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- Copyright © 2013 Shannon Novosad et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract
Hindawi Publishing Corporation Journal of Allergy Volume 2013, Article ID 538642, 9 pages http://dx.doi.org/10.1155/2013/538642 Review Article Role of Obesity in Asthma Control, the Obesity-Asthma Phenotype 1 2 2 1 Shannon Novosad, Supriya Khan, Bruce Wolfe, and Akram Khan Pulmonary and Critical Care Medicine, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, UHN67, Portland, OR 97239-3098, USA Oregon Health and Science University, Portland, OR, USA Correspondence should be addressed to Akram Khan; khana@ohsu.edu Received 29 December 2012; Accepted 11 March 2013 Academic Editor: Allan Linneberg Copyright © 2013 Shannon Novosad et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Asthma is a disease with distinct phenotypes that have implications for both prognosis and therapy. Epidemiologic studies have demonstrated an association between asthma and obesity. Further studies have shown that obese asthmatics have poor asthma control and more severe asthma. This obese-asthma group may represent a unique phenotype. The mechanisms behind poor asthma control in obese subjects remain unclear, but recent research has focused on adipokines and their eeff cts on the airways as well as the role of oxidative stress. Both surgical and nonsurgical weight loss therapy have shown promising results with improvements in asthma control and decreased asthma severity. Comorbid conditions such as gastroesophageal reu fl x disease and obstructive sleep apnea may also have a role in poor asthma control in obese asthmatics. Further research is needed to define the mechanisms behind this phenotype which will guide the development of targeted therapies. 1. Introduction to the Obese-Asthma Both cross-sectional epidemiologic investigations and prospective studies have shown an association between Phenotype asthma and obesity with a relative risk (RR) of up to 3.0 Obesity and asthma are major public health problems affect- [5–8]. A meta-analysis of seven prospective studies showed ing large numbers of individuals across the globe. Obesity an increased odds ratio (OR) for incident asthma of 1.92 is oen ft classified using body mass index (BMI) ( Table 1) (1.43–2.59) in those with obesity versus normal weight and [1]. Worldwide obesity has more than doubled since 1980. concluded that the odds of incident asthma increased by In 2008,morethan1.4 billionadults, ≥20 years, were 50% in overweight/obese individuals [9]. There was a dose- overweight. Of these, over 200 million men and nearly 300 response relationship between body weight and asthma million women were obese. It is estimated that at least 2.8 with increasing odds of incident asthma as BMI increased million adults die each year as a result of being overweight (𝑃 < 0.0001 for trend) [9]. Recent prospective studies have or obese [2]. confirmed these earlier findings [ 10]. Studies have also shown The World Health Organization estimates that 235 mil- an association between increased BMI and asthma in women lion people currently suffer from asthma and that asthma is as opposed to men suggesting that there may be sex-specific differences in the association between asthma and obesity under diagnosed and undertreated [3]. Asthma prevalence (the percentage of people who have ever been diagnosed with [11, 12]. Thisassociation hashowever notalwaysbeenborne asthma and still have asthma) increased from 7.3% in 2001 to out as some studies did not find a significant effect by sex [ 9]. 8.4% in 2010 in the United States [4]. In 2010, an estimated The American Thoracic Society workshop in 2010 25.7 millionpeoplehad asthma:18.7million adults aged 18 concluded that “asthma in the obese may represent a unique phenotype of asthma, with more severe disease that and over, and 7.0 million children aged 0–17 years [4]. 2 Journal of Allergy Table 1: WHO body mass index (BMI) Classification [ 1]. well controlled asthma (𝑃 < 0.001 )had BMIgreater than or equal to 30 kg/m [20]. Laforest et al. examined 1282 Classification BMI (kg/m ) Risk of comorbidities French patients identified by pharmacists (having at least one Low(butriskofother antiasthma medication prescribed), and multivariate analysis Underweight <18.5 clinical problems showed that BMI greater than 30 kg/m was an independent increased) predictor of poor asthma control (OR 1.72 [1.11–2.65]) [21]. Normal range 18.5–24.9 Average Stanford et al. enrolled 2238 outpatient adults and 2429 Overweight 25.0–29.9 Mildly increased children across the United States and found that BMI greater (preobese) than 30 kg/m was a predictor of uncontrolled asthma in Obese ≥30.0 adults but not in children (OR 1.54) [18]. Class 1 30.0–34.9 Moderate Other studies have looked more specifically at obesity Class 11 35.0–39.9 Severe itself as a risk factor or attempted to define the association Class 111 ≥40.0 Very severe between obesity and asthma control/severity in a specicfi population. eTh majority of the studies have conrfi med an association between obesity and worsened asthma control does not respond as well to conventional therapy” [13]. [22–26], quality of life [23, 25, 27], and/or severity [25, 28– There is ongoing research to discover the etiology of this 30](Table 2). relationship and further define a distinct obesity-asthma Mosen et al. looked at both asthma control and sever- phenotype. This review will focus on the relationship between ity using the Asthma era Th py Assessment Questionnaire obesity and asthma and the most current evidence regarding (ATAQ), self-report of the number of asthma-related hos- an “obesity-asthma” phenotype which is thought to have pitalizations in the previous year, and Juniper mini-Asthma worsened asthma control and severity as well as a differential Quality of Life Questionnaire (AQLQ) [25]. They found response to medications. that aer ft adjusting for demographics, smoking status, oral corticosteroid use, GERD, and inhaled corticosteroids, a BMI ≥30 kg/m was significantly associated with poor asthma 2. Obese-Asthma Phenotype: Increased control (OR 2.7), poor asthma-specific quality of life (OR Severity and Decreased Control 2.8), and history of asthma-related hospitalizations (OR 4.6). Similarly in a Canadian outpatient population, higher BMI In the United States, asthma remains inadequately controlled wasassociatedwithworsenedasthmacontrol andquality in up to 41–55% of patients [14, 15]. Identifying risk factors for of life but not asthma severity [23]. Taylor et al. found uncontrolled asthma and using these risk factors to develop that obese subjects with asthma were more likely to report interventions is an active area of research. These identified continuous symptoms, miss work days, and use short-acting factors can help define a specific phenotype. Asthma phe- beta agonists and inhaled corticosteroids and were more notypes previously identified include allergic, occupational, likely to have severe persistent asthma [29]. Weight gain can exercise-induced, nocturnal, aspirin-sensitive, and severe lead to worsening asthma control or inability to gain control asthma [13]. Increased asthma severity and poor asthma of asthma. Haselkorn et al. showed that asthma patients who control are characteristics of the obese-asthma phenotype. gained five or more pounds over a 12-month period were Asthma control is defined in terms of both impairment more likely to have worsened asthma control and quality of and risk [16]. Impairment is thefrequency andintensity life as well as the need for more steroid bursts than those of symptoms as well as the functional limitations a person patients who maintained their weight [31]. experiences. It is measured using various validated question- Most studies have shown worsened asthma control, qual- naires such as the Asthma Control Test (ACT) or the Asthma ity of life, and/or severity in obese asthmatics; however, some Control Questionnaire (ACQ) [16, 17]. Risk is determined by studies have not found a significant association ( Table 2) the possibility of future adverse events such as exacerbations [32, 33]. A group of 292 people with asthma were recruited and hospitalizations [16]. Severity can refer to a spectrum of from five community-based outpatient primary care centers n fi dings including loss of function of the organs from asthma in urban settings, and asthma control was evaluated using or to the occurrence of severe acute exacerbations [18]. four different validated asthma control questionnaires. eTh y Epidemiologic studies evaluating a number of risk factors did not find any significant association between obesity and and their association with asthma control have shown a asthma control using the four different questionnaires. This significant association between obesity and poor asthma n fi ding persisted after adjusting for FEV1 (forced expiratory control (Table 2). Schatz et al. used the ACT questionnaire volume in onesecond),smoking status,race, sex, selected to examine factors associated with asthma control in 570 comorbid illnesses, and long-term asthma controller use [33]. patients aged 35 years and older enrolled in a large managed Sastre et al. used the ACQ, ACT, and physician perception healthcare organization [19]. In a multiple linear regression of control to evaluate asthma control in 607 Spanish adults. analysis, a higher BMI was an independent predictor of poor They did not nd fi a significant association between BMI and asthma control (𝑃 = 0.01 ). Demoly et al. studied 2337 asthma control but did n fi d that the percentage of patients Europeans with self-reported physician diagnosis of asthma with poor control was slightly greater in patients with low and used the ACT questionnaire to measure asthma control. 2 2 30% of those with poor asthma control versus 22.7% with BMI (<18.5 kg/m )and high BMI(≥30 kg/m )[32]. The lack Journal of Allergy 3 Table 2: Studies of obesity as a risk factor for asthma control and severity. Number of subjects Study Study population Results Patients with severe Barros et al., 2011 [22] Obese asthmatics had worse asthma control asthma in Brazil Obese asthmatics had worse quality of life and lower Adult outpatients in Peters et al., 2011 [27] FVC but no difference in asthma severity and health South Texas care utilization Obese asthmatics had more severe disease and higher Youkou et al., 2011 [30] Japanese outpatients utilization of inhaled salmeterol and leukotriene receptor antagonists No significant association between obesity and asthma Sastre et al., 2010 [32] Spanish outpatients 607 control Obesity was associated with worsened asthma control Stanford et al., 2010 [18]Americanoutpatients 2238 as measured by ACT Clerisme-Beaty et al., Urban outpatients in the No association between asthma control and obesity 2009 [33] United States European internet Obesity was associated with worsened asthma control Demoly et al., 2009 [20] survey as measured by ACT Haselkorn et al., 2009 [31] Adult outpatients Worsened control of asthma with weight gain Adult outpatients in Lessard et al., 2008 [24] 88 Obese asthmatics had worse asthma control Canada Adult members of Obese asthmatics had worse asthma-related quality of Mosen et al., 2008 [25] managed care 1113 life, asthma control, and history of asthma related organization hospitalizations Outpatient adults from 4 Obese asthmatics had worse more severe asthma based Taylor et al., 2008 [29] states on measurement of several different factors Adult members of Obesity was associated with worsened asthma control Schatz et al., 2007 [19] managed care as measured by ACT organization Obesity was associated with worsened asthma control Laforest et al., 2006 [21]Frenchoutpatients as measured by ACT Obese asthmatics had worse asthma control and quality Lavoie et al., 2006 [23] Canadian outpatients of life but not asthma severity French outpatients, from Overweight/obese asthmatics less likely to develop Saint-Pierre et al., 2006 [26] 4 university-based better control of asthma clinics Adults outpatients in the Akermanetal.,2004[28] Linear relationship between asthma severity and BMI United States of association in these studies compared to the majority of end point was asthma control days (ACD), and other end other studies could be due to differences in baseline asthma points included FEV1, beta-agonist use, and night-time control and the percent of obese patients in the study groups. awakenings. eTh placebo response for all end points was It is not clear at this time if obesity is associated with increased generally lower with increasing BMI. For ACD, there was mortality in asthmatics. a decrease in the response to the inhaled corticosteroid (beclomethasone) with increasing BMI, whereas the response to the leukotriene antagonist (montelukast) remained stable 3. Obese-Asthma Phenotype: [34]. Boulet and Franssen found that obese individuals do Response to Medications not respond as well to an inhaled corticosteroid or inhaled The response to asthma medications may be influenced by corticosteroid/long-acting bronchodilator combination [35]. obesity. Studies have shown differential responses to therapy Farrah et al. examined asthma control aer ft treatment with in overweight or obese asthmatics compared to those with inhaled corticosteroid and found similar improvements across BMI groups in spirometry, airway inflammation, and normal BMI (Table 3). Peters-Golden et al. performed a post hoc analysis of more than 3000 subjects with mod- airway hyperresponsiveness. In this study there was still an erate asthma who were enrolled in 4 different random- association with ACQ scores and BMI aer ft treatment sug- ized controlled trials [34]. The trials randomized patients gesting an eeff ct of obesity on asthma independent of airway to montelukast, beclomethasone, or placebo. eTh primary inflammation [ 36]. Sutherland et al. found decreased in-vitro 4 Journal of Allergy response to glucocorticoids in obese asthmatics [37]. In this 6. Obese-Asthma Phenotype: Bariatric Surgery study, immune cells derived from both the peripheral blood and Asthma Control and lungs showed reduced induction of mitogen-activated In 1999, Dixon et al. evaluated 32 patients with asthma protein kinase phosphatase-1 (MKP-1) expression in response twelve months aer ft Lap-Band surgery [ 43]. Mean BMI was to dexamethasone in overweight/obese asthmatics compared 2 2 46 kg/m prior to surgery and 33 kg/m at follow-up. Signi-fi to normal weight asthmatics [37]. The trial “The Study of cant improvements were seen in severity, daily impact, med- the Eeff ctiveness of Low Dose Theophylline as Add-On ications needed, hospitalization, sleep, and exercise. Eleven therapy in Poorly Controlled Asthma” or “LODO” enrolled patients reported no longer having asthma symptoms. Man- 488 subjects and compared theophylline, montelukast, and iscalco et al. compared twelve obese asthmatic females who placebo in subjects with mild-moderate asthma who were not underwent laparoscopic adjustable gastric banding (LAGB) controlled on their current therapy. This group of patients to ten nonoperated obese asthmatic females [44]. After was categorized by Dixon et al. as normal weight, overweight, surgery, those undergoing surgery had improved ACT scores andobese accordingtoBMI.They foundthatobese patients compared to the group without surgery (18.7 to 22.2,𝑃< who took theophylline had a trend towards an increased rate 0.001). Shortness of breath and rescue medication use were of exacerbations compared to placebo (8.1 versus 4.8 events signicfi antly improved after surgery. In a prospective study, per year,𝑃 = 0.06 ) and the relative risk for exacerbation Dixon et. al. compared 23 asthmatic (mean BMI 51 kg/m ) associated with obesity among patients on theophylline was and 21 nonasthmatic (mean BMI 38 kg/m ) patients under- 3.7 (𝑃 < 0.001 ). eTh re were no signicfi ant differences in going bariatric surgery [45]. At baseline, asthmatic patients response to treatment with montelukast [38]. had a lower FEV1 and FVC. Twelve months aer ft surgery the asthmatic patients experienced significant improvements 4. Obese-Asthma Phenotype: Effect of in asthma control (asthma control score 1.55 to 0.74,𝑃< 0.0001) and asthma quality of life (4.87 to 5.87,𝑃<0.0001 ). Weight Loss In addition, they had a significant improvement in airway In general, studies have shown improvement in various responsiveness to methacholine but no significant changes in inflammatory markers [ 45]. parameters of asthma control and severity with weight-loss interventions ranging from diet modification to bariatric surgery. Juel et al. published a systematic review of weight- 7. Potential Mechanisms of Interaction loss interventions in 2012 and concluded that all papers between Asthma and Obesity reviewed showed some positive eect ff of weight loss on asthma control [39]. The association between asthma and obesity is well estab- lished, and obese asthmatics have been shown to have worsened asthma control and increased asthma severity. 5. Obese-Asthma Phenotype: Nonsurgical The mechanisms behind this are still under investigation Weight Loss Interventions and likely multifactorial. This has made it more difficult to measure the impact of obesity on objective asthma traits such In an open, randomized parallel group study, Stenius- as the measurement of specicfi inflammatory mediators or Aarniala et al. investigated the effects of a supervised weight airway hyperreactivity. reduction program (eight-week, very low-energy diet) and found signicfi ant improvements in FEV1, forced vital capacity 8. Atopy and Eosinophilic (FVC), dyspnea, the use of rescue medications, and the number of exacerbations [40]. An uncontrolled study which Airway Inflammation included 24 obese women with asthma enrolled in a program Eosinophilic airway inflammation is a characteristic of atopic consisting of a 900 kcal per day diet and regular exercise asthma. Studies have found that the relationship between found improvements in FEV1, FVC, and total lung capacity obesity and asthma is stronger in nonatopic individuals [47– (TLC) butnosignicfi antimprovementsinairwayrespon- 50]. Appleton et al. looked at the association between asthma siveness (defined as responsiveness to inhaled methacholine) and obesity as measured by waist circumference (WC) and [41]. waist-to-hip ratio (WHR) and whether or not atopy modified In a recent Cochrane review, Adeniyi and Young assessed this relationship. eTh y used skin prick tests to a panel the eeff ct of various weight-loss interventions on asthma of allergens to den fi e atopic status. When they stratiefi d control [42]. They included four studies with total of 197 according to atopic status, they found that the relationship adults. Interventions included supervised physical activity, between obesity and asthma was signicfi ant only in nonatopic low calorie diet, and antiobesity drugs. eTh y decided that individuals when using WC and WHR as a marker of obesity there were methodological flaws in the studies with an [48]. Chen et al. examined the association between obesity unclearriskofselection bias,highriskofdetection bias, and asthma in both atopic and nonatopic individuals. Allergy and small sample size. eTh y concluded that the benefit of skin tests were used to measure atopic status. In nonatopic weight loss remains uncertain and there is a need for more subjects, the odds ratio for asthma with a BMI of at least randomized controlled trials. 30 kg/m was 2.01 (95% CI 1.13, 3.59). eTh association between Journal of Allergy 5 Table 3: Studies of responses to therapy in overweight or obese asthmatics compared to normal BMI. Study Number of subjects Asthma therapy Results Similar improvements in asthma control, spirometry, Farah et al., 2011 [36] Fluticasone/salmeterol 49 airway inflammation, and airway hyperresponsiveness across BMI groups Fluticasone greater improvement across all BMI Sutherland et al., 2010 [46] 1052 Fluticasone, montelukast categories when compared to montelukast Decreased in vitro response to glucocorticoids in obese Sutherland et al., 2008 [37] 45 Glucocorticoids asthmatics Fluticasone with salmeterol resulted in improved Fluticasone with or asthma control in both groups compared to fluticasone Boulet and Franssen 2007 [35] 1242 without salmeterol alone but overall decreased effectiveness with both regimens in obese patients Increased risk of exacerbations in obese subjects treated Theophylline, Dixon et al., 2006 [38] 488 with theophylline but no difference in montelukast montelukast, placebo treatment groups Less improvement in asthma control days with inhaled Beclomethasone, Peters-Golden et al., 2006 [34] 3073 corticosteroid with increasing BMI, no difference with montelukast, placebo montelukast asthma and obesity was not statistically significant in atopic increased in obesity. Serum adiponectin is lower in obesity subjects [49]. Fenger et al. explored the association between and has important antiinflammatory effects in obesity [ 59]. adiposity (using six different measurements) and asthma. Shore et al. showed that giving exogenous leptin to They found that all adiposity measurements were associated sensitized mice augmented airway hyperreactivity aer ft aller- with a higher prevalence of asthma but only among nonatopic gen challenge [60]. Lugogo et al. examined 42 subjects individuals [50]. with asthma and 46 healthy controls [61]. They found that leptin levels were increased in overweight/obese subjects Fraction of exhaled nitric oxide (FeNO) is used as a regardless of asthma status (𝑃=0.013 )but were signicfi antly marker of airway inflammation and as an indirect mea- higher in those with asthma. Levels of TNF-alpha were surement of the presence of airway eosinophils [51, 52]. also higher in overweight/obese subjects with asthma [61]. Studies have not shown a relationship between obesity and Alveolar macrophage response to bacterial lipopolysaccha- eosinophilic airway inflammation [ 53]. Others have shown ride (LPS) was most robust in overweight/obese subjects an inverse relationship between sputum eosinophils and with asthma. Preexposure to high-dose leptin enhanced waist circumference in asthmatics [24]. Todd et al. found no proinflammatory response. Leptin alone induced production significant differences in sputum eosinophil counts between of proinflammatory cytokines from macrophages derived obese and nonobese asthmatics [54]. Decreased levels of from overweight/obese subjects with asthma showing that FeNO have been found in obese individuals who report macrophages from overweight/obese people with asthma are wheezing [55]. Scott et al. found that obesity had no eeff ct on more sensitive to leptin. In another study, a cohort of obese sputum eosinophil counts in asthmatics, but obese asthmatics women with and without asthma were followed for 12 months did have a higher sputum neutrophil percentage [56]. These aer ft gastric surgery [ 62]. o Th se with asthma had increased findings suggest that obesity is not associated with increased macrophage infiltration of visceral adipose tissue ( 𝑃<0.01 ), airway eosinophilic inflammation and that allergic inflam- increased expression of leptin (𝑃 < 0.01 ), and decreased mation cannot explain the association between obesity and adiponectin (𝑃 < 0.001 ) when controlled for BMI [62]. asthma. Airway epithelial cells expressed receptors for leptin and adiponectin, and airway reactivity was signicfi antly related to visceral fat leptin expression. 9. Leptin and Adiponectin A bidirectional relationship between adiponectin and Obesity is characterized by chronic low-grade systemic in- asthma has been noted in mice where allergen inhala- flammation. Obese adipose tissue is infiltrated by macro- tion reduces serum adiponectin and exogenous adiponectin phages that are a source of inflammatory cytokines [ 57]. attenuates airway hyperreactivity [59]. Sood et al. showed TNF-alpha, Il-6, and leptin have been shown to be higher in a protective association between high serum adiponectin obese asthmatics patients than in nonobese asthmatics [58]. and odds for clinical diagnosis of asthma in premenopausal More than 50 different adipokines are secreted by adipocytes. women independent of BMI and later showed that low serum Adipokines are proteins that help regulate various body adiponectin was predictive of future incident asthma [63, 64]. functions [59]. Sutherland et al. were not able to confirm these ndin fi gs Leptin and adiponectin are two adipokines that are being in 1000 32-year-olds in New Zealand. eTh y found that studied to determine their association with asthma. Serum higher serum adiponectin concentrations were associated leptin is proinflammatory, and serum levels are markedly with increased prevalence of reversible airflow obstruction 6 Journal of Allergy and lower levels of exhaled nitric oxide among men suggest- phenotype or may themselves be associated with asthma. ing a proinflammatory effect among men [ 65]. eTh se include gastro-esophageal reu fl x disease (GERD) and obstructive sleep apnea (OSA). GERD is frequently cited as a reason for uncontrolled 10. Lung Function asthma in both the literature and in clinical practice. Obese Obesity has an effect on lung function independent of patients are frequently bothered by GERD. A recent meta- its eeff ct on asthma which may contribute to the poor analysis that included eleven trials covering 2524 patients control and increased severity of asthma in this phenotype. found that patients had a higher mean morning peak expi- Functional residual capacity (FRC) and expiratory reserve ratory flow (PEF) rate after treatment with proton pump volume (ERV) have been consistently shown to decrease with inhibitory (PPI) but no signicfi ant difference in asthma increasing BMI [66, 67]. At a BMI of 30 kg/m ,FRC andERV symptoms score, asthma quality of life questionnaire, evening areonly75% and45% of thevaluesseeninthose with BMI PEF rate, and FEV1. Overall they found insufficient evidence of 20 kg/m [66]. The changes in TLC associated with obesity to recommend empirical use of PPIs for routine treatment are smaller, and TLC is usually well preserved until a patient of asthma [78]. These results conflict with current clinical becomes markedly obese [66, 68]. Obesity is not typically practices and overall lead to the question of whether treating associated with airflow obstruction, and the FEV1/FVC ratio GERD would improve asthma control regardless of BMI. is preserved [66, 69]. Obese patients have increased airway Julien et al. performed an overnight home polysomnog- resistance. This could be at least partially explained by the fact raphy on 26 patients with severe asthma, 26 patients with that they breathe at a lower FRC leading to closure of smaller moderateasthma, and26controlswithout asthma of similar airways [68, 70]. The distribution of adipose tissue (upper age and BMI. They measured flow rates as well as asthma versus lower body) may be the most important determinant control and quality of life. They found that OSA was present of altered lung mechanics [71]. in 50% of the subjects with severe asthma, 23% with moderate Obesity may have an effect on airway smooth muscle asthma, and 12% of controls (𝑃=0.007 )[79]. They also found leading to increased airway hyperreactivity but the current that apnea-hypopnea severity measures were signicfi antly evidence is conflicting. A study of non-obese, asthmatic worse for both asthmatic groups compared to controls. eTh y subjects showed increased response when they had an acute did not find any significant correlation between severity of reduction in lung volumes [72]. Salome et al. found no sleep-disordered breathing and asthma severity or control significant differences in the response to methacholine in obese and non-obese subjects [73]. They did find that with measures. Dixon et al. looked at both GERD and OSA in a bronchoconstriction, obese subjects develop increased elastic group of asthmatic patients participating in a trial of reflux loads which could lead to greater perception of dyspnea. treatment [80]. They found that witnessed apnea had the A study evaluating the dynamic changes in lung volumes strongest association with decreased asthma control and before and after methacholine challenge found that dynamic that there was a highly significant relationship between the changes with bronchoconstriction were greater in obese than number of symptoms of OSA reported by subject and asthma nonobese asthmatics [74]. control [80]. They found no relationship between GERD and asthma control in obese patients. Teodorescu et al. studied 472 patients with asthma who 11. Oxidative Stress completed the Sleep Apnea Scale of the Sleep Disorders Increased oxidative stress either systemically or in the airways Questionnaire (SA-SDQ) and ACQ [81]. High OSA risk was has been studied in association with both asthma and associatedwith2.87timeshigheroddsofpoorasthmacontrol obesity. Higher serum F2-isoprostane levels were associated (95% CI, 1.54–5.32;𝑃=0.0009 ) aeft r adjustment for obesity with asthma, but the association was not signica fi nt aeft r and other factors [81]. adjusting for obesity or gender [75]. Another study showed OSAhas been showntoworsennocturnal asthma [82]. an association between exhaled 8-isoprostane and BMI in Teodorescu et al. looked at the association between OSA and asthmatics only [76]. Exhaled and serum 8-isoprostane were daytime asthma in a group of asthmatic patients at tertiary- measured in a group of moderate-to-severe asthmatics and care centers. Subjects completed the SA-SDQ, and medical controls. Obesity was associated with increased exhaled 8- records were reviewed for established diagnosis of OSA isoprostane in both asthmatics and controls, while plasma and CPAP use. After using modeling to control for obesity levels were higher in asthmatics than in controls. er Th e was and other risk factors, they found that high OSA risk was no correlation between the serum and exhaled levels [77]. At associated with persistent daytime (OR = 1.96 [1.31–2.94]) present, it is difficult to know what role oxidative stress plays and nighttime symptoms (1.97 [1.32–2.94]). A diagnosis of in the obese-asthma phenotype. OSA was associated with persistent daytime symptoms (2.08 [1.13–3.82]) but not nighttime symptoms (1.48 [0.82–2.69]). 12. Obese-Asthma Phenotype: Role of Using CPAP lowered the risk of persistent daytime symptoms (0.46 [0.23–0.94]). They concluded that both questionnaire- Comorbid Conditions den fi ed OSA risk and historical diagnosis were associated Obesity is associated with a number of comorbid conditions with persistent daytime asthma symptoms equal to or greater that may either contribute to the observed obese-asthma than the association with nighttime asthma symptoms [83]. Journal of Allergy 7 13. Recommendations [8] E. S. Ford, “eTh epidemiology of obesity and asthma,” Journal of Allergy and Clinical Immunology, vol. 115, no. 5, pp. 897–910, Asthma and obesity exhibit a well-established relation- ship with evidence pointing towards a more severe and [9] D. A. Beuther and E. R. Sutherland, “Overweight, obesity, and difficult-to-control obese-asthma phenotype that has altered incident asthma: a meta-analysis of prospective epidemiologic responses to controller medications. This phenotype is more studies,” American Journal of Respiratory and Critical Care likely to have a worse quality of life, more daily symptoms, Medicine,vol.175,no. 7, pp.661–666,2007. and more exacerbations as well as use more rescue medica- [10] V. Hjellvik, A. Tverdal, and K. Furu, “Body mass index as tions. predictor for asthma: a cohort study of 118,723 males and females,” European Respiratory Journal,vol.35, no.6,pp. 1235– Research is underway to better define the mechanisms 1242, 2010. responsible for this distinct phenotype, which will allow for [11] W. S. Beckett, D. R. Jacobs, Y. U. Xinhua, C. Iribarren, and targeted therapies. eTh increased risk in this phenotype may O. Dale Williams, “Asthma is associated with weight gain be due to changes in inflammation from altered levels of lep- in females but not males, independent of physical activity,” tin and adiponectin, increased oxidative stress, and/or obesity American Journal of Respiratory and Critical Care Medicine,vol. induced changes in lung volumes. The authors recommend 164, no. 11, pp. 2045–2050, 2001. that due to the varying response to controller medications, [12] Y. Chen, D. Rennie, Y. Cormier, and J. Dosman, “Sex specificity which makes it difficult to know which medication regimen of asthma associated with objectively measured body mass is ideally suited to treat this phenotype, clinicians taking care index and waist circumference: the Humboldt study,” Chest,vol. of patients with asthma should follow the obese asthmatic 128, no. 4, pp. 3048–3054, 2005. closely to assess response to medications. It is possible that [13] A. E. Dixon, F. Holguin, A. Sood et al., “An official American obese asthmatics may not respond as well to corticosteroids Thoracic Society Workshop report: obesity and asthma,” Pro- as compared to individuals of normal weight. Rather than ceedings of the American or Th acic Society ,vol.7,no. 5, pp.325– increasing doses of medications when an obese patient does 335, 2010. not respond as expected and increasing the risk of side eeff cts, [14] A. Fuhlbrigge,M.L.Reed,D.A.Stempel,H.O.Ortega, K. the clinician could focus on alternative methods of disease Fanning, and R. H. Stanford, “eTh status of asthma control in management. Besides medications to control asthma, weight the U.S. adult population,” Allergy and Asthma Proceedings,vol. management programs and early detection and management 30,no. 5, pp.529–533,2009. of OSA may oer ff targeted therapies that can improve [15] T. Haselkorn, H. Chen, D. P. Miller et al., “Asthma control and asthma control. Weight loss interventions, both surgical and activity limitations: insights from the Real-world Evaluation nonsurgical, can improve asthma control in the appropriate of Asthma Control and Treatment (REACT) Study,” Annals of candidate. Efforts focused on prevention of obesity may be Allergy, Asthma and Immunology,vol.104,no. 6, pp.471–477, the most beneficial therapy for this phenotype. [16] National Asthma Education and Prevention Program, “Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and References Management of Asthma-Summary Report 2007,” The Journal of Allergy and Clinical Immunology,vol.120,no. 5, pp.S94–S138, [1] “Classification of Overweight and Obesity by BMI, Waist Circumference, and Associated Disease Risks,” 2012, http:// [17] M. M. Cloutier, M. Schatz, M. Castro et al., “Asthma outcomes: www.nhlbi.nih.gov/health/public/heart/obesity/lose wt/bmi composite scores of asthma control,” JournalofAllergy and dis.htm. Clinical Immunology,vol.129,no. 3, supplement,pp. S24–S33, [2] “Obesity and Overweight,” Fact sheet no. 311, 2012, http://www .who.int/mediacentre/factsheets/fs311/en/. [18] R. H. Stanford,A.W.Gilsenan, R. Ziemiecki, X. Zhou,W.R. [3] “Asthma,” Fact sheet no. 307, 2011, http://www.who.int/media- Lincourt, and H. Ortega, “Predictors of uncontrolled asthma in centre/factsheets/fs307/en/index.html. adult and pediatric patients: analysis of the asthma control char- acteristics and prevalence survey studies (ACCESS),” Journal of [4] L.J.Akinbami, J. E. Moorman, C. Bailey,H.S.Zahran, M. King, Asthma,vol.47, no.3,pp. 257–262, 2010. and X. Liu, “Trends in asthma prevalence, health care use, and [19] M. Schatz,D.M.Mosen,M.Kosinskietal.,“Predictors of mortality in the United States, 2001–2010,” NCHS Data Brief,no. asthma control in a random sample of asthmatic patients,” 94, pp. 1–8, 2012. Journal of Asthma,vol.44, no.4,pp. 341–345, 2007. [5] C.A.Camargo,S.T.Weiss,S.Zhang,W.C.Willett, andF.E. [20] P. Demoly, P. Paggiaro, V. Plaza et al., “Prevalence of asthma Speizer, “Prospective study of body mass index, weight change, control among adults in France, Germany, Italy, Spain and the and risk of adult- onset asthma in women,” Archives of Internal UK,” European Respiratory Review,vol.18, no.112,pp. 105–112, Medicine,vol.159,no. 21,pp. 2582–2588, 1999. [6] S. Guerra, D. L. Sherrill, A. Bobadilla, F. D. Martinez, and R. A. [21] L. Laforest,E.Van Ganse, G. Devouassouxetal.,“Inufl ence Barbee, “eTh relation of body mass index to asthma, chronic of patients’ characteristics and disease management on asthma bronchitis, and emphysema,” Chest, vol. 122, no. 4, pp. 1256– control,” Journal of Allergy and Clinical Immunology,vol.117,no. 1263, 2002. 6, pp. 1404–1410, 2006. [7] E. Huovinen, J. Kaprio, and M. Koskenvuo, “Factors associated [22] L. L. Barros, A. Souza-Machado, L. B. Correa ˆ et al., “Obesity and to lifestyle and risk of adult onset asthma,” Respiratory Medicine, poor asthma control in patients with severe asthma,” Journal of vol. 97,no. 3, pp.273–280,2003. Asthma,vol.48, no.2,Article ID 554940,pp. 171–176, 2011. 8 Journal of Allergy [23] K. L. Lavoie, S. L. Bacon, M. Labrecque, A. Cartier, and B. [40] B. Stenius-Aarniala, T. Poussa, J. Kvarnstrom, ¨ E. L. Gron ¨ lund, Ditto, “Higher BMI is associated with worse asthma control and M. Ylikahri, and P. Mustajoki, “Immediate and long term eeff cts quality of life but not asthma severity,” Respiratory Medicine,vol. of weight reduction in obese people with asthma: randomised 100, no.4,pp. 648–657, 2006. controlled study,” British Medical Journal,vol.320,no. 7238,pp. 827–832, 2000. [24] A. Lessard, H. Turcotte,Y.Cormier, andL.P.Boulet, “Obesity and asthma: a specific phenotype?” Chest,vol.134,no. 2, pp. [41] S. D. Aaron, D. Fergusson, R. Dent, Y. Chen, K. L. Vandemheen, 317–323, 2008. and R. E. Dales, “Eeff ct of weight reduction on respiratory function and airway reactivity in obese women,” Chest,vol.125, [25] D. M. Mosen, M. Schatz, D. J. Magid, and C. A. Camargo, “eTh no. 6, pp. 2046–2052, 2004. relationship between obesity and asthma severity and control in adults,” Journal of Allergy and Clinical Immunology,vol.122,no. [42] F. B. Adeniyi and T. Young, “Weight loss interventions for 3, p. 507, 2008. chronic asthma,” Cochrane Database of Systematic Reviews,vol. 7, Article ID CD009339, 2012. [26] P. Saint-Pierre, A. Bourdin, P. Chanez, J. P. Daures, and P. Godard, “Are overweight asthmatics more difficult to control?” [43] J. B. Dixon, L. Chapman, and P. O’Brien, “Marked improvement Allergy,vol.61, no.1,pp. 79–84, 2006. in asthma aer ft Lap-Band surgery for morbid obesity,” Obesity Surgery,vol.9,no. 4, pp.385–389,1999. [27] J. I. Peters,J.M.McKinney,B.Smith,P.Wood,E.Forkner,and A. D. Galbreath, “Impact of obesity in asthma: evidence from a [44] M. Maniscalco, A. Zedda, S. Faraone et al., “Weight loss and largeprospective diseasemanagementstudy,” Annals of Allergy, asthma control in severely obese asthmatic females,” Respiratory Asthma and Immunology, vol. 106, no. 1, pp. 30–35, 2011. Medicine,vol.102,no. 1, pp.102–108,2008. [28] M. J. H. Akerman, C. M. Calacanis, and M. K. Madsen, [45] A. E. Dixon, R. E. Pratley, P. M. Forgione et al., “Eeff cts of obesity “Relationship between asthma severity and obesity,” Journal of and bariatric surgery on airway hyperresponsiveness, asthma Asthma,vol.41, no.5,pp. 521–526, 2004. control, and inflammation,” JournalofAllergy andClinical Immunology, vol. 128, no. 3, pp. 508.e2–515.e2, 2011. [29] B. Taylor, D. Mannino, C. Brown, D. Crocker, N. Twum-Baah, and F. Holguin, “Body mass index and asthma severity in the [46] E. R. Sutherland,C.A.Camargo,W.W.Busse et al., “Compara- National Asthma Survey,” Thorax ,vol.63, no.1,pp. 14–20, 2008. tive effect of body mass index on response to asthma controller therapy,” Allergy and Asthma Proceedings,vol.31, no.1,pp. 20– [30] A. Youkou, T. Hasegawa, K. Suzuki et al., “Influence of obesity 25, 2010. on control in asthmatic Japanese patients defined by the Japanese definition of obesity,” Internal Medicine,vol.50, no.18, [47] D. Jarvis, S. Chinn, J. Potts, and P. Burney, “Association of body pp. 1911–1916, 2011. mass index with respiratory symptoms and atopy: results from the European Community Respiratory Health Survey,” Clinical [31] T. Haselkorn, J. E. Fish, B. E. Chipps, D. P. Miller, H. Chen, and and Experimental Allergy,vol.32, no.6,pp. 831–837, 2002. S. T. Weiss, “Effect of weight change on asthma-related health outcomes in patients with severe or difficult-to-treat asthma,” [48] S. L. Appleton,R.J.Adams,D.H.Wilson, A. W. Taylor,and R. Respiratory Medicine,vol.103,no. 2, pp.274–283,2009. E. Ruffin, “Central obesity is associated with nonatopic but not atopic asthma in a representative population sample,” Journal of [32] J. Sastre,J.M.Olagu´ıbe, A. L. Vin˜a,J.M.Vega, V. DelPozo, Allergy and Clinical Immunology,vol.118,no. 6, pp.1284–1291, and C. Picado, “Increased body mass index does not lead to a worsening of asthma control in a large adult asthmatic population in spain,” Journal of Investigational Allergology and [49] Y. Chen, D. Rennie, Y. Cormier, and J. Dosman, “Atopy, Clinical Immunology,vol.20, no.7,pp. 551–555,2010. obesity, and asthma in adults: the Humboldt study,” Journal of [33] E. M. Clerisme-Beaty, S. Karam, C. Rand et al., “Does higher Agromedicine,vol.14, no.2,pp. 222–227,2009. body mass index contribute to worse asthma control in an urban [50] R. V. Fenger, A. Gonzalez-Quintela, C. Vidal et al., “Exploring population?” JournalofAllergy andClinicalImmunology,vol. the obesity-asthma link: do all types of adiposity increase the 124, no. 2, pp. 207–212, 2009. risk of asthma?” Clinical and Experimental Allergy,vol.42, no. [34] M. Peters-Golden, A. Swern, S. S. Bird, C. M. Hustad, E. Grant, 8, pp. 1237–1245, 2012. and J. M. Edelman, “Inu fl ence of body mass index on the [51] A. M. Fortuna, T. Feixas, M. Gonzalez, ´ and P. Casan, “Diag- response to asthma controller agents,” European Respiratory nostic utility of inflammatory biomarkers in asthma: exhaled Journal,vol.27, no.3,pp. 495–503, 2006. nitric oxide and induced sputum eosinophil count,” Respiratory [35] L. P. Boulet and E. Franssen, “Influence of obesity on response Medicine,vol.101,no. 11, pp.2416–2421,2007. to fluticasone with or without salmeterol in moderate asthma,” [52] A. Jatakanon, S. Lim, S. A. Kharitonov, K. F. Chung, and P. Respiratory Medicine,vol.101,no. 11, pp.2240–2247,2007. J. Barnes, “Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with [36] C. S. Farah, J. A. Kermode, S. R. Downie et al., “Obesity is a determinant of asthma control independent of inflammation mild asthma,” Thorax ,vol.53, no.2,pp. 91–95, 1998. and lung mechanics,” Chest,vol.140,no. 3, pp.659–666,2011. [53] S. H. Kim, T. H. Kim, J. S. Lee et al., “Adiposity, adipokines, and [37] E. R. Sutherland,E.Goleva, M. Strand,D.A.Beuther,and D. Y. exhaled nitric oxide in healthy adults without asthma,” Journal M. Leung, “Body mass and glucocorticoid response in asthma,” of Asthma, vol. 48, no. 2, Article ID 529223, pp. 177–182, 2011. American Journal of Respiratory and Critical Care Medicine,vol. [54] D. C. Todd,S.Armstrong,L.D’Silva,C.J.Allen,F.E.Hargreave, 178, no. 7, pp. 682–687, 2008. and K. Parameswaran, “Effect of obesity on airway inflamma- [38] A. E. Dixon, D. M. Shade, R. I. Cohen et al., “Effect of obesity tion: a cross-sectional analysis of body mass index and sputum on clinical presentation and response to treatment in asthma,” cell counts,” Clinical and Experimental Allergy,vol.37, no.7,pp. Journal of Asthma,vol.43, no.7,pp. 553–558, 2006. 1049–1054, 2007. [39] C. T. Juel -B,Z.Ali,L.Nilas,and C. S. Ulrik, “Asthmaand [55] C. M. Berg,D.S.Thelle,A.Rosengren,L.Lissner,K.Tor en, ´ and obesity: does weight loss improve asthma control? A systematic A. C. Olin, “Decreased fraction of exhaled nitric oxide in obese review,” Journal of Asthma and Allergy, no. 5, pp. 21–26, 2012. subjects with asthma symptoms: data from the population study Journal of Allergy 9 INTERGENE/ADONIX,” Chest,vol.139,no. 5, pp.1109–1116, [73] C. M. Salome, P. A. Munoz, N. Berend, C. W. Thorpe, L. M. 2011. Schachter, and G. G. King, “Eeff ct of obesity on breathlessness and airway responsiveness to methacholine in non-asthmatic [56] H. A. Scott, P. G. Gibson,M.L.Garg, andL.G.Wood, subjects,” International Journal of Obesity,vol.32, no.3,pp. 502– “Airway inflammation is augmented by obesity and fatty acids 509, 2008. in asthma,” European Respiratory Journal,vol.38, no.3,pp. 594– 602, 2011. [74] T. J. T. Sutherland,J.O.Cowan,and D. R. Taylor,“Dynamic hyperinflation with bronchoconstriction: differences between [57] K. E. Wellen and G. S. Hotamisligil, “Obesity-induced inflam- obese and nonobese women with asthma,” American Journal of matory changes in adipose tissue,” Journal of Clinical Investiga- Respiratory and Critical Care Medicine,vol.177,no. 9, pp.970– tion,vol.112,no. 12,pp. 1785–1788, 2003. 975, 2008. [58] M. Cano¨z,F.Erdenen,H.Uzun, C. Muder ¨ risogl ˇ u, and S. Aydin, [75] A. Sood, C. Qualls, A. Arynchyn et al., “Obesity-asthma “eTh relationship of inflammatory cytokines with asthma and association: is it explained by systemic oxidant stress?” Chest, obesity,” Clinical and Investigative Medicine,vol.31, no.6,pp. vol. 136, no. 4, pp. 1055–1062, 2009. E373–E379, 2008. [76] S. Komakula, S. Khatri, J. Mermis et al., “Body mass index [59] N. AliAssad andA.Sood,“Leptin, adiponectinand pulmonary is associated with reduced exhaled nitric oxide and higher diseases,” Biochimie, vol. 94, no. 10, pp. 2180–2189, 2012. exhaled 8-isoprostanes in asthmatics,” Respiratory Research,vol. [60] S. A. Shore, I. N. Schwartzman, M. S. Mellema, L. Flynt, A. 8, article 32, 2007. Imrich, and R. A. Johnston, “Effect of leptin on allergic airway [77] F. Holguin and A. Fitzpatrick, “Obesity, asthma, and oxidative responses in mice,” Journal of Allergy and Clinical Immunology, stress,” Journal of Applied Physiology,vol.108,no. 3, pp.754–759, vol. 115, no. 1, pp. 103–109, 2005. [61] N. L. Lugogo,J.W.Hollingsworth,L.G.Que et al., “Alveolar [78] W. W. Chan, M. E. Chiou, K. L. Obstein, A. S. Tignor, and macrophages from overweight/obese subjects with asthma T. L. Whitlock, “eTh efficacy of proton pump inhibitors for demonstrate a proinflammatory phenotype,” American Journal the treatment of asthma in adults: a meta-analysis,” Archives of of Respiratory and Critical Care Medicine,vol.186,no. 5, pp. Internal Medicine,vol.171,no. 7, pp.620–629,2011. 404–411, 2012. [79] J. Y. Julien,J.G.Martin, P. Ernstetal.,“Prevalence of obstructive [62] O. Sideleva, B. T. Suratt, K. E. Black et al., “Obesity and asthma: sleep apnea-hypopnea in severe versus moderate asthma,” an inflammatory disease of adipose tissue not the airway,” Journal of Allergy and Clinical Immunology,vol.124,no. 2, pp. American Journal of Respiratory and Critical Care Medicine,vol. 371–376, 2009. 186, no. 7, pp. 598–605, 2012. [80] A. E. Dixon, E. M. Clerisme-Beaty, E. A. Sugar et al., “Eeff cts of [63] A. Sood, X. Cui, C. Quails et al., “Association between asthma obstructivesleep apneaand gastroesophageal reufl xdisease on and serum adiponectin concentration in women,” Thorax ,vol. asthma control in obesity,” Journal of Asthma,vol.48, no.7,pp. 63,no. 10,pp. 877–882, 2008. 707–713, 2011. [64] A. Sood, C. Qualls, M. Schuyler et al., “Low serum adiponectin [81] M. Teodorescu,D.A.Polomis,S.V.Halletal.,“Association predicts future risk for asthma in women,” American Journal of of obstructive sleep apnea risk with asthma control in adults,” Respiratory and Critical Care Medicine,vol.186,no. 1, pp.41–47, Chest,vol.138,no. 3, pp.543–550,2010. [82] C. Shu Chan, A. J. Woolcock, and C. E. Sullivan, “Nocturnal [65] T.J.T.Sutherland,M.R.Sears,C.R.McLachlan,R.Poulton,and asthma:roleofsnoring andobstructive sleepapnea,” American R. J. Hancox, “Leptin, adiponectin, and asthma: findings from a Review of Respiratory Disease, vol. 137, no. 6, pp. 1502–1504, 1988. population-based cohort study,” Annals of Allergy, Asthma and [83] M. Teodorescu,D.A.Polomis,M.C.Teodorescuetal.,“Associ- Immunology,vol.103,no. 2, pp.101–107,2009. ation of obstructive sleep apnea risk or diagnosis with daytime [66] R. L. Jones and M. M. U. Nzekwu, “The effects of body mass asthma in adults,” Journal of Asthma,vol.49, no.6,pp. 620–628, index on lung volumes,” Chest,vol.130,no. 3, pp.827–833,2006. [67] W. Ladosky, M. A. M. Botelho, and J. P. Albuquerque, “Chest mechanics in morbidly obese non-hypoventilated patients,” Respiratory Medicine,vol.95, no.4,pp. 281–286, 2001. [68] I. Rubinstein, N. Zamel, L. DuBarry, and V. Hoffstein, “Airflow limitation in morbidly obese, nonsmoking men,” Annals of Internal Medicine,vol.112,no. 11, pp.828–832,1990. [69] D. D. Sin, R. L. Jones, andS.F.PaulMan,“Obesityisarisk factor for dyspnea but not for airflow obstruction,” Archives of Internal Medicine,vol.162,no. 13,pp. 1477–1481, 2002. [70] R. A. Watson and N. B. Pride, “Postural changes in lung volumes and respiratory resistance in subjects with obesity,” Journal of Applied Physiology, vol. 98, no. 2, pp. 512–517, 2005. [71] L. C. Collins, P. D. Hoberty, J. F. Walker, E. C. Fletcher, and A. N. Peiris, “eTh eeff ct of body fat distribution on pulmonary function tests,” Chest,vol.107,no. 5, pp.1298–1302,1995. [72] D. J. Ding,J.G.Martin, andP.T.Macklem,“Eeff cts of lung vol- ume on maximal methacholine-induced bronchoconstriction in normal humans,” Journal of Applied Physiology,vol.62, no. 3, pp. 1324–1330, 1987. 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