Defining Disease Modification in Chronic Obstructive Pulmonary Disease

Figures & data

Figure 1 Schematic illustration of effects of an intervention on disease progression. Broken lines detail natural progression of a marker of disease progression; solid lines detail the change in this marker resulting from the intervention. (A) an intervention leading to a sustained change in the rate of progression that is maintained even after the intervention ceases; (B) an intervention leading to a sustained change in the rate of progression that occurs only during the time the therapy is administered; (C) an intervention that leads to a sustained improvement in a marker of disease status but has no effect on the rate of change of that marker over time; (D) an intervention that improves the marker of disease status during the time it is administered but provides no lasting effect on that marker once it is stopped.

Table 1 Potential outcome measures that could be key markers of disease modification in COPD

Outcome measure	Method	Potential to measure disease progression	Practicality
Pathophysiologic
Macrophages, neutrophils, CD4^+ and CD8^+ lymphocytes	Bronchoalveolar lavage, endobronchial biopsy, transbronchial biopsy	Not yet clear whether this is an accurate surrogate of disease progression	Invasive – not practical beyond small-scale investigation
Airway structural components	Transbronchial biopsy	Not yet clear whether this is an accurate surrogate of disease progression	Invasive – not practical beyond small-scale investigation
Cytokines, chemokines	Induced sputum	Little is known concerning long-term reproducibility and correlation with disease progression	Relatively easy and well tolerated but induction procedure can induce neutrophilic inflammation, and sputum solubilization may interfere with radioimmune assays. Samples predominantly the larger airways and may not reflect inflammation of the small airways
NO, CO, Volatile hydrocarbons (alkanes, pentanes, ethane)	Exhaled air	NO and CO only slightly elevated in COPD and little known about correlation with disease progression	Readily accessible and repeatable but CO assay is confounded by active and passive smoking
		Ethane correlates with disease progression	Ethane assay is too complex for routine use
Oxidative products, leukotrienes, cytokines, and pH (which reflects tissue acidification due to inflammation)	Exhaled breath condensate (EBC)	Accuracy of EBC as a valid reflection of alveolar lining fluid has been questioned	Noninvasive and simple but wide variability observed due to dilution from water vapor during condensation and low concentrations of the biomarkers
IL-6, IL-8, TNF-α, and CRP	Plasma/serum sampling	Serum CRP and serum TNF-α do not correlate with disease severity. Data on serum IL-6, IL-8, and fibrinogen are insufficient and inconclusive	Readily accessible and repeatable
Physiologic
FEV1	Spirometry	Worsens over time. Exhibits sustained improvement with pharmacologic interventions	Readily accessible and repeatable
		Rate of change not easily altered by pharmacologic interventions, which may suggest this measure is resistant to change or that pharmacologic approaches applied to date are ineffective.
		Historically considered by many the paradigm of disease progression
Patient-centered outcomes
Dyspnea	Baseline Dyspnea Index, Transition Dyspnea Index	Worsens over time and exhibits sustained improvement with pharmacologic and nonpharmacologic interventions – could be considered a surrogate marker for disease progression	Simple to perform and repeatable, but standardization of administration in clinical trials and validity as a measure of dyspnea has been questioned. The Transition Dyspnea Index measures changes in dyspnea from the initial or baseline state
Exercise capacity	6MWD progressive	Worsens over time and exhibits variable improvement with pharmacologic and nonpharmacologic interventions – could be considered a surrogate marker for disease progression	6MWD and progressive cycloergometry show poor repeatability, learning effects and effort dependence.
	cycloergometry, constant work
	rate submaximal exercise test		Constant work rate submaximal exercise test is reliable and repeatable
Health-related quality of life	Disease-specific questionnaires, e.g., St George's Respiratory Questionnaire	Worsens over time and exhibits variable improvement with pharmacologic and nonpharmacologic interventions. Health status measures reflect the effects of the disease rather than the disease itself – could be considered a surrogate marker for disease progression	Simple to monitor
Exacerbations	Patient/physician reports	May increase in frequency over time and exhibit reduced frequency with pharmacologic interventions; however, low frequency in mild COPD would limit utility of this measure at the early stages of disease	Relatively easy to measure, although definitions differ between clinical trials
Mortality
Mortality rate	Physician report	Ultimate measure of disease progression and useful to study disease modification in populations, but not suitable for monitoring progression in an individual patient	Complicated by co-morbid conditions that could contribute to mortality independently or additionally, but not exclusively to COPD

CO, carbon monoxide; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; FEV₁, forced expiratory volume in 1 second; IL, interleukin; 6MWD, 6-minute walking distance; NO, nitric oxide; TNF, tumor necrosis factor.

Figure 2 Airway inflammatory response, as measured by the percentage of the airways containing polymorphonuclear neutrophils (PMNs), macrophages, and eosinophils, among patients at each Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage ([4]). Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, Paré PD. N Engl J Med 2004;350:2645–2653. Copyright © [2004] Massachusetts Medical Society. All rights reserved.

Figure 3 Natural history of lung function decline in smokers and nonsmokers ([13]). British Medical Journal, 1977,1,1645–1648, reproduced/amended with the permission from the BMJ publishing group.

Figure 4 Effect of smoking cessation on the decline in lung function (forced respiratory volume in 1 second [FEV₁] % predicted) over 5 years ([16]). Scanlon PD, Connett JE, Waller LA, Altose MD, Bailey WC, Buist AS; Lung Health Study investigators/ 2000/ Smoking cessation and lung function in mild-to-moderate chronic obstructive pulmonary disease/ American Journal of Respiratory and Critical Care Medicine/ 161/381–390. Official Journal of the American Thoracic Society © American Thoracic Society.

Figure 5 Effect on forced respiratory volume in 1 second (FEV₁) of salmeterol and fluticasone propionate administered either alone or in combination versus placebo over 156 weeks ([24]). Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; TORCH investigators. N Engl J Med 2007;356:775–789. Copyright © [2007] Massachusetts Medical Society. All rights reserved.

Figure 6 Effect of tiotropium on trough forced expiratory volume in 1 second (FEV₁) following treatment with tiotropium or administration with placebo from (A) Days 8–355 and (B) Days 50–344 ([26]). Reprinted from Pulmonary Pharmacology and Therapeutics, 18, Anzueto A, Tashkin D, Menjoge S, Kesten S, One-year analysis of longitudinal changes in spirometry in patients with COPD receiving tiotropium, 75–81., Copyright (2005), with permission from Elsevier.

Figure 7 Air trapping links pathophysiology and patient-centered outcomes in COPD ([37]). Reprinted from American Journal of Medicine, 119, Cooper CB, The connection between chronic obstructive pulmonary disease symptoms and hyperinflation and its impact on exercise and function, S21–S31., Copyright (2006), with permission from Elsevier.

Figure 8 Slope of deterioration in health status calculated using estimates from a random coefficients hierarchical model for patients treated with fluticasone proprionate or placebo over 3 years ([49]). Spencer S, Calverley PM, Sherwood Burge P, Jones PW; ISOLDE Study Group/ 2001/ Health status deterioration in patients with chronic obstructive pulmonary disease/ American Journal of Respiratory and Critical Care Medicine/ 163/ 122–128. Official Journal of the American Thoracic Society © American Thoracic Society.

Figure 9 Change in Health-related Quality of Life (HRQoL) over 156 weeks following treatment with placebo, fluticasone proprionate, salmeterol or fluticasone proprionate and salmeterol administered in combination ([24]). Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; TORCH investigators. N Engl J Med 2007;356:775–789. Copyright © [2007] Massachusetts Medical Society. All rights reserved.

Figure 10 Direct and indirect ways by which interventions impact on mortality.

Hogg J C, Chu F, Utokaparch S, Woods R, Elliott W M, Buzatu L, Cherniack R M, Rogers R M, Sciurba F C, Coxson H O, Paré P D. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004; 350: 2645–2653

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Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ 1977; 1: 1645–1648

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Scanlon P D, Connett J E, Waller L A, Altose M D, Bailey W C, Buist A S. Smoking cessation and lung function in mild-to-moderate chronic obstructive pulmonary disease. The Lung Health Study. Am J Respir Crit Care Med 2000; 161: 381–390, (2 Pt 1)

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Calverley P M, Anderson J A, Celli B, Ferguson G T, Jenkins C, Jones P W, Yates J C, Vestbo J, TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356: 775–789

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Anzueto A, Tashkin D, Menjoge S, Kesten S. One-year analysis of longitudinal changes in spirometry in patients with COPD receiving tiotropium. Pulm Pharmacol Ther 2005; 18: 75–81

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Cooper C B. The connection between chronic obstructive pulmonary disease symptoms and hyperinflation and its impact on exercise and function. Am J Med 2006; 119(10A Suppl)S21–S31

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Spencer S, Calverley P M, Sherwood Burge P, Jones P W, ISOLDE Study Group. Health status deterioration in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 163: 122–128

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