Small Airways and Interstitial Pulmonary Disease
1980; Elsevier BV; Volume: 77; Issue: 4 Linguagem: Inglês
10.1378/chest.77.4.470
ISSN1931-3543
AutoresJack D. Fulmer, William C. Roberts,
Tópico(s)Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
ResumoThe concept of disease of the small airways was introduced in 1968 by Hogg and associates.1Hogg JC Macklem PT Thurlbeck WM Site and nature of airway obstruction in chronic obstructive lung disease.N Engl J Med. 1968; 278: 1355-1360Crossref PubMed Scopus (978) Google Scholar These workers defined the site and nature of obstruction of the airways in chronic obstructive pulmonary disease (COPD) at the small airways. Morphologically, small (less than 2 mm) airways were narrowed or obliterated by inflammation, mucus, or fibrosis. The concept of two components to disease of the small airways was introduced by them, ie, a reversible component due to acute inflammation or mucous plugging and an irreversible component due to fibrosis, distortion, and narrowing or obliteration of small airways. These findings suggested that disease of the small airways may be one of the earliest changes in COPD, and current data strongly support that suggestion.2Cosio M Ghezzo H Hogg JC et al.The relations between structural changes in small airways and pulmonary function tests.N Engl J Med. 1977; 298: 1277-1281Crossref Scopus (608) Google Scholar, 3Thurlbeck WM Changes in lung structure.in: Macklem PT Permutt S The lung in the transition between health and disease. Marcel Dekker, Inc, New York1979: 17-41Google Scholar, 4Macklem PT Changes in lung mechanics: pressure-volume and pressure-flow relations.in: Macklem PT Permutt S The lung in the transition between health and disease. Marcel Dekker, Inc, New York1979: 53-71Google Scholar The role of small airway disease in the eventual development of COPD, particularly emphysema, is unclear;3Thurlbeck WM Changes in lung structure.in: Macklem PT Permutt S The lung in the transition between health and disease. Marcel Dekker, Inc, New York1979: 17-41Google Scholar, 4Macklem PT Changes in lung mechanics: pressure-volume and pressure-flow relations.in: Macklem PT Permutt S The lung in the transition between health and disease. Marcel Dekker, Inc, New York1979: 53-71Google Scholar however, it is likely that small airway disease contributes to trapping of air and mechanical disruption of alveolar septae4Macklem PT Changes in lung mechanics: pressure-volume and pressure-flow relations.in: Macklem PT Permutt S The lung in the transition between health and disease. Marcel Dekker, Inc, New York1979: 53-71Google Scholar and to the development of a distal chronic alveolitis. Once this last process has been initiated, the release of macrophagic or neutrophilic proteases may result in degradation of elastin and subsequent emphysema.5Kuhn C Senior RM The role of elastases in the development of emphysema.Lung. 1978; 155: 185-197Crossref Scopus (34) Google ScholarIn contrast to its occurrence in COPD, disease of the small airways was not considered to be a part of interstitial pulmonary disease until recently. Although grouped together because of common clinical, roentgenographic, physiologic, and morphologic features, interstitial pulmonary diseases are heterogeneous and have a variety of causes.6Fulmer JD Crystal RG Interstitial lung diseases.in: Simmons DE Current pulmonology. 1. Houghton Mifflin Professional Publishers, Boston1979: 1-65Google Scholar Just as COPD is characterized by an obstructive ventilatory defect with normal or increased pulmonary volumes, interstitial pulmonary disease has classically been characterized by a restrictive defect (reduced pulmonary volumes and compliance) without evidence of obstruction to airflow.6Fulmer JD Crystal RG Interstitial lung diseases.in: Simmons DE Current pulmonology. 1. Houghton Mifflin Professional Publishers, Boston1979: 1-65Google Scholar Because interstitial pulmonary disease is characterized morphologically by fibrosis of the supporting tissues of lung, primarily alveolar interstitium,6Fulmer JD Crystal RG Interstitial lung diseases.in: Simmons DE Current pulmonology. 1. Houghton Mifflin Professional Publishers, Boston1979: 1-65Google Scholar the concept of a restrictive ventilatory defect in this disorder is easy to accept. However, recent physiologic and morphologic observations indicate that disease of the small airways is not limited to COPD and that many of the morphologic and pathophysiologic features of COPD may be evident in interstitial pulmonary disease.Although narrowing of small airways in acute idiopathic pulmonary fibrosis was mentioned by Hamman and Rich7Hamman L Rich AR Acute diffuse interstitial fibrosis of the lungs.Bull Johns Hopkins Hosp. 1944; 74: 177-212Google Scholar in their original communication, only recently has emphasis been placed on small airways in interstitial pulmonary disease. Except for the “bronchiolitis obliterans interstitial pneumonia” described by Liebow and Carrington,8Liebow AA Carrington CB Alveolar diseases: the interstitial pneumonias.in: Simon M Potchen EJ LeMay M Frontiers of Pulmonary Radiology. Grune and Stratton, Inc, New York1967: 102-141Google Scholar most reports have concentrated on alveolar pathologic abnormalities. The suggestion that functional alterations in interstitial pulmonary disease were consistent with small airway disease was made in 1973 by Ostrow and Cherniack9Ostrow D Cherniack RM Resistance to airflow in patients with diffuse interstitial lung disease.Am Rev Respir Dis. 1973; 108: 205-210PubMed Google Scholar and subsequently by Yernalt et al.10Yernalt JC Dejoinghe M DeCoster A et al.Pulmonary mechanics in diffuse fibrosing alveolitis.Bull Physiopathol Respir. 1975; 11: 231-244PubMed Google Scholar Both groups found that some patients with interstitial pulmonary disease had evidence of increased resistance to airflow in small airways. In a study of 29 patients with idiopathic pulmonary fibrosis we11Roberts WC Histologic observations in idiopathic pulmonary fibrosis. (pp 773-776). In: Crystal RG (moderator). Idiopathic pulmonary fibrosis: clinical, histologic, radiographic, physiologic, scintigraphic, cytologic, and biochemical aspects.Ann Intern Med. 1976; 85: 769-788Crossref PubMed Scopus (501) Google Scholar found small airways to be narrowed in 20 patients (70 percent). A detailed physiologic-morphologic correlative study of 18 of these 29 patients was made by obtaining pulmonary tissue and performing detailed testing of pulmonary function in the same patients.12Fulmer JD Roberts WC Von gal ER et al.Small airways in idiopathic pulmonary fibrosis: comparison of morphologic and physiologic observations.J Clin Invest. 1977; 60: 595-610Crossref PubMed Scopus (96) Google Scholar Seventeen (94 percent) had peribronchiolar fibrosis or inflammation or bronchiolitis, and 12 (71 percent) of these 17 had narrowed small airways.12Fulmer JD Roberts WC Von gal ER et al.Small airways in idiopathic pulmonary fibrosis: comparison of morphologic and physiologic observations.J Clin Invest. 1977; 60: 595-610Crossref PubMed Scopus (96) Google Scholar Furthermore, a good correlation was seen between the finding of narrowed small airways in the specimens from biopsy and two physiologic studies considered to be useful detectors of small-airway disease, ie, dynamic compliance and maximum expiratory flow-volume curves. Our study demonstrated that idiopathic pulmonary fibrosis is a disease that can involve small airways and that physiologic studies can define the function of small airways in this disease. Subsequent studies have shown that other diseases with pulmonary morphologic changes that can be indistinguishable from idiopathic pulmonary fibrosis (interstitial pulmonary disease associated with specific collagen vascular diseases and essential mixed cryoglobulinemia) may also have physiologic alterations consistent with disease of the small airways.13Guttadauria M Ellman H Emmanuel G et al.Pulmonary function in scleroderma.Arthritis Rheumatism. 1977; 20: 1071-1079Crossref PubMed Scopus (62) Google Scholar, 14Wohlgelernter D Loke J Matthay RA et al.Systemic and discoid lupus erythematosis: analysis of pulmonary function.Yale J Biol Med. 1978; 51: 157-164PubMed Google Scholar, 15Bombardieri S Paoletti P Ferri C et al.Lung involvement in essential mixed cryoglobulinemia.Am J Med. 1979; 66: 748-755Abstract Full Text PDF PubMed Scopus (113) Google ScholarGranulomatous interstitial pulmonary disease may also involve small airways. Young and associates16Young Jr, RC Carr C Shelton TG et al.Sarcoidosis: relationship between changes in lung structure and function.Am Rev Respir Dis. 1967; 95: 224-238PubMed Google Scholar in 1967 demonstrated such an involvement by graulomata in patients with sarcoidosis. Although these workers noted no evidence of obstruction to airflow on simple spirometric testing, this publication preceded our current concepts of the relative insensitivity of this test to mild degrees of obstruction to airflow. Subsequent studies have shown that granulomata can involve small airways and that patients with sarcoidosis can have physiologic alterations consistent with disease of the small airways.17Young Jr, RC Headings VE Bose S et al.Alpha-1 antitrypsin levels in sarcoidosis: relationship to disease activity.Chest. 1973; 64: 39-45Crossref PubMed Scopus (6) Google Scholar, 18Kaneko K Sharma OP Airway obstruction in pulmonary sarcoidosis.Bull Eur Physiopathol Respir. 1977; 13: 231-240PubMed Google Scholar, 19Levinson RS Metzger LF Stanley NN et al.Airway function in sarcoidosis.Am J Med. 1977; 62: 51-59Abstract Full Text PDF PubMed Scopus (68) Google Scholar, 20Carrington CB Gaensler EA Mikus JP et al.Structure and function in sarcoidosis.NY Acad Sci. 1976; 278: 265-283Crossref PubMed Scopus (140) Google ScholarAt least three occupational or environmental interstitial diseases (hypersensitivity pneumonitis, asbestosis, and coal dust disease) have been shown to have physiologic alterations consistent with disease of the small airways.21Allen DH Williams GV Woolcock AJ Bird breeders’ hypersensitivity pneumonitis: progress studies of lung function after cessation of exposure to the provoking antigen.Am Rev Respir Dis. 1976; 114: 555-566PubMed Google Scholar, 22Jodoin G Gibbs GW Macklem PT et al.Early effects of asbestos exposure on lung function.Am Rev Respir Dis. 1971; 104: 525-535PubMed Google Scholar, 23Seaton A Lapp NL Morgan WKC Lung mechanics and frequency dependence of compliance in coal miners.J Clin Invest. 1972; 51: 1203-1211Crossref PubMed Scopus (32) Google Scholar A bronchiolo-alveolitis, the characteristic morphologic finding of hypersensitivity pneumonitis, is the morphologic equivalent of such functional abnormalities.24Seal RME Hapke EJ Thomas GO et al.The pathology of the acute and chronic stages of farmers lung.Thorax. 1968; 23: 469-489Crossref PubMed Scopus (141) Google Scholar Similarly, the early morphologic change of coal dust disease is the coal macula which involves the small airways.23Seaton A Lapp NL Morgan WKC Lung mechanics and frequency dependence of compliance in coal miners.J Clin Invest. 1972; 51: 1203-1211Crossref PubMed Scopus (32) Google ScholarAlthough many studies have now demonstrated its occurrence in interstitial pulmonary disease, small airway disease is not always present,25Schofield NM Davies RJ Cameron IR et al.Small airways in fibrosing alveolitis.Am Rev Respir Dis. 1976; 113: 729-735PubMed Google Scholar, 26DeTroyer A Yernalt JC Dierekx P et al.Lung and airways mechanics in early pulmonary sarcoidosis.Bull Eur Physiopathol Respir. 1978; 14: 299-310Google Scholar, 27Bjerke RD Tashkin DP Clements DJ et al.Small airways in progressive systemic sclerosis.Am J Med. 1979; 66: 201-209Abstract Full Text PDF PubMed Scopus (48) Google Scholar which suggests that several factors must determine its occurrence. These factors might include severity of the disease process, chronicity of the disease, susceptibility of the host, and certain environmental factors.6Fulmer JD Crystal RG Interstitial lung diseases.in: Simmons DE Current pulmonology. 1. Houghton Mifflin Professional Publishers, Boston1979: 1-65Google Scholar, 12Fulmer JD Roberts WC Von gal ER et al.Small airways in idiopathic pulmonary fibrosis: comparison of morphologic and physiologic observations.J Clin Invest. 1977; 60: 595-610Crossref PubMed Scopus (96) Google Scholar, 26DeTroyer A Yernalt JC Dierekx P et al.Lung and airways mechanics in early pulmonary sarcoidosis.Bull Eur Physiopathol Respir. 1978; 14: 299-310Google Scholar, 27Bjerke RD Tashkin DP Clements DJ et al.Small airways in progressive systemic sclerosis.Am J Med. 1979; 66: 201-209Abstract Full Text PDF PubMed Scopus (48) Google Scholar The functional significance of disease of the small airways is also variable. While it is likely that small airway disease is the earliest functional alteration in COPD, the significance of small airway disease in interstitial pulmonary disease is speculative. It is likely that disease of the small airways contributes to the ventilation-perfusion mismatching in interstitial pulmonary disease and hence to the hypoxemia of this disease.6Fulmer JD Crystal RG Interstitial lung diseases.in: Simmons DE Current pulmonology. 1. Houghton Mifflin Professional Publishers, Boston1979: 1-65Google Scholar, 12Fulmer JD Roberts WC Von gal ER et al.Small airways in idiopathic pulmonary fibrosis: comparison of morphologic and physiologic observations.J Clin Invest. 1977; 60: 595-610Crossref PubMed Scopus (96) Google Scholar In addition, small airway disease may be partly responsible for alterations in pulmonary recoil and pulmonary volumes4Macklem PT Changes in lung mechanics: pressure-volume and pressure-flow relations.in: Macklem PT Permutt S The lung in the transition between health and disease. Marcel Dekker, Inc, New York1979: 53-71Google Scholar for example, trapping of air may mask the effects of alveolar fibrosis. Perhaps this is why pulmonary volumes correlate poorly or not at all with the severity of fibrosis in interstitial pulmonary fibrosis and in many of the inorganic dust diseases.28Fulmer JD Roberts WC Von Gal ER et al.Morphologic-physiologic correlates of the severity of fibrosis and degree of cellularity in idiopathic pulmonary fibrosis.J Clin Invest. 1979; 63: 665-676Crossref PubMed Scopus (163) Google Scholar, 29Gaensler EA Carrington CB Coutu RE et al.Radiographic physiologic-pathologic correlates in interstitial pneumonias.Prog Respir Res. 1975; 8: 223-241Crossref Google Scholar Disease of the small airways may also contribute to the development of chronic obstruction of airflow in interstitial pulmonary disease. Indeed, it is well documented but poorly recognized that some patients with interstitial pulmonary disease progress to show a pattern of chronic obstruction of airflow. The most notable example is chronic sarcoidosis, in which there may be functional evidence of chronic obstruction of airflow with an increased residual volume and normal or near normal total lung capacity.30Miller A Teirstein AS Jackler I et al.Airway function in chronic pulmonary sarcoidosis with fibrosis.Am Rev Respir Dis. 1974; 109: 179-189PubMed Google Scholar, 31DeRemee RA Andersen HA Sarcoidosis: a correlation of dyspnea with radiographic stage and pulmonary function changes.Mayo Clin Proc. 1974; 49: 742-745PubMed Google Scholar Roentgenographically, there are dense areas of fibrosis with coexisting cystic lesions and hyperinflation.31DeRemee RA Andersen HA Sarcoidosis: a correlation of dyspnea with radiographic stage and pulmonary function changes.Mayo Clin Proc. 1974; 49: 742-745PubMed Google Scholar Similarly, chronic obstruction of airflow may be present in patients with chronic hypersensitivity pneumonitis,32Braun SR doPico GA Tsiatis A et al.Farmer's lung disease: long-term clinical and physiologic outcome.Am Rev Respir Dis. 1979; 119: 185-191PubMed Google Scholar some of the inorganic dust diseases,33Morgan WKC Seaton A Occupational lung diseases. WB Saunders Co, Philadelphia1975: 132-134Google Scholar and chronic histiocytosis X of lung.34Basset F Corrin B Spence H et al.Pulmonary histiocytosis X.Am Rev Respir Dis. 1978; 118: 811-820PubMed Google Scholar Although there are scant data on the mechanism of obstruction of airflow in these forms of interstitial pulmonary disease, both intrinsic narrowing of small airways and loss of elastic recoil probably contribute to the obstruction.6Fulmer JD Crystal RG Interstitial lung diseases.in: Simmons DE Current pulmonology. 1. Houghton Mifflin Professional Publishers, Boston1979: 1-65Google Scholar, 18Kaneko K Sharma OP Airway obstruction in pulmonary sarcoidosis.Bull Eur Physiopathol Respir. 1977; 13: 231-240PubMed Google ScholarIn this issue (see page 473), McCarthy and associates describe two patients with idiopathic pulmonary fibrosis which rapidly progressed to COPD. Both patients initially had restrictive ventilatory defects (with normal timed spirometric data), but, in addition, both had evidence of increased resistance to airflow in small airways. Pulmonary biopsies in each showed an active alveolitis and either an obliterative bronchiolitis or endobronchiolar fibrosis. Both patients were treated with corticosteroids and improved initially. Six to 12 months later, both had physiologic, clinical, and radiographic findings typical of COPD. Pressure-flow studies indicated that a reduction in flow during maximum expiration was due mainly to reduced elastic recoil and increased dynamic compression. These data would be consistent with emphysema.35Leaver DG Tattersfield AE Pride NB Contributions of loss of lung recoil and of enhanced airways collapsibility to the airflow obstruction of chronic bronchitis and emphysema.J Clin Invest. 1973; 52: 2117-2134Crossref PubMed Scopus (48) Google Scholar The report of McCarthy et al and the data cited in this editorial strongly support the concept that there are distinctive similarities between the interstitial and obstructive pulmonary diseases. The report by McCarthy et al also raises questions on the possibility of acute interstitial injury as a cause for COPD. It is well documented that acute bronchiolar injury can lead to COPD, for example, that resulting from acute inhalation of smoke.36Kirkpatrick MB Bass JB Severe obstructive lung disease after smoke inhalation.Chest. 1979; 76: 108-110Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Could an acute viral alveolitis and bronchiolitis or subclinical idiopathic pulmonary fibrosis do the same? Current data suggest that lobar emphysema is associated with acute viral pneumonias.37Fraser RG Paré JAP Diagnosis of diseases of the chest. WB Saunders Co, Philadelphia1979: 1431Google Scholar Certainly, influenza can be associated with physiologic alterations consistent with disease of the small airways.38Little JW Hall WJ Douglas RG et al.Amantadine effect on peripheral airways abnormalities in influenza.Ann Intern Med. 1976; 85: 177-182Crossref PubMed Scopus (44) Google Scholar This type of injury in the susceptible person may lead to classic COPD or to chronic obstructive disease of the small airways, as described by Macklem and colleagues.39Macklem PT Thurlbeck WM Fraser RG Chronic obstructive disease of small airways.Ann Intern Med. 1971; 74: 167-177Crossref PubMed Scopus (67) Google Scholar Recently, Miller et al40Miller A Teirstein AS Chuang MT The sequence of physiologic changes in pulmonary sarcoidosis: correlation with radiographic stages and response to therapy.Mt Sinai J Med. 1977; 44: 852-865PubMed Google Scholar suggested that sarcoidosis may cause diffuse bullous emphysema.The report by McCarthy and associates also raises important therapeutic questions. Whereas Ostrow and Cherniack9Ostrow D Cherniack RM Resistance to airflow in patients with diffuse interstitial lung disease.Am Rev Respir Dis. 1973; 108: 205-210PubMed Google Scholar and we12Fulmer JD Roberts WC Von gal ER et al.Small airways in idiopathic pulmonary fibrosis: comparison of morphologic and physiologic observations.J Clin Invest. 1977; 60: 595-610Crossref PubMed Scopus (96) Google Scholar observed improvement in the physiologic abnormalities of small airways on treatment with corticosteroids, the two patients of McCarthy et al developed obstructive pulmonary disease despite corticosteroid treatment. This suggests that most small airways were irreversibly damaged, perhaps with fibrosis. Could agents that interfere with collagen synthesis, secretion, or cross-linking have altered the disease process? Of even greater importance is the question of the overall significance of small airway disease in interstitial pulmonary disease. Clearly, we should be actively investigating mechanisms of alveolar and bronchiolar injury and repair in both the “interstitial” and “obstructive” pulmonary diseases. The functional distinction between these two classes of diseases becomes less distinct as our knowledge of them increases. The concept of disease of the small airways was introduced in 1968 by Hogg and associates.1Hogg JC Macklem PT Thurlbeck WM Site and nature of airway obstruction in chronic obstructive lung disease.N Engl J Med. 1968; 278: 1355-1360Crossref PubMed Scopus (978) Google Scholar These workers defined the site and nature of obstruction of the airways in chronic obstructive pulmonary disease (COPD) at the small airways. Morphologically, small (less than 2 mm) airways were narrowed or obliterated by inflammation, mucus, or fibrosis. The concept of two components to disease of the small airways was introduced by them, ie, a reversible component due to acute inflammation or mucous plugging and an irreversible component due to fibrosis, distortion, and narrowing or obliteration of small airways. These findings suggested that disease of the small airways may be one of the earliest changes in COPD, and current data strongly support that suggestion.2Cosio M Ghezzo H Hogg JC et al.The relations between structural changes in small airways and pulmonary function tests.N Engl J Med. 1977; 298: 1277-1281Crossref Scopus (608) Google Scholar, 3Thurlbeck WM Changes in lung structure.in: Macklem PT Permutt S The lung in the transition between health and disease. Marcel Dekker, Inc, New York1979: 17-41Google Scholar, 4Macklem PT Changes in lung mechanics: pressure-volume and pressure-flow relations.in: Macklem PT Permutt S The lung in the transition between health and disease. Marcel Dekker, Inc, New York1979: 53-71Google Scholar The role of small airway disease in the eventual development of COPD, particularly emphysema, is unclear;3Thurlbeck WM Changes in lung structure.in: Macklem PT Permutt S The lung in the transition between health and disease. Marcel Dekker, Inc, New York1979: 17-41Google Scholar, 4Macklem PT Changes in lung mechanics: pressure-volume and pressure-flow relations.in: Macklem PT Permutt S The lung in the transition between health and disease. Marcel Dekker, Inc, New York1979: 53-71Google Scholar however, it is likely that small airway disease contributes to trapping of air and mechanical disruption of alveolar septae4Macklem PT Changes in lung mechanics: pressure-volume and pressure-flow relations.in: Macklem PT Permutt S The lung in the transition between health and disease. Marcel Dekker, Inc, New York1979: 53-71Google Scholar and to the development of a distal chronic alveolitis. Once this last process has been initiated, the release of macrophagic or neutrophilic proteases may result in degradation of elastin and subsequent emphysema.5Kuhn C Senior RM The role of elastases in the development of emphysema.Lung. 1978; 155: 185-197Crossref Scopus (34) Google Scholar In contrast to its occurrence in COPD, disease of the small airways was not considered to be a part of interstitial pulmonary disease until recently. Although grouped together because of common clinical, roentgenographic, physiologic, and morphologic features, interstitial pulmonary diseases are heterogeneous and have a variety of causes.6Fulmer JD Crystal RG Interstitial lung diseases.in: Simmons DE Current pulmonology. 1. Houghton Mifflin Professional Publishers, Boston1979: 1-65Google Scholar Just as COPD is characterized by an obstructive ventilatory defect with normal or increased pulmonary volumes, interstitial pulmonary disease has classically been characterized by a restrictive defect (reduced pulmonary volumes and compliance) without evidence of obstruction to airflow.6Fulmer JD Crystal RG Interstitial lung diseases.in: Simmons DE Current pulmonology. 1. Houghton Mifflin Professional Publishers, Boston1979: 1-65Google Scholar Because interstitial pulmonary disease is characterized morphologically by fibrosis of the supporting tissues of lung, primarily alveolar interstitium,6Fulmer JD Crystal RG Interstitial lung diseases.in: Simmons DE Current pulmonology. 1. Houghton Mifflin Professional Publishers, Boston1979: 1-65Google Scholar the concept of a restrictive ventilatory defect in this disorder is easy to accept. However, recent physiologic and morphologic observations indicate that disease of the small airways is not limited to COPD and that many of the morphologic and pathophysiologic features of COPD may be evident in interstitial pulmonary disease. Although narrowing of small airways in acute idiopathic pulmonary fibrosis was mentioned by Hamman and Rich7Hamman L Rich AR Acute diffuse interstitial fibrosis of the lungs.Bull Johns Hopkins Hosp. 1944; 74: 177-212Google Scholar in their original communication, only recently has emphasis been placed on small airways in interstitial pulmonary disease. Except for the “bronchiolitis obliterans interstitial pneumonia” described by Liebow and Carrington,8Liebow AA Carrington CB Alveolar diseases: the interstitial pneumonias.in: Simon M Potchen EJ LeMay M Frontiers of Pulmonary Radiology. Grune and Stratton, Inc, New York1967: 102-141Google Scholar most reports have concentrated on alveolar pathologic abnormalities. The suggestion that functional alterations in interstitial pulmonary disease were consistent with small airway disease was made in 1973 by Ostrow and Cherniack9Ostrow D Cherniack RM Resistance to airflow in patients with diffuse interstitial lung disease.Am Rev Respir Dis. 1973; 108: 205-210PubMed Google Scholar and subsequently by Yernalt et al.10Yernalt JC Dejoinghe M DeCoster A et al.Pulmonary mechanics in diffuse fibrosing alveolitis.Bull Physiopathol Respir. 1975; 11: 231-244PubMed Google Scholar Both groups found that some patients with interstitial pulmonary disease had evidence of increased resistance to airflow in small airways. In a study of 29 patients with idiopathic pulmonary fibrosis we11Roberts WC Histologic observations in idiopathic pulmonary fibrosis. (pp 773-776). In: Crystal RG (moderator). Idiopathic pulmonary fibrosis: clinical, histologic, radiographic, physiologic, scintigraphic, cytologic, and biochemical aspects.Ann Intern Med. 1976; 85: 769-788Crossref PubMed Scopus (501) Google Scholar found small airways to be narrowed in 20 patients (70 percent). A detailed physiologic-morphologic correlative study of 18 of these 29 patients was made by obtaining pulmonary tissue and performing detailed testing of pulmonary function in the same patients.12Fulmer JD Roberts WC Von gal ER et al.Small airways in idiopathic pulmonary fibrosis: comparison of morphologic and physiologic observations.J Clin Invest. 1977; 60: 595-610Crossref PubMed Scopus (96) Google Scholar Seventeen (94 percent) had peribronchiolar fibrosis or inflammation or bronchiolitis, and 12 (71 percent) of these 17 had narrowed small airways.12Fulmer JD Roberts WC Von gal ER et al.Small airways in idiopathic pulmonary fibrosis: comparison of morphologic and physiologic observations.J Clin Invest. 1977; 60: 595-610Crossref PubMed Scopus (96) Google Scholar Furthermore, a good correlation was seen between the finding of narrowed small airways in the specimens from biopsy and two physiologic studies considered to be useful detectors of small-airway disease, ie, dynamic compliance and maximum expiratory flow-volume curves. Our study demonstrated that idiopathic pulmonary fibrosis is a disease that can involve small airways and that physiologic studies can define the function of small airways in this disease. Subsequent studies have shown that other diseases with pulmonary morphologic changes that can be indistinguishable from idiopathic pulmonary fibrosis (interstitial pulmonary disease associated with specific collagen vascular diseases and essential mixed cryoglobulinemia) may also have physiologic alterations consistent with disease of the small airways.13Guttadauria M Ellman H Emmanuel G et al.Pulmonary function in scleroderma.Arthritis Rheumatism. 1977; 20: 1071-1079Crossref PubMed Scopus (62) Google Scholar, 14Wohlgelernter D Loke J Matthay RA et al.Systemic and discoid lupus erythematosis: analysis of pulmonary function.Yale J Biol Med. 1978; 51: 157-164PubMed Google Scholar, 15Bombardieri S Paoletti P Ferri C et al.Lung involvement in essential mixed cryoglobulinemia.Am J Med. 1979; 66: 748-755Abstract Full Text PDF PubMed Scopus (113) Google Scholar Granulomatous interstitial pulmonary disease may also involve small airways. Young and associates16Young Jr, RC Carr C Shelton TG et al.Sarcoidosis: relationship between changes in lung structure and function.Am Rev Respir Dis. 1967; 95: 224-238PubMed Google Scholar in 1967 demonstrated such an involvement by graulomata in patients with sarcoidosis. Although these workers noted no evidence of obstruction to airflow on simple spirometric testing, this publication preceded our current concepts of the relative insensitivity of this test to mild degrees of obstruction to airflow. Subsequent studies have shown that granulomata can involve small airways and that patients with sarcoidosis can have physiologic alterations consistent with disease of the small airways.17Young Jr, RC Headings VE Bose S et al.Alpha-1 antitrypsin levels in sarcoidosis: relationship to disease activity.Chest. 1973; 64: 39-45Crossref PubMed Scopus (6) Google Scholar, 18Kaneko K Sharma OP Airway obstruction in pulmonary sarcoidosis.Bull Eur Physiopathol Respir. 1977; 13: 231-240PubMed Google Scholar, 19Levinson RS Metzger LF Stanley NN et al.Airway function in sarcoidosis.Am J Med. 1977; 62: 51-59Abstract Full Text PDF PubMed Scopus (68) Google Scholar, 20Carrington CB Gaensler EA Mikus JP et al.Structure and function in sarcoidosis.NY Acad Sci. 1976; 278: 265-283Crossref PubMed Scopus (140) Google Scholar At least three occupational or environmental interstitial diseases (hypersensitivity pneumonitis, asbestosis, and coal dust disease) have been shown to have physiologic alterations consistent with disease of the small airways.21Allen DH Williams GV Woolcock AJ Bird breeders’ hypersensitivity pneumonitis: progress studies of lung function after cessation of exposure to the provoking antigen.Am Rev Respir Dis. 1976; 114: 555-566PubMed Google Scholar, 22Jodoin G Gibbs GW Macklem PT et al.Early effects of asbestos exposure on lung function.Am Rev Respir Dis. 1971; 104: 525-535PubMed Google Scholar, 23Seaton A Lapp NL Morgan WKC Lung mechanics and frequency dependence of compliance in coal miners.J Clin Invest. 1972; 51: 1203-1211Crossref PubMed Scopus (32) Google Scholar A bronchiolo-alveolitis, the characteristic morphologic finding of hypersensitivity pneumonitis, is the morphologic equivalent of such functional abnormalities.24Seal RME Hapke EJ Thomas GO et al.The pathology of the acute and chronic stages of farmers lung.Thorax. 1968; 23: 469-489Crossref PubMed Scopus (141) Google Scholar Similarly, the early morphologic change of coal dust disease is the coal macula which involves the small airways.23Seaton A Lapp NL Morgan WKC Lung mechanics and frequency dependence of compliance in coal miners.J Clin Invest. 1972; 51: 1203-1211Crossref PubMed Scopus (32) Google Scholar Although many studies have now demonstrated its occurrence in interstitial pulmonary disease, small airway disease is not always present,25Schofield NM Davies RJ Cameron IR et al.Small airways in fibrosing alveolitis.Am Rev Respir Dis. 1976; 113: 729-735PubMed Google Scholar, 26DeTroyer A Yernalt JC Dierekx P et al.Lung and airways mechanics in early pulmonary sarcoidosis.Bull Eur Physiopathol Respir. 1978; 14: 299-310Google Scholar, 27Bjerke RD Tashkin DP Clements DJ et al.Small airways in progressive systemic sclerosis.Am J Med. 1979; 66: 201-209Abstract Full Text PDF PubMed Scopus (48) Google Scholar which suggests that several factors must determine its occurrence. These factors might include severity of the disease process, chronicity of the disease, susceptibility of the host, and certain environmental factors.6Fulmer JD Crystal RG Interstitial lung diseases.in: Simmons DE Current pulmonology. 1. Houghton Mifflin Professional Publishers, Boston1979: 1-65Google Scholar, 12Fulmer JD Roberts WC Von gal ER et al.Small airways in idiopathic pulmonary fibrosis: comparison of morphologic and physiologic observations.J Clin Invest. 1977; 60: 595-610Crossref PubMed Scopus (96) Google Scholar, 26DeTroyer A Yernalt JC Dierekx P et al.Lung and airways mechanics in early pulmonary sarcoidosis.Bull Eur Physiopathol Respir. 1978; 14: 299-310Google Scholar, 27Bjerke RD Tashkin DP Clements DJ et al.Small airways in progressive systemic sclerosis.Am J Med. 1979; 66: 201-209Abstract Full Text PDF PubMed Scopus (48) Google Scholar The functional significance of disease of the small airways is also variable. While it is likely that small airway disease is the earliest functional alteration in COPD, the significance of small airway disease in interstitial pulmonary disease is speculative. It is likely that disease of the small airways contributes to the ventilation-perfusion mismatching in interstitial pulmonary disease and hence to the hypoxemia of this disease.6Fulmer JD Crystal RG Interstitial lung diseases.in: Simmons DE Current pulmonology. 1. Houghton Mifflin Professional Publishers, Boston1979: 1-65Google Scholar, 12Fulmer JD Roberts WC Von gal ER et al.Small airways in idiopathic pulmonary fibrosis: comparison of morphologic and physiologic observations.J Clin Invest. 1977; 60: 595-610Crossref PubMed Scopus (96) Google Scholar In addition, small airway disease may be partly responsible for alterations in pulmonary recoil and pulmonary volumes4Macklem PT Changes in lung mechanics: pressure-volume and pressure-flow relations.in: Macklem PT Permutt S The lung in the transition between health and disease. Marcel Dekker, Inc, New York1979: 53-71Google Scholar for example, trapping of air may mask the effects of alveolar fibrosis. Perhaps this is why pulmonary volumes correlate poorly or not at all with the severity of fibrosis in interstitial pulmonary fibrosis and in many of the inorganic dust diseases.28Fulmer JD Roberts WC Von Gal ER et al.Morphologic-physiologic correlates of the severity of fibrosis and degree of cellularity in idiopathic pulmonary fibrosis.J Clin Invest. 1979; 63: 665-676Crossref PubMed Scopus (163) Google Scholar, 29Gaensler EA Carrington CB Coutu RE et al.Radiographic physiologic-pathologic correlates in interstitial pneumonias.Prog Respir Res. 1975; 8: 223-241Crossref Google Scholar Disease of the small airways may also contribute to the development of chronic obstruction of airflow in interstitial pulmonary disease. Indeed, it is well documented but poorly recognized that some patients with interstitial pulmonary disease progress to show a pattern of chronic obstruction of airflow. The most notable example is chronic sarcoidosis, in which there may be functional evidence of chronic obstruction of airflow with an increased residual volume and normal or near normal total lung capacity.30Miller A Teirstein AS Jackler I et al.Airway function in chronic pulmonary sarcoidosis with fibrosis.Am Rev Respir Dis. 1974; 109: 179-189PubMed Google Scholar, 31DeRemee RA Andersen HA Sarcoidosis: a correlation of dyspnea with radiographic stage and pulmonary function changes.Mayo Clin Proc. 1974; 49: 742-745PubMed Google Scholar Roentgenographically, there are dense areas of fibrosis with coexisting cystic lesions and hyperinflation.31DeRemee RA Andersen HA Sarcoidosis: a correlation of dyspnea with radiographic stage and pulmonary function changes.Mayo Clin Proc. 1974; 49: 742-745PubMed Google Scholar Similarly, chronic obstruction of airflow may be present in patients with chronic hypersensitivity pneumonitis,32Braun SR doPico GA Tsiatis A et al.Farmer's lung disease: long-term clinical and physiologic outcome.Am Rev Respir Dis. 1979; 119: 185-191PubMed Google Scholar some of the inorganic dust diseases,33Morgan WKC Seaton A Occupational lung diseases. WB Saunders Co, Philadelphia1975: 132-134Google Scholar and chronic histiocytosis X of lung.34Basset F Corrin B Spence H et al.Pulmonary histiocytosis X.Am Rev Respir Dis. 1978; 118: 811-820PubMed Google Scholar Although there are scant data on the mechanism of obstruction of airflow in these forms of interstitial pulmonary disease, both intrinsic narrowing of small airways and loss of elastic recoil probably contribute to the obstruction.6Fulmer JD Crystal RG Interstitial lung diseases.in: Simmons DE Current pulmonology. 1. Houghton Mifflin Professional Publishers, Boston1979: 1-65Google Scholar, 18Kaneko K Sharma OP Airway obstruction in pulmonary sarcoidosis.Bull Eur Physiopathol Respir. 1977; 13: 231-240PubMed Google Scholar In this issue (see page 473), McCarthy and associates describe two patients with idiopathic pulmonary fibrosis which rapidly progressed to COPD. Both patients initially had restrictive ventilatory defects (with normal timed spirometric data), but, in addition, both had evidence of increased resistance to airflow in small airways. Pulmonary biopsies in each showed an active alveolitis and either an obliterative bronchiolitis or endobronchiolar fibrosis. Both patients were treated with corticosteroids and improved initially. Six to 12 months later, both had physiologic, clinical, and radiographic findings typical of COPD. Pressure-flow studies indicated that a reduction in flow during maximum expiration was due mainly to reduced elastic recoil and increased dynamic compression. These data would be consistent with emphysema.35Leaver DG Tattersfield AE Pride NB Contributions of loss of lung recoil and of enhanced airways collapsibility to the airflow obstruction of chronic bronchitis and emphysema.J Clin Invest. 1973; 52: 2117-2134Crossref PubMed Scopus (48) Google Scholar The report of McCarthy et al and the data cited in this editorial strongly support the concept that there are distinctive similarities between the interstitial and obstructive pulmonary diseases. The report by McCarthy et al also raises questions on the possibility of acute interstitial injury as a cause for COPD. It is well documented that acute bronchiolar injury can lead to COPD, for example, that resulting from acute inhalation of smoke.36Kirkpatrick MB Bass JB Severe obstructive lung disease after smoke inhalation.Chest. 1979; 76: 108-110Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Could an acute viral alveolitis and bronchiolitis or subclinical idiopathic pulmonary fibrosis do the same? Current data suggest that lobar emphysema is associated with acute viral pneumonias.37Fraser RG Paré JAP Diagnosis of diseases of the chest. WB Saunders Co, Philadelphia1979: 1431Google Scholar Certainly, influenza can be associated with physiologic alterations consistent with disease of the small airways.38Little JW Hall WJ Douglas RG et al.Amantadine effect on peripheral airways abnormalities in influenza.Ann Intern Med. 1976; 85: 177-182Crossref PubMed Scopus (44) Google Scholar This type of injury in the susceptible person may lead to classic COPD or to chronic obstructive disease of the small airways, as described by Macklem and colleagues.39Macklem PT Thurlbeck WM Fraser RG Chronic obstructive disease of small airways.Ann Intern Med. 1971; 74: 167-177Crossref PubMed Scopus (67) Google Scholar Recently, Miller et al40Miller A Teirstein AS Chuang MT The sequence of physiologic changes in pulmonary sarcoidosis: correlation with radiographic stages and response to therapy.Mt Sinai J Med. 1977; 44: 852-865PubMed Google Scholar suggested that sarcoidosis may cause diffuse bullous emphysema. The report by McCarthy and associates also raises important therapeutic questions. Whereas Ostrow and Cherniack9Ostrow D Cherniack RM Resistance to airflow in patients with diffuse interstitial lung disease.Am Rev Respir Dis. 1973; 108: 205-210PubMed Google Scholar and we12Fulmer JD Roberts WC Von gal ER et al.Small airways in idiopathic pulmonary fibrosis: comparison of morphologic and physiologic observations.J Clin Invest. 1977; 60: 595-610Crossref PubMed Scopus (96) Google Scholar observed improvement in the physiologic abnormalities of small airways on treatment with corticosteroids, the two patients of McCarthy et al developed obstructive pulmonary disease despite corticosteroid treatment. This suggests that most small airways were irreversibly damaged, perhaps with fibrosis. Could agents that interfere with collagen synthesis, secretion, or cross-linking have altered the disease process? Of even greater importance is the question of the overall significance of small airway disease in interstitial pulmonary disease. Clearly, we should be actively investigating mechanisms of alveolar and bronchiolar injury and repair in both the “interstitial” and “obstructive” pulmonary diseases. The functional distinction between these two classes of diseases becomes less distinct as our knowledge of them increases.
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