Chronic obstructive pulmonary disease: Prognostic factors and comorbid conditions

INTRODUCTION — A variety of clinical factors are thought to influence the natural history and prognosis of patients with chronic obstructive pulmonary disease (COPD) [1-3]. These factors and the impact of acute exacerbations and comorbidities on disease outcome will be reviewed here.

The diagnosis and management of COPD are discussed elsewhere. (See "Chronic obstructive pulmonary disease: Diagnosis and staging" and "COPD exacerbations: Management" and "Stable COPD: Initial pharmacologic management".)

PROGNOSTIC FACTORS — A number of factors have been identified as prognostic indicators for COPD. The forced expiratory volume in one second (FEV₁), a measure of severity of airflow limitation is most often used; other predictors of accelerated lung function decline, diminished physical function, and/or mortality in patients with COPD include the following [4-18]:

●Airways responsiveness

●Cigarette smoking

●Low body-mass index (BMI ≤21)

●Human immunodeficiency virus (HIV) infection

●Increased airway bacterial load

●Decreased exercise capacity

●Diffusing capacity for carbon monoxide (DLCO)

●Peak oxygen consumption (VO₂), measured by cardiopulmonary exercise testing

●Elevated C-reactive protein (>3 mg/L)

●Male sex

●Chest computed tomography (CT) showing presence or progression of emphysema or mucus plugging

Forced expiratory volume in one second — The FEV₁ is the parameter most commonly used to assess the severity of COPD and to predict future changes in lung function and survival [19-23]. The change in FEV₁ over time has been assessed in several studies and is affected by smoking status, but is highly variable among individual patients [20,24,25].

●In a three-year study, the changes in the FEV₁ measured after administration of bronchodilator were assessed in 2163 subjects with COPD [20]. The overall rate of decline was 33 mL per year, although almost 40 percent of the subjects had a decline of more than 40 mL per year. A high variability in the rate of decline in FEV₁ was noted, with higher rates in current smokers (54 mL per year), patients with bronchodilator reversibility, and patients with emphysema on CT.

●In the United States Lung Health Study, the rate of decline in post-bronchodilator FEV₁ was assessed in 5887 smokers with mild to moderate COPD [21]. The unadjusted annual decline was 53.1 mL/year at year 5 and 53.9 mL/year by year 12, by which time 46 percent were still active smokers.

The postbronchodilator FEV₁ has also been used to predict survival [19]. Among 200 patients with COPD, who were followed for 15 years, after controlling for age, the postbronchodilator FEV₁ was the best predictor of survival (table 1). However, wide individual variability in prognosis was noted.

BODE index — A multidimensional index (the BODE index) was developed to assess an individual's risk of death from COPD. The four factors included in the index are weight (BMI), airway obstruction (FEV₁), dyspnea (Medical Research Council dyspnea score), and exercise capacity (six-minute walk distance) (calculator 1). The BODE index is superior for prediction of mortality compared with unidimensional assessment based on the FEV₁ value alone [4,12]. The utility of the BODE index is not confined to assessing the risk of death; it can also predict hospitalization [26].

The majority of patients with COPD have a stable BODE index over time, as demonstrated in a longitudinal study of 751 patients who were followed for a median of 64 months [24]. A statistically significant decrease in the BODE index was noted in 18 percent, the BODE index remained stable in 68 percent, and the BODE index increased in 14 percent. Patients with an increase in the BODE index had more severe obstruction at baseline than those with a stable BODE index.

A modified BODE (mBODE) index uses an alternate dyspnea questionnaire (ie, UCSD SOBQ) and is a better predictor of mortality than its separate components [27]. (See "Chronic obstructive pulmonary disease: Diagnosis and staging", section on 'Assessment of severity and staging'.)

Body mass — BMI is an independent risk factor in COPD. Decreasing body mass is associated with increasing mortality [28-30]. Further weight loss increases mortality risk, whereas weight gain improves prognosis [31,32].

The fat-free mass index (FFMI) provides information beyond that provided by the BMI.

●The FFMI can identify a subgroup of patients with an increased mortality risk despite a normal BMI. This was illustrated by a prospective cohort study of 1898 patients with COPD who were followed for a mean of seven years [33]. Both BMI and FFMI were predictors of mortality. Among patients with a normal BMI, FFMI was a predictor of mortality (26 percent had an FFMI lower than the tenth percentile).

●The FFMI is a better predictor of disease severity. While both BMI and FFMI correlate with the six-minute walk test, only FFMI correlates with the degree of chronic dyspnea, the FEV₁, the FEV₁/forced vital capacity (FVC) ratio, or the stage of disease, according to one observational study [34]. A larger study verified a strong correlation between FFMI and 6MWD in underweight patients [35]. Furthermore, compared with BMI, stratification by FFMI demonstrated improved classification of patients according to lung function, exercise capacity, physical activity, quality of life, and respiratory symptoms. Interestingly, FFMI was not useful as a marker of disease severity in obese patients.

Mucus plugging — Excess production, hypersecretion, and reduced clearance of mucus in the airways lead to an accumulation of mucus plugs in the lungs of patients with COPD [36]. There is growing evidence that mucus plugging in both the small and large airways impacts prognosis independently of other clinical risk factors.

The presence of mucus plugging on CT imaging is associated with airway obstruction independently of emphysema and correlates with lower oxygen saturations, reduced exercise capacity, and lower respiratory quality of life [37,38]. For most patients with mucus plugging, the airway blockages persist on repeated CT scans, and up to 30 percent of patients with mucus plugging do not report symptoms of chronic bronchitis.

The degree of mucus plugging in both large and small airways is independently associated with increased mortality [39,40]:

●In one study, 4363 patients with COPD were evaluated for baseline mucus plugging in medium to large airways (2 to 10 mm in diameter) using submillimeter resolution CT scans with enhancing algorithms and followed for a median of 9.5 years [40]. After adjusting for age, sex, BMI, race/ethnicity, smoking status and history, degree of airway obstruction, and CT measures of emphysema and airway wall thickness, mucus plugging showed an independent association with all-cause mortality (adjusted hazard ratio 1.15 and 1.24 for mucus plugs affecting one to two lung segments and ≥3 lung segments compared with zero segments, respectively). These associations were similar even after further adjusting for chronic bronchitis, BODE index, or concomitant asthma, but they were modestly attenuated after inclusion of exacerbation history.

●In a separate study of 101 patients with severe COPD undergoing surgical lung volume reduction, histologically verified mucus plugging in the small (<2 mm diameter) airways was associated with earlier mortality (highest versus lowest quartile HR 3.3, 95% CI 1.5-6.9) [39]. This association was not influenced by correcting for age, level of respiratory symptoms, or level of expiratory flow limitation.

Airway hyperresponsiveness and bronchodilator response — Airway hyperresponsiveness (eg, methacholine provocation concentration of 4 mg/mL or less) affects approximately 25 percent of patients with COPD and is associated with more rapid decline in lung function and mortality [6,41,42]. Combined data from two large studies (5938 total participants) found that airway hyperresponsiveness was associated with greater respiratory mortality (HR 2.38; 95% CI, 1.38-4.11) and greater decline in FEV₁ (12 to 13 mL/year) compared with absence of airway hyperresponsiveness [41].

Histamine-induced airway hyperresponsiveness is also a predictor of greater mortality [6]. However, it is uncertain whether bronchodilator reversibility following inhaled short-acting beta-agonist (eg, albuterol) predicts mortality.

Types of COPD — Only a few studies have focused on prognosis of specific types of COPD (such as emphysema) or severity of airflow limitation. In one study of 609 patients with severe emphysema (mean FEV₁ 27 percent of predicted), the following factors predicted mortality: advanced age (≥70 years), supplemental oxygen use, total lung capacity (<140 percent of predicted), residual volume (≥262 percent of predicted), maximal workload during cardiopulmonary exercise testing (≤25 W for females, ≤40 W for males), BODE index (≥7), and increased emphysema in the lower lung zones and/or greater blood flow to the lower relative to the upper lung zones [43]. A separate study demonstrated that presence and severity of centrilobular emphysema, but not paraseptal emphysema, are associated with lung function decline and mortality in patients with COPD [44]. (See "Chronic obstructive pulmonary disease: Diagnosis and staging", section on 'Definitions'.)

Acute exacerbations — Compared with patients who do not have acute exacerbations, patients with COPD exacerbations are at increased risk for mortality and respiratory death. In one study with mean four-year follow-up, patients with exacerbations requiring medical therapy over a three-year baseline period had increased adjusted risk of overall mortality (hazard ratio 1.6, 95% CI 1.4-1.8 in the first year and 1.15, 95% CI 1.1-1.2 thereafter) [45]. Patients with exacerbations were also more likely to die of respiratory causes (40 versus 29 percent) compared with non-exacerbators, who were more likely to die of malignancies or cardiovascular disease during follow-up.

Patients with exacerbations severe enough to require hospitalization are also likely at higher risk for subsequent mortality, but estimates of risk vary widely [46-53].

In a study of 1016 patients hospitalized with a COPD exacerbation complicated by hypercapnia (PaCO₂ >50 mmHg at admission), the in-hospital, 60-day, 90-day, one-year, and two-year mortality rates were 11, 20, 33, 43, and 49 percent, respectively [48]. Patient characteristics associated with death at six months included:

●Chronic health status

●Nutritional status

●Coexisting cardiac disease

●Severity of the acute illness (determined by the Acute Physiologic And Chronic Health Evaluation [APACHE] score and the PaO₂/FiO₂ ratio)

Interestingly, the presence of heart failure or cor pulmonale was associated with a longer survival time after adjustment for other variables. This may be the result of the relatively good response of these disorders to acute therapy.

Subsequent studies have identified additional factors associated with poor outcome after hospitalization for COPD exacerbation. Decreased levels of serum albumin [46], low BMI [46], advanced pulmonary disease [52], and nonrespiratory organ dysfunction [52] are predictive of long-term mortality. In contrast, advanced age [52], prolonged hospital length of stay before ICU admission [52], severe respiratory dysfunction [52,53], and severe nonrespiratory organ dysfunction are associated with in-hospital mortality [52,53].

Hypercapnia — Hypercapnia induced by an acute exacerbation of COPD does not predict increased mortality compared to eucapnia. In a five-year observational study of 85 patients admitted to the hospital with a COPD exacerbation, survival was similar among eucapnic patients (33 percent) and acutely hypercapnic patients (28 percent) [49]. In contrast, patients with chronic hypercapnia had a decreased five-year survival (11 percent) (figure 1). All three groups had similar levels of pulmonary function, as measured by FEV₁ and FVC. Only 24 percent of the patients who became hypercapnic during the acute illness subsequently developed chronic hypercapnia.

Acute respiratory failure — Acute respiratory failure due to a COPD exacerbation does not appear to be associated with diminished long-term survival [50,52]. In an observational study of 36 patients with acute respiratory failure due to an acute exacerbation of COPD, two-year survival was 72 percent [50]. Compared with controls with similar baseline pulmonary function, there was no difference in two-year mortality.

A common clinical question is whether recurrent episodes of acute respiratory failure and mechanical ventilation affect the prognosis of COPD. Unfortunately, few data exist to answer this question.

A retrospective cohort study of 74 patients with severe COPD (mean FEV₁ 0.74 L) complicated by acute respiratory failure and ICU admission found an in-hospital mortality of 20 percent [53]. In this population, the cumulative mortality at one, two, and three years was 48, 58, and 64 percent, respectively. The degree of hypercarbia and higher APACHE II scores were correlated with in-hospital mortality; however, clinical factors independently associated with long-term survival could not be identified.

COVID-19 infection — COPD increases the morbidity and mortality associated with coronavirus disease 2019 (COVID-19; caused by severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) [54-56]. Vaccination for either influenza or SARS-CoV-2 is associated with a decreased risk of death for patients with COPD [54,57]. Vaccination for patients with COPD is discussed separately. (See "Stable COPD: Overview of management", section on 'Advice related to COVID-19' and "Stable COPD: Overview of management", section on 'Vaccination' and "COVID-19: Vaccines".)

C-reactive protein — C-reactive protein (CRP) is an acute phase reactant that is a sensitive, but not specific predictor of inflammation. An elevated CRP has been associated with increased morbidity and mortality and declining pulmonary function in some studies of patients with COPD [10,58], but not others [59,60]. (See "Acute phase reactants", section on 'C-reactive protein'.)

In the European Prospective Investigation Into Cancer (EPIC)-Norfolk study, high-sensitivity CRP levels and spirometry were assessed in 18,110 participants at baseline, 4 years (spirometry only), and 13 years [58]. An elevated baseline CRP was associated with lower baseline FEV₁ and FVC. In addition, an increase in CRP over time correlated with a slightly greater rate of decline in FEV₁ and FVC multivariate analysis. However, the baseline CRP level was not predictive of the annual rate of change in FEV₁ or FVC.

COMORBID DISEASES — COPD has been linked to a number of comorbid conditions [1], such as lung cancer, cardiovascular diseases [61-66], sleep-related breathing disorders, diabetes mellitus [67,68], kidney insufficiency [69], osteoporosis [70-73], gastroesophageal reflux disease, psychiatric illness (eg, depression and anxiety) [74-82], and cognitive dysfunction [83-86]. Proactive identification and treatment of comorbidities can potentially improve outcomes [87].

Lung cancer — COPD is an independent risk factor for lung cancer, and increases the risk of lung cancer by 6 to 13-fold relative to individuals without COPD [88]. Lung cancer and COPD occur as comorbid diseases at a higher rate than would be expected if they were independently triggered [89]. The association of emphysema with lung cancer is stronger than the association of airflow limitation and lung cancer, although both contribute to increased risk [1,90]. (See "Cigarette smoking and other possible risk factors for lung cancer".)

Lung cancer is the main cause of death among patients with COPD [1]. The most important intervention to reduce death from lung cancer is smoking cessation. (See "Overview of smoking cessation management in adults" and "Benefits and consequences of smoking cessation".)

The role of low-dose computed tomography (LDCT) in screening for lung cancer is described separately. (See "Screening for lung cancer".)

Cardiovascular disease — Cardiovascular diseases, such as coronary heart disease, heart failure, arrhythmias, peripheral vascular disease, and hypertension, are all increased in patients with COPD [1,67].

●Coronary heart disease – Major cardiovascular risk factors are often poorly monitored and undertreated in patients with COPD [91]. Patients with COPD have a two to five times higher risk of ischemic heart disease than the general population [92], so a high level of clinical suspicion is appropriate to avoid overlooking this common comorbid condition.

For ambulatory patients with COPD and symptoms that could be attributable to myocardial ischemia, we typically perform a baseline electrocardiogram and dobutamine stress imaging, as exercise limitations may preclude exercise stress testing, and potential bronchoconstriction is often a contraindication to vasodilator radionuclide myocardial perfusion imaging. (See "Management of the patient with COPD and cardiovascular disease", section on 'Myocardial ischemia'.)

For patients presenting to the hospital with a COPD exacerbation, screening measures generally include obtaining an electrocardiogram and measuring serum troponin [87].

●Heart failure – Patients with COPD are at risk for both heart failure with preserved ejection fraction (HFpEF) and with reduced ejection fraction (HFrEF) [1].Heart failure is an independent predictor of all-cause mortality in patients with COPD [1], with HFrEF demonstrating higher risk compared with HFpEF [93].

Heart failure can go unrecognized in stable ambulatory patients with COPD and can mimic or present concomitantly with COPD exacerbations [94]. Helpful tests in evaluating patients with suspected heart failure include N-terminal pro-brain natriuretic peptide (NT pro-BNP) measurement and echocardiography [95,96]. (See "Management of the patient with COPD and cardiovascular disease", section on 'Heart failure'.)

●Arrhythmias – Arrhythmias, particularly atrial fibrillation, are common in COPD [1]. The risk of atrial fibrillation increases as the forced expiratory volume in one second (FEV₁) decreases. The occurrence of atrial and ventricular arrhythmias and their management in COPD are discussed separately. (See "Arrhythmias in COPD".)

●Peripheral artery disease – Peripheral artery disease (PAD) is more prevalent in patients with COPD compared with non-COPD controls (9 percent versus 2 percent) [1,97]. Comorbid PAD can further impair exercise tolerance. (See "Clinical features and diagnosis of lower extremity peripheral artery disease".)

Focused questions about lower extremity discomfort that might be indicative of PAD and assessment of pedal pulses can help identify PAD. Concerning features should be further evaluated with measurement of ankle-brachial index (ABI). (See "Clinical features and diagnosis of lower extremity peripheral artery disease".)

●Hypertension – Hypertension is a common comorbidity of COPD and can contribute to development of diastolic ventricular dysfunction and coronary heart disease [1,98]. Hypertension, when present, should be treated according to the usual guidelines with a goal of optimal blood pressure control [1]. Furthermore, COPD does not need to be treated differently in patients with hypertension. (See "Overview of hypertension in adults".)

Sleep-disordered breathing disorders — Sleep-related breathing disorders (SRBD), including sleep-related hypoxemia, obstructive sleep apnea, central sleep apnea, respiratory effort-related arousals (RERAs), and sleep-related hypoventilation, are present in approximately 40 percent of patients with COPD [99]. Moderate-to-severe obstructive sleep apnea (OSA) is present in 10 to 30 percent of patients with COPD, similar to the prevalence in the general population. However, the combination of OSA and COPD leads to a worse prognosis compared with either COPD or OSA alone [1].

As SRBD is often unreported by patients with COPD, it is prudent to obtain a specific sleep history (table 2). The evaluation and management of SRBD in COPD are discussed separately. (See "Sleep-related breathing disorders in COPD".)

Metabolic syndrome and diabetes mellitus — Metabolic syndrome is estimated to be present in 30 percent of patients with COPD [100]. The prevalence of diabetes is greater among patients with COPD than in a non-COPD control population (OR 1.22, 95% CI 1.07-1.38) based on a systematic review [101]; a separate review reported similar results [92].

Comorbid diabetes is associated with a higher risk of hospitalization and mortality [102]. For patients with COPD and diabetes who are active cigarette smokers, smoking cessation is essential to improving long-term outcomes. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Smoking cessation'.)

The initial evaluation and diagnosis of metabolic syndrome and diabetes mellitus are discussed separately. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)" and "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults".)

Osteoporosis — Osteopenia, osteoporosis, and osteoporotic fractures (especially vertebral) are common in COPD patients [1].

●A systematic review and meta-analysis that included 58 studies (8753 participants with COPD) found a prevalence of osteoporosis of 38 percent (95% CI 34-43) [73]. Risk factors for osteoporosis were body mass index (BMI) <18.5 kg/m² (OR 4.26) and sarcopenia (OR 3.65), while a lower FEV₁ was not.

●In a separate study of vertebral bone mineral density (vBMD) in 3321 current and ex-smokers, low vBMD was noted in 58 percent overall and in 84 percent of participants with very severe COPD [72]. Vertebral fractures were present in 37 percent and were associated with lower vBMD.

Smoking, reduced physical activity, low body weight, and low vitamin D can all contribute to development of osteoporosis. Identifying low bone mineral density and initiating treatment can help prevent fractures. Guidelines for screening for osteoporosis are reviewed separately. (See "Screening for osteoporosis in postmenopausal women and men".)

Use of oral glucocorticoids (and possibly inhaled high-dose glucocorticoids) can increase the risk of osteoporotic fracture. Steps to reduce glucocorticoid-induced bone loss are discussed separately. (See "Major adverse effects of systemic glucocorticoids", section on 'Bone and muscle effects' and "Major side effects of inhaled glucocorticoids", section on 'Osteoporosis and fracture risk in adults' and "Prevention and treatment of glucocorticoid-induced osteoporosis".)

Renal insufficiency — A potential association between COPD and renal insufficiency is suggested by observational data [69,103]. In a series of 356 older adults (mean age 75.4 years) with COPD, renal insufficiency (glomerular filtration rate [GFR] <60 mL/min/1.73 m²) was detected in 43 percent, compared with 23 percent of older adults without COPD [69]. In addition, approximately half of the patients with COPD and a reduced GFR had a normal serum creatinine. This latter group of patients with "covert" renal insufficiency was more likely to have a low serum albumin and low muscle mass.

Gastroesophageal reflux disease — Estimates of the prevalence of gastroesophageal reflux disease (GERD) in patients with COPD vary widely (19 to 78 percent), but are generally higher than estimates of GERD in otherwise healthy control patients (18 percent) [104,105]. GERD may contribute to COPD exacerbations, although the mechanism is unclear [1,106]. Lacking data to suggest otherwise, recommendations for the diagnosis and treatment of GERD follow those for the general population. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults" and "Medical management of gastroesophageal reflux disease in adults".)

Depression and anxiety — Patients with COPD have a higher risk of depression and anxiety than smokers without COPD or nonsmokers [1,79,107]. A three-year observational study, the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, examined the prevalence of depression among 2118 subjects with COPD, 335 smokers without COPD, and 243 nonsmokers [79]. Depression was more prevalent among subjects with COPD (26 percent), than smokers without COPD (12 percent) or nonsmokers (7 percent) and was associated with worse health and functional status.

Additional studies are needed to determine the optimal methods for the diagnosis [80,81] and treatment of depression in patients with COPD. Comprehensive pulmonary rehabilitation programs appear helpful in reducing depression and anxiety [108]. Pulmonary rehabilitation and the diagnosis and management of depression and anxiety are reviewed separately. (See "Pulmonary rehabilitation", section on 'Psychological support' and "Screening for depression in adults" and "Unipolar major depression in adults: Choosing initial treatment" and "Unipolar depression in adults: Supportive psychotherapy" and "Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis" and "Generalized anxiety disorder in adults: Management".)

Cognition impairment — Several studies have reported cognitive dysfunction in patients with COPD, predominantly in severe COPD [83,109-111]. In a survey of 4150 older adults, the adjusted mean cognition scores of those with severe COPD were significantly lower than those with nonsevere or absent COPD [83]. (See "Mild cognitive impairment: Epidemiology, pathology, and clinical assessment".)

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SUMMARY AND RECOMMENDATIONS

●The natural history and prognosis of COPD are variable and factors influencing this variability are incompletely understood. (See 'Introduction' above.)

●Factors, such as genetic predisposition, severity of disease, environmental exposures, comorbidities, and, to a lesser degree, acute exacerbations appear to influence prognosis. (See 'Prognostic factors' above.)

●Short-term (ie, in-hospital) survival for patients with COPD and respiratory failure is determined by the overall severity of acute illness, rather than the degree of respiratory failure. In comparison, long-term survival is primarily influenced by the severity of COPD and the presence of comorbid conditions. (See 'Acute exacerbations' above and 'Acute respiratory failure' above.)

●COPD is associated with a number of comorbid conditions, such as lung cancer, cardiovascular diseases, sleep-disordered breathing, diabetes mellitus, renal insufficiency, osteoporosis, psychiatric illness (eg, depression and anxiety), and cognitive dysfunction. (See 'Comorbid diseases' above.)

•Lung cancer is the main cause of death among patients with COPD. To reduce mortality from lung cancer, all patients with COPD should be strongly encouraged to stop smoking and patients who meet criteria for screening should be offered the choice of low-dose computed tomography (LDCT). (See 'Lung cancer' above.)

•Cardiovascular diseases, such as coronary heart disease, heart failure, peripheral artery disease, and hypertension, are common comorbidities of COPD. A high index of suspicion and appropriate testing should be employed to avoid overlooking opportunities for directed treatment. (See 'Cardiovascular disease' above.)

•Sleep-related breathing disorders (SRBD) are common in COPD and can contribute to poor quality of life and increased morbidity and mortality. As SRBD may be unreported by patients, a specific sleep history should be obtained (table 2) and followed by a formal sleep evaluation as indicated. (See 'Sleep-disordered breathing disorders' above.)

•Metabolic syndrome, diabetes mellitus, and renal insufficiency are increased among patients with COPD. (See 'Metabolic syndrome and diabetes mellitus' above and 'Renal insufficiency' above.)

•Patients with COPD have a higher risk of depression and anxiety than smokers without COPD or nonsmokers. Pulmonary rehabilitation can help reduce depression and anxiety. (See 'Depression and anxiety' above.)