Going for the Gold Standard


Vol. 17 •Issue 6 • Page 28
Chronic Obstructive Pulmonary Disease

Going for the Gold Standard

COPD is a fierce opponent, but new research and tools are changing the game

“Swifter, Higher, Stronger” — the Olympic motto that will inspire competitors in Beijing in the coming weeks — easily could apply to the respiratory experts worldwide who are training harder than ever to beat chronic obstructive pulmonary disease. In the past year, they have championed swifter means to diagnose the disease, higher levels of understanding to prevent it, and stronger methods of treatment to manage it.

Genomic research

The most comprehensive study of COPD ever untaken was launched in October at National Jewish Medical and Research Center in Denver and Brigham and Women’s Hospital in

Boston. Researchers received a $37 million grant from the National Heart, Lung, and Blood Institute to fund the five-year trial, which will examine the genetic factors that may cause COPD.

“This study is a concerted, well-designed multi-institutional effort to begin to unravel the complex genetics of this common and debilitating disease,” said Geoffrey McLennan, MD, PhD, FRACP, principal investigator of the clinical study center at University of Iowa, Iowa City. “The results will lead to new knowledge and to new directions for prevention and treatment.”

Sixteen clinical study centers across the U.S. will enroll 10,500 smokers with and without COPD. About 3,500 of the participants will be African-American, offering researchers a chance to gain more insight into this understudied, increasingly affected population. Researchers will obtain a blood sample for DNA analysis from participants at a single study visit and then will contact them twice a year for five years to collect follow-up data.

Experts say it makes sense that genomics would find a place in COPD as emerging studies indicate there are different phenotypes of patients. “There must be some intercept between the genome and the expression of lung disease in smokers,” said John E. Heffner, MD, who served as American Thoracic Society president from 2006 to 2007. “(If we can understand that link), we may be able to develop interventions that click off the switch that induces 15 percent of patients to progress to advanced COPD, but doesn’t promote clinically significant degrees of COPD in the remainder of patients who have an equivalent smoking history.”

The future of genomics in COPD appears to be bright. By 2017, COPD will be classified and staged based on patterns of gene expression in lung cells, James Kiley, PhD, director of NHLBI’s division of lung diseases predicted at this year’s ATS meeting in Toronto.

Digging deeper into alpha-1The Alpha-1 Foundation and the American Association of Respiratory Care began enrollment in December for a study to determine the prevalence of undetected alpha-1antitrypsin deficiency in COPD patients. Researchers at 15 academic sites in the U.S. will test 5,000 COPD patients for the genetic mutation.

“My prediction is that we will find about one out of every 100 routine COPD patients with a long smoking history will turn out to have alpha-1,” said Robert A. Sandhaus, MD, PhD, clinical director of the Alpha-1Foundation and principal investigator of the study. “And many more patients, maybe 10 times as many, will be carriers of a single gene for alpha-1

Detecting even a single gene could help to identify an at-risk family that might have hidden alpha-1 Uncovering alpha-1also has significant potential to improve treatment. Participants diagnosed with the deficiency will be immediate candidates for augmentation therapy, which has been shown to improve survival and slow or even stop lung function decline, Dr. Sandhaus said.

The study also has provided a way to channel respiratory therapists’ research interests. One of its secondary goals is to demonstrate the effectiveness of using RTs to conduct significant pulmonary clinical research.

“They’ve been really enthusiastic, and it’s been a pleasure working with this group,”

Dr. Sandhaus said. “Interestingly, they’re the ones who have been most receptive to the idea of testing COPD patients for alpha-1in the general clinical setting.” He expects to have the study fully enrolled in a year.

Redefining the GOLD standard

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) this past year released the first complete revision of its guidelines for COPD. The report’s most significant addition consists of three small but important words: “preventable and treatable.”

GOLD incorporated this phrase into its definition of COPD to recognize the need to present a more positive outlook to patients and to encourage preventive efforts and effective management programs.1The new definition reflects the belief that many of us who see COPD patients regularly have had for a long time, Dr. Sandhaus said. “COPD is treatable; it isn’t a death sentence.”

In another important revision, GOLD cut its spirometric classification of severity down to four stages, removing Stage 0: At Risk. The at-risk category, defined as normal spirometry with chronic cough and sputum production, got the ax because there is incomplete evidence to show that those who meet the definition progress to Stage 1: Mild COPD.1

“I think it’s important that they got rid of that category because it really had no clinical significance (and) that really confuses the issue about what COPD is,” said Kenneth Lin, MD, a medical officer with the Agency for Healthcare Research and Quality. “I think it’s important (that) they’re trying to better define what COPD is, so we know who to target with the medications that are available.”

Spirometry debate

Some experts consider the worst news of the year to be the misinterpretation of the U.S. Preventive Services Task Force’s clinical guidelines summarizing the use of spirometry as a screening tool for COPD. “Basically, their statement says that you shouldn’t test asymptomatic patients who aren’t at risk for COPD,” Dr. Sandhaus said. “But it’s been widely misinterpreted as claiming that people shouldn’t be testing patients with spirometry anymore.”

Most of the professional organizations recommend spirometry for patients who are age 40 or above, have respiratory symptoms, a history of smoking, or other risk factors for COPD. Many in the respiratory community have concerns that misinterpretation of the USPSTF’s statement may reverse progress made in encouraging physicians to use spirometry to diagnose COPD.

Dr. Lin, an author of the evidence summary that supported the USPSTF’s recommendations, stands by the guidelines. “It’s very clear from the first part of the recommendations that (USPSTF) only makes recommendations for patients who don’t have symptoms of the disease,” he said. The task force is not refuting the benefits of screening symptomatic patients for COPD with spirometry, rather they are suggesting physicians should hold off on screening asymptomatic smokers, he explained.

Based on the evidence, they concluded that more than 800 smokers over age 40 would need to be screened just to avoid one person having a COPD exacerbation. They also found significant potential for harm because false positives could lead to unnecessary medical management, carrying the risk of adverse effects. “Overall, the task force found that when you look at the net benefit, it’s either zero or possibly it’s a net harm,” Dr. Lin said.

Evolving therapies for emphysema

The burgeoning role of interventional approaches to emphysema treatment has continued to expand this year with more progress in clinical trials. “It’s been really good to see for the first time in years that we can actually offer some relief to this patient group,” said Dr. McLennan, a principal investigator in several clinical trials testing these techniques.

With the Phase 3 VENT trial completed, the Federal Drug Administration now is reviewing bronchoscopic lung volume reduction using endobronchial valves, which will likely be the first therapy available to the general public. Right on its heels are two other procedures currently in Phase 3 trials — airway bypass with drug-eluting stents and bronchial valve treatment using umbrella-shaped valves.

First-in-man studies now are looking at two other novel techniques, including a bronchoscopic system that treats diseased areas of the lung with steam and a biologic lung volume reduction system that uses a biodegradable hydrogel to deliver relief. Researchers still need to evaluate the effectiveness of these newer procedures, but they appear to have good safety profiles.

One issue researchers are still hammering out is how much of the lung to treat initially. For instance, they need to determine if it is best to treat a lobe of the lung or perhaps a smaller segment of the lung most affected by disease. No one knows the best approach yet, but experts have not ruled out the possibility of using these techniques in concert.

“It makes sense to me that there may be several of these approaches used in the same patient, but staggered over time,” Dr. McLennan said. “I see this in the future as being an ongoing therapy program rather than one shot, and that’s it.”

Many experts share this belief and anticipate that in four or five years clinicians will have a series of novel therapies they can tailor to the patients’ needs, depending on their emphysema characteristics. Interventional approaches likely will become standard of care in emphysema treatment just as stent and valve placement are commonplace in patients with coronary artery disease, Dr. McLennan said.

“Had we stopped smoking 50 years ago, we might not be having this conversation, but we failed to prevent these diseases through both education and legislation against smoking,” he said. “Having failed at that, then we’re left with having to devise therapies (to treat them).”

Certifying COPD care

The Joint Commission recognized the importance of improved care for COPD by launching its new Disease-Specific Care Program for COPD in October. Many experts see this as an important step because of the influence the Joint Commission has on hospitals, physicians, hospital services, and especially hospital budgets.

“Many physicians have been frustrated in the past because their health care systems or hospitals haven’t been willing to invest in the services that would improve the clinical outlook of their patients with COPD,” said Dr. Heffner, who also is Garnjobst chair of medical education at Providence Portland Medical Center in Portland. “The Joint Commission now recognizes that frustration and is offering a supportive program wherein hospitals can be rewarded with a certification if they do provide these services.”

Developed in collaboration with the American Lung Association, the new program outlines standards and performance measurement requirements based on the GOLD report and ATS/ERS guidelines for COPD. Tenets of the program include staff education requirements, use of spirometry, smoking cessation, risk factor reduction, patient education about self-management of COPD, and coordination of care.

“There are ancillary monetary benefits to hospitals that can be achieved by creating

centers of excellence,” Dr. Heffner said. “So I think that this program will encourage hospitals to innovate to provide the full set of resources and bundles of care that these patients need.”

In May, Easy Breathing Clinic LLC., Augusta, Maine, became the first organization in the country to receive the new certification. The Joint Commission currently is accepting applications at www.jointcommission.org.

Reference

1. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007;176(6):532-55.

Colleen Mullarkey is assistant editor of ADVANCE. She can be reached at cmullarkey@advanceweb.com. Top Trials in COPD

Several trials this past year continue the search for winning preventive, therapeutic, and pharmacologic interventions for COPD. Keep an eye out for results from these completed and ongoing studies:

  • INSPIRE looked at variations in exacerbation rates and related outcomes linked to salmeterol/fluticasone propionate and tiotropium bromide.
  • UPLIFT examined the potential long-term impacts on function with tiotropium.
  • MACRO is studying the effectiveness of azithromycin in reducing the number or severity of exacerbations.
  • PNUEMO will compare the immune response of adults with COPD on two different types of pneumococcal vaccines.
  • LUEKO will evaluate the effectiveness of zileuton in reducing the length of stay for adults hospitalized for an exacerbation or worsening of symptoms.

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