Review Article
Smoking-related interstitial lung disease

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Abstract

Pulmonary diseases associated with tobacco smoking are a complex group of disorders ranging from chronic obstructive pulmonary disease (COPD) to lung cancer. Interstitial lung diseases (ILDs) have only recently been linked to smoking. The ILDs related to smoking include respiratory bronchiolitis–associated interstitial lung disease, desquamative interstitial pneumonia, and pulmonary Langerhans cell histiocytosis. The relationship of smoking with each of these entities has been largely established on the weight of epidemiologic evidence. Although they have been retained as distinct and separate conditions in various classifications of interstitial lung diseases, these 3 entities share a number of clinical, radiologic, and pathologic features suggesting that they represent a spectrum of patterns of interstitial lung disease occurring in predisposed individuals who smoke. Evaluation of histologic features, particularly in surgical lung biopsy samples, is important in making the distinction between these disorders. However, even after tissue biopsy, it may sometimes be difficult to clearly separate these entities. The importance of making the distinction between them lies in the different clinical management strategies used. Further experimental evidence, including genetic information, may be important in improving our understanding of these diseases.

Introduction

Tobacco smoke consists of a myriad of chemical compounds with a host of different pulmonary and systemic effects [1], [2]. Traditional lung diseases associated with smoking are a varied group of disorders ranging from chronic obstructive pulmonary disease (COPD) to lung cancer. More recently, a growing list of interstitial lung diseases (ILDs) have also been associated with smoking.

Interstitial lung diseases are a rather complex and heterogeneous group of diffuse lung parenchymal disorders (DLPDs) of either known or unknown cause, characterized clinically by dyspnea, restrictive pulmonary function, impaired gas exchange, and radiologically by diffuse lung infiltrates [3], [4], [5], [6], [7]. Diffuse lung parenchymal disorders of unknown cause are also known as idiopathic interstitial pneumonias (IIPs), the classification of which has undergone changes over time [8]. Cigarette smoking has only relatively recently been implicated as an important cause of ILDs, including certain entities previously or currently classified as IIPs [9]. By and large, the clinical and epidemiologic evidence for this association far outweighs the experimental evidence. Nevertheless, with the growing body of knowledge in this area, it may be appropriate to reclassify some of the IIPs into a group of “smoking-related interstitial lung diseases” (SRILDs) [10], [11], [12]. Smoking has been causatively associated with the following ILDs: (1) respiratory bronchiolitis–associated interstitial lung disease (RB-ILD); (2) desquamative interstitial pneumonia (DIP); and (3) pulmonary Langerhans cell histiocytosis (PLCH). This review will examine the interrelationship of these smoking-related disorders, enumerate the salient clinical, radiologic, and histologic features of each condition, discuss the diagnostic roles of lung biopsy and bronchoalveolar lavage (BAL), and briefly review other ILDs in which smoking may play a role.

Section snippets

Relationship of smoking with interstitial lung diseases

The relationship of smoking with certain types of interstitial lung diseases is almost wholly predicated on clinical and epidemiologic studies. Within the diversity and abundance of experimental data linking tobacco smoke to lung disease, there is little definitive evidence to suggest a direct link between smoking and ILD. However, smoking is known to be associated with inflammation in the airways and lung parenchyma [2]. The classic studies of Hammond and colleagues [13] in long-term smoking

Respiratory bronchiolitis–associated interstitial lung disease

Bronchiolar inflammatory diseases may be idiopathic or caused by a variety of insults other than tobacco smoke, including infection, aspiration, drugs, systemic disorders (eg, collagen vascular diseases) and transplant rejection. Small airways disease due to smoking encompasses inflammation and remodeling in preacinar membranous, and intraacinar respiratory bronchioles, referred to generically as “smokers' bronchiolitis” (Fig. 1) [9], [34]. After the recognition of RB in young cigarette

Desquamative interstitial pneumonia

Desquamative interstitial pneumonia is currently included in the American Thoracic Society/European Respiratory Society consensus classification as a form of IIP characterized histologically by the diffuse exudation of pigmented macrophages within alveolar spaces [8]. Desquamative interstitial pneumonia was originally defined in 1965 by Liebow and colleagues who believed the prominent large intraalveolar cells to be reactive alveolar pneumocytes that had “desquamated” from the alveolar surface

Pulmonary Langerhans cell histiocytosis

Langerhans cell histiocytosis refers to a group of disorders with variable organ involvement by proliferations of LCs (a dendritic-histiocytic cell type) accompanied by other inflammatory and immune effector cells. The Langerhans cell histiocytoses are of diverse biologic behavior, ranging from localized, self-limited conditions to fulminant multisystem disorders. There is evidence that some of these disorders may involve clonal proliferations of LCs. Lung involvement may be seen as part of a

Role of lung biopsy and BAL cytology in the evaluation of SRILD

With the exception of PLCH, the diagnosis of SRILD can be established only with surgical lung biopsy (thoracoscopic or open lung procedures). The subtle distinctions of macrophage distribution and intensity, and the patterns of interstitial fibrosis across the secondary lobule, upon which the diagnoses of RB, RBILD and DIP are predicated, cannot be achieved in the limited samples provided by transbronchial biopsy (TBB) or core needle biopsy. The presence of DIP-like reactions around a variety

Are RB-ILD and DIP part of a continuum of SRILD?

This is a somewhat controversial area. There is an argument that RB-ILD and DIP should be reclassified as a single entity because of their common smoking association, overlapping HRCT findings, and histologic features [12]. We have, in our practice (RNR and LDG), seen a patient whose radiographic features appeared to show progression from RB-ILD to DIP. The initial HRCT showed asymmetrical nodular thickening, more on the right side, suggestive of RB-ILD (Fig. 3A). A TBB performed concurrently

Smoking and other interstitial lung diseases

In UIP/IPF, an etiologic contribution of cigarette smoking has been suggested but is less certain. A relationship between UIP/IPF and smoking had been proposed as early as 1969 [74]. Subsequent studies have shown a variable prevalence of smoking in patients with IPF (ranging from 43% to 83%), and more recently, UIP/IPF has been included among SRILDs [12]. Baumgartner and colleagues [75], in a large case-controlled epidemiologic study of risk factors in IPF, found that 72% of patients with IPF

Conclusions

Although the pathogenetic role of cigarette smoking in the causation of these diseases is not definitive, there is enough strong clinical and epidemiologic linkage, and histologic overlap to warrant a designation of SRILDs for RB-ILD, DIP, and PLCH. We agree with the suggestion that future classifications of IIPs take into consideration the role of smoking in the causation of this group of diseases. It may be useful to think of them as a disease spectrum of patterns of interstitial lung injury

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