an the effects on airway hyperreactivity are yet to be efine (124). Moreover, weight loss is one of the more ifficult clinical interventions to successfully implement. CONCLUSIONS AND FUTURE DIRECTIONS The writing committee summarize the main finings of the workshop an outline major topics that shoul be the focus of future research stuies. Epiemiology Current knowlege: Obesity is significantly associate with both prevalent an incient asthma. Over-iagnosis of asthma is similar in obese an lean iniviuals. Future irections: Define the natural history of asthma in the obese with longituinal stuies of well-characterize (in terms of both obesity an asthma) participants. Determine the effect of obesity an sex on incient an prevalent asthma at ifferent evelopmental time points (in utero, early chilhoo, puberty, ault onset). Effect of obesity on previously iagnose asthma compare with asthma eveloping in the setting of obesity. Pathogenesis Current knowlege: The primary effect of obesity on lung function is a reuction in functional resiual capacity an expiratory reserve volume. Obesity oes not usually cause airway obstruction, an any effects on airway caliber are usually normalize after ajusting for lung volume. Obesity has little effect on the severity of airway hyperresponsiveness in subjects with asthma. Aipose tissue secretes a large number of proinflammatory cytokines an factors moulating immune function. Many factors prouce by aipose tissue an ysregulate in obesity have been associate with asthma. Macronutrient intake may contribute to oxiative stress an systematic inflammation. Future irections: Investigate the interaction between obesity an both genetic an epigenetic factors on asthma. Investigate the role of comorbiities of obesity, such as insulin resistance, sleep apnea, an gastroesophageal reflux, on the evelopment of asthma in the obese. Determine the effect of obesity on airway evelopment an structure/function relationships in the lung. Determine the effect of obesity on innate an aaptive immunity as it pertains to asthma. Unerstan the role of macronutrients an exercise on the evelopment of asthma in the obese.

8 332 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL Phenotype an Treatment Response in Asthma Current knowlege: Asthma severity appears to be increase in the obese. Response to controller therapy may be altere in obese iniviuals with asthma. Future irections: Prospective stuies of the treatment of asthma in obese iniviuals with asthma, using multiple outcomes incluing control, physiology, oxiative stress, an airway inflammation. This Workshop Report was prepare by an a hoc subcommittee of the Assembly on Respiratory Structure an Function Writing Committee: ANNE E. DIXON, M.A., B.M., B.Ch. FERNANDO HOLGUIN, M.D., M.P.H. AKSHAY SOOD, M.D., M.P.H. CHERYL M. SALOME, Ph.D. RICHARD E. PRATLEY, M.D. DAVID A. BEUTHER, M.D. JUAN C. CELEDÓN M.D., Dr.P.H. STEPHANIE A. SHORE, Ph.D. Author Disclosure: A.E.D. was a consultant to Merck (up to $1000) an receive a research grant from NIH (more than $100,001). F.H. receive research grants from the American Lung Association ($50, ,000) an NIH (more than $100,001). A.S. serve on an avisory boar of Merck ($ ) an receive a research grant from the American Lung Association ($10,001 50,000). C.M.S. receive lecture fees from AstraZeneca (up to $1000) an Merck ($ ), an research grants from Boehringer Ingelheim ($50, ,000), GlaxoSmith- Kline ($50, ,000), an the National Health an Meical Research Council of Australia (more than $100,001). R.E.P. serve as a consultant to GlaxoSmith- Kline, Merck, Novartis, NovoNorisk an Takea, an receive lecture fees from Merck, Novartis an Takea (amounts not receive); he receive research grants from Eli Lilly, GlaxoSmithKline, Mannkin, Merck, Novartis, Pfizer, Roche, Sanofi Aventis, Takea, an the National Institute of Diabetes an Digestive an Kiney Diseases an National Heart, Lung an Bloo Institute (amounts not receive); he hel stock in Novartis (amount not receive). D.A.B. receive lecture fees from AstraZeneca ($50, ,000) an a research grant from Merck ($10,001 50,000). J.C.C. reporte he ha nothing to isclose relevant to this manuscript. S.A.S. serve on an avisory boar of Schering Plough ($ ), an receive lecture fees from Merck ($ ) an Merck Frosst Canaa (up to $1000); she receive a research grant from NIH (more than $100,001). The other members of the a hoc subcommittee were: LOUIS PHILIPPE BOULET, M.D. CHRISTOPHER O DONNELL, Ph.D. MARC PETERS-GOLDEN, M.D. MONICA KRAFT, M.D. SALLY WENZEL, M.D. QUATYBA HAMID, M.D., Ph.D. PARESH DANDONA, M.B.B.S., D.Phil. GIAMILLA FANTUZZI, Ph.D. ANTHONY FERRANTE, M.D., Ph.D. CHRISTOPHER HUG, M.D., Ph.D. References 1. For ES. The epiemiology of obesity an asthma. J Allergy Clin Immunol 2005;115: Celeon JC, Palmer LJ, Litonjua AA, Weiss ST, Wang B, Fang Z, Xu X. Boy mass inex an asthma in aults in families of subjects with asthma in Anqing, China. Am J Respir Crit Care Me 2001;164: Braback L, Hjern A, Rasmussen F. 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