Lung function decline and physical activity The burden of COPD Lung function decline and physical activity

The Fletcher-Peto curve: classical model for the natural history of COPD 100 Never smoked or not susceptible to smoke 75 Smoked regularly and susceptible to its effects FEV1 (% of value at age 25) 50 Stopped at 45 25 Stopped at 65 Reference Fletcher C and Peto R. Br Med J 1977;1:1645–8. Death 25 50 75 Age (years) COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second Fletcher C, Peto R. Br Med J 1977;1:1645–8

New evidence challenges the concept that lung function decline accelerates over time Males A 100 75 50 25 NS FEV1 (% value at age 25) CS* FEV1 declines progressively with age in continuous smokers1 10 20 30 40 50 60 70 80 90 Age (years) Females B 100 75 50 25 NS FEV1 (% value at age 25) CS* Figures reproduced from Kohansal et al.1 CS = continuous smoker; FEV1 = forced expiratory volume in 1 second; NS = never smoker Kohansal R et al. Am J Respir Crit Care Med 2009;180:3–10 Decramer M, Cooper CB. Thorax 2010;65:837–41 10 20 30 40 50 60 70 80 90 Age (years)

Lung function declines more rapidly in the early stages of COPD Data from TORCH and UPLIFT show that decline in pulmonary function is faster in early stages of COPD1 ~50 mL/year in GOLD stage II ~30 ml/year in GOLD stage IV In the ECLIPSE study, mean rates of decline in FEV1 were:2 35 mL/year for patients in GOLD stage II 33 mL/year for patients in GOLD stage III 25 mL/year for patients in GOLD stage IV GOLD = Global Initiative for Obstructive Lung Disease; FEV1 = forced expiratory volume in 1 s Decramer M, Cooper CB. Thorax 2010;65:837–41 Vestbo J et al. N Engl J Med 2011;365:1184–92

Limitations of the Fletcher-Peto curve More recent study shows that loss of lung function is more accelerated during the initial stages of COPD 100 Stage I ∆ 40 mL/yr 80 Stage II ∆ 47–79 mL/yr FEV1 (% predicted) 50 Stage III ∆ 56–59 mL/yr 30 Stage IV Reference Tantucci C and Modina D. Int J COPD 2012;7:95–9. ∆ <35 mL/yr Range of average rates of FEV1 decline in patients with COPD, according to initial severity of airflow limitation The dashed segment of the line highlights any stage or part of it where consistent information is still lacking. COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second Tantucci C, Modina D. Int J COPD 2012;7:95–9

In heavy smokers with mostly normal or mildly impaired lung function: Accelerated lung function decline occurs long before FEV1/FVC falls to threshold for definition of COPD In heavy smokers with mostly normal or mildly impaired lung function: Decline was greatest in patients with “normal” lung function1 These patients would be classified as not having COPD GOLD and ERS/ATS thresholds for COPD (FEV1/FVC <70% or less than lower limit of normal) miss the stage of most rapid decline2,3 Diagnosis of COPD cannot be excluded in heavy smokers when based on above-threshold lung-function test at a single time point1 Mohamed Hoesein FA, Zanen P, Boezen HM, Groen HJ, van Ginneken B, de Jong PA, Postma DS, Lammers JW. Lung function decline in heavy male smokers relates to baseline airflow obstruction severity. Chest 2012; 142(6):1530-8 Rabe, K. F., S. Hurd, A. Anzueto, P. J. Barnes, S. A. Buist, P. Calverley, Y. Fukuchi, C. Jenkins, R. Rodriguez-Roisin, W. C. van, and J. Zielinski. 2007. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am.J Respir Crit Care Med 176:532-555. Celli, B. R. and W. MacNee. 2004. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur.Respir J 23:932-946. ATS = American Thoracic Society; COPD = chronic obstructive pulmonary disease; ERS = European Respiratory Society; FEV1 = forced expiratory volume in 1 s; FVC = forced vital capacity; GOLD = Global Initiative for Obstructive Lung Disease Mohamed Hoesein FA et al. Chest 2012;142:1530–8 Rabe KF et al. Am J Respir Crit Care Med 2007;176:532–55 Celli BR et al. Eur Respir J 2004;23:932–46

Fast decliners may be a distinct phenotype The definition of fast decliners is not fully characterized, however, fast decliners have particular characteristics1 Fast decliners have been characterized by: Current smoking (vs former smokers)2,3 Bronchodilator reversibility3,4 Emphysema3 High levels of airway and systemic inflammatory markers, possibly due to frequent exacerbations5,6 Higher baseline lung function3 Low body mass index7 Friedlander AL et al. Phenotypes of Chronic Obstructive Pulmonary Disease. COPD 2007;4:355-84. Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist AS, Conway WA, Jr., Enright PL, Kanner RE, O’Hara P, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of fev1. The lung health study. JAMA 1994; 272:1497–1505. Vestbo J et al. Changes in Forced Expiratory Volume in 1 Second over Time in COPD. NEJM 2011;365:1184-92. Tashkin DP, Altose MD, Connett JE, Kanner RE, Lee WW, Wise RA. Methacholine reactivity predicts changes in lung function over time in smokers with early chronic obstructive pulmonary disease. The lung health study research group. Amer J Respir Crit Care Med 1996; 153:1802–1811. Crooks SW, Bayley DL, Hill SL, et al. Bronchial inflammation in acute bacterial exacerbations of chronic bronchitis: the role of leukotriene B4. Eur Respir J 2000; 15: 274–280. Anzueto A. Impact of exacerbations on COPD. Eur Respir Rev 2010; 19: 116, 113–118. Watson et al. Predictors of lung function and its decline in mild to moderate COPD in association with gender: Results from the Euroscop study. Respiratory Medicine (2006) 100, 746–753. Friedlander et al. COPD 2007;4:355–84 Anthonisen et al. JAMA 1994;272:1497–505 Vestbo et al. New Engl J Med 2011;365:1184–92 Tashkin et al. Am J Respir Crit Care Med 1996;153:1802–11 Crooks et al. Eur Respir J 2000;15: 274–80 Anzueto. Eur Respir Rev 2010; 19: 116, 113–8 Watson et al. Respir Med 2006; 100: 746–53

Physical activity declines as disease severity worsens Activity declines significantly as COPD worsens in severity and is reduced even in mild COPD 12,000 10,000 8,000 6,000 4,000 2,000 Steps per day Reference Watz H et al. Eur Respir J 2009;33:262–72. CB 1 2 3 4 GOLD classification of airflow limitation Data are mean ± 95% CI; p<0.001 for linear relationship between steps per day and GOLD stage of severity. CB = chronic bronchitis; GOLD = Global Initiative for Obstructive Lung Disease; CI = confidence interval; COPD = chronic obstructive pulmonary disease Adapted from Watz H. Eur Respir J 2009;33:262–72

Shortness of breath and reduced exercise endurance are seen in patients with all severities of COPD 40 Mean=1.3 25 Mean=405 20 30 15 GOLD II 20 10 n=954 10 5 40 Mean=1.8 25 Mean=356 30 20 15 GOLD III Proportion of subjects (%) 20 Proportion of subjects (%) 10 n=911 10 5 40 25 Mean=2.3 Mean=289 20 30 Reference 1. Agusti A et al. Respir Res 2010;11:122. 15 GOLD IV 20 10 n=296 10 5 0 1 2 3 4 >0–30 >30–90 >90–150 >150–210 >210–270 >270–330 >330–390 >390–450 >450–510 >510–570 >570–630 >630–690 >690–750 >750–810 mMRC score Data are from ECLIPSE, a 3-year observational, longitudinal and controlled study of COPD patients and controls Mean=mean mMRC score or mean distance walked. mMRC, modified Medical Research Council Dyspnoea Scale. Distance walked (m) Agusti A. Respir Res 2010;11:122.

Functional limitations of COPD are at least as great in young patients as in older patients In the Confronting COPD study, functional limitations imposed by COPD on persons of <65 years were equal to or greater than those aged >65 years in sports and recreation, social activities, household chores, sex life and family activities Only in normal physical exertion did significantly fewer persons aged <65 yrs (55.7%) than >65 yrs (62.3%) report being significantly limited as a result of their condition (p<0.05) Key A = Sports and recreation B = Normal physical C = Social D = Sleep E = Household chores F = Sex life G = Family exertion *p<0.05 <65 years ≥65 years In the Confronting COPD study, 201,921 households were screened by random-digit dialling in USA, France, Canada, Germany, The Netherlands, UK and Spain. 3,265 patients with a diagnosis of COPD, chronic bronchitis or emphysema were identified. Patients had a mean age 63.3 years with 44% female. Information regarding limitations to their activities of daily living due to COPD were obtained by asking ’How much do you feel your respiratory condition limits what you can do in each of the following areas? – Do you feel it restricts you a lot, some, only a little or not at all in: "Sports and Recreation"; "Normal Physical Exertion"; "Social Activities"; "Sleeping"; "Household Chores"; "Sex Life"; "Family Activities". This survey identified over 3,000 subjects with a diagnosis of COPD, chronic bronchitis or emphysema, and showed that middle aged individuals with COPD have a disease burden equal to and in some cases greater than that of older subjects. The functional limitations imposed by COPD on persons of <65 yrs were reported to be equal to or greater than those aged >65 yrs in sports and recreation, social activities, household chores, sex life and family activities. Only in normal physical exertion did significantly fewer persons aged <65 yrs (55.7%) than >65 yrs (62.3%) report being significantly limited as a result of their condition (p<0.05). Furthermore, in subjects <65 yrs, 45.3% reported work loss during the past year. In summary, COPD affects all aspects of daily life especially those related to physical activity. Reference Rennard et al. Impact of COPD in North America and Europe in 2000: subjects’ perspective of Confronting COPD International Survey. Eur Respir J 2002;20:799–805. COPD = chronic obstructive pulmonary disease Rennard S et al. Eur Respir J 2002;20:799–805

COPD limits the amount of work individuals are able to perform In the COPD Uncovered study, 70% of COPD patients were no longer working Of these 26% reported giving up work because of COPD Mean age for those retiring early was 58.33 years (range 45–68 years) Of those who continued to work, WPAI scores showed: Impairment with regular activities was more marked than overall work loss and impaired work activity levels ‘Presenteeism’ more of a problem than absenteeism COPD = chronic obstructive pulmonary disease; WPAI = Work Productivity and Activity Impairment Fletcher et al. BMC Public Health 2011;11:612

Shortness of breath/inactivity downward spiral Patients avoid shortness of breath by becoming less active, leading to a shortness of breath/inactivity downward spiral Shortness of breath with activities Patient becomes more sedentary to avoid activity producing shortness of breath (decreases activity)1 References Gysels M et al. J Pain Symptom Manage 2008;36:451–60. ZuWallack R. COPD 2007;4:293–7. Reardon JZ et al. Am J Med 2006;119:32–37. De-conditioning aggravates shortness of breath; patients adjust by reducing activity further1 Figure adapted from Reardon JZ Am J Med 2006.2 1. ZuWallack R COPD 2007;4:293–7 2. Reardon JZ et al. Am J Med 2006;119(10 Suppl 1):32–72

Health status and physical activity are predictors of survival in COPD Prognostic research in COPD has established several assessments beyond airflow limitation1 Physical activity is the strongest predictor of all-cause mortality in patients with COPD1,2,3 It has been speculated that physical inactivity leads to dysregulated cellular and molecular circuitry, which directly contributes to multiple chronic health disorders4 Impaired health status has also been shown to be a strong predictor of mortality in COPD5,6 COPD = chronic obstructive pulmonary disease Waschki et al. Chest. 2011;140:331–42 Garcia-Aymerich  et al. Thorax 2006;619:772–8 ZuWallack RL. Monaldi Arch Chest Dis 2003;59:230–3 Booth et al. J Appl Physiol 2002;931:3–30 Oga et al. Am J Respir Crit Care Med 2003;1674:544–9 Halpin et al. Respir Med 2008;102:1615–24

Pulmonary rehabilitation and patient education Exercise training is a cornerstone of pulmonary rehabilitation and significantly improves muscle function1 Improved exercise endurance is associated with a number of positive outcomes Reduced hyperinflation (which may reduce shortness of breath)2 Improved overall pulmonary function2 Improved health-related quality of life2 Exercise training may also: Reduce the risk of hospital readmission3 Reduce mortality3 Patient education programmes may also improve health status and reduce healthcare resource utilization4 Reduced risk of hospital admission4 Improved SGRQ total score, and improved ‘Activity’ and ‘Impact’ sub-scale scores4 References Nici L et al. Am J Respir Crit Care Med 2006;173:1390–413. http://dx.doi.org/10.1164/rccm.200508-1211ST. Yoshimi K et al. J Thorac Dis 2012;4:259–64. Puhan MA et al. Respir Res 2005;6:54. Bourbeau J et al. Arch Intern Med 2003;163:585–91. SGRQ = St George’s Respiratory Questionnaire. Nici L, et al. Am J Respir Crit Care Med 2006;173:1390–413. Yoshimi K, et al. J Thorac Dis 2012;4:259–64. Puhan MA, et al. Respir Res 2005;6:54. Bourbeau J, et al. Arch Intern Med 2003;163:585–91.

Conclusions Patients with mild/moderate COPD show different rates of lung function decline depending on smoking status and presence of respiratory symptoms1 Lung function decline is faster during the initial stages of COPD2 Physical inactivity is present in the early stages of COPD3,4 Activity continues to decline as COPD worsens5 Physical activity is the strongest predictor of all-cause mortality in patients with COPD6–8 COPD impairs functional abilities and limits ability to work9,10 Early intervention in COPD may interrupt the downward spiral of symptoms and activity limitation11,12 Pulmonary rehabilitation (exercise training) improves muscle function and may reduce hospital admissions and mortality13,14 COPD = chronic obstructive pulmonary disease 1. de Marco R. Am J Respir Crit Care Med 2009;180;956–63; 2. Tantucci C, Modina D. Int J COPD 2012;7:95–9; 3. Walz H et al. Am J Respir Crit Care Med 2008;177:743–51; 4. Decramer M, Cooper CB. Thorax 2010;65:837–41; 5. Walz H. Eur Respir J 2009;33:262–72; 6. Waschki et al. Chest. 2011;140:331–42; 7. Garcia-Aymerich  et al. Thorax 2006;619:772–8; 8. ZuWallack RL. Monaldi Arch Chest Dis 2003;59:230–3; 9. Rennard S et al. Eur Respir J 2002;20:799–805; 10. Fletcher et al. BMC Public Health 2011;11:612; 11. Reardon JZ et al. Am J Med 2006;119(10 Suppl 1):32–72; 12. ZuWallack R COPD 2007;4:293–7; 13. Nici L et al. Am J Respir Crit Care Med 2006;173:1390–413; 14. Puhan MA et al. Respir Res 2005;6:54