Does Improving Exercise Capacity and Daily Activity Represent the Holistic Perspective of a New COPD Approach?

Abstract

In COPD patients a reduced daily activity has been well documented, resulting from both respiratory and non-respiratory manifestations of the disease. An evaluation by multisensory armband has confirmed that daily physical activity is mainly associated with dynamic hyperinflation, regardless of COPD severity. This aspect is crucial, since exercise capacity is closely correlated to life expectancy. Notwithstanding the causal key role of lung impairment in the patient's symptoms, some authors have suggested that other factors, such as systemic inflammation and co-morbidities, have an important role, particularly as mortality risk factors. Many studies suggest the efficacy of bronchodilators and rehabilitation in improving exercise capacity, and, speaking in terms of daily life, in increasing the number of days in which patients are able to perform their usual activities. On this evidence, the first aim in the management of COPD should be to improve exercise capacity and daily activity since these outcomes have direct effects on patients’ quality of life, co-morbidities (heart and metabolic diseases), and prognosis. Thus, improving physical activity represents a modern approach aimed at dealing with both pulmonary and systemic manifestations of the disease. It is however worth of notice to remember that in patients affected by COPD the relationship between the improvement of “potential” exercise capacity and daily physical activity has been found to be only moderate to weak. Obtaining a significant behavior modification with regard to daily physical activity, together with the optimization of therapy thus represents currently the true challenge.

Keywords:

• airflow limitation
• inflammation
• co-morbidities
• dyspnea
• bronchodilation
• rehabilitation

Introduction

Chronic obstructive pulmonary disease (COPD) is now the fourth-leading cause of death worldwide, and it will become the third-leading cause of death by 2020 (1). The hallmark feature of COPD is a reduction of expiratory flow, resulting from chronic bronchiolitis and emphysema; on this basis, the gold standard for diagnosis is spirometry (2,3), and bronchodilators are the first-line treatment for all patients, with inhaled steroids limited to more severe patients prone to frequent exacerbations (3,4). In COPD patients exercise limitation is mainly due to dynamic hyperinflation (5), even if the contribution of other factors, such as an imbalance between respiratory and locomotor muscles for limited energy supply (6), limb muscle dysfunction (7), and co-morbidities (e.g., left ventricle diastolic dysfunction) (8), can be clinically significant.

Notwithstanding the causal key role of lung impairment in the patient's symptoms, some authors have suggested that other factors, such as ­systemic inflammation (9) and co-morbidities (10), play roles of not negligible importance, particularly as mortality risk factors. The same authors pointed out that pulmonary functional impairment is not reversible and, therefore, relatively less relevant if compared with co-morbidities, which are directly linked to mortality, and can be treated (9). This review is focused on the role of reduced exercise capacity and daily activity in COPD, both in the lung-related and systemic aspects of the disease, and on the clinical importance of their improvement.

Two different ways to consider COPD

The “lung-centered” view

As previously stated, the hallmark feature of COPD is airflow limitation, resulting from chronic bronchiolitis and emphysema (2). The role of dynamic hyperinflation in the development of exercise limitation has been well documented, also in patients with mild obstruction (11). Even if shortness of breath is a complex symptom (12), several studies have confirmed that dyspnea severity is correlated with indexes of mechanical restriction such as dynamic hyperinflation and an increased ratio between tidal volume and inspiratory capacity (13–15), with an expected reduction of dyspnea after bronchodilation and lung volumes reduction (16). This is why the GOLD document, such as many national guidelines, suggests bronchodilators as the first line treatment for all patients (3,4). These drugs have proven to provide long-term improvements in lung function, quality of life, exacerbations, reduction of lung hyperinflation and dyspnea (17–23). Moreover, tiotropium, the long-acting bronchodilator with the highest number of studied patients in randomized clinical trials, demonstrated to significantly reduce mortality in the UPLIFT study (24), even if not in the intention to treat analysis carried out 30 days after the end of the trial.

A reduced lung function has been demonstrated to significantly affect survival not only in COPD patients, but also in case of heart failure, both in out- (25) and in-patient settings (26). Moreover, the BODE index, a more comprehensive approach to better establish the prognosis of COPD patients, includes at least two parameters other than FEV₁, linked to lung impairment (shortness of breath, and reduced exercise capacity) (27).

In the “lung-centered view”, the extra-pulmonary conditions frequently detected in COPD patients are considered as: (1) the direct complications of the lung impairment (e.g., pulmonary hypertension); (2) the indirect effect of lung impairment (e.g., osteoporosis due to reduced daily activity), (3) the clinical outcome of the exposure to the same risk factors (e.g., coronary heart disease and smoking), (4) the side effects of the pharmacotherapy used in the treatment of COPD (e.g., steroids and osteoporosis, or muscle wasting) or, finally, (5) the coincidental presence of another disease associated with the age of the patients.

The systemic inflammation and “co-morbidome” view

Even if the diagnosis and assessment of severity of COPD are based on the degree of airflow limitation at spirometry, increasing scientific evidence suggests that symptoms, prognosis, and airflow limitation are poorly correlated, and a comprehensive approach to the disease requires the evaluation of exercise tolerance and body-mass index other than spirometry (27). Moreover, COPD is undoubtedly a disease that encompasses an abnormal inflammatory reaction in the lung, but accumulating evidence shows that it is also associated with systemic inflammation (28,29). It has been proved that systemic inflammation is increased during exacerbations of the disease (30), even if not in all patients, also in case of severe obstruction (31). This is the background that induced Leonardo Fabbri and Klaus Rabe to state in 2007 that “COPD can no longer be judged a disease only of the lungs”, with the proposal to add the term “chronic systemic inflammation syndrome” to the diagnosis of COPD (32). This viewpoint stimulated the publication of hundreds of papers on COPD and systemic inflammation.

The consequences potentially related to systemic inflammation include cardiovascular disease, obesity, hypertension, type 2 diabetes, depression, deconditioning, malnutrition, atrophy and dysfunction of skeletal muscles, osteoporosis, anemia and bone marrow dysfunction (33–40), with some of these clinical conditions affecting the course of the disease (10,41). This new perspective points out the issue of the treatment of some frequent and clinically relevant co-morbidities (e.g., ischemic heart disease, chronic heart failure, hypertension, diabetes, osteoporosis, and depression). In 2012, Divo et al, who evaluated the role of co-morbidities on mortality, proposed the “co-morbidome,” a graphic expression of co-morbidities with a prevalence >10% in COPD. The 12 co-morbidities with the strongest association with an increased mortality resulted to be: cancer (lung, pancreatic, esophageal, and breast cancer), pulmonary fibrosis, atrial fibrillation/flutter, congestive heart failure, coronary artery disease, gastric or duodenal ulcers, liver cirrhosis, diabetes with neuropathy, and anxiety. Fabbri et al proposed a link between systemic inflammation, current smoking, obesity and co-morbidities, with the possibility that systemic inflammation itself may have an extra-pulmonary origin (e.g., abdominal fat in obese patients) (9).

How to improve exercise capacity and daily activity in COPD

Approximately 60 years ago, the foundational works of Jeremy Morris and colleagues showed that the incidence of coronary heart disease in bus conductors who climbed up and down stairs of double-deck buses collecting tickets and in postal carriers who delivered the mail on foot was lower than that of the relatively inactive bus drivers or postal office workers who spent most of their occupational time sitting (42,43). Since then, numerous other investigators have confirmed the strong link between physical activity and health in a variety of populations. The American Heart Association includes physical inactivity as a major risk factor for coronary artery disease since 1992 (44,45). A recent report characterized the impact of physical inactivity as similar to that of smoking in relation to the burden of uncommunicable diseases worldwide (46).

Exercise capacity is closely correlated to life expectancy, not only in patients with respiratory, cardiac of metabolic diseases, but even in healthy subjects (47,48). In COPD patients a reduced daily activity has been well documented, resulting from both respiratory and non-respiratory manifestations of the disease (49,50).

In COPD patients the level of physical activity is decreased after hospitalization, particularly when hospitalization is due to a COPD-related respiratory reason (51,52). Moreover, the level of physical activity itself is associated with the risk of acute exacerbation of COPD, hospitalization, and re-hospitalization (53–57). Finally, it has been demonstrated that reduced physical activity, together with respiratory failure and increased systemic inflammation, are factors associated with a higher healthcare resource utilization (58).

The relationship between a reduced daily activity and COPD is probably complex. However, as previously discussed, exercise limitation is mainly due to dynamic hyperinflation (5). By the use of multisensory armband it has recently confirmed that daily physical activity of patients with COPD is mainly associated with dynamic hyperinflation, regardless of COPD severity (59): even in case of mild functional impairment (i.e., FEV₁>80% of predicted values), dynamic hyperinflation can be detected.

The evaluation of exercise capacity in COPD patients is quite complex; several tools are available, from the relatively simple 6-minute walking test, to cardio-pulmonary exercise testing; the heterogeneity of the tests used to asses exercise capacity may explain the conflicting results described in the scientific literature (60). Many studies, however, suggest the efficacy of bronchodilators in improving exercise capacity evaluated by constant load cardio-pulmonary exercise testing (17,21–23,61), the test characterized by the highest sensitivity (23). This benefit can justify the increased number of days in which patients are able to perform usual activities after bronchodilation with one or two drugs, when compared with placebo (62,63).

However, as previously stated, reduced exercise capacity is not merely due to a respiratory impairment, since also non-respiratory manifestations of the disease significantly affect this attitude. In this context, exercise training, one of the key factors of pulmonary rehabilitation, has been proven to be beneficial in COPD patients in terms of exercise tolerance and quality of life by improving peripheral muscle function (64–67). Furthermore, pulmonary rehabilitation has proved to be effective in decreasing hospital admission rate and mortality, and in improving health-related quality of life in patients who have recently suffered a COPD exacerbation requiring hospitalization (68), even if a recent study failed to demonstrate that early rehabilitation during hospital admission for chronic respiratory disease reduced the risk of subsequent readmission or enhanced recovery of physical function following the event over 12 months (69).

Improving exercise capacity: Can it represent the link between the “lung centered” and “systemic inflammation and co-morbidome” views?

Both bronchodilators and pulmonary rehabilitation are able to improve exercise capacity in COPD, outcome important from the patients’ point of view, and crucial in the “lung-centered” perspective.

The deleterious effects of physical inactivity are associated with many chronic diseases, frequently linked to COPD, such as type 2 diabetes mellitus, hypertension, obesity, osteoporosis, and breast and colorectal cancers (46). As indicated by the American Diabetes Association it is now well established that regular physical activity improves blood glucose control, preventing or delaying type 2 diabetes, improving lipid metabolism, blood pressure, quality of life and decreasing cardiovascular events, mortality (70).

Physical activity reduces the risk of cardiovascular events (71,72); the association between higher levels of activity and lower cardiovascular disease rates can be explained in large part by renown risk factors, with inflammatory and haemostatic biomarkers making the largest contribution to lowering the risk, followed by blood pressure, lipids, and body mass index (73). Chronic inflammation is an important risk factor for several diseases, such as cardiovascular diseases and type 2 diabetes mellitus. Inflammatory and pro-inflammatory cytokines are elevated in obesity, mainly in case of abdominal obesity (74–77). Thus so far, physical inactivity may represent a link between “lung” and “systemic centered” views of the disease.

Even if some aspects are still debated, in obese patients exercise training has demonstrated potential positive effects (77) on: (i) muscle tissue, with an increased release of IL-6 responsible for improving balance between pro-inflammatory, and anti-inflammatory cytokines (78); (ii) adipose tissue, with a reduction of macrophage infiltration due to an increase of angiogenesis, and blood supply (79,80); (iii) endothelial cells with a reduced vascular wall inflammation due to a reduced production of adhesion molecules and an increase of cell regeneration (81–83); and (iv) immune cells, with a reduction of toll-like receptors and inflammatory monocytes, together with an increase of regulatory T cells (84). Through these mechanisms, exercise training reduces chronic inflammation in obese patients, independently of its effects on weight loss (77). Finally, although the dose and domain of physical activity varied across studies, evidence suggests that even low doses of physical activity may be protective against depression (85).

However, in COPD moderate-to-weak relationship between the improvement of “potential” exercise capacity and daily physical activity has been found (86). In fact, even if a treatment with long-acting bronchodilators allows patients to climb stairs, they will continue to use the lift if they were used to have this behavior; obtaining a significant behavior modification with regard to daily physical activity is the true challenge.

Some potential limitations about our perspective should be underlined. First of all, the link between physical activity and “systemic inflammation” probably requests new literature evidence, since some papers highlight how physical activity has anti-inflammatory effect, but others suggest the opposite, mainly in muscle-wasted patients (87). Moreover, in our review, we did not deal with the complexity of COPD, condition that includes patients with different features (e.g., prevalent emphysema vs. airway disease, or cachectic vs. non-cachectic). Finally, we generalized the effect of physical activity; actually, it is well known that the response to exercise training during a rehabilitation program can be different with responders and non-responders (88).

Conclusions

As previously discussed, two distinct “views” of COPD are currently proposed: the first more focused on the lung, the second on systemic inflammation and co-morbidities, deemed not as a complication of the lung impairment but, rather, as an extra-pulmonary manifestation of COPD. If physical inactivity represents a link between “lung” and “systemic-centered” views of the disease, in the management of COPD patients the first aim should be to improve exercise capacity and daily activity since these outcomes have direct effects on patients’ quality of life, co-morbidities (heart and metabolic diseases), and prognosis. But how to reach this outcome in COPD patients if not by treating hyperinflation, the main cause of exercise limitation?

Moreover, due to the weak relationship between the improvement of “potential” exercise capacity, that can be achieved with bronchodilators and pulmonary rehabilitation, and daily physical activity, to reach the best possible results it is important to change COPD patients’ behavior (Figure 1).

Figure 1. The crucial role of daily activity in COPD.

Declaration of Interest Section

FDM has received honoraria for lectures at national and international meetings from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Dompé, Guidotti/Malesci, GSK, Menarini, Novartis, Zambon. He has served as consultant for Astra Zeneca, Chiesi Farmaceutici, Novartis, and Zambon. He has received financial support for research from Novartis.

PS has received financial support for research from AirLiquide, Chiesi Farmaceutici and Almirall. He has received support for national and international meetings attendance from Chiesi Farmaceutici, Novartis, Menarini, AstraZeneca, Boehringer Ingelheim. He has received honoraria for lectures at national and international meetings from Chiesi Farmaceutici, Novartis, Zambon, AstraZeneca, Boehringer Ingelheim, Menarini, Almirall. He has served as consultant for Zambon, Astra Zeneca, Novartis, Chiesi Farmaceutici.

GS and FB have nothing to disclose.

SC has received honoraria for lectures at national and international meetings from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Dompé, Guidotti/Malesci, GSK, Menarini, Novartis, Zambon. He has served as consultant for Astra Zeneca, Chiesi Farmaceutici, Novartis, and GSK. He has received financial support for research from Novartis, and Pfizer.

The authors alone are responsible for the content and writing of the paper.