The Spectrum of Smoking-Related Interstitial Lung Disorders: The Never-Ending Story of Smoke and Disease

Abstract

Cigarette smoking affects many organs and remains the most preventable cause of morbidity and premature death.1American Thoracic Society Cigarette smoking and health.Am J Respir Crit Care Med. 1996; 153: 861-865Crossref PubMed Scopus (204) Google Scholar2Bartecchi CE MacKenzie TD Schrier RW The human costs of tobacco use.N Engl J Med. 1994; 330: 907-912Crossref PubMed Scopus (408) Google ScholarIn lungs, it has been primarily associated to COPD and bronchogenic carcinoma. However, an increasing body of evidence supports the notion that cigarette smoke may also cause some diffuse parenchymal lung diseases. Thus, at least three interstitial lung diseases (ILDs) have been related to cigarette smoking: respiratory bronchiolitis (RB)-associated ILD (RB-ILD), desquamative interstitial pneumonia (DIP), and pulmonary Langerhans cell histiocytosis (PLCH).3Myers JL Veal Jr, CF Shin MS et al.Respiratory bronchiolitis causing interstitial lung disease: a clinicopathological study of six cases.Am Rev Respir Dis. 1987; 135: 880-884Crossref PubMed Scopus (300) Google Scholar4Fraig M Shreesha U Savici D et al.Respiratory bronchiolitis: a clinicopathologic study in current smokers, ex-smokers, and never-smokers.Am J Surg Pathol. 2002; 26: 647-653Crossref PubMed Scopus (187) Google Scholar5American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias.Am J Respir Crit Care Med. 2002; 165: 277-304Crossref PubMed Scopus (3356) Google Scholar6Carrington CB Gaensler EA Coutu RE et al.Natural history and treated course of usual and desquamative interstitial pneumonia.N Engl J Med. 1978; 298: 801-809Crossref PubMed Scopus (598) Google Scholar7Sundar KM Gosselin MV Chung HL et al.Pulmonary Langerhans cell histiocytosis: emerging concepts in pathobiology, radiology, and clinical evolution of disease.Chest. 2003; 123: 1673-1683Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar8Travis WD Borok Z Roum JH et al.Pulmonary Langerhans cell granulomatosis (histiocytosis X): a clinicopathologic study of 48 cases.Am J Surg Pathol. 1993; 17: 971-986Crossref PubMed Scopus (276) Google ScholarAlthough the pathogenic mechanisms that link tobacco smoke exposure to these disorders have not been elucidated, there is growing evidence that in all these diseases the primary target appears to be the terminal and/or respiratory bronchioles.RB was first described by Niewhoehner et al9Niewhoehner DE Kleinerman J Rice DB Pathologic changes in the peripheral airways of young cigarette smoking.N Engl J Med. 1974; 291: 755-758Crossref PubMed Scopus (699) Google Scholaras a discrete histopathologic entity occurring in young smokers. This disorder, also called “smoker’s bronchiolitis,” is usually found as an incidental histologic abnormality in otherwise asymptomatic smokers, and it is characterized by the accumulation of cytoplasmic golden brown-pigmented macrophages within respiratory bronchioles.10Colby TV Bronchiolitis: pathologic considerations.Am J Clin Pathol. 1998; 109: 101-109Crossref PubMed Scopus (180) Google ScholarImportantly, RB may persist in some patients for many years after stopping smoking.4Fraig M Shreesha U Savici D et al.Respiratory bronchiolitis: a clinicopathologic study in current smokers, ex-smokers, and never-smokers.Am J Surg Pathol. 2002; 26: 647-653Crossref PubMed Scopus (187) Google ScholarFurthermore, the presence of areas of RB or DIP-like reaction can be considered as a sensitive histologic marker of cigarette smoking. Therefore, in long-term smokers it is not infrequent to find these changes, as well as some areas of emphysema, as coexistent lesions of a number of lung diseases such as idiopathic pulmonary fibrosis.However, a small proportion of smokers acquire a more exaggerated response that, in addition to the respiratory bronchioles-centered lesions, provokes interstitial and airspace inflammation and fibrosis extending to the nearby alveoli. This entity is what we called RB-ILD, and contrasting with what occurs in the “pure” RB, this disorder results in clinical symptoms, primarily dyspnea and cough, and in a restrictive or mixed pulmonary function pattern.11Moon J du Bois RM Colby TV et al.Clinical significance of respiratory bronchiolitis on open lung biopsy and its relationship to smoking related interstitial lung disease.Thorax. 1999; 54: 1009-1014Crossref PubMed Scopus (205) Google Scholar12Park JS Brown KK Tuder RM et al.Respiratory bronchiolitis-associated interstitial lung disease: radiologic features with clinical and pathologic correlation.J Comput Assist Tomogr. 2002; 26: 13-20Crossref PubMed Scopus (134) Google ScholarActually, in the first description by Myers et al,3Myers JL Veal Jr, CF Shin MS et al.Respiratory bronchiolitis causing interstitial lung disease: a clinicopathological study of six cases.Am Rev Respir Dis. 1987; 135: 880-884Crossref PubMed Scopus (300) Google Scholarpatients showed clinical, physiologic, and radiologic evidence of chronic ILD, while the open-lung biopsy specimens only exhibited changes of RB with some nonspecific thickening of the alveolar septa by inflammation and fibrosis in alveoli adjacent to respiratory bronchioles.DIP was initially described by Liebow et al,13Liebow AA Steer A Billingsley JG Desquamative interstitial pneumonia.Am J Med. 1965; 39: 369-404Abstract Full Text PDF PubMed Scopus (282) Google Scholarand in the following 2 decades it was considered as the putative early stage of the usual interstitial pneumonia (UIP), an idea that was abandoned at the beginning of the 1990s. This disease is characterized by the widespread accumulation of intra-alveolar macrophages, with usually mild interstitial reaction, although some conditions may evolve to fibrosis and end-stage lung disease. Currently, it is well known that the histopathologic patterns of RB-ILD and DIP may overlap, and the key feature to differentiate both disorders is the distribution and extent of the lesions: bronchiolocentric in the RB-ILD, or diffuses in the DIP.14Desai SR Ryan SM Colby TV Smoking-related interstitial lung disease: histopathological and imaging perspectives.Clin Radiol. 2003; 58: 259-268Abstract Full Text Full Text PDF PubMed Scopus (51) Google ScholarIn this context, it has been proposed that RB, RB-ILD, and DIP may be different components of the same histopathologic disease spectrum, representing diverse degrees of severity of the same process caused by chronic smoking.15Yousem SA Colby TV Gaensler EA Respiratory bronchiolitis associated interstitial lung disease and its relationship to desquamative interstitial pneumonia.Mayo Clin Proc. 1989; 64: 1373-1380Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar16Heyneman LE Ward S Lynch DA et al.Respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease, and desquamative interstitial pneumonia: different entities or part of the spectrum of the same disease process?.Am J Radiol. 1999; 173: 1617-1622Google ScholarNonetheless, it is important to emphasize that although rare, DIP is one of the most common forms of ILDs in children, probably representing the same morphologic pattern of a different disease not related to smoking.17Stillwell PC Norris DG O'Connell EJ et al.Desquamative interstitial pneumonitis in children.Chest. 1980; 77: 165-171Crossref PubMed Scopus (54) Google Scholar18Barbato A Panizzolo C Recent advances: chronic interstitial lung disease in children.Paediatr Respir Rev. 2000; 1: 172-178Abstract Full Text PDF PubMed Scopus (17) Google ScholarPLCH, also known as eosinophilic granuloma of the lung, is a disorder of unknown etiology, but also strongly related to cigarette smoking.8Travis WD Borok Z Roum JH et al.Pulmonary Langerhans cell granulomatosis (histiocytosis X): a clinicopathologic study of 48 cases.Am J Surg Pathol. 1993; 17: 971-986Crossref PubMed Scopus (276) Google ScholarIt has been reported that children with Langerhans cell histiocytosis acquire pulmonary involvement only after several years of smoking.19Bernstrand C Cederlund K Ashtrom L et al.Smoking preceded pulmonary involvement in adults with Langerhans cell histiocytosis diagnosed in childhood.Acta Paediatr. 2000; 89: 1389-1392Crossref PubMed Scopus (29) Google ScholarMoreover, the hallmark pathologic feature in PLCH, the lung proliferation/infiltration by Langerhans cells, has also been found in healthy cigarette smokers.20Casolaro MA Bernaudin JF Saltini C et al.Accumulation of Langerhans cells on the epithelial surface of the lower respiratory tract in normal subjects in association with cigarette smoking.Am Rev Respir Dis. 1988; 137: 406-411Crossref PubMed Scopus (159) Google ScholarLikewise, mice passively exposed to tobacco smoke acquire a pulmonary granulomatous inflammation rich in Langerhans cells, which disappear after ceasing exposure to tobacco smoke.21Zeid NA Muller HK Tobacco smoke induced lung granulomas and tumors: association with pulmonary Langerhans cells.Pathology. 1995; 27: 247-254Abstract Full Text PDF PubMed Scopus (62) Google ScholarThe pathogenic mechanisms are unclear, but patients with PLCH display an abnormal T-cell proliferative response to tobacco glycoproteins.22Youkeles LH Grizzanti JN Liao Z et al.Decreased tobacco-glycoprotein-induced lymphocyte proliferation in vitro in pulmonary eosinophilic granuloma.Am J Respir Crit Care Med. 1995; 151: 145-150Crossref PubMed Scopus (57) Google ScholarThe earliest lesions are composed by cellular infiltrates containing large aggregates of Langerhans cells associated with lymphocytes and eosinophils, affecting small airways in an acinar distribution.23Kambouchner M Basset F Marchal J et al.Three-dimensional characterization of pathologic lesions in pulmonary Langerhans cell histiocytosis.Am J Respir Crit Care Med. 2002; 166: 1483-1490Crossref PubMed Scopus (89) Google ScholarThis inflammatory lesion is followed by a fibrotic reaction leading to the formation of stellate scars and cystic changes. The outcome of this disease is variable and unpredictable, ranging from an asymptomatic course to progressive fibrotic disease.24Vasallo R Ryu JH Schroeder DR et al.Clinical outcomes of pulmonary Langerhans cell histiocytosis in adults.N Engl J Med. 2002; 346: 484-490Crossref Scopus (339) Google ScholarInterestingly, RB-ILD, DIP, and PLCH belong to the subgroup of ILDs that cause the formation of pulmonary cysts clearly visible on high-resolution CT.25Koyama M Johkoh T Honda O et al.Chronic cystic lung disease: diagnostic accuracy of high-resolution CT in 92 patients.AJR Am J Roentgenol. 2003; 180: 827-835Crossref PubMed Scopus (107) Google ScholarCystic changes in RB-ILD and DIP usually represent areas of emphysema superimposed on areas of ground-glass attenuation; in general, these cysts lack perceptible walls.25Koyama M Johkoh T Honda O et al.Chronic cystic lung disease: diagnostic accuracy of high-resolution CT in 92 patients.AJR Am J Roentgenol. 2003; 180: 827-835Crossref PubMed Scopus (107) Google ScholarLikewise, multiple cysts are typical radiologic findings in patients with PLCH; but in this case, wall thickness varies from thin and barely perceptible to several millimeters. In this disease, cystic lesions result from the destruction of the bronchiolar wall, with progressive dilatation of the lumen, which is subsequently surrounded by fibrous tissue.23Kambouchner M Basset F Marchal J et al.Three-dimensional characterization of pathologic lesions in pulmonary Langerhans cell histiocytosis.Am J Respir Crit Care Med. 2002; 166: 1483-1490Crossref PubMed Scopus (89) Google ScholarIn this context, although PLCH has been traditionally associated with spontaneous pneumothorax, putatively provoked by the disruption of subpleural cysts, this pathological abnormality may also occur in RB-ILD and DIP.26Cottin V Streichenberger N Gamondes JP et al.Respiratory bronchiolitis in smokers with spontaneous pneumothorax.Eur Respir J. 1998; 12: 702-704Crossref PubMed Scopus (83) Google ScholarAlthough RB, RB-ILD, DIP, and PLCH are considered as discrete entities of long-term smokers, it is not infrequent to find a mixture of pathologic features rendering histopathologic diagnosis a difficult task. Thus, for example, patients with PLCH often exhibit RB and emphysematous lesions, or in some instances, a profuse intra-alveolar macrophage accumulation mimicking DIP.8Travis WD Borok Z Roum JH et al.Pulmonary Langerhans cell granulomatosis (histiocytosis X): a clinicopathologic study of 48 cases.Am J Surg Pathol. 1993; 17: 971-986Crossref PubMed Scopus (276) Google Scholar14Desai SR Ryan SM Colby TV Smoking-related interstitial lung disease: histopathological and imaging perspectives.Clin Radiol. 2003; 58: 259-268Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar27Colby TV Lombard C Histiocytosis X in the lung.Hum Pathol. 1983; 14: 847-856Abstract Full Text PDF PubMed Scopus (166) Google Scholar28Colby TV Carrington CB Interstitial lung disease.in: Thurlbeck WM Churg AM Pathology of the lung. Thieme Medical Publishers, New York, NY1995: 589-737Google ScholarIn this issue of CHEST (see page 1199), Vassallo and colleagues provide additional evidence of this overlapping, demonstrating that varying degrees of RB/DIP-like changes are usually present in the lungs of adult smoking patients with otherwise histologically proven PLCH. Moreover, in some cases the RB/DIP changes were severe enough to cause prominent ground-glass attenuation on high-resolution CT scans, an unusual finding in “pure” PLCH. In addition, the evaluation of the lungs of 14 patients with PLCH also showed that the extent of involvement of RB/DIP changes significantly correlated with the cumulative exposure to cigarettes smoked at the time of the biopsy, but did not correlate with the lung function abnormalities.An important clinical/pathologic consideration is related to the definite diagnosis. The question that arises is do patients showing PLCH lesions overlapped with severe and widespread RB-ILD or DIP-like changes have more than one disease? As Vasallo and coworkers state, it is improbable that these patients have two diseases but rather PLCH with prominent features of other smoking-associated parenchymal lesions. As mentioned before, a similar situation occurs in smoker patients with UIP and changes of RB, or in patients with UIP showing areas of nonspecific interstitial pneumonia. In both examples, the specific diagnosis would be UIP.A final consideration is that the relationship between cigarette smoke and ILDs has not been completely revealed and will continue unfolded. There is strong evidence supporting a potential causal role for the development of some ILDs, such as RB-ILD, DIP, and PLCH. Nevertheless, cigarette smoking exhibits also a paradoxical effect on parenchymal lung inflammation and fibrosis. Actually, it may promote or inhibit these pathologic processes, influencing the incidence, severity, or natural history of a wide array of ILDs. For example, current and former smokers show an increased risk for acquiring idiopathic pulmonary fibrosis, though smokers seem to have a better survival rate than nonsmokers.29King Jr, TE Tooze JA Schwarz MI et al.Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model.Am J Respir Crit Care Med. 2001; 164: 1171-1181Crossref PubMed Scopus (730) Google ScholarBy contrast, cigarette smoking appears to have a protective effect on the development of a number of ILD including hypersensitivity pneumonitis, sarcoidosis, and radiation-induced pneumonitis.30Selman M Hypersensitivity pneumonitis.in: Schwarz MI King TE Interstitial lung disease. BC Decker, Hamilton, Ontario2003: 452-484Google Scholar31Douglas JG Middleton WG Gaddie J et al.Sarcoidosis: a disorder commoner in non-smokers?.Thorax. 1986; 41: 787-791Crossref PubMed Scopus (79) Google Scholar32Johansson S Bjermer L Franzen L et al.Effects of ongoing smoking on the development of radiation-induced pneumonitis in breast cancer and oesophagus cancer patients.Radiother Oncol. 1998; 49: 41-47Abstract Full Text Full Text PDF PubMed Scopus (88) Google ScholarTherefore, the window between long-term cigarette smoking and ILDs remains open. Cigarette smoking affects many organs and remains the most preventable cause of morbidity and premature death.1American Thoracic Society Cigarette smoking and health.Am J Respir Crit Care Med. 1996; 153: 861-865Crossref PubMed Scopus (204) Google Scholar2Bartecchi CE MacKenzie TD Schrier RW The human costs of tobacco use.N Engl J Med. 1994; 330: 907-912Crossref PubMed Scopus (408) Google ScholarIn lungs, it has been primarily associated to COPD and bronchogenic carcinoma. However, an increasing body of evidence supports the notion that cigarette smoke may also cause some diffuse parenchymal lung diseases. Thus, at least three interstitial lung diseases (ILDs) have been related to cigarette smoking: respiratory bronchiolitis (RB)-associated ILD (RB-ILD), desquamative interstitial pneumonia (DIP), and pulmonary Langerhans cell histiocytosis (PLCH).3Myers JL Veal Jr, CF Shin MS et al.Respiratory bronchiolitis causing interstitial lung disease: a clinicopathological study of six cases.Am Rev Respir Dis. 1987; 135: 880-884Crossref PubMed Scopus (300) Google Scholar4Fraig M Shreesha U Savici D et al.Respiratory bronchiolitis: a clinicopathologic study in current smokers, ex-smokers, and never-smokers.Am J Surg Pathol. 2002; 26: 647-653Crossref PubMed Scopus (187) Google Scholar5American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias.Am J Respir Crit Care Med. 2002; 165: 277-304Crossref PubMed Scopus (3356) Google Scholar6Carrington CB Gaensler EA Coutu RE et al.Natural history and treated course of usual and desquamative interstitial pneumonia.N Engl J Med. 1978; 298: 801-809Crossref PubMed Scopus (598) Google Scholar7Sundar KM Gosselin MV Chung HL et al.Pulmonary Langerhans cell histiocytosis: emerging concepts in pathobiology, radiology, and clinical evolution of disease.Chest. 2003; 123: 1673-1683Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar8Travis WD Borok Z Roum JH et al.Pulmonary Langerhans cell granulomatosis (histiocytosis X): a clinicopathologic study of 48 cases.Am J Surg Pathol. 1993; 17: 971-986Crossref PubMed Scopus (276) Google ScholarAlthough the pathogenic mechanisms that link tobacco smoke exposure to these disorders have not been elucidated, there is growing evidence that in all these diseases the primary target appears to be the terminal and/or respiratory bronchioles. RB was first described by Niewhoehner et al9Niewhoehner DE Kleinerman J Rice DB Pathologic changes in the peripheral airways of young cigarette smoking.N Engl J Med. 1974; 291: 755-758Crossref PubMed Scopus (699) Google Scholaras a discrete histopathologic entity occurring in young smokers. This disorder, also called “smoker’s bronchiolitis,” is usually found as an incidental histologic abnormality in otherwise asymptomatic smokers, and it is characterized by the accumulation of cytoplasmic golden brown-pigmented macrophages within respiratory bronchioles.10Colby TV Bronchiolitis: pathologic considerations.Am J Clin Pathol. 1998; 109: 101-109Crossref PubMed Scopus (180) Google ScholarImportantly, RB may persist in some patients for many years after stopping smoking.4Fraig M Shreesha U Savici D et al.Respiratory bronchiolitis: a clinicopathologic study in current smokers, ex-smokers, and never-smokers.Am J Surg Pathol. 2002; 26: 647-653Crossref PubMed Scopus (187) Google ScholarFurthermore, the presence of areas of RB or DIP-like reaction can be considered as a sensitive histologic marker of cigarette smoking. Therefore, in long-term smokers it is not infrequent to find these changes, as well as some areas of emphysema, as coexistent lesions of a number of lung diseases such as idiopathic pulmonary fibrosis. However, a small proportion of smokers acquire a more exaggerated response that, in addition to the respiratory bronchioles-centered lesions, provokes interstitial and airspace inflammation and fibrosis extending to the nearby alveoli. This entity is what we called RB-ILD, and contrasting with what occurs in the “pure” RB, this disorder results in clinical symptoms, primarily dyspnea and cough, and in a restrictive or mixed pulmonary function pattern.11Moon J du Bois RM Colby TV et al.Clinical significance of respiratory bronchiolitis on open lung biopsy and its relationship to smoking related interstitial lung disease.Thorax. 1999; 54: 1009-1014Crossref PubMed Scopus (205) Google Scholar12Park JS Brown KK Tuder RM et al.Respiratory bronchiolitis-associated interstitial lung disease: radiologic features with clinical and pathologic correlation.J Comput Assist Tomogr. 2002; 26: 13-20Crossref PubMed Scopus (134) Google ScholarActually, in the first description by Myers et al,3Myers JL Veal Jr, CF Shin MS et al.Respiratory bronchiolitis causing interstitial lung disease: a clinicopathological study of six cases.Am Rev Respir Dis. 1987; 135: 880-884Crossref PubMed Scopus (300) Google Scholarpatients showed clinical, physiologic, and radiologic evidence of chronic ILD, while the open-lung biopsy specimens only exhibited changes of RB with some nonspecific thickening of the alveolar septa by inflammation and fibrosis in alveoli adjacent to respiratory bronchioles. DIP was initially described by Liebow et al,13Liebow AA Steer A Billingsley JG Desquamative interstitial pneumonia.Am J Med. 1965; 39: 369-404Abstract Full Text PDF PubMed Scopus (282) Google Scholarand in the following 2 decades it was considered as the putative early stage of the usual interstitial pneumonia (UIP), an idea that was abandoned at the beginning of the 1990s. This disease is characterized by the widespread accumulation of intra-alveolar macrophages, with usually mild interstitial reaction, although some conditions may evolve to fibrosis and end-stage lung disease. Currently, it is well known that the histopathologic patterns of RB-ILD and DIP may overlap, and the key feature to differentiate both disorders is the distribution and extent of the lesions: bronchiolocentric in the RB-ILD, or diffuses in the DIP.14Desai SR Ryan SM Colby TV Smoking-related interstitial lung disease: histopathological and imaging perspectives.Clin Radiol. 2003; 58: 259-268Abstract Full Text Full Text PDF PubMed Scopus (51) Google ScholarIn this context, it has been proposed that RB, RB-ILD, and DIP may be different components of the same histopathologic disease spectrum, representing diverse degrees of severity of the same process caused by chronic smoking.15Yousem SA Colby TV Gaensler EA Respiratory bronchiolitis associated interstitial lung disease and its relationship to desquamative interstitial pneumonia.Mayo Clin Proc. 1989; 64: 1373-1380Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar16Heyneman LE Ward S Lynch DA et al.Respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease, and desquamative interstitial pneumonia: different entities or part of the spectrum of the same disease process?.Am J Radiol. 1999; 173: 1617-1622Google ScholarNonetheless, it is important to emphasize that although rare, DIP is one of the most common forms of ILDs in children, probably representing the same morphologic pattern of a different disease not related to smoking.17Stillwell PC Norris DG O'Connell EJ et al.Desquamative interstitial pneumonitis in children.Chest. 1980; 77: 165-171Crossref PubMed Scopus (54) Google Scholar18Barbato A Panizzolo C Recent advances: chronic interstitial lung disease in children.Paediatr Respir Rev. 2000; 1: 172-178Abstract Full Text PDF PubMed Scopus (17) Google Scholar PLCH, also known as eosinophilic granuloma of the lung, is a disorder of unknown etiology, but also strongly related to cigarette smoking.8Travis WD Borok Z Roum JH et al.Pulmonary Langerhans cell granulomatosis (histiocytosis X): a clinicopathologic study of 48 cases.Am J Surg Pathol. 1993; 17: 971-986Crossref PubMed Scopus (276) Google ScholarIt has been reported that children with Langerhans cell histiocytosis acquire pulmonary involvement only after several years of smoking.19Bernstrand C Cederlund K Ashtrom L et al.Smoking preceded pulmonary involvement in adults with Langerhans cell histiocytosis diagnosed in childhood.Acta Paediatr. 2000; 89: 1389-1392Crossref PubMed Scopus (29) Google ScholarMoreover, the hallmark pathologic feature in PLCH, the lung proliferation/infiltration by Langerhans cells, has also been found in healthy cigarette smokers.20Casolaro MA Bernaudin JF Saltini C et al.Accumulation of Langerhans cells on the epithelial surface of the lower respiratory tract in normal subjects in association with cigarette smoking.Am Rev Respir Dis. 1988; 137: 406-411Crossref PubMed Scopus (159) Google ScholarLikewise, mice passively exposed to tobacco smoke acquire a pulmonary granulomatous inflammation rich in Langerhans cells, which disappear after ceasing exposure to tobacco smoke.21Zeid NA Muller HK Tobacco smoke induced lung granulomas and tumors: association with pulmonary Langerhans cells.Pathology. 1995; 27: 247-254Abstract Full Text PDF PubMed Scopus (62) Google ScholarThe pathogenic mechanisms are unclear, but patients with PLCH display an abnormal T-cell proliferative response to tobacco glycoproteins.22Youkeles LH Grizzanti JN Liao Z et al.Decreased tobacco-glycoprotein-induced lymphocyte proliferation in vitro in pulmonary eosinophilic granuloma.Am J Respir Crit Care Med. 1995; 151: 145-150Crossref PubMed Scopus (57) Google ScholarThe earliest lesions are composed by cellular infiltrates containing large aggregates of Langerhans cells associated with lymphocytes and eosinophils, affecting small airways in an acinar distribution.23Kambouchner M Basset F Marchal J et al.Three-dimensional characterization of pathologic lesions in pulmonary Langerhans cell histiocytosis.Am J Respir Crit Care Med. 2002; 166: 1483-1490Crossref PubMed Scopus (89) Google ScholarThis inflammatory lesion is followed by a fibrotic reaction leading to the formation of stellate scars and cystic changes. The outcome of this disease is variable and unpredictable, ranging from an asymptomatic course to progressive fibrotic disease.24Vasallo R Ryu JH Schroeder DR et al.Clinical outcomes of pulmonary Langerhans cell histiocytosis in adults.N Engl J Med. 2002; 346: 484-490Crossref Scopus (339) Google Scholar Interestingly, RB-ILD, DIP, and PLCH belong to the subgroup of ILDs that cause the formation of pulmonary cysts clearly visible on high-resolution CT.25Koyama M Johkoh T Honda O et al.Chronic cystic lung disease: diagnostic accuracy of high-resolution CT in 92 patients.AJR Am J Roentgenol. 2003; 180: 827-835Crossref PubMed Scopus (107) Google ScholarCystic changes in RB-ILD and DIP usually represent areas of emphysema superimposed on areas of ground-glass attenuation; in general, these cysts lack perceptible walls.25Koyama M Johkoh T Honda O et al.Chronic cystic lung disease: diagnostic accuracy of high-resolution CT in 92 patients.AJR Am J Roentgenol. 2003; 180: 827-835Crossref PubMed Scopus (107) Google ScholarLikewise, multiple cysts are typical radiologic findings in patients with PLCH; but in this case, wall thickness varies from thin and barely perceptible to several millimeters. In this disease, cystic lesions result from the destruction of the bronchiolar wall, with progressive dilatation of the lumen, which is subsequently surrounded by fibrous tissue.23Kambouchner M Basset F Marchal J et al.Three-dimensional characterization of pathologic lesions in pulmonary Langerhans cell histiocytosis.Am J Respir Crit Care Med. 2002; 166: 1483-1490Crossref PubMed Scopus (89) Google ScholarIn this context, although PLCH has been traditionally associated with spontaneous pneumothorax, putatively provoked by the disruption of subpleural cysts, this pathological abnormality may also occur in RB-ILD and DIP.26Cottin V Streichenberger N Gamondes JP et al.Respiratory bronchiolitis in smokers with spontaneous pneumothorax.Eur Respir J. 1998; 12: 702-704Crossref PubMed Scopus (83) Google Scholar Although RB, RB-ILD, DIP, and PLCH are considered as discrete entities of long-term smokers, it is not infrequent to find a mixture of pathologic features rendering histopathologic diagnosis a difficult task. Thus, for example, patients with PLCH often exhibit RB and emphysematous lesions, or in some instances, a profuse intra-alveolar macrophage accumulation mimicking DIP.8Travis WD Borok Z Roum JH et al.Pulmonary Langerhans cell granulomatosis (histiocytosis X): a clinicopathologic study of 48 cases.Am J Surg Pathol. 1993; 17: 971-986Crossref PubMed Scopus (276) Google Scholar14Desai SR Ryan SM Colby TV Smoking-related interstitial lung disease: histopathological and imaging perspectives.Clin Radiol. 2003; 58: 259-268Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar27Colby TV Lombard C Histiocytosis X in the lung.Hum Pathol. 1983; 14: 847-856Abstract Full Text PDF PubMed Scopus (166) Google Scholar28Colby TV Carrington CB Interstitial lung disease.in: Thurlbeck WM Churg AM Pathology of the lung. Thieme Medical Publishers, New York, NY1995: 589-737Google Scholar In this issue of CHEST (see page 1199), Vassallo and colleagues provide additional evidence of this overlapping, demonstrating that varying degrees of RB/DIP-like changes are usually present in the lungs of adult smoking patients with otherwise histologically proven PLCH. Moreover, in some cases the RB/DIP changes were severe enough to cause prominent ground-glass attenuation on high-resolution CT scans, an unusual finding in “pure” PLCH. In addition, the evaluation of the lungs of 14 patients with PLCH also showed that the extent of involvement of RB/DIP changes significantly correlated with the cumulative exposure to cigarettes smoked at the time of the biopsy, but did not correlate with the lung function abnormalities. An important clinical/pathologic consideration is related to the definite diagnosis. The question that arises is do patients showing PLCH lesions overlapped with severe and widespread RB-ILD or DIP-like changes have more than one disease? As Vasallo and coworkers state, it is improbable that these patients have two diseases but rather PLCH with prominent features of other smoking-associated parenchymal lesions. As mentioned before, a similar situation occurs in smoker patients with UIP and changes of RB, or in patients with UIP showing areas of nonspecific interstitial pneumonia. In both examples, the specific diagnosis would be UIP. A final consideration is that the relationship between cigarette smoke and ILDs has not been completely revealed and will continue unfolded. There is strong evidence supporting a potential causal role for the development of some ILDs, such as RB-ILD, DIP, and PLCH. Nevertheless, cigarette smoking exhibits also a paradoxical effect on parenchymal lung inflammation and fibrosis. Actually, it may promote or inhibit these pathologic processes, influencing the incidence, severity, or natural history of a wide array of ILDs. For example, current and former smokers show an increased risk for acquiring idiopathic pulmonary fibrosis, though smokers seem to have a better survival rate than nonsmokers.29King Jr, TE Tooze JA Schwarz MI et al.Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model.Am J Respir Crit Care Med. 2001; 164: 1171-1181Crossref PubMed Scopus (730) Google ScholarBy contrast, cigarette smoking appears to have a protective effect on the development of a number of ILD including hypersensitivity pneumonitis, sarcoidosis, and radiation-induced pneumonitis.30Selman M Hypersensitivity pneumonitis.in: Schwarz MI King TE Interstitial lung disease. BC Decker, Hamilton, Ontario2003: 452-484Google Scholar31Douglas JG Middleton WG Gaddie J et al.Sarcoidosis: a disorder commoner in non-smokers?.Thorax. 1986; 41: 787-791Crossref PubMed Scopus (79) Google Scholar32Johansson S Bjermer L Franzen L et al.Effects of ongoing smoking on the development of radiation-induced pneumonitis in breast cancer and oesophagus cancer patients.Radiother Oncol. 1998; 49: 41-47Abstract Full Text Full Text PDF PubMed Scopus (88) Google ScholarTherefore, the window between long-term cigarette smoking and ILDs remains open.