Curr Pulmonol Rep (2015) 4:179–190 DOI 10.1007/s13665-015-0128-2

SMOKING CESSATION (S VEERARAGHAVAN, SECTION EDITOR)

Computed tomography of smoking-related lung disease: review and update Karen S. Zheng 1 & Travis S. Henry 2 & Brent P. Little 1

Published online: 13 October 2015 # Springer Science+Business Media New York 2015

Abstract Traditionally recognized smoking-related lung diseases include chronic obstructive pulmonary disease (COPD), respiratory bronchiolitis/interstitial lung disease, desquamative interstitial pneumonitis, and pulmonary Langerhans cell histiocytosis. More recently described smoking-related entities include combined pulmonary fibrosis and emphysema and respiratory bronchiolitis with fibrosis. We review the important past and current literature pertaining to these diseases, including recent developments in quantitative imaging of COPD and in CT characterization of smokingrelated fibrosis.

Keywords Smoking . Smoking-related lung disease . Interstitial lung disease . Computed tomography . Chronic obstructive pulmonary disease . Emphysema

This article is part of the Topical Collection on Smoking Cessation * Brent P. Little [email protected] Travis S. Henry [email protected] 1

Division of Cardiothoracic Imaging, Department of Radiology and Imaging Sciences, Emory University, 1365 Clifton Road, Atlanta, GA 30322, USA

2

Division of Cardiothoracic Imaging, Department of Radiology, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, USA

Introduction Tobacco use is the largest preventable cause of morbidity and mortality in the USA. According to the Centers for Disease Control and Prevention (CDC), 42 million American adults (approximately 17.8 %) were current cigarette smokers in 2013 [1]. More than 16 million Americans suffer from a smoking-related disease, with direct medical costs of smoking amounting to approximately $130 billion annually and total economic costs of smoking costing approximately $300 billion annually [2]. While smoking-related lung diseases have traditionally been labeled Binterstitial,^ recent articles have emphasized the widespread pathologic effects of smoking on the lungs, with deleterious, often concurrent, effects on the airways, interstitium, and alveoli [3]. A mixed pattern of Binterstitial^ lung diseases in smokers is common, and a combination of multiple pathologic patterns is often seen both at thin-section chest CT and histopathology; emphysema, airway abnormalities, and fibrosis, traditionally viewed as separate diseases, are now known to be intimately associated with other abnormalities in the lungs of smokers [4] [5]. Therefore, the term Bdiffuse smoking-related lung disease^ is used throughout this article, encompassing the full spectrum of lung disease that occurs in smokers. The traditionally recognized diffuse smoking-related lung diseases include respiratory bronchiolitis (RB), respiratory bronchiolitis-interstitial lung disease (RB-ILD), desquamative interstitial pneumonitis (DIP), pulmonary Langerhans cell histiocytosis (PLCH), and chronic obstructive pulmonary disease (COPD); acute eosinophilic pneumonia also has been linked to cigarette smoking. Over the past decade, combined pulmonary fibrosis/emphysema (CPFE) and respiratory bronchiolitis with fibrosis (RBF) have been added to the panoply of smoking-related lung disease. This article will provide an

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overview of the latest literature published regarding the spectrum of smoking-related lung disease. Chronic obstructive pulmonary disease Clinical presentation and histopathology COPD encompasses both emphysema (alveolar damage and loss) and chronic bronchitis (obstructive airways disease) [6], and these conditions often coexist. Of the smoking-related lung diseases, COPD is a significant cause of morbidity and mortality, with the annual economic cost in the USA estimated to be $4.7 billion [7]. It is predicted that COPD will become the third leading cause of death worldwide by the year 2020 [8]. Clinically, COPD is categorized by the Global Initiative for chronic Obstructive Lung Disease (GOLD) staging system, which stratifies patients based on the forced expiratory volume in 1 s (FEV1) as well as its ratio to the forced vital capacity (FEV/FVC) [9••]. Patients in the same GOLD stage can have different morphologic manifestations on CT, with some patients demonstrating a predominance of emphysema and others demonstrating a predominance of bronchial wall thickening [9••, 10]. A 2014 study of over 1000 patients with predominantly mild COPD (GOLD stage 1) found that only 51 % of patients had significant CT manifestations, which were divided into emphysema, air trapping, and airway wall thickening. Of these patients, approximately 25 % demonstrated predominantly emphysema, 16 % air trapping, and 23 % airway wall thickening. Thirty-six percent of patients demonstrated a combination of these findings [11]. Much research has been dedicated toward quantifying the degree of emphysema and airways disease on CT in order to target therapies for patients with different phenotypic manifestations [7].

Fig. 1 69-Year-old female smoker with a combination of paraseptal and centrilobular emphysema; axial CT image. Paraseptal emphysema (arrows, right lung) is confined to the subpleural lung and has a round, thin-walled, cystic appearance. Unlike honeycombing in pulmonary fibrosis, paraseptal emphysema has thin rather than thick walls and has a single layer rather than a stacked appearance. Centrilobular emphysema (arrowheads, left lung) typically has no visible walls in the absence of prominent smoking-related fibrosis

predominant, bullous emphysema that replaces more than one third of the lung parenchyma. The condition is typically seen in young to middle age male smokers, and the emphysema may be disproportionately severe compared to the smoking history (Fig. 3) [9••]. Quantitative imaging of emphysema Prior to using CT to evaluate for emphysema, the formal diagnosis required lung tissue, either surgical biopsy or postmortem specimens, and was identified as holes in the lungs

Emphysema Emphysema is the irreversible destruction of alveoli [7, 8, 12]. Morphologies of pulmonary emphysema include centrilobular, panlobular, and paraseptal [9••]. Centrilobular emphysema is identified as lucencies without walls centered within secondary pulmonary lobules, with severity ranging from trace to confluent (Fig. 1). Paraseptal emphysema manifests as rounded lucencies along pleural and fissural margins (Fig. 1). Both centrilobular and paraseptal emphysema are associated with tobacco smoking and often occur in the same patient; however, cases of relatively isolated paraseptal emphysema tend to be associated with less severe symptoms. Panlobular emphysema refers to the destruction of all acini within a lung lobule. It is associated with alpha-1-antitrypsin deficiency and is lower lobe predominant (Fig. 2) [9••]. The term Bgiant bullous emphysema^ or Bvanishing lung syndrome^ has been given to severe, usually upper-lobe-

Fig. 2 59-Year-old woman with alpha-1 antitrypsin deficiency; coronal reformatted CT image. The lungs are hyperinflated, with lower-lobepredominant panacinar emphysema. Notice the severe lower lung parenchymal destruction and architectural distortion

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related to an inflammatory reaction in the lungs of current smokers causing increased lung attenuation and thus masking the true degree of emphysema due to partial volume averaging [13••]. Airway disease

Fig. 3 56-Year-old man with giant bullous emphysema or Bvanishing lung syndrome^; coronal reformatted CT image. Large, confluent bullae replace most of the upper to mid lung parenchyma, and paraseptal and centrilobular emphysema are seen in the lower lobes

Airway disease can be categorized into bronchial disease and small airway disease. Bronchial disease clinically corresponds to chronic bronchitis and manifests as segmental and subsegmental airway wall thickening on CT; this is thought to be due to bronchial wall inflammation and remodeling. Small airway disease manifests as centrilobular ground glass nodules (inflammatory) or air trapping (obstructive). Air trapping appears as patchy areas of preserved lung attenuation on expiratory CT; normally, the lungs should homogenously increase in attenuation [9••]. Quantitative imaging of airway disease

without obvious fibrosis [7]. The difference in CT attenuation of normal lung and emphysematous lung is the basis for using CT to quantify emphysema. Normal lung has an attenuation of approximately −850 Hounsfield units (HU) on inspiratory CT. Emphysematous destruction of normal lung results in CT attenuation closer to −1000 HU. The density mask technique uses voxel analysis to measure the attenuation of CT pixels, with emphysema being defined as a pixel attenuation below a certain threshold [13••]. The threshold was initially set at −910 HU based on research that correlated this threshold to holes greater than 5 mm in diameter on gross pathologic specimens. More recent studies using high-resolution CT have shown that a threshold of −950 HU has a better histologic correlation [7]. Thus, the term %LAA950 (percentage of low-attenuation areas, threshold −950 HU) is the current nomenclature for the quantification of emphysema [13••]. The %LAA on CT correlates with the clinical degree of dyspnea as well as multiple spirometric measurements including forced expiratory volume in 1 s (FEV1), ratio of FEV1 to forced vital capacity (FEV1/FVC), residual volume (RV), diffusing capacity of the lung for carbon monoxide (DLCO), and the ratio of DLCO to alveolar volume (DLCO/VA) [6, 8]. The degree of baseline %LAA is also a good predictor of future morbidity and mortality [14, 15]. The %LAA can also be followed longitudinally to monitor progression of emphysema and has been shown to be more sensitive than FEV1 or DLCO [16], and patients with more frequent COPD exacerbations experience a greater increase in %LAA [17]. Interestingly, some studies have shown a paradoxical correlation between smoking status and the quantified degree of emphysema on CT, with current smokers having a lesser degree of emphysema on CT than former smokers [13••, 18, 19]. Furthermore, the extent of emphysema on CT increases following smoking cessation [20, 21]. This is thought to be

Analysis of the airways on CT requires automated measurement of lumen area and wall thickness. The determination of area lumen airway area is based on the density mask method, with a cutoff threshold between −500 and −577 HU [7, 8]. The most common method to determine wall thickness is the Bfullwidth-at-half maximum^ technique, which uses pixel value distribution of attenuation between the center of the lumen and the airway wall and between the lung parenchyma and the airway wall to determine the inner and outer borders of the airway wall [7]. Air trapping is quantified on expiratory CT as the percentage of low-attenuation areas set at a threshold of −850 HU, which is the attenuation of normal lung on inspiratory CT. Other measurements of air trapping include the ratio of inspiratory to expiratory lung volume or lung attenuation and the relative volume change of voxels with attenuation between −860 and −950 HU between expiration and inspiration [13••]. The degree of air trapping on expiratory CT strongly correlates with FEV1 and FEV1/FVC on spirometry [22•]. Similarly, there is a strong correlation between extrapolated expiratory lung volume on CT and COPD stage as well as FEV1/FVC ratio, with higher end expiratory volumes corresponding to worse FEV1/ FVC ratio and higher COPD stage [20]. In terms of quantifying bronchial disease on CT, Sasaki et al. showed that ratios of peripheral to central airway lumen area significantly decreased with increasing GOLD stage of COPD. The ratio of peripheral to central percentage of wall area also increased with increasing GOLD stage [23], indicating worsening peripheral bronchiolar wall thickening. A 2015 study by Mohamed et al. found that while the degree of emphysema correlated most with FEV1/FVC, airway wall thickness best correlated with FEV1 and air trapping with residual volume [12]. Peak bronchial wall attenuation for peripheral

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airways also increases with worsening FEV1. The posited pathophysiologic basis for the correlation between airway wall thickness and FEV1 is that the degree of mural fibrosis and calcification increases with worsening disease [24, 25]. It therefore makes sense that wall thickness of peripheral airways differs significantly between COPD patients and controls, but did not change significantly with bronchodilator use. However, airway lumen area and percentage of wall area differ significantly after bronchodilator use [26]. Pulmonary Langerhans cell histiocytosis Clinical presentation and histopathology Pulmonary Langerhans cell histiocytosis (PLCH) affects young adult smokers in the 30–40-year-old age range with equal distribution between males and females [27, 28]. Symptoms of PLCH include dyspnea, cough, and chest pain [27, 29•]. Approximately 15 % of patients present with chest pain and pneumothorax, due to cyst rupture [27]; up to 36 % of patients are asymptomatic at presentation [29•]. Pathophysiologically, a cellular infiltrate of Langerhans cells, eosinophils, lymphocytes, macrophages, plasma cells, and fibroblasts deposits in the interstitium of respiratory bronchioles and alveoli and undergoes fibrosis to form a nodule. Over time, central necrosis occurs within the nodule, thus forming cysts [27, 29•]. Recent research has suggested that PLCH may be a neoplastic process, with approximately 50 % of PLCH patients found to have a mutation in the oncogene BRAF V600E [30]. Although the diagnosis of PLCH is usually made based on imaging characteristics on high-resolution CT, bronchoalveolar lavage (BAL) can aid in differentiating PCLH from other types of diffuse smoking-related lung disease, particularly in the late stage of the disease where the CT manifestation is primarily cystic. The presence of more than 5 % Langerhans cells on BAL sampling strongly suggests PLCH [30]. Smoking cessation is the standard therapy for PCLH [28], with most patients experiencing stabilization or regression of disease [10]. About 25 % of patients experience disease progression despite smoking cessation [10]. In these patients, steroid therapy as well as other chemotherapeutic agents such methotrexate, cyclophosphamide, and vinblastine have been tried. More recently, therapy with cladribine, a drug used in leukemia treatment, has shown promising activity in PCLH patients. Patients with severely progressive disease refractory to these treatments are considered for lung transplantation [30]. Imaging findings The CT hallmark of PLCH is a combination of nodules and cysts, which are often bizarre shaped (Fig. 4) [27–28, 29•, 31].

Fig. 4 38-Year-old man with pulmonary Langerhans cell histiocytosis (PLCH); axial CT image. Scattered upper-lobe-predominant, thin-walled cysts with irregular shapes are seen (arrows); a few solid and ground glass nodules measuring 5 mm or less are also present in the adjacent upper lobes (arrowheads)

The nodules have a peribronchiolar distribution with upperlobe predominance, often sparing the costophrenic angles [28, 29•], and are usually subcentimeter, often micronodular (sub5 mm). When nodules cavitate, they often have a thin wall, prompting the label Bcheerio sign,^ an appearance shared by nodules of certain other etiologies [32]. The coexistence of Bbizarre-shaped^ cysts helps to differentiate PLCH from other diffuse nodular pulmonary diseases, such as lymphangiomyoamatosis, sarcoidosis, and metastatic disease [29•]. In the early course of the disease, nodules predominate over cysts, and as the disease progresses, the nodules cavitate into cysts, which can become confluent (Fig. 5) [29•, 33, 34]. Although PLCH can coexist with emphysema, the cysts of PLCH are distinguished from emphysema by the presence of thick or thin walls, whereas the lung lucencies in emphysema lack walls [33]. Research regarding the CT evolution of PLCH has found that nodules progress into thick-walled cysts, which progress then into thin-walled cysts [33]. In advanced disease, CT findings may progress to extensive fibrosis, honeycombing, and architectural distortion, predominantly in the upper lobes [27].

Respiratory bronchiolitis and respiratory bronchiolitis-interstitial lung disease Clinical presentation and histopathology Thought to be a reaction to smoke-related bronchial injury, RB is a common finding in active and even former smokers, usually detected as an incidental finding at chest CT or in pathologic specimens obtained for unrelated conditions. RB was first described in 1974 as a finding at autopsy of patients who experienced sudden death due to non-pulmonary causes, found in all 19 smokers studied and in only a small minority (5/20) of non-smokers, most of whom had environmental

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Imaging findings

Fig. 5 49-Year-old female with advanced pulmonary Langerhans cell histiocytosis (PLCH); axial CT image. Thin-walled cysts with irregular shapes and sizes are confluent within the upper lobes. Although there is a background of centrilobular emphysema, most of the lucencies have discernable walls, and displace the adjacent parenchyma. In centrilobular emphysema alone, the centrilobular arteriole and bronchiole are normally seen within lucencies that do not have well-defined walls

exposures [35]; larger studies later confirmed the ubiquity of RB, found at open lung biopsy in all 83 active smokers studied and in 49 % of ex-smokers [36]. Bronchial lavage typically shows an elevated number of macrophages; histologic specimens show Bsmoker’s^ pigmented alveolar macrophages within the alveoli [37]. RB-ILD is defined as RB with clinical findings suggesting interstitial lung disease not attributable to another cause. RB-ILD affects a small subset of smokers, usually those with a greater than 30-pack-year history [38]. Although RB and RB-ILD are almost always attributable to smoking, rare cases have been seen from inhalational exposures, including industrial solder fumes [39]. However, some authors invoke the term Bvariant respiratory bronchiolitis^ in these cases, contrasting the eosinophilic pigment present in the lungs of affected individuals and the typical brown-pigmented macrophages found in smoking-related RB [36, 40]. Patients with RB-ILD can present with dyspnea, cough, and even hemoptysis; digital clubbing is sometimes present [39]. Pulmonary function tests can show an obstructive or mildly restrictive pattern, and a decrease in DLCO is sometimes seen. At pathology, RB and RB-ILD are indistinguishable, both showing the typical brownpigmented macrophages within respiratory bronchioles and adjacent alveoli [41]. Many patients respond to smoking cessation, the first-line intervention for RBILD; however, up to one third of cases persist or recur 5 years after quitting and a small subset of cases have endured for several decades [36]. Corticosteroids and even immunosuppressive drugs have been used in refractory cases, with variable success [40].

While most current smokers show evidence of respiratory bronchiolitis in pathologic specimens, the incidence of typical findings of RB at imaging is much lower, involving a small subset of the smoking population. Chest radiographs are often either normal or show only findings associated with chronic obstructive pulmonary disease. At thin-section CT, findings include upper-lobe-predominant nodules with a hazy, Bground glass^ appearance and indistinct borders; smaller subsets of patients with RB and RB-ILD have a diffuse distribution or mid lung distribution of findings [42]. The nodules have a centrilobular distribution, following the courses of the firstand second-order bronchioles (Fig. 6). A small amount of patchy ground glass opacity is variably seen. Patients classified as having BRB-ILD^ have substantially the same findings as those with BRB,^ with centrilobular ground glass nodules and patchy ground glass opacities seen in both conditions [42]. While reticulation has been described as a finding in RB-ILD, it has been reported in only a minority of patients with the disease (25 % in one study) and can be seen in smokers without RB-ILD. Bronchial wall thickening is common in RB and RB-ILD but is also a common finding in smokers in general. Thus, some authors argue that distinguishing RB and RB-ILD by imaging alone is not possible [43]. The imaging findings of RB and RB-ILD overlap with those of other acute and chronic lung diseases. Upper-lobepredominant centrilobular ground glass nodules typical of RB and RB-ILD are also commonly observed in subacute hypersensitivity pneumonitis (HP), but the history of smoking in RB is usually sufficient to distinguish between these conditions; in addition, in our experience, mosaic attenuation with lobular air trapping at CT is much more common in HP than in patients with RB. The substantial overlap in CT appearance of desquamative interstitial pneumonitis (DIP) and RB-ILD and the presence of both DIP and RB-ILD in pathologic

Fig. 6 44-Year-old man with respiratory bronchiolitis (RB); axial CT image. Upper-lobe-predominant centrilobular ground glass nodular opacities and scattered regional ground glass opacities are present. A lobectomy for other reasons showed respiratory bronchiolitis

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specimens from the same lung prompt many to consider the two diseases as being along the same spectrum. Desquamative interstitial pneumonitis Clinical presentation and histopathology Desquamative interstitial pneumonitis (DIP) is a rare diffuse lung disease that usually occurs in smokers in the fifth through seventh decades; males are twice as commonly affected as females. Although 90 % of cases are attributable to smoking, the disease does not occur exclusively in smokers and can occur as a result of other exposures, including marijuana smoke, toxic fumes, and rarely as a drug reaction [44] [37]. DIP has even been reported as a rare manifestation of connective tissue diseases such as systemic lupus erythematosis, scleroderma, rheumatoid arthritis, and polymyositis [45] [46]; idiopathic cases in nonsmokers have also been reported [47]. Common symptoms in DIP are an insidious onset of cough and shortness of breath; a subset of patients has ongoing systemic complaints, such as weight loss or fatigue [48]. The most conspicuous finding on PFTs is a decrease in diffusing capacity. Many cases of DIP respond to smoking cessation; in the remaining cases, a response to corticosteroid therapy is often seen, a feature distinguishing the disease from usual interstitial pneumonitis (UIP). However, without treatment, and in some cases even in spite of treatment, the outcome can be poor and overall mortality in DIP can be as high as 28 % [37, 49]. Liebow first used the term Bdesquamative interstitial pneumonitis^ to describe a pathologic pattern of diffuse lung disease that he characterized as the accumulation of sloughed alveolar epithelial cells within the alveoli [50]. This abnormal profusion of cells within alveoli is now known to represent collections of pigmented macrophages, often accompanied by interstitial inflammation and fibrosis. Although the exact etiology of the disease remains obscure, some evidence points to a smoking-related increase in activation of granulocytemacrophage colony-stimulating factor (GM-CSF) in the airways, with an infection serving as a Bsecond hit,^ recruiting large numbers of inflammatory cells to the alveoli, including the macrophages seen in DIP [51, 52]. Imaging findings Radiographs may be normal (up to 22 % of patients) or show ill-defined hazy opacities, sometimes with a reticular or reticulonodular appearance [53]. At thin-section chest CT, ground glass opacity is the most common finding, seen in up to 100 % of patients; mild reticulation can be seen in up to 50 % of cases, and sub-centimeter thin-walled cysts are often seen in areas within or adjacent to ground glass opacity, present in about one third of cases (Fig. 7) [54]. A peripheral

Fig. 7 41-Year-old woman with desquamative interstitial pneumonitis (DIP); axial CT. Patchy ground glass opacities with a slight basilar predominance are noted. In addition, small cysts with thin walls are noted in some of the areas of ground glass opacities in the upper lobes, which have been described in DIP; these may in part represent emphysema with areas of surrounding fine fibrosis

distribution of the ground glass opacities is most common, seen in over one half of cases; either a patchy random or a diffuse distribution can be seen in just under half of cases. A lower-lobe predominance is usual, but the upper lobes are involved in a substantial subset of patients, 82 % in one series [54]. Notable fibrosis, including honeycombing, is usually absent, although it can be seen in a minority of patients, 1/ 23 patients in one study [37] and 5/14 patients in another study [55]. Although DIP is thought of as a relatively uncommon interstitial lung disease, it often accompanies other smokingrelated lung diseases, with RB, PLCH, and DIP often present in the same pathologic specimen, often correlating with ground glass opacity at CT [56]. In addition, the appearance of DIP can be very similar to RB-ILD, with patchy or diffuse ground glass opacity, a feature of both diseases; a study of a series of 35 patients with smoking-related RB-ILD or DIP found no significant differences in the radiologic findings, PFTs, or clinical findings between the two conditions [37]. In practice, we typically suggest the diagnosis of RB or RBILD when upper-lobe-predominant centrilobular ground glass nodules and a small amount of ground glass opacity are

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identified and include DIP in the differential diagnosis when more extensive patchy or regional ground glass opacities are present. Acute eosinophilic pneumonia Clinical presentation and histopathology Episodes of acute eosinophilic pneumonia can occur in smokers, especially those who are young or new smokers. Rapidly worsening cough, dyspnea, and hypoxemia are typical, caused by large numbers of eosinophils recruited to the alveoli and interstitium. The disease can usually be diagnosed by bronchoalveolar lavage showing elevated numbers of eosinophils and is quite responsive to corticosteroid therapy [51]. Imaging findings Radiographs may show patchy, hazy, and bilateral airspace opacities, and CT may show patchy or diffuse ground glass opacity and interlobular septal thickening. The acute presentation and history of a new or worsening smoking habit is important in suggesting the diagnosis, as the findings can be similar to those of other conditions, including infectious pneumonia and chronic smoking-related lung diseases such as DIP. Treatment with corticosteroids results in rapid clearing of imaging abnormalities. Combined pulmonary fibrosis and emphysema Clinical presentation and histopathology Histopathologic and gross anatomy studies have confirmed an association of smoking, fibrosis, and emphysema, with degree of fibrosis directly related to total pack-years of smoking [57]. Damage through cytokine induction, collagen deposition, macrophage impairment, free-radical production, and many other mechanisms is a possible cause of fibrosis in smoking; a growing body of recent evidence also implicates premature telomere shortening [58]. Imaging findings of fibrosis such as reticulation and honeycombing have been found in up to 4 % of chest CTs performed on smokers in lung cancer screening programs [59••]. While some degree of fibrosis is thus a not infrequent finding in smokers’ lungs, a Bcombined pulmonary fibrosis and emphysema^ (CPFE) pattern, with prominent lower-zone-predominant fibrosis and upper-lobepredominant emphysema, severe dyspnea on exertion, and preserved lung volumes, has been increasingly recognized over the past decade. Although classified as an example of two coexisting smoking-related conditions rather than a distinct Binterstitial lung disease^ according to the American Thoracic Society guidelines [60], CPFE has increasingly been

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recognized as an important constellation of typical clinical, radiologic, and PFT findings. A subset of smokers with pulmonary fibrosis and relatively normal lung volumes, normal or near normal FEV1, FVC and FEV1/FVC ratio, and a markedly low DLCO has been recognized for decades, attributed to the competing obstructive physiology of emphysema and restrictive physiology of fibrosis [61, 62]. More recently, this pattern of lung pathology has been termed CPFE [63], and the accompanying pattern of normal spirometry with very low diffusing capacity labeled Bpseudonormalization.^ CPFE patients typically have severe dyspnea, a lower DLCO [64], a higher risk of pulmonary hypertension [65], and a poorer prognosis in cases of lung cancer [66] than in patients with IPF alone. Some recent studies have shown a higher overall mortality rate in patients classified as having CPFE than in those with fibrosis alone [64]. Choi et al. found a median survival of 6.0 years in a group of patients with CPFE and 10.0 years in a comparison group with pulmonary fibrosis without emphysema [67]. However, the largest and most well-designed multicenter study to date by Ryerson et al. found no significant difference in mortality between CPFE cases and those with pulmonary fibrosis alone, even when adjusted for CT quantification of fibrosis [68], possibly because patients with fibrosing lung diseases other than IPF/UIP were excluded from the Ryerson study, while patients with these less severe forms of ILD may have been included in other studies. This may be the cause of the longer-than-expected survival of the fibrosis patients in some such studies (10 years in Choi et al.) [67]. Pathologic specimens can show the superimposition of typical centrilobular and at times paraseptal emphysema in the upper lobes, and a UIP pattern of fibrosis with subpleural honeycombing in the lower lung zones, often indistinguishable from the histologic patterns seen in the Bpure^ forms of these conditions [69]. A fine fibrosis associated with areas of upper-lobe emphysema has recently been described by some pathologists, likely representing the presence of Brespiratory bronchiolitis with fibrosis^ (RBF), further described in the next section [41]. However, most pathologists currently distinguish the Blocal fibrosis^ in RBF from the Bdiffuse fibrosis^ present in CPFE cases; these different forms can be readily distinguished from one another at thin-section CT. Imaging findings Chest radiographs in CPFE may show relatively normal lung volumes with basilar reticular opacities, and may show upperlobe lucency representing emphysema; however, both fibrosis and emphysema can be missed or underestimated by radiography in a substantial percentage of cases [70]. Highresolution CT (HRCT) is the gold standard for depicting the typical combination of lower lobe fibrosis and usually upper-

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lobe-predominant emphysema in CPFE. At HRCT, basilarpredominant inter- and intralobular septal thickening and stacked thick-walled subpleural honeycombing in a UIP pattern is typical, correlating with a usual interstitial pneumonitis (UIP) pattern at pathology (Fig. 8) [71]. Emphysema in CPFE is typically upper lobe predominant and can have centrilobular or paraseptal morphology, with paraseptal emphysema occurring with a higher frequency in CPFE than in patients with emphysema alone [72]. Recent literature has suggested standardization of the definition of CPFE at CT, reserving the label for those cases demonstrating typical UIP pattern basilar fibrosis with greater than or equal to 10 % emphysematous parenchymal involvement at CT, a level of emphysema that has been shown to have good inter-reader correlation and noticeable physiologic effects [67, 68]. Ground glass opacity can be seen in up to 66 % of cases characterized as CPFE [63], but the contribution of other smoking-related diseases such as RB-ILD and DIP is uncertain [73].

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In Bclassic^ cases, the CT pattern of fibrosis and emphysema in CPFE can be indistinguishable from the CT appearance of the Bpure^ forms of these diseases, with some authors describing CPFE as the superimposition of these two classic patterns [69]. In our experience, however, the same challenges and pitfalls in general diagnosis of a UIP pattern at HRCT apply to the diagnosis of fibrosis in CPFE. For example, irregular reticulation at the lung bases without macroscopic honeycombing—a Bpossible UIP pattern^ by American Thoracic Society criteria [74]—can be seen in diseases other than CPFE, and some degree of fine basilar reticulation is often seen as a result of normal aging or chronic aspiration, creating the possibility of overdiagnosis of CPFE at CT. Moreover, the CT appearance of CPFE, with a typical lower lobe pattern of reticulation, honeycombing, and architectural distortion, needs to be distinguished from the patchy, often upper-lobe peripheral reticulation and thickening of the walls of emphysematous parenchyma often seen in smoking-related fibrosis with an RBF pattern (discussed in the BRespiratory bronchiolitis with fibrosis/smoking-related interstitial fibrosis^ section), as CPFE carries a much bleaker prognosis. As is the rule in diffuse lung disease in general, the most reasonable, effective approach to diagnosing CPFE involves a synthesis of clinical, imaging and, when obtained, histopathologic findings. Quantitative studies have shown that the extent of parenchymal disease as assessed by chest CT in CPFE correlates poorly with spirometry but correlates well with DLCO, underscoring the essential role of CT in characterizing the relative contributions of emphysema and fibrosis to the typically low DLCO seen in the disease [67]. Interestingly, a recent quantitative study of fibrosis and emphysema in CPFE found good correlation between DLCO and degree of fibrosis, but not extent of emphysema [75]. Respiratory bronchiolitis with fibrosis/smoking-related interstitial fibrosis Clinical presentation and histopathology

Fig. 8 54-Year-old man with combined pulmonary fibrosis and emphysema (CPFE); axial CT images. Top: image through the upper lobes shows confluent centrilobular and paraseptal emphysema, with large bullae. Bottom: image through the lower lobes shows a usual interstitial pneumonitis (UIP) pattern of fibrosis, with multiple thick-walled layers of cysts extending from the subpleural lung inward, a Bhoneycombing^ appearance

Although the CPFE pattern of imaging and PFT findings has gained widespread recognition among thoracic radiologists, pathologists, and pulmonologists, a more recent category of fibrosis related to smoking has gained acceptance over the past 5 years, variously labeled Brespiratory bronchiolitis with fibrosis^ (RBF), Bairspace enlargement with fibrosis^ [76], and Bsmoking-related interstitial fibrosis^ (SRIF) [77]. As these terms appear to refer to substantially the same pathologic and imaging findings, BRBF^ will be used throughout this section. RBF was originally described in the pathology literature as a pattern of fibrosis different from the basilarpredominant reticulation and honeycomb UIP pattern typically seen in CPFE [78]. A fairly common finding, Kawabata

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et al. reported RBF in pathologic specimens in 6.5 % of mild smokers and 17.7 % of moderate smokers [76]; Katzenstein et al. found RBF in 45 % of all lobectomy specimens of smokers studied [79]; English et al. found an appearance consistent with RBF in 7 % of CTs of smokers in a screening program [80•]. In contrast to cases of CPFE, patients with RBF may have only a mild to moderate reduction in DLCO; while obstruction is often mild to moderate, restriction has not been reported as a predominant finding [79]. When not accompanied by another dominant pattern of smoking-related lung disease, patients have a benign course and the importance of the entity consists mainly in distinguishing it from other types of fibrosis in smoking-related ILDs, most importantly CPFE/UIP [77, 80•]. The typical histopathologic findings of RBF have been described as thickening and expansion of interstitium and alveolar septa by hyalinized collagen, accompanied by adjacent emphysema and respiratory bronchiolitis. The pattern lacks the architectural distortion, honeycombing, spatial and temporal heterogeneity, and prominent fibroblastic foci typical of UIP/CPFE. Thin-walled cysts and thickened alveolar walls and septa are seen; unlike the thicker-walled, more confluent cysts of honeycombing seen in UIP [76, 79]. RBF has been described as occurring in both subpleural and peribronchial/ bronchiolar distribution, usually within and surrounding areas of emphysema [76, 79]. The peribronchial fibrosis pattern typical for RBF is not a common feature of CPFE; for example, one study found an absence of significant airway-centered fibrosis in patients with CPFE defined as emphysema and a lower lobe UIP pattern [71]. Imaging findings Although understanding of the imaging correlates of RBF is still evolving, the largest recent studies have found a typical CT appearance of multiple thin-walled cysts with a peripheral, often upper-lobe predominance, occurring within or adjacent to areas of emphysema (Fig. 9). Often, the cysts do not touch the pleural surface, unlike honeycombing. The typical cysts have definable walls, unlike other cases of Bpure^ emphysema, but are thinner than the cysts of typical honeycombing in UIP; in one study, the cysts of RBF had a mean thickness of 0.8 mm, while those of honeycombing averaged 1.6 mm [81]. Reticular opacities are common, with a wide range of reported frequencies across studies, from 27 % [81] to 100 % [80•]. Interestingly, the centrilobular ground glass nodules and patchy ground glass opacities frequent in cases recognized as RB/RB-ILD are much less commonly found in series of patients with RBF, detected in just 2 of 14 patients in one series [80•], while traction bronchiectasis, architectural distortion, and honeycombing seen in UIP are absent in areas of Bpure^ RBF. However, RBF is often found in the setting of UIP/CPFE; in these cases, a lower lobe distribution of typical

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Fig. 9 69-Year-old man with emphysema and respiratory bronchiolitis with fibrosis (RBF) appearance; axial CT image. Centrilobular and paraseptal emphysema with well-defined walls, peripheral reticulation, and subtle subpleural patchy ground glass opacity. These findings are typical for RBF

honeycombing and an upper-lobe distribution of RBF are often present [81]. In a study of 200 smokers undergoing serial thin-section CTs in a lung cancer chemoprevention trial, findings compatible with RBF were detected in 7 % [80•], at the low end of the frequency with which RBF has been detected in studies of pathologic specimens from smokers; as in the case of RB, the condition is likely even more common in smokers than CT findings suggest. Patients with RBF as the dominant finding had no or only mild progression of findings over a followup period of 2–6 years in the same study, the largest longitudinal CT study of the condition [80•].

Conclusion Although the many smoking-related diffuse lung diseases differ in clinical significance, prevalence, and prognosis, many share similar imaging characteristics and can also coexist in the same patient. Advances in quantitative CT techniques have improved our imaging of COPD, allowing correlation with spirometric measures and prediction of future morbidity. Our understanding of smoking-related fibrosis also continues to evolve with further characterization of disease entities such as CPFE and RBF.

Compliance with Ethics Guidelines Conflict of Interest The authors of this article have no conflicts of interests to disclose. Human and Animal Rights and Informed Consent This article contains no studies with human or animal subjects performed by the author.

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