The Need for an Integrated and Holistic Care Approach for Patients with COPD and Comorbidities

COPD is a leading and increasingly prevalent cause of morbidity and mortality, and is projected to become the third most common cause of worldwide death by 2030. People with COPD often present with comorbidities that need to be considered in the severity scale of their COPD diagnosis. Furthermore, treatment approaches need to take comorbidities into consideration and aim for holistic and multidisciplinary therapy. This blog post will take a look at the issue of managing comorbidities in COPD.

What are comorbidities?

Most people with COPD have additional chronic illnesses. Also known as comorbidities, these issues often significantly impact health-related quality of life (QOL) in the early stages of COPD as well as on mortality in the late stages of disease. They significantly increase the burden of COPD management with regards to health-care costs and cause therapeutic dilemmas for health-care providers. Most commonly, COPD is associated with the following:

Various Cancers (Most Commonly Lung Cancer)
Asthma
Obstructive Sleep Apnea (OSA)
Hypertension
Cardiovascular Disease
Diabetes
Metabolic Syndrome
Dysfunctional Skeletal Myopathies
Osteoporosis
Mental Disorders

The lack of information on how to effectively treat COPD and associated diseases is due to the common exclusion of COPD patients with multiple chronic diseases from clinical trials.

Now let’s take a more detailed look at the most common and most important comorbidities that present in COPD patients.

PULMONARY COMORBIDITIES

Asthma

Airflow limitations and abnormal inflammatory responses are present in both COPD and asthma. Although the symptoms differ in patients with either disease, some patients have symptoms of both, leading to the definition of COPD/asthma overlap syndrome (ACOS). ACOS can be very hard to distinguish from either COPD or asthma alone, but recent new guidelines provide a stepwise approach for differential diagnosis of COPD, asthma and ACOS (http://www.ginasthma.org/local/uploads/files/ACOS_2015.pdf). ACOS is especially common in elderly patients, and causes more frequent and severe exacerbations and a reduced QOL when compared to patients with COPD only. Clear treatment guidelines for combination therapy are lacking to date, however standard treatment approaches include the use of anti-inflammatory drugs.

Lung Cancer

COPD patients have a four-fold increased risk of developing lung cancer when compared to the general population, and about 50% of all lung cancer patients have moderate to severe COPD. COPD might prevent lung cancer patients from qualifying for surgery due to impaired lung function. This results in a worse prognosis for patients who have both, and leads to reduced survival rates. Lung cancer is, together with cardiovascular diseases, the most common cause of death in COPD patients with mild-to-moderate disease.

Pulmonary fibrosis

Patients with pulmonary fibrosis and COPD have characteristic lung function tests, with normal spirometry values but severely reduced gas exchange. Those patients are at higher risk of developing pulmonary hypertension, and have worse a prognosis than patients with either pulmonary fibrosis or COPD alone.

CARDIOVASCULAR COMORBIDITIES

Hypertension

Hypertension – or high blood pressure – is more common in patients with COPD, and leads to more severe dyspnea and airway obstruction as well as to reduced exercise capacity. The prevalence of hypertension in COPD patients has been estimated between 18% and 52%.

Congestive heart failure

The co-presence of COPD and congestive heart failure (CHF) is common, as the underlying causes are connected. While the prevalence of CHF ranges from 3.2% to 16% in people with stable COPD, it reaches up to 48% in patients with exacerbations. CHF is associated with worse prognoses and is one of the most common causes of death among COPD patients, while COPD in turn is considered an independent risk factor in people with CHF. In addition, coexistence of these diseases can impact both left and right ventricular function, the latter of which often goes unnoticed.

Coronary heart disease

The prevalence of coronary heart disease has been estimated to lie around 30% or higher. Strikingly, some evidence shows that coronary heart disease has not been diagnosed or has been misdiagnosed in up to 70% of the cases. This is clinically meaningful as coronary heart disease leads to worse prognoses and requires specific management. Reasons for the low rate of diagnosis might include the underlying systemic inflammation, which is common to both diseases.

Atrial fibrillation

The prevalence of atrial fibrillation and nonsustained ventricular tachycardia reaches up to 23.3% and 13% of COPD patients, respectively, while 18% of patients with atrial fibrillation have COPD. The presence of COPD increases hospitalization mortality rate in patients with arrhythmia from 8% in patients without COPD to 31%.

Pulmonary artery hypertension and subsequent right heart failure

Pulmonary artery hypertension (PHT) occurs in up to 40% of COPD patients, and is caused by the remodelling of the arteries in the lungs due to the COPD-mediated destructive events. PHT leads to more severe dyspnea, exercise limitation, greater desaturation during exercise, and higher mortality. PHT is often associated with right ventricular dysfunction and heart failure, which might go undiagnosed.

Venous thromboembolism

The prevalence of venous thromboembolism lies around 29% during an exacerbation. Other comorbidities of COPD, such as hypertension, coronary artery disease or cancer further increase the risk of venous thromboembolism. The presence of venous thromboembolism increases hospitalization by 4.4 days on average and one-year mortality by 30%. If left untreated, the presence of venous thromboembolism during exacerbations increases the risk of death by 25%. Underlying reasons for the frequent coexistence of venous thromboembolism and COPD include common pathophysiology such as systemic inflammation, and endothelial and pulmonary dysfunction.

Stroke

COPD patients are at higher risk of smoking due to common associated risk factors such as smoking and age, as well as due to COPD-mediated systemic inflammation and coagulopathy. There is a linear correlation between the degree of airflow obstruction and stroke risk. Around 8% of COPD patients have a history of stroke, while stroke causes death in about 4% of COPD patients.

METABOLIC COMORBIDITIES

Diabetes and metabolic syndrome

The prevalence of diabetes and metabolic syndrome in COPD patients lie around 18.7% and 22.5%, respectively. COPD patients are at increased risk of developing diabetes, and vice versa. The high rate of co-development is based on common risk factors such as smoking, but also by interacting factors in the common underlying systemic inflammation. Diabetes worsens prognosis in COPD patients by reducing exercise capacity, increasing hospitalization risk and risk of mortality during exacerbation. It also worsens the 5-year mortality rate in COPD patients.

Osteoporosis

The prevalence of osteoporosis reaches up to 69% in COPD patients, caused by common risk factors such as age and smoking, but also due to COPD-mediated effects from systemic inflammation and reduced exercise capacity. Osteoporosis-caused vertebral fractures in turn can impair lung mechanisms and accelerate lung function decline. Patients with COPD and osteoporosis have further reduced exercise capacity, more severe dyspnea and more severe airway obstruction.

Cachexia and myopathy

Loss of fat-free mass (cachexia) and skeletal muscle dysfunction (myopathy) occur in up to 50% and 32% of COPD patients, respectively, including the obese. The presence of COPD supports their development due to systemic inflammation, physical inactivity and oxidative stress. Skeletal muscle weakness in turn leads to reduced exercise capacity, activity and strength, and is associated with reduced QOL, and increased risk of hospitalization, exacerbations, health care utilization, and death. The development of skeletal weakness early in during the disease might indicate a more aggressive form of COPD.

MENTAL COMORBIDITIES

Anxiety and depression

Anxiety affects up to 19% of COPD patients and is associated with worse perception of dyspnea, and higher rates of mortality and readmission after exacerbations. Anxiety represents one of the most deadly comorbidities, especially among female COPD patients.
Depression has been reported by up to 60% of COPD patients, and is associated with reduced activity, QOL, and adherence to treatment, as well as with increased risk of exacerbations and mortality. Coexisting depression is not diagnosed or misdiagnosed in about 15% of cases, and remains untreated in about two third of cases. This can also contribute to unaddressed anxiety symptoms.

OTHER COMORBIDITIES

Obstructive sleep apnea syndrome

In contrast to earlier findings, the Sleep and Heart Study has found that the prevalence of obstructive sleep apnea syndrome (OSA) is no higher in COPD patients than in the general population. However, given the high prevalence of both diseases in the population, OSA affects around 14% of COPD patients. The presence of OSA leads to increased risk of exacerbations and death, and to the development of cardiovascular diseases including right heart failure and PHT.

Gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) is common in asthma, but also affects up to 60% of COPD patients. It is associated with decreased QOL and increased risk of exacerbations.

Chronic renal failure

Renal insufficiency affects about 22% of COPD patients, and they have a twofold higher risk of acute renal failure and a threefold higher risk of chronic renal failure than age-matched people. Especially in elderly COPD patients, around 25% of chronic renal failure cases might remain undiagnosed. Renal complications especially affect COPD patients with hypoxemia and hypercapnea, and are caused by increased rigidity of the arteries and endothelial dysfunction in COPD patients. Renal dysfunction in turn correlates with increased airway obstruction and inflammation.

Now that we know all about the most common and most important comorbidities in COPD patients, let’s take a look at the links between COPD and comorbidities in order to better understand how these comorbidities affect initial diagnosis and overall treatment.

LINKS BETWEEN COPD AND COMORBIDITIES

Recent advances in our understanding of the mechanisms causing COPD enable us to identify those comorbidities that have a cause-and-effect relationship with COPD (COPD dependent comorbidities) and those that don’t (independent). The current hypothesis suggests that the systemic inflammation associated with COPD contributes to the development of dependent diseases, such as cancer, cardiovascular diseases and even diabetes, via misregulation of involved of inflammatory mediators such as interferons, interleukins, C-reactive protein, fibrinogen, amyloid protein, etc. These could enter the peripheral system via distant airways and effect other internal organs.
Downstream effects of systemic inflammation might also occur in the opposite direction. Inflammatory mediators produced in other organs due to chronic heart failure or coronary artery disease may contribute to the development of COPD.
Another underappreciated contribution to the development of comorbidities might stem from COPD medication itself. Evidence suggests that bronchodilators can cause arrhythmias and tremors, and inhaled anticholinergics might affect cardiovascular function. Systemic corticosteroids, which are often overprescribed in COPD patients, could contribute to hypertension, renal insufficiency, diabetes, osteoporosis and muscle dysfunction. Cause and effect might be blurred however, as heart, liver and kidney comorbidities might change the pharmacokinetics of medication and lead to less favorable side effects.

BURDEN ON HEALTH CARE COST

As the prevalence of COPD is increasing in developed countries, associated healthcare costs are expected to rise. In the US, direct costs for COPD have increased dramatically from $18billion in 2002 to $29.5billion in 2010, while total costs could amount to twice the amount. Average lifetime earning losses due to early retirement have been estimated around $316,000 per person per year. The total annual costs of COPD in Europe are €38.7billion.
The total costs of COPD are directly correlated with comorbidities, as these increase hospitalization rates and costs. Exacerbations are the leading cause for hospitalizations, and account for 40-70% of total costs. Despite higher hospitalization costs, COPD patients with comorbidities also use about 50% more cardiovascular agents, and twice as many analgesics, antibiotics, and psychotherapeutic medications.
On average, healthcare costs of a COPD patient with comorbidities is 4.7% higher than of a COPD patient without comorbidities. Compared with non-COPD patients, COPD patients consume 3.4 times more healthcare resources.

MULTIMORBIDITIES AND OUTCOMES

Comorbidities are highly prevalent in COPD patients, as studies show that 94% of COPD patients have one comorbidity, and 46% have three or more. In mild to moderate COPD patients, lung cancer and cardiovascular disease are the most common causes of death, while respiratory failure is predominant in severe COPD.
Different indices are available to assess the presence of comorbidities and their prognostic value, such as the COTE index (a COPD-specific comorbidity test) and the COMCOLD index (Comorbidities in chronic obstructive lung disease). These indices are useful to identify high risk patients and for patient-tailored treatment approaches.

TREATMENT AND MANAGEMENT

Treatment should be in accordance with guideline recommendations, with special awareness of important novel findings and guideline changes for comorbidities.
While long acting ß2-agonists, oral corticosteroid and theophylline can be detrimental to patients with cardiovascular problems, tiotropium might have a protective effect. Close monitoring and patient-tailored treatment strategies are important.

Treatment of ACOS can include bifunctional drugs, and inhaled corticosteroids, but not long-acting bronchodilators, for those with primarily asthma symptoms, and bronchodilators, but not inhaled corticosteroids, for those with COPD symptoms. These recommendations highlight the complexity of treatment regimes and the importance of correct diagnosis.
Cardiovascular treatment of COPD patients is often suboptimal, despite guideline recommendations supporting the use of beta-blockers, statins and angiotensin-converting-enzyme (ACE).

Treatment of OSA in COPD patients resembles that in other OSA patients, emphasizing the need for oxygenation, weight loss and CPAP.

Non-pharmacological treatment options include smoking cessation, influenza and pneumococcal vaccinations and pulmonary rehabilitation. Pulmonary rehabilitation might have the benefit to act on comorbidities as well, eg by increasing exercise, self-management, behavioral change and psychological support.

In summation, there is a need for an integrated and holistic care approach for patients with COPD and comorbidities, which is currently lacking from guidelines. Such an approach would be incredibly helpful to the prognoses and treatment of patients.

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References

Hillas G., et al. Managing comorbidities in COPD. Int J Chron Obstruct Pulmon Dis. 2015; 10: 95–109.

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