Nosology is the discipline of classification and terminology of diseases. In this essay I define the general term “disease.” The features that govern the terminology of a particular disease are elucidated, using chronic obstructive pulmonary disease (COPD) as an illustration. J. G. Scadding (1–6) has suggested rules to govern the nosology of COPD and I have published some clarifications (7–10). An expanded version of this essay will appear as a book chapter (11).
Why undertake this task? More recent pulmonology literature shows differences in how expert panels approach definitions of disease (12–15). The definition and the diagnostic criteria of a particular disease or syndrome are often conflated. Confusing or erroneous terminology of disease has no immediate adverse effect on the care of patients as long as the diagnosis is correct, although patients may be confused about the nature of the disease from which they suffer. The main purpose of sound nosology is to enhance communication among researchers and health care givers. I hope this essay will reach and influence academic authors who undertake writing definitions, diagnostic criteria, or staging systems for diseases.
In the era of Hippocrates, disease was considered to be a morbid phenomenon sui generis; disease manifestations, such as fever, dropsy, diarrhea, or cyanosis, were used as names of diseases (16). In the terms of philosophy, this approach represents a realist or essentialist definition (17, 18). During the 17th century, Thomas Sydenham founded the discipline of nosology by insisting that diseases had their own natural history and could be described and classified on the basis of their specific characteristics (19). This concept did not have a major impact until the latter part of the 19th century, when the observational techniques of physical examination—percussion, auscultation, sphygmomanometry, and thermometry—had been developed (19, 20).
Current belief is that diseases are due to interactions between the host and one or more causes of disease, thus permitting an infinite number of interactions. Every patient's illness is unique. However, there are groups of patients who have some common features to their illness. We have developed diagnoses as names or verbal symbols for these diseases, which are important tools for effective communication. In the terms of philosophy, this approach represents a nominalist definition (17, 18). Given that nosology lumps together groups of unique patents with some common feature of a disease, it is not surprising that success in crafting definitions and diagnostic criteria is incomplete; some patients will not fit.
Popper (18) makes the point that scientists do not depend on definitions; all definitions can be omitted without loss to the information imparted. They take care that the statements made should never depend on the meaning of their terms. Terms are always a little vague (since they are used only in practical applications). Precision is attained not by reducing vagueness, but rather by keeping well within it; by carefully phrasing sentences in such a way that the possible shades of meaning do not matter.
I have modified Scadding's definition of the term “disease” (6):
The term disease is defined as a condition or state in a group of persons who have specified characteristics by which they differ from the norm in a way that is biologically disadvantageous. The name of the disease should refer succinctly to the etiology of the disease or the abnormal phenomena displayed by the affected group of persons.
The name of a disease should be as brief and descriptive as possible and need give no indication of its cause. Even when a disease is defined in terms of etiology, the diagnosis gives only limited information as to the disease manifestations in the sick person. The diagnosis of tuberculosis indicates that a disease caused by Mycobacterium tuberculosis is present, but gives little indication of the exact nature of the patient's illness or even whether an illness is overtly manifest.
There are three main features of terminology of particular diseases: the definition, diagnostic criteria, and a system for staging severity.
The defining characteristics of a disease are the common properties specifying the group of abnormal persons on whom the description of the disease is based (6). In the case of an infection, the microorganism causing the disease would be a defining characteristic. In a disease without a single etiology but with well-defined pathology, such as mitral stenosis, the pathology of the heart valve would be the defining characteristic. If etiology was not single, and pathology was not specific, well-defined pathophysiology would be used as a defining characteristic—in the case of COPD, nonremitting airflow obstruction. In the absence of a single etiology and specific alterations in structure or function, clinical findings, or a set of clinical findings (a syndrome), would be used as the defining characteristic.
Briefly, then, the characteristics specifying the population of interest may be an etiologic agent, a specified disorder of structure or function, or a consistent syndrome. These four levels indicate progressively decreasing knowledge of the disease and therefore decreasing priority as defining characteristics: etiology has the highest priority, altered structure or function, respectively, have intermediate priority, and clinical features have the lowest priority. Definitions based purely on etiology are most easily written for diseases caused by infectious agents and are almost impossible to write for chronic diseases with multiple risk factors; however, etiology can be included as part of a compound definition.
Compound definitions use defining characteristics from two or more fields of study and define subsets of patients with overlapping characteristics (6). For example, pneumococcal pneumonia represents an overlapping subset of patients with pneumonia (defined in pathologic terms) and infection with Streptococcus pneumoniae (defined in etiologic terms).
Diagnostic criteria are features of the disease that are found by empiric research to best distinguish the disease from other diseases that resemble it; they may or may not include features of the defining characteristics and frequently contain disease features that do not appear in the definition. When the defining characteristic is clinically based, the diagnostic criteria must include them.
As pointed out earlier, definitions are useful in communication but they are not critical to doing good clinical or scientific work. On the other hand, diagnostic criteria, which will vary depending on how they are to be used, are critically important for both sound clinical and research work. They should be specified as precisely as possible.
Staging systems may be based on clinical features, pathophysiology, the pathology, or a combination of features. The features used in staging should be validated by comparison with independent outcome variables such as mortality, morbidity, health status, or medical resource utilization. The cut points used in establishing grades of severity are usually arbitrary but should be tied to outcome variables as closely as possible.
Patients meeting diagnostic criteria should undergo additional study by available means, thus extending the description of the disease. As more information becomes available, the description, definition, and diagnostic criteria may undergo revision, although we do not usually redefine the disease to include inconstant features.
In the mid 20th century the high morbidity and mortality from chronic obstructive respiratory diseases resulted in initiation of epidemiologic studies (21–23). In 1958, a Ciba Guest Symposium led to published definitions of disorders associated with chronic airflow obstruction (24). Similar definitions were published by the American Thoracic Society in 1962 (25).
Chronic obstructive pulmonary disease afflicts a group of persons with longstanding exposure to cigarette smoke and other toxic inhalants. These persons have nonremitting airflow obstruction of variable severity, which is associated with airway hyperreactivity, chronic productive cough, and decreased tolerance for exercise. As the disease progresses, hypoxemia followed by hypercapnia and worsening hypoxemia supervenes. Cor pulmonale may be manifest. Altered oxidant–antioxidant balance, circulating levels of inflammatory mediators and acute-phase proteins, weight loss, loss of muscle mass, and muscle dysfunction are evidence of a systemic component to the disease (10, 26, 27).
Definitions of COPD have been prepared by expert panels of the American Thoracic Society in 1995 (12), the European Respiratory Society in 1995 (13), the British Thoracic Society in 1997 (14), and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) in 2001 (15).
Chronic obstructive pulmonary disease is defined as a disease state characterized by the presence of airflow obstruction due to chronic bronchitis or emphysema; the airflow obstruction is generally progressive, may be accompanied by airway hyperreactivity, and may be partially reversible.
This compound definition uses the combination of chronic bronchitis defined in clinical terms, emphysema in anatomical terms, and airflow obstruction representing a physiologic state. The report (12) states:
Patients with chronic airflow obstruction that is not due to chronic bronchitis, emphysema, or persistent asthma are not considered to have COPD, for example, patients with cystic fibrosis or obliterative bronchiolitis. Readers are referred to two excellent reviews that discuss other causes of chronic airflow limitation (28, 29).
COPD is diagnosed in patients with airflow obstruction and either chronic bronchitis or emphysema. Most patients with COPD have both chronic bronchitis and emphysema.
Although the lack of specificity of the airway pathology in chronic bronchitis precludes its use as a defining characteristic, the pathology is well described and we know that bronchiolitis is a cause of airflow obstruction in COPD, in addition to the loss of elastic recoil and rupture of alveolar attachments to small airways caused by emphysema.
Asthma and not COPD is diagnosed in patients with asthma who have completely reversible airway obstruction. It is difficult to distinguish patients with nonremitting asthma from patients with chronic bronchitis or emphysema who have airway hyperreactivity and such patients are included within the rubric COPD.
COPD is defined as a disorder characterized by reduced maximum expiratory flow and slow forced emptying of the lungs, features which do not change markedly over several months. Most of the airflow limitation is slowly progressive and irreversible. The airflow limitation is due to varying combinations of airway disease and emphysema; the relative contribution of the two processes is difficult to define in vivo.
This report (13) reviews the mechanisms of production of airflow obstruction by small airway disease and by emphysema.
It is pointed out that patients with COPD often exhibit minimal reversibility of airflow obstruction with bronchodilators and that airway hyperresponsiveness and recurrent or persistent cough is common. It is usually, but not always, possible to distinguish between asthma and COPD.
By convention, a number of specific causes of chronic airflow obstruction, including cystic fibrosis, bronchiectasis, and bronchiolitis obliterans, have been excluded from COPD.
COPD is defined as a chronic, slowly progressive disorder characterized by airways obstruction (FEV1 < 80% predicted and FEV1/FVC ratio < 70%) which does not change markedly over several months. The impairment of lung function is largely fixed but is partially reversible by bronchodilator (or other) therapy.
The report (14) states the following:
COPD arises from varying combinations of airway disease and pulmonary emphysema; it is difficult to define the relative importance of each in an individual patient.
Chronic bronchitis, defined as chronic productive cough for at least 3 months in each of two successive years, does not necessarily signify the presence of airway obstruction.
The differentiation of severe COPD from chronic severe asthma is difficult, since some improvement in FEV1 (reversibility) can often be produced by bronchodilator therapy. Unlike asthma, airflow limitation in COPD as measured by the FEV1 can never be returned to normal values.
Most (but not all) cases of COPD are caused by tobacco smoking.
The term COPD is not conventionally used to include other specific conditions that can cause airway obstruction such as cystic fibrosis, bronchiectasis, or bronchiolitis obliterans.
Most recently, an international workshop on COPD, the Global Initiative for Chronic Obstructive Lung Disease (15), based their definition on physiology, etiology, and pathology:
COPD is a disease state characterized by airflow limitation that is not fully reversible. The airflow obstruction is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.
The workshop report states the following:
Airflow limitation is measured by spirometry, as this is the most widely available, reproducible test of lung function.
The authors state that the terms emphysema and chronic bronchitis were not used in the GOLD report because the term emphysema is often incorrectly used clinically; emphysema is only one of several structural abnormalities present in the lungs of persons with COPD. Chronic bronchitis, essentially chronic productive cough for at least 2 months in each of two successive years, remains a clinically and epidemiologically useful term. However, it does not reflect the major impact of airflow limitation on morbidity and mortality of patients with COPD. Also, productive cough may precede the development of airflow limitation; conversely, some patients develop significant airflow limitation without chronic cough and sputum production.
Airflow limitation in asthma is often completely reversible, either spontaneously or with treatment, whereas in COPD it is never completely reversible. Some patients have features of both diseases, with asthma-like and COPD-like inflammation. Although asthma can usually be differentiated from COPD, this is not possible in some patients.
Poorly reversible airflow limitation associated with bronchiectasis, cystic fibrosis, tuberculosis, or asthma is not included except insofar as these conditions overlap with COPD.
In the combination of their definitions, discussions, and diagnostic criteria, which are here called “diagnostic systems,” all four expert panels make essentially the same key points:
Irreversible airflow obstruction is a cardinal feature of COPD.
Limited reversibility of airflow obstruction in response to bronchodilator drugs is common; the absence of such reversibility does not preclude bronchodilator treatment.
Asthma with complete reversibility is not included within the rubric COPD.
Chronic airflow obstruction due to other diagnosable conditions such as cystic fibrosis, obliterative bronchiolitis, or panbronchiolitis is not included in COPD.
Tobacco smoking is the major, but not the only, risk factor for COPD.
The cause of the irreversible airflow obstruction in COPD is the presence in the lungs of bronchiolitis or small airway disease, and emphysema, which are present in a variable mix among patients.
There are some differences among the four systems. All four systems exclude from the diagnosis COPD those patients with emphysema or chronic bronchitis who do not have airflow obstruction. The progressive nature of airflow obstruction is clearly described in all four systems but is part of the definition of the European Respiratory Society 1995 system (13), the British Thoracic Society 1997 system (14), and the GOLD system (15). The American Thoracic Society 1995 system does not give spirometric criteria for airflow obstruction; specifically, it does not mention the use of a decreased FEV1/FVC ratio as an indicator of airflow obstruction; the European Respiratory Society 1995 system does so and makes the point that the ratio is a relatively sensitive index of mild airflow limitation. The British Thoracic Society 1997 system and the GOLD system both stress the spirometric diagnosis of airflow obstruction and require both an FEV1/FVC ratio < 70% and an FEV1 < 80% predicted. The GOLD system specifies that the spirometric measurements should be made after bronchodilator treatment. The GOLD staging system (16) classifies patients with normal spirometry but chronic cough or sputum production as “at risk” (of COPD) with a severity grade of “0.” The intent of the “0” stage appears to be to encourage intensified efforts at primary prevention.
A major strength of the GOLD definition (15) is its widespread acceptance, simplicity, and emphasis on spirometry as the standard for the diagnosis of airflow obstruction. This approach should permit reasonable comparisons among various populations in different countries.
Inflammation may be defined as “the response of tissues to injury.” Accordingly, the meaning of the term “…abnormal inflammatory response of the lungs…” in the GOLD definition is not clear. I suggest that the next iteration of the GOLD definition might read as follows:
COPD is a disease state characterized by incompletely reversible, progressive airflow obstruction that is associated with inflammation in the lungs due to prolonged exposure to tobacco smoke and other noxious particles and gases.
The literature on COPD often uses the terms airflow limitation and airflow obstruction as synonyms. Expiratory airflow can be limited by severe restrictive disease or impaired muscle function, although the use of the FEV1/FVC ratio in the staging system should exclude these conditions. Airflow obstruction means that something is blocking the expiratory flow of air. As pointed out earlier, in COPD the airflow obstruction is due either to bronchiolitis or, with emphysema, to collapse of small airways due to loss of elastic recoil and small airway tethering, which cause closure of small airways at abnormally large lung volumes during exhalation. Bronchiolitis and collapse of small airways in emphysema cause airway narrowing. The term “airflow obstruction” seems preferable to “airflow limitation.”
Emphysema has been defined in morphologic terms since the Ciba symposium (24). There have been clarifications from time to time (30, 31). In the latest of these (31), emphysema was defined as follows:
Emphysema is defined as a condition of the lung characterized by abnormal permanent enlargement of the airspaces distal to the terminal bronchioles accompanied by destruction of their walls and without obvious fibrosis. Destruction is defined as non-uniformity in the pattern of respiratory airspace enlargement; the orderly appearance of the acinus and its components is disturbed and may be lost. Emphysema may occur with or without airflow obstruction.
In 1985, the expert panel (31) also defined a condition termed airspace enlargement with fibrosis:
Air space enlargement with fibrosis occurs with obvious fibrosis, associated with infectious granulomatous disease such as tuberculosis, noninfectious granulomatous disease such as sarcoidosis, or fibrosis of undetermined etiology. The scarring is readily evident in the chest radiograph, or in the inflation-fixed lung specimen, and is apparent to the naked eye. This form of airspace enlargement with fibrosis was formerly termed irregular or paracicatricial emphysema. It is not included under the umbrella of COPD, although it may occur with or without airflow obstruction.
The separation of airspace enlargement with fibrosis and emphysema is not as clean as was formerly thought. One review (32) presents evidence suggesting that emphysema is multifactorial in its pathogenesis and respiratory airspace enlargement is a stereotyped response of the lungs to a variety of injuries. Microscopic fibrosis is observed in the mild airspace enlargement of centriacinar emphysema (33); biochemically, collagen concentration is increased in these lesions (34, 35). These lesions may represent a form of focal airspace enlargement with fibrosis. It is time to remove the phrase “without obvious fibrosis” from the 1985 definition of emphysema (31). Also, it seems preferable to use the term “scar emphysema,” rather than airspace enlargement with fibrosis, and to include the condition under the rubric COPD.
Scar emphysema is defined as respiratory air space enlargement occurring with obvious fibrosis that is associated with infectious or noninfectious granulomatous disease, pneumoconiosis, or fibrosis of undetermined etiology. The scarring is readily evident in the chest radiograph and is apparent to the naked eye in the inflation-fixed lung specimen. Scar emphysema may occur with or without airflow obstruction.
The diagnosis of a patient with a fibrosing condition of the lungs, who has scar emphysema with chronic airflow obstruction, should include a primary diagnosis concerning the cause of scarring (e.g., tuberculosis), with COPD as a secondary diagnosis.
Tobacco smoking has been identified as the major risk factor for the development of COPD (36, 37), accounting for 80 to 90% of the risk for developing the disease in the United States (38, 39). The proportion of risk attributable to tobacco smoking is less in developing countries, where occupational, environmental, and domestic air pollution play a much larger role.
Since 1990, experimental exposure of rodents to cigarette smoke has been shown to consistently produce emphysema (40, 41). The emphysema is mild, requiring about 6 months of smoke exposure for its induction. The strong epidemiologic evidence indicting cigarette smoke as a risk factor for COPD proves an association between cigarette smoke exposure and COPD. The evidence that prolonged cigarette smoke induces emphysema in rodents establishes an etiologic role for cigarette smoke exposure in COPD.
However, there are multiple risk factors, not all identified. Although α1-antitrypsin deficiency is the only proven genetic susceptibility, others must exist. Studies indicate that inhalation of smoke from burning biomass fuels in unventilated indoor spaces accounts for more than 400,000 persons with COPD in the developing world (42). Other, minor risk factors include exposure to siliceous dusts and irritant gases and particulate urban air pollutants less than 10 μm in diameter (43). There are also possible roles for infection and atopy (39). It is thus inappropriate to attempt to write a purely etiology-based definition for COPD at this time.
Diagnostic criteria are much more important than definitions in either clinical practice or research. As long as diagnostic criteria are clearly stated, the definition does not matter. It is the diagnostic criteria and not the definition that determine the diagnosis of a particular patient's disease. It is the diagnostic criteria and the specific inclusion and exclusion criteria that determine the precise makeup of a population of research participants.
A diagnosis of COPD requires a history of chronic progressive symptoms (cough, sputum production, wheeze, or dyspnea). Physical examination may reveal evidence of airflow obstruction in the form of wheezes on auscultation or the forced expiratory time may be found to be prolonged (44). However, objective evidence of airflow obstruction determined by forced expiratory spirometry is the standard for demonstrating and quantifying airflow obstruction. Indices such as the FEV1 and FEV1/FVC ratio should be measured after bronchodilator drug inhalation. It may also be necessary in some instances to show that spirometric values do not return to normal with treatment over an extended period of time. (The spirometric criteria for airflow obstruction were discussed earlier.) There will usually but not always be a history of prolonged cigarette smoking; risk factors such as the inhalation of toxic gases and particles should be sought. Other diseases causing airflow obstruction should be excluded by CXR and other appropriate studies.
Staging the severity of a disease can be helpful in establishing a prognosis, in setting standards for appropriate investigation of patients, in making recommendations for treatment, and for allocating healthcare resources. Staging should ideally be based on a composite of factors including symptoms, severity of airflow obstruction, degree of blood gas abnormality, and a measure of the systemic effects of the illness such as body mass index. Obviously, one would like the predictive power of a staging system to be as great as possible. The staging of a disease should be based on correlative studies; for example, there should be a strong correlation between stage of the disease and mortality data. Such a correlation exists between FEV1 and mortality (45) and between body mass index and mortality (46). Although there is a relation between severity of airflow obstruction and outcome variables, as noted earlier, the development of cut points to define several stages is arbitrary. The staging systems recommended by the four expert panels (12–15) are based mainly on spirometry (Table 1)
. The reasons for the quite different cut points among the four systems are not clear.The members of the international academic community who serve on expert panels that define and develop diagnostic criteria and stage pulmonary diseases need to agree on a set of rules that will govern nosology. An international expert panel should then be convened to resolve the differences that now exist in the diagnostic criteria and staging of COPD. Agreement on a definition is less important but would enhance communication between the pulmonary and primary care communities.
The author thanks Stephen Rennard, Neil Pride, and four anonymous reviewers for valuable suggestions during the writing of this essay
| 1. | Scadding JG. Principles of definition in medicine. Lancet 1959;1:323–325. |
| 2. | Scadding JG. Meaning of diagnostic terms in bronchopulmonary disease. BMJ 1963;2:1425–1430. |
| 3. | Scadding JG. The semantics of medical diagnosis. Biomed. Comput. 1972;3:83–90. |
| 4. | Scadding JG. Talking clearly about bronchopulmonary diseases. In: Scadding JG, Cumming G, editors. Scientific foundations of respiratory medicine. Philadelphia: W. B. Saunders; 1981. Chapter 2. |
| 5. | Scadding JG. Health and disease: what can medicine do for philosophy? J Med Ethics 1988;14:118–124. |
| 6. | Scadding JG. Definition of asthma. In: Weiss EB, Stein M, editors. Bronchial asthma, mechanisms and therapeutics, 3rd ed. Boston: Little Brown; 1993. p. 1–13. |
| 7. | Snider GL. Pathogenesis and terminology of emphysema [letter]. Am J Respir Crit Care Med 1994;149:1382–1383. |
| 8. | Snider GL. What's in a name? Names, definitions, descriptions, and diagnostic criteria of diseases, with emphasis on chronic obstructive pulmonary disease. Respiration 1995;62:297–301. |
| 9. | Snider GL. Defining chronic obstructive pulmonary disease. In: Calverley PMA, Pride NB, editors. Chronic obstructive pulmonary disease, 1st ed. London: Chapman & Hall; 1995. p. 1–9. |
| 10. | Piquette CA, Rennard SI, Snider GL. Chronic bronchitis and emphysema. In: Murray JF, Nadel JA, Mason RJ, Boushey HA Jr, editors. Textbook of respiratory medicine, 3rd ed. Philadelphia: W. B. Saunders; 2000. p. 1187–1246. |
| 11. | Snider GL. Defining chronic obstructive pulmonary disease. In: Calverly PMA, MacNee W, Rennard S, Pride NB, editors. Chronic obstructive pulmonary disease, 2nd ed. London: Arnold; 2003. |
| 12. | American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease [official statement]. Am J Respir Crit Care Med 1995;152:S77–S121. |
| 13. | Siafakas NM, Vermeire P, Pride NB, Paoletti P, Gibson J, Howard P, Yernault JC, Decramer M, Higenbottam T, Postma DS, et al. Optimal assessment and management of chronic obstructive pulmonary disease (COPD). European Respiratory Society Task Force. Eur Respir J 1995;8:1398–1420. |
| 14. | British Thoracic Society Group of the Standards of Care Committee. BTS guidelines for the management of chronic obstructive pulmonary disease. COPD Guidelines Group of the Standards of Care Committee of the BTS. Thorax 1997;52:S1–S28. |
| 15. | Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163:1256–1276. |
| 16. | Adams F. The genuine works of Hippocrates, translated from the Greek, with a preliminary discourse and annotations. Vol. II: aphorisms iii-12 and iii-31. London: Sydenham Society; 1849. |
| 17. | Crookshank FG. The importance of a theory of signs and a critique of language in the study of medicine. In: Ogden CK, Richards IA, editors. The meaning of meaning [first published in 1923]. New York: Harcourt Brace Jovanovich; 1956. p. 327–355. |
| 18. | Popper KR. The open society and its enemies. Princeton, NJ: Princeton University Press; 1963. |
| 19. | Garrison FH. History of medicine. Philadelphia, NJ: W. B. Saunders; 1929. |
| 20. | Feinstein AR. An analysis of diagnostic reasoning. 1. The domains and disorders of clinical macrobiology. Yale J Biol Med 1973;46:212–232. |
| 21. | Reid LM. Pathology of chronic bronchitis. Lancet 1954;1:275–279. |
| 22. | Oswald NC, Medvei VC. Chronic bronchitis; the effect of cigarette smoking. Lancet 1955;2:843–844. |
| 23. | Stuart-Harris CH, Hanley T, Clifton M, Platts MM, Hammond JDS, Whitaker W. Chronic bronchitis, emphysema and cor pulmonale. Bristol, UK: John Wright and Sons; 1957. |
| 24. | Ciba Foundation Guest Symposium. Terminology, definitions and classification of chronic pulmonary emphysema and related conditions. Thorax 1959;14:286–299. |
| 25. | American Thoracic Society. Chronic bronchitis, asthma and pulmonary emphysema: a statement by the Committee on Diagnostic Standards for Nontuberculous Respiratory Diseases. Am Rev Respir Dis 1962;85:762–768. |
| 26. | Maltais F, LeBlanc P, Jobin J, Casaburi R. Peripheral muscle dysfunction in chronic obstructive pulmonary disease. Clin Chest Med 2000;21:665–677. |
| 27. | Wouters EFM, Creutzberg EC, Schols AMJW. Systemic effects of COPD. Chest 2002;121:127S–130S. |
| 28. | Girod CE, Schwartz MI. Other large-airway diseases that limit airflow. In: Voelkel NF, MacNee W, editors. Chronic obstructive lung diseases. Hamilton, ON, Canada: B. C. Decker; 2002. p. 184–198. |
| 29. | Girod CE, Schwartz MI. Diffuse interstitial lung diseases resulting in airflow limitation. In: Voelkel NF, MacNee W, editors. Chronic obstructive lung diseases. Hamilton, ON, Canada: B. C. Decker; 2002. p. 199–213. |
| 30. | World Health Organization. Epidemiology of chronic non-specific lung disease. Bull World Health Organ 1975;132:182–185. |
| 31. | National Heart Lung and Blood Institute. The definition of emphysema: report of a Division of Lung Diseases workshop. Am Rev Respir Dis 1985;132:182–185. |
| 32. | Snider GL. Emphysema: the first two centuries—and beyond: a historical overview, with suggestions for future research [part 2]. Am Rev Respir Dis 1992;146:1615–1622. |
| 33. | Leopold JG, Gough J. The centrilobular form of hypertrophic emphysema and its relation to chronic bronchitis. Thorax 1957;12:219–235. |
| 34. | Cardoso WV, Sekhon HS, Hyde DM, Thurlbeck WM. Collagen and elastin in human pulmonary emphysema. Am Rev Respir Dis 1993;147:975–981. |
| 35. | Lang MR, Fiaux GW, Gillooly M, Stewart JA, Hulmes DJ, Lamb D. Collagen content of alveolar wall tissue in emphysematous and non-emphysematous lungs. Thorax 1994;49:319–326. |
| 36. | U.S. Department of Health and Human Services. The health consequences of smoking: chronic obstructive lung disease. Washington, DC: U.S. Government Printing Office; 1984. USDHHS Publication No. 84–50205. |
| 37. | Davis RM, Novotny TE. The epidemiology of cigarette smoking and its impact on chronic obstructive pulmonary disease. Am Rev Respir Dis 1989;140:S82–S84. |
| 38. | Burrows B, Knudson RJ, Cline MG, Lebowitz MD. Quantitative relationships between cigarette smoking and ventilatory function. Am Rev Respir Dis 1977;115:195–205. |
| 39. | Silverman EK, Speizer FE. Risk factors for the development of chronic obstructive pulmonary disease. Med Clin North Am 1996;80:501–522. |
| 40. | Wright JL, Churg A. Cigarette smoke causes physiologic and morphologic changes of emphysema in the guinea pig. Am Rev Respir Dis 1990;142:1422–1428. |
| 41. | Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 1997;277:2002–2004. |
| 42. | Smith KR. Inaugural article: national burden of disease in India from indoor air pollution. Proc Natl Acad Sci USA 2000;97:13286–13293. |
| 43. | Garshick E, Schenker MB, Dosman JA. Occupationally induced airways obstruction. Med Clin North Am 1996;80:851–878. |
| 44. | Straus SE, McAlister FA, Sackett DL, Deeks JJ. Accuracy of history, wheezing, and forced expiratory time in the diagnosis of chronic obstructive pulmonary disease. J Gen Intern Med 2002;17:684–688. |
| 45. | Hodgkin JE. Prognosis in chronic obstructive pulmonary disease. Clin Chest Med 1990;11:555–569. |
| 46. | Landbo C, Prescott E, Lange P, Vestbo J, Almdal TP. Prognostic value of nutritional status in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160:1856–1861. |
