Vol. 11 •Issue 1 • Page 34
The Changing Face of COPD
Health Officials are Struggling to Define COPD, Much Less Cure It
Life expectancy in America is rising, but two recalcitrant diseases are trying to drag it back down. One is AIDS. And the other is … heart disease? Cancer? No and no. The other, according to Claude L’enfant, MD, head of the National Heart, Lung, and Blood Institute, is COPD, the nonreversible silent strangler that slowly renders lungs inelastic and useless.
Chronic obstructive pulmonary disease is now the only major disease still climbing in prevalence, and it ranks as the fourth leading cause of death worldwide. If current trends persist, it could become third in mortality and fifth in morbidity in another two decades, predicts an article in the Lancet.1
Clinicians have diagnosed 16 million Americans with some form of COPD, an umbrella term that refers mainly to emphysema and chronic bronchitis. They estimate that another 16 million go undiagnosed. COPD killed more than 112,000 Americans in 1998, according to the National Center for Health Statistics, and accounted for 13.2 million doctors’ office visits in 1997. To date, 24 governors have issued proclamations emphasizing the need for COPD education and initiatives.
As patients worsen during the roughly 30-year timetable of COPD, disease management likely will involve, in order, smoking cessation, exercise, vaccinations, beta-agonists, theophylline, inhaled corticosteroids, supplemental oxygen, lung surgery and, lastly, mechanical ventilation. All of this care costs the nation about $31.9 billion each year, according to the American Lung Association.
Of particular concern is the dramatic rise of COPD in women, due overwhelmingly to one factor: smoking, the equal opportunity disaster (See Sidebar, page 38). “The last decade has seen a 100 percent increase in COPD in women,” Dr. L’enfant said.
COPD also is increasing worldwide. “COPD is a major cause of morbidity and mortality in this country, but rates here pale in comparison to those of Asia and elsewhere in the world,” said outgoing American Thoracic Society President William Martin II, MD. Asia has 258 million sufferers, Latin America 27.7 million and Europe 22.5 million, according to the Lancet.
To make matters worse, knowledge about COPD — including its definition, its categories of severity and its recommended pharmacotherapy — is in a state of flux today.
A GLOBAL ASSAULT
In an attempt to sort through the confusion, a massive worldwide assault on COPD is now under way called GOLD, an acronym that stands for the Global Initiative for Chronic Obstructive Lung Disease. A partnership between the National Institutes of Health and the World Health Organization, GOLD “will provide a road map to translate all genetic, environmental and behavioral research into practical terms,” Bartolome Celli, MD, professor of medicine at Tufts University, Boston, enthused at an ATS press conference last year.
That will be a godsend because, right now, the overall body of knowledge about COPD is “a hodge podge of mixtures and numbers,” said Carlos Camargo, MD, an epidemiologist from the Harvard School of Public Health, Boston.
“No tight case definition exists for COPD,” he told ATS members at a separate symposium last year. “Different definitions lead to contradictory results. One recent paper claims it is under diagnosed; another, that it is over diagnosed. There is an urgent need for standardized and epidemiologically consistent criteria for COPD.”
GOLD defines COPD as a disease state characterized by airflow limitation that is progressive, not fully reversible, often preceded by cough and phlegm, and associated with abnormal inflammatory response of the lungs to noxious gases or particles. Indicators include a post-bronchodilator FEV1 of less than 80 percent and FEV1/FVC of less than 70 percent. However, only some patients with chronic bronchitis have chronic airflow obstruction, Dr. Camargo noted.
RECLASSIFICATION NEEDED
Few patients fit the classic thin emphysemic “pink puffer” or chronic bronchitic “blue bloater” profiles, noted Frank Sciurba, MD, an associate professor of medicine in the division of pulmonary and critical care medicine at the University of Pittsburgh.
“Most fall somewhere in between these stereotypes,” Dr. Sciurba told the National Association for Medical Direction of Respiratory Care last year.
He proposed this alternative way to classify COPD, based on the effect of accepted treatments:
• Type and location of inflammation: Lung tissue analysis confirms that mild and severe COPD patients show dramatic increases in inflammation cells. However, different patients have varying degrees of inflammation. Not only that, but the same patient will have varying degrees of inflammation in different regions of his lungs.
Researchers have learned that latent viral disease targets lung epithelium and incorporates itself into type-2 cell DNA. Emphysema patients have an excess of these cells, which get “revved up” when exposed to cigarette smoke.
• Degree of small airway involvement: The problem of small airway fibrosis and narrowing in COPD patients is underappreciated. However, a patient with pronounced emphysema might have a better FEV1 than a patient whose emphysema is less advanced. “There’s a disassociation between the pathology and the physiology that is not easily explained by our classic classification paradigms,” Dr. Sciurba said.
• Disease distribution: “We see a lot of (emphysema) patients who don’t have the classic upper lobe distribution,” he said, another factor that affects intervention strategy.
• Genetics: Researchers have identified familial tendencies toward emphysema independent of alpha1-antitrypsin deficiency. These include TNF-alpha, glutathione S-transferase (an antioxidant), cyto-chrome P450 isozyme Cyp1A1 (a tobacco detoxifying enzyme also associated with lung cancer) and matrix-degrading enzymes.
PHARMACOTHERAPY
No existing COPD medication modifies the long-term decline in lung function that characterizes this disease. Pharmacotherapy can only improve symptoms and/or decrease complications.
Nevertheless, “the idea that the disease is progressive, relentless and has no effective treatment is a myth,” Dr. Celli told delegates at the 2001 American College of Chest Physicians meeting.
Bronchodilators such as salmeterol and ipratropium improve FEV1 from baseline compared to placebo, he said, citing a 1999 study.2 More recently, salmeterol and, to a lesser degree, theophylline, slowed the rate of FEV1 decline, lowered exacerbations and relieved dyspnea in 1,000 COPD patients with FEV1 less than 40 percent predicted.3
“Bronchodilators work well,” Dr. Celli said, although they can’t match the benefits of quitting smoking.
As for inhaled corticosteroids, their role remains controversial. Administration of these drugs is no trifling matter. Long-term steroid use can lead to bone density loss and other serious side effects. Yet so great is the need to stabilize COPD’s ever-tightening chokehold on its victims that most clinicians remain committed to using these powerful agents.
Those in favor of steroids maintain they lessen exacerbations in severe sufferers. One study demonstrated that 60 mg of prednisone leads to better dyspnea scores and improved airflow than vitamin 6 used as placebo.4 And a 1998 study showed that inhaled fluticasone can slow rate of decline of health status and decrease exacerbations in the worst patients.5
Clinicians involved with GOLD recommend that patients with FEV1 less than 50 percent predicted who suffer repeated exacerbations requiring antibiotics and/or oral steroids qualify as candidates for regular ICS therapy.
The fact that many long-time users of steroids feel worse once taken off them either means they truly are beneficial — or else pa-tients are just suffering withdrawal symptoms, noted Stephen Rennard, MD, of Omaha, Neb. Steroids “clearly have some benefits but may also have some hazards,” he offered.
Those who are against steroids contend they don’t affect neutrophils, so they don’t work against an inflammatory disease like COPD. Clinical trials show they decrease exacerbations but do not modify long-term decline in FEV1, Dr. Sciurba said. However, because of their unfavorable risk-to-benefit ratio, he avoids chronic treatment with systemic glucocorticosteroids. “You’re killing patients long-term,” he warned. “Wean them ASAP.”
This controversy will require more comprehensive and exacting research to solve, Dr. Rennard suggested. “We need studies that look at different endpoints,” he said. “It’s unlikely every COPD patient has the same inflammatory pathogenesis. We need to separate them into different categories.”
Dr. Celli concurred. Larger studies involving 7,000 patients or more are necessary, he said, “so you can stratify different agents and different treatments on different sub groups within the trial population.”
‘SCARY AND EXCITING TIME’
In summing up, Dr. Sciurba called the present “both a scary and exciting time for research in COPD.”
It’s scary because he regards the oft-stated figure of 16 million undiagnosed COPD sufferers as naive. “If we really screened everyone in this country, we’d find much more than 50 million.”
It’s exciting because of what remains to be learned. For instance, only 10 percent to 20 percent of smokers develop severe COPD, while only 50 percent develop some level of it. What mysterious shield protects the rest? No one knows.
It’s also exciting because at least one new strategy holds tantalizing hope of reversing the physiological consequences of COPD, heretofore considered nonreversible.
In 1997, researchers Gloria and Donald Massaro of Georgetown University discovered that giving rats a derivative of vitamin A called All-Trans-Retinoic Acid (ATRA) stabilized their emphysema in 28 days and promoted the growth of alveolar units.
Experts speculate retinoids may modify COPD’s protease/antiprotease balance and modulate airway/parenchymal inflammation. Retinoic acid regulates expression of more than 300 gene products that affect epithelial cell proliferation, tissue repair, morphogenesis and cell differentiation. “So the hypothesis is not completely insane,” Dr. Sciurba said.
The NIH has launched a multi-center human trial called Feasibility of Retinoid Therapy for Emphy-sema, or FORTE. Participating sites include University of California, Los Angeles; Boston University; Col-umbia University; University of California, San Diego; and the University of Pittsburgh.
Perhaps the confusion surrounding COPD is a blessing in disguise. With so much still unknown, and with so many lives at stake, researchers see in COPD a Fertile Crescent of opportunity where contributions can be made. *
REFERENCES
1. Murray CJ, Lopez A. Alternative projections of mortality and disability by cause 1990-2020: Global burden of disease study. Lancet. 1997;349:1498.
2. Mahler DA, et al. Efficacy of salmeterol xinafoate in the treatment of COPD. Chest. 1999;115:957-65.
3. ZuWallack RL, et al. Salmeterol plus theophylline combination therapy in the treatment of COPD. Chest. 2001;119:1661-70.
4. Thompson WH, Nielson CP, et al. Controlled trial of oral prednisone in outpatients with acute COPD exacerbations. Am J Respir Crit Care Med. 1996;154:407-12.
5. Paggiaro PL, et al. Inhaled fluticasone in chronic obstructive pulmonary disease. Lancet. 1998;351:773.
Michael Gibbons is senior associate editor of ADVANCE.
