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The Proceedings of the American Thoracic Society 5:848-856 (2008)
© 2008 The American Thoracic Society
doi: 10.1513/pats.200809-101TH
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Treatment of Chronic Obstructive Pulmonary Disease and Its Comorbidities

Fabrizio Luppi1, Francesca Franco2, Bianca Beghé1 and Leonardo M. Fabbri1

1 Department of Respiratory Diseases, University of Modena and Reggio Emilia, Modena, Italy; and 2 Department of Internal Medicine, C. Magati Hospital, Scandiano, Reggio Emilia, Italy

Correspondence and requests for reprints should be addressed to Leonardo M. Fabbri, M.D., Department of Respiratory Diseases, University of Modena and Reggio Emilia, Via del Pozzo, 71, 41100 Modena, Italy. E-mail: leonardo.fabbri{at}unimore.it

ABSTRACT

While chronic obstructive pulmonary disease (COPD) is still characterized and diagnosed by lung function measurements, there is increasing evidence that the chronic diseases that frequently develop with COPD in response to the common risk factors (smoking, aging, obesity) may contribute significantly to its clinical manifestations and severity. Considering that pharmacologic and nonpharmacologic treatments of COPD, such as pulmonary rehabilitation, are primarily symptomatic, it is reasonable to hope that a more comprehensive management of COPD that takes into account its comorbidities may improve the response to treatment and reduce mortality in patients with COPD. Thus, as comorbidities are often underdiagnosed and undertreated, it is important to search for their coexistence in COPD and in all chronic diseases, possibly by adopting recommendations for diagnosis of single diseases. This means that while careful cardiovascular, metabolic, and endocrinologic examinations should be increasingly used in assessing patients with COPD, lung function measurements may become useful in patients with chronic cardiovalscular, metabolic, and endocrinologic diseases. The increasing evidence that active treatment of comorbidities (by, e.g., statins and β-blockers) may reduce morbidity and mortality in patients with COPD suggests the urgent need for randomized clinical trials that hopefully will provide the evidence for more comprehensive clinical guidelines for these patients.

Key Words: chronic obstructive pulmonary disease • comorbidities • statins • angiotensin-converting enzyme • steroids

Chronic diseases make up a huge proportion of human illness. It has been estimated that in 2005 more than 35 million people died from heart disease, stroke, cancer, and other chronic diseases (1–3). Cardiovascular diseases, chronic respiratory diseases, and diabetes are the most frequent chronic degenerative disorders, particularly in the elderly; more than half of all elderly people have at least three chronic medical conditions, and a significant proportion have five or more (4), that are often unrecognized and untreated (5). Because of an expected sharp increase in chronic diseases in the next 10 years, this is an important area of concern for health authorities (1–3, 6). Chronic diseases share largely preventable risk factors, in particular poor socioeconomic conditions, poor diet, smoking, obesity, and hypertension (7).

Chronic diseases such as chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD) often develop together with one or more co-morbid conditions and never alone (7, 8). Not only may a coexisting chronic disease contribute to the clinical manifestations and the severity and life expectancy of the patients (9), but it may also influence the efficacy and safety of patient management. While common clinical practice is to treat chronic disease as a single condition, there is an urgent need to update the terminology and classification, and to develop new criteria for the diagnosis, assessment of severity, and management of patients with multiple chronic diseases.

COPD AND ITS CHRONIC COMORBIDITIES

COPD is still defined as a disease state characterized by poorly reversible airflow limitation induced by cigarette smoke and/or other noxious particle and gases, and spirometry is recommended to establish the diagnosis and assess the severity of airflow limitation (10). However, spirometric assessment poorly correlates with the clinical manifestations of COPD, and a large proportion of smokers with chronic respiratory symptoms do not meet the spirometric criteria (11, 12).

Cigarette smoking, the most important and best-established risk factor for COPD, is also a major risk factor for all other chronic diseases and cancer, not only because it damages the lung directly, but also because it may simultaneously cause systemic effects affecting all organs (13, 14).

The most common comorbidities of COPD that are possibly related to the systemic effects of smoking are CHF, arrhythmias, hypertension, peripheral and coronary artery diseases, diabetes and metabolic syndrome, osteoporosis, cancer (particularly lung cancer), pulmonary vascular abnormalities, psychiatric disorders, cachexia, skeletal muscle abnormalities, and infections (7, 15, 16).

Thus, the systemic effects of smoking may significantly contribute not only to the respiratory abnormalities, symptoms, and functional impairment associated with COPD, but also to the clinical respiratory and nonrespiratory clinical manifestations related to the chronic diseases often associated with COPD (7, 17). Low-grade systemic inflammation induced by smoking and other risk factors has also been implicated in the pathogenesis of cardiovascular events and chronic myopathy of the skeletal muscle; since patients with COPD suffer from excess morbidity and mortality related to cardiovascular events, it has been suggested that systemic inflammation may be the common link (18).

COPD is an independent risk factor for cardiovascular disease (19). Arterial wall stiffness, which relates to cardiovascular risk, is increased in patients with COPD compared with control subjects who smoke (20, 21). This suggests that COPD may result in systemic endothelial dysfunction, which may be a mechanism for the enhanced cardiovascular risk in COPD (19). Systemic arterial wall stiffness is also independently related to emphysema as assessed by CT scanning (22, 23) and correlates with osteoporosis, another systemic complication of COPD (20). These studies raise the intriguing possibility that mechanisms that result in alveolar wall destruction and emphysema may also produce increased cardiovascular risk and osteoporosis in patients with COPD.

Comorbidities are highly likely to affect health outcomes in COPD, and patients with COPD are more likely to die of cardiovascular complications or cancer than of respiratory failure (24). Progressive respiratory failure accounts for approximately one third of COPD-related deaths; therefore, factors other than the progression of lung disease must play a substantial role.

The number of preexisting comorbidities in patients with COPD is associated with increased in-hospital mortality (25). Co-morbid conditions that have been associated with an increased mortality risk in patients with COPD include chronic renal failure, cor pulmonale (26), and pulmonary vascular disease. Underlying heart diseases have not been consistently associated with a higher mortality risk. However, because COPD is frequently underreported, it is difficult to make an accurate estimate of how co-morbid conditions influence COPD mortality or, conversely, how COPD affects the outcome of other diagnoses (24).

In addition to smoking, the other major risk factor for cardiovascular and other chronic co-morbid conditions is obesity (27, 28). Although obesity by itself may affect lung function (29), its relationship with COPD has been poorly investigated and is still unclear. However, obesity may affect respiratory function in a number of ways. Multiple cross-sectional studies have demonstrated an inverse relationship between FEV1 and body mass index (30). This is of particular importance because FEV1 is an independent predictor of all-cause mortality (31) and a strong risk factor for cardiovascular disease, stroke, and lung cancer (32). Thus, considering the frequent comorbidities, the concept of COPD as a disease diagnosed and monitored with lung function (e.g., FEV1) is becoming outdated and likely compromises patient care. It is suggested that patients would benefit from an earlier, broad-based, and aggressive approach to management (33).

COPD AS A COMORBIDITY OF OTHER CHRONIC DISEASES

Smoking and obesity are the two major risk factors for chronic diseases (34, 35). Obese individuals who smoke have a markedly reduced life expectancy, and smoking and obesity may interact synergistically in a vicious circle at different levels and with different mechanisms, causing endothelial dysfunction and cardiovascular disease (35, 36). Both obesity and smoking are associated with insulin resistance, oxidative stress, and increased concentrations of various (adipo) cytokines and inflammatory markers, all of which ultimately lead to endothelial dysfunction and cardiovascular diseases (30). Consequently, weight loss can reverse many of these problems.

On the other side (vide infra), cachexia and even low body weight in patients with COPD are associated with impaired pulmonary status, reduced diaphragmatic mass, lower exercise capacity, and higher mortality rate when compared with adequately nourished individuals with this disease. Nutritional support may therefore be a useful part of their comprehensive care (37, 38).

Patients with peripheral and coronary artery diseases (39, 40), CHF (41), increased cardiovascular risk (20), diabetes and metabolic syndrome (42), cerebrovascular disorders (43), cancer (44) (particularly lung cancer [45]), osteoporosis (46–48), chronic inflammatory bowel diseases (49, 50), chronic renal failure (51, 52), rheumatoid arthritis (53), psoriasis (54), and premature aging (55) directly or indirectly share the same major risk factors, particularly smoking and aging (56–58), and/or have an increased risk of developing COPD.

CLINICAL GUIDELINES FOR COPD AND CHRONIC DISEASES

Clinical practice guidelines have been shown to significantly improve the quality of clinical care. However, most guidelines ignore the fact that the majority of individuals with a chronic disease have one or more comorbidities. COPD, CHF, peripheral artery disease, diabetes, and non–life-threatening cancer have a major impact on individuals with a chronic condition, particularly in the elderly. Also, adhering to current clinical practice guidelines in caring for an older person with several comorbidities may have undesirable effects (4). Randomized clinical trials provide the evidence supporting clinical guidelines, but because of inclusion/exclusion criteria, randomized clinical trials conducted in patients with chronic disease select subjects who are younger and have milder disease, and exclude those with significant comorbidities (59). Thus, clinical practice guidelines do not provide adequate guidance for patients with complex chronic diseases (4, 60), and a more comprehensive approach is recommended (61).

According to the most recent clinical guidelines for COPD (62–64), the available treatments, both pharmacologic and nonpharmacologic, are essentially symptomatic, with the exception of two interventions that may also increase life expectancy: smoking cessation in all patients with COPD, and long-term oxygen treatment in patients with COPD and respiratory failure.

The main achievable goals of COPD management today include relief from symptoms, improvement of exercise tolerance and quality of life, and prevention and management of exacerbations. These goals can be achieved by reduction of risk factors, management of stable COPD and its comorbidities, and prompt recognition and management of COPD exacerbation (62–64).

Prevention is important in COPD. Smoking cessation is the most effective intervention to reduce symptoms and to decrease the risk of development and progression of COPD (65) and almost all other chronic diseases (66). Pharmacotherapy (nicotine replacement, buproprion/nortryptiline, and/or varenicline) may help patients stop smoking (67). As part of prevention, protection from occupational, indoor, and outdoor pollution is recommended, although solid data on the effects of this type of intervention are lacking.

Pharmacologic treatment may relieve symptoms, reduce the frequency and severity of exacerbations, improve health status, and improve exercise tolerance. Although the mechanisms are poorly understood, bronchodilators, particularly inhaled bronchodilators, are central to pharmacologic management of COPD, both on an as-needed basis to relieve intermittent or worsening symptoms, and on a regular basis to suppress persistent symptoms and prevent exacerbations. Nonpharmacologic treatment includes rehabilitation, oxygen therapy, and surgical interventions (62–64), all of which provide relief from symptoms and may also increase life expectancy.

In the following sections we discuss the potential effects of a more comprehensive approach to the treatment of COPD, by analyzing the evidence suggesting that (1) treatments for COPD may positively affect morbidity and mortality linked to comorbidities of COPD, and (2) treatments for comorbidities may positively affect morbidity and mortality linked to COPD. We do not discuss (1) mechanisms of symptomatic effects (e.g., potential effects of different treatments on respiratory symptoms or exacerbations), (2) adverse effects of treatments of COPD on comorbidities (e.g., systemic steroids used for COPD exacerbations in patients with COPD and diabetes), or (3) adverse effects of treatment of comorbidities on COPD (e.g., β-blockers in patients with both asthma and COPD).

EFFECTS OF TREATMENT OF COPD ON ITS COMORBIDITIES

There is evidence to suggest that some interventions in patients with COPD may affect mortality because of their effects on co-morbid conditions.

Smoking Cessation
Anthonisen and coworkers (68) showed in a 14.5-year follow-up of patients with COPD examined in the Lung Health Study, that smoking cessation reduces all-cause mortality, even when successful in only a minority of participants.

Interestingly, the main effect of smoking cessation is on mortality due to myocardial infarction and cancer. Indeed, the leading causes of death in the Lung Health Study were lung cancer and coronary heart disease, and smoking cessation was of benefit in both (Figure 1). This confirms the findings of previous cohort and case-control studies that showed a decline in death from coronary heart disease and lung cancer after smoking cessation. Importantly, these results suggest that mechanisms by which smoking induces coronary events and lung cancer are apparently reversible to some extent, at least in the short term.


Figure 1
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  		Figure 1. Mortality rates at 14.5 years by cause and smoking status, suggesting that in chronic obstructive pulmonary disease (COPD) patients' smoking cessation reduces mortality by cardiovascular diseases and cancer more than by lung diseases. (Reproduced by permission from Reference 68.)

 
Rehabilitation
Pulmonary rehabilitation is an essential component of the comprehensive management of patients with symptomatic COPD (69). Rehabilitation includes teaching and supervising of respiratory therapy techniques (e.g., oxygen, inhalers and nebulizers, breathing techniques, chest physical therapy, postural drainage), exercise conditioning (upper and lower extremities), and activities of daily living (work simplification, energy conservation) (63). Pulmonary rehabilitation can change outcomes that predict survival (70) and can improve the systemic component of COPD and its comorbidities with a potential effect on survival (71). Because exercise training is the most important component of a pulmonary rehabilitation program, and because comorbidities are very frequent in patients undergoing rehabilitation (72), the positive effect of exercise training on cardiovascular (73), metabolic (74, 75), and endocrine (e.g., osteoporosis) (76) components is highly likely.

Supplemental Oxygen Therapy
Long-term supplemental oxygen therapy reduces mortality from all causes in patients with hypoxemic COPD (77, 78), but whether it specifically reduces cardiovascular, respiratory, metabolic, or cancer mortality is not known. However, in addition to its effect on mortality, long-term oxygen therapy reduces dyspnea, polycythemia, pulmonary artery pressures, sleep disorders, nocturnal arrhythmias, and neuropsychiatric abnormalities and improves exercise tolerance, suggesting that its effects go far beyond the lungs (79, 80). An interesting model comes from the evidence that oxygen therapy improves renal function in patients with COPD (81).

Pharmacologic Treatment
The first and only COPD randomized clinical trial to address the effect of pharmacologic combination therapy with salmeterol and fluticasone on overall mortality in COPD was the TORCH trial (Toward a Revolution in COPD Health [82]). The study initially involved 6,112 patients with moderate-to-severe COPD, and its primary endpoint was to compare the effect of salmeterol/fluticasone versus placebo on all-cause mortality over 3 years. The effect on all-cause mortality almost reached statistical significance. Interestingly, careful analysis of the cause of individual deaths by a panel of experts showed that—in this population—the cause-specific mortality was 27% cardiovascular, 35% respiratory, 21% cancer, 10% other, and 8% unknown. Forty percent of deaths were definitely or probably related to COPD (83). In addition, the effect of combination treatment, although statistically not significant, was almost equally distributed between respiratory and other causes, suggesting that this treatment also has nonpulmonary effects.

The effects of inhaled steroids on mortality in patients with COPD is controversial. A pooled analysis, based on intention to treat, of individual patient data from seven randomized trials of at least 12 months' duration in patients with stable COPD suggested that inhaled corticosteroids may markedly reduce all-cause mortality (84). However, the 3-year prospective TORCH study not only did not confirm the effect on mortality, but it showed a trend toward increased mortality in patients treated with inhaled corticosteroids alone. This striking discrepancy should further recommend that retrospective analysis be considered purely hypothesis generating, rather than solid evidence.

EFFECT OF TREATMENTS OF COMORBIDITIES ON COPD

Pharmacologic treatment of chronic disease is complex, especially considering that drugs are usually developed for single diseases. However, drugs designed for one specific disease may also favorably affect other diseases. For example, glucose control with insulin or oral antidiabetic agents not only controls diabetes, but also prevents systemic effects and comorbidities (85). Similarly, treatments for CHF may positively influence arterial hypertension (86), and antihypertensive agents used to control blood pressure may prevent coronary and cerebrovascular disease (87). Thus, considering that pharmacologic interventions may indeed reduce mortality from cardiovascular and metabolic diseases, and considering the increased risk of patients with COPD to have these chronic diseases as well, it seems reasonable to recommend a careful search for these comorbidities in patients with COPD, followed by proper treatment. Also, interestingly, some of these agents, used in particular for cardiovascular diseases, have been recently found in retrospective analyses to have the potential of positively affecting COPD. As with the above-mentioned example of inhaled corticosteroids, these retrospective studies should be considered only hypothesis generating, as the confirmatory evidence should come from prospective randomized clinical trials.

Statins
A large case-control study has shown that statins, angiotensin-converting enzyme inhibitors (ACEs), and angiotensin receptor blockers (ARBs) may have dual cardiopulmonary protective properties, thereby substantially altering the prognosis of patients with COPD (88).The combination of statins and ACE inhibitors or ARBs was associated with a reduction in COPD hospitalization and total mortality in all patients with COPD, in both the high and the low cardiovascular risk cohorts. Furthermore, this drug combination reduced myocardial infarction in the COPD cohort with high cardiovascular risk. Benefits were similar when steroid users were included (Figure 2). Statins may also reduce the decline in pulmonary function, independently of the underlying lung disease (89). In another case-control study, statins even appeared to protect against the development of lung cancer (90).


Figure 2
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  		Figure 2. Fully adjusted risk ratios are plotted for the end points of hospitalization for COPD, myocardial infarction, death, and myocardial infarction or death. Treatments analyzed were angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), statins, and the combination of statins with ACE inhibitors or angiotensin receptor blockers (combination) in the population of patients with COPD with prior revascularization (high risk). (Reproduced by permission from Reference 88.)

 
Statins are used primarily as lipid-lowering agents in the treatment of metabolic syndrome, but they also have potent antiinflammatory properties that might explain their positive effect on frequent comorbidities of both metabolic syndrome, for example, CHF and vascular disease, and COPD (91–94). The interest in these agents was further enhanced by the discovery that statins may cause regression of atherosclerosis lesions (95, 96) (Figure 3), an effect that has not previously been observed in COPD with any intervention, not even after successful smoking cessation (97).


Figure 3
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  		Figure 3. Example of regression of atherosclerosis induced by statin treatment in a patient in the ASTEROID trial. EEM = external elastic membrane. (Reprinted by permission from Reference 95.)

 
Considering that statins' effects on mortality, even in subjects at risk of developing cardiovascular diseases (98, 99), significantly reduces cardiovascular morbidity and mortality, the results of these studies on cardiovascular diseases increase the hopes of reducing mortality from other chronic diseases, such as COPD.

ACEs and ARBs
As previously mentioned, Mancini and colleagues showed that the combination of statins and ACE inhibitors or ARBs is associated with a reduction in COPD hospitalization and total mortality in all patients with COPD (88) (Figure 2). The renin-angiotensin system plays a key role in maintaining blood pressure homeostasis, as well as fluid and salt balance. Angiotensin II, a key effector peptide of the system, causes vasoconstriction and exerts multiple biological functions. ACE plays a central role in generating angiotensin II from angiotensin I, and capillary blood vessels in the lung are one of the major sites of ACE expression and angiotensin II production in the human body. The rennin–angiotensin system has been implicated in the pathogenesis of pulmonary hypertension and fibrosis, both of which potentially develop in COPD (100) Also, in COPD the sympathetic nervous system, as well as the renin–angiotensin system, may be activated with possible negative systemic effects on skeletal muscles (101). Angiotensin II type-1 receptor blockers inhibit the sympathetic and renin–angiotensin systems and might thus improve skeletal and respiratory muscle strength in patients in whom these systems are activated. Unfortunately, angiotensin II receptor blockade by irbesartan given over 4 months did not modify respiratory muscle strength in patients with COPD (102). However, the observed changes in hematocrit and lung volumes suggest that there were potential direct beneficial effects to the lung in patients with COPD, which, combined with the recognized effects on cardiovascular comorbidities of COPD, might help to modify the natural course of the disease.

β-Blockers
β-blockers improve health outcomes in patients with cardiovascular disease, and are recommended as first-line therapy for CHF, a frequent comorbidity of COPD. However, there is some concern that prescribing β-blockers for patients with COPD may cause bronchoconstriction and worsen respiratory symptoms, even though there is increasing evidence that cardioselective β blockade is quite safe in patients with COPD. In fact, a recent metaanalysis that evaluated the relationship between cardioselective β-blockers and COPD found no significant differences in FEV1 or respiratory symptoms between those treated with a cardio-selective β-blocker and those treated with a placebo, even in patients with severe COPD (103–105). The analysts concluded that, given their demonstrated benefit in conditions such as heart failure, coronary artery disease, and hypertension, cardioselective β-blockers should not be routinely withheld from patients with COPD.

Two recent studies suggested that β-blockers may, in fact, have positive effects in patients with COPD with cardiovascular diseases. Dransfield and coworkers examined a large population of inpatients admitted for acute exacerbations of COPD, and found that the use of β-blockers was associated with reduced in-hospital mortality. The benefit of β-blockers was observed despite the fact that those who received the drugs were older, had longer hospital stays, and had a greater prevalence of congestive heart failure and cerebrovascular disease, all factors that are independent predictors of in-hospital mortality (106). van Gestel and colleagues showed that the use of cardioselective β-blockers is associated with reduced mortality in patients with COPD undergoing vascular surgery, and suggested that in selected patients with COPD, the use of cardioselective β-blockers may be safe and associated with reduced mortality (107).

Neurohumoral activation in patients with COPD, similar to that in CHF and other diseases, may have negative effects such as systemic inflammation, cachexia, effects on ventilation, and skeletal muscle dysfunction, that might explain the increased cardiovascular morbidity and mortality in patients with COPD. Thus, β-blockers and other agents that are now proved to be well tolerated in COPD, such as ARBs or ACEs (see above), might have unexpected beneficial effects on COPD and its comorbidities (101).

Treatments for other important comorbidities of COPD, such as cachexia, anemia, and chronic renal failure, should be explored further.

The causes of cachexia in patients with COPD are multifactorial and include decreased oral intake, increased work of breathing due to abnormal respiratory mechanics, and chronic systemic inflammation and comorbidities (37, 38). While active nutritional supplementation in undernourished patients with COPD may lead to weight gain and improvements in respiratory muscle function and exercise performance, a recent metaanalysis provided no evidence that nutritional support has a significant effect on anthropometric measures, lung function, or exercise capacity in patients with stable COPD (108). In contrast, repeated administration of ghrelin, a novel growth hormone–releasing peptide that is reduced in COPD (109), may improve body composition, muscle wasting, and functional capacity in cachectic patients with COPD, suggesting the possibility of reversing some of the systemic aspects of COPD (110). In conclusion, it remains unknown whether long-term weight gain by using enhanced caloric intake, with or without anabolic steroids or appetite stimulants, furthers survival or provides other benefits to patients with COPD. However, there are indications from single-center trials that this is an avenue well worth exploring (37).

Anemia frequently occurs in patients with COPD, and inadequate hemoglobin levels could aggravate tissue hypoxia and have a negative prognostic impact (111, 112). Blood cell transfusion in anemic patients with COPD reduces minute ventilation and the work of breathing (113), suggesting that correcting low hemoglobin levels could alleviate dyspnea and improve exercise capacity. In a small set of anemic ventilator-dependent patients with COPD, raising hemoglobin levels to more than 12 g/dl seemed to improve patients' breathing enough to make ventilator weaning possible (114).

Chronic renal failure is a gradual and progressive loss of the ability of the kidneys to excrete wastes, concentrate urine, and conserve electrolytes. It may range from mild dysfunction to severe renal failure and end-stage renal disease, which is associated with significant comorbidities (51, 115). Diabetes and hypertension (high blood pressure) account for the majority of cases of chronic renal failure and end-stage renal disease, and both renal failure and ischemic heart disease are highly relevant to the prognosis of patients with COPD discharged from the hospital after an acute exacerbation. These co-morbid diseases probably act as markers of frailty by increasing the fatality rate of later COPD exacerbations (116).

CONCLUSIONS

As mentioned, most clinical practice guidelines ignore the fact that the majority of individuals with a chronic disease have one or more chronic comorbidities (e.g., CHF, peripheral artery disease, diabetes, or non–life-threatening cancer), that may have a major impact on COPD and on chronic diseases in general (9). Thus, although comorbidities are quite common in patients with COPD, most recent evidence-based guidelines provide little guidance in caring for patients with COPD with multiple chronic diseases (62–64). Most patients with chronic diseases are given multidrug regimens, which clearly provide added disease-specific benefits for at least some subpopulations of patients, unlike single-drug therapy. Less clear, however, are the long-term net benefits and harm associated with the combination of medications that are taken in adherence to disease-specific guidelines by patients with several coexisting health conditions (117, 118). Thus, as comorbidities are often underdiagnosed and undertreated, it is important to search for their co-existence with COPD and with all chronic diseases, possibly by adopting recommendations for the diagnosis of single diseases. This means that, while careful cardiovascular, metabolic, and endocrinologic examinations should be increasingly used in assessing patients with COPD, lung function measurements may be useful in patients with chronic cardiovascular, metabolic, and endocrinologic diseases as well.

Considering that pharmacologic (62–64), and even nonpharmacologic treatment of COPD such as pulmonary rehabilitation (69), are primarily symptomatic, and considering the frequent chronic comorbidities of COPD (7), it is reasonable to hope that a more comprehensive approach to COPD together with its comorbidities may identify novel targets for treatment and modify the natural course of the disease (60, 61). This is particularly relevant for those conditions that appear more preventable and treatable than COPD, such as cardiovascular and metabolic disorders. The increasing evidence that treatment of comorbidities may reduce morbidity and mortality in patients with COPD suggests the urgent need for randomized clinical trials that hopefully will provide the evidence for more comprehensive clinical guidelines for these patients.

ACKNOWLEDGMENTS

The authors are indebted to M. McKenney for editing the manuscript and to E. Veratelli for her scientific secretarial assistance.

FOOTNOTES

Conflict of Interest Statement: F.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. L.M.F. reports having served as a consultant to Altana Pharma, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche, and Pfizer. He has been paid lecture fees by Altana Pharma, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche, and Pfizer. He has received grant support from Altana Pharma, AstraZeneca, Boehringer Ingelheim, Menarini, Miat, Schering Plough, Chiesi Farmaceutici, GlaxoSmithKline, Merck Sharp & Dohme, UCB Pharma, Pfizer, Italian Ministry of Health, and Italian Ministry for University and Research.

(Received in original form September 3, 2008; accepted in final form September 9, 2008)

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