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Mexico City, Mexico
Dr. Selman is Director of Research, Instituto Nacional de Enfermedades Respiratorias.
Correspondence to: Moisés Selman, MD, FCCP, Instituto Nacional de Enfermedades Respiratorias Tlalpan 4502; Col. Sección 16 México DF, CP 14080, México; e-mail: mselman{at}sni.conacyt.mx
Cigarette smoking affects many organs and remains the most preventable cause of morbidity and premature death.1 2 In 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).3 4 5 6 7 8 Although 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 al9 as 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.10 Importantly, RB may persist in some patients for many years after stopping smoking.4 Furthermore, 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.11 12 Actually, in the first description by Myers et al,3 patients 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,13 and 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.14 In 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.15 16 Nonetheless, 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.17 18
PLCH, also known as eosinophilic granuloma of the lung, is a disorder of unknown etiology, but also strongly related to cigarette smoking.8 It has been reported that children with Langerhans cell histiocytosis acquire pulmonary involvement only after several years of smoking.19 Moreover, the hallmark pathologic feature in PLCH, the lung proliferation/infiltration by Langerhans cells, has also been found in healthy cigarette smokers.20 Likewise, mice passively exposed to tobacco smoke acquire a pulmonary granulomatous inflammation rich in Langerhans cells, which disappear after ceasing exposure to tobacco smoke.21 The pathogenic mechanisms are unclear, but patients with PLCH display an abnormal T-cell proliferative response to tobacco glycoproteins.22 The 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.23 This 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.24
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.25 Cystic 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.25 Likewise, 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.23 In 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.26
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.8 14 27 28
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.29 By 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.30 31 32 Therefore, the window between long-term cigarette smoking and ILDs remains open.
References
This article has been cited by other articles:
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  A. Caminati and S. Harari Smoking-related Interstitial Pneumonias and Pulmonary Langerhans Cell Histiocytosis. Proceedings of the ATS, January 1, 2006; 3(4): 299 - 306. [Abstract] [Full Text] [PDF]
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 P. G. Woodruff, L. L. Koth, Y. H. Yang, M. W. Rodriguez, S. Favoreto, G. M. Dolganov, A. C. Paquet, and D. J. Erle A Distinctive Alveolar Macrophage Activation State Induced by Cigarette Smoking Am. J. Respir. Crit. Care Med., December 1, 2005; 172(11): 1383 - 1392. [Abstract] [Full Text] [PDF]
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 D. Bernhard, A. Csordas, B. Henderson, A. Rossmann, M. Kind, and G. Wick Cigarette smoke metal-catalyzed protein oxidation leads to vascular endothelial cell contraction by depolymerization of microtubules FASEB J, July 1, 2005; 19(9): 1096 - 1107. [Abstract] [Full Text] [PDF]
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