National Jewish: At the forefront of COPD Research

Print PDF Version

Barry J. Make, MD Senior Faculty Member Director, Emphysema Center, Pulmonary Rehabilitation, and Respiratory Care National Jewish Medical and Research Center Professor, Division of Pulmonary Sciences and Critical Care Medicine University of Colorado School of Medicine

Introduction

II. National Emphysema Treatment Trial

During the last century, various surgical procedures have been employed in an attempt to improve symptoms of emphysema by reducing lung size. One promising approach has been LVRS, the surgical excision of lung tissue to reduce the volume of the hyperinflated lung parenchyma, first described in the late 1950s by Brantigan and Mueller. While clinical improvement was reported in a majority of subjects in this very early study, objective documentation was lacking and operative mortality was high (18%). LVRS has been reexamined in the last ten years with mixed success. A review of historical data revealed insufficient objective assessments and the potential for strong biases in follow-up. To remedy this lack of critical information, the National Emphysema Treatment Trial (NETT) has been designed to compare medical therapy to medical therapy plus LVRS in patients with severe bilateral emphysema.1 NETT should provide answers about patient selection, risks, efficacy, safety, and costs of LVRS.

NETT is a multicenter, randomized clinical trial, with a recruitment goal of 2500 patients and 19 participating centers. National Jewish Medical and Research Center is participating in this five-year study as one of the clinical trial centers. Eligible participants include patients with moderate to severe emphysema. Both arms of the study include state of the art medical therapy similar to that described in the 1995 guidelines of the American Thoracic Society.2 Medical therapy includes:

Bronchodilators to open up the air passages and reduce the work of breathing

Oxygen therapy as needed to maintain arterial oxygen saturation at or above 90%

Influenza and pneumococcal vaccinations

Comprehensive pulmonary rehabilitation

Additional medical measures tailored to individual needs

Pulmonary rehabilitation for all subjects includes education, exercise training, and both psychosocial and nutritional counseling. Pulmonary rehabilitation focuses on optimizing exercise capacity and increases physical fitness before surgery to improve early postoperative mobility and provide a baseline for objective comparisons with postoperative functioning.

Following medical treatment and pulmonary rehabilitation, patients are randomly assigned to undergo LVRS or to continue maximal medical therapy. Patients treated with LVRS undergo a lung operation with excision to remove functionally useless lung tissue as identified by preoperative computed tomography (CT) scans and perfusion scans. Approximately 25 to 30% of total lung tissue is typically removed from each side. The surgical approach varies by study site, with medial sternotomy (MS) performed at most sites, and six centers randomizing patients to either MS or video-assisted thoracoscopic surgery (VATS).

Primary outcome measures are survival and maximum exercise capacity. Survival was selected because it is a critical measure that can be objectively assessed and quantified. Maximum exercise capacity provides an assessment of cardiopulmonary and physical performance; a stationary bicycle test is used to evaluate maximal, incremental symptom-limited exercise.

Secondary outcome measures include:

Quality of life and related disease-specific symptoms

Pulmonary function and gas exchange

Radiologic studies

Oxygen requirement

6-minute walk distance

Cardiovascular measures

Cost-effectiveness analysis

Preliminary results were recently released.3 Researchers identified a subpopulation of patients for whom surgical intervention was linked to much higher 30-day and overall mortality rates. These patients had FEV1 values less than 20% of predicted and either homogeneous distribution of emphysema by CAT scan or markedly reduced carbon monoxide diffusing capacity (?20% predicted). Patients in this category who survived did not receive clinically meaningful benefit from the surgery; therefore, LVRS is contraindicated in this subpopulation of patients with emphysema.

In addition to serving as a major clinical trial site, National Jewish is also participating in several NETT sub-studies. Specialized exercise and lung mechanics testing is being conducted to determine mechanisms of improvement following LVRS. Drs. Barry J. Make and Reuben Cherniack are studying lung mechanics to determine which patient characteristics are most predictive of successful outcome from LVRS. Chest CT scans and LVRS-resected specimens are being analyzed in collaboration with Dr. James Hogg of Vancouver to determine the extent of parenchymal destruction and airway disease. An ongoing study in collaboration with Dr. Martin Zamora and Dr. Rob Quaife at University Hospital in Denver, Colorado is evaluating whether cardiac function improves following LVRS. Dr. Elizabeth Kozora and colleagues are evaluating the neuropsychological outcomes of LVRS.

III. Effects of Air Pollution in COPD   

• Introduction 
• National Emphysema Treatment Trial
• Effects of Air Pollution in COPD
• Pulmonary Rehabilitation
• Selected Additional Studies
• References

Philip E. Silkoff, MD is principal investigator in a study funded by the Environmental Protection Agency (EPA) to ascertain the effects of ambient air pollution on subjects with COPD at the high altitude of Denver. Oxidative stress and airway inflammation are two interrelated processes that may result in worsening airway function and gas exchange in COPD, and air pollution has been proposed to worsen both these modalities. This project explores the specific relationship of ambient air pollution to pulmonary function and symptoms during winter months in subjects with moderate to severe COPD. Subjects record spirometry and complete a symptom questionnaire twice daily. The feasibility of measuring subjects’ exhaled nitric oxide, exhaled breath condensate, and induced sputum is being assessed. Pollution data being collected includes particulates, ozone, nitrogen oxides, SO2, CO, and visibility (haze). These measures will be used to ascertain the magnitude and time lag of the effect of changes in air pollution on COPD symptoms and spirometry results

IV. Pulmonary Rehabilitation    

• Introduction 
• National Emphysema Treatment Trial
• Effects of Air Pollution in COPD
• Pulmonary Rehabilitation
• Selected Additional Studies
• References
• Table 1

Pulmonary rehabilitation plays a primary role in the clinical management of patients with COPD. A recent summary of pulmonary rehabilitation written by the American Thoracic Society (ATS) described its principal goals:4

Reduce symptoms

Decrease disability

Increase participation in physical and social activities

Improve the overall quality of life

Much of the disability arising from COPD arises from treatable associated unidentified medical problems rather than from the disease process per se, enabling these positive changes to occur if the secondary morbidities are identified and managed with pulmonary rehabilitation. For example, most patients become inactive because their shortness of breath is worsened with activity. Thus, these patients develop muscle deconditioning which can be reversed allowing patients to walk farther with less breathlessness, even though the hyperinflation of COPD will not be appreciably improved with pulmonary rehabilitation. Other types of secondary morbidity that can be addressed include respiratory muscle dysfunction; nutritional abnormalities; cardiac deconditioning; skeletal disease such as osteoporosis; sensory deficits caused by medications; and psychosocial impairments including anxiety, depression, and sleep disturbances.

Pulmonary rehabilitation is indicated for patients with dyspnea, reduced exercise tolerance, or restrictions in daily activities due to COPD. As emphasized by the ATS, the need for pulmonary rehabilitation should be determined by the patient’s level of disability, not by the degree of physiologic impairment of the lungs; pulmonary rehabilitation should not be reserved just for patients with severe, advanced disease. Earlier referral enables the patient to receive preventive strategies such as smoking cessation and recommendations for exercise much earlier in the course of the disease. Some indications for referral for pulmonary rehabilitation include anxiety or breathlessness while engaging in daily activity; limitations with social, leisure, or basic daily activities; and loss of independence.4

Essential components of pulmonary rehabilitation include exercise training, education, psychosocial/behavioral interventions, and outcome assessments.4 Exercise training should be comprehensive, and include aerobic training, upper and lower extremity endurance training, and strength training.

Education is critical and should focus on improving healthy behaviors such as regular use of prescribed medications. Subject matter recommended by the ATS includes breathing strategies, energy conservation, proper use of medications, and other topics listed in Table 1.

Psychosocial and behavioral interventions can include regular educational sessions and support groups devoted to special topics such as stress reduction; family members or friends should also be included and may wish to participate in pulmonary rehabilitation support groups.

Outcome assessments are important for determining the overall effectiveness of pulmonary rehabilitation programs as well as the progress of individual patients. A variety of standardized tools can be used, including incremental exercise tests, submaximal exercise tests, walking tests, and measures of exertional and overall dyspnea. Standardized questionnaires and profiles are available to assess general health status, and respiratory-specific health and functional status.

Pulmonary rehabilitation at National Jewish Medical and Research Center is a comprehensive program that includes exercise training, breathing retraining, energy management, nutritional counseling, psychosocial interventions, and collaborative self-management. While most community-based pulmonary rehabilitation programs extend for 12 weeks or more, the National Jewish pulmonary rehabilitation team successfully implemented a fast-track pulmonary rehabilitation program. The three-week program was designed to meet the needs of both local and out-of-state patients who seek care at National Jewish.

Researchers recently summarized the National Jewish program’s impact on participants. In 69 participants studied during over six months, the Disease Management Program for COPD reduced:

• ICU admissions related to COPD 27%
• ER visits related to COPD by 27%
• Urgent physician office visits by 64%
• Missed days from work by 36%
• Participants (n=31) reported improvements of
• 21% in mood disturbance
• 19% in breathlessness
• 19% in their concern for health
• 15% in their social disruption
• 19% in their total quality of life

Several additional aspects of the program were assessed in detail, including exercise capacity, quality of life, neuropsychological effects, and radiologic-physiologic correlations.

Exercise capacity: The intensive five-day-a-week program incorporates exercise training using a cycle ergometer or treadmill. In a group of 26 patients, maximal work on an incremental cycle ergometer exercise test increased by 10% following pulmonary rehabilitation. Heart rate was lower at any level of exercise, suggesting improvement in cardiac function in patients with severe airflow limitation. Functional capacity measured by the six minute walk also improved.

Quality of life: Quality of life measured by the widely used generic Health Status Index, SF-36, was assessed before and after our pulmonary rehabilitation program. Substantial improvements in five of nine domains of the SF-36 (physical function, role emotional, vitality, mental health and health change) were identified after rehabilitation. The absence of correlation between improvements in quality of life and walk distance indicates that these measures are assessing different domains.

Neuropsychological effects: National Jewish researchers, under the leadership of Elizabeth Kozora, PhD, investigated changes in cognitive function following pulmonary rehabilitation. Patients with COPD who received pulmonary rehabilitation were compared to COPD patients who were not participating in a rehabilitation process (untreated) and to healthy control subjects. The treated group improved on measures of exercise endurance and emotional distress with clinical levels of improvement on measures of visual attention and verbal memory. Additionally, a significant reduction in depressive symptoms occurred in the treated compared to the untreated group. These findings have formed the basis for further investigations in this area.

Radiologic-physiologic correlations after pulmonary rehabilitation: Treatment for emphysema can be assessed by both pulmonary function tests and radiologic analyses. However, physiologic assessment to determine exercise capacity is time-consuming and difficult for the patient. National Jewish investigations have shown that exercise capacity may be predicted by quantitative analysis of chest CT scan. Current investigations are focusing on the usefulness of CT to predict improvement in exercise capacity following pulmonary rehabilitation.

V. Selected Additional Studies    

• Introduction 
• National Emphysema Treatment Trial
• Effects of Air Pollution in COPD
• Pulmonary Rehabilitation
• Selected Additional Studies
• References
• Table 1

Genetic Determinants of COPD

Dr. Make is a principal investigator in a multicenter trial evaluating siblings with COPD in order to identify genes that cause smoking-related lung diseases. The National Jewish research team is hoping to enroll as many as 600 families in its COPD genetics study. The purpose of this study is to understand why only some individuals who smoke develop clinically severe COPD while others have no or only minimal lung problems.

Sputum Production

Esther Langmack, MD is investigating the effects of Montelukast (an anti-inflammatory drug) on sputum volume, pulmonary function, and selected features of airway inflammation in sputum-producing subjects with COPD. Lipid mediator levels are being measured in the induced sputum in collaboration with Jay Westcott, PhD.

Cognitive improvement after rehabilitation

Elizabeth Kozora, PhD and Barry Make, MD recently presented the results of a study of cognitive improvement following rehabilitation.5 Thirty patients completed three weeks of rehabilitation. They were evaluated before and after treatment on measures of cognition, depression, pulmonary function, and exercise capacity. Results were compared to those of untreated COPD patients (n=29) and healthy control subjects (n=21). Improvements were noted in digit vigilance and semantic fluency in the treated versus untreated COPD groups. The six-minute walk test also showed improvements in the treated COPD group (vs. untreated COPD) and this improvement was significantly correlated with improved digit vigilance. A clinical decline in depressive symptoms was also noted in the treated COPD group. The researchers conclude that changes in selective cognitive functions and exercise capacity occur COPD patients receiving rehabilitation.

Viral infection and COPD

Sally Billstrom Schroeder, PhD, is studying the association of prior viral infection with the development of COPD. The serum of COPD patients is being tested for IgG-specific antibodies to two viruses associated with lung infections, respiratory syncytial virus (RSV) and cytomegalovirus (CMV). Preliminary results suggest that prior infection with one or both of these viruses is common in patients with COPD. Additional research will continue the study of patients with COPD and extend the investigation to control individuals without COPD.

References        

• Introduction 
• National Emphysema Treatment Trial
• Effects of Air Pollution in COPD
• Pulmonary Rehabilitation
• Selected Additional Studies
• References
• Table 1

Return to the table of contents.

The National Emphysema Treatment Trial Research Group. Rationale and design of the National Emphysema Treatment Trial: a prospective randomized trial of lung volume reduction surgery. Chest. 1999;116:1750-1761.

American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1995;152(Suppl):S77-S121

The National Emphysema Treatment Trial Research Group. Patients at high risk of death after lung-volume-reduction surgery. N Engl J Med. 2001, 345;15:1075-1083.

American Thoracic Society. Pulmonary Rehabilitation -1999. Am J Respir Crit Care Med. 1999;159:1666-1682.

Kozora E, Make BJ. Cognitive improvement following rehabilitation in patients with COPD. Chest. 2000;117(Suppl);249S.