Systemic Inflammation in Chronic Obstructive Pulmonary Disease and ...

Systemic Inflammation in Chronic Obstructive Pulmonary Disease and Asthma: Relation with Comorbidities Helgo Magnussen1,2 and Henrik Watz1 1 Hospital Grosshansdorf, Center for Pneumology and Thoracic Surgery, and 2Pulmonary Research Institute at Hospital Grosshansdorf, Grosshansdorf, Germany

Markers of systemic inflammation have been shown to be elevated in blood of patients with chronic obstructive pulmonary disease (COPD) when compared with control subjects without COPD. The origin of systemic inflammation in COPD is unclear. COPD is often accompanied by other chronic diseases that are also associated with systemic inflammation, such as chronic heart failure, diabetes, and arteriosclerosis. Physical inactivity and metabolic syndrome are relevant conditions leading to systemic inflammation in the general population. Recent data indicate that physical inactivity and coexisting metabolic syndrome are also independently related to systemic inflammation in patients with COPD. Concerning asthma, only limited data about systemic inflammatory markers exist. Some studies found systemic inflammatory markers to be elevated in patients with nonallergic asthma and obese patients with asthma. Further research should elucidate the complex relationship between obstructive lung disease, coexisting conditions, systemic inflammation accompanying these different conditions, and the causative role of systemic inflammation for comorbidities in COPD and asthma. Keywords: chronic obstructive pulmonary disease; asthma; systemic inflammation; physical activity; metabolic syndrome

CHRONIC OBSTRUCTIVE PULMONARY DISEASE: THE CLINICAL ROLE OF COMORBIDITIES Chronic obstructive pulmonary disease (COPD) is defined as a preventable and treatable disease with significant extrapulmonary effects that may contribute to its severity in individual patients (1). Comorbidities such as chronic heart failure, cardiovascular disease, depression, diabetes, muscle wasting, weight loss, lung cancer, and osteoporosis can frequently be found in patients with COPD and are considered to be part of the commonly prevalent nonpulmonary sequelae of the disease (2, 3). Cardiovascular disease and lung cancer play an important role for mortality in mild and severe COPD (4, 5). Weight loss and loss of fat-free mass have an impact on prognosis in patients with COPD (6, 7). Depressive symptoms in patients with COPD are associated with poorer survival, longer hospital stay, increased symptom burden, and poorer physical and social functioning (8). Left heart dysfunction is independently associated with reduced physical activity in patients with COPD of different severity (9). Patients with COPD are affected in their health-related quality of life by multiple comorbidities (10).

(Received in original form May 10, 2009; accepted in final form August 15, 2009) Correspondence and requests for reprints should be addressed to Helgo Magnussen, M.D., Pulmonary Research Institute at Hospital Grosshansdorf, Center for Pneumology and Thoracic Surgery, Woehrendamm 80, 22927 Grosshansdorf, Germany. E-mail: [email protected] Proc Am Thorac Soc Vol 6. pp 648–651, 2009 DOI: 10.1513/pats.200906-053DP Internet address: www.atsjournals.org

Recent reviews provide a detailed overview about comorbidities in COPD (2, 3, 11).

SYSTEMIC INFLAMMATION IN COPD Several studies found markers of systemic inflammation, such as high-sensitivity C-reactive protein (hs-CRP), to be higher in blood of patients with COPD when compared with the blood values of subjects without COPD (12, 13). The origin of systemic inflammation is unclear (14). The question arises whether systemic inflammation is the result of a spill-over of local inflammation to the systemic compartment or whether systemic inflammation might be a systemic component of COPD not necessarily related to the local inflammatory processes in the lung (2, 15, 16). Of interest, systemic inflammation failed to show substantial relations with airway obstruction so far (17–19), whereas at least moderate correlations are reported between local inflammatory processes and airway obstruction (20–22). Evidence for the dissociation of local inflammation and systemic inflammation in patients with COPD is given in a recent publication, which could not find a relationship between sputum neutrophils and hs-CRP (23). Observations like these might indicate that systemic inflammation in patients with COPD is more than a systemic marker of local inflammatory processes in the lung. This review focuses on chronic diseases and medical conditions that are associated with systemic inflammation and might also have a role for the presence of systemic inflammation in patients with COPD as they frequently coexist in this population (Figure 1).

SYSTEMIC INFLAMMATION IN CHRONIC DISEASES OTHER THAN COPD The presence of systemic inflammation seems to be a common feature of chronic diseases in older adults across several chronic diseases (24). In patients with diastolic and systolic heart failure, higher levels of interleukin-6 and hs-CRP have been found when compared with the levels in elderly subjects without heart failure (25). Peripheral arterial disease is associated with increased circulating levels of interleukin-6, fibrinogen, and Creactive protein compared with persons without peripheral arterial disease (26). Patients with stable coronary artery disease have higher levels of interleukin-6 and C-reactive protein (27). Patients with impaired glucose tolerance, diabetes, or impaired fasting glucose have higher levels of hs-CRP and interleukin-6 compared with subjects with normal glucose tolerance, even after adjusting for fat mass (28). Because each of these conditions might be found in a considerable number of patients with COPD (3) it seems likely that further research about systemic inflammation in patients with COPD must take coexisting chronic diseases into account when the causative role of COPD for systemic inflammation in each patient is investigated.

Magnussen and Watz: Systemic Inflammation in COPD and Asthma

649

Figure 1. Patient with very severe chronic obstructive pulmonary disease according to the Global Initiative for Chronic Obstructive Lung Disease and coexisting conditions according to his medical history and the assessment of the physical activity level. Each of his listed conditions has been observed to be associated with systemic inflammation.

PHYSICAL INACTIVITY AND THE METABOLIC SYNDROME: TWO CONDITIONS RELATED TO SYSTEMIC INFLAMMATION IN THE GENERAL POPULATION A growing body of evidence derived from epidemiological studies demonstrates that persons who report to be physically inactive have higher levels of systemic inflammatory and hemostatic markers compared with persons who report to be physically active (29, 30). The Women’s Health Study has recently investigated the mediating effects of systemic inflammation due to physical inactivity for incident cardiovascular events. It could be shown that the reduced risk of cardiovascular events in physically active women compared with inactive women can be best explained by differences in inflammatory/ hemostatic factors (31). The mechanisms underlying the relationship between physical inactivity and systemic inflammation have not been clarified so far. The metabolic syndrome represents a cluster of risk factors (abdominal obesity, atherogenic dyslipidemia, hypertension, insulin resistance) that predispose affected patients to diabetes and cardiovascular disease (32). Approximately 40% to 50% of individuals older than 60 years of age in industrialized countries meet the criteria of the metabolic syndrome (33). The visceral adipose tissue has been identified to be an important source of proinflammatory cytokines such as interleukin-6, which induces the synthesis of hs-CRP by hepatocytes. Accordingly, obesity as the prerequisite of the metabolic syndrome is a major determinant of systemic inflammation in the general population and close relationships are reported between body mass index/waist circumference and systemic inflammation (28, 34).

Recently, the additive effects of obesity and physical inactivity for systemic inflammation have been investigated. Mora and colleagues could demonstrate that within body mass index categories physical inactivity was an independent parameter related to systemic inflammation in study subjects (30).

PHYSICAL INACTIVITY AND THE METABOLIC SYNDROME: TWO CONDITIONS RELATED TO SYSTEMIC INFLAMMATION IN PATIENTS WITH COPD Patients with COPD are physically inactive (35). Compared with a group of patients with normal lung function and symptoms of

Figure 2. High-sensitivity C-reactive protein in patients with chronic bronchitis (CB) (normal spirometry) and chronic obstructive pulmonary disease of different severity according to the Global Initiative for Chronic Obstructive Lung Disease with and without a coexisting metabolic syndrome. (Figure modified by permission from Reference 19.)

650

chronic bronchitis who were matched for social and lifestyleassociated confounders of physical activity, we found physical activity to be significantly reduced from Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II and higher (36). In a further study we analyzed the association of physical inactivity with systemic inflammation. We found a reduced physical activity level to be an independent predictor of hs-CRP, interleukin-6, and fibrinogen (19). In line with our findings, Garcia-Aymerich and colleagues demonstrated that regular physical activity reduced the risk of having high levels of circulating tumor necrosis factor (TNF)-a and C-reactive protein in patients with COPD (37). The exact prevalence of a coexisting metabolic syndrome in patients with COPD has not yet been investigated. Heavy smoking seems to be associated with greater body weight (38). This association is likely to reflect a cluster of risky behaviors in terms of reduced physical activity, poor diet, and smoking (38). A former study found some components, such as hypertension, diabetes, and/or dyslipidemia, to be frequently present in patients with COPD (39). We recently investigated the frequency of the metabolic syndrome in 200 patients with chronic bronchitis (current or ex-smokers with normal spirometry) and patients with COPD of different severity in detail (19). According to the criteria of the International Diabetes Federation, the frequency of the metabolic syndrome in patients with chronic bronchitis, GOLD stage I, II, III, and IV, was 53%, 50%, 53%, 37%, and 44%, respectively (total, 47.5%). The coexisting metabolic syndrome was an independent predictor of hs-CRP (Figure 2) and interleukin-6 in our study (19). Our observation is supported by data of another group, who found serum levels of interleukin-6 and TNF-a to be higher in patients with moderate COPD and a coexisting metabolic syndrome compared with patients with severe COPD but without a coexisting metabolic syndrome (40). These data about the potential role of physical inactivity and the metabolic syndrome for systemic inflammation in patients with COPD suggest that future studies related to this topic should incorporate the characteristics of these two conditions.

SYSTEMIC INFLAMMATION: A MARKER OF MORBIDITY AND MORTALITY IN COPD Recent data show that systemic inflammation is associated with morbidity and mortality in patients with COPD. Dahl and colleagues demonstrated in the Copenhagen City Heart Study that elevated plasma fibrinogen was associated with an increased risk of COPD (41). A further analysis of the Copenhagen City Heart Study revealed that the risks for COPD hospitalization and death in individuals with C-reactive protein greater than 3 mg/L was higher compared with individuals with a C-reactive protein below this threshold (42). The Lung Health Study confirmed the relationship between increasing C-reactive protein and mortality in mild to moderate COPD (43). There are also cross-sectional data available showing an inverse relationship of C-reactive protein levels with exercise capacity and health-related quality of life in patients with COPD (17, 18).

SYSTEMIC INFLAMMATION: A MARKER OF MORBIDITY AND MORTALITY IN CHRONIC DISEASES OTHER THAN COPD Hs-CRP emerged as an established marker of cardiovascular risk as it predicts incident myocardial infarction, stroke, peripheral arterial disease, and sudden cardiac death among healthy individuals with no history of cardiovascular disease (44, 45). It has been shown that hs-CRP confers additional prognostic values at all levels of cholesterol, Framingham coronary risk score, and

PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 6

2009

severity of the metabolic syndrome (45, 46). In patients already affected by cardiovascular disease hs-CRP provides prognostic information about recurrent cardiac events (44). Elevated levels of interleukin-6 and C-reactive protein were demonstrated to predict the development of type 2 diabetes mellitus in the Women’s Healthy Study, even after adjustment for body mass index (47). In a population-based risk factor survey with a follow-up of 12 years it could be shown that even a slight increase in serum C-reactive protein level was associated with an increased risk of developing metabolic syndrome (48).

SYSTEMIC INFLAMMATION IN ASTHMA Data regarding systemic inflammation in patients with asthma are rare. There is one study available showing that hs-CRP is higher in patients with nonallergic asthma compared with patients with allergic asthma or healthy controls (49). Another study investigated the role of obesity for local and systemic inflammation in patients with asthma (50). Sutherland and colleagues found hs-CRP to be higher in patients with obesity and asthma compared with patients with obesity or asthma alone. In contrast, local inflammation as reflected by eosinophils, neutrophils, and cytokines in sputum was not different between obese patients with asthma and normal-weight subjects with asthma, indicating that no relationship between local and systemic inflammation could be observed (50). The association of systemic inflammation with comorbidities in asthma has not been investigated so far.

CONCLUSIONS Although frequently observed in patients with COPD, systemic inflammation in COPD is far from being understood so far. Further research should elucidate the complex relationship between obstructive lung disease, coexisting conditions, systemic inflammation accompanying these different conditions, and the causative role of systemic inflammation for comorbidities in COPD and asthma. Conflict of Interest Statement: H.M. has received reimbursement for consultancies with Boehringer Ingelheim ($1,001–$5,000) and has also served on Advisory Boards for Novartis ($1,001–$5,000), Chiesi ($1,001–$5,000), Almirall ($1,001– $5,000), and Astra Zeneca ($1,001–$5,000). He has received honoraria for lectures with Boehringer Ingelheim ($1,001–$5,000), Chiesi ($1,001–$5,000), Cilag-Janssen ($1,001–$5,000), Novartis ($1,001–$5,000), and Astra Zeneca ($1,001–$5,000). He has also received reimbursement for research with Astra Zeneca ($100,001 or more), Almirall ($100,001 or more), GSK ($100,001 or more), Boehringer Ingelheim ($100,001 or more), and Schering Plough ($100,001 or more). H.W. has received reimbursement for consultancies with Boehringer Ingelheim (up to $1,000), honoraria for lectures with Boehringer Ingelheim ($1,001–$5,000), Chiesi ($1,001–$5,000), and Cilag-Janssen ($1,001–$5,000). He has also received reimbursement for research with Astra Zeneca ($100,0011), GSK ($100,001 or more), Boehringer Ingelheim ($100,001 or more), Almirall ($100,001 or more), and Schering Plough ($100,001 or more).

References 1. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: GOLD Executive Summary. Am J Respir Crit Care Med 2007;176:532–555. 2. Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J 2009;33:1165–1185. 3. Chatila WM, Thomashow BM, Minai OA, Criner GJ, Make BJ. Comorbidities in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2008;5:549–555. 4. Anthonisen NR, Skeans MA, Wise RA, Manfreda J, Kanner RE, Connett JE. The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann Intern Med 2005;142:233–239. 5. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J. Salmeterol and fluticasone propionate and

Magnussen and Watz: Systemic Inflammation in COPD and Asthma

6.

7.

8.

9.

10.

11. 12.

13.

14.

15. 16. 17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356:775–789. Landbo C, Prescott E, Lange P, Vestbo J, Almdal TP. Prognostic value of nutritional status in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160:1856–1861. Vestbo J, Prescott E, Almdal T, Dahl M, Nordestgaard BG, Andersen T, Sorensen TI, Lange P. Body mass, fat-free body mass, and prognosis in patients with chronic obstructive pulmonary disease from a random population sample: findings from the Copenhagen City Heart Study. Am J Respir Crit Care Med 2006;173:79–83. Ng TP, Niti M, Tan WC, Cao Z, Ong KC, Eng P. Depressive symptoms and chronic obstructive pulmonary disease: effect on mortality, hospital readmission, symptom burden, functional status, and quality of life. Arch Intern Med 2007;167:60–67. Watz H, Waschki B, Boehme C, Claussen M, Meyer T, Magnussen H. Extrapulmonary effects of chronic obstructive pulmonary disease on physical activity: a cross-sectional study. Am J Respir Crit Care Med 2008;177:743–751. Ferrer M, Alonso J, Morera J, Marrades RM, Khalaf A, Aguar MC, Plaza V, Prieto L, Anto JM. Chronic obstructive pulmonary disease stage and health-related quality of life. The Quality of Life of Chronic Obstructive Pulmonary Disease Study Group. Ann Intern Med 1997; 127:1072–1079. Sin DD, Anthonisen NR, Soriano JB, Agusti AG. Mortality in COPD: Role of comorbidities. Eur Respir J 2006;28:1245–1257. Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 2004;59:574–580. Pinto-Plata VM, Mullerova H, Toso JF, Feudjo-Tepie M, Soriano JB, Vessey RS, Celli BR. C-reactive protein in patients with COPD, control smokers and non-smokers. Thorax 2006;61:23–28. Agusti A. Systemic effects of chronic obstructive pulmonary disease: what we know and what we don‘t know (but should). Proc Am Thorac Soc 2007;4:522–525. Fabbri LM, Rabe KF. From COPD to chronic systemic inflammatory syndrome? Lancet 2007;370:797–799. Fabbri LM, Luppi F, Beghe B, Rabe KF. Complex chronic comorbidities of COPD. Eur Respir J 2008;31:204–212. Broekhuizen R, Wouters EF, Creutzberg EC, Schols AM. Raised CRP levels mark metabolic and functional impairment in advanced COPD. Thorax 2006;61:17–22. de Torres JP, Cordoba-Lanus E, Lopez-Aguilar C, Muros de Fuentes M, Montejo de Garcini A, Aguirre-Jaime A, Celli BR, Casanova C. Creactive protein levels and clinically important predictive outcomes in stable COPD patients. Eur Respir J 2006;27:902–907. Watz H, Waschki B, Kirsten A, Muller KC, Kretschmar B, Meyer T, Holz O, Magnussen H. The metabolic syndrome in patients with chronic bronchitis and COPD: frequency and associated consequences for systemic inflammation and physical inactivity. Chest 2009;136:1039– 1046. Peleman RA, Rytila PH, Kips JC, Joos GF, Pauwels RA. The cellular composition of induced sputum in chronic obstructive pulmonary disease. Eur Respir J 1999;13:839–843. Turato G, Zuin R, Miniati M, Baraldo S, Rea F, Beghe B, Monti S, Formichi B, Boschetto P, Harari S, et al. Airway inflammation in severe chronic obstructive pulmonary disease: relationship with lung function and radiologic emphysema. Am J Respir Crit Care Med 2002; 166:105–110. Baraldo S, Turato G, Badin C, Bazzan E, Beghe B, Zuin R, Calabrese F, Casoni G, Maestrelli P, Papi A, et al. Neutrophilic infiltration within the airway smooth muscle in patients with COPD. Thorax 2004;59: 308–312. Roy K, Smith J, Kolsum U, Borrill Z, Vestbo J, Singh D. COPD phenotype description using principal components analysis. Respir Res 2009;10:41. Brinkley TE, Leng X, Miller ME, Kitzman DW, Pahor M, Berry MJ, Marsh AP, Kritchevsky SB, Nicklas BJ. Chronic inflammation is associated with low physical function in older adults across multiple comorbidities. J Gerontol A Biol Sci Med Sci 2009;64:455–461. Wisniacki N, Taylor W, Lye M, Wilding JP. Insulin resistance and inflammatory activation in older patients with systolic and diastolic heart failure. Heart 2005;91:32–37. McDermott MM, Guralnik JM, Corsi A, Albay M, Macchi C, Bandinelli S, Ferrucci L. Patterns of inflammation associated with peripheral arterial disease: the InCHIANTI study. Am Heart J 2005; 150:276–281.

651 27. Nijm J, Wikby A, Tompa A, Olsson AG, Jonasson L. Circulating levels of proinflammatory cytokines and neutrophil-platelet aggregates in patients with coronary artery disease. Am J Cardiol 2005;95:452–456. 28. Thorand B, Baumert J, Doring A, Herder C, Kolb H, Rathmann W, Giani G, Koenig W. Sex differences in the relation of body composition to markers of inflammation. Atherosclerosis 2006;184:216–224. 29. Wannamethee SG, Lowe GD, Whincup PH, Rumley A, Walker M, Lennon L. Physical activity and hemostatic and inflammatory variables in elderly men. Circulation 2002;105:1785–1790. 30. Mora S, Lee IM, Buring JE, Ridker PM. Association of physical activity and body mass index with novel and traditional cardiovascular biomarkers in women. JAMA 2006;295:1412–1419. 31. Mora S, Cook N, Buring JE, Ridker PM, Lee IM. Physical activity and reduced risk of cardiovascular events: potential mediating mechanisms. Circulation 2007;116:2110–2118. 32. Dandona P, Aljada A, Chaudhuri A, Mohanty P, Garg R. Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation 2005;111:1448–1454. 33. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002;287:356–359. 34. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. JAMA 1999; 282:2131–2135. 35. Pitta F, Troosters T, Spruit MA, Probst VS, Decramer M, Gosselink R. Characteristics of physical activities in daily life in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;171:972–977. 36. Watz H, Waschki B, Meyer T, Magnussen H. Physical activity in patients with COPD. Eur Respir J 2009;33:262–272. 37. Garcia-Aymerich J, Serra I, Gomez FP, Farrero E, Balcells E, Rodriguez DA, de Batlle J, Gimeno E, Donaire-Gonzalez D, Orozco-Levi M, et al. Physical activity and clinical and functional status in COPD. Chest 2009;136:62–70. 38. Chiolero A, Faeh D, Paccaud F, Cornuz J. Consequences of smoking for body weight, body fat distribution, and insulin resistance. Am J Clin Nutr 2008;87:801–809. 39. Crisafulli E, Costi S, Luppi F, Cirelli G, Cilione C, Coletti O, Fabbri LM, Clini EM. Role of comorbidities in a cohort of patients with COPD undergoing pulmonary rehabilitation. Thorax 2008;63:487–492. 40. Poulain M, Doucet M, Drapeau V, Fournier G, Tremblay A, Poirier P, Maltais F. Metabolic and inflammatory profile in obese patients with chronic obstructive pulmonary disease. Chron Respir Dis 2008;5:35–41. 41. Dahl M, Tybjaerg-Hansen A, Vestbo J, Lange P, Nordestgaard BG. Elevated plasma fibrinogen associated with reduced pulmonary function and increased risk of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1008–1011. 42. Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;175: 250–255. 43. Man SF, Connett JE, Anthonisen NR, Wise RA, Tashkin DP, Sin DD. C-reactive protein and mortality in mild to moderate chronic obstructive pulmonary disease. Thorax 2006;61:849–853. 44. Bassuk SS, Rifai N, Ridker PM. High-sensitivity C-reactive protein: clinical importance. Curr Probl Cardiol 2004;29:439–493. 45. Ridker PM, Brown NJ, Vaughan DE, Harrison DG, Mehta JL. Established and emerging plasma biomarkers in the prediction of first atherothrombotic events. Circulation 2004;109:IV6–IV19. 46. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8year follow-up of 14 719 initially healthy American women. Circulation 2003;107:391–397. 47. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001;286:327–334. 48. Hassinen M, Lakka TA, Komulainen P, Gylling H, Nissinen A, Rauramaa R. C-reactive protein and metabolic syndrome in elderly women: a 12-year follow-up study. Diabetes Care 2006;29:931–932. 49. Olafsdottir IS, Gislason T, Thjodleifsson B, Olafsson I, Gislason D, Jogi R, Janson C. C reactive protein levels are increased in non-allergic but not allergic asthma: a multicentre epidemiological study. Thorax 2005;60:451–454. 50. Sutherland TJ, Cowan JO, Young S, Goulding A, Grant AM, Williamson A, Brassett K, Herbison GP, Taylor DR. The association between obesity and asthma: interactions between systemic and airway inflammation. Am J Respir Crit Care Med 2008;178:469–475.