COPD Therapeutics: Picking the Low-Hanging Fruit

In considering advances in therapies to improve the lives of patients with COPD, we can distinguish between those that show potential for enabling innovations that can be introduced within the next few years and those for which the promise is more distant. Both, of course, should be pursued. But our patients are justifiably impatient! We need to consider how best to satisfy their needs. Which approaches are likely to yield short-term progress; where is the low-hanging fruit?

Two papers in this issue advance our understanding in two important areas of COPD therapeutics. Yanbaeva et al., from the incredibly productive group in Maastricht, explore the possibility that predisposition for the inflammatory response seen in COPD may be genetically programmed [[1]]. Swisher et al. investigate, in an animal model, the link between emphysemic lung injury and dysfunction of the muscles of ambulation [[2]].

Both of these studies contribute to lines of research that promise therapeutic advances. We are at least 5 years into the era in which an essential component of the definition of COPD is that it is disease of inflammation. But it may be argued that, in most patients, the inflammation is low grade, smoldering rather than burning with a bright flame as it does in some other diseases (e.g., rheumatoid arthritis, ulcerative colitis). While this inflammation may well have played a role in disease progression, therapies quelling inflammation may require years to yield discernable benefits. In contrast, peripheral muscle dysfunction is not part of the COPD definition, but it is seen commonly enough that it is an important contributor to exercise intolerance. Importantly, it has been demonstrated that muscle dysfunction is largely reversible [[3]], making it a good target for yielding short-term benefits.

What follows is a somewhat speculative list of research foci that might help ease the burden of those currently suffering with COPD.

1. Promoting combination long-acting bronchodilator therapy. Studies promoted by the pharmaceutical industry tend to contrast the benefits of one agent with another. A slew of studies now tell us that both long-acting beta agonists and long-acting anticholinergics benefit most COPD patients. But, except for those with very mild disease, a single agent does not bring lung function to anywhere near normal. Recent research [[4]] suggests that, when given chronically, combining the two classes of agents yields increases in FEV₁ larger than ever previously seen. This insight needs to be explored further and the message promoted that combination therapy of long-acting agents should be generally prescribed. Futher, the possibility that other agents with different mechanisms (e.g., theophylline, phosphodiesterase-4 inhibitors) may usefully add to the bronchodilation obtained with beta-agonists and anticholinergics should not be discounted.

2. Expanding availability of pulmonary rehabilitation. Substantial evidence exists that pulmonary rehabilitation improves exercise tolerance and improves quality of life of COPD patients better than any other intervention currently available [[3]]. Exercise training is the key component and, for more than a decade, strategies to improve the effectiveness of rehabilitation have been put forward. Yet rehabilitation remains available to only a small fraction of the patients who would benefit. A national coverage policy establishing reimbursement for pulmonary rehabilitation as an essential component of COPD management would be of great help. Primary care practitioners, who care for so many COPD patients, should be educated regarding the benefits of a referral for rehabilitation.

3. Optimizing anti-exacerbation therapy. When patients get ill, especially when they require hospitalization, it takes a high personal toll. Moreover, COPD hospitalizations account for a substantial fraction of the health care costs associated with the disease [[5]]. It stands to reason that there should be preventative measures that reduce the chance of COPD exacerbation. Indeed, in recent years, long-term clinical trials have appeared that show that the frequency of exacerbations can be reduced; published studies on inhaled steroids, long-acting beta agonists, long-acting anticholinergics, pulmonary rehabilitation and N-acetylcysteine are available [[3], [6], [7]] (though N-acetylcysteine only reduced exacerbations in those not taking inhaled steroids). Ongoing studies seek to determine whether antibiotics, phosphosdiesterase-4 inhibitors or other anti-inflammatory agents are similarly effective. Surprisingly, a number of the published studies have shown that each of these agents (when contrasted to standard therapy or placebo) reduces exacerbation by (on the order of) 25%. But are these agents additive in their effect on exacerbations? The studies to answer this question will require large patient groups with long periods of observation, but should be done.

4. Defining new uses for supplemental oxygen. Although we have known for 25 years that supplemental oxygen prolongs life in hypoxemic COPD patients and spawned an industry consuming 2.2 billion dollars annually in the United States, we have done remarkably little work to explore other long-term benefits of supplemental oxygen [[5]]. COPD patients who are not clinically hypoxemic nonetheless demonstrate substantial improvements in exercise tolerance when given supplemental oxygen [[8]]. A large-scale National Institutes of Health project is getting underway that seeks to determine if providing long-term supplemental oxygen to patients with only moderate hypoxemia will improve their prognosis.

Clearly, we should be working toward finding the ultimate cure for COPD. Recent work shows how this might be done [[9], [10]]. But we must be honest with our patients; a cure is not in the cards for those currently afflicted with COPD. But there is a lot we can do to make their lives substantially better. Let's get to work!