Pulmonary Pharmacology & Therapeutics (2002) 15, 341-351 doi:10.1006/pupt.2002.0380, available online at http://www.idealibrary.com on IDEAL®

Pulmonary
Pharmacology
& Therapeutics

COPD Corner Series

COPD: Clinical Phenotypes

Thomas L. Petty
University of CO Health Sciences, Denver, USA


SUMMARY: Different phenotypic presentations in advanced stages of COPD are less common than in years past because of therapies that alter the manifestations of disease. Early stages of COPD are often asymptotic, but may present as asthma, chronic bronchitis, emphysema or combinations. Unusual presentations at young age are not common, but may be dramatic. © 2002 Published by Elsevier Science Ltd

KEY WORDS: Asthma, Asthmatic bronchitis, Chronic bronchitis. Emphysema, COPD, Clinical phenotypes.


INTRODUCTION

This chapter is based upon more than 40 years of clinical observations of a large number of patients with COPD, with emphasis on late stages of disease. It is also based upon extensive studies of structure-function relationships in whole, fresh, excised human lungs available immediately following death and autopsy. The use of an artificial thorax to study physiological and pathological relationships offered a unique opportunity to understand the lesions of airways and alveoli that accompanied airflow obstruction in patients who were observed during life and whose lungs could be studied after death.1-9 These observations were made in a bygone era when it was the rule to obtain autopsies in virtually all patients, in order to better under- stand the disease process that led to their death.

In addition, clinical observations made during the development and implementation of a pulmonary rehabilitation program, beginning in the 1960s, and the use of ambulatory oxygen is also background for this chapter.10-14 During this early period, we learned that treatment modified the course and prognosis in the disease spectrum.

Contemporary observations in patients, including studies of asymptomatic individuals, are now emerging to give a new perspective on the various stages of COPD with different presenting phenotypes.

COPD IN PERSPECTIVE

COPD is a disease complex, which is characterized by a long asymptomatic period, followed by the emer- gence of the cardinal symptoms of chronic cough, mucus hypersecretion and dyspnea on exertion. The symptoms of COPD are progressive over time and result in limitation of physical activities, impaired quality of life and premature mortality.

COPD is characterized pathologically by inflam- mation of the conducting airways, both large and small (chronic bronchitis) and dissolution or loss of alveolar wall, loss of elastic recoil (emphysema). A bronchospastic component may accompany airways inflammation and may properly be called 'asthmatic bronchitis'. Although loss of elastic recoil and dis- appearance of alveolar walls are parallel processes, they are not necessarily related.15 Significant loss of alveolar walls may occur with normal elastic recoil and elastic recoil may be reduced with no loss of alveolar walls.

COPD is characterized physiologically by progressive limitation of expiratory airflow as judged by simple spirometric tests such as the forced expiratory volume in one second (FEV1). Hyperinflation may or may not be present. Hyperinflation is a marker of loss of elastic recoil. Reduction in the diffusion surface occurs in emphysema, when loss of alveolar walls is present. Inflammatory obliteration of small airways may lead to blood gas abnormalities because of ventilation-perfusion mismatching, which may impact on the clinical manifestations ofCOPD.

THE BLUE BOATER AND PINK PUFFER PRESENTATION IN ADVANCED COPD

Historically, Dornhorst offered a landmark descrip- tion of two extreme clinical phenotypes in the mid-fifties.16 The classic 'Blue Bloater' was described as a younger patient with chronic bronchitis, who often presented with congestive right heart failure. The classic 'Pink Puffer' was an older and skeletal muscle-wasting patient who had unrelenting, disabling dyspnea and clear evidence of emphysema.

Two patients showing bloating and puffer characteristicsTwo such patients were encountered during the enrollment period of a pulmonary rehabilitation program. Their photographs are presented in Fig. 1. This figure has been reproduced many times, but it is still valuable because of the knowledge of the clinical course, prognosis and pathological features that these two individuals revealed, as they were observed and treated, up to the time of their death. Fig. 2 presents the PA chest X-ray of the Blue Bloater patient on the left and the Pink Puffer patient on the right. Notice both the enlarged cardiac silhouette and prominent pulmonary arteries of the Blue Bloater (left); with marked hyperinflation, vascular cut-off beyond the central and also enlarged pulmonary arteries of the Pink Puffer (right).

Figure 1. Photographs of classic 'Blue Bloater' (left) and 'Pink Puffer' (right). Notice the ankle swelling from congestive heart failure (left), compared with loss of muscle mass (right).

X-rays of the chest from the two patientsFigure. 2. Posterior-anterior chest X-rays from patients illustrated in Fig. 1. Notice the enlarged cardiac silhouette and prominent pulmonary arteries and the absence of hyperinflation (left), compared with marked hyperinflation, a small vertical heart and decreased peripheral lung markings (right).

The clinical and pathological features of these two patients are presented in Table 1. The clinical features are briefly summarized in Table 2. Following death and autopsy, pathological findings in relation to the loss of alveolar walls (emphysema), the presence of mucous gland hyperplasia as expressed by the REID index,17,18 and inflammation of small airways and right ventricular thickness are summarized in Table 3.

Table 1 Spirometry, blood gases, pH
  Patient A Patient B
FVC 2.82 (4.22) 2.32 (3.64)
FEV1 1.22(3.14) 0.61 (3.12)
PO2 52 (65-75) 58 (65-75)
PEVS 49 (49-40) 39 (34-40)
pH 7.31 7.46
HCT 59% 44%

Table 2 Clinical Factors
  Patient A Patient B
Age 52 65
Symptoms 10 years chronic cough; repeatedchest infections 10 years progressivedyspnea; no chestinfections
Death 56.4 68

Table 3 Major pathological features
  Patient A Patient B
Loss of alveolarwalls 35% 65%
Mucus glandhyperplasia REID index 60% Absent(REID index 20%)
Bronchiolitis 47 of 53 bronchioles Minimal inflammation
RV thickness 10 mm 6 mm
     
     

These two extreme phenotypes are rarely encountered today. This is because most patients with COPD are identified and treated with bronchodilators and antibiotics for acute exacerbations of chronic obstructive pulmonary disease. Quite frequently, corti- costeroids are used for exacerbations and, in some cases, patients' maintenance of corticosteroids, either by the oral or inhaled route is used.19,20 These inflammatory airway processes may be modified by these therapies. In addition, the use of oxygen to correct hypoxemia and reverse reactive pulmonary hypertension and right ventricular afterload, polycythemia and cor pulmonale grossly modify the course of the so-called Blue Bloater. It should be emphasized that the Blue Bloater should not be equated with underlying chronic bronchitis, although chronic bronchitis may predominate. Nor should emphysema be equated with the Pink Puffer-type of disease. Both airway changes and loss of alveolar walls were present in these classic phenotypes at autopsy.

Another factor of phenotype is respiratory center responsiveness, which appears to be on a genetic basis. First degree family members of patients with the Blue Bloater vs. Pink Puffer phenotype have different respiratory center responses to chemical signals that drive respiration. Thus, a Blue Bloater might be considered to have a 'lazy' respiratory center and the Pink Puffer, one of high responsiveness or high 'gain' in the respiratory center.21

COPD is sometimes associated with deficiency of glycoprotein alpha-1-antitrypsin is associated with advanced emphysema, occurring at a young age and clustering in families. Men and women appear to be at equal risk. It is clearly established that the homo- zygote state ZZ or z-null is associated with the accel- erated rate of emphysema, particularly in smokers.22

An example is the case of a 39-year-old nurse, who experienced dyspnea while engaging in high school athletic beginning at age 14. Increasing dyspnea inter- fered with work and sexual activities beginning at age 22. A rapid decline in exercise capacity followed a bout of influenza at age 28. She was unable to work after age 35. She was house-bound because of the dyspnea. Examination revealed a thin, nervous woman who appeared older than her stated age. Her chest was prominent and breath sounds were greatly reduced throughout. Cardiac sounds were distant. No signs of pulmonary hypertension were present. Wast- ing of the extremities was noted. The chest X-ray PA and lateral is shown in Figure 3, along with selected ventilatory function tests. Obviously this is very precocious emphysema, marked by hyperinflation. The patient died in her 40s.

X-rays hsowing alpha antitrypism deficiency
Figure 3. Posterior-anterior and lateral chest X-rays from a young nurse, aged 39, with alpha antitrypsin deficiency (PIZZ). Spirometric values and blood gas measurements are indicated on the posterior and anterior images.

Patients with alpha antitrypsin deficiency may have near normal and even normal lung function.23 They may also present with chronic cough and mucus hypersecretion, signifying chronic bronchitis or wheeze, mimicking bronchial asthma.24 Today, alpha-1-antitrypsin replacement therapy appears to retard the rate of decline in FEV1 in uncontrolled cohort studies.

The youngest patient with advanced emphysema, seen by the author, was a 14-year-old teenager who was admitted to the children's asthma center in Denver many years ago. She also had the alpha antitrypsin deficiency state. She died in her late teens. This case has been previously reported.25

The author has seen other patients with precocious emphysema. One patient was a 21-year-old man, who was visiting from Germany. PA and lateral X-rays are printed in Fig. 4a and b. This individual was a non-smoker who had a vague recollection of other members in the family with chronic lung disease. Alpha-1-antitrypsin levels were normal. The patient returned to Germany and could not be followed up.

Xrays showing hyperinflation in a man with normal alpha-antitrypsin levels
Figure 4. Chest X-rays show marked hyperinflation in a 21-year-old man with normal alpha-antitrypsin levels. Selected spirometric values, oxygenation and CO are reduced as stated on the films.

A most interesting clinical variant of COPD presented following case scenario. This patient was a 27-year-old Caucasian man, who was evaluated for progressive dyspnea five months, associated with a massive ankle and leg edema. His clinical history began with asthma since childhood, with episodes of wheeze, dyspnea, and responses to beta agonists and inhaled bronchodilators. Chronic progressive dyspnea had occurred during the previous two years. He had never smoked tobacco or any other material. A strong family history of asthma was present and a suggestion of emphysema in distant relatives was reported.

In addition, he was extremely dyspneic with a respiratory rate of 32. Pulsus paradoxus of 14 mm Hg was present. Chest examination revealed markedly reduced breath sounds, an absence of wheezes or rhonchi. Marked prolongation of the expiration phase was noted. Signs of pulmonary hypertension were present. A loud pulmonic second sound and a right ventricular lift were observed, along with increased jugular venous pressure. The liver was enlarged and tender, and marked ankle edema was present. The patient was admitted to the hospital. The patient's FVC was 2.72 1, FEV1 0.95 Vs, P02 38 mm, PCOz 55 and pH 7.38. The patient's PA and lateral chest X-rays are presented in Fig. 5. With oxygen and diuretics, manifestations of the right-side heart failure gradually subsided. Full doses of inhaled beta agonists; theophylline and corticosteroids were given throughout the hospitalization. The alpha-1-antitrypsin phenotype was MM and the alpha-antitrypsin level was 254; sweat electrolytes were normal. At time of discharge, the FEV1 was 1.54 and FVC was 3.29, thus giving evidence of a degree of reversibility in his airflow obstruction. POz was 48, PCOz 45, pH 7.41 while breathing room air. The patient was discharged on continuous oxygen.

X-rays of man with advanced emphysema and pulonary hypertension
Figure 5. Posterior-anterior and lateral chest X-rays of a 27-year-old man with advanced emphysema and marked pulmonary hypertension. The original presentation was asthma.

Later the patient had right-side cardiac catheterization. This revealed pulmonary pressures of 106/61, while breathing air. With oxygen, the pulmonary pressure dropped to 89 over 95, wedge pressure was 5; cardiac output was 3.8 1/min. Pulmonary vascular resistance ranged from 23 to 28.4 Wood units (normal less than 4). A 10% reduction in vascular resistance occurred during a protocol infusion ofdiltiazem. Subsequently, he was managed with diuretics, oxygen, and an experimental protocol of diltiazem, which was initially associated with a reduction in pulse rate and gradual clearing of leg and ankle edema. However, two months later he suffered sudden deterioration with pulmonary edema and terminal ventricular fibrillation. Resuscitation was unsuccessful.

At postmortem examination, heart weight was 450 g, the tricuspid valve was 14 cm, right ventricular thickness was 0.7 cm and left ventricular thickness was 1.3 cm. Lungs revealed marked, emphysematous blebs. The right lung weighed 800 g and the left lung 690 g. A postmortem bronchogram is shown in Fig. 6. This shows marked narrowing of the bronchi filled with contrast material and multiple gross emphyse- matous spaces. Sections of the lungs are shown in Fig. 7. Gross emphysema is obvious and extensive (Fig. 6). A microscopic study of his lungs revealed extensive architectural replacement of lung and panacinar emphysema changes. Bronchioles revealed hypertrophy of smooth muscles, many goblet cells and thickened basement membrane, increased eosino- phils and mucus plugging. These are the histologic findings of asthma. Marked pulmonary hypertensive vascular changes were present, including muscular hypertrophy and intimal changes.

Postmortem bronchogram of the patientFigure 6. Postmortem bronchogram of the patient whose X-ray is shown in Figure 5. Note marked narrowing of the conducting airways filled with barium and events of emphysema, as well as central pulmonary edema.

Section of lung showing emphysema Figure 7. This section of lung from patient illustrated in Figures 5 and 6. Note marked emphysema, particularly in the upper lung regions.


Table 4 Initial pulmonary function tests at age 27
Post-bronchodilator Pre-bronchodilator
FVC 4.041 3.90 (95%)
FEVi 2.30 2.07 (63%)
FEVe/FVC 76% 57%
Diffusion   22 (27 ±8)
RV   2.03 (120%*)
TLC   5.94 (106%*)

* Percent of predicted or predicted value.


Comment: There is little question about the diagnosis of asthma from the clinical description during childhood, along with the response to bronchodi- lators. Also the presence of severe emphysema is not in doubt. The degree of pulmonary hypertension was marked and far more severe than found in most cases of advanced emphysema. This is truly an unusual case presentation.

CLINICAL PHENOTYPES IN MILD TO MODERATE STAGES OF DISEASE

The Third National Health and Nutrition Examination Study (NHANES III) was conducted in a large, non-institutional population of ambulatory subjects in the USA.26 NHANES III revealed a gross under- diagnosis of COPD, because few of the subjects had ever been tested by spirometry, even when sympto- matic with chronic cough, excess mucus, wheeze or dyspnea on exertion.26

The Lung Health Study revealed a marked degree of nonspecific airways hyperreactivity in an inhaled methacholine challenge.27'28 Approximately twice as many women had a 72.0% decline in FEV1 after inhalation of <25 mg/mil methylcholine (85.1% in women vs. 58.9% in men). The same female predominance in airway hyperreactivity was found in inhaling <0.5-mg/mil methylcholine (46.6% in women vs. 23.9% in men).28

In men, AHR was significantly related to symp- toms of wheeze, chronic cough and/or sputum and a history of asthma or hay fever, but not to current or former cigarette smoking. By contrast, AHR was not significantly associated with chronic cough or mucus hypersecretion, or a past history of asthma or hay fever in women. In women, AHR was related to wheeze and current asthma, as well as to total pack years of tobacco smoking. The reasons for these striking sex differences are not clear. These functions may determine different clinical presentations in women compared with men.

A case example that illustrates some of the difficulties in separating adult onset asthma from smoking-related COPD is presented below.

JJ was a 27-year-old woman when she was first seen by the author for a chronic cough and episodic wheeze. Her maternal grandfather was also a patient of the author. He died of chronic obstructive pul- monary disease (COPD) at age 72. Her mother was (also cared for by the author) died of emphysema complicated by a pulmonary lymphoma at age 57. The patient reported that she had had 'asthma', with wheezing intermittently for the previous four years.

On physical examination she had a strong cigarette odor. Otherwise, she appeared healthy with pulse 82 and blood pressure 110/80. She had a predominant chest. Fair air entry and exit was present, but her diaphragms were low on percussion. Scattered rhonchi and wheezes were present. Her cardiac, abdominal, and extremity examinations were normal. Clubbing and edema were absent. The patient's pulmonary function tests, including lung compart- ment and diffusion tests, on initial evaluation are presented in Table 4. Her forced vital capacity (FVC), was 3.90 1 (95%) and her forced expiratory volume in one second (FEV1), 2.07 (63%).

Does the patient have asthma, COPD, or both?

These tests reveal mild airflow obstruction with no significant response to an inhaled beta agonist bronchodilator. The total lung capacity is normal, but the residual volume is increased, suggesting air trapping. The diffusion test is normal, indicating an intact air blood interface. The diffusion test is within the normal range, but at the low end of normal. Since emphysema has been defined as loss of alveolar walls, it is common to conclude that a normal diffusion test rules out emphysema. Emphysema begins with a loss of elastic recoil due to the release of elastases in susceptible smokers. Loss of elastic recoil and loss of alveolar walls progress in the same direction, but they are separate processes, although both are related to smoking. Thus, it is possible to have loss of elastic recoil as an index of emphysema but a normal dif- fusion test, because the alveolar walls are not yet destroyed. Measurement of elastic recoil is only done in research laboratories. Airflow obstruction may be due to inflammatory or bronchospastic narrowing of the conducting airways, loss of elastic recoil, or both.

Initial bronchodilator responses are not necessarily indicative of responses to long-term bronchodilator therapy.29 Response to an inhaled bronchodilator does not reliably separate asthma from COPD.29 It is a fact that complete normalization of the FEV1 is confirmatory evidence of asthma. However, early stages of COPD may have a significant degree of reversibility, which may increase the FEV1 to within the normal range, that is above 80% of predicted. In later stages of COPD, lesser degrees of reversibility are the rule.

The subsequent clinical course will determine whether this patient has asthma, COPD, or both. It is important to comment about the practice of the labeling in COPD and asthma. Although the inflam- matory mechanisms of asthma and COPD are somewhat different, there is a large area of overlap. Both diseases are characterized by airflow obstruction, episodes of exacerbations, and often significant responses to bronchodilating agents. Chronic, persistent asthma in non-smokers, however, is not characterized by a rapid rate of decline in FEV1 if the disease is treated with systematic pharmacologically oriented therapy, including inhaled corticosteroids or leukotriene modifiers and bronchoactive drugs including beta agonists, anticholinergics, and theophyllines. By contrast, in smokers with COPD, a more rapid rate of decline in FEV1i is the rule. Thus, over time with progressive airflow obstruction, chronic asthma or 'asthmatic bronchitis' with or without an element of emphysema becomes a component of COPD, the more inclusive term.30 The designation of COPD includes components of asthmatic bronchitis, chronic bronchitis and emphysema. The usual decline in FEV1 in all forms of COPD is often 60-80 cc per year, or more in patients who continue to smoke. The rate of decline is reduced in successful quitters to the age-related rate of decline of 20-30 cc per year.

The patient was initially referred to the author for smoking cessation advice and management. She was given instructions in modifying her patterns of smoking behavior and advised to pick a quit date and stop, 'cold turkey'. She was also given an inhaled beta agonist bronchodilator to use for episodes of wheeze and to assist in mucociliary clearance.

The patient persisted in trying to stop smoking, but could never get below ten cigarettes per day. A trial of clonidine therapy was instituted by transdermal patch. This was in conjunction with a clinical trial of clonidine in smoking cessation. When next evaluated nine months later when she was clinically stable, the patient's FVC was 4.50 (111%), her FEV1 was 2.71 (83% of predicted), and her FEV1/FVC was 60%, which is still abnormal. Normal FEV1/FVC at her age is >76% (see Table 5). This represents an im- provement in FEV1 of 0.64 1 compared with her ori- ginal FEV1. She had taken her albuterol MDI 2 h before this spirometer test. Accordingly, this was a post-bronchodilator assessment of her ventilatory function. Nonetheless, this result was an improve- ment over her previous post-bronchodilator FEV1 and represents a clinically significant improvement in airflow. This response is compatible with a diagnosis of chronic persistent asthma with reversibility or 'asthmatic bronchitis', or 'a reversible component of COPD'. Here, we are dealing with labels again.


Table 5 Pulmonary function tests nine months after use of a beta agonist bronchodilator
FVC 4.501(111%*)
FEVi 2.71 1 (83%*)
FEVi/FVC 60%

* Percent of perdicted


The patient next moved out-of-state and was lost to direct follow-up. The author continued to approve albuterol metered dose inhalers by telephone for symptomatic relief. The patient finally succeeded in stopping smoking after her father offered her a $500 gift if she would completely stop smoking for a full year. With this incentive, she finally achieved total abstinence. At this time, she was 37. After picking a quit date, she stopped 'cold turkey'. She had moderate nicotine withdrawal symptoms of irrita- bility, poor concentration, and some emotional lab- ility with frequent crying. She did not take any of the over-the-counter nicotine replacement products (gum or patch), even though she was aware that these agents could be effective in reducing nicotine with- drawal symptoms. Her husband also stopped smok- ing at the same time. After three months, she no longer wanted a cigarette and found the odor of tobacco repulsive. At the time of stopping smoking she had already smoked 1.5 packs per day since beginning smoking 19 years before (28.5 pack years).

At the request of the author, the patient returned for a follow-up evaluation of her respiratory status, 13 years after the first evaluation. At age 40, she reported gaining nearly 50 pounds since she stopped smoking. Her current weight was 179 pounds. Most patients have much less weight gain on smoking cessation. Most commonly, this is no more than three-five kilograms, on an average. This degree of weight gain can usually be reversed over time through dietary manipulation and regular exercise.

She reported no chest infections since stopping. She frequently used her albuterol metered dose inhaler for symptoms of wheeze and dyspnea. She was not limited in her professional activities, or in her activ- ities of daily living. Her sister, who reported no pul- monary symptoms, accompanied her. Her sister's FVC and FEVi were normal.

On physical evaluation, the patient was now moderately obese, with blood pressure 140/80. An examination of the head and neck was normal. Breath sounds were normal. Deep breathing was associated with an expiratory wheeze. The expiratory time was prolonged to 8 s (normal is less than 6 s). Precordial activity was normal. No signs of pulmonary hyper- tension were present. Auscultation in the valvular areas revealed no murmurs. The abdominal and extremities examinations were normal. Clubbing and edema were absent.

The patient's pulmonary function evaluations on this visit are summarized on Table 6. The expiratory and inspiratory flow volume curve is presented in Fig. 8, in relation to the normal expiratory flow volume curve, a solid line. Note the position of the expiratory curve, which is shifted to the left, demon- strating hyperinflation and an elevated residual volume. The patient's post-bronchodilator FVC was now 4.62 1, which is 119% of predicted for age 40. This is 720 cc higher than the post-bronchodilator value obtained 13 years earlier.


Table 6 Pulmonary function tests at age 40, 13 years after initial
Pre-bronchodilator Post-bronchodilator
FVC 4.43(114%*) 4.62 (+4%)
FEV1 2.34 (77%) 2.32 (-1%)
FEV6/FVC 53%  
Diffusion 22.9 (25 ±7)  
RV 2.69 (141%*)  
TLC 6.80 (120%*)  

* Percent of predicted or predicted value.


Chart showing expiratory and inspiratory flow volume loops in patient.
Fig. 8 Expiratory and inspiratory flow volume loops in patient. Note hyperinflation and increased residual volume indicating trapping. No bronchodilator responsiveness is indicated.

This increased FVC was in spite of a nearly 50 pound weight gain, which tends to reduce the FVC. The patient's pre- bronchodilator FEVi was 2.34 1, 77% of predicted at age 40. There was no significant change following inhalation of a bronchodilating aerosol (2.32 1 or 1%). The patient's total lung capacity was 6.8 1, 120% of predicted. This represents an 860 cc increase in total lung capacity over 13 years. The patient's functional residual capacity was 2.69 1 (141% of predicted). This represents a 660 cc increase in functional residual capacity. Thus, her lungs are both hyperinflated and represent impaired emptying, as judged by the elevated residual volume. The patient's FEVi/FVC ratio is 53%. This is distinctly low, since a normal FEVi/FVC ratio for her age should be 77%.

The elevated forced vital capacity, elevated residual volume, and increased total lung capacity, all point to hyperinflation, a hallmark of the emphysema form of COPD. These values generally reduce slightly over time, and ordinarily would be lower after 13 years of follow-up. The fact that they are increased is highly significant. The forced vital capacity, of course, is the amount of air that can be blown out of fully inflated lungs. This is increased. The residual volume is that air which remains in the lungs after a forced expiration. This is also increased, representing what has commonly been called 'air-trapping'. This air-trapping is due to collapse of small airways, due to loss of elastic recoil, which occurs in emphysema. The patient's FEVi/FVC ratio is markedly reduced for two reasons. This is because the FEVi is only 77% of predicted, but the FVC is 114% of predicted. Thus, the numerator is low and the denominator is high. This is the reason why the FEVi as a percent of FVC is such a sensitive (if non-specific) indicator of the presence of airflow obstruction.

Her diffusion test results of 22.9, are almost iden- tical to those observed 13 years earlier. A normal diffusion test indicates an intact air-blood interface. But, loss of elastic recoil in emphysema may occur before the development of loss of alveolar surface.

In view of the patient's course thus far, does she have asthma, COPD, or both?

This patient's mild degree of airflow obstruction did not show a significant increase following inhalation of a beta agonist bronchodilator when initially seen, and on the evaluation 13 years later. However, there was a significant degree of improvement in FEVi in the nine-month interval between the original spirometric test and the follow-up, when she was clinically stable. The patient's symptom complex of episodes of cough, wheeze and dyspnea are consistent with asthma. This designation is consistent with the initial improvement of FEVi after nine months of the regular use of albu- terol for her symptoms of dyspnea, cough and wheeze. Her FEVi had improved to 83% of predicted, which is in the normal range. However, similar symp- toms occur in patients with 'asthmatic bronchitis,' one of the components of the spectrum of COPD.

When she was re-evaluated at age 40, her FEVi was now reduced to 77% of normal. On this occasion, there was no improvement in FEVi following inhala- tion of a beta agonist and bronchodilator. The FEVi/FVC ratio was quite abnormal. Also on this occasion, significant hyperinflation and increased total lung capacity, that is TLC and air trapping, with increased residual volume, were present. At this point in her disease progression, the correct diagnosis is the asthmatic bronchitis form of COPD and an emphysema component of COPD. It must be emphasized that the distinction between asthmatic bronchitis, COPD, and chronic irreversible asthma is not clear-cut.

Comment

This patient's pulmonary function changes over 13 years are indicative of the early course of the asthmatic bronchitis form of COPD. These results also point to an element of emphysema because of the hyperinflation and air-trapping. Thus, the 'bot- tom line' diagnosis here is COPD with components of both asthmatic bronchitis and emphysema. Does she have chronic bronchitis, too? Answer: Yes, but there is a huge overlap between asthmatic bronchitis and chronic bronchitis with the same symptoms and signs and spirometric tests. Asthmatic bronchitis and chronic bronchitis are probably the same disease. Becoming bogged down in semantics is not useful. This is why many prefer the all-encompassing term, COPD, for such patients. Postmortem studies in whole fresh excised human lungs demonstrate a loss of elastic recoil and increased TLC in early stages of emphysema.31 In human studies, an increased FVC is often seen, even with a decreasing FEVi.32 This is why the FEVi/FVC ratio is so sensitive in the detec- tion of COPD. With a decreased numerator (FEVi) and an increased denominator (FVC), the ratio drops early in the course of the disease. It is probably note- worthy that the patient's FEVi/FVC ratio dropped from 60% to 53% in the 13-year interval.

What is this patient's prognosis?

The prognosis of COPD relates to the rate of decline of FEVi over time and whether or not the patient is successful in abstinence from smoking.33 Those patients who stopped smoking in the Lung Health Study had slight increases in lung function over the first year after stopping, followed by a gradual decline in FEVi over the full five years.27 By contrast, the patients that continued to smoke had accelerated loss of FEVi, but not to the threshold of activity-limiting symptoms, which is an FEVi of approximately 1.5 1/s. Some patients are not limited by symptoms until their FEVi reaches 1.2 or less for an average-sized man or woman in their 50s or 60s.

This patient presented with features of asthma at age 27. By age 40, it is more appropriate to use the designation COPD because of the chronicity of her symptoms and evidence of irreversible airflow obstruction.

What were the risk factors that caused the COPD at an early age?

The risk factors in this patient are smoking, family history, and repeated chest infections during childhood.34 COPD is known to be a 'smoker's dis- ease which clusters in families, and worsens with age'. The patient had a very heavy smoking history, her most important risk factor. She also had a strong family history of emphysema. Both her mother and maternal grandfather were heavy smokers with rapidly progressive disease and premature death. The alpha-1-antitrypsin phenotypes of the patient and her mother were PIMM (normal) and the alpha-1-antitrypsin levels were within the normal range of 180-200. CLINICAL PHENOTYPES AND EARLY STAGE DISEASE

Today there's emerging emphasis on early identifica- tion and intervention in emphysema/COPD. Two initiatives are the National Lung Health Education Program35 and the Global Initiative in Obstructive Lung Disease.36 Both of these initiatives recognize that there is no recognizable clinical presentation of COPD in its early and asymptomatic stages. Although most patients are smokers, that is up to 85% of individuals who are suffering progressive and irre- versible losses of airflow obstruction, some 15% of patients are non-smokers. In order to identify these patients, the National Lung health Education Program recommends spirometric testing in all smokers age 45 or older and anyone with chronic cough, dyspnea, mucus hypersecretion or wheeze.37 It is only through the widespread use of spirometry that patients can be identified in early incipient stages. Stopping smoking, the use of bronchoactive and anti- inflammatory agents may well alter the early natural course of the disease. New therapies, including longer-acting anticholinergics,38 mucotropic drugs and imunomodulators, and monoclonal antibodies against inflammatory cytokines are on the horizon.

Spirometric testing will also identify patients with undiagnosed asthma, as well as patients with chronic asthma who have irreversible airflow obstruction due to airway remodeling.39

In summary, although there are recognizable clin- ical phenotypes in COPD, these manifestations are only present in advanced stages of disease. Today, therapy obliterates the phenotypic differences. Early stages of disease are not characterized by any recog- nizable symptoms, signs or X-ray abnormalities. Early identification of COPD through the widespread use of spirometers in all primary care physicians' offices and clinics, as well as specialists' offices, that is pulmonologists, cardiologists, and others is required at this time. A widespread grass-roots effort in early identification and intervention is the only thing that will change the prevalence and socioeco- nomic impact of this expanding disease spectrum.

REFERENCES

1. Petty T L, Miercort R, Ryan S et al. The functional and bronchographic evaluation of postmortem human lungs. Am Rev Respir Dis 1965; 92: 450-458.

2. Silvers G W, Maisel J C, Petty T L et al. Central airway resistance in excised emphysematous lungs. Chest 1972; 61: 603-612.

3. Silvers G W, Maisel J C, Petty T L et al. Flow limitation during forced expiration in excised human lungs. J Appi Physiol 1974; 36: 737-744.

4. Silvers G W, Petty T L, Stanford R E et al. The elastic properties of lobes of excised human lungs. Am Rev Respir Dis 1979; 120: 207-209.

5. Petty T L, Silvers G W, Stanford R E. Small airway disease is associated with elastic recoil changes in excised human lungs. Am Rev Respir Dis 1984; 130: 42^5. 6. Petty T L, Silvers G W, Stanford R E. Radial traction and small airways disease in excised human lungs. Am Rev Respir Dis 1986; 133: 132-135.

7. Silvers G W, Petty T L, Stanford R E. Elastic recoil changes in early emphysema. Thorax 1980; 35: 490-495.

8. Petty T L, Silvers G W, Stanford R E et al. Small airway pathology is related to increased closing capacity and abnormal slope of phase III in excised human lungs. Am Rev Respir Dis 1980; 121: 449^t56.

9. Petty T L, Silvers G W, Stanford R E. Mild emphysema is associated with reduced elastic recoil and increased lung size but not with airflow limitation. Am Rev Respir Dis 1987; 136: 867-871.

10. Petty T L, Nett L M, Finigan M M et al. A comprehensive care program for chronic airway obstruction. Methods and preliminary evaluation of symptomatic and functional improvement. Ann Intern Med 1969; 70: 1109-1120.

11. Petty T L, Brink G A, Miller M W et al. Objective functional improvement in chronic airway obstruction. Chest 1970; 57: 216-223.

12. Petty T L, Finigan M M. Clinical evaluation of prolonged ambulatory oxygen therapy in chronic airway obstruction. Am J Med 1968; 45: 242-252,

13. Petty T L, NeffT A, Creagh C E et al. Outpatient oxygen therapy in chronic obstructive pulmonary disease. A review of 13 years' experience and an evaluation of modes of therapy. Arch Intern Med 1979; 139: 28-32.

14. Petty T L (Chairman). Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease. A clinical trial. Nocturnal Oxygen Therapy Trial Group. Ann Int Med 1980; 93: 391-398.

15. Thurlbeck W M. Pathophysiology: Clinic pathologic correlations. In: Thurlbeck W M ed. Chronic obstructive lung disease, ch. 9. WB Saunders, Philadelphia 1976, p 456.

16. Dornhorst A C. Respiratory insufficiency (Frederick Price Memorial Lecture). Lancet 1955; 1: 1185-1187.

17. Reid L. Measurement of the bronchial moucous gland layer: a diagnostic yardstick in chronic bronchitis.

18. Mitchell R S, Ryan S F, Petty T L et al. The significance of morphologic chronic hyperplastie bronchitis. Am Rev Respir Dis 1966; 93: 720-729.

19. Niewoehner D E, Erbland M L, Deupree R H et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. N Engi J Med 1999; 340: 1941-1947.

20. van den Boom G, Ratten-van Molken M P, Molema J et al. The cost effectiveness of early treatment with fluticasone propionate 250 ug twice a day in subjects with obstructive airway disease. Results of the DIMCA program. Am J Respir Crit Care Med 2001; 164: 2057-2066.

21. Mountain R C, Zwillich C W, Weil J V. Hypoventilation in obstructive lung disease. The role of familial factors. N Engi J Med 1978; 298: 521-525.

22. Shapiro S D. The pathogenesis of emphysema: the elastase: antielastase hypothesis 30 years later. Proc Assoc of Am Physicians 1995; 107: 346-352.

23. Silverman E K, Pierce J A, Province M D et al. Variability of pulmonary function in alpha-1-antitrypsin deficiency: clinical correlates. Ann Intern Med 1989; 111: 982-991.

24. Gaillard M C, Kilroe-Smith T A, Noqueira C et al. Alpha-1-protease inhibitor in bronchial asthma: phenotypes and biochemical characteristics. Am Rev Respir Dis 1992; 145: 1311-1315.

25. Dunand P, Cropp G A, Middleton E Jr: Clinical conference: severe obstructive lung disease in a 14 year old girl with alpha-1-antitripsin deficiency. J Allergy Clin Immunol 1976; 57: 615-622.

26. Mannino D M, Gagnon R C, Petty T L et al. Obstructive lung disease and low lung function in adults in the United States: data from the National Health and Nutrition Examination Survey, 1988-1994. Arch Intern Med 2000; 160: 1683-1689.

27. Anthonisen N R, Connett J E, Kiley J P et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline ofFEVi. The Lung Health Study. JAMA 1994; 272: 1497-1505.

28. Tashkin D P, Altose M D, Connett J E et al. Methacholine reactivity predicts changes in lung function over time in smokers with early chronic obstructive pulmonary disease. The Lung health Study Research Group. Am J Respir Crit Care Med 1996; 153: 1802-1811.

29. Guyatt G H, Townsend M, Nogradi S et al. Acute response to bronchodilator. An imperfect guide for bronchodilator therapy in chronic airflow limitation. Arch Intern Med 1988; 148: 1949-1952.

30. Burrows B, Bloom J W, Traver G A et al. The course and prognosis of different forms of chronic airways obstruction in a sample from the general population. N Engi J Med 1987; 317: 1309-1314.

31. Petty T L, Silvers G W, Stanford R E. Mild emphysema is associated with reduced elastic recoil and increased lung size, but not with airflow limitation. Am Rev Respir Dis 1987; 136: 867-871.

32. Burrows B, Knudson R J, Camilli A E et al. The 'horse racing effect' and predicting the decline in forced expiratory volume in one second from screening spirometry. Am Rev Respir Dis 1987; 135: 788-793.

33. Peto R, Speizer F E, Cochrane A L et al. The relevance in adults of airflow obstruction, but not of mucus COPD: Clinical Phenotypes 351 hypersecretion, to mortality from chronic lung disease. Results from 20 years of prospective observation. Am Rev Respir Dis 1983; 128: 491-500.

34. Tager I B, Segal M R, Munoz A et al. The effect of maternal cigarette smoking on the pulmonary function of children and adolescents. Analyses of data from two populations. Am Rev Respir Dis 1987; 136: 1366-1370.

35. Petty T L, Weinmann G G. Building a national strategy for the prevention and management of and research in chronic obstructive pulmonary disease. JAMA 1997; 277: 246-253. 36. Pauwels R A, Buist S A, Calverley G et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Am J Respit Crit care Med 2001; 163: 1256-1276.

37. Ferguson G T, Enright P L, Buist S et al. Office spirometry for lung health assessment in adults: a consensus statement from the National Lung Health Education Program. Chest 2000;117: 1148-1161.

38. Barnes P J. Chronic Obstructive Pulmonary Disease. N Engi J Med 2000; 343: 269-280.

39. Brown P J, Greville H W, Finucane K E. Asthma and irreversible airflow obstruction. Thorax 1984; 39: 131-136. Date received: 12 April 2002. Date accepted: 18 April 2002.


Author for correspondence: T. L. Petty, NLHEP 1850 High Street, 80218 Denver, USA. Tel: 001 303 839 6755; E-mail: tlpdoc@ aol.com