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COPD in Perspective^*

^* From the University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: Thomas L. Petty, MD, Master FCCP, 1850 High Street, Denver, CO 80218; e-mail: TLPdoc{at}aol.com

	Abstract

TOP Abstract Historical Notes Structure/Function Relationship... Pathogenesis of COPD Experimental Emphysema Natural History of COPD Treatment of COPD: Past,... COPD as a Systemic... The Future References

 
In the last 200 years or so, the recognition, diagnosis, and understanding of the pathogenesis of COPD have evolved considerably. Over the past few decades, various definitions of COPD and its "components" also have developed. Despite this, however, the treatment options for patients with this relentlessly progressive disorder are relatively limited. In the mid-19th century, the introduction of the spirometer yielded a powerful tool for the diagnosis of COPD. The currently available small, cheap spirometers hold great promise to help patients and their physicians closely monitor lung function. Early recognition of the close associations among emphysema and, more recently, small airways disease, and impaired airflow is discussed. This review also stresses the importance of the identification of COPD in its initial stages and the early onset of appropriate treatment. The therapy for COPD has changed in the last 40 years. Drug therapies in the 1960s included potassium iodide and ephedrine. Corticosteroids were not used, and oxygen therapy and exercise were actually contraindicated. Modern therapy for COPD is now more systematic and includes the use of bronchodilators and corticosteroids to improve airflow, in addition to oxygen therapy, pulmonary rehabilitation and, in selected patients, lung volume reduction surgery. The causal link between the chronic inhalation of tobacco smoke and COPD is beyond doubt, and smoking cessation remains the most important goal for patients. It is hoped that new, more effective therapies will soon be available for the treatment of this disabling disorder to provide improvement in symptoms and patient quality of life and to reduce or stop the rate of disease progression and mortality in patients with COPD.

Key Words: chronic bronchitis • COPD • definition • emphysema • history • oxygen therapy

The purpose of this introduction is to review how our knowledge about COPD has evolved over the past 2 centuries. Our own studies of the structure and functional relationships of human lungs will be briefly cited. I will review the development of present-day treatment strategies that can mitigate the burden of COPD. A look to the future offers exciting new strategies for the treatment of COPD. New understandings of the mechanisms of damage to airways and alveoli will soon lead to early identification of the disease and to new interventions for patients with COPD. Emphasis on early identification and treatment in the early and incipient stages of the disease will help to prevent the progress of COPD into advanced stages of disease with premature morbidity and mortality.

	Historical Notes

TOP Abstract Historical Notes Structure/Function Relationship... Pathogenesis of COPD Experimental Emphysema Natural History of COPD Treatment of COPD: Past,... COPD as a Systemic... The Future References

 
The word catarrh goes back to antiquity. Badham¹ recognized that chronic bronchitis was a serious and disabling disorder in 1808. In 1819, Laënnec² invented the stethoscope, which became the first instrument by which lung structure and function could be indirectly studied. Laënnec first described the symptoms and physical signs of emphysema in his treatise of disease of the chest, in 1827.² Hutchinson³ invented the spirometer in 1846. Today, this instrument is the key to diagnosing COPD in all of its stages and to assessing responses to therapy.

In 1944, Christie suggested that, "The diagnosis should only be considered certain when dyspnea on exertion, of insidious onset, not due to bronchospasm, or left ventricular failure, appears in a patient who has some of the physical signs of emphysema together with chronic bronchitis or asthma."⁴

Oswald et al⁵ described the clinical features of 1,000 cases of chronic bronchitis in 1953. Two landmark conferences, the CIBA Guest Symposium⁶ and the American Thoracic Society symposium,⁷ developed the first agreed-on definitions of chronic bronchitis and emphysema in 1959 and 1962, respectively. By 1966, Burrows et al⁸ offered a unifying hypothesis to reconcile the differences between British chronic bronchitis and American emphysema. Both experts concluded that patients in the United Kingdom and in the United States shared common features of both chronic bronchitis and emphysema.⁸ They suggested that the spectrum should be called chronic obstructive lung disease, or COPD. The latter acronym survived.

	Structure/Function Relationship in COPD

TOP Abstract Historical Notes Structure/Function Relationship... Pathogenesis of COPD Experimental Emphysema Natural History of COPD Treatment of COPD: Past,... COPD as a Systemic... The Future References

 
Using an artificial thorax, the Denver Group⁹ began a series of systematic studies that were designed to evaluate structure/function relationships and the major lesions associated with COPD, loss of alveolar walls (emphysema), and mucous gland hyperplasia (chronic bronchitis). By ventilating a whole fresh excised human lung that had been obtained at autopsy, and occasionally was available at the time of donation of organs for transplantation, it was possible to study lung mechanics both in healthy subjects and in patients with various stages of COPD. We could measure many physiologic indexes, including FEV₁, FVC, maximum midexpiratory flow, residual volume, and nitrogen washout tests, to study lesions of the small airways.^{10 11} The measurement of the postmortem FEV₁ bore a close correlation with the FEV₁ measured during life in the majority of patients (r = 0.891), adjusted for both lungs.⁹ Progressive grades of emphysema were associated with reductions in FEV₁. The lesion of mucous gland hyperplasia (ie, the Reid index) did not have a close correlation with airflow measurements. Dynamic airway collapse of the central airways was related to reductions in FEV₁.

Smoking histories were available in 154 patients who had consumed > 20 pack-years of cigarettes. Lesions of mucous gland hyperplasia and emphysema were found in 84 of the 154 patients who had smoked 20 pack-years.¹² Fifty smokers did not have these lesions. Only 8 of 37 nonsmokers had lesions of mucous gland hyperplasia⁴ or emphysema.⁴ Whether or not these patients had other risk factors for the development of the pathologic lesions associated with COPD is not known. This study was performed before the era of the understanding of the contributions of small airway pathology to airflow obstruction.

The working definition for COPD in the 1970s might be summarized as follows: "COPD is a mixture of chronic bronchitis and emphysema. It is associated with smoking and is characterized by cough and dyspnea, and premature morbidity and mortality."

The landmark study by Hogg et al¹³ in 1968 ushered in the era of small airways disease. In order to learn whether or not the nitrogen washout test would identify the lesions of small airways disease, the Denver Group performed additional studies on this and other tests that purported to identify early lesions in patients with COPD with emphysema and on the pathology of small airways.^{14 15} Cosio et al¹⁶ provided his grading photomicrographs of mild, moderate, and severe inflammation and mild, moderate, and severe fibrosis of small airways. Emphysema was found to relate to a reduction in elastic recoil and in the percentage of the predicted FEV₁.¹⁰ Elastic recoil was inversely proportional to the closing capacity and the slope of phase III disease.¹¹ In addition, the maximum expiratory flow volume was not related to emphysema.¹⁵ Fairly good correlations were found among the FEV₁, FVC, and static lung recoil at 70% of inflation.^{14 15}

During the course of these studies, several unusual patients with COPD were encountered, including a 29-year-old man who died of end-stage emphysema and a 19-year-old man who had severe pulmonary hypertension, emphysema, and marked narrowing of the conducting airways of the lungs. Our studies also identified the lesion of duct ectasia (ie, an unwinding of alveolar ducts due to loss of elastic recoil) in nonsymptomatic aged individuals.¹⁷

By the 1980s, the clinical spectrum of COPD was known to cover a 30-year process and wore the labels of chronic bronchitis, asthmatic bronchitis, and emphysema.

The working diagnosis of COPD in 1980 was "COPD is a smoker’s disease with progressive airflow obstruction, which clusters in families and worsens with age."

	Pathogenesis of COPD

TOP Abstract Historical Notes Structure/Function Relationship... Pathogenesis of COPD Experimental Emphysema Natural History of COPD Treatment of COPD: Past,... COPD as a Systemic... The Future References

 
The close association between tobacco smoking and the development of emphysema, chronic bronchitis, and a full spectrum of COPD has been known for many years. Some studies have shown that smoking creates oxidative stress, attracts neutrophils to the lungs, and creates inflammation through a multiplicity of inflammatory cytokines that also involve the CD8 lymphocyte, the alveolar macrophage, the neutrophil, and a multitude of proteases, both those that are neutrophil-derived and those derived from the cells of the bronchial epithelium.^{18 19}

Both asthma and COPD have a familial component and are inflammatory and bronchospastic processes, but asthma is much more reversible than COPD in its response to therapy, bronchodilators, and corticosteroid drugs. Airflow obstruction in patients with chronic asthma tends to be slowly progressive as a consequence of airway remodeling and fibrosis. By contrast, COPD is much less reversible in response to bronchoactive drugs and tends to be inexorably progressive.

	Experimental Emphysema

TOP Abstract Historical Notes Structure/Function Relationship... Pathogenesis of COPD Experimental Emphysema Natural History of COPD Treatment of COPD: Past,... COPD as a Systemic... The Future References

 
As a junior medical student, I was interested in the experimental production of emphysema in dogs.²⁰ However, the placement of a tracheal device, which caused more expiratory resistance than inspiratory resistance, did not result in increased air trapping or hyperinflation in long-term experiments. This and other approaches to the experimental production of emphysema were reported at the First Aspen Emphysema Conference in June 1958.²¹ Among the many experts in emphysema and COPD who attended that landmark conference, the late Averill A. Liebow presented evidence supporting his hypothesis that emphysema is a result of ischemia and damage to capillaries that traverse alveolar walls.²²

Investigators at the University of Colorado Health Sciences Center have continued to pursue a similar theme using a new and novel approach.^{23 24} Experimental emphysema in rats was produced by the blockade of the vascular endothelial growth factor (VEGF) receptor. This results in increased apoptosis of the pulmonary capillary bed and production of the lesions of emphysema.²³ Evidence is presented that VEGF is necessary to maintain the integrity of the capillary endothelium. VEGF responses, including the amount produced, its location in the lungs, the possibility of blockade of VEGF receptors, or intrinsic malfunction of VEGF receptors all have implications in the pathogenesis of emphysema. VEGF may be vulnerable to oxidative stress in excess proteolytic activity as a consequence of tobacco smoking. Increased apoptosis due to a reduction of VEGF also has been detected in resected specimens of human lungs in regions of emphysema.²⁴

	Natural History of COPD

TOP Abstract Historical Notes Structure/Function Relationship... Pathogenesis of COPD Experimental Emphysema Natural History of COPD Treatment of COPD: Past,... COPD as a Systemic... The Future References

 
The natural history of COPD begins with complex biochemical and cellular events in the small airways and surrounding alveoli. Very soon, damage to the structure leads to a loss of elastic recoil.^{25 26 27} The lungs begin to increase in size, and the FVC increases.²⁶ This results in early physiologic alterations that can be readily identified by simple spirometry.^{27 28} By the time that both clinical and radiographic signs are present, COPD is in a moderate-to-advanced stage.

Pathologic evidence of emphysema can be derived from CT studies or from resectional material, such as when solitary nodules are removed. The only practical way to diagnose and to access the progress of COPD is with spirometry. The initial smoking-induced injury to the human lungs appears to be in the small conducting air passages and surrounding alveoli. When alveoli become damaged or lost, the elastic supporting structure of the lung is reduced (Fig 1 , 2 ). This results in both a loss of elastic recoil and in increased airways resistance, since airways are no longer tethered by the radial traction forces of the surrounding alveolar attachments. Mural inflammation of small airways and airways remodeling also reduce the airway lumen.

View larger version (83K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Small respiratory bronchiole with surrounding alveolar attachments. These alveolar attachments serve to tether small airways.

View larger version (66K): [in this window] [in a new window] [Download PPT slide]   Figure 2. A drawing describing the mechanisms of airflow obstruction due to the loss of elastic recoil and airway narrowing.

It is interesting that early stages of emphysema are characterized by both hyperinflation and an increased FVC.^{26 27} This is the reason why the FEV₁/FVC ratio is such an exquisitely sensitive test for early stages of airflow obstruction. An FEV₁/FVC of < 70% heralds the onset of rapid declines in FEV₁ over the course of a 10-year period.²⁸ The time course of these changes in alveoli and small airways is illustrated in Figure 3 . Thirty or more years of progressive loss in airflow may take place before the threshold to dyspnea on exertion occurs, which is usually at < 1.5 L/s and may be as low as 1.0 L/s in smaller persons.

View larger version (17K): [in this window] [in a new window] [Download PPT slide]   Figure 3. A hypothetical natural history of COPD. Injury begins with biochemical and cellular events occurring in small airways and surrounding alveoli. This leads to abnormalities in spirometry relatively early in the natural history of COPD. Clinical and radiographic signs are only found in later stages of disease.

	Treatment of COPD: Past, Present, and Future

TOP Abstract Historical Notes Structure/Function Relationship... Pathogenesis of COPD Experimental Emphysema Natural History of COPD Treatment of COPD: Past,... COPD as a Systemic... The Future References

Beginning in the early 1960s, patients with COPD began to be saved with the use of mechanical ventilators for the management of acute respiratory failure. The development of systematic therapy for nonhospitalized patients can be traced to the Eighth Aspen Emphysema Conference, which was held in June 1965.²⁹ This was the only Aspen Emphysema Conference devoted entirely to treatment. The Denver Group presented their first observations on ambulatory oxygen at the conference. The many topics discussed by clinicians and scientists at the conference included principles of pulmonary rehabilitation, the treatment of cor pulmonale, home care for chronic pulmonary insufficiency, and surgical treatments for emphysema. The subsequent 22nd, 26th, and 42nd Aspen Lung Conferences had COPD as their theme. In the first Denver studies of ambulatory oxygen, patients with chronic stable hypoxemia experienced remarkable reductions in pulmonary hypertension and erythrocytosis, along with a great increase in exercise tolerance.³⁰ This and several other early pilot studies resulted in the design of the Nocturnal Oxygen Therapy Trial.³¹ The British Medical Research Council Clinic Trial compared 15 h of oxygen vs air breathing.³² Together, these two studies established the scientific basis of long-term oxygen therapy, which is the only treatment that has been proven to alter the course of disease and prognosis of patients with advanced COPD.³³

Pulmonary rehabilitation evolved from that earlier era.³⁴ The systematic use of drugs to restore pulmonary function, including bronchoactive drugs (ie, bronchodilators and corticosteroids) began to gain popularity in the 1990s. An emphasis on the importance of smoking cessation became a feature of treatment in the 1990s.

The Lung Health Study³⁵ taught us a great deal about the course and prognosis of early stages of disease and about the favorable response in pulmonary function to smoking cessation. The Lung Health Study became the basis of the National Lung Health Education Program (NLHEP), a new health-care initiative that was designed to involve primary care physicians in the early diagnosis of and intervention in COPD.³⁶ The NLHEP implores primary care physicians to perform spirometry in the office to identify and to treat patients in early stages of the disease. Industry has responded with a new family of simple, accurate, and inexpensive, handheld spirometers that are suitable for clinical and office use. These devices, which sell for < $500, should become as popular as the sphygmomanometer in the early identification of early COPD and related disorders.

Other therapies for advanced disease include lung volume reduction surgery and transplantation. A discussion of these surgeries is beyond the scope of this article.

A working definition for COPD in the 1990s might be summarized as follows: "COPD is a chronic disease characterized by progressive airflow obstruction, chronic cough, and dyspnea in advanced stages, caused by smoking, environmental, and hereditary factors." This underscores the reality that there are genetically determined susceptibility factors that result in one in five patients succumbing to the harmful effects of tobacco smoke.

Five studies^{37 38 39 40 41} that were conducted in the 1990s on therapy with inhaled corticosteroids have resulted in interesting and somewhat conflicting conclusions. Although a small subset of patients has a slight step-up in FEV₁ following the administration of inhaled corticosteroids, the rate of decline in FEV₁ is not retarded in any of the studies completed thus far. However, symptoms of cough, expectoration, and exacerbations of chronic bronchitis were significantly reduced in patients in the treatment groups compared with those in the placebo group. Symptomatic benefits need to be weighed against the possibility of systemic side effects (eg, reduced bone density) if inhaled corticosteroids are to be used in the long term.⁴¹

	COPD as a Systemic Disease

TOP Abstract Historical Notes Structure/Function Relationship... Pathogenesis of COPD Experimental Emphysema Natural History of COPD Treatment of COPD: Past,... COPD as a Systemic... The Future References

 
It has been learned that patients with only mild stages of COPD may have significant cardiovascular physiologic impairments. These individuals cannot achieve maximum oxygen uptake or a maximum heart rate. Their exercise performance is limited and is likely due to physical deconditioning, even in patients with only mild degrees of airflow obstruction and without hypoxemia.⁴² We must now recognize COPD as a systemic disease and start to understand the metabolic and musculoskeletal implications of this generalized process.^{43 44 45} We need to learn much more about the molecular genetics of COPD.⁴⁶ Why do only 15 to 20% of smokers develop airflow obstruction?⁴⁷

The definition of COPD in the year 2001 might be the following: "a heterogeneous disease, usually associated with smoking and a result of chronic inflammatory damage of airways and alveoli, and characterized by progressive airflow obstruction that is not responsive to corticosteroids in the long-term."

	The Future

TOP Abstract Historical Notes Structure/Function Relationship... Pathogenesis of COPD Experimental Emphysema Natural History of COPD Treatment of COPD: Past,... COPD as a Systemic... The Future References

 
The challenge for the 2000s is to identify and to treat patients with COPD in the early stages of the disease. It is projected that COPD will become a huge burden for the entire world in < 20 years. In the United States, the NLHEP aims to educate patients about the importance of stopping smoking and of finding out about lung function.

The future promises new, important pharmacologic agents that can deal with mild-to-moderate stages of COPD.^{45 47} Thus, it is hoped that a new therapeutic armamentarium will soon emerge that can be applied to patients in incipient stages of disease, to prevent or to forestall premature morbidity and mortality from this rapidly growing health problem.

	Footnotes

 
Abbreviations: NLHEP = National Lung Health Education Program; VEGF = vascular endothelial growth factor

	References

TOP Abstract Historical Notes Structure/Function Relationship... Pathogenesis of COPD Experimental Emphysema Natural History of COPD Treatment of COPD: Past,... COPD as a Systemic... The Future References

 

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This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Petty, T. L. Search for Related Content PubMed PubMed Citation Articles by Petty, T. L.