Comorbidities in Chronic Obstructive Pulmonary Disease

Abstract

Comorbidities such as cardiac disease, diabetes mellitus, hypertension, osteoporosis, and psychological disorders are commonly reported in patients with chronic obstructive pulmonary disease (COPD) but with great variability in reported prevalence. Tobacco smoking is a risk factor for many of these comorbidities as well as for COPD, making it difficult to draw conclusions about the relationship between COPD and these comorbidities. However, recent large epidemiologic studies have confirmed the independent detrimental effects of these comorbidities on patients with COPD. On the other hand, many of these comorbidities are now considered to be part of the commonly prevalent nonpulmonary sequelae of COPD that are relevant not only to the understanding of the real burden of COPD but also to the development of effective management strategies.

Comorbidities, defined as other chronic medical conditions, including coronary artery disease, diabetes mellitus, osteoporosis and muscle weakness, are common in chronic obstructive pulmonary disease (COPD), but their prevalence varies tremendously between studies (Table 1). van Manen and colleagues reported that over 50% of 1,145 patients with COPD had 1 to 2 comorbidities, 15.8% had 3 to 4 comorbidities, and 6.8% had 5 or more comorbid conditions (1). In another study that selected 200 patients with COPD from 1,522 patients in a managed care organization, Mapel and coworkers reported that the COPD cohort had an average of 3.7 comorbidities versus 1.8 for the control subjects, and only 6% of patients with COPD did not have another chronic medical condition (2). Unfortunately, the presence of both COPD and other comorbidities is often ominous and contributes significantly to poor health outcomes (3–6). Regarding patients with COPD with the major emphysema phenotype, no studies have compared the prevalence and impact of their comorbidities to other COPD phenotypes.

TABLE 1.

CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND THE PREVALENCE OF COMORBIDITIES (%)

Source	n	Arthritis	Cardiac	HTN	Diabetes	Lipids	Psych	GI	Cancer	Osteoporosis
van Manen and colleagues (1)	1,145	36	13	23	5	—	9	15	6	—
Mapel and colleagues (2)	200	22	65	45	12	—	17	32	18	—
Soriano and colleagues (114)	2,699	28	22	—	—	—	10	26	4	—
Sidney and colleagues (9)	45,966	—	18	18	2	9	—	—	—	—
Walsh and Thomashow (115)	3,000	70	50	52	16	51	38	62	4	32

Definition of abbreviations: — = no available data; GI = gastrointestinal disturbances; HTN = hypertension.

COPD, COMORBIDITIES, AND HOSPITALIZATIONS

COPD is a leading cause of hospitalizations in adults, particularly older adults (7). Comorbidities are a common cause, or a contributing cause, to many of these hospitalizations. In the Lung Health Study 12.8% of the 5,887 smokers were hospitalized, with 42% of the hospitalizations secondary to cardiovascular events or pulmonary complications (8). In the review by Holguin and colleagues, comorbidities were frequently reported in hospitalized patients with primary or secondary COPD diagnoses: hypertension 17%, cardiac disease 25%, diabetes 11%, pneumonia 12%; all higher than in the control group (6). In a study of over 45,000 patients with COPD, heart failure was the leading cause of hospitalization, followed by myocardial infarction and stroke (9). Curkendall and coworkers found that the prevalence of all cardiovascular diseases was higher in patients with COPD compared with control subjects, and that the risk of hospitalization and mortality due to cardiovascular causes was also elevated in patients with COPD (10). In another study of 270 hospitalized patients with COPD, Antonelli Incalzi and coworkers noted hypertension in 28%, diabetes in 14%, and ischemic heart disease in 10% (5). Kinnunen and colleagues found that comorbidities had an impact on the duration of COPD hospitalizations, and reported a mean length of stay of 7.7 days without any comorbidity compared with 10.5 days if a concurrent disease was present (11).

COPD, COMORBIDITIES, AND MORTALITY

COPD is the fourth leading cause of death in adults in the United States, and is projected to be the third most common cause of death by 2020 (12). Between 1970 and 2002, death rates due to stroke and heart disease decreased (63% and 52%, respectively), while death rates due to COPD increased 100% (13). Some studies evaluating the cause of death in patients with COPD suggest that patients are more likely to die of comorbid conditions than from COPD, whereas others revealed that COPD is the more likely cause of death (Table 2). Patient selection and severity of disease probably account for these reported differences.

TABLE 2.

REPORTED CAUSES OF MORTALITY IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (%)

Author	Site	Patients with COPD Dying	Cause: COPD (%)	Cause: Cardiovascular (%)	Cause: Malignancy (%)	Cause: Other Respiratory (%)
Mannino and colleagues (14)	United States	1.1 million	43	26	8	—
Hansell and colleagues (17)	England	312,000	60	26	8	4
Camilli and colleagues (116)	Tucson	86	23	42	9	26
Huiart and colleagues (15)	Canada	2,000	14	38	—	—
Anthonisen and colleagues (8)	United States	149	< 15	25	60	—
Zielinski and colleagues (41)	Europe	215	38	27	7	21
Waterhouse and colleagues (120)	Europe	103	49	22	21	—
Keistinen and colleagues (118)	Europe	973	22	37	21	4
Vilkman and colleagues (117)	Europe	1,070	30	37	20	—
Celli and colleagues (119)	United States, Spain, Venezuela	162	61	14	12	—

Mannino and coworkers evaluated obstructive lung disease deaths in the United States from 1979 through 1993, and found that 2.5 million (8.2%) individuals had the diagnosis of COPD listed on their death certificate (14). Of these, 1.1 million (43.3%) had COPD listed as a cause of death. Between 1979 and 2001, there were 47 million hospital discharges (8.5% of all hospitalizations in adults) with a primary or secondary diagnosis of COPD (21% and 79%, respectively) (6). Their reported hospital mortality was 5.9%, with 37% related to respiratory failure, 25% related to pneumonia, and 43% related to heart disease (6). In the Canadian study by Huiart and colleagues of 2,553 COPD deaths, cardiovascular disease was a much more common cause of death than COPD (37.6% versus 14.3%) (15). Similarly, Sidney and coworkers found that over 3 years, patients with COPD were more likely to die, particularly from cardiovascular causes (9). There were 149 deaths in the Lung Health Study (2.5%), with 25% dying of cardiovascular disease. Lung cancer was the cause of 38% of the deaths, while other cancers accounted for 22% (8).

RELATIONSHIP BETWEEN COPD AND COMORBIDITIES

Smoking, aging, and other factors such as polypharmacy, medication interactions, lack of treatment of comorbidities (16), diagnosis coding accuracy (17), and lack of specific case definitions for comorbidities (18) add to the complexity of studying comorbidities and outcomes in patients with COPD. β-Blockers may worsen lung function in a subset of patients with COPD, but their avoidance in many patients with COPD may contribute to increased cardiovascular events, especially in those at risk. In contrast, bronchodilators may contribute to tachyarrhythmias. Inhaled anticholinergics may affect intraocular pressure or bladder function. Inhaled corticosteroids may predispose to cataracts, skin bruising, and, potentially in high doses, osteoporosis. Systemic corticosteroids are frequently overused in the population with COPD, and may contribute to osteoporosis, diabetes, hypertension, muscle dysfunction, and adrenal insufficiency (19). Despite these limitations, mounting evidence has identified links between some comorbidities and COPD, such as its association with cardiovascular disease, even after allowing for common factors (20–23), with much focus on the pivotal role of systemic inflammation that characterizes many chronic medical diseases (21).

Pulmonary Embolism

Pulmonary embolism (PE) may be a more common comorbid condition of COPD than was previously thought, but the data are limited and contradictory to date. A diagnosis of PE could easily be missed in COPD, since the main presenting symptoms of PE overlap with those of a COPD exacerbation. Some evidence points to the importance of considering PE in patients who present with acute exacerbation of COPD with no obvious cause (24–26). In a study of 211 consecutive patients admitted for severe exacerbation of COPD of unknown origin and undergoing spiral CT or ultrasonography, Tillie-Leblond and colleagues reported that 25% of patients had PE (24). The authors further reported that a low Geneva score, which reflects a low clinical suspicion for PE, was insufficient to exclude the diagnosis of PE. Monreal and colleagues reported that 14% of patients in a symptomatic PE registry had COPD (25). In contrast, Rutschmann and coworkers recently reported a low incidence of PE in 123 consecutive patients admitted for acute exacerbation of COPD: 6.2% of patients with a clinical suspicion of PE, and only 1.3% of those with low suspicion (26).

Pneumonia

COPD is more frequently associated with pneumonia compared with other chronic diseases. Of 707 patients presenting with community-acquired pneumonia, 19% had COPD. Moreover, in 10% of the cases, pneumonia led to the new diagnosis of COPD. As expected, COPD contributes to longer hospital stays, increased intensive care admissions, and mortality (33). Pneumonia is viewed by some as part of the spectrum of COPD exacerbations; however, there are important differences between pneumonia and acute COPD exacerbations without pneumonia. Lieberman and colleagues evaluated and compared exacerbations in patients with COPD with and without pneumonia, and found that those with pneumonia had more abrupt onset of symptoms, more severe illness, longer length of stay, and higher rates of ICU admission and death (27). In addition, interventions that are effective at reducing the risk of exacerbations, such as salmeterol and fluticasone, may actually increase the risk of pneumonia (28). Distinguishing COPD exacerbations from pneumonia may be important for management purposes. In general, the literature supporting antibiotic usage in acute exacerbations of COPD shows a modest benefit at best. In contrast, prompt antibiotic delivery is associated with striking benefits in patients with pneumonia (29, 30). Corticosteroids are standard of care for acute exacerbations of COPD (31), with well-documented and important clinical benefits, but their role in the management of patients with COPD with pneumonia is less defined (32).

Lung Cancer

Lung cancer is an important cause of mortality in COPD. Studies relying on national databases for secondary diagnoses on death certificates in Europe and the United States reported that 7 to 10% of COPD deaths are related to lung cancer (14, 17). In comparison, studies that followed patients with COPD prospectively found lung cancer as the cause of death in 7% and 38% of cases (8, 41). Patients with COPD with comorbid conditions, including lung cancer, have higher hospitalization and mortality rates (6, 34, 36, 42, 43). Lange and coworkers, and Hole and colleagues, reported hazard ratios as high as 3.9 and 4.4 for lung cancer mortality in patients with the lowest lung function independent of smoking status (34, 42).

Lung cancer and COPD seem to be casually linked by the pathobiology of COPD rather than COPD being an epimarker of a greater exposure to smoking (23). Although smoking causes COPD and lung cancer, airways obstruction has a greater risk on developing lung cancer than status or degree of smoking (34, 35). In the presence of moderate to severe airways obstruction, the incidence of lung cancer was almost as high among ex-smokers (6.8%) as among current smokers (10.8%) (23). Moreover, the risk of developing lung cancer has been shown to be proportional to the severity of airways obstruction. Compared with smokers with normal lung function, hazard ratios for developing lung cancer for patients with mild to moderate and severe COPD ranged between 1.4 and 2.7 and 2.8 and 4.4, respectively (23, 34). Even small reductions in lung function in smokers were associated with a significant increase in the risk of lung cancer, but this relationship may be less pronounced in men than in women (35–37). The risk of lung cancer was 3.5-fold higher for women than men at similar levels of FEV₁ (35).

The relationship between lung cancer and obstructive lung disease suggests a possible overlap in their biology. The mechanisms that are potentially involved seem to revolve around a particular histologic subtype, namely squamous cell carcinoma, and may be different between men and women. Malhotra and coworkers demonstrated no relationship between the severity of airflow obstruction and risk of having adenocarcinoma (38), which is the leading histologic subtype in women with lung cancer. In contrast, squamous cell carcinoma has a strong association with smoking, and the presence of COPD increases the risk by 2.5 and 3.5 times of having this subtype (39, 40).

Musculoskeletal Dysfunction

Musculoskeletal dysfunction (MSD) contributes to exercise limitation and disability in COPD (44–46). Coronell and colleagues (47) recently demonstrated that patients with COPD have a decreased ability to sustain repetitive muscular contractions and that their muscles fatigue rapidly. Qualitative changes in the activity of aerobic enzymes (48) and muscle fiber atrophy have been reported in patients with COPD (49). Moreover, MSD may be one of the systemic manifestations of COPD that have some bearing on survival and other comorbidities such as osteoporosis (50). Some studies demonstrated lower survival rates in underweight patients (44–46), while others suggested that loss of fat-free mass may be a more accurate measure of functional debilitation than the more traditional measure such as body mass index (51).

Patients with COPD have many reasons to have MSD, including periods of relative inactivity, use of systemic glucocorticoids, malnutrition, and possibly systemic inflammation and oxidative stress (52, 53). Cardiopulmonary function shows a significant decline with bed rest, including increased resting and submaximal heart rates and reduced maximum oxygen uptake (54, 55). There is also a 1 to 1.5% per day loss of muscle strength with prolonged bed rest (56). Nutritional status in patients with advanced COPD can be also compromised, with some patients becoming overtly cachectic or undernourished (57, 58). In addition, ongoing systemic inflammation and oxidative stress may potentially contribute to muscle wasting and reduced exercise tolerance. Pinto-Plata and coworkers reported that CRP levels were elevated in patients with COPD and correlated inversely with 6-minute walk distance (59). In another study of 102 patients with severe COPD, higher CRP levels were associated with poorer quality of life and reduced exercise endurance (60). Current recommendations in the management of MSD revolve around minimizing deconditioning, enrolling in pulmonary rehabilitation, and avoiding systemic corticosteroids (61). So far, results of nutritional supplementation and hormonal replacement have not been encouraging (62–66).

Osteoporosis

Patients with COPD are at an increased risk of osteoporosis because of their age, limited physical activity (67), low BMI (68), smoking, hypogonadism, malnutrition, and use of corticosteroids (69, 70). Males in their mid to late 60s with a smoking history of greater than 60 pack-years have a prevalence rate of vertebral fractures similar to, and possibly greater than, postmenopausal women greater than or equal to 65 years old (70). Limited studies suggest a significant association between COPD and osteoporosis independent of corticosteroids (70–72). In a study of 28 patients with advanced COPD, Shane and colleagues found a very high incidence of both osteoporosis and osteopenia (73). The prevalence rate of vertebral fractures was 29% in patients with COPD. In another study of 62 patients with severe COPD, 68% had osteoporosis or osteopenia and 24% had previously undiagnosed compression fractures (74), Systemic corticosteroids remain the most common cause of drug-related osteoporosis, and a meta-analysis concluded that the use of more than 6.25 mg prednisone daily led to decreased BMD and increased fracture risk (75). In contrast, the effects of the long-term use of inhaled corticosteroids on BMD remain debatable (69, 76–79).

Dietary supplementation with calcium, vitamin D, and life style modification with enrollment in a pulmonary rehabilitation program may be helpful (Table 3). The use of bisphosphonates is appealing, but their effectiveness has not been demonstrated in COPD. A recent nonrandomized study found a significant improvement in BMD and osteoporosis rates in a group of patients with emphysema who underwent lung volume reduction surgery compared with those who refused the surgery (80). The study was limited due to lack of information on medication use and other bone interventions. Nonetheless, the finding of increased BMD in a subgroup of surgery patients who continued systemic steroids suggests that bone health could be improved with effective COPD treatment strategies.

TABLE 3.

MANAGEMENT OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE WITH OSTEOPOROSIS OR AT HIGH RISK FOR OSTEOPOROSIS

1. Screening of high-risk patients: men and women with a significant smoking history, those with advanced chronic obstructive pulmonary disease, and those being treated with continuous high-dose inhaled glucocorticoids or low-to-medium dose inhaled glucocorticoids with frequent courses of oral glucocorticoids

2. Dietary supplementation with calcium (recommended daily allowance 1,000–1,500 mg) and vitamin D (recommended daily allowance 400–800 IU) as needed

3. Lifestyle modification and enrollment in a pulmonary rehabilitation program

4. Risedronate (5 mg/d) or alendronate (5 or 10 mg/d) are recommended as first-line therapy for the prevention and treatment of osteopenia and osteoporosis

5. Screening for metabolic abnormalities and hormonal deficiencies

Gastroesophageal Reflux

An increased prevalence of gastroesophageal reflux (GER) disease and other esophageal disorders has been reported in COPD (81–83). Mokhlesi and coworkers recently reported an increased prevalence of GER symptoms among patients with COPD compared with control subjects (19% versus 0%; P < 0.001) (81). They noted that GER symptoms were more common in those with an FEV₁ less than or equal to 50%, as compared with those with an FEV₁ greater than 50% (P = 0.08). A recent study of 42 patients with severe COPD using 24-hour esophageal pH monitoring reported that 62% had pathological GER, and notably 58% of these 26 patients reported no symptoms of GER (84). On the other hand, a retrospective study found an increased risk of COPD in those with GER (85). Despite this evidence, the exact nature and significance of this relationship remains clouded by a paucity of evidence. The impact of GER on COPD is currently undefined. Hypotheses include that aspiration of Helicobacter pylori or its exotoxins may amplify the airway inflammation (86), or that increased rates of COPD exacerbations are related to GER symptoms.

METABOLIC CHANGES

Diabetes Mellitus

The reported prevalence of diabetes among patients with COPD ranges from 1.6 to 16% (Table 1). As in COPD, smoking has been established as a risk factor for diabetes (87–90), but quitting for more than 5 to 10 years mitigates that risk (89). The evidence for an interaction between diabetes and COPD is supported by studies that demonstrate reduced lung function as a risk factor for the development of diabetes (91–93). In addition, TNF-α, IL-6, and CRP, which are elevated in COPD, are also increased in diabetes (94–97). The impact of glucocorticoids on the management of diabetes during COPD exacerbations and the effect of diabetes control on COPD outcomes is of great clinical concern. In one study, mortality was found to be significantly higher in patients having poor glycemic control who were hospitalized for acute COPD exacerbation (98), and even after discharge, diabetes remained a risk factor for mortality (99). It is uncertain if tighter glucose control can improve COPD outcome.

Dyslipidemia

Smoking causes an increase in low-density lipoprotein (LDL)-C, triglycerides, and very low-density lipoprotein (VLDL) and a decrease in high-density lipoprotein (HDL) (100, 101), but lipid profiles have not been well characterized in COPD. Studies on dyslipidemia in COPD are limited (Table 1) and have generally relied on questionnaire or diagnostic codes to determine frequency. Therefore, it is unknown if dyslipidemia is another independent factor that could explain the increased risk of cardiovascular morbidity and mortality in COPD.

Regardless of cholesterol levels, robust evidence supports the role of CRP levels in predicting cardiovascular disease (102), and when CRP is added to the Global Initiative for Obstructive Lung Disease (GOLD) criteria or pulmonary function testing, the combined scores have greater predictive power for cardiovascular morbidity than either single assessment (103, 104). Consequently, it is expected to observe a significant reduction in cardiovascular disease with statin therapy in smokers (25 to 35%), but it is unclear if this reduction in morbidity is more prominent in those with COPD (105).

Anemia

Untreated hypoxemia is associated with secondary erythrocytosis, but like other chronic diseases, COPD potentially could affect hematopoesis. The observed hematopoietic suppression in chronic inflammatory diseases is likely mediated by three different mechanisms: shortened red blood cell survival, bone marrow erythropoietin resistance, and dysregulation of iron homeostasis (106). Underlying factors influencing these aforementioned mechanisms are thought to be related to smoking (and smoking-related morbidities), malnutrition, and probably the systemic inflammation that accompanies COPD. Systemic inflammation in COPD has been characterized by elevations in levels of IL-6, IL-8, CRP, and TNF-α, (22) with the latter two mediators potentially contributing to a reduction in red blood cells lifespan, impaired iron utilization, and increased erythropoietin resistance (106). A recent study by John and colleagues showed significantly higher CRP and erythropoietin levels in anemic compared with nonanemic patients with COPD (107). They also found a strong inverse correlation between hemoglobin and erythropoietin (r = −0.84) in anemic patients with COPD only, supporting further the association between inflammation and erythropoietin resistance (107).

Anemia is common in COPD and is associated with higher comorbidity, mortality, and health costs (96, 108, 110). In a cohort of 2,524 patients with COPD on long-term oxygen therapy, 13% of men and 8% of women were reported to have anemia (108). Recently, Mannino and coworkers presented data indicating anemia is present in one third of 2,404 patients with COPD (109). Two additional large studies reported the anemia prevalence to be 21% and 23% (110, 111). Risk factors for anemia with COPD include older age, severity of airways obstruction, lower BMI, and having other comorbidities (108). Small intervention studies suggest that correcting anemia in patients with COPD by blood transfusion improves physiologic and clinical parameters (112, 113), but it is uncertain if pharmacologic therapy in anemic patients with COPD can raise their hemoglobin levels or have an impact on their long-term outcome.

CONCLUSIONS

For years the relevance and impact of comorbidities on COPD was not well understood. The emerging evidence on the detrimental interrelationship of comorbidities and COPD is mounting, but this area of research is in its early stages. It is yet to be determined if nonpulmonary interventions such as those that reduce the systemic inflammatory burden, improve anemia, prevent osteoporosis, reverse malnutrition, or the like, will alter the natural history of COPD. In addition, more studies are needed to better define the burden of COPD on various comorbidities and to discover the influence of various COPD treatment strategies on these comorbidities.