Changing the Natural History of COPD

The COPD Epidemic?

“Few chronic illnesses present as significant disease burden as chronic obstructive pulmonary disease (COPD) does,” said Scott Weiss MD, Professor of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA. “But the most important thing about COPD is that it is the most rapidly rising cause of death in the segment of the U.S. population that is also growing the most rapidly, those over 65.”

Smoking statistics show that this problem is not likely to go away soon. Although clearly the most important environmental cause of COPD, only about 10% to 15% of all smokers go on to get the disease (Fletcher C, Peto R. BMJ. 1977;1:1645).

Dr. Weiss notes three principle reasons. The first is “depletion of susceptibles”, as smokers often die from something else first. There is also a detection bias since those with airflow obstruction often have something else written on their death certificate.

The other important issue is that smoking explains less than 10% of the variance in forced expiratory volume in 1 minute (FEV1 ) and less than 1% of the decline. One reason is that it is difficult to capture the effects of environmental smoke early in life.

Dr. Weiss and others completed an unpublished cohort study of lung function changes between 36- and 55-years-old. The cohort was divided into two groups with the first measurements being taken between 18 and 35 to capture how the plateau phase might be useful in predicting function later in life. Their models showed that respiratory symptoms, cumulative smoking experience, and airway responsiveness were important predictors in both genders.

“The important point is that for those in the bottom quartile of lung function in early adulthood, fixed airflow obstruction between 36 and 55 was 15-fold greater for males and 12-fold greater for females,” said Dr. Weiss. “This indicates that even if lung function is normal, those in the bottom quartile are at significantly increased risk for COPD later in life. There is tremendous predictive power in a very simple test we do all the time.”

Possibly 10% to 15% of adults over 45 have undiagnosed airflow obstruction, that figure increases with age, and doctors may only diagnose half of COPD. Dr. Weiss noted that finding and treating these cases might mean a change in the natural history of the disease.

Factors Involved in Accelerated Loss of Lung Function

“It is an iron law of biology that you reach your maximum in a physiological variable between 18 and 25 years of age, and this applies to lung function,” said Professor Neil Barnes, Respiratory Physician, London Chest Hospital in the United Kingdom. “When we are thinking of interventions, the best we can do is to get people back to the normal rate of decline.”

Social deprivation in childhood has been related to lung function later in life. Those with higher degrees of deprivation (measured by variables such as the lack of inside toilets) had lower FEV1 than those with less deprivation (Lawlor D, et al. Thorax. 2004;59:199).

Another influence may be life events. Shaheen, et al. gathered information from patients between 67- and 74-years-old living in Derbyshire, UK, whose medical records from birth were available. They compared three diseases in childhood to current lung function. Those with pneumonia in childhood had a decrease in FEV1 in their 60s and 70s (Shaheen S et al Am J Respir Crit Care Med. 1995;151:1649).

Recent biopsy studies by Prof. Barnes and others give an indication there appears to be a small window to quit smoking. Inflammatory cells, such as CD8 T cells, show no differences between smokers and quitters. The same finding is seen with CD68, macrophages, sub-epithelial neutrophils, positive CD4 cells and TNF-alpha (Gamble E et al. American Thoracic Society Annual Meeting, 2003, abstract).

“It may be that those who smoke long enough, build up inflammation in the lungs that becomes autonomous,” said Prof. Barnes.

Treatment options to prevent decline in lung function are limited. Two meta-analyses of inhaled steroids by Highland and Sutherland came to different conclusions, partly related to a numerical mistake. However, Professor Barnes noted that even in the Sutherland meta-analysis, the differences were modest (Highland KB et al. Ann Int Med. 2003;138:969 ; Sutherland E et al. Thorax. 2003;58:937).

“What is going to be really interesting is when we get the long-term studies,” said Professor Barnes. “We can then look at whether long-acting bronchodilators impact the rate of decline of FEV1 .”

Early studies show a possible slowing of decline by treating inflammation. Gamble and others showed a marked decrease in CD4 positive T-cells, CD8, CD68, macrophages, and sub-epithelial neutrophils in the groups actively treated using phosphodiesterase-4 (PDE4) inhibitors (Gamble E, et al. AJRCCM. 2003;168:976).

“It will be interesting to see the full data on this drug to see if it really does slow the rate of decline of lung function,” he said.

Challenges in Evaluating the Natural Course of COPD: What We Can Learn for Our Experience

When studying the natural history of COPD, therapeutic changes have to be differentiated from normal decline in measurements such as FEV1 .. If a patient declines 60 mLs a year and normal loss is 20 mL/year, the treatment effect may be only half the difference.

“Because the decline in FEV1 is so small, studies on COPD will be a major undertaking,” said Marc Decramer, Professor of Medicine at the Katholieke Universiteit Leuven in Belgium. “There are several long-term trials where the decline measured is below the threshold of accuracy of FEV1.”

One complexity is patient dropouts. In the COPD trials reviewed by Professor Decramer, dropout rates ran from 25% in the active treatment groups to as high as half in the placebo. Since the dropout rate in the placebo group is greater than active treatment, this cannot be ascribed to random chance and affects the completeness of the study.

“The consequences are that completers are not representative of the entire population,” said Prof. Decramer. “Their decline over time is underestimated as are the differences between active treatment and placebo.”

Therapeutic Interventions for COPD: The Potential for Impacting the Long-Term Course of COPD

“What I would like to convey to you is the idea that we are making advances in treating COPD,” said Bartolome R. Celli, MD, Professor of Medicine, Chief of Pulmonary and Critical Care Medicine at Caritas St. Elizabeth’s Medical Center, in Boston, MA. “I propose that that the FEV1 , currently viewed as a diagnostic tool, is also a variable we can change.”

Cardiologists have lowered high blood pressure to change outcomes. Dr. Celli suggests that the FEV1 – forced vital capacity (FVC) ratio should be used to measure outcomes in dyspnea and respiratory failure.

“We define the disease as being irreversible and then give bronchodilators to see how much the disease reverses,” noted Dr. Celli. “We do have medications that change the value of FEV1 even though we have selected ‘irreversible’ patients. This is a positive result.”

People are screened at every doctor’s visit for high blood pressure. Thus most people with hypertension know they have it and are treated. The same cannot be said in COPD.

“I am often asked at these meetings which bronchodilator I would give first and I say ‘spirometry’,” said Dr Celli.

A study by Michael Belman and others with albuterol, and more recently another one by O’Donnell and co-workers, found that the endurance time for a submaximal constant load exercise increased in those taking the bronchodilator versus placebo. There was also an improvement in functional dyspnea as measured by the transitional dyspnea index score in those getting tiotropium (Belman M et al. Am J Respir Crit Care Med.1996;153:967; O’Donnell D et al. Eur Respir J. 2004;23:832).

“We are making gains in impacting on dyspnea and exacerbations,” he noted. “We should give ourselves a pat on the back. “I believe the golden era of COPD has come.”

Why Hyperinflation Occurs in COPD Patients

Hyperinflation of the lungs impacts on efficient lung function, impairs respiratory muscle use, alters gas exchange, and affects the work of breathing. All of these have clinical implications.

“We are beginning to understand that lung volume may be a better marker for some kinds of impairment than FEV1,” said Gary Ferguson, M.D. from the Pulmonary Research Institute of Southeast Michigan in Livonia.

In COPD, there can be a loss of elastic tissue in the lungs so airways collapse easier. The net effect is that the forces driving respiration and airflow are smaller. The lack of tethering in the small airways leads to airway resistance and flow limitation.

“Many of our patients have some degree of increased hyperinflation or an increase in end expiratory lung volumes (EELV),” noted Dr. Ferguson. “This relates largely to dynamic hyperinflation.”

In COPD, patients do not have time to fully exhale. An imbalance of respiratory airflows and expiratory timing combine to gradually trap air and change the end expiratory volume.

As Dr. Ferguson noted, “The important message is that the difference between end expiratory lung volume and total lung capacity (TLC) begins to shrink. As the lungs hyperinflate, the residual volume (RV) and EELV are getting bigger and the inspiratory capacity (IC) is getting smaller.”

Exercise can make this worse. As the patient breathes faster, they are unable to get all the air exhaled because of the expiratory airflow limitation and their lungs blow up like a balloon.

“We are taking our COPD patients, who are starting at higher volumes because of intrinsic changes in their FEV, and asking them to breathe faster,” said Dr. Ferguson. “The net effect is that they aren’t able to recruit additional TV, their IC is further restricted and the only way to increase minute ventilation is to breathe faster. By breathing faster, they further shorten their expiratory time triggering a cascade of progressive hyperinflation.”

With COPD, there are changes in the distribution of pressure as a person breathes. The curve is shifted up, increasing the work of breathing. As you move into these ranges, there are very significant pressure changes with very little tidal volume (TV) change. There again is the paradox of working harder while doing worse.

“We typically talk about bronchodilator responses in terms of changes in FEV1 or FEV1 /FVC ratios,” said Dr. Ferguson. “Small changes in airflows may not reflect that a medication lowers the EELV, increases IC, and patients can take a deeper breath.”

When dynamic hyperinflation is identified and treated by short-acting bronchodilators, there is a cycle of better breathing followed by a return of hyperinflation. Long-acting bronchodilators can sustain reductions in hyperinflation for hours.

Tiotropium is one of the first 24-hour inhalers with the potential to be a useful treatment. A study by O’Donnell et al. in acute patients noted few had changes in the FEV1 /FVC ratio, but all had significant IC changes, especially in functional residual capacity (FRC) and RV when compared to placebo (O’Donnell DE et al. Eur Resp J. 2004; 23:832).

Other studies have shown the persistence of tiotropium. One by Celli and others looked at lung function measures 23-hours after administration. Even when drug levels were at their lowest, there were still significant effects on EELV for extended periods (Celli B et al. Chest 2003;124:1743).

“COPD produces significant negative effects on both static and dynamic lung volumes leading to restrictions and gas trapping,” said Dr. Ferguson. “Long-acting bronchodilators may be able to significantly improve hyperinflation and positively impact outcomes.”

The Link Between Lung Hyperinflation, Respiratory Discomfort and Exercise Intolerance in COPD

“We realize from clinical experience that the development of lung hyperinflation in COPD is a slow, insidious process,” said Denis O’Donnell, M.D., Professor, Department of Medicine, Queen’s University, Kingston, Ontario, Canada. “We also understand that as the respiratory system slowly adapts to overinflated lungs, the whole chest wall reconfigures to accommodate them and the ventilatory muscles also adapt to chronic loading.”

When ventilation suddenly in-creases, compensatory mechanisms are overwhelmed by dynamic hyperinflation as a result of air-trapping. These patients can achieve only a small increase in TV even as inspiratory effort increases with exercise. Even if these patients could double their inspiratory efforts, there would be no additional TV for expansion.

When compared with healthy individuals, much greater pleural pressures are needed for a given TV expansion in COPD. Acute-on-chronic hyperinflation during increased ventilation leads to elastic loading, “high-end” restrictive mechanics, and a tachypneic response that rebounds to cause more dynamic hyperinflation in a vicious cycle.

Dr. O’Donnell and his group asked a group of healthy individuals and another cohort of COPD patients to complete a task that left them breathless and then to describe the nature of their dyspnea using a standard list of qualitative descriptors. Healthy participants reported their breathing required more effort or work. Those with COPD also reported increased effort, but added a distressing sensation of “unsatisfied inspiration” and confirmed that the problem is perceived as one of inspiration instead of expiration (O’Donnell D et al. Am J Respir Crit Care Med. 1997; 155:109).

“The ability of patients with COPD to exercise depends on the maximal expiratory flow rates available over the operating range where TV is positioned,”
said Dr. O’Donnell. “Bronchodilators markedly improved dynamic airway function in this critical range and the patient can empty their lungs more
with each breath, thus allowing lung deflation.”

Bronchodilators therefore, improve resting IC and open up greater inspiratory reserve compared to the pre-dose situation. TV expands and the patient can exercise longer before reaching the critical mechanical limit.

Dr. O’Donnell and colleagues studied the impact of bronchodilators on dyspnea. They looked at a group of patients who undertook an endurance exercise at a constant work rate before and after tiotropium or placebo (O’Donnell D et al. Eur Respir J. 2004; 23:832).

“Following tiotropium, patients could get a much better tidal volume response than with placebo for a similar or lower expiratory effort (as measured by esophageal balloon),” noted Dr. O’Donnell. “It is possible with modern-day pharmacotherapy to achieve sustained volume reduction and improved dynamic mechanics.”

“In flow-limited patients, dynamic hyperinflation during activity creates negative sensory and mechanical effects,” he said. “With bronchodilators we deflate the lungs, reduce the elastic and resistive loads on respiratory muscles and, importantly, we allow greater tidal volume expansion for a given neural drive to breathe.”

This translates into measurable improvement in exercise performance and dyspnea. Dr. O’ Donnell and others looked at a large COPD population randomized to placebo or tiotropium and compared the effects on dyspnea and exercise endurance over 42 days. They found no changes in the placebo group. There was a highly significant and immediate improvement in dyspnea and exercise performance in the treatment cohort, which progressively improved over time (O’Donnell D et al. Eur J Respir. 2004; 23:832).

Non-Pharmacologic Volume Reduction

COPD is a heterogeneous disease with blebs and bullae that prevent relatively more normal lung from inflating. When you get these to deflate or can remove them, a person can breathe in a more optimal part of the compliance curve.

A group of 20 patients underwent surgery in a study at the University of Pittsburgh. The coefficient of retraction (the maximal elastic recoil divided by TLC) was significantly improved. At three months there were significant drops in TLC, FRC, and RV. Even at two years, there was still a persistent reduction of a liter below baseline in RV (Sciurba F et al. NEJM. 1996;334:1095).

“With hyperinflation, the lung remains inflated and the chest wall rests on it like a big pillow,” said Frank Sciurba, M.D., Associate Professor of Medicine, University of Pittsburgh. “Following lung reduction surgery, the negative and end expiratory pleural pressure changes allow the diaphragm to have a more favorable configuration.”

Martinez and others extended these findings in their published research by documenting significant reductions in exercise-induced hyperinflation following surgery. They found a significant relationship between exercise Borg dyspnea scores and changes in the EELV (Martinez F et al. Am J Respir Crit Care Med.1996;153:1536 ).

Dr. Sciurba found that the greatest predictor of improvement in maximal exercise minute ventilation in subjects following surgery was a reduction of RV with maintenance of TLC (Patel S et al. Am J Respir Crit Care Med.2002;165: A504).

Pharmacological Approaches to the Problem of Lung Hyperinflation

“I don’t think we fully realize that we have some options to treat hyperinflation in our COPD patients,” said Richard Casaburi, M.D., Professor of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, CA . “The chief complaint of this disease, exercise intolerance, is linked to dynamic hyperinflation and we now have physiologically-based strategies to reduce it.”

In the O’Donnell study discussed earlier, exercise tolerance was determined by serial constant work-rate tests. Hyperinflation was tracked using IC at the same work rate and time (isotime). There were no changes in the placebo group. In the tiotropium group IC increased by 200 mLs, signifying reduced hyperinflation (O’Donnell D et al. Eur Respir J. 2004;23:832).

“Tiotropium decreases expiratory airflow resistance, thereby decreasing dynamic lung hyperinflation during exercise and improving exercise tolerance,” said Dr. Casaburi. “This is a cause-and-effect relationship.”

Inhaled gas mixtures have also been studied as a possible therapy. Dr. Casaburi’s group took 10 patients with severe COPD, but without substantial exercise-induced hypoxemia, and had them do constant work-rate tests. They were randomized to breathe room air, 30%, 50%, 75%, or 100% oxygen. With room air, the patients were breathing 28 times a minute, but only 21 breaths a minute with 50% oxygen. As respiratory rates slowed, more time was allowed for exhalation and dynamic hyperinflation declined, marked by a doubling of inspiratory reserve volume. As a consequence of the reduced hyperinflation, exercise tolerance time more than doubled (Somfay A et al. Eur Respir J. 2001;18:77).

“Supplemental oxygen decreases ventilatory drive and slows breathing,” he said. “We are decreasing ventilatory drive and slowing breathing, therefore decreasing dynamic hyperinflation.”

Heliox (a helium/oxygen combination) also increases exercise tolerance in COPD by reducing hyperinflation. In constant work-rate testing, the heliox group achieved higher peak ventilation as airflow resistance was reduced. There was a higher IC at isotime of about 150 to 200 mLs in the heliox group, resulting in improved exercise tolerance (Goto S et al. Am J Respir Crit Care Med. 2004;169:A467).

Rehabilitation exercise programs also decrease hyperinflation. Training decreases lactic acidosis which decreases ventilatory drive at a given level of exercise. The lower respiratory rate yields less hyperinflation and greater exercise tolerance (Casaburi R et al. Am Rev Respir Dis.1991;143:9; Porszaz J et al. Eur Respir J. 2003;22:205s).

Combined bronchodilator and rehabilitative therapy are synergistic. Dr. Casaburi and colleagues randomized 93 COPD patients to either tiotropium or placebo. Treadmill tolerance was assessed periodically.

In the 5-week pre-rehabilitation phase, tiotropium increased endurance by about 16% initially. Rehabilitation therapy increased exercise tolerance in both groups. By the end of the 8- week long rehabilitation program, exercise tolerance was 32% greater in the tiotropium group than in the placebo group (Casaburi R et al. Am J Respir Crit Care Med. 2004;169:A756).

Dr. Casaburi stressed, “If you are going to the trouble of rehabilitating patients, you make the program substantially more effective by giving optimal bronchodilators and supplemental oxygen”.