ATLANTA—Today, asthma and chronic obstructive pulmonary disease (COPD) are generally seen as separate diseases. But more than 40 years ago, an alternative view—now called the Dutch Hypothesis—proposed that the two disorders share common origins and should be considered points on a common disease continuum in some patients. At the annual meeting of the American Thoracic Society, an expert panel discussed the relevance of the Dutch Hypothesis in light of recent findings about asthma and COPD.[1]

Presenters discussed the clinical characteristics of the diseases (both in humans and in animal models), the similar physiological changes that occur in both conditions, and the processes of inflammation that underlie each. One of the presenters, Monica Kraft, MD, reiterated one of the main assertions of the Dutch Hypothesis—that atopy and airway hyperresponsiveness are markers of a basic pulmonary disturbance that predisposes to chronic nonspecific lung disease.

That statement may not actually be true for atopy, but it certainly is for airway hyperresponsiveness, said Dr. Kraft, Associate Professor of Pulmonary Medicine at the University of Colorado in Denver. Airway hyperresponsiveness has been strongly associated with annual declines in forced expiratory volume in one second (FEV1) and with an increased risk of respiratory symptoms, she reported.[2,3]

CLINICAL SIMILARITIES

Asthma and COPD share many clinical features. Patients with either disease may cough, wheeze, or show airway hyperresponsiveness, for example. In addition, both diseases have been associated with atopy and chlamydia infection, noted Dirkje S. Postma, MD, Professor of Pulmonary Diseases at the University of Groningen in the Netherlands. In fact, airway hyperresponsiveness carries a fourfold risk of irreversible airflow obstruction. The more responsive someone is, the more lung function will decline.

Also, some patients with COPD may display reversible airflow obstruction, day-to-day variability, eosinophilia, or lack of sputum production—all features typical of asthma. Similarly, some asthma patients may develop the irreversible airflow obstruction usually seen in COPD.

Neutrophils or CD8 cells may be present in persistent or severe asthma, as they are in COPD. “There is evidence that early-onset asthma predicts COPD development later in life,” Dr. Postma added. Smoking appears to hasten lung function declines in COPD but not in asthma, however.

Exacerbations of both COPD and asthma usually improve with oral corticosteroids, which are sometimes effective for the stable forms of both diseases. “But inhaled corticosteroids do not prevent the decline of lung function in COPD,” Dr. Postma noted.

IL-13 OVEREXPRESSION

Much of the evidence that interleukin 13 (IL-13) is overexpressed in both COPD and asthma has come from mouse studies, but the results of these studies may well apply to humans, stated Jack A. Elias, MD. Indeed, exaggerated IL-13 levels have been detected in autopsy specimens from the lungs of smokers with COPD.

The murine data demonstrating IL-13’s effects on the airways are intriguing. In lung tissue from mice that were genetically altered to overexpress IL-13, investigators have observed eosinophil- and mononuclear cell–rich airway and alveolar inflammation, aggregates of activated macrophages, enlarged alveoli, and subepithelial airway and parenchymal fibrosis. “This looks very much like a merging of asthma and COPD with asthma-like inflammation, mucus metaplasia, and airway remodeling; and COPD-like mucus responses and emphysema. The fibrotic response also looks like that which we have begun to appreciate in the distal lungs from COPD patients,” remarked Dr. Elias, Chief of Pulmonary and Critical Care Medicine at the Yale University School of Medicine in New Haven, Connecticut. The murine studies also showed that IL-13 is a potent inducer of matrix metalloproteinases, cathepsins, and adenosine, all of which have been linked to COPD and asthma in humans.

But IL-13 is not the only molecule that can produce these abnormalities; clinicians must start considering the phenotypic variability of COPD and asthma, rather than use crude and inflexible definitions of these diseases, Dr. Elias stressed. “Multiple pathways may be operating in our patients,” he said.

PSEUDOPHYSIOLOGIC EMPHYSEMA

Arthur F. Gelb, MD, has puzzled for some time over the marked loss of lung elastic recoil discovered in patients with persistent moderate and severe asthma. He and his colleagues have not yet determined the reasons for the loss, which they liken to a pseudophysiologic emphysema. However, their work thus far challenges the belief that intrinsic airway obstruction secondary to airway remodeling is the only major cause of airflow limitation in chronic asthma.

The researchers studied 18 patients with persistent severe asthma who had no significant emphysema, as indicated by normal diffusion capacity and high-resolution computed tomography findings. Fifteen of the patients had substantially decreased lung elastic recoil, which accounted for up to 50% of the drop in their maximum expiratory airflow at 70% and 80% of total lung capacity.[4]

Subsequent research has supported these findings. It has also suggested that, even with optimal therapy, loss of lung elastic recoil combined with intrinsic airway disease causes airflow limitation in asthmatic patients between the ages of 16 and 42 years with persistent moderate and severe asthma.

The cause for decreased recoil in these patients remains a mystery, perhaps related to recurrent bronchospasm,[5] said Dr. Gelb, Director of the Pulmonary Division at Lakewood Regional Medical Center and Clinical Professor of Medicine at UCLA School of Medicine. “Aggressive and effective therapy to normalize the FEV1 would appear most prudent,” he observed.

SAME SITE OF INFLAMMATION

Inflammation in COPD clearly involves the small airways and the most distal lung areas, whereas asthma is more often thought of as a disease of central airway inflammation. “But we are finding out that both asthma and COPD can have small airways inflammation and distal lung alveolar tissue area inflammation,” reported Richard J. Martin, MD, Head of the Pulmonary Division at the National Jewish Medical and Research Center in Denver.

Indeed, studies performed at his institution have shown that transbronchial biopsy specimens from patients with nocturnal asthma have extensive eosinophilic infiltration of alveolar tissue. Other investigators have found eosinophils and T cells in surgical specimens from the smaller airways of asthma patients; major basic protein has been detected even more distally at the alveolar attachments. Asthma has also been associated with peripheral airway resistance that increases proportionally with airflow and progressively larger histamine challenges.

However, inflammation in COPD appears to be related mainly to increased CD8-positive T-lymphocytes, whereas increases in CD4-positive T-lymphocytes predominate in asthma, said Dr. Martin. Moreover, he noted, the two diseases typically display different pressure-volume curves, and COPD causes more airway destruction than asthma does.

CONCLUSIONS

Given the available data, is the Dutch Hypothesis correct? Do asthma and COPD have common origins? “Of course,” said Stephen I. Rennard, MD, Chief of the Pulmonary and Critical Care Medicine Section at the University of Nebraska in Omaha.

It is unlikely, though, that asthma and COPD have exactly the same origins, noted Dr. Rennard, because the two diseases are extremely heterogeneous and multifactorial. Rather, he suggested, their origins are probably only partly shared.

Like Dr. Elias, Dr. Rennard advised better phenotyping and more studies of the mechanisms of the two diseases to facilitate the development of better treatments. “This will be more difficult,” he acknowledged, “but it will clearly be the way forward.”

—Timothy Begany

References
1. Kraft M, Postma DS, Elias JA, et al. The Dutch Hypothesis revisited: Do asthma and COPD have a common origin? Presented at: Annual Meeting of the American Thoracic Society; May 19, 2002; Atlanta, Ga.
2. Rijcken B, Schouten JP, Xu X, et al. Airway hyperresponsiveness to histamine associated with accelerated decline in FEV1. Am J Respir Crit Care Med. 1995;151:1377-1382.
3. Xu X, Rijcken B, Schouten JP, Weiss ST. Airways responsiveness and development and remission of chronic respiratory symptoms in adults. Lancet. 1997;350:1431-1434.
4. Gelb AF, Zamel N. Unsuspected pseudophysiologic emphysema in chronic persistent asthma. Am J Respir Crit Care Med. 2000;162:1778-1782.
5. Gelb AF, Licuanan J, Shinar CM, Zamel N. Unsuspected loss of lung elastic recoil in chronic persistent asthma. Chest. 2002;121:715-721.

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