EDITORIALS
Multimorbidity in Elderly Patients with Chronic Obstructive Pulmonary Disease: Stop Smoking! Go Exercise? Chronic obstructive pulmonary disease (COPD) is often associated with other chronic diseases, which have been called comorbidities. Thus, lung cancer, cardiovascular diseases (e.g., left heart failure and coronary artery disease), metabolic diseases (e.g., diabetes), and musculoskeletal diseases (e.g., muscle weakness and osteoporosis) are highly prevalent in patients with COPD (1, 2). Awareness of the importance of coexisting diseases in patients with COPD has grown due to the recognition that their presence was associated with worse prognosis (2) and increased cost of treatment (3). However, the nature of the relationship between COPD and coexisting diseases remains controversial. Some authors have suggested that COPD favors the development of other diseases via spilling of inflammatory mediators from the lung into the systemic circulation (4). In support of this hypothesis, patients with COPD included in the large observational ECLIPSE study were found to have higher prevalence of coexisting diseases than smokers without COPD (1). Others have suggested that the association of COPD and cardiovascular diseases was largely due to common risk factors (5). The study by Van Remoortel and coworkers (pp. 30–38), published in this issue of the Journal (6), challenges the hypothesis that coexisting diseases are more frequent in patients with COPD; it supports the hypothesis that common smoking habits and physical inactivity are independently associated with their development. In an elegant study design, the authors compared 60 patients with preclinical COPD, recruited from a population-based lung cancer screening study, with age- and gender-matched healthy controls with or without a smoking history. Their results showed that the prevalence of premorbid risk factors (prediabetes, systemic hypertension, dyslipidemia, and obesity) and coexisting diseases (cardiovascular, metabolic, and musculoskeletal diseases) was comparable in patients with COPD and in smokers, but was higher than in healthy nonsmokers. Indeed, 65% of the nonsmokers presented with no chronic disease and 33% had only one chronic disease; thus, multiple chronic diseases were almost exclusively found in smokers. Importantly, the proportion of subjects with two or more coexisting diseases was comparable in smokers with (20%) and without (14%) preclinical COPD. Most importantly, physical inactivity and smoking, but not COPD per se, increased the risk (by three- and eightfold, respectively) of having two or more coexisting diseases. This study is important for several reasons. First, this is the only study showing that premorbid conditions (prediabetes, hypertension, dyslipidemia, and obesity) and the coexistence of pooled or single cardiovascular, metabolic, and musculoskeletal
diseases are more frequent in adults exposed to smoking and/or developing mild COPD, diagnosed in a population-based sample (6). To date, the presence of comorbidities in moderate to severe COPD was based on patient-based samples, which may have been enriched in patients with multiple chronic diseases (1, 2). In the latter studies, coexisting diseases were self-reported and/or obtained in medical records (1, 2). Comorbidities (e.g., left heart failure) are often underdiagnosed in patients with COPD (7), and a major strength of the study by Van Remoortel and colleagues relates to the systematic assessment of comorbidities, as recently proposed by other authors (8). The second and main finding of the study is that increased prevalence of cardiovascular and metabolic risk factors and comorbidities was not driven by the presence of preclinical COPD, but rather by smoking and physical inactivity. These findings are in line with those of Thomsen and colleagues, who reported that risks of cardiovascular comorbidities and all-cause mortality were increased in COPD (ex-) smokers, but not in never-smokers with COPD (9). The finding that risk of comorbidities was independent of the presence of COPD, even at an early and preclinical stage of the disease, underlines the concept of chronic complex patients with COPD rather than that of patients with COPD with chronic comorbidities (10). The present study (6) tackles the hierarchical view of COPD with comorbidities, and supports the modern concept of multimorbid patients with chronic diseases (see also the scheme in their Figure 3). On the one hand, there is still little evidence that one chronic disease dominates and is the cause of the other concomitant disorders, and, on the other hand, the body of evidence that various chronic diseases develop simultaneously in response to common risks is growing rapidly (11), also highlighting the tremendous impact of multimorbidity both on the healthcare system and medical education (12). Different from the comorbidity concept, multimorbidity in elderly adults is a clinical feature recognizing common risks and premorbid conditions, among which smoking and inactivity appear here to be the strongest, and requiring a comprehensive approach (see Table 1). The present study suggests that smoking and physical inactivity may represent appropriate targets for primary and/or secondary prevention of multimorbidity in aging COPD subjects. Implementation of effective tobacco control policies (i.e., smoking ban laws) have been shown to result in reduction of smoking, with rapid improvement in the risks of noncommunicable chronic diseases (e.g., cardiovascular diseases and lung cancer) (13). Thus,
Table 1: Comorbidity and Multimorbidity: Summary of Different Concepts and Approaches Comorbidity Disease(s) Relationship among diseases
A main disease is responsible for influencing the health status Hierarchical
Basic goal of definition Therapeutic approach
Administrative Based on the main disease
Editorials
Multimorbidity It is assumed that all the diseases may variably influence the health status It is assumed that all the diseases may variably influence the health status Epidemiological Comprehensive care
7
EDITORIALS although smoking cessation is difficult to achieve, it likely provides important benefits both on an individual and a collective basis. Physical inactivity is an important predictor of mortality in patients with COPD (14), but there is little evidence that current intervention (including pulmonary rehabilitation and counseling) can indeed durably increase physical activity in patients with COPD. Importantly, there is even less evidence that increase in physical activity would result in favorable outcomes in these patients, suggesting that it may be too early to advocate increase in physical activity. Objective methods to quantify the individual’s physical activity in humans are now available (15) and will allow further research in this area. Notwithstanding the association here reported between risk factors (e.g., smoking and inactivity) and the occurrence of preclinical chronic conditions including COPD, the cross-sectional design of the study represents a limit in the interpretation of data. How physical activity measured at the age of 60 years could be representative of the behavior in the previous decades remains unclear. Moreover, mechanisms underlying possible effects of physical inactivity and smoking in the development of multimorbidity were not identified. Systemic inflammation could be an important link, although it was not shown by the present data. Last, but not least, authors have reported the impact of important comorbidities, but did not examine others (e.g., cancer, depression, and sarcopenia/cachexia). The relationship between premorbid risk factors, COPD, and each of other comorbidities could have been different. Taking all the limitations of the present study into account, the findings have to be considered novel and promising for future research. The focus should be moved to the complex chronic patients with COPD, and healthcare providers should carefully consider developing early and specific strategies (other than smoking cessation) (16) for primary and secondary prevention to contrast the development of multimorbidity in the elderly adults. n
References
COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) investigators. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010;11:122. 2. Divo M, Cote C, de Torres JP, Casanova C, Marin JM, Pinto-Plata V, Zulueta J, Cabrera C, Zagaceta J, Hunninghake G, et al.; BODE Collaborative Group. Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;186:155–161. 3. Charlson M, Charlson RE, Briggs W, Hollenberg J. Can disease management target patients most likely to generate high costs? The impact of comorbidity. J Gen Intern Med 2007;22:464–469. 4. Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J 2009;33:1165–1185. 5. Johnston AK, Mannino DM, Hagan GW, Davis KJ, Kiri VA. Relationship between lung function impairment and incidence or recurrence of cardiovascular events in a middle-aged cohort. Thorax 2008;63: 599–605. 6. Van Remoortel H, Hornikx M, Langer D, Burtin C, Everaerts S, Verhamme P, Boonen S, Gosselink R, Decramer M, Troosters T, et al. Risk factors and comorbidities in the preclinical stages of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2014;189:30–38. 7. Rutten FH, Cramer MJM, Grobbee DE, Sachs APE, Kirkels JH, Lammers JWJ, Hoes AW. Unrecognized heart failure in elderly patients with stable chronic obstructive pulmonary disease. Eur Heart J 2005;26: 1887–1894. 8. Vanfleteren LEGW, Spruit MA, Groenen M, Gaffron S, van Empel VPM, Bruijnzeel PLB, Rutten EPA, Op ’t Roodt J, Wouters EFM, Franssen FME. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;187:728–735. 9. Thomsen M, Nordestgaard BG, Vestbo J, Lange P. Characteristics and outcomes of chronic obstructive pulmonary disease in never smokers in Denmark: a prospective population study. Lancet Respir Med 2013; 1:543–550. 10. Clini E, Beghe´ B, Fabbri LM. Chronic obstructive pulmonary disease is just one component of the complex multimorbidities in patients with COPD. Am J Respir Crit Care Med 2013;187:668–671. 11. Marengoni A, Angleman S, Melis R, Mangialasche F, Karp A, Garmen A, Meinow B, Fratiglioni L. Aging with multimorbidity: a systematic review of the literature. Ageing Res Rev 2011;10: 430–439. 12. Barnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet 2012;380:37–43. 13. Glantz S, Gonzalez M. Effective tobacco control is key to rapid progress in reduction of non-communicable diseases. Lancet 2012; 379:1269–1271. 14. Waschki B, Kirsten A, Holz O, Muller ¨ K-C, Meyer T, Watz H, Magnussen H. Physical activity is the strongest predictor of all-cause mortality in patients with COPD: a prospective cohort study. Chest 2011;140: 331–342. 15. Rabinovich RA, Louvaris Z, Raste Y, Langer D, Van Remoortel H, Giavedoni S, Burtin C, Regueiro EM, Vogiatzis I, Hopkinson NS, et al.; PROactive consortium. Validity of physical activity monitors during daily life in patients with COPD. Eur Respir J 2013;42: 1205–1215. 16. de Waure C, Lauret GJ, Ricciardi W, Ferket B, Teijink J, Spronk S, Myriam Hunink MG. Lifestyle interventions in patients with coronary heart disease: a systematic review. Am J Prev Med 2013;45: 207–216.
1. Agusti A, Calverley PM, Celli B, Coxson HO, Edwards LD, Lomas DA, MacNee W, Miller BE, Rennard S, Silverman EK, et al.; Evaluation of
Copyright © 2014 by the American Thoracic Society
Author disclosures are available with the text of this article at www.atsjournals.org. Pierre-Regis ´ Burgel, M.D., Ph.D. Universite´ Paris Descartes Sorbonne Paris Cite´ Paris, France and Department of Respiratory Medicine Hopital ˆ Cochin, AP-HP Paris, France Enrico M. Clini, M.D. Department of Medical and Surgical Sciences University of Modena Reggio Emilia Modena, Italy and Ospedale Villa Pineta Pavullo n/F, Italy
8
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 1 | January 2014
Multimorbidity in Elderly Patients with Chronic Obstructive Pulmonary Disease: Stop Smoking! Go Exercise? Chronic obstructive pulmonary disease (COPD) is often associated with other chronic diseases, which have been called comorbidities. Thus, lung cancer, cardiovascular diseases (e.g., left heart failure and coronary artery disease), metabolic diseases (e.g., diabetes), and musculoskeletal diseases (e.g., muscle weakness and osteoporosis) are highly prevalent in patients with COPD (1, 2). Awareness of the importance of coexisting diseases in patients with COPD has grown due to the recognition that their presence was associated with worse prognosis (2) and increased cost of treatment (3). However, the nature of the relationship between COPD and coexisting diseases remains controversial. Some authors have suggested that COPD favors the development of other diseases via spilling of inflammatory mediators from the lung into the systemic circulation (4). In support of this hypothesis, patients with COPD included in the large observational ECLIPSE study were found to have higher prevalence of coexisting diseases than smokers without COPD (1). Others have suggested that the association of COPD and cardiovascular diseases was largely due to common risk factors (5). The study by Van Remoortel and coworkers (pp. 30–38), published in this issue of the Journal (6), challenges the hypothesis that coexisting diseases are more frequent in patients with COPD; it supports the hypothesis that common smoking habits and physical inactivity are independently associated with their development. In an elegant study design, the authors compared 60 patients with preclinical COPD, recruited from a population-based lung cancer screening study, with age- and gender-matched healthy controls with or without a smoking history. Their results showed that the prevalence of premorbid risk factors (prediabetes, systemic hypertension, dyslipidemia, and obesity) and coexisting diseases (cardiovascular, metabolic, and musculoskeletal diseases) was comparable in patients with COPD and in smokers, but was higher than in healthy nonsmokers. Indeed, 65% of the nonsmokers presented with no chronic disease and 33% had only one chronic disease; thus, multiple chronic diseases were almost exclusively found in smokers. Importantly, the proportion of subjects with two or more coexisting diseases was comparable in smokers with (20%) and without (14%) preclinical COPD. Most importantly, physical inactivity and smoking, but not COPD per se, increased the risk (by three- and eightfold, respectively) of having two or more coexisting diseases. This study is important for several reasons. First, this is the only study showing that premorbid conditions (prediabetes, hypertension, dyslipidemia, and obesity) and the coexistence of pooled or single cardiovascular, metabolic, and musculoskeletal
diseases are more frequent in adults exposed to smoking and/or developing mild COPD, diagnosed in a population-based sample (6). To date, the presence of comorbidities in moderate to severe COPD was based on patient-based samples, which may have been enriched in patients with multiple chronic diseases (1, 2). In the latter studies, coexisting diseases were self-reported and/or obtained in medical records (1, 2). Comorbidities (e.g., left heart failure) are often underdiagnosed in patients with COPD (7), and a major strength of the study by Van Remoortel and colleagues relates to the systematic assessment of comorbidities, as recently proposed by other authors (8). The second and main finding of the study is that increased prevalence of cardiovascular and metabolic risk factors and comorbidities was not driven by the presence of preclinical COPD, but rather by smoking and physical inactivity. These findings are in line with those of Thomsen and colleagues, who reported that risks of cardiovascular comorbidities and all-cause mortality were increased in COPD (ex-) smokers, but not in never-smokers with COPD (9). The finding that risk of comorbidities was independent of the presence of COPD, even at an early and preclinical stage of the disease, underlines the concept of chronic complex patients with COPD rather than that of patients with COPD with chronic comorbidities (10). The present study (6) tackles the hierarchical view of COPD with comorbidities, and supports the modern concept of multimorbid patients with chronic diseases (see also the scheme in their Figure 3). On the one hand, there is still little evidence that one chronic disease dominates and is the cause of the other concomitant disorders, and, on the other hand, the body of evidence that various chronic diseases develop simultaneously in response to common risks is growing rapidly (11), also highlighting the tremendous impact of multimorbidity both on the healthcare system and medical education (12). Different from the comorbidity concept, multimorbidity in elderly adults is a clinical feature recognizing common risks and premorbid conditions, among which smoking and inactivity appear here to be the strongest, and requiring a comprehensive approach (see Table 1). The present study suggests that smoking and physical inactivity may represent appropriate targets for primary and/or secondary prevention of multimorbidity in aging COPD subjects. Implementation of effective tobacco control policies (i.e., smoking ban laws) have been shown to result in reduction of smoking, with rapid improvement in the risks of noncommunicable chronic diseases (e.g., cardiovascular diseases and lung cancer) (13). Thus,
Table 1: Comorbidity and Multimorbidity: Summary of Different Concepts and Approaches Comorbidity Disease(s) Relationship among diseases
A main disease is responsible for influencing the health status Hierarchical
Basic goal of definition Therapeutic approach
Administrative Based on the main disease
Editorials
Multimorbidity It is assumed that all the diseases may variably influence the health status It is assumed that all the diseases may variably influence the health status Epidemiological Comprehensive care
7
EDITORIALS although smoking cessation is difficult to achieve, it likely provides important benefits both on an individual and a collective basis. Physical inactivity is an important predictor of mortality in patients with COPD (14), but there is little evidence that current intervention (including pulmonary rehabilitation and counseling) can indeed durably increase physical activity in patients with COPD. Importantly, there is even less evidence that increase in physical activity would result in favorable outcomes in these patients, suggesting that it may be too early to advocate increase in physical activity. Objective methods to quantify the individual’s physical activity in humans are now available (15) and will allow further research in this area. Notwithstanding the association here reported between risk factors (e.g., smoking and inactivity) and the occurrence of preclinical chronic conditions including COPD, the cross-sectional design of the study represents a limit in the interpretation of data. How physical activity measured at the age of 60 years could be representative of the behavior in the previous decades remains unclear. Moreover, mechanisms underlying possible effects of physical inactivity and smoking in the development of multimorbidity were not identified. Systemic inflammation could be an important link, although it was not shown by the present data. Last, but not least, authors have reported the impact of important comorbidities, but did not examine others (e.g., cancer, depression, and sarcopenia/cachexia). The relationship between premorbid risk factors, COPD, and each of other comorbidities could have been different. Taking all the limitations of the present study into account, the findings have to be considered novel and promising for future research. The focus should be moved to the complex chronic patients with COPD, and healthcare providers should carefully consider developing early and specific strategies (other than smoking cessation) (16) for primary and secondary prevention to contrast the development of multimorbidity in the elderly adults. n
References
COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) investigators. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010;11:122. 2. Divo M, Cote C, de Torres JP, Casanova C, Marin JM, Pinto-Plata V, Zulueta J, Cabrera C, Zagaceta J, Hunninghake G, et al.; BODE Collaborative Group. Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;186:155–161. 3. Charlson M, Charlson RE, Briggs W, Hollenberg J. Can disease management target patients most likely to generate high costs? The impact of comorbidity. J Gen Intern Med 2007;22:464–469. 4. Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J 2009;33:1165–1185. 5. Johnston AK, Mannino DM, Hagan GW, Davis KJ, Kiri VA. Relationship between lung function impairment and incidence or recurrence of cardiovascular events in a middle-aged cohort. Thorax 2008;63: 599–605. 6. Van Remoortel H, Hornikx M, Langer D, Burtin C, Everaerts S, Verhamme P, Boonen S, Gosselink R, Decramer M, Troosters T, et al. Risk factors and comorbidities in the preclinical stages of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2014;189:30–38. 7. Rutten FH, Cramer MJM, Grobbee DE, Sachs APE, Kirkels JH, Lammers JWJ, Hoes AW. Unrecognized heart failure in elderly patients with stable chronic obstructive pulmonary disease. Eur Heart J 2005;26: 1887–1894. 8. Vanfleteren LEGW, Spruit MA, Groenen M, Gaffron S, van Empel VPM, Bruijnzeel PLB, Rutten EPA, Op ’t Roodt J, Wouters EFM, Franssen FME. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;187:728–735. 9. Thomsen M, Nordestgaard BG, Vestbo J, Lange P. Characteristics and outcomes of chronic obstructive pulmonary disease in never smokers in Denmark: a prospective population study. Lancet Respir Med 2013; 1:543–550. 10. Clini E, Beghe´ B, Fabbri LM. Chronic obstructive pulmonary disease is just one component of the complex multimorbidities in patients with COPD. Am J Respir Crit Care Med 2013;187:668–671. 11. Marengoni A, Angleman S, Melis R, Mangialasche F, Karp A, Garmen A, Meinow B, Fratiglioni L. Aging with multimorbidity: a systematic review of the literature. Ageing Res Rev 2011;10: 430–439. 12. Barnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet 2012;380:37–43. 13. Glantz S, Gonzalez M. Effective tobacco control is key to rapid progress in reduction of non-communicable diseases. Lancet 2012; 379:1269–1271. 14. Waschki B, Kirsten A, Holz O, Muller ¨ K-C, Meyer T, Watz H, Magnussen H. Physical activity is the strongest predictor of all-cause mortality in patients with COPD: a prospective cohort study. Chest 2011;140: 331–342. 15. Rabinovich RA, Louvaris Z, Raste Y, Langer D, Van Remoortel H, Giavedoni S, Burtin C, Regueiro EM, Vogiatzis I, Hopkinson NS, et al.; PROactive consortium. Validity of physical activity monitors during daily life in patients with COPD. Eur Respir J 2013;42: 1205–1215. 16. de Waure C, Lauret GJ, Ricciardi W, Ferket B, Teijink J, Spronk S, Myriam Hunink MG. Lifestyle interventions in patients with coronary heart disease: a systematic review. Am J Prev Med 2013;45: 207–216.
1. Agusti A, Calverley PM, Celli B, Coxson HO, Edwards LD, Lomas DA, MacNee W, Miller BE, Rennard S, Silverman EK, et al.; Evaluation of
Copyright © 2014 by the American Thoracic Society
Author disclosures are available with the text of this article at www.atsjournals.org. Pierre-Regis ´ Burgel, M.D., Ph.D. Universite´ Paris Descartes Sorbonne Paris Cite´ Paris, France and Department of Respiratory Medicine Hopital ˆ Cochin, AP-HP Paris, France Enrico M. Clini, M.D. Department of Medical and Surgical Sciences University of Modena Reggio Emilia Modena, Italy and Ospedale Villa Pineta Pavullo n/F, Italy
8
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 1 | January 2014
