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Diffuse smoking-related lung disease: emphysema and interstitial lung disease Stephanie Cheng MD, Tan Lucien H. Mohammed MD, FCCP
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Seminar in Roentgenology
Cite this article as: Stephanie Cheng MD, Tan Lucien H. Mohammed MD, FCCP, Diffuse smoking-related lung disease: emphysema and interstitial lung disease, Seminar in Roentgenology, http://dx.doi.org/10.1053/j.ro.2014.04.009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Diffuse smokingrelated lung disease: emphysema and interstitial lung disease Stephanie Cheng, MD Tan Lucien H. Mohammed, MD, FCCP Virginia Mason Medical Center Department of Radiology 1100 Ninth Ave. Seattle, WA 98101 For correspondence please contact Dr. Mohammed at: Tan‐Lucien H. Mohammed, M.D., FCCP (corresponding author) Virginia Mason Medical Center Department of Radiology Mail code C5‐XR 1100 Ninth Street Seattle, Washington 98101 (206) 223‐6851 E‐mail: [email protected] Introduction
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Approximately 19% of adults in the United States are current smokers (1). Cigarette smoke is a complex mixture containing over 4,000 compounds, many of which have toxic effects both on the lungs and throughout the body (2‐4). Smoking is estimated to cost the United States approximately $96 billion in medical expenses and $97 billion in lost productivity every year (5). It is the leading cause of preventable deaths in the United States and developed world (2,3,6). The main causes of smoking related deaths are lung cancer, chronic obstructive pulmonary disease (COPD), and ischemic heart disease. Smoking has also been strongly associated with several interstitial lung diseases (ILDs), namely pulmonary Langerhans’ cell histiocytosis (PLCH), respiratory bronchiolitis (RB), respiratory bronchiolitis‐ associated interstitial lung disease (RB‐ILD), and desquamative interstitial pneumonia (DIP). This article reviews the major diffuse pulmonary diseases affecting smokers, including emphysema and smoking‐related interstitial lung diseases. We will describe the histologic and radiologic features of the different forms of emphysema (centrilobular, panlobular, and paraseptal). Finally, we will then discuss the clinical, histopathologic, and radiologic characteristics of smoking related interstitial lung diseases, including PLCH, RB, RB‐ILD, and DIP. Bronchogenic carcinoma will not be covered in this article. Anatomy of the secondary pulmonary lobule
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In order to better understand the different types of emphysema and smoking related interstitial lung disease, it is helpful to review the basic anatomy of the secondary pulmonary lobule. The secondary pulmonary lobule is the smallest unit of lung that is surrounded by connective tissue. It is polyhedral in shape, and is supplied by a centrally located bronchiole and pulmonary arterial branch. The interlobular septae are the connective tissues that form its borders and contain pulmonary venules and lymphatics. The central bronchiole divides into several terminal bronchioles – the last airway to be solely conducting. The lung distal to a terminal bronchiole is defined as an acinus. The terminal bronchiole then divides into respiratory bronchioles, which contain alveoli and help with both conduction and air exchange. These finally end in alveolar ducts, sacs, and alveoli (10). Emphysema COPD is a common disease in smokers that is characterized by airflow limitation that is not fully reversible (7). Emphysema is a component of COPD, defined by the American Thoracic Society (ATS) as the “abnormal permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of the alveolar walls, without obvious fibrosis” (8). This is thought to occur due to lung inflammation, which leads to an imbalance of proteases and anti‐proteases (9). Emphysema is generally categorized into three different types depending on the distribution of destruction within the secondary pulmonary lobule: centrilobular, panlobular, and paraseptal.
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Centrilobular emphysema Centrilobular emphysema is the most common type of emphysema seen in smokers (11). It is characterized by destruction of the parenchyma surrounding the respiratory bronchioles (12,13). Early in the disease the distal alveolar ducts and sacs are spared. Chest radiographs demonstrate areas of increased lucency and decreased vascularity, typically affecting the upper lungs. This is often quite subtle unless the degree of destruction is severe. However, the areas of lucency become more obvious when there is surrounding airspace disease such as edema, pneumonia, or hemorrhage. Airway obstruction is often associated with emphysema and is seen on chest radiographs as lung hyperinflation. Findings include depression and flattening of the hemidiaphragms as well as widening of the retrosternal airspace (14‐17). On computed tomography (CT), centrilobular emphysema can be manifest as multiple small, rounded areas of low attenuation lesions with imperceptible walls (FIGURE 1). These cysts typically measure several millimeters to 1cm in diameter and are seen surrounding the centrilobular artery branch at the center of the secondary pulmonary lobule. The vascular architecture is preserved and can often be seen as a central dot. The upper lobes are more affected more than the lower lobes. Over time, the disease can become more confluent and the centrilobular distribution may no longer be identifiable (14,18).
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Panlobular emphysema Panlobular emphysema is defined by loss of the alveolar septa throughout the entire secondary pulmonary lobule (12). On CT this manifests as decreased attenuation in a confluent, panlobular distribution as well as decreased vessel caliber in the affected areas. This predominately involves the lower lungs with relative sparing of the upper lungs (14,18). Smoking can exacerbate panlobular emphysema, however this is rare. The most common cause is alpha‐1‐antitrypsin deficiency with other less common etiologies including Swyer‐James syndrome, Ritalin abuse, and senescent change (19‐21). Alpha‐1‐antitrypsin deficiency is an autosomal recessive disorder resulting in decreased serum levels of alpha‐1‐antitrypsin. This enzyme inactivates neutrophil elastase. Without alpha‐1‐antitrypsin, neutrophil elastase builds up and causes parenchymal destruction leading to emphysema. Emphysema is severely exacerbated with smoking (22). Additional CT findings include bronchiectasis or bronchial wall thickening (23). Swyer‐James syndrome is a form of post‐infectious bronchiolitis obliterans. Patients typically have a history of a viral respiratory infection sustained in early childhood. This causes damage to the terminal and respiratory bronchioles which leads to incomplete development of alveoli. CT findings are usually unilateral and include hypoattenuation of the lung, air trapping, and bronchiectasis. Although lung volumes are usually decreased, emphysema is seen histologically (19,24). Ritalin has been abused by the intravenous injection of
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crushed tablets, resulting in “Ritalin lung”. This causes a panlobular emphysema which is most prominent at the lung bases. Although the pathogenesis is unknown, it is postulated that the talc used as a binder in the tablets likely plays an important role. Histologic identification of microscopic talc granulomas and clinical history help differentiate Ritalin lung from alpha‐1‐antitrypsin (20,25). Panlobular emphysema may be difficult to differentiate from the small airway obstruction and air trapping seen in obliterative bronchiolitis when focal destructive lung changes are minimal. Severe centrilobular emphysema can also appear similar to panlobular emphysema when the destructive changes lose their discrete centrilobular distribution. Paraseptal emphysema Paraseptal emphysema affects the most distal portions of the acinus (the alveolar sacs and ducts) with sparing of the respiratory bronchioles (12). It most commonly involves the upper lungs in a subpleural location. It can be a cause for spontaneous pneumothorax, particularly in tall, thin males in the third or fourth decade of life (26,27). The etiology of paraseptal emphysema is less well understood than the other two subtypes. Although paraseptal emphysema is commonly seen in non‐ smokers, findings are often exacerbated in smokers. CT findings include dilated distal airspaces that are rectangular in shape and share thin walls. Large areas of paraseptal emphysema are called bullae, defined by a
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diameter greater than 1cm with a thin wall measuring less than 1mm (12). Bullae are most commonly seen with paraseptal emphysema but can be seen with the other types of emphysema as well as in isolation. Although honeycombing may have a similar appearance, the cysts are usually more rounded, smaller in size, and have thicker walls. Honeycombing is also more likely to be seen at the lung bases. While paraseptal emphysema is restricted to the subpleural lung, honeycombing can extend deeper into the lung parenchyma (18). Interstitial lung disease Pulmonary Langerhans Cell Histiocytosis (PLCH) Langerhans cell histiocytosis is a heterogeneous group of diseases characterized by an abnormal accumulation of CD1+ histiocytes (Langerhans cells), which may involve the bones, lungs, pituitary gland, mucous membranes, skin, lymph nodes and liver. Previously known as Histiocytosis X, LCH has been reclassified by the Histiocyte Society into variants that involve a single organ system (such as eosinophilic granuloma) and those that are multisystemic (such as Letterer‐Siwe disease and Hand‐Schuller‐Christian disease) (28,29). Pulmonary Langerhans cell histiocytosis is a form of LCH found in adults. PLCH is strongly associated with smoking and is usually isolated to the lungs (30). Extrapulmonary manifestations occur in only 5‐15% of patients and include lytic bone lesions diabetes insipidus, and skin lesions (23,24>31,32). While other forms of LCH may also involve the
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lungs, these are usually multisystemic, more commonly diagnosed in children, and are not related to smoking. More than 90% of all patients with PLCH are either current or previous smokers (33,34). Patients are usually young adults aged 20 to 40 years. Men and women are equally affected (31). The most common clinical symptoms of PLCH are dyspnea, cough, and chest pain although up to a quarter of patients may be asymptomatic (35,36). Constitutional symptoms such as weight loss, fever, night sweats, and anorexia are less common but occur in up to one‐third of patients. Up to 10% of patients with PLCH may present with spontaneous pneumothorax (34,37). Pulmonary function tests (PFTs) most commonly demonstrate a decrease in carbon monoxide diffusing capacity (DLCO) (31,33‐35,38). Chest radiographs demonstrate nodular or reticulonodular opacities in the upper lungs with more cystic changes as the disease progresses (33,34). High resolution computed tomography (HRCT) demonstrates small, ill‐defined centrilobular nodules early in the disease course. These represent the infiltration of Langerhans’ cells centered on small airways (30,34,39,40). The nodules may enlarge and cavitate, forming cysts (FIGURE 2). As the disease progresses, the cysts coalesce and become irregularly shaped, classically described as “bizarre” shaped (36,41). Findings are predominately seen in the upper lung zones with relative sparing at the bases (31,33,42). (FIGURE 3) The differential diagnosis includes pulmonary lymphangiomyomatosis, however this entity typically has more rounded, more
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organized cysts and will usually involve the entire lung without sparing of the bases (31,34,39). HRCT findings are usually characteristic of the disease and the diagnosis can usually be made without lung biopsy (FIGURE 4). Smoking cessation should be strongly encouraged in patients with PLCH. Prognosis after smoking cessation is good with 5‐ and 10‐year survival rates of 74.6% and 63.9% respectively (36,43). The use of corticosteroids may be considered in severely symptomatic patients although their effectiveness is controversial (31,35,44). Chemotherapeutic agents such as vinblastine, cyclophosphamide, and methotrexate have been used in cases that are unresponsive to corticosteroids, although there is limited data regarding their efficacy (31,35,44,45). Non‐responsive patients may go on to develop severe pulmonary hypertension, which is a poor prognostic indicator (44,46,47). In patients with severe disease, lung transplantation can be considered although there have been several documented cases of PLCH recurrence in the transplanted lung (48,49). Patients with pneumothorax often require pleurodesis due to the high rate of recurrence (50). Respiratory Bronchiolitis and Interstitial Lung Disease (RB and RBILD) Respiratory bronchiolitis is an incidental finding seen in virtually all cigarette smokers. It is characterized by the accumulation of pigmented macrophages within respiratory bronchioles. Any interstitial inflammation is limited to the respiratory bronchioles and adjacent airspaces (51). (FIGURE 5) By definition, patients with RB are asymptomatic (52). A small number of smokers have respiratory bronchiolitis‐
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associated interstitial lung disease, which has histological findings identical to RB but is associated with symptoms or physiologic abnormalities (53). Patients are usually current cigarette smokers with a history of greater than 30‐ pack years of smoking. Less commonly, RB‐ILD has been reported in patients with other exposures including second‐hand smoke, solder fumes, and fiberglass (52,54,55). Most patients present as young adults in their 30s to 40s with symptoms of mild dyspnea and cough (54). PFTs typically demonstrate a decreased DLCO with a mixed obstructive / restrictive pattern (53,54,56). Chest radiographs are often normal but findings can include fine bilateral upper lobe predominant reticulonodular opacities (32). Findings on HRCT include centrilobular nodules, patchy ground glass opacities, bronchial wall thickening and air trapping (54,57,58). The upper lung zones are more frequently involved (54,58). There is also often a background of centrilobular emphysema (FIGURE 6). Subacute hypersensitivity pneumonia is in the differential for the radiologic findings of RB‐ ILD, however the clinical history helps to differentiate the two (36). Imaging findings can also be similar to DIP (described below) and non‐specific interstitial pneumonitis (NSIP) (32). A thoracoscopic lung biopsy may be necessary for definitive diagnosis. Transbronchial biopsy will be unable to distinguish RB‐ILD from DIP (59,60). (FIGURE 7)
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Smoking cessation is the mainstay of treatment for RB‐ILD and may lead to symptomatic and radiologic improvement (61,62). However, a significant percentage of patients may remain symptomatic despite successful smoking cessation (61). Corticosteroids have been used to treat patients with significant respiratory impairment or continued symptoms after smoking cessation although their efficacy has not been proven (44,53,63). Prognosis is generally good with no documented cases of death or respiratory failure directly attributable to RB‐ILD (32,34). Desquamative Interstitial Pneumonia DIP is a rare form of interstitial pneumonia that is histologically similar to RB‐ILD. Both are characterized by abnormal macrophage accumulation and are often considered to be along the same spectrum of disease (58). DIP is the more severe entity with macrophages seen diffusely within the acini, unlike RB‐ILD which is limited to a bronchocentric distribution (64‐66). Because of this diffuse distribution, histologic samples will look uniform from field to field at low magnification. There is often associated interstitial fibrosis, which differs in severity from patient to patient, however the interstitial changes are always less prominent than the intra‐alveolar macrophage accumulation. The term “desquamative interstitial pneumonia” is a misnomer because desquamated pneumocytes are not the predominant histologic pattern as was originally thought (34).
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DIP has a very strong association with smoking; a positive smoking history is seen in up to 90% of patients (66,67). However, DIP can occasionally be seen with other disorders including connective tissue diseases, drug reactions, dust inhalation, and infection (63,66,67). Patients typically present in the fourth or fifth decades of life with symptoms of dyspnea and cough (63,65,66,68). Clubbing is a frequent finding on physical exam and is seen in up to half of patients and is unique among the smoking related ILDs (66,67,69). The most frequently seen PFT abnormality is a markedly reduced DLCO with reductions of up to 50% or more of predicted values (63,66,69). About half of patients also have a restrictive defect (63,66,67). Chest radiographs may show basilar predominant ground glass opacities, however 3‐22% of chest radiographs are normal (41,70,71). HRCT also demonstrates bilateral symmetric ground glass attenuation, usually with a basilar and peripheral predominance although this distribution may not always be present (65,71,72). (FIGURE 8) Reticular densities representing areas of fibrosis are usually seen in the subpleural regions of the lower lung zones (66,67). Honeycombing is atypical but, when present, signifies advanced disease. Small well‐defined cysts are sometimes present and may represent dilated small airways (70). Thoracoscopic lung biopsy can be performed for definitive diagnosis and may be helpful to rule out more aggressive forms of ILD (34). Smoking cessation is the first line treatment for DIP and may halt the progression of disease (73,74). Treatment with oral corticosteroids is also recommended for most
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patients with significant symptoms, PFT abnormalities, or radiologic findings, although this has not been proven to be effective (34). There is a much higher response rate to corticosteroids compared to usual interstitial pneumonia (UIP) with approximately two thirds of patients showing stabilization or improvement of symptoms (63,66). A small number of patients have progressive disease requiring lung transplantation, although recurrent disease in the transplanted lung has been reported (75,76). Overall, prognosis is generally good particularly in comparison with idiopathic pulmonary fibrosis (IPF). 5‐ and 10‐year survival rates for DIP are 95.2% and 69.6% respectively (66). There is some data to suggest that DIP has a worse prognosis than RB‐ILD (63). Conclusion Beyond bronchogenic carcinoma, smoking is strongly associated with a variety of other lung diseases such as emphysema and several interstitial pneumonias including PLCH, RB‐ILD, and DIP. The smoking related ILDs in particular affect patients who are young and have the potential to lose many years of productivity. Therefore, it is important to recognize these disease processes both to make the diagnosis and to assess the response to smoking cessation, as a lack of response may prompt further treatment. In the near future, there will likely be a significant increase in the number of smokers receiving low dose chest CT for lung cancer screening given the results of
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the National Lung Screening Trial. At the time of this writing, a draft recommendation statement has been published by the United States Preventative Services Task Force (USPSTF) and recommends annual screening in high‐risk smokers with a Grade B rating (77). While the primary goal is the early detection of lung cancer, it will also be important to identify the other lung diseases that affect smokers. References: 1) Centers for Disease Control and Prevention: Current cigarette smoking among adults – United States, 2001. Morbidity and Mortality Weekly report 61(44):889‐894,
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Figure Legends Figure 1. 51‐year old man with centrilobular emphysema. Coronal CT image shows upper lobe predominant cystic disease in a patient with a 35‐pack year of smoking. Note lack of cystic disease in the lung bases. Image courtesy of Howard Mann, MD. Figure 2. Transverse (A) and coronal (B) HRCT images of a 39‐year old male smoker with PLCH show multiple cysts, some of which have irregular shapes, predominating in the upper lobes. Scattered poorly marginated nodules are also present. Images courtesy of Howard Mann, MD. Figure 3. 20‐year old man with PLCH. Chest radiograph (A) shows upper lobe predominant reticulation, along with small, subtle nodules. HRCT (B) better delineates upper lobe predominant cystic disease with multiple associated scattered nodules. Note the expansile left rib lesion (Arrow).
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Figure 4. Axial (A) and coronal (B) HRCT images of a 38‐year old male smoker with moderate PLCH show multiple cysts, some of which have irregular shapes, predominating in the upper lobes. Few scattered small nodules are also present. Figure 5. A 37‐year‐old asymptomatic female smoker with RB. HRCT image through the upper lobes shows subtle poorly marginated centrilobular nodules (Arrow). Figure 6. A 35‐year‐old female smoker with RB. HRCT image through the upper lobes shows multiple small, poorly defined centrilobular nodules (Arrows). Image courtesy of Jeffrey Kanne, MD. Figure 7. A 44‐year‐old male smoker with RB‐ILD. Transverse (A) and coronal (B) HRCT images demonstrate patchy ground‐glass attenuation (Arrows) with some lobular sparing in the upper and lower lung zones. Image courtesy of Jeffrey Kanne, MD. Figure 8. A 52‐year‐old male smoker with DIP. Axial (A) and coronal (B) CT images show basilar predominant ground‐glass attenuation, mild reticulation, and a few scattered cysts (arrows). Images courtesy of Howard Mann, MD.
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Diffuse smoking-related lung disease: emphysema and interstitial lung disease Stephanie Cheng MD, Tan Lucien H. Mohammed MD, FCCP
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S0037-198X(14)00022-4 http://dx.doi.org/10.1053/j.ro.2014.04.009 YSROE50476
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Seminar in Roentgenology
Cite this article as: Stephanie Cheng MD, Tan Lucien H. Mohammed MD, FCCP, Diffuse smoking-related lung disease: emphysema and interstitial lung disease, Seminar in Roentgenology, http://dx.doi.org/10.1053/j.ro.2014.04.009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Diffuse smokingrelated lung disease: emphysema and interstitial lung disease Stephanie Cheng, MD Tan Lucien H. Mohammed, MD, FCCP Virginia Mason Medical Center Department of Radiology 1100 Ninth Ave. Seattle, WA 98101 For correspondence please contact Dr. Mohammed at: Tan‐Lucien H. Mohammed, M.D., FCCP (corresponding author) Virginia Mason Medical Center Department of Radiology Mail code C5‐XR 1100 Ninth Street Seattle, Washington 98101 (206) 223‐6851 E‐mail: [email protected] Introduction
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Approximately 19% of adults in the United States are current smokers (1). Cigarette smoke is a complex mixture containing over 4,000 compounds, many of which have toxic effects both on the lungs and throughout the body (2‐4). Smoking is estimated to cost the United States approximately $96 billion in medical expenses and $97 billion in lost productivity every year (5). It is the leading cause of preventable deaths in the United States and developed world (2,3,6). The main causes of smoking related deaths are lung cancer, chronic obstructive pulmonary disease (COPD), and ischemic heart disease. Smoking has also been strongly associated with several interstitial lung diseases (ILDs), namely pulmonary Langerhans’ cell histiocytosis (PLCH), respiratory bronchiolitis (RB), respiratory bronchiolitis‐ associated interstitial lung disease (RB‐ILD), and desquamative interstitial pneumonia (DIP). This article reviews the major diffuse pulmonary diseases affecting smokers, including emphysema and smoking‐related interstitial lung diseases. We will describe the histologic and radiologic features of the different forms of emphysema (centrilobular, panlobular, and paraseptal). Finally, we will then discuss the clinical, histopathologic, and radiologic characteristics of smoking related interstitial lung diseases, including PLCH, RB, RB‐ILD, and DIP. Bronchogenic carcinoma will not be covered in this article. Anatomy of the secondary pulmonary lobule
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In order to better understand the different types of emphysema and smoking related interstitial lung disease, it is helpful to review the basic anatomy of the secondary pulmonary lobule. The secondary pulmonary lobule is the smallest unit of lung that is surrounded by connective tissue. It is polyhedral in shape, and is supplied by a centrally located bronchiole and pulmonary arterial branch. The interlobular septae are the connective tissues that form its borders and contain pulmonary venules and lymphatics. The central bronchiole divides into several terminal bronchioles – the last airway to be solely conducting. The lung distal to a terminal bronchiole is defined as an acinus. The terminal bronchiole then divides into respiratory bronchioles, which contain alveoli and help with both conduction and air exchange. These finally end in alveolar ducts, sacs, and alveoli (10). Emphysema COPD is a common disease in smokers that is characterized by airflow limitation that is not fully reversible (7). Emphysema is a component of COPD, defined by the American Thoracic Society (ATS) as the “abnormal permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of the alveolar walls, without obvious fibrosis” (8). This is thought to occur due to lung inflammation, which leads to an imbalance of proteases and anti‐proteases (9). Emphysema is generally categorized into three different types depending on the distribution of destruction within the secondary pulmonary lobule: centrilobular, panlobular, and paraseptal.
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Centrilobular emphysema Centrilobular emphysema is the most common type of emphysema seen in smokers (11). It is characterized by destruction of the parenchyma surrounding the respiratory bronchioles (12,13). Early in the disease the distal alveolar ducts and sacs are spared. Chest radiographs demonstrate areas of increased lucency and decreased vascularity, typically affecting the upper lungs. This is often quite subtle unless the degree of destruction is severe. However, the areas of lucency become more obvious when there is surrounding airspace disease such as edema, pneumonia, or hemorrhage. Airway obstruction is often associated with emphysema and is seen on chest radiographs as lung hyperinflation. Findings include depression and flattening of the hemidiaphragms as well as widening of the retrosternal airspace (14‐17). On computed tomography (CT), centrilobular emphysema can be manifest as multiple small, rounded areas of low attenuation lesions with imperceptible walls (FIGURE 1). These cysts typically measure several millimeters to 1cm in diameter and are seen surrounding the centrilobular artery branch at the center of the secondary pulmonary lobule. The vascular architecture is preserved and can often be seen as a central dot. The upper lobes are more affected more than the lower lobes. Over time, the disease can become more confluent and the centrilobular distribution may no longer be identifiable (14,18).
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Panlobular emphysema Panlobular emphysema is defined by loss of the alveolar septa throughout the entire secondary pulmonary lobule (12). On CT this manifests as decreased attenuation in a confluent, panlobular distribution as well as decreased vessel caliber in the affected areas. This predominately involves the lower lungs with relative sparing of the upper lungs (14,18). Smoking can exacerbate panlobular emphysema, however this is rare. The most common cause is alpha‐1‐antitrypsin deficiency with other less common etiologies including Swyer‐James syndrome, Ritalin abuse, and senescent change (19‐21). Alpha‐1‐antitrypsin deficiency is an autosomal recessive disorder resulting in decreased serum levels of alpha‐1‐antitrypsin. This enzyme inactivates neutrophil elastase. Without alpha‐1‐antitrypsin, neutrophil elastase builds up and causes parenchymal destruction leading to emphysema. Emphysema is severely exacerbated with smoking (22). Additional CT findings include bronchiectasis or bronchial wall thickening (23). Swyer‐James syndrome is a form of post‐infectious bronchiolitis obliterans. Patients typically have a history of a viral respiratory infection sustained in early childhood. This causes damage to the terminal and respiratory bronchioles which leads to incomplete development of alveoli. CT findings are usually unilateral and include hypoattenuation of the lung, air trapping, and bronchiectasis. Although lung volumes are usually decreased, emphysema is seen histologically (19,24). Ritalin has been abused by the intravenous injection of
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crushed tablets, resulting in “Ritalin lung”. This causes a panlobular emphysema which is most prominent at the lung bases. Although the pathogenesis is unknown, it is postulated that the talc used as a binder in the tablets likely plays an important role. Histologic identification of microscopic talc granulomas and clinical history help differentiate Ritalin lung from alpha‐1‐antitrypsin (20,25). Panlobular emphysema may be difficult to differentiate from the small airway obstruction and air trapping seen in obliterative bronchiolitis when focal destructive lung changes are minimal. Severe centrilobular emphysema can also appear similar to panlobular emphysema when the destructive changes lose their discrete centrilobular distribution. Paraseptal emphysema Paraseptal emphysema affects the most distal portions of the acinus (the alveolar sacs and ducts) with sparing of the respiratory bronchioles (12). It most commonly involves the upper lungs in a subpleural location. It can be a cause for spontaneous pneumothorax, particularly in tall, thin males in the third or fourth decade of life (26,27). The etiology of paraseptal emphysema is less well understood than the other two subtypes. Although paraseptal emphysema is commonly seen in non‐ smokers, findings are often exacerbated in smokers. CT findings include dilated distal airspaces that are rectangular in shape and share thin walls. Large areas of paraseptal emphysema are called bullae, defined by a
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diameter greater than 1cm with a thin wall measuring less than 1mm (12). Bullae are most commonly seen with paraseptal emphysema but can be seen with the other types of emphysema as well as in isolation. Although honeycombing may have a similar appearance, the cysts are usually more rounded, smaller in size, and have thicker walls. Honeycombing is also more likely to be seen at the lung bases. While paraseptal emphysema is restricted to the subpleural lung, honeycombing can extend deeper into the lung parenchyma (18). Interstitial lung disease Pulmonary Langerhans Cell Histiocytosis (PLCH) Langerhans cell histiocytosis is a heterogeneous group of diseases characterized by an abnormal accumulation of CD1+ histiocytes (Langerhans cells), which may involve the bones, lungs, pituitary gland, mucous membranes, skin, lymph nodes and liver. Previously known as Histiocytosis X, LCH has been reclassified by the Histiocyte Society into variants that involve a single organ system (such as eosinophilic granuloma) and those that are multisystemic (such as Letterer‐Siwe disease and Hand‐Schuller‐Christian disease) (28,29). Pulmonary Langerhans cell histiocytosis is a form of LCH found in adults. PLCH is strongly associated with smoking and is usually isolated to the lungs (30). Extrapulmonary manifestations occur in only 5‐15% of patients and include lytic bone lesions diabetes insipidus, and skin lesions (23,24>31,32). While other forms of LCH may also involve the
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lungs, these are usually multisystemic, more commonly diagnosed in children, and are not related to smoking. More than 90% of all patients with PLCH are either current or previous smokers (33,34). Patients are usually young adults aged 20 to 40 years. Men and women are equally affected (31). The most common clinical symptoms of PLCH are dyspnea, cough, and chest pain although up to a quarter of patients may be asymptomatic (35,36). Constitutional symptoms such as weight loss, fever, night sweats, and anorexia are less common but occur in up to one‐third of patients. Up to 10% of patients with PLCH may present with spontaneous pneumothorax (34,37). Pulmonary function tests (PFTs) most commonly demonstrate a decrease in carbon monoxide diffusing capacity (DLCO) (31,33‐35,38). Chest radiographs demonstrate nodular or reticulonodular opacities in the upper lungs with more cystic changes as the disease progresses (33,34). High resolution computed tomography (HRCT) demonstrates small, ill‐defined centrilobular nodules early in the disease course. These represent the infiltration of Langerhans’ cells centered on small airways (30,34,39,40). The nodules may enlarge and cavitate, forming cysts (FIGURE 2). As the disease progresses, the cysts coalesce and become irregularly shaped, classically described as “bizarre” shaped (36,41). Findings are predominately seen in the upper lung zones with relative sparing at the bases (31,33,42). (FIGURE 3) The differential diagnosis includes pulmonary lymphangiomyomatosis, however this entity typically has more rounded, more
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organized cysts and will usually involve the entire lung without sparing of the bases (31,34,39). HRCT findings are usually characteristic of the disease and the diagnosis can usually be made without lung biopsy (FIGURE 4). Smoking cessation should be strongly encouraged in patients with PLCH. Prognosis after smoking cessation is good with 5‐ and 10‐year survival rates of 74.6% and 63.9% respectively (36,43). The use of corticosteroids may be considered in severely symptomatic patients although their effectiveness is controversial (31,35,44). Chemotherapeutic agents such as vinblastine, cyclophosphamide, and methotrexate have been used in cases that are unresponsive to corticosteroids, although there is limited data regarding their efficacy (31,35,44,45). Non‐responsive patients may go on to develop severe pulmonary hypertension, which is a poor prognostic indicator (44,46,47). In patients with severe disease, lung transplantation can be considered although there have been several documented cases of PLCH recurrence in the transplanted lung (48,49). Patients with pneumothorax often require pleurodesis due to the high rate of recurrence (50). Respiratory Bronchiolitis and Interstitial Lung Disease (RB and RBILD) Respiratory bronchiolitis is an incidental finding seen in virtually all cigarette smokers. It is characterized by the accumulation of pigmented macrophages within respiratory bronchioles. Any interstitial inflammation is limited to the respiratory bronchioles and adjacent airspaces (51). (FIGURE 5) By definition, patients with RB are asymptomatic (52). A small number of smokers have respiratory bronchiolitis‐
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associated interstitial lung disease, which has histological findings identical to RB but is associated with symptoms or physiologic abnormalities (53). Patients are usually current cigarette smokers with a history of greater than 30‐ pack years of smoking. Less commonly, RB‐ILD has been reported in patients with other exposures including second‐hand smoke, solder fumes, and fiberglass (52,54,55). Most patients present as young adults in their 30s to 40s with symptoms of mild dyspnea and cough (54). PFTs typically demonstrate a decreased DLCO with a mixed obstructive / restrictive pattern (53,54,56). Chest radiographs are often normal but findings can include fine bilateral upper lobe predominant reticulonodular opacities (32). Findings on HRCT include centrilobular nodules, patchy ground glass opacities, bronchial wall thickening and air trapping (54,57,58). The upper lung zones are more frequently involved (54,58). There is also often a background of centrilobular emphysema (FIGURE 6). Subacute hypersensitivity pneumonia is in the differential for the radiologic findings of RB‐ ILD, however the clinical history helps to differentiate the two (36). Imaging findings can also be similar to DIP (described below) and non‐specific interstitial pneumonitis (NSIP) (32). A thoracoscopic lung biopsy may be necessary for definitive diagnosis. Transbronchial biopsy will be unable to distinguish RB‐ILD from DIP (59,60). (FIGURE 7)
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Smoking cessation is the mainstay of treatment for RB‐ILD and may lead to symptomatic and radiologic improvement (61,62). However, a significant percentage of patients may remain symptomatic despite successful smoking cessation (61). Corticosteroids have been used to treat patients with significant respiratory impairment or continued symptoms after smoking cessation although their efficacy has not been proven (44,53,63). Prognosis is generally good with no documented cases of death or respiratory failure directly attributable to RB‐ILD (32,34). Desquamative Interstitial Pneumonia DIP is a rare form of interstitial pneumonia that is histologically similar to RB‐ILD. Both are characterized by abnormal macrophage accumulation and are often considered to be along the same spectrum of disease (58). DIP is the more severe entity with macrophages seen diffusely within the acini, unlike RB‐ILD which is limited to a bronchocentric distribution (64‐66). Because of this diffuse distribution, histologic samples will look uniform from field to field at low magnification. There is often associated interstitial fibrosis, which differs in severity from patient to patient, however the interstitial changes are always less prominent than the intra‐alveolar macrophage accumulation. The term “desquamative interstitial pneumonia” is a misnomer because desquamated pneumocytes are not the predominant histologic pattern as was originally thought (34).
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DIP has a very strong association with smoking; a positive smoking history is seen in up to 90% of patients (66,67). However, DIP can occasionally be seen with other disorders including connective tissue diseases, drug reactions, dust inhalation, and infection (63,66,67). Patients typically present in the fourth or fifth decades of life with symptoms of dyspnea and cough (63,65,66,68). Clubbing is a frequent finding on physical exam and is seen in up to half of patients and is unique among the smoking related ILDs (66,67,69). The most frequently seen PFT abnormality is a markedly reduced DLCO with reductions of up to 50% or more of predicted values (63,66,69). About half of patients also have a restrictive defect (63,66,67). Chest radiographs may show basilar predominant ground glass opacities, however 3‐22% of chest radiographs are normal (41,70,71). HRCT also demonstrates bilateral symmetric ground glass attenuation, usually with a basilar and peripheral predominance although this distribution may not always be present (65,71,72). (FIGURE 8) Reticular densities representing areas of fibrosis are usually seen in the subpleural regions of the lower lung zones (66,67). Honeycombing is atypical but, when present, signifies advanced disease. Small well‐defined cysts are sometimes present and may represent dilated small airways (70). Thoracoscopic lung biopsy can be performed for definitive diagnosis and may be helpful to rule out more aggressive forms of ILD (34). Smoking cessation is the first line treatment for DIP and may halt the progression of disease (73,74). Treatment with oral corticosteroids is also recommended for most
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patients with significant symptoms, PFT abnormalities, or radiologic findings, although this has not been proven to be effective (34). There is a much higher response rate to corticosteroids compared to usual interstitial pneumonia (UIP) with approximately two thirds of patients showing stabilization or improvement of symptoms (63,66). A small number of patients have progressive disease requiring lung transplantation, although recurrent disease in the transplanted lung has been reported (75,76). Overall, prognosis is generally good particularly in comparison with idiopathic pulmonary fibrosis (IPF). 5‐ and 10‐year survival rates for DIP are 95.2% and 69.6% respectively (66). There is some data to suggest that DIP has a worse prognosis than RB‐ILD (63). Conclusion Beyond bronchogenic carcinoma, smoking is strongly associated with a variety of other lung diseases such as emphysema and several interstitial pneumonias including PLCH, RB‐ILD, and DIP. The smoking related ILDs in particular affect patients who are young and have the potential to lose many years of productivity. Therefore, it is important to recognize these disease processes both to make the diagnosis and to assess the response to smoking cessation, as a lack of response may prompt further treatment. In the near future, there will likely be a significant increase in the number of smokers receiving low dose chest CT for lung cancer screening given the results of
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the National Lung Screening Trial. At the time of this writing, a draft recommendation statement has been published by the United States Preventative Services Task Force (USPSTF) and recommends annual screening in high‐risk smokers with a Grade B rating (77). While the primary goal is the early detection of lung cancer, it will also be important to identify the other lung diseases that affect smokers. References: 1) Centers for Disease Control and Prevention: Current cigarette smoking among adults – United States, 2001. Morbidity and Mortality Weekly report 61(44):889‐894,
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Figure Legends Figure 1. 51‐year old man with centrilobular emphysema. Coronal CT image shows upper lobe predominant cystic disease in a patient with a 35‐pack year of smoking. Note lack of cystic disease in the lung bases. Image courtesy of Howard Mann, MD. Figure 2. Transverse (A) and coronal (B) HRCT images of a 39‐year old male smoker with PLCH show multiple cysts, some of which have irregular shapes, predominating in the upper lobes. Scattered poorly marginated nodules are also present. Images courtesy of Howard Mann, MD. Figure 3. 20‐year old man with PLCH. Chest radiograph (A) shows upper lobe predominant reticulation, along with small, subtle nodules. HRCT (B) better delineates upper lobe predominant cystic disease with multiple associated scattered nodules. Note the expansile left rib lesion (Arrow).
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Figure 4. Axial (A) and coronal (B) HRCT images of a 38‐year old male smoker with moderate PLCH show multiple cysts, some of which have irregular shapes, predominating in the upper lobes. Few scattered small nodules are also present. Figure 5. A 37‐year‐old asymptomatic female smoker with RB. HRCT image through the upper lobes shows subtle poorly marginated centrilobular nodules (Arrow). Figure 6. A 35‐year‐old female smoker with RB. HRCT image through the upper lobes shows multiple small, poorly defined centrilobular nodules (Arrows). Image courtesy of Jeffrey Kanne, MD. Figure 7. A 44‐year‐old male smoker with RB‐ILD. Transverse (A) and coronal (B) HRCT images demonstrate patchy ground‐glass attenuation (Arrows) with some lobular sparing in the upper and lower lung zones. Image courtesy of Jeffrey Kanne, MD. Figure 8. A 52‐year‐old male smoker with DIP. Axial (A) and coronal (B) CT images show basilar predominant ground‐glass attenuation, mild reticulation, and a few scattered cysts (arrows). Images courtesy of Howard Mann, MD.
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