Cutting Edge COPD: From Epidemiology to Treatment

Current Understanding of Epidemiology and Natural History of COPD: Implications for Practice

One of the most striking aspects of chronic obstructive pulmonary disease (COPD) is that it is very heterogeneous. There are many different presentations, with differing intensities of symptoms and even differing responses to medications. Sorting out what accounts for this phenomenon, and how treatments can be best individualized, is of concern to both basic and clinical scientists.

The clinical outlook on COPD is changing quickly as more is discovered about the natural history of the disease, according to Stephen Rennard, MD, University of Nebraska Medical Center, Omaha. However, much work remains to be done.

Research has shown that an individual’s lung function, as measured by FEV1, grows until he or she reaches young adulthood before beginning to decline about 20 mls a year. The average smoker loses lung function at about twice that rate, but some smokers can lose it even faster.

The natural history of the disease is not yet fully described, however. Do people lose lung function at an accelerated rate throughout life? Is there a sudden drop-off? Do they have remissions and exacerbations that cause them to lose function episodically over the years? Which of these possible histories is most important in the development of COPD is hard to know since all three tend to be superimposed by the time patients present for diagnosis in their 50s and 60s.

What is known is that maximally attained lung function in the young adult is a determinant of COPD risk later. Like bone density in osteoporosis, the higher the lung function, the less risk you have for COPD regardless of smoking history.

Dr. Rennard noted that COPD risk might be seen as early as birth. He cited a ten-year- old study by Barker and colleagues of nearly 6,000 men born in Hertfordshire, England between 1910 and 1930. When followed up in the 1980s, there was no relationship between birth weight and lung cancer. However, there were significant relationships between those born weighing less than 5.5 pounds and likelihood of dying from COPD in later life (Barker JA, et al. J. Appl. Physiol. 1988;65:829-34).

A large percentage of the 1,100 original cohort members still living in the area agreed to visit a doctor for a medical history and spirometry test. As was expected, smoking was the biggest risk factor. However, when the results were stratified by smoking history (never, ex-smoker or current smoker) lung function was significantly related to birth weight in all three groups.

“While we certainly need to think of COPD as a smoker’s disease, it is not only a disease of smokers,” said Dr. Rennard. “I think one of the disservices we do to our community as a whole is our tendency to emphasize smoking to the exclusion of other risk factors.”

Alpha-1 antitrypsin deficiency is the only genetic abnormality that has yet been shown to have an impact on lung function. There are a growing number of genes that have been implicated, but the literature on the subject is inconsistent at best.

He also noted research showing large individual differences in the response to diminished lung function. He referred to the results of a study by Paul Jones that showed a low correlation between FEV1 measurements and results of the St. George’s Respiratory Questionnaire, a measure of health status. This indicates there are many people with low FEV1s who have good health status and many with high FEV1s who are sick (Jones PW, et al. Chest 1995;107:187S-193S).

In many cases, according to Dr. Rennard, the person does not come to see the doctor for dyspnea, but because he is not doing things he used to do. He likes to use as an example the man who sees a physician because he can no longer walk from the golf cart to the tees. When he comes in he thinks he was well five years before, but that is when he gave up walking the golf course. Ten years before that he gave up jogging and ten years before that he stopped playing basketball.

According to Dr. Rennard, dyspnea is only related to FEV1 indirectly and dynamic hyperinflation is probably the major driver of dyspnea in this group. Although it is hard to rigorously measure dynamic hyperinflation, inspiratory capacity has been proposed as a useful surrogate. He pointed to a recent study by Marin and colleagues (Am J Respir Crit Care Med 2001;163:1395-9) that measured inspiratory capacity at rest as well as following a six-minute walk and then related it to dyspnea evaluated by the Borg scale and the Medical Research Council’s dyspnea scale. They found that with increasing inspiratory capacity, participants could walk further.

Not only did they find a relationship between inspiratory capacity and performance, but also between inspiratory capacity and dyspnea experienced by the patients. “People with COPD deal with dyspnea on exertion by not exerting,” said Rennard. “This means that the diagnosis is made very late. If we were more aggressively asking them about changes in lifestyle and activity, I suspect that we would be able to get a much earlier diagnosis in patients with COPD.”

The Latest in COPD Diagnosis

When discussing the diagnosis of COPD there are problems with definition, according to Barry Make, MD, from the University of Colorado School of Medicine in Denver.

“Just about every country in the world has their own definition of (the disease). In thinking about diagnosis, we need to consider three major clinical criteria because we can’t diagnose the disease in most patients in anything other than gross clinical terms without more sophisticated tests.”

The first clinical criteria suggested by Dr. Make is a sufficient exposure to those things known to cause COPD. Although cigarette smoking is the major factor, he stressed that there is a growing list that currently includes air pollution, environmental issues, second-hand smoke and occupational exposures.

The second criterion combines physiologic and clinical features: either abnormal spirometry demonstrating chronic airflow limitation or cough and sputum production. He includes the latter because those symptoms often precede airflow limitations.

“The third is very important,” said Dr. Make. “We need to think about excluding other diagnoses. It is the particular responsibility of pulmonologists to make sure they exclude other diagnoses.”

This diagnostic criterion is one that does not show up consistently in the current guidelines, noted Dr. Make.

Effective use of CT scans where there is a high index of suspicion that this patient may not fit the usual profile is an important thing to remember at all times. For example, CT scans can be helpful in distinguishing COPD from bronchiectasis.

“Most non-pulmonary physicians think they can diagnose this disease based on X-rays, but they usually cannot,” noted Dr. Make. “Because of the use of antibiotics, patients frequently don’t have cough and tremendous quantities of sputum which have historically been the hallmark of bronchiectasis. Sometimes they have just a repeated history of respiratory ‘infections’ that are not well characterized.”

When viewing CT scans, it is often possible to see the caliber of an airway is greater than its accompanying blood vessel. According to Dr. Make, the blood vessel and airway should be the same size. An airway larger than the vessel suggests bronchiectasis.

New CT scanning protocols on the horizon may prove useful not only in diagnosis, but also to discover how much useful lung is left. The CT scan information can be put into a quantitative format that allows computer programs currently being investigated to measure the percentage of lung that is emphysematous. CT scanning may soon be applied to the small airways as well.

Although not ready for “prime time”, Dr. Make thinks that many diagnostic modalities are on the horizon to help not only with case finding, but also possibly to individualize treatments. As of now, there is little information to suggest that identifying the different phenotypes and characteristics in individual patients will lead to alterations in treatments.

“If I come back and give this talk again in 2010, I hope that the top 12 things in COPD diagnosis will include more than spirometry,” said Dr. Make. “By measuring lung function, airway reactivity, exercise symptoms, health status, blood gases, and a quantitative CT, we will be better able to identify how and why one patient is different from another.”

Novel Aspects of Pharmacological Treatment for COPD

There are currently many new treatment options for COPD being explored. Some of them include drugs in clinical trials, others new uses for old standbys.

One older class of medications that may be seeing a resurgence of interest is the macrolide antibiotics. In addition to the bacteriocidal effects, they inhibit neutrophil oxidative bursts and reduce IL-6 and IL-8. There are also indications that they might have an impact on lipopolysaccharide damage and mucous hypersecretion.

Among the newer drugs is tiotropium, a long-acting antimuscarinic agent.

“Tiotropium is very slow to begin working,” said James Donohue, MD, University of North Carolina, Chapel Hill. “What is marvelous with this drug is the trough, the overnight effect.”

In data from Europe there is a very long bronchodilator effect lasting up to 24 hours with some effects seen many days after usage. Another plus is lack of tolerance even in studies lasting up to one-year. Tiotropium seems to have a large impact on forced vital capacity, air trapping and dynamic hyperinflation (Barnes PJ Drugs 2001;10:733-40).

Dr. Donohue has a paper in press comparing tiotropium with salmeterol. Over the course of a six-month trial with 623 patients, the anticholinergics were superior to the long acting bronchodilators. He noted that the results of this study may prove to be controversial since they showed some loss of bronchodilatation effect with salmeterol. (Chest 2002;122:47-55)

Another class of new drugs that could be approved for marketing in the United States during 2002 or early 2003 are the phosphodiesterase-4 (PDE4) inhibitors. Their major clinical effect is on bronchoconstriction, but they also have anti-inflammatory effects on smooth muscles and may affect neutrophils.

One study by Zamel looked at cilomilast. What makes this study different is that it selected out patients whose symptoms could not be reversed by bronchodilators. This gave investigators a chance to look at effects of the medication other than in bronchodilation. Possibly related to less hyperinflation, there was a reduction in lung volume. In this study, cilomilast was superior to placebo (Am J Respir Crit Care Med 2002;165:A226).

In addition, airway biopsy studies from Europe found positive changes in various inflammatory cells that are relevant to COPD (Gamble E. AJCCM 2002;165:A227).

“This class is interesting,” says Dr. Donohue. “If longer studies show the anti-inflammatory effects are preserved over time, this may have disease modification properties.”

Although there is scant data, some interest has been generated by the stereoisomers of medications already in use. For instance, albuterol currently exists in a racemic mixture.

“One tries to separate the good twin from the bad twin,” noted Donohue. “Laboratory models have shown the S-isomer to be harmful. If anything, results of the clinical trials show that it seems more inert.”

By and large, Donohue thinks there is not yet sufficient data to come to any firm conclusions about this class of drug.

Overall, the medications that he sees as most interesting in the near term are lead by tiotropium and cilomilast. The PDE4 inhibitors and the stereoisomers may also help patients with COPD be a little less breathless and perhaps more functional.

Emerging Therapeutic Options

The major changes in the treatment of COPD focus on the use of combination medications. Stanley Fiel, MD, from the Drexel University College of Medicine, Philadelphia believes that there is probably a better chance of good therapeutic outcomes by using combination therapies.

“We learned in medical school that a combination therapy of beta agonists, theophylline and anticholinergic approaches should work, but there weren’t many studies that proved the concept,” said Dr. Fiel. Now the evidence is beginning to be seen in the literature.

A study by Mahler (Chest 1999;115: 957-65) compared the bronchodilation effects of long-acting beta agonists, specifically salmeterol versus ipratropium. Bronchodilation was maintained for 10-12 hours using salmeterol allowing for twice-a-day dosing. Other data from the same study showed a decrease in exacerbations during the 12-week treatment phase. According to Dr. Fiel there appears to be some theoretical proof of concept of cytoprotection as well as the potential for decreases in exacerbations in addition to bronchodilation.

Considerable controversy continues over the uses of inhaled corticosteroids and where they fit in the treatment of COPD. Although the FDA has not approved them for use in this population, many doctors are using them with good results.

“There are four reasonably good studies of close to 2,000 patients looking at different patients with different FEV1,”says Dr. Fiel. “Most, if not all, of the studies show no real significant change in loss of lung function. Some data show a decrease in exacerbations and their severity even without improvement in FEV1.”

He also pointed to the work done by Sin and Tu. Their observational analysis of information from an Ontario, Canada database of 22,620 patients showed a 30% reduction in mortality in patients who were prescribed inhaled corticosteroids following admission to the hospital (Am J Respir Crit Care Med 2001;164:580-84).

Dr. Fiel suggested that patients with FEV1 less than 50% with frequent exacerbations, those requiring steroid and/or antibiotics or with symptomatic COPD might benefit from these medications. A six-weeks to three- month long trial of inhaled steroids should be considered.

Results from trials using long-acting beta-2 agonists in combination with theophylline and anticholinergics are also showing promise. A study by ZuWallack and colleagues looked at the responses of 1,000 patients using salmeterol and theophyline either separately or together. During the 12-week study, the two drugs together showed better bronchodilation. In addition, exacerbations were reduced (Chest 2001;119:1347-56).

Studies by vanNoord, et al showed combinations of anticholinergics and long acting beta-2 agonists are better than the agonists on their own (Eur Respir J 2000; 15: 878-85). A. D’urzo’s recent study in Chest showed similar data when comparing formoterol with anticholinergics (2001;119:1247-56).

Unpublished studies combining fluticasone and salmeterol show a significant improvement when compared with the component parts at 24 weeks. A longer, one-year study, showed pre-dose FEV1 significantly improved in the combined group. Exacerbation rates were also significantly reduced in the combined group.

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