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The Proceedings of the American Thoracic Society 3:262-269 (2006)
© 2006 The American Thoracic Society

Approaches to Improving Health Status in Chronic Obstructive Pulmonary Disease

One or Several?

Emiel F. M. Wouters

University Hospital Maastricht, Maastricht, The Netherlands

Correspondence and requests for reprints should be addressed to Prof.dr. Emiel F.M. Wouters, M.D., Ph.D., Department of Respiratory Medicine, University Hospital Maastricht, P.O. Box 5800, 6202 Az Maastricht, The Netherlands. E-mail: e.wouters{at}lung.azm.nl

ABSTRACT

Health outcomes represent a broad group of endpoints used in clinical practice to assess the efficacy and effectiveness of interventions and to assess disease outcomes. Health status is one of the widely applied patient-reported health outcomes. The outcome of a variety of interventions, targeting local impairment or local airway inflammation, is evaluated by health status measurements; these global or summative outcomes indeed quantify the overall effect of a number of biological processes. Targeting the systemic compartment to improve health status is already widely applied in the domain of pulmonary rehabilitation. Challenging developments targeting systemic inflammation and biological processes related to systemic inflammation are particularly addressed in this review.

Key Words: outcome measures • pulmonary rehabilitation • systemic inflammation • therapy

HEALTH STATUS AS A HEALTH OUTCOME

Health outcomes represent a broad group of endpoints used in clinical research to assess the efficacy or effectiveness of interventions and to assess disease outcomes (1). Traditional health outcomes include mortality, numbers of hospital admissions, and, particularly in the field of respiratory medicine and chronic obstructive pulmonary disease (COPD), lung function parameters such as FEV1. Recently, there is a growing body of research concerning endpoints that are assessed directly by patients and can be termed patient-reported health outcomes (2). The patient-reported health outcomes can be divided in the following categories: health status, health utilities, adherence to treatment, and patient satisfaction with healthcare (2). Health status can be defined as the impact of health on a person's ability to perform and derive fulfillment from the activities of daily life. A patient's self-reported health status, therefore, includes health-related quality of life and functional status (2). Health-related quality of life is defined as the degree to which a patient's health status affects their self-determined evaluation of satisfaction or quality of life, whereas functional status refers to a person's ability to perform a variety of physical, emotional, and social activities. Accordingly, instruments that are used in determining health status include those that measure both functional status and health-related quality of life (2).

Health-status instruments are designed to measure either the general health status or the effect of a specific disease on health status. Generic instruments are broad in their scope and applicability, and are capable of detecting the effects of diverse aspects of one disease beyond those captured by a disease-specific measure. In addition, generic instruments offer the opportunity to compare health status across multiple diseases (3). The disease-specific instruments focus on one condition and attempt to define its effects on a patient's health status (2). Two disease-specific questionnaires are widely used for patients with COPD: the Chronic Respiratory Questionnaire (CRQ) (4) and the St. George's Respiratory Questionnaire (SGRQ) (5). The CRQ contains 20 questions that cover four domains: dyspnea, fatigue, emotional function, and mastery (4). The instrument has proven to be reliable, valid, and responsive to change: a difference in score of 0.5 per domain has been determined to be a minimally important difference (6–11). The SGRQ covers three domains: symptoms, activity, and impact (5). The instrument has been demonstrated to be valid, reliable, and responsive among patients with COPD: the minimally important difference is four for all domains (5, 12–14).

Health-status instruments are global or additive outcomes: they quantify the overall effect in patients of a number of different biological processes (15). Global outcomes are especially useful when a treatment has multiple beneficial actions. Global outcomes may also be more sensitive to treatment than specific outcomes because they have the potential to aggregate multiple small effects together and they are high-level outcomes and, therefore, closer to constructs that are relevant to patients. Global outcomes cannot identify the mechanisms responsible for an effect of intervention (16).

APPROACHES TO IMPROVING HEALTH STATUS: TARGETING LOCAL (PULMONARY) IMPAIRMENT IN COPD

One of the critical issues in COPD is a lack both of a cohesive definition for the disease and of established phenotypes. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria, "COPD is a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases" (17). Spirometric evaluation should be used to confirm the diagnosis of COPD when suggestive symptomatology is present. Although reliable physiologic testing can define disease severity and occurrence, it is only of limited value in identifying the different phenotypes of COPD and in understanding the heterogeneity of the disease. Airflow limitation in COPD, assessed by FEV1 measurements, can reflect different underlying pathophysiologic mechanisms: decline in FEV1 can be the result of airway wall pathology as well as of the loss of alveolar attachments caused by emphysema. Largely based on the analysis of induced sputum in patients with COPD, researchers get a better understanding of the inflammatory processes in the airways. However, repeatable and reliable markers of airway inflammation are still lacking and assessment of the inflammatory process is not yet part of the diagnostic work-up of the patient suffering from COPD.

The introduction of high-resolution computed tomography (HRCT) has brought a new dimension to the study of COPD. HRCT scanning offers a real opportunity to study the pathophysiologic processes involved in structural changes within the lung. HRCT may provide a link between the anatomy and physiology and may allow early recognition of structural changes in the lung parenchyma (18, 19). Future targeting of local impairment may therefore involve modulation of airflow limitation and inflammation as well as attenuation of progression of the structural changes in the respiratory system. The approaches to improve health status by intervention with bronchodilator and/or antiinflammatory drugs are discussed in the present issue.

Bronchodilator Interventions and Health Status in COPD
Two major classes of bronchodilator drugs, the ß2-adrenoceptor agonists and the M3-muscarinic antagonists (anticholinergics), are widely used in the management of airway obstruction. The former agents induce bronchodilatation by activating cell surface ß2-adrenoceptors expressed in bronchial smooth muscle. Due to specific pharmacokinetic and pharmacodynamic properties, the long-acting ß2-agonists, typified by formoterol and salmeterol, have relatively prolonged bronchodilator activity in human subjects such that they usually can be administered twice daily. Cholinergic nerves arising in the vagus mediate neural bronchoconstriction in human and animal airways, and anticholinergic drugs have been used for hundreds of years in the treatment of airway diseases. Such cholinergic nerve-mediated bronchoconstriction (and mucus secretion) is via activation by acetylcholine of muscarinic receptors on airway smooth muscle cells and submucosal glands. Ipratropium bromide, a muscarinic receptor antagonist that has no subtype selectivity, has for many years been a widely prescribed bronchodilator in the therapy for COPD. Recently, an important step was the development of tiotropium bromide, a long-acting M3-specific muscarinic antagonist that is currently available for the therapy for COPD in several major markets (20).

To provide clinical evidence that these bronchodilator agents exert beneficial actions in human lung disease, a specific outcome measure such as the FEV1 can be used. Indeed, spirometric assessment of bronchodilator responsiveness (reversibility of airflow limitation) is recommended by most of the guidelines for the therapy for COPD (17, 21). A key problem of bronchodilator reversibility, however, is that it is not a constant feature in the individual patient (22, 23). Furthermore, despite the wide use of reversibility testing in COPD, the minimal clinically important differences for this and other lung function parameters are unknown (24). The possible role of increased FEV1 responses to bronchodilators in the clinical management of COPD recently has been questioned further: the Lung Health Study demonstrated that there was no relationship between the bronchodilator response and subsequent rate of decline of pulmonary function (23).

However, although the effects of bronchodilators have focused previously on measures of expiratory airflow, bronchodilators may also have important effects on lung volumes (25–27) (see also article by Calverley in this issue, pp. 239–244). Furthermore, others have demonstrated that many patients experience improved lung volumes in response to bronchodilators without showing marked changes in FEV1 (28). Pharmacologic lung volume reduction may be very important for patients as the increase in lung volumes seen frequently in COPD impose mechanical constraints that increase the work of breathing and decrease the patient's ability to respond to increased ventilatory demand (25, 29). Assessment of health status is, therefore, integrated in the designs of clinical studies of bronchodilator agents to aggregate all of these flow and volume effects.

Small effects on health status, consistent with small changes in lung function, were reported after therapy with salbutamol and ipratropium bromide (30, 31). There are several reports of the effects of long-acting bronchodilators on health status (32–36). Although health status scores after administration of such drugs were superior to placebo in most studies, the minimal clinically important difference was reached only in a limited number (Figure 1). Despite the widely accepted recommendation that bronchodilators are evidence-based to alleviate respiratory symptoms, disease-specific measures support a more modest conclusion (13, 32–36).


Figure 1
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  		Figure 1. Changes in health status assessed by the St. George's Respiratory Questionnaire by use of long-acting bronchodilating agents (minimal clinically important difference [MCID]: 4 points). Data from References 13 and 32–36.

 
Inhaled Steroids and Health Status in COPD
COPD is characterized by chronic airflow limitation, and the predominant cellular pattern of inflammation in stable COPD consists of CD8+ T lymphocytes, CD68+ macrophages, and neutrophils in conducting airways and lung parenchyma (37–40). Neutrophil chemotactic mediators, such as interleukin-8 and leukotriene B4, and proinflammatory cytokines, such as tumor necrosis factor (TNF)-{alpha}, are also increased in the sputum of patients with COPD, as compared with those of normal subjects (41, 42). The role of inhaled corticosteroids in COPD is under scrutiny, as there is little evidence of their effect on various inflammatory markers in this disorder (41, 43). The effects of corticosteroids on the various inflammatory cell types associated with COPD remain relatively poorly understood. In one study, a significant decrease in the number of mast cells was reported after intervention with inhaled corticosteroids, whereas the number of neutrophils increased in biopsy samples (44). Others have reported marginal reductions in cell indices of inflammation after intervention with inhaled corticosteroids (45).

Because of current uncertainty about the roles of such biological variables in COPD, the selection of appropriate outcomes is difficult. Despite all of these uncertainties, however, health status measurements have been integrated in various clinical trials. As can appreciated from the data summarized in Figure 2, only small effects on health status were reported and the changes observed rarely exceeded the minimally clinical important differences for the health status instrument used (46).


Figure 2
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  		Figure 2. Changes in health status assessed by the St. George's Respiratory Questionnaire by use of inhaled steroids (MCID: 4 points). Data from References 32–34 and 46.

 
Combination Therapy and Health Status in COPD
The combination of an inhaled long-acting ß2-agonist and an inhaled corticosteroid has demonstrably beneficial effects in both asthma and COPD. Corticosteroids can up-regulate the numbers of ß2-receptors on the cell membrane and ß2-agonists may increase the nuclear localization of glucocorticoid receptors (47). Formoterol and budesonide in combination are more effective at reducing proliferation of airway smooth muscle than either drug alone as a result of synchronized cellular signaling (48). On the basis of such data in vitro and the success of combination therapy in the management of asthma (49, 50), clinical trials have been conducted in COPD to evaluate combination of these classes of drugs against placebo and both components individually (32–34). Of particular note, in a study by Calverley and colleagues evaluating maintenance therapy with a combination of budesonide and formoterol (34), health status improved significantly and exceeded minimal clinically important differences in the total score as well as in the domains of symptoms, activity, and impact (Figure 3).


Figure 3
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  		Figure 3. Changes in health status assessed by the St. George's Respiratory Questionnaire by use of combination therapy (MCID: 4 points). Data from References 32–34.

 
With the exception of the data reported by Calverley and colleagues (34), it can be concluded that, despite explicit and hidden biases in the different study designs, most pharmacologic interventions do not reach the level of minimal clinically important difference—that is, the smallest change that is important to patients.

APPROACHES TO IMPROVING HEALTH STATUS: TARGETING THE SYSTEMIC COMPARTMENT

Because COPD causes disability and handicap to patients, the role of rehabilitation programs for improving health has been recognized. The concept of pulmonary rehabilitation fits very well with our current approach to COPD as a multicomponent disease process (51). Different studies reported significant and clinically important improvements in health status assessed by tools such as SGRQ and the CRQ (52–54) (Figure 4). There is a growing body of evidence in the literature to identify the mechanisms underlying such improvements in health status. Reduction in muscle mass is reported to be associated with a more impaired health status (55, 56), and body compositional analysis indicates a rise in muscle mass after intervention with physical training (57). Pulmonary rehabilitation studies report a significant improvement in exercise capacity and a reduction in dyspnea after such intervention (58–61). Improvement in exercise capacity is related to improved aerobic capacity in the skeletal muscles (62, 63). Attention to the psychopathologic problems of these patients, as well as the increasing burden to their families, forms an important component in a multidisciplinary rehabilitation program.


Figure 4
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  		Figure 4. Changes in health status assessed by the Chronic Respiratory Questionnaire (CRQ) after pulmonary rehabilitation (MCID: a difference score of 0.5/domain). Data from References 52 (yellow bars) and 53 (blue bars).

 
Interestingly, C-reactive protein (CRP), an acute-phase protein often used as a clinical marker of inflammation (64), discriminates in COPD for an impaired energy metabolism, functional capacity, and health status. Indeed, patients with stable COPD with increased levels of CRP showed a higher resting energy expenditure, whereas maximal and submaximal exercise capacity as well as 6-min walking distance were lower than in subjects who did not have COPD. Patients with elevated CRP had worse health status than patients with normal CRP (difference in total SGRQ score, 6.7). Regression analysis showed that, adjusted for FEV1, age, fat-free mass, and sex, CRP was a significant predictor for the symptom score of the SGRQ (65). Further studies are needed to explore this relationship between systemic inflammation and heath status in COPD.

Interestingly, previous studies have demonstrated that CRP is a predictor of acute exacerbations of COPD (66) and for hospitalization and mortality in chronic respiratory failure (67), and is associated with increased cardiovascular morbidity (68). Systemic inflammation is probably also an important component in muscle wasting (69, 70) and in bone loss (71, 72). Both processes seem to be closely related in patients with COPD (73). Furthermore, evidence is growing that systemic inflammation is related to the increased cardiovascular morbidity and mortality reported in patients with COPD (68, 74).

Systemic inflammation in COPD is characterized not only by increased plasma levels of proinflammatory cytokines and chemokines but is also associated with increased oxidative stress (75, 76). Increased oxidative stress has been proposed to contribute to disease progression and is likely to contribute to the metabolic derangements and muscle weakness in patients with COPD. A potential mediating factor linking systemic inflammation and oxidative stress to a disturbed energy metabolism in COPD is the nuclear enzyme poly(ADP-ribose)polymerase (PARP)-1 (77). PARP-1 catalyzes the formation of linear and branched poly(ADP-ribose) polymers from its substrate, nicotinamide adenine dinucleotide (NAD+). These polymers are bound covalently to PARP-1 itself, as well as to other nuclear proteins, including histone proteins, and proteins involved in DNA repair, transcription regulation, cellular differentiation, and cell cycle regulation (78, 79). The production of negatively charged poly (ADP-ribose) polymers by PARP-1 is considered to underlie its best known function—that is, loosening of the chromatin structure and facilitating processes like base excision DNA repair and transcription regulation (79). During increased oxidative stress—for instance, during exacerbations in COPD (80)—reactive oxygen species–induced DNA strand breaks cause high levels of activation of the enzyme to such a great extent that the utilization of the substrate NAD+ becomes the predominant biological effect. Resynthesis of one molecule of NAD+ requires four molecules of ATP, and hence PARP-1 activation poses a large demand on cellular energy metabolism. As a consequence of low cellular NAD+, the rate of glycolysis, mitochondrial respiration, and the production of high-energy phosphates are reduced and a cellular energy crisis develops (78, 79). If this crisis cannot be overcome, cell death by apoptotic or necrotic pathways may occur, depending on the amount of ATP present in the cell. Even under relatively normal conditions, PARP-1 has been reported to be the main determinant of cellular NAD+ turnover, because pharmacologic inhibition of PARP-1 (with dexamethasone or benzamide) in nonactivated macrophages and lymphocytes was observed to increase their cellular NAD+ content up to 60% within a few hours (81, 82).

An increased frequency of PARP-1–positive cells in circulating mononuclear cells has been reported in patients with stable COPD (n=23) when compared with healthy age-matched control subjects (n = 8) (76). This suggests that patients with COPD may be subject to chronic PARP-1 activation. NAD+ levels in peripheral mononuclear leukocytes of these patients with stable COPD were not reduced compared with healthy control subjects, however (76).

These and other data suggest a possible link between systemic inflammation and chronic oxidative stress, on the one hand, and PARP-1 activation and increased NAD+ turnover, on the other, possibly affecting cellular energy metabolism and function. There are other reports of disturbances in energy metabolism in resting muscle of patients with stable COPD (83). The ratio of ATP/ADP as well as the phosphocreatine/creatine ratio were significantly lower in the muscles of patients with COPD. Furthermore, inosine monophosphate, a des-amination product of adenosine monophosphate was found in the majority of these patients, particularly those with impaired gas exchange. On the basis of these results, an imbalance between the utilization and resynthesis of ATP in resting muscle of patients with stable COPD was suggested. Others reported that muscle fatigue is a dominant feature in patients with stable COPD (84).

Targeting Systemic Inflammation in COPD
Pulmonary rehabilitation programs generally assess the outcome of intervention using global outcome parameters such as health status or exercise performance. Other studies have targeted such systemic effects of COPD as weight loss and muscle wasting, based largely on restoration of energy balance by modulation of macronutrients (85, 86). Only limited data are available on the effects of specific intervention on systemic inflammation in COPD.

In the cardiovascular literature, several behavioral and pharmacologic interventions known to reduce the risk of clinical cardiovascular events have been linked to lower CRP levels. However, definitive evidence that lowering CRP levels will necessarily lead to a reduction in clinical cardiovascular events is not yet available (87). Control of body weight, physical activity, and avoidance of smoking are important behavioral aspects to reduce CRP levels (87).

It has been reported that polyunsaturated fatty acids can modulate local and systemic cytokine biology (88). A recent placebo-controlled intervention with polyunsaturated fatty acids failed to demonstrate any decrease in systemic inflammatory parameters such as CRP in patients with COPD (89).

Several pharmacologic agents with demonstrated cardioprotective activities appear to reduce CRP levels. Lipid-modulating medications reported to affect CRP levels favorably include 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), fibrates, and niacin. Of these, the findings for statins are by far the most robust (87). Indeed, several studies have now demonstrated that statin therapy results in a greater clinical benefit when levels of the inflammatory biomarker CRP are elevated in cardiovascular disease, and that statins can lower CRP levels in a manner that is largely independent of low-density lipoprotein cholesterol levels (90–95). The role of these drugs in modulation of systemic inflammation in patients with COPD is not yet studied.

Recently reported pilot data suggest that inhaled corticosteroids may modulate the level of systemic inflammation in COPD (96). Further studies are needed to strengthen these early observations. The concept of overflow of the local inflammation in the lungs to the systemic compartment in patients with stable COPD may challenge this hypothesis (42). Inhibitors of phosphodiesterase-4 have the potential to modulate systemic inflammation as this is the main isoform of this enzyme expressed in inflammatory cells and airway smooth muscle (97, 98).

Mitogen-activated protein (MAP) kinases may have important roles in chronic inflammation: for example, p38 MAP kinase is a key signaling molecule in the expression of interleukin-8, TNF-{alpha}, and some matrix metalloproteinases. Nonpeptide inhibitors of p38 MAP kinase have been shown to have a wide range of antiinflammatory activities in experimental animals (99), and studies need to be conducted to confirm such activity in humans. New antioxidant therapies may play a role in targeting both the local and systemic component of COPD. Finally, antiinflammatory drugs targeted against TNF-{alpha} may be suitable treatments for COPD, based the orchestrating role of TNF-{alpha} in the local and systemic inflammatory process. It should be noted that a recent 6-wk study with an anti–TNF-{alpha} antibody, infliximab, in 14 patients with COPD reported no effects on various short-term clinical outcomes, including lung function, resting energy expenditure, airway inflammation, or quality of life (100).

CONCLUSIONS

COPD is a complex, multicomponent disease, comprising a number of pathophysiologic processes that interact with each other. Several interventions may possess the potential to improve health status, although considering the complexity and heterogeneity of this disorder, most pharmacologic interventions available at present to treat COPD do not reach the level of minimally important clinical difference, despite the higher sensitivity of these global outcome instruments. More specific interventions are needed to evaluate the role of systemic inflammation on patient-reported health status. When using a global outcome measure, it is important to realize that this instrument does not identify mechanisms. Health status as a global outcome measure should be used for hypothesis generation and not for hypothesis testing. Clinical science needs to explore mechanisms underlying the improvement or lack of improvement in health status based on firm insights of the biological processes involved and modulated by the intervention. Health-status instruments will have an important role in assessing the efficacy and effectiveness of future new treatments for patients with COPD.

FOOTNOTES

Conflict of Interest Statement: E.F.M.W. received research grants between 2003 and 2005 from GlaxoSmithKline ({euro}385,000), AstraZeneca ({euro}146,000), Boehringer Ingelheim ({euro}183,000), Centocor ({euro}120,000), and Numico ({euro}120,000).

(Received in original form November 9, 2005; accepted in final form February 7, 2006)

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