Management of Stable Chronic Obstructive Pulmonary Disease
Case 2
A 70-year-old male with severe COPD on oxygen therapy and obstructive sleep apnea treated on nocturnal CPAP was seen in the pulmonary clinic for evaluation of his dyspnea. He was symptomatic with minimal activity and had chronic cough with some sputum production. He had been hospitalized 3 times over the past 12 months and had been to the emergency department (ED) the same number of times for dyspnea. Pertinent medications included as-needed albuterol inhaler, inhaled steroids, and tiotropium 18 mcg inhaled daily. He demonstrated good inhaler technique. On examination, his vital signs were pulse 99 bpm, SpO2 94% on 2L/min oxygen by nasal cannula, blood pressure 126/72 mm Hg, respiratory rate 15, and BMI 35 kg/m2. He appeared chronically ill but in no acute distress. No wheezing or rales were heard. He had no lower extremity edema. The remainder of the exam was within normal limits. His last pulmonary function test demonstrated moderate obstruction with significant bronchodilator response to 2 puffs of albuterol. The side effects of chronic steroid therapy were impressed upon the patient and 500 mg of roflumilast was started daily. Over the course of the next 3 months, he had no further exacerbations. Roflumilast was continued. He has not required any further hospitalizations, ED visits, or oral steroid use since the last clinic visit.
What is the significance of acute exacerbations of COPD?
Acute exacerbation of COPD (AECOPD) is a frequently observed complication for many patients with COPD [61,62]. AECOPD is associated with accelerated disease progression, augmented decline in health status and quality of life, and increased mortality [63]. Exacerbations account for most of the costs associated with COPD. Estimates suggest that the aggregate costs associated with the treatment of AECOPDs are between $3.2 and $3.8 billion, and that annual health care costs are 10-fold greater for patients with COPD associated with acute exacerbations than for patients with COPD but without exacerbations [64]. Hence, any intervention that could potentially minimize or prevent this complication will have far-reaching benefits to patients with COPD as well as provide significant cost saving.
How is acute exacerbation of COPD defined?
COPD exacerbation is defined as a baseline change of the patient’s dyspnea, cough, and/or sputum that is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD [65]. Exacerbation in clinical trials has been defined on the basis of whether an increase in the level of care beyond regular care is required primarily in the hospital or ED [66]. Frequent exacerbations are defined as 3 symptom-defined exacerbations per year or 2 per year if defined by the need for therapy with corticosteroids, antibiotics, or both [67].
What is the underlying pathophysiology?
AECOPD is associated with enhanced upper and lower airway and systemic inflammation. The bronchial mucosa of stable COPD patients have increased numbers of CD8+ lymphocytes and macrophages. In mild AECOPD, eosinophils are increased in the bronchial mucosa and modest elevation of neutrophils, T lymphocytes (CD3), and TNF alpha positive cells has also been reported [62]. With more severe AECOPD, airway neutrophils are increased. Oxidative stress is a key factor in the development of airway inflammation in COPD [61]. Patients with severe exacerbations have augmented large airway interleukin-8 (IL-8) levels and increased oxidative stress as demonstrated by markers such as hydrogen peroxide and 8-isoprostane [66].
How do acute exacerbations affect the course of the disease?
In general, as the severity of the underlying COPD increases, exacerbations become both more severe and more frequent. The quality of life of patients with frequent exacerbations is worse than patients with a history of less frequent exacerbations [68]. Frequent exacerbations have also been linked to a decline in lung function, with studies suggesting that there might be a decline of 7 mL in FEV1 per lower respiratory tract infection per year [59,69] and approxi-mately 8 mL per year in patients with frequent exacerbations as compared to those with sporadic exacerbations [70].
What are the triggers for COPD exacerbation?
Respiratory infections are estimated to trigger approximately two-thirds of exacerbations [62]. Viral and bacterial infections cause most exacerbations. The effect of the infective triggers is to increase inflammation, cause bronchoconstriction, edema, and mucus production, with a resultant increase in dynamic hyperinflation [71]. Thus, any intervention that reduces inflammation in COPD reduces the number and severity of exacerbations, whereas bronchodilators have an impact on exacerbation by their effects on reducing dynamic hyperinflation. The triggers for the one-third of exacerbations not triggered by infection are postulated to be related to other medical conditions, including pulmonary embolism, aspiration, heart failure, and myocardial ischemia [66].
What are the pharmacologic options available for prevention of AECOPD?
In recognition of the importance of preventing COPD exacerbations, the American College of Chest Physicians and Canadian Thoracic Society [65] have published an evidence-informed clinical guideline specifically examining the prevention of AECOPD, with the goal of assisting clinicians in providing optimal management for COPD patients. The following pharmacologic agents have been recognized as being effective at reducing the frequency of acute exacerbations without any impact on the severity of COPD itself.
Roflumilast
Phosphodiesterase 4 (PDE4) inhibition appears to have inflammatory modulating properties in the airways, although the exact mechanism of action is unclear. Some have proposed that it reduces inflammation by inhibiting the breakdown of intracellular cyclic adenosine monophosphate [72]. In 2 large clinical trials [73,74], daily use of a PDE4 inhibitor (roflumilast) showed a significant (15%–18%) reduction in yearly AECOPD incidence (approximate number needed to treat: 4). This benefit was seen in patients with GOLD stage 3–4 disease (FEV1 < 50% predicted) with the chronic bronchitic phenotype and who had experienced at least 1 exacerbation in the previous year.
Importantly, these clinical trials specifically prohibited the use of ICS and LAMAs. Thus, it remains unclear if PDE4 inhibition should be used as an add-on to ICS/LAMA therapy in patients who continue to have frequent AECOPD or whether PDE4 inhibition could be used instead of these standard therapies in patients with well-controlled daily symptoms without ICS or LAMA therapy but who experience frequent exacerbations.
Of note, earlier trials with roflumilast included patients with ICS and LAMA use [73,75]. These trials were focused on FEV1 improvement and found no benefit. It was only in post ad hoc analyses that a reduction in AECOPD in patients with frequent exacerbations was found among those taking roflumilast, regardless of ICS or LAMA use [76]. While roflumilast has documented benefit in improving lung function and reducing the rate of exacerbations, it has not been reported to decrease hospitalizations [64]. This indicates that although the drug reduces the total number of exacerbations, it may not be as useful in preventing episodes of severe exacerbations of COPD.
