High-Resolution Computed Tomography Features of Smoking-Related Interstitial Lung Disease Arjun Nair, MBChB, MRCP, FRCR*, and David M. Hansell, MD, FRCP, FRCR*,† The smoking-related interstitial lung diseases (ILDs) comprise several diseases that often coexist. In this review, the high-resolution computed tomography (CT) features and pathologic correlates of the traditional smoking-related ILDs (respiratory bronchiolitis–associated ILD, desquamative interstitial pneumonia, and pulmonary Langerhans cell histiocytosis) and those ILDs with less clearly defined relationships to smoking are described. The degree to which these entities coexist and overlap is explored on high-resolution CT scans. Emerging evidence about the link between smoking and lung fibrosis (from lung cancer–screening trials with CT), and smoking as a factor in ageing of the lung, is also discussed. Semin Ultrasound CT MRI 35:59-71 C 2014 Elsevier Inc. All rights reserved.

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moking-related interstitial lung disease (ILD) comprises a heterogeneous group of disorders that have traditionally been viewed as individual entities, each with its own constellation of clinical, radiologic, and histopathologic manifestations. In practice, these disorders frequently coexist with the more common sequelae of cigarette smoking–induced lung injury: chronic obstructive pulmonary disease (COPD) and bronchogenic carcinoma. The morbidity and mortality attributable exclusively to ILD related to smoking is thus difficult to ascertain, but their recognition is essential for appropriate management and prognostication. Over the past 20 years, high-resolution computed tomography (HRCT) has been crucial to understanding the phenotype of smoking-related damage and its clinicopathologic implications. We review the HRCT features and pathologic correlates of traditional smoking-related ILDs—namely respiratory bronchiolitis–associated ILD (RB-ILD), desquamative interstitial pneumonia (DIP), and pulmonary Langerhans cell histiocytosis (PLCH)—as well as ILDs with less clearly defined relationships to cigarette smoking. The overlap between these various entities and arguments for and against encompassing them within a singular spectrum of smoking-related ILD are discussed. We also explore recent evidence suggesting that

*Department of Radiology, Royal Brompton Hospital, Royal Brompton & Harefield NHS Foundation Trust, London, UK. †National Heart and Lung Institute, Imperial College London, London, UK. Address reprint requests to David Hansell, MD, FRCP, FRCR, Department of Radiology, Royal Brompton Hospital, Sydney St, London SW3 6NP, London, UK. E-mail: [email protected]

0887-2171/$-see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.sult.2013.10.005

COPD and pulmonary fibrosis are manifestations of the ageing lung, with cigarette smoke playing a role in the ageing process.

Smoking-Related ILD: Traditional Entities Respiratory Bronchiolitis–Associated Interstitial Lung Disease RB is a common incidental finding in smokers' lungs at pathologic examination. Niewoehner et al1 first described this lesion in a necropsy study of 39 young male patients in 1974, finding it in all 19 smokers who were mostly asymptomatic. RB was subsequently thought to cause at most mild (but still subclinical) derangement of lung function.2-4 However, in 1987, Myers et al5 described six patients with clinical, radiographic, and physiological manifestations of a restrictive chronic ILD, but only RB on open lung biopsy. They postulated that this entity may be related to, or even represent an early stage of, DIP. The term “respiratory bronchiolitis– associated interstitial lung disease” was subsequently introduced by Yousem et al6 in an attempt to discriminate between this newly recognized entity and DIP. RB-ILD is thus contemporarily viewed as the rare instance where the pathologic lesion of RB manifests clinically as an ILD.7 It is indeed rare, occurring in only 1 patient of the 109 cases with histologically proven RB in the largest biopsy series to date.8 RB-ILD usually presents insidiously with cough and dyspnea in the third to sixth decades, often with a male preponderance.5,6,9-12 Current heavy smokers are more frequently 59

60 affected. For example, Ryu et al11 found that 83% of patients with RB-ILD were current smokers, with a median smoking history of 25 pack-years. Pulmonary function tests usually reveal a mixed but predominantly restrictive defect, with a mild to moderate reduction in the diffusing lung capacity for carbon monoxide (DLco)6,9-12; only rarely is the physiological deficit severe.13 The histologic hallmark of RB is bronchiolocentric clusters of pigmented macrophages within respiratory bronchioles extending to adjacent alveolar ducts and alveoli, associated with a variable but mild amount of nonspecific peribronchiolar thickening of the alveolar septa by a combination of fibroblasts, collagen deposition, and a mild chronic mononuclear cell infiltrate. The macrophages (so-called smoker's macrophages) contain a light brown, finely granular pigment giving a “glassy” quality to their cytoplasm.5,6 Both the extent of cytoplasmic pigmentation and peribronchiolar fibrosis (but not the overall extent of RB) correlate with the number of pack-years smoked.8 The manifestations of RB-ILD on HRCT images strictly speaking are those of RB, although they may be more extensive in RB-ILD (the overlap between these entities and others are discussed later). RB manifests as poorly defined centrilobular ground-glass nodules, patchy ground-glass opacity (GGO), bronchial wall thickening, and areas of ground-glass attenuation (Fig. 1). In an important study comparing 124 ever-smokers (98 current and 26 ex-smokers) with 51 never-smokers, Remy-Jardin et al14 demonstrated parenchymal ill-defined ground-glass micronodules scattered within the pulmonary lobule in 27% of current smokers and none of the never-smokers, with an exclusive upper zone distribution in 71% of patients. Additionally, areas of groundglass attenuation were detected in 20% of current smokers, also with an upper lobe and diffuse distribution. A subsequent allied study of HRCT-histopathologic correlation15

Figure 1 Patchy upper-lobe ground-glass opacity in a cigarette smoker with RB-ILD.

A. Nair and D.M. Hansell found that micronodules corresponded histologically to changes compatible with RB, whereas ground-glass attenuation represented one, or a combination of three, histologic findings, namely RB and alveolar wall thickening with a cellular inflammatory infiltrate similar to RB but with no intraalveolar exudate. These HRCT features and pathologic relationships have been confirmed in subsequent studies,9-12,16-19 though with varying frequency and zonal predominance. Centrilobular nodules and ground-glass attenuation have been the predominant abnormalities in most studies. Only one study to date has demonstrated central and peripheral bronchial wall thickening (likely the HRCT correlate of chronic bronchitis) as the dominant feature in RB-ILD, occurring in 90% and 86% of cases, respectively.10 The preponderance of bronchial wall thickening in that study was not attributable to differences in smoking history in their study group. Interestingly, the same authors found a significant correlation between the extent of micronodules and ground-glass attenuation with the extent of macrophage accumulation in respiratory bronchioles, alveoli, and alveolar ducts.10 Such continuing inflammatory change is a likely explanation for the observed higher frequency of ground-glass attenuation and increased profusion of micronodules in current and continuing smokers.20 Conversely, partial regression of centrilobular micronodules and groundglass attenuation occurs with smoking cessation, with or without treatment, although the number of subjects who quit smoking in such studies has been small.10,19,20 Areas of hypoattenuation, likely reflecting obliterative small airways disease but more prevalent in lower lobes, have also been reported in RB-ILD.10 Given that centrilobular nodules, ground-glass attenuation, and small airways disease (but not usually bronchial wall thickening) are also features of subacute hypersensitivity pneumonitis (Fig. 2), it is important to elicit evidence of smoking for a more confident diagnosis of RB-ILD on the basis of appearances on HRCT scans alone. In this regard, the presence of emphysema on CT scan sometimes helps: upper-lobe predominant emphysema is frequently present in patients with RB-ILD and may be paraseptal or

Figure 2 Subacute hypersensitivity pneumonitis (HP) in a 15-year-old boy as a consequence of exposure to mould. Diffuse ill-defined centrilobular ground-glass nodularity is also seen in RB-ILD, although usually less profuse and pronounced than in this case. A clear exposure history and the young age of the patient in this case helped to secure a diagnosis of HP in this case.

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centrilobular. However, as the emphysema in RB-ILD on HRCT scan is usually mild or even inconspicuous, the absence of emphysema does not preclude the diagnosis, as minimal emphysema may not be visible on HRCT scan.21-23 Intriguingly, the longitudinal HRCT study by Remy-Jardin et al20 demonstrated the replacement of micronodularity with centrilobular emphysema in 5 of 19 persistent smokers, adding support to the hypothesis that RB is a precursor to the destructive emphysematous lesion.24-26

Desquamative Interstitial Pneumonia DIP was first described by Liebow et al27 in 1965, in a series of 18 patients with uniform filling of the alveoli by what was thought to be desquamated “large alveolar cells” accompanied by slight thickening of the alveolar walls. Since then, it has been recognized that the alveolar infiltrate actually represents macrophage accumulation rather than alveolar desquamation28,29; nevertheless, the term “DIP” has been retained7 for consistency with the historical literature, even if it is descriptively less accurate. It is noteworthy that no exposure to cigarette smoke was documented and no obvious noxious agent could be identified in Liebow et al's27 original description of DIP. However, the association with smoking has been repeatedly demonstrated, with at least 90% of patients having a smoking history,6,30 although there are rare instances of DIP caused by dust inhalation,31,32 drugs,33,34 and Gaucher disease.35 DIP usually presents in the fourth to sixth decade, in a similar insidious fashion to RB-ILD. Unlike RB-ILD, however, almost half of patients develop digital clubbing.6,30 Men are affected more than women by a ratio of approximately 2:1.6,36 Pulmonary function tests are consistently restrictive in DIP, with a reduction in DLco also present, providing a useful marker for disease severity.37 Histopathologically, the large numbers of macrophages that fill the alveoli in DIP are very similar to those seen in RB-ILD, with cytoplasmic pigmentation and “glassy” cytoplasm except in those rare cases with a nonsmoking etiology.6 However, DIP can be histologically distinguished from RB-ILD on the basis of extent and distribution. The alveolar filling in DIP is usually more extensive and uniform, accompanied by a widespread (albeit mild) interstitial fibrosis and a mononuclear cell interstitial infiltrate. Both the macrophage accumulation and septal fibrosis also lack the bronchiolocentricity that is a key feature of RB-ILD.6,38 Furthermore, cases of DIP tend to have a greater extent of lymphoid follicles and eosinophilic infiltration.38 The fibroblastic foci, severe architectural distortion, honeycombing, and heterogeneity of findings seen in usual interstitial pneumonia (UIP)39 are notable by their absence in DIP. The almost invariable HRCT finding of DIP is widespread ground-glass attenuation,18,36,40 which is usually bilateral and more or less symmetrical.11,36 The ground-glass attenuation has a predilection for the lower lobes, sometimes with a tendency toward a peripheral distribution. In a HRCT series of 22 patients with biopsy-proven DIP, Hartman et al36 noted ground-glass attenuation in the middle and lower zones in all 22 patients, with 73% demonstrating a lower lobe

Figure 3 A 57-year-old male cigarette smoker with biopsy-proven DIP (note the surgical clips in the anterior left lower lobe, identified by the black arrowhead). Patchy ground-glass opacity in a predominantly subpleural and mid to lower zone distribution coexists with paraseptal emphysema (black arrow) and multiple “cystic” airspaces (white arrow); it is conceivable such airspaces also represent emphysema. No definite architectural distortion or traction bronchiectasis heralding progression to fibrosis is seen.

predominance and a peripheral, patchy, and diffuse distribution in 59%, 23%, and 18%, respectively. Occasionally smokers with DIP may also have ill-defined centrilobular nodules on HRCT images that probably represent coexistent foci of RB. HRCT evidence of limited fibrosis in the form of intralobular lines, traction bronchiectasis, and architectural distortion has been noted less consistently, with a reported frequency of between 17% and 63%.18,36,40 The apparently high frequency of fibrosis (63%) reported by Heyneman et al18 may be an overestimate, because this figure encompassed the findings of fibrosis and what was deemed honeycombing. The “honeycombing” reported in HRCT studies on DIP is thus potentially confusing, as it may in fact represent cystic spaces, another feature seen in DIP, the nature of which is unclear. Hartman et al36 equated the predominantly peripheral cysts seen in 32% of their initial series to the “subpleural cystic changes” seen in UIP. However, in a later series, they found a lower prevalence of honeycombing, occurring in 1 of 12 patients41 and in agreement with other studies.11 Akira et al40 found that although patients with DIP had a higher frequency of cystic spaces (75%), these were not associated with architectural distortion, and no honeycombing was seen at corresponding sites of these cysts on surgical biopsies. Instead, they found the cysts probably corresponded to dilated alveolar ducts or “pulmonary cysts.” It is conceivable that these cysts represent foci of emphysema (Fig. 3), but emphysema in DIP tends to be

62 minor in extent.18,36 However, the fact that some of these cysts may regress makes it unlikely that they are a marker of severe fibrosis. Progression to severe fibrosis is rare in DIP, although a background of coexistent nonspecific interstitial pneumonia (NSIP) is frequent.

Pulmonary Langerhans Cell Histiocytosis Langerhans cell histiocytosis (LCH) is the contemporary term for a variety of histiocytic disorders, including histiocytosis X, Langerhans cell granuloma, eosinophilic granuloma, Letterer-Siwe disease, and Hand-Schüller-Christian disease.42 Both Letterer-Siwe disease (an often fatal condition in infants) and Hand-Schüller-Christian disease (usually in children) represent disseminated forms of LCH, whereas the lungs are usually the only organ affected in PLCH. PLCH is a rare disease, although its exact incidence and prevalence have not been fully documented.43 For example, in one early series PLCH was found in only 5% of biopsy specimens performed for chronic infiltrative lung disease.44 Patients are usually young adults, in their third to fourth decades, and they present with chronic cough, dyspnea, and occasionally chest pain. However, 16%-36% of patients are reportedly asymptomatic at presentation.45,46 Langerhans cells are differentiated non-malignant cells of dendritic lineage that function as antigen-presenting cells. They are distinguished from normal denditric cells on electron microscopy by the presence of Birbeck granules (rod-shaped five-layered intracellular inclusions) and by strong immunohistochemical staining for the CD1a antigen, although this is not entirely specific.42 The culprit lesion of PLCH is an excess of activated Langerhans cells, which aggregate together to form nodules varying in size from 1-5 mm in diameter (but can be as large as 20 mm), centered along the distal airways.45,47-49 Variable and frequently numerous eosinophils may be associated with these nodules (hence the old term “eosinophilic granuloma” for these lesions), whereas neutrophils and lymphocytes are present to a lesser extent.50 The nodules become less cellular and more fibrous as the disease progresses, developing a stellate morphology, with cavitation and thinwalled cyst formation. The mechanisms of cavitation and cyst formation are still not entirely clear, but it has been demonstrated that the cavities within nodules represent airway enlargement (as a result of fibrosis), and subsequent coalescence of these airways and cysts leads to airspace enlargement and emphysematous destruction.48 The progression of lesions at different rates leads to the temporal heterogeneity of lesions within a single biopsy.45,49 The association between smoking and PLCH, first noted in 1981,45 is now irrefutable: over 90% of patients with the disease have a history of smoking.45-47 The number of cells of dendritic and Langerhans lineage in smokers' lungs is increased 2-fold,51 and Langerhans cells seem to migrate to the epithelial surface of the respiratory tract, leading to their presence in the bronchoalveolar lavage of smokers.52 Although the exact mechanisms causing this proliferation remain unclear, it seems likely that the increased proliferation of Langerhans cells in

A. Nair and D.M. Hansell smokers is an inflammatory response; the disease does not behave in a neoplastic manner.53 On HRCT, a variety of well-documented features may be seen simultaneously, mirroring the heterogeneity of lesions on pathologic examination. Nevertheless, the relative proportion of these abnormalities depends on the stage of disease.54-56 The two most frequently encountered features are nodules and cysts, often bizarre shaped, this combination being virtually pathognomonic of PLCH.54,57,58 The nodules are usually less than 10 mm in diameter but may be as large as several centimeters and may show cavitation (Fig. 4). The micronodular (nodules less than 5-mm diameter) form of PLCH may superficially resemble pulmonary sarcoidosis, but is distinguished by the coexistence of characteristic small cysts. Cysts may be thick- or thin-walled; although their occasional bronchocentricity and shape may mimic bronchiectasis, they can generally be distinguished from bronchiectatic airways on close scrutiny.58 In the early stages, the intervening parenchyma may appear completely normal, but as the disease progresses, features of fibrosis and architectural distortion supervene. Upper and midzone predominance, with sparing of the costophrenic angles, is typical, but there is no predilection for the central or peripheral lung.

Figure 4 Pulmonary Langerhans cell histiocytosis (PLCH) in a 44-yearold female smoker presenting with progressive dyspnoea. (A) An initial HRCT demonstrated multiple small cysts of varying wall thickness, as well as tiny nodules, consistent with PLCH. Following smoking cessation, her dyspnoea markedly improved. (B) A follow-up HRCT after 1 year demonstrating almost complete regression of the cysts and nodules; such regression is common.

Smoking-related interstitial lung disease Serial HRCT has been instrumental in documenting the evolution of abnormalities in PLCH. Brauner et al54 observed a higher frequency of nodules and thick-walled cysts on HRCT images in patients with symptoms of less than 6 months' onset, whereas confluent cysts were the dominant feature when disease had been present for longer than 3 years. In a later study, they confirmed these observations and also recorded either the regression of nodules (Fig. 4) or the transformation of large nodules into thick-walled cysts, and later the change of thick-walled cysts into thin-walled cysts.55 The sequence of nodule, cavitating nodule, thick-walled cyst, thin-walled cyst, and coalescent cysts leading to fibrobullous destruction and a quasi-emphysematous appearance (Fig. 5) are now well recognized. In a more recent study, only 14 of 27 (52%) patients with PLCH who were followed up using HRCT over a mean period of 21 months showed a decreased extent of lesions, even though 22 of the 27 patients stopping smoking.56 In other words, progression of disease may occur despite removal of the inciting agent (ie, cigarette smoke). The mechanisms behind such progression remain to be elucidated. Perhaps unsurprisingly, the development of a predominantly cystic pattern correlates strongly with a decrease in

63 FEV1-FVC ratio and DLco.59 These parameters, in turn, are predictors of shorter survival.60 However, it should be noted that although the appearance of thin-walled cysts on HRCT images may be considered the harbinger of advanced disease, corresponding to fibrous cysts devoid of Langerhans cells histopathologically, this is not always the case; these cysts may harbor cavitary granulomas61 or a pericystic inflammatory cell infiltrate.56 As such, they have the potential to regress.56 Notwithstanding this caveat, HRCT remains a useful surveillance tool, alongside other clinical evidence of disease activity.62,63 Emphysema may be identifiable on HRCT at any stage of PLCH, given that many of these patients are smokers. However, the distinction between coalescent cysts and de novo emphysema becomes more difficult as the disease progresses, and indeed advanced PLCH is virtually indistinguishable from emphysema on HRCT images (Fig. 5). Occasional reports of GGO probably reflect the coexistence of a macrophage infiltrate (ie, DIP or RB-ILD).

Smoking and Other Interstitial Pneumonias Idiopathic Pulmonary Fibrosis or UIP

Figure 5 A 36-year-old male smoker with a biopsy-confirmed diagnosis of pulmonary Langerhans cell histiocytosis (PLCH) 15 years earlier. A combination of well-circumscribed thin-walled cysts (arrow in A) and ill-defined cysts that are indistinguishable from centrilobular emphysema (arrowhead in B) is present, while nodules and thickwalled cavities are absent.

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneumonia of unknown cause, demonstrating the characteristic histologic features of UIP on surgical biopsy.7 Ever-smokers have been overrepresented in studies on the clinical features and survival in IPF.30,64-67 However, it is difficult to understand the precise nature of the recognized association between cigarette smoking and IPF, also previously known as cryptogenic fibrosing alveolitis (CFA). Sources of difficulty have primarily been (1) the use of multiple different terms for this entity before the accepted nomenclature of IPF or CFA39 and (2) the lack of standardized diagnostic definitions for IPF in studies predating the consensus classifications of IPF68 and idiopathic interstitial pneumonias.7 Consequently, several entities that are now recognized as distinct from IPF, such as NSIP, DIP, and RB-ILD, were probably included in previous studies. Some studies have documented an increased risk of IPF in current or former smokers as compared with nonsmokers, with odds ratios varying from 1.57-2.9.69-71 For example, Baumgartner et al71 compared 248 cases of IPF with 491 control subjects, documenting an odds ratio of 1.6 for IPF in ever-smokers. More recently, a study of families with familial IPF found HRCT abnormalities compatible with early ILD in 22% of asymptomatic relatives; the symptomatic and asymptomatic ILD groups both had significantly higher smoking prevalence (67% and 45%, respectively) compared with those with no HRCT evidence of ILD.72 Two recent studies have also demonstrated the effects of smoking on survival in IPF. King et al73 showed that the extent of fibroblastic foci was an independent predictor of survival in IPF, and that an improved survival in current

64 smokers compared with never-smokers or former smokers was probably a consequence of the lower degree of fibroblastic foci found in current smokers. Subsequently, however, Antoniou et al74 have shown that such a paradoxical survival effect of smoking may be a spurious consequence of the “healthy smoker” effect (whereby symptomatic smokers with progressive disease may stop smoking and would therefore be designated former smokers).75 Although they initially replicated the improved survival of current smokers compared with former smokers, adjustment for disease severity using a composite physiological index abolished this improved survival and furthermore amplified the higher mortality noted in former smokers as compared with nonsmokers.74 Smoking may thus contribute to disease progression in IPF, possibly via oxidative stress. Nevertheless, the pathogenetic role of smoking in IPF remains unclear.

Nonspecific Interstitial Pneumonia The term NSIP, first coined by Katzenstein and Fiorelli,76 describes an uncommon and previously unclassified interstitial pneumonia that is now known to be associated with collagen vascular disease, hypersensitivity pneumonitis, drug-induced lung injury, and as a histopathologic pattern with potential prognostic implications.77,78 In recent years, a possible pathogenetic role for smoking in some patients with NSIP has been proposed using HRCTderived observations. Craig et al38 found that in 25 cases with histologic patterns of DIP, HRCT features of one previous smoker and one current smoker were more compatible with an NSIP pattern, leading the authors to postulate that some cases of DIP could evolve into or coexist with NSIP, as macrophage accumulation recedes and temporally uniform fibrosis develops. Indirect support for the relationship between NSIP and smoking comes from a study by Marten et al,79 showing that (1) emphysema was equally prevalent in both NSIP and COPD and (2) emphysema was more prevalent and also more extensive at HRCT in patients with NSIP, compared with “healthy” ex-smokers. Importantly, patients with previous exposure to environmental agents or connective tissue disease were excluded from that study to avoid confounding factors. It is unlikely that longitudinal studies to test the a priori hypothesis that smoking can lead to fibrotic ILD will ever be undertaken. However, opportunistic evaluation and follow-up of patients enrolled in trials of lung cancer screening80-83 and COPD84,85 are beginning to provide further insights into this relationship. Interstitial lung abnormalities on CT scans have been reported with a prevalence of between 1.3%80 and 9.7%83 in lung cancer–screening trials involving asymptomatic subjects with a heavy smoking history. The largest evaluation of interstitial lung abnormalities comes from the COPDGene study, in which Washko et al85 reported a prevalence of 8% in 2416 HRCT studies. Importantly, all studies have documented a positive association of such abnormalities with current smoking status and the level of cigarette smoke exposure. At follow-up CT, progression of interstitial abnormalities may be seen in up to 37% of patients.82,83 In a recent analysis from the National Lung Screening Trial,83 interstitial lung abnormalities

A. Nair and D.M. Hansell classified as nonfibrotic (GGO, mosaic attenuation, and consolidation) improved in almost half of cases, but progressed in 11%, whereas fibrotic abnormalities, defined as a combination of GGO and reticulation, reticulation alone, or honeycombing—that is, probably representing a mixture of predominantly UIP and NSIP cases—progressed in 37%. Whether continued smoking is responsible for such progression is still open to debate: Sverzellati et al82 found that all patients, who showed progression of what they termed an “other chronic interstitial pneumonia”–like pattern, were all persistent smokers, but the National Lung Screening Trial data did not find any association between smoking status or cigarette smoke exposure and progression.83 It should be noted that the definitions of interstitial lung abnormalities have varied between these screening studies, although the majority have not considered centrilobular ground-glass nodularity (suggestive of RB) as sufficient for the definition of an interstitial abnormality. Furthermore, the reduced radiation-dose protocol used in lung cancer–screening studies could result in less sensitivity or, conversely, overestimation of the extent of GGO in particular (Fig. 6).86

HRCT Features of UIP and NSIP in Smokers The appearances of a typical UIP pattern on HRCT scans are well known: a reticular pattern containing honeycombing (honeycombing being a prerequisite for a definitive HRCT diagnosis) in a subpleural and basal distribution.87 The appearances of fibrotic NSIP are more variable but have also been well characterized; they consist of symmetric bilateral

Figure 6 Low-dose CT performed for a lung cancer screening trial. There is a suggestion of increased lung attenuation, with co-existent centrilobular emphysema. However, increased image noise as a consequence of the low-dose technique (rather than increased density from alveolar macrophage filling as a result of a smoking-related ILD) should be recognised as a potential cause of such an appearance.

Smoking-related interstitial lung disease areas of GGO with superimposed fine reticular opacities, with or without traction bronchiectasis and bronchiolectasis but with no or only minimal honeycombing.88,89 The findings on HRCT scans of a less than typical UIP (ie, when honeycombing is absent) may thus resemble those of NSIP. In smokers with emphysema, the presence, extent, and nature of pulmonary fibrosis on HRCT scans can be difficult to ascertain, even when “typical” features of UIP or NSIP are present. Central and paraseptal emphysema in the upper lobes can become confluent with the areas of honeycombing in the lower lobes,90,91 but it may be difficult to assign the relative contributions of emphysema and fibrosis (Fig. 7). As such, it may be too easy to assume that cystic spaces in a subpleural distribution in the lower lobes represent honeycombing (and are thus typical of UIP). Indeed, in a recent study, interobserver agreement among 43 observers for the presence of honeycombing was diminished by the presence of emphysema.92 Furthermore, the usefulness of features that may distinguish NSIP from UIP (such as less coarse reticulation, absence of honeycombing, and relative subpleural sparing) is reduced in smokers with concurrent emphysema. Traction bronchiolectasis is useful in this regard: Akira et al93 demonstrated that although both the reticular opacity-toGGO ratio and traction bronchiolectasis were the best overall discriminatory features for biopsy-proven UIP over NSIP, only traction bronchiolectasis distinguished UIP from NSIP

65 in patients with concurrent emphysema on multivariate analysis. However, such a feature is not useful for discriminating between UIP and NSIP on HRCT in patients with milder degrees of disease; in this regard integration of all clinical, physiological, and pathologic data to achieve a “bestfit” diagnosis (as with any interstitial pneumonia) remains the most practical approach.94 It has been suggested that the combination of pulmonary fibrosis and emphysema represents a distinct phenotype, termed combined pulmonary fibrosis and emphysema (CPFE) syndrome,91,95,96 rather than just the coincident occurrence of two diseases associated with smoking.97 This syndrome is characterized by preserved spirometry, severe gas exchange impairment, a high prevalence of pulmonary hypertension, and poor survival. The argument for viewing CPFE as a separate entity rests on the following observations: (1) Men are overrepresented in CPFE descriptions, even allowing for the preponderance of male smokers in emphysema; (2) pulmonary hypertension is more frequently observed than in IPF alone; and (3) the prognosis of CPFE (with reported median survival ranging from 2.1-8.5 years) may differ from that of patients with IPF alone.95 The prognostic implications of differentiating UIP and NSIP in such patients are probably diminished in this setting.96 However, it is already known that patients with both emphysema and fibrosis have a characteristic combination of preserved lung volumes but a marked reduction in gas

Figure 7 A combination of emphysema and pulmonary fibrosis in a 59-year-old ex-smoker with a 25-pack-year smoking history. A fibrotic lung disease consisting of subpleural lower lobe predominant coarse reticulation coexists with paraseptal emphysema (A-B). It is difficult to be certain that the subpleural cystic changes (arrow) in the anterior basal region (C) represent only paraseptal emphysema rather than fibrotic honeycombing, particularly as this appearance was not conspicuous on a CT performed 18 months earlier (D). However, no honeycombing is seen at the extreme bases to suggest a definite UIP pattern. The patient was too unwell for a biopsy, and a diagnosis of combined emphysema and idiopathic pulmonary fibrosis was made. Note the enlarged main pulmonary artery:ascending aorta ratio in (A), suggestive of pulmonary hypertension.

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diffusing capacity, and poor survival. Recent evidence suggests that fibrosis and COPD are the sequelae of abnormal ageing that may be accelerated by smoking, through oxidative stress and telomere shortening.98 Indirect support for this assertion comes from the observation that findings, such as subpleural reticulation, are more frequent in elderly asymptomatic patients regardless of smoking history.99 A constellation of genotypic or phenotypic features that might predict whether a smoker would fall into this particular morphologic subset has not yet been defined; thus, the case for viewing CPFE as a distinct entity has yet to be fully made.

Miscellaneous Smoking-Related Diffuse Parenchymal Diseases Several reports, mainly from Japan, have emerged of acute eosinophilic pneumonia (AEP) related to cigarette smoking.100-105 The mechanism underlying AEP is unknown, but a study of 22 patients with AEP showed a close temporal association between initiating smoking and the onset of AEP, with 6 of 8 smokers developing AEP within 3 months of beginning to smoke.102 Uchiyama et al105 found further evidence of a causal relationship between smoking and AEP. Of their 33 patients with AEP, 32 were current smokers and had developed AEP within 1 month of smoking. More compellingly, the 9 patients who underwent a cigarette provocation test demonstrated deterioration in either clinical or imaging parameters. The HRCT characteristics of AEP in smokers seem similar to those documented in AEP in general,106 with a predominance of patchy bilateral consolidation and GGO associated with interlobular septal thickening and thickening of bronchovascular bundles, as well as a striking frequency (61%) of pleural effusions (Fig. 8).105 A history of smoking also seems to be an important prerequisite for rheumatoid arthritis–associated fibrosing lung disease.107-109 Interestingly, smoking may predispose to a UIP rather than NSIP pattern of rheumatoid arthritis–associated ILD, and this in turn may be responsible for the higher observed mortality in smokers seen in this particular population (Fig. 9).109

Overlaps and Coexistence of ILDs Associated With Smoking It is evident from the preceding descriptions that a considerable amount of clinical, radiologic, and pathologic overlap exists among RB-ILD, DIP, LCH, and the fibrotic interstitial pneumonias associated with smoking. We discuss this overlap with respect to the overlap between (1) the “traditional” entities that make up SR-ILD and (2) the patterns of smoking-related fibrosis.

Overlap Between the Individual Entities of SR-ILD Whether RB and RB-ILD can be distinguished histologically is controversial: a histologic distinction between RB and RB-ILD

Figure 8 Acute eosinophilic pneumonia (AEP) in a smoker. Patchy consolidation, together with ground-glass opacity, interlobular septal thickening, and a small pleural effusion are typical signs of AEP. (Reproduced with permission from reference 105, Uchiyama et al, Chest 2008;133[5]: 1174-1180, copyright American College of Chest Physicians).

has been suggested on the basis that the latter has a greater degree of peribronchiolar inflammation and fibrosis.6,9,18 This view has been challenged,8,37,110,111 largely on the basis of observations by Fraig et al, who found that only 1 patient with alveolar septal fibrosis out of 109 patients with RB could be diagnosed with RB-ILD clinically, despite 47 cases demonstrating such fibrosis. In considering these arguments, it is salutary that: (1) Niewoehner's original description of RB in asymptomatic smokers already incorporated an element of peribronchiolar fibrosis.1 (2) The impetus for the original description of RB associated with ILD was to identify this subset of patients as unique from those with other prognostically worse ILDs, and not to propose histologic discrimination between incidental RB and that manifesting with an ILD.5 A pragmatic approach is to consider the diagnosis of RB-ILD in a patient with clinical evidence of ILD but only findings of RB on HRCT and histology. It is possible that patients with more clinically advanced ILD will demonstrate more interlobular septal thickening as well as features of RB,110 but the rarity of such thickening as a finding in patients with RB-ILD limits its use as a discriminator between RB and RB-ILD. The degree to which RB-ILD and DIP overlap on HRCT is also difficult to define, as the 2 appearances may, of course, coexist within the same patient and present with similar degrees of symptomatic and functional derangement. Histopathologic distinction normally relies on the greater profusion and uniformity of macrophage infiltration in DIP, but the point at which peribronchiolar macrophage accumulation is interpreted as generalized is bound to be somewhat arbitrary; this point led Katzenstein and Myers39 to suggest the term DIP be

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Figure 9 Combination of pulmonary fibrosis and emphysema in a 70-year-old woman with rheumatoid arthritis and a 20pack-year smoking history. Upper lobe predominant emphysema (A) and lower lobe predominant subpleural reticulation with suspected honeycombing suggestive of UIP (despite the potentially confounding paraseptal emphysema) (B) are not unique to patients with rheumatoid arthritis-associated ILD who smoke. However, rapid progression and poorer survival are seen in such patients with a UIP pattern, as in this case where a follow-up CT just seven months later (C, D) demonstrates increased volume loss and increasing honeycombing (arrow in D), corresponding to a marked clinical decline.

discarded altogether, in favor of RB-ILD as an encompassing term. Histopathologic distinction of RB-ILD and DIP is also subject to sampling bias. Nevertheless, significant differences in the number of lymphoid follicles, extent of established fibrosis, and eosinophilic infiltration between DIP and RB-ILD have been noted.38 DIP is also a more clinically aggressive disease than RB-ILD, and as mentioned earlier, is not confined to cigarette smokers; on this basis it seems reasonable at present to view the 2 diseases as overlapping manifestations of alveolar macrophage filling with different (but overall favorable) clinical courses. On HRCT, RB-ILD and DIP demonstrate considerable overlap in features9,18 and undoubtedly coexist in some patients. As such, predicting whether a patient will follow an RB-ILD or DIP clinical course based on imaging features alone at a single point in time is not a productive exercise. As noted earlier, features of RB and DIP may also be encountered in patients with PLCH. In fact, such changes may be very common: Vassallo et al112 found RB- and DIP-like changes in all biopsy specimens of 14 patients with PLCH, and in 3 patients randomly distributed, ground-glass attenuation was noted. The fact that the extent of RB- and DIP-like change did not correlate with physiological derangements indicates that in such patients the lesions of PLCH, rather than RB or DIP, dominate the clinical picture.

Overlap Between Patterns of Smoking-Related Fibrosis The pathologic descriptions of smoking-related fibrosis have been substantially refined since the observation that fibrosis was

Figure 10 Smoking-related NSIP. Subpleural ground-glass opacity is superimposed over emphysema, giving a variegated quality to the ground-glass opacity, and traction bronchiectasis and honeycombing are absent. At biopsy, features of both NSIP and DIP together with emphysema were found, underscoring the overlap of, and possible evolutionary link, between these two pathological entities.

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68 identifiable in the alveolar walls of smokers by Auerbach et al.113 In addition to RB-ILD and DIP, several other terms with slight differences in histopathologic findings have been introduced: airspace enlargement with fibrosis (AEF),114 RB-ILD with fibrosis,115 and smoking-related interstitial fibrosis (SRIF).116 The term “RB-ILD with fibrosis” was proposed by Yousem115 in a report of 9 patients (8 of whom were eversmokers) with a mixed ventilatory defect and markedly reduced diffusing capacity. These patients were initially thought to have NSIP, but on review of their biopsies, a dense bronchiolocentric collagenized thickening of the alveolar septa (absent in NSIP and not as extensive in RBILD), patchy paucicellular interstitial infiltrate (more extensive in NSIP), and absent type 2 pneumocyte hyperplasia (usually present in NSIP and DIP) were detected. Smokers' macrophages were not as diffuse as might be expected in DIP. In other words, this constellation of findings seemed to lie between RB-ILD and DIP. AEF, as proposed by Kawabata et al,114 is defined by fibrous hyalinized interstitium, in association with emphysema and structural remodeling, in a bronchiolocentric distribution. Fibroblasitc foci are absent. It seems likely that AEF is similar to the SRIF described by Katzenstein et al116 in lobectomy specimens, from patients with lung cancer who were otherwise asymptomatic. Such patients demonstrated deeply staining collagen with minimal

inflammation (in contrast to NSIP). It is conceivable that this entity develops into, or is pathologically synonymous with, RB-ILD with fibrosis, with the only difference being the lack of referable symptoms. This probably also explains why HRCT features in Yousem's115 series were more pronounced (consisting of an admixture of micronodules, ground-glass attenuation, and emphysema) than in SRIF.116 It is now accepted that DIP is distinct from and does not evolve into UIP.77,117 However, the fact that NSIP may be more prevalent in smokers has led to speculation that DIP may instead evolve into NSIP in some cases.38 The observation that NSIP may evolve from DIP is intriguing because such smoking-related NSIP may have its own distinct variegated appearance of GGO superimposed over emphysema (Fig. 10), that is recognizably different from the “crazy-paving” pattern sometimes encountered in NSIP,118 and never seen in smokers.79 Given that the descriptions of smoking-related fibrosis have relied on histologic specimens, it is inevitable that the constellation of findings on HRCT will be variable and reflect the relative proportions of the various patterns at any given time. The evolution of changes on HRCT combined with serial pulmonary function test results will probably serve as a guide to the development of fibrosis in a particular patient (Fig. 11).

Figure 11 Progressive fibrotic lung disease in a 69-year-old female smoker. Initial HRCT appearances (A, B) were suggestive of smoking-related NSIP, with peripheral subpleural ground glass opacity and superimposed centrilobular emphysema without any conspicuous traction bronchiectasis. The patient continued to smoke. HRCT performed five years later when she had deteriorated significantly demonstrates increased ground glass opacity, coarser reticulation, and suspected honeycombing with traction bronchiectasis (C, D), which could indicate a UIP pattern and/or progressive fibrotic NSIP secondary to continued smoking.

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Conclusion The smoking-related ILDs represent an intriguing and diverse group of processes. Although an increasing number of pathologic descriptions have come under the umbrella of smoking-related lung diseases in the past 20 years, the mechanisms underlying these entities and their precise relationship to cigarette smoke exposure remain to be fully elucidated. As HRCT provides a comprehensive evaluation of the whole lung, it is in pole position to provide further imaging insights about the degree and extent of overlap between these entities, and their evolution, particularly if advantage is taken of follow-up data from patients enrolled in lung cancer and other screening trials using HRCT. Such imaging evaluation, if combined with further radiologicpathologic correlation studies of ageing lung and of other diseases known to have both positive and negative associations with smoking, should help radiologists, pathologists, and clinicians to better define the clinically relevant features of these fascinating diseases.

References 1. Niewoehner DE, Kleinerman J, Rice DB: Pathologic changes in the peripheral airways of young cigarette smokers. N Engl J Med 291: 755-758, 1974 2. Cosio MG, Hale KA, Niewoehner DE: Morphologic and morphometric effects of prolonged cigarette smoking on the small airways. Am Rev Respir Dis 122:265-271, 1980 3. Wright JL, Lawson LM, Pare PD, et al: Morphology of peripheral airways in current smokers and ex-smokers. Am Rev Respir Dis 127:474-477, 1983 4. Wright JL, Hobson J, Wiggs BR, et al: Effect of cigarette smoking on structure of the small airways. Lung 165:91-100, 1987 5. Myers JL, Veal CF Jr, Shin MS, et al: Respiratory bronchiolitis causing interstitial lung disease. A clinicopathologic study of six cases. Am Rev Respir Dis 135:880-884, 1987 6. Yousem SA, Colby TV, Gaensler EA: Respiratory bronchiolitis-associated interstitial lung disease and its relationship to desquamative interstitial pneumonia. Mayo Clin Proc 64:1373-1380, 1989 7. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 165:277-304, 2002 8. Fraig M, Shreesha U, Savici D, et al: Respiratory bronchiolitis: A clinicopathologic study in current smokers, ex-smokers, and neversmokers. Am J Surg Pathol 26:647-653, 2002 9. Moon 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 54:1009-1014, 1999 10. Park JS, Brown KK, Tuder RM, et al: Respiratory bronchiolitis-associated interstitial lung disease: Radiologic features with clinical and pathologic correlation. J Comput Assist Tomogr 26:13-20, 2002 11. Ryu JH, Myers JL, Capizzi SA, et al: Desquamative interstitial pneumonia and respiratory bronchiolitis-associated interstitial lung disease. Chest 127:178-184, 2005 12. Portnoy J, Veraldi KL, Schwarz MI, et al: Respiratory bronchiolitisinterstitial lung disease: Long-term outcome. Chest 131:664-671, 2007 13. Sadikot RT, Johnson J, Loyd JE, et al: Respiratory bronchiolitis associated with severe dyspnea, exertional hypoxemia, and clubbing. Chest 117:282-285, 2000 14. Remy-Jardin M, Remy J, Boulenguez C, et al: Morphologic effects of cigarette smoking on airways and pulmonary parenchyma in healthy adult volunteers: CT evaluation and correlation with pulmonary function tests. Radiology 186:107-115, 1993 15. Remy-Jardin M, Remy J, Gosselin B, et al: Lung parenchymal changes secondary to cigarette smoking: Pathologic-CT correlations. Radiology 186:643-651, 1993

69 16. Holt RM, Schmidt RA, Godwin JD, et al: High resolution CT in respiratory bronchiolitis-associated interstitial lung disease. J Comput Assist Tomogr 17:46-50, 1993 17. Gruden JF, Webb WR: CT findings in a proved case of respiratory bronchiolitis. Am J Roentgenol 161:44-46, 1993 18. Heyneman 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 Roentgenol 173:1617-1622, 1999 19. Nakanishi M, Demura Y, Mizuno S, et al: Changes in HRCT findings in patients with respiratory bronchiolitis-associated interstitial lung disease after smoking cessation. Eur Respir J 29:453-461, 2007 20. Remy-Jardin M, Edme JL, Boulenguez C, et al: Longitudinal follow-up study of smoker's lung with thin-section CT in correlation with pulmonary function tests. Radiology 222:261-270, 2002 21. Klein JS, Gamsu G, Webb WR, et al: High resolution CT diagnosis of emphysema in symptomatic patients with normal chest radiographs and isolated low diffusing capacity. Radiology 182:817-821, 1992 22. Bergin C, Müller NL, Nichols DM, et al: The diagnosis of emphysema. A computed tomographic-pathologic correlation. Am Rev Respir Dis 133:541-546, 1986 23. Sanders C, Nath PH, Bailey WC: Detection of emphysema with computed tomography. Correlation with pulmonary function tests and chest radiography. Invest Radiol 23:262-266, 1988 24. Adesina AM, Vallyathan V, McQuillen EN, et al: Bronchiolar inflammation and fibrosis associated with smoking. A morphologic cross-sectional population analysis. Am Rev Respir Dis 143:144-149, 1991 25. Willems LN, Kramps JA, Stijnen T, et al: Relation between small airways disease and parenchymal destruction in surgical lung specimens. Thorax 45:89-94, 1990 26. Saetta M, Kim WD, Izquierdo JL, et al: Extent of centrilobular and panacinar emphysema in smokers' lungs: Pathological and mechanical implications. Eur Respir J 7:664-671, 1994 27. Liebow AA, Steer A, Billingsley JG: Desquamative interstitial pneumonia. Am J Med 39:369-404, 1965 28. Tubbs RR, Benjamin SP, Reich NE, et al: Desquamative interstitial pneumonitis. Cellular phase of fibrosing alveolitis. Chest 72:159-165, 1977 29. Fromm GB, Dunn LJ, Harris JO: Desquamative interstitial pneumonitis. Characterization of free intraalveolar cells. Chest 77:552-554, 1980 30. Carrington CB, Gaensler EA, Coutu RE, et al: Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med 298:801-809, 1978 31. Herbert A, Sterling G, Abraham J, et al: Desquamative interstitial pneumonia in an aluminum welder. Hum Pathol 13:694-699, 1982 32. Abraham JL, Hertzberg MA: Inorganic particulates associated with desquamative interstitial pneumonia. Chest 80:67-70, 1981 33. Bone RC, Wolfe J, Sobonya RE, et al: Desquamative interstitial pneumonia following long-term nitrofurantoin therapy. Am J Med 60:697-701, 1976 34. Hamadeh MA, Atkinson J, Smith LJ: Sulfasalazine-induced pulmonary disease. Chest 101:1033-1037, 1992 35. Amir G, Ron N: Pulmonary pathology in Gaucher's disease. Hum Pathol 30:666-670, 1999 36. Hartman TE, Primack SL, Swensen SJ, et al: Desquamative interstitial pneumonia: Thin-section CT findings in 22 patients. Radiology 187:787-790, 1993 37. Wells AU, Nicholson AG, Hansell DM: Challenges in pulmonary fibrosis. 4: Smoking-induced diffuse interstitial lung diseases. Thorax 62:904-910, 2007 38. Craig PJ, Wells AU, Doffman S, et al: Desquamative interstitial pneumonia, respiratory bronchiolitis and their relationship to smoking. Histopathology 45:275-282, 2004 39. Katzenstein AL, Myers JL: Idiopathic pulmonary fibrosis: Clinical relevance of pathologic classification. Am J Respir Crit Care Med 157:1301-1315, 1998 40. Akira M, Yamamoto S, Hara H, et al: Serial computed tomographic evaluation in desquamative interstitial pneumonia. Thorax 52:333-337, 1997

70 41. Hartman TE, Primack SL, Kang EY, et al: Disease progression in usual interstitial pneumonia compared with desquamative interstitial pneumonia. Assessment with serial CT. Chest 110:378-382, 1996 42. Favara BE, Feller AC, Pauli M, et al: Contemporary classification of histiocytic disorders. The WHO Committee on Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Med Pediatr Oncol 29:157-166, 1997 43. Vassallo R, Ryu JH, Colby TV, et al: Pulmonary Langerhans'-cell histiocytosis. N Engl J Med 342:1969-1978, 2000 44. Gaensler EA, Carrington CB: Open biopsy for chronic diffuse infiltrative lung disease: Clinical, roentgenographic, and physiological correlations in 502 patients. Ann Thorac Surg 30:411-426, 1980 45. Friedman PJ, Liebow AA, Sokoloff J: Eosinophilic granuloma of lung. Clinical aspects of primary histiocytosis in the adult. Medicine (Baltimore) 60:385-396, 1981 46. Schonfeld N, Frank W, Wenig S, et al: Clinical and radiologic features, lung function and therapeutic results in pulmonary histiocytosis X. Respiration 60:38-44, 1993 47. Colby TV, Lombard C: Histiocytosis X in the lung. Hum Pathol 14:847-856, 1983 48. Kambouchner M, Basset F, Marchal J, et al: Three-dimensional characterization of pathologic lesions in pulmonary langerhans cell histiocytosis. Am J Respir Crit Care Med 166:1483-1490, 2002 49. Travis WD, Borok Z, Roum JH, et al: Pulmonary Langerhans cell granulomatosis (histiocytosis X). A clinicopathologic study of 48 cases. Am J Surg Pathol 17:971-986, 1993 50. Hansell DM, Nicholson AG: Smoking-related diffuse parenchymal lung disease: HRCT-pathologic correlation. Semin Respir Crit Care Med 24:377-392, 2003 51. Soler P, Moreau A, Basset F, et al: Cigarette smoking-induced changes in the number and differentiated state of pulmonary dendritic cells/ Langerhans cells. Am Rev Respir Dis 139:1112-1117, 1989 52. Casolaro 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 137:406-411, 1988 53. Yousem SA, Colby TV, Chen YY, et al: Pulmonary Langerhans' cell histiocytosis: Molecular analysis of clonality. Am J Surg Pathol 25:630-636, 2001 54. Brauner MW, Grenier P, Mouelhi MM, et al: Pulmonary histiocytosis X: Evaluation with high-resolution CT. Radiology 172:255-258, 1989 55. Brauner MW, Grenier P, Tijani K, et al: Pulmonary Langerhans cell histiocytosis: Evolution of lesions on CT scans. Radiology 204:497-502, 1997 56. Kim HJ, Lee KS, Johkoh T, et al: Pulmonary Langerhans cell histiocytosis in adults: High-resolution CT-pathology comparisons and evolutional changes at CT. Eur Radiol 21:1406-1415, 2011 57. Bonelli FS, Hartman TE, Swensen SJ, et al: Accuracy of high-resolution CT in diagnosing lung diseases. Am J Roentgenol 170:1507-1512, 1998 58. Moore AD, Godwin JD, Müller NL, et al: Pulmonary histiocytosis X: Comparison of radiographic and CT findings. Radiology 172:249-254, 1989 59. Canuet M, Kessler R, Jeung MY, et al: Correlation between highresolution computed tomography findings and lung function in pulmonary Langerhans cell histiocytosis. Respiration 74:640-646, 2007 60. Vassallo R, Ryu JH, Schroeder DR, et al: Clinical outcomes of pulmonary Langerhans'-cell histiocytosis in adults. N Engl J Med 346:484-490, 2002 61. Soler P, Bergeron A, Kambouchner M, et al: Is high-resolution computed tomography a reliable tool to predict the histopathological activity of pulmonary Langerhans cell histiocytosis? Am J Respir Crit Care Med 162:264-270, 2000 62. Choi WI, Jeong YC, Kim SY, et al: New clinical score for disease activity at diagnosis in Langerhans cell histiocytosis. Korean J Hematol 46:186-191, 2011 63. Donadieu J, Piguet C, Bernard F, et al: A new clinical score for disease activity in Langerhans cell histiocytosis. Pediatr Blood Cancer 43:770-776, 2004

A. Nair and D.M. Hansell 64. Weiss W: Cigarette smoking and diffuse pulmonary fibrosis. Am Rev Respir Dis 99:67-72, 1969 65. Schwartz DA, Van Fossen DS, Davis CS, et al: Determinants of progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 149:444-449, 1994 66. Schwartz DA, Helmers RA, Galvin JR, et al: Determinants of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 149:450-454, 1994 67. Johnston ID, Prescott RJ, Chalmers JC, et al: British Thoracic Society study of cryptogenic fibrosing alveolitis: Current presentation and initial management. Fibrosing Alveolitis Subcommittee of the Research Committee of the British Thoracic Society. Thorax 52:38-44, 1997 68. Idiopathic pulmonary fibrosis: Diagnosis and treatment. Am J Respir Crit Care Med 161:646-664, 2000 69. Iwai K, Mori T, Yamada N, et al: Idiopathic pulmonary fibrosis. Epidemiologic approaches to occupational exposure. Am J Respir Crit Care Med 150:670-675, 1994 70. Hubbard R, Lewis S, Richards K, et al: Occupational exposure to metal or wood dust and aetiology of cryptogenic fibrosing alveolitis. Lancet 347:284-289, 1996 71. Baumgartner KB, Samet JM, Stidley CA, et al: Cigarette smoking: A risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 155:242-248, 1997 72. Rosas IO, Ren P, Avila NA, et al: Early interstitial lung disease in familial pulmonary fibrosis. Am J Respir Crit Care Med 176:698-705, 2007 73. King TE Jr, Schwarz MI, Brown K, et al: Idiopathic pulmonary fibrosis: Relationship between histopathologic features and mortality. Am J Respir Crit Care Med 164:1025-1032, 2001 74. Antoniou KM, Hansell DM, Rubens MB, et al: Idiopathic pulmonary fibrosis: Outcome in relation to smoking status. Am J Respir Crit Care Med 177:190-194, 2008 75. Becklake MR, Lalloo U: The ‘healthy smoker’: A phenomenon of health selection? Respiration 57:137-144, 1990 76. Katzenstein AL, Fiorelli RF: Nonspecific interstitial pneumonia/fibrosis. Histologic features and clinical significance. Am J Surg Pathol 18:136-147, 1994 77. Bjoraker JA, Ryu JH, Edwin MK, et al: Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 157:199-203, 1998 78. Nicholson AG, Colby TV, du Bois RM, et al: The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 162:2213-2217, 2000 79. Marten K, Milne D, Antoniou KM, et al: Non-specific interstitial pneumonia in cigarette smokers: A CT study. Eur Radiol 19:1679-1685, 2009 80. MacRedmond R, Logan PM, Lee M, et al: Screening for lung cancer using low dose CT scanning. Thorax 59:237-241, 2004 81. van de Wiel JC, Wang Y, Xu DM, et al: Neglectable benefit of searching for incidental findings in the Dutch-Belgian lung cancer screening trial (NELSON) using low-dose multidetector CT. Eur Radiol 17:1474-1482, 2007 82. Sverzellati N, Guerci L, Randi G, et al: Interstitial lung diseases in a lung cancer screening trial. Eur Respir J 38:392-400, 2011 83. Jin GY, Lynch D, Chawla A, et al: Interstitial lung abnormalities in a CT lung cancer screening population: Prevalence and progression rate. Radiology 2013; [Published ahead of print] 84. Washko GR, Lynch DA, Matsuoka S, et al: Identification of early interstitial lung disease in smokers from the COPDGene study. Acad Radiol 17:48-53, 2010 85. Washko GR, Hunninghake GM, Fernandez IE, et al: Lung volumes and emphysema in smokers with interstitial lung abnormalities. N Engl J Med 364:897-906, 2011 86. Zwirewich CV, Mayo JR, Müller NL: Low-dose high-resolution CT of lung parenchyma. Radiology 180:413-417, 1991 87. Raghu G, Collard HR, Egan JJ, et al: An official ATS/ERS/JRS/ALAT statement: Idiopathic pulmonary fibrosis: Evidence-based guidelines for

Smoking-related interstitial lung disease

88.

89.

90.

91.

92.

93.

94.

95. 96.

97.

98.

99.

100.

101. 102.

103.

diagnosis and management. Am J Respir Crit Care Med 183:788-824, 2011 MacDonald SL, Rubens MB, Hansell DM, et al: Nonspecific interstitial pneumonia and usual interstitial pneumonia: Comparative appearances at and diagnostic accuracy of thin-section CT. Radiology 221:600-605, 2001 Hartman TE, Swensen SJ, Hansell DM, et al: Nonspecific interstitial pneumonia: Variable appearance at high-resolution chest CT. Radiology 217:701-705, 2000 Grubstein A, Bendayan D, Schactman I, et al: Concomitant upper-lobe bullous emphysema, lower-lobe interstitial fibrosis and pulmonary hypertension in heavy smokers: Report of eight cases and review of the literature. Respir Med 99:948-954, 2005 Cottin V, Nunes H, Brillet PY, et al: Combined pulmonary fibrosis and emphysema: A distinct underrecognised entity. Eur Respir J 26:586-593, 2005 Watadani T, Sakai F, Johkoh T, et al: Interobserver variability in the CT assessment of honeycombing in the lungs. Radiology 266:936-944, 2013 Akira M, Inoue Y, Kitaichi M, et al: Usual interstitial pneumonia and nonspecific interstitial pneumonia with and without concurrent emphysema: Thin-section CT findings. Radiology 251:271-279, 2009 Galvin JR, Frazier AA, Franks TJ: Collaborative radiologic and histopathologic assessment of fibrotic lung disease. Radiology 255:692-706, 2010 Jankowich MD, Rounds SI: Combined pulmonary fibrosis and emphysema syndrome: A review. Chest 141:222-231, 2012 Kishaba T, Shimaoka Y, Fukuyama H, et al: A cohort study of mortality predictors and characteristics of patients with combined pulmonary fibrosis and emphysema. BMJ Open 2:e000988, 2012 Wiggins J, Strickland B, Turner-Warwick M: Combined cryptogenic fibrosing alveolitis and emphysema: The value of high resolution computed tomography in assessment. Respir Med 84:365-369, 1990 Faner R, Rojas M, MacNee W, et al: Abnormal lung aging in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 186:306-313, 2012 Copley SJ, Wells AU, Hawtin KE, et al: Lung morphology in the elderly: Comparative CT study of subjects over 75 years old versus those under 55 years old. Radiology 251:566-573, 2009 Miki K, Miki M, Okano Y, et al: Cigarette smoke-induced acute eosinophilic pneumonia accompanied with neutrophilia in the blood. Intern Med 41:993-996, 2002 Nakajima M, Manabe T, Sasaki T, et al: Acute eosinophilic pneumonia caused by cigarette smoking. Intern Med 39:1131-1132, 2000 Philit F, Etienne-Mastroianni B, Parrot A, et al: Idiopathic acute eosinophilic pneumonia: A study of 22 patients. Am J Respir Crit Care Med 166:1235-1239, 2002 Shintani H, Fujimura M, Yasui M, et al: Acute eosinophilic pneumonia caused by cigarette smoking. Intern Med 39:66-68, 2000

71 104. Shorr AF, Scoville SL, Cersovsky SB, et al: Acute eosinophilic pneumonia among US Military personnel deployed in or near Iraq. J Am Med Assoc 292:2997-3005, 2004 105. Uchiyama H, Suda T, Nakamura Y, et al: Alterations in smoking habits are associated with acute eosinophilic pneumonia. Chest 133:1174-1180, 2008 106. King MA, Pope-Harman AL, Allen JN, et al: Acute eosinophilic pneumonia: Radiologic and clinical features. Radiology 203:715-719, 1997 107. Dawson JK, Fewins HE, Desmond J, et al: Fibrosing alveolitis in patients with rheumatoid arthritis as assessed by high resolution computed tomography, chest radiography, and pulmonary function tests. Thorax 56:622-627, 2001 108. Gochuico BR, Avila NA, Chow CK, et al: Progressive preclinical interstitial lung disease in rheumatoid arthritis. Arch Intern Med 168:159-166, 2008 109. Lee HK, Kim DS, Yoo B, et al: Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease. Chest 127:2019-2027, 2005 110. Churg A, Müller NL, Wright JL: Respiratory bronchiolitis/interstitial lung disease: Fibrosis, pulmonary function, and evolving concepts. Arch Pathol Lab Med 134:27-32, 2010 111. Caminati A, Cavazza A, Sverzellati N, et al: An integrated approach in the diagnosis of smoking-related interstitial lung diseases. Eur Respir Rev 21:207-217, 2012 112. Vassallo R, Jensen EA, Colby TV, et al: The overlap between respiratory bronchiolitis and desquamative interstitial pneumonia in pulmonary Langerhans cell histiocytosis: High-resolution CT, histologic, and functional correlations. Chest 124:1199-1205, 2003 113. Auerbach O, Stout AP, Hammond EC, et al: Smoking habits and age in relation to pulmonary changes: Rupture of alveolar septums, fibrosis and thickening of walls of small arteries and arterioles. N Engl J Med 268:1045-1054, 1963 114. Kawabata Y, Hoshi E, Murai K, et al: Smoking-related changes in the background lung of specimens resected for lung cancer: A semiquantitative study with correlation to postoperative course. Histopathology 53:707-714, 2008 115. Yousem SA: Respiratory bronchiolitis-associated interstitial lung disease with fibrosis is a lesion distinct from fibrotic nonspecific interstitial pneumonia: A proposal. Mod Pathol 19:1474-1479, 2006 116. Katzenstein AL, Mukhopadhyay S, Zanardi C, et al: Clinically occult interstitial fibrosis in smokers: Classification and significance of a surprisingly common finding in lobectomy specimens. Hum Pathol 41:316-325, 2010 117. Travis WD, Matsui K, Moss J, et al: Idiopathic nonspecific interstitial pneumonia: Prognostic significance of cellular and fibrosing patterns: Survival comparison with usual interstitial pneumonia and desquamative interstitial pneumonia. Am J Surg Pathol 24:19-33, 2000 118. Rossi SE, Erasmus JJ, Volpacchio M, et al: “Crazy-paving” pattern at thinsection CT of the lungs: Radiologic-pathologic overview. Radiographics 23:1509-1519, 2003