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Smoking-Related Interstitial Lung Diseases
Smoking-Related Interstitial Lung Diseases Jonathan H. Chung, MD,* and Jeffrey P. Kanne, MD†
C
igarette smoke contains a mixture of over 4000 chemicals, many of which are toxic. Smoking-related illnesses are the leading cause of preventable deaths in the United States accounting of 440,000 deaths per year (nearly onefifth of total annual deaths).1 The most common smokingrelated illnesses include chronic obstructive pulmonary disease, bronchogenic carcinoma, and ischemic heart disease. However, the role of cigarette smoking in the pathogenesis of interstitial lung diseases is becoming increasingly apparent. The relationship between cigarette smoking and pulmonary Langerhans cell histiocytosis (PLCH), respiratory bronchiolitis (RB), respiratory bronchiolitis–associated interstitial lung disease (RB-ILD), and desquamative interstitial pneumonia (DIP) is well described.2-5 Data suggesting an association between cigarette smoking and acute eosinophilic pneumonia (AEP) are emerging. The relationship between cigarette smoking and idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia remains uncertain.6,7 Given how common smoking is and how uncommon these conditions are, other unknown factors presumably play a role in the pathogenesis of smoking-related interstitial lung disease.5 Patients afflicted with smoking-related interstitial lung disease tend to be younger with fewer comorbidities; hence, early diagnosis and treatment (primarily with smoking cessation) are paramount.5 This article discusses the clinical and histopathologic features of PLCH, RB, RB-ILD, DIP, and AEP and illustrates their respective imaging appearances, focusing primarily on highresolution computed tomography (HRCT).
monoclonal or polyclonal. PLCH, the term used when LCH is limited to the lungs, occurs almost exclusively in smokers.8,9 Initially, a very strong male predominance was reported. However, more recent studies demonstrate no definite sex predilection, which may reflect recent changes in smoking habits.10 The exact mechanism by which cigarette smoking leads to the development of PLCH has yet to be elucidated. However, the low incidence of PLCH relative to the high prevalence of smoking implies that host-related factors predispose patients to developing PLCH.10 Patients most often present with nonspecific cough or dyspnea, which are often attributed to smoking. Hence, a delay in diagnosis is common.10 Patients may also be asymptomatic in up to a quarter of cases.11 A small minority of patients may present with spontaneous pneumothorax.12 Physical examination is usually noncontributory except in cases of the pneumothorax. Definitive diagnosis is made by transbronchial or surgical lung biopsy. However, tissue diagnosis is often unnecessary in a smoker with characteristic findings on HRCT. Chest radiographs are abnormal in most patients with PLCH.13 The most common findings are reticular opacities, nodules, and cysts.14 Relative sparing of the lower lung zones and costophrenic sulci is typical. Lung volumes are usually normal or may be increased. Less common radiographic manifestations of PLCH include pleural effusions, hilar lymphadenopathy, and pneumothorax.7
PLCH PLCH belongs to the group of diseases comprising Langerhans cell histiocytosis (LCH) diseases characterized by the abnormal accumulation of CD1⫹ histiocytes (Langerhans cells) in any organ. Langerhans cell proliferation can be *Division of Thoracic Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA. †Division of Cardiothoracic Imaging, Department of Radiology, University of Wisconsin-Madison, MC. Address reprint requests to Jeffrey P. Kanne, MD, Division of Cardiothoracic Imaging, Department of Radiology, University of Wisconsin-Madison, MC 3235, 600 Highland Ave., Madison, WI 53572. E-mail: jkanne@ uwhealth.org
0037-198X/10/$-see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1053/j.ro.2009.07.006
Figure 1 A 44-year-old male smoker with PLCH. HRCT image through the upper lungs shows multiple small nodules, many of which are poorly defined and bronchocentric.
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Figure 2 Transverse (A) and coronal (B) HRCT images of a 55-yearold male smoker with PLCH show scattered thin-wall cysts (arrows) in the upper lobes with a few scattered small nodules.
Figure 3 A 52-year-old female smoker with PLCH. HRCT image through the upper lungs shows numerous small cysts.
J.H. Chung and J.P. Kanne
Figure 4 Transverse (A) and coronal (B) HRCT images of a 48-yearold female smoker with PLCH show multiple cysts, some of which have irregular shapes, predominating in the upper lobes. Scattered small nodules are also present.
HRCT is accurate in both diagnosis and follow-up of PLCH. Small, poorly defined nodules (1-10 mm) are present early in the disease course15 (Fig. 1). The nodules tend to be centrilobular, reflecting a bronchiolocentric distribution of the disease. Nodules in PLCH may enlarge and cavitate, resulting in development of lung cysts (Figs. 2 and 3). With progression, these cysts can coalesce and develop irregular shapes (Fig. 4). In prolonged, severe disease, the large cysts may progress to diffuse emphysema with fibrobullous destruction of the lung2 (Fig. 5). The combination of nodules and cysts in the upper and mid lung zones with relative sparing of the costophrenic sulci is highly suggestive of PLCH.15 Less commonly, interlobular septal thickening, micronodules, and ground-glass opacities may be present (Fig. 6). The ground-glass opacities may represent a DIP-like reaction, related to smoking (see DIP discussion).2 Groundglass opacities and thick-walled cysts may regress after smoking cessation (Fig. 7); however, linear opacities, thin-walled cysts, and emphysema usually persist.7 Spontaneous and recurrent pneumothorax may also occur.
Smoking-related interstitial lung disease When considering all cases of PLCH, prognosis is good with smoking cessation. Five- and 10-year survival rates are 74.6% and 63.9%, respectively.16 However, a subset of patients has progressive disease despite smoking cessation. In patients who are severely symptomatic, corticosteroid therapy may be considered in combination with smoking cessation, although the effectiveness of corticosteroids for PLCH is controversial.4 Therapy with other immunosuppressive agents, such as methotrexate, cyclophosphamide, and vinblastine4,17 has been reported, but their effectiveness for treating PLCH remains unclear. Development of pulmonary hypertension portends a poor prognosis in PLCH.4 In end-stage fibrosis, lung transplant may be an option.18 Pneumothorax may require tube thoracostomy; pleurodesis is often required because of the high rate of recurrence.
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Figure 6 HRCT image of a 39-year-old female smoker with PLCH shows small thin-wall cysts (arrows). Additionally, patchy groundglass opacity present, more so on the right, likely a manifestation of a DIP-like reaction.
Respiratory Bronchiolitis and RB-ILD RB is an extremely common finding in smokers, originally described by Niewoehner in 1974,19 and, by definition, patients are asymptomatic. Histologically, alveolar macrophages accumulate in the respiratory bronchioles. Interstitial inflammation is limited primarily to the respiratory bronchi-
Figure 5 A 59-year-old man with end-stage PLCH. HRCT images (A, B) demonstrate diffuse emphysema in both lungs. The patient ultimately underwent lung transplant.
Figure 7 HRCT image of a 53-year-old male smoker with PLCH (A) demonstrates diffuse ground-glass opacity, scattered small poorly defined lung nodules. Paraseptal emphysema is also present. HRCT image 1 year later after smoking cessation (B) shows resolution of nodules and ground-glass opacity. Paraseptal emphysema is unchanged.
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oles with minimal involvement of adjacent airspaces. RB-ILD shares the same histologic features as RB. However, in contrast with RB, patients with RB-ILD demonstrate clinical and physiological abnormalities. RB-ILD occurs almost exclusively in smokers or former smokers.3 Only a small minority of smokers develop RB-ILD, suggesting that other factors may also play a role. Moreover, RB-ILD may occasionally develop even with limited cigarette exposure. RB-ILD has been reported to develop after exposure to solder fumes, fiber glass, and diesel smoke, although this occurrence is very uncommon.20,21 Patients with RB-ILD usually present in the fourth or fifth decade of life with mild chronic cough or dyspnea.20 An acute presentation is less common. Inspiratory crackles are present in about half of patients.3 A mixed obstructiverestrictive pattern (though mostly restrictive) with decreased diffusion capacity is typical on pulmonary function tests.22 However, a substantial number of patients may have normal pulmonary function tests (20% in 1 series).23 Interestingly, up to 10% of patients respond favorably to bronchodilator therapy.24 Chest radiographs are normal in up to 20%-30% of cases; however, in cases of overt clinical RB-ILD, diffuse or basilar reticular or nodular opacities are present in most patients.20,25 Lung volumes are generally preserved. RB is characterized on HRCT by small, poorly defined centrilobular nodules in the upper lobes (Fig. 8). HRCT findings of RB-ILD include minute, poorly defined centrilobular nodules often superimposed on a background of patchy ground-glass opacity (Fig. 9). The upper lung zones are more often and more extensively involved than the lower zones. Bronchial wall thickening is common.26 Scattered secondary pulmonary lobules may have decreased attenuation and attenuated pulmonary vessels, reflecting air trapping from small airways disease (Fig. 10). Smoking-related emphysema may be present in a centrilobular or paraseptal distribution, but is usually not the major finding.27 On occasion, mild subpleural reticulation may be present, indicating interstitial fibrosis. The HRCT findings of RB-ILD are similar to those of subacute hypersen-
Figure 9 A 50-year-old male smoker with RB-ILD. Transverse (A, B) and coronal (C) HRCT images demonstrate diffuse ground-glass opacity with some lobular sparing in the lower lung zones. Mild paraseptal emphysema is also present (arrowheads).
Figure 8 A 47-year-old asymptomatic female smoker with RB. HRCT image through the upper lobes shows numerous small, poorly defined centrilobular nodules.
sitivity pneumonitis, although clinical history is often adequate to distinguish these 2 entities. Moreover, cigarette smoking may be somewhat protective against developing hypersensitivity pneumonitis.28 Prognosis is believed to be relatively good after smoking cessation with or without steroid administration.3,24,26,29 One study estimated that ⬎75% of patients survived for ⬎7 years after diagnosis.24 In mild disease, smoking cessation may result in radiographic and clinical improvement.24,30 How-
Smoking-related interstitial lung disease
33 Most but not all cases of DIP are related to smoking.31 DIP or DIP-like histology has also been associated with PLCH, dust inhalation, drug reaction, usual interstitial pneumonia, nonspecific interstitial pneumonia, collagen vascular disease, and infection.27,32,33 Patients commonly present with dyspnea or nonproductive cough in the fourth and fifth decades of life (Fig. 11).12 As in RB-ILD, chest auscultation usually reveals crackles. Clubbing of digits may be present in up to half of patients.23 Pulmonary function tests are often abnormal and may show restrictive, obstructive, mixed, or nonspecific patterns.5 Radiographic features of DIP include reticular or nodular opacities with a basal predominance.2,15 However, patients with active DIP may have normal chest radiographs.7 On HRCT, ground-glass opacity is typically present in the periphery and bases of the lungs, although this distribution is not always present.2,34 Mild reticulation may be present within basal foci of ground-glass opacity. Honeycombing is unusual and indicates advanced disease.27 Small, well-defined cysts may develop in areas of ground-glass opacity34
Figure 10 A 47-year-old female smoker with RB-ILD. HRCT image through the upper lungs (A) shows diffuse poorly defined centrilobular nodules similar but more profuse than those in Figure 8. HRCT image more caudad (B) demonstrates extensive ground-glass opacity with sparing some secondary lobules.
ever, a significant percentage of patients may not improve even with smoking cessation. In 1 series, 25% of patients had little symptomatic improvement despite smoking cessation; in fact, a larger proportion of patients had subjective worsening of their symptoms (44%).24 Similarly, although smoking cessation often results in normalization of histology in patients with RB, pathologic abnormalities in those with RBILD usually persist.21 Corticosteroids are often administered in cases of moderate or severe respiratory impairment though their effectiveness in RB-ILD is questionable.4
DIP DIP is a very rare interstitial pneumonia, which shares a similar histopathology to RB-ILD. In fact, some investigators propose that these 2 entities represent different spectrums of the same pathologic process. On histopathology, the cardinal feature of DIP is diffuse acinar collections of pigmented intraalveolar macrophages, which contrast with the bronchocentric distribution of macrophages in RB-ILD.31 Interstitial fibrosis, lymphoid follicles, and eosinophilic infiltration are also more common in DIP than in RB-ILD.31 Nevertheless, pathologists often struggle differentiating these 2 entities.15
Figure 11 A 55-year-old female smoker with DIP. Transverse (A) and coronal (B) HRCT images show patchy, ground-glass opacity with a basal and peribronchial predominance.
J.H. Chung and J.P. Kanne
34 (Fig. 12). The nature of these cysts is unknown, but they may represent dilation of small airways or mild centrilobular emphysema.2 Prognosis is generally good, with a considerably better outcome than in idiopathic pulmonary fibrosis. Survival at 10 years is approximately 70%.35 However, evidence suggests that DIP may have a worse prognosis than RB-ILD.25 In addition, with continual smoking, DIP tends to progress.23 Standard therapy, as in RB-ILD, includes smoking cessation and corticosteroids.
AEP AEP is a severe acute febrile illness; patients are usually very dyspneic and hypoxemic. AEP is more common in younger adults, although patients of any age can be affected.36 Acutely, abundant eosinophils are present on bronchoalveolar lavage in the absence of blood eosinophilia. Histologically, diffuse alveolar damage develops in association with tissue eosinophilia. Although the pathogenesis of AEP is unknown, helper T-cell (Th2) activation may play a role.37 Most cases of AEP are idiopathic. However, AEP associated with infection, drug reaction, toxin exposure, and cigarette smoking have been reported.4 The link between cigarette smoking and AEP is
Figure 13 A 19-year-old female smoker with AEP. HRCT image of the right lung shows septal thickening (arrowheads), ground-glass opacity, and nodular consolidation (arrows). (Courtesy of Dr Kiminori Fujimoto, Department of Radiology Kurume University School of Medicine, Kurume, Japan.) (Reprinted with permission.15)
less clear than between smoking and PLCH, RB-ILD, and DIP. However, multiple case reports and small case series from Japan suggest some link between smoking and AEP.38-41 One recent case series of US military personnel demonstrated a strong relationship between cigarette smoking and the development of AEP.42 All patients in this series were smokers. Furthermore, 14 of the 18 afflicted had recently started smoking. AEP mimics pulmonary edema on chest radiographs. Reticular opacities and interlobular septal thickening are present early in the disease process. Lower-lung predominant airspace consolidation may develop with disease progression, and most patients have small bilateral pleural effusions.43 On HRCT, patchy ground-glass opacity, smooth interlobular septal thickening, and pleural effusions are common (Fig. 13). Lung consolidation may develop as the disease evolves.44,45 Spontaneous resolution of AEP is uncommon. Most patients with AEP require respiratory support or mechanical ventilation.46 Rapid response after corticosteroid administration is typical, with clinical improvement occurring within hours or a couple of days. Prognosis is excellent, and most patients recover completely or with only mild residual dyspnea.36 Relapse after corticosteroid therapy is extremely rare.
Conclusion Figure 12 A 60-year-old male smoker with DIP. HRCT images (A, B) show basal predominant ground-glass opacity, mild reticulation, and a few scattered cysts (arrows). There is mild paraseptal emphysema.
Smoking has long been associated with chronic obstructive pulmonary disease, bronchogenic carcinoma, and ischemic heart disease. There are now ample data suggesting a strong association between smoking and PLCH, RB-ILD, and DIP.
Smoking-related interstitial lung disease Although not as definitive, smoking may also be associated with AEP. Correlation of HRCT findings and clinical presentation in smoking-related interstitial lung disease may preclude the need for histologic diagnosis. Additionally, HRCT is a useful tool to assess the response to smoking cessation— the primary treatment for these diseases.
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24. 25.
26.
References 1. Mokdad A, Marks J, Stroup D, et al: Actual causes of death in the United States, 2000. J Am Med Assoc 291:1238-1245, 2004 2. Hansell D, Nicholson A: Smoking-related diffuse parenchymal lung disease: HRCT-pathologic correlation. Semin Respir Crit Care Med 24:377-392, 2003 3. Ryu J, Colby T, Hartman T, et al: Smoking-related interstitial lung diseases: a concise review. Eur Respir J 17:122-132, 2001 4. Patel R, Ryu J, Vassallo R: Cigarette smoking and diffuse lung disease. Drugs 68:1511-1527, 2008 5. Vassallo R, Ryu J: Tobacco smoke-related diffuse lung diseases. Semin Respir Crit Care Med 29:643-650, 2008 6. Baumgartner K, Samet J, Stidley C, et al: Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 155:242248, 1997 7. Desai S, Ryan S, Colby T: Smoking-related interstitial lung diseases: histopathological and imaging perspectives. Clin Radiol 58:259-268, 2003 8. Caminati A, Harari S: Smoking-related interstitial pneumonias and pulmonary Langerhans cell histiocytosis. Proc Am Thorac Soc 3:299-306, 2006 9. Howarth D, Gilchrist G, Mullan B, et al: Langerhans cell histiocytosis: diagnosis, natural history, management, and outcome. Cancer 85:22782290, 1999 10. Tazi A: Adult pulmonary Langerhans’ cell histiocytosis. Eur Respir J 27:1272-1285, 2006 11. Travis W, Borok Z, Roum J, et al: Pulmonary Langerhans cell granulomatosis (histiocytosis X). A clinicopathologic study of 48 cases. Am J Surg Pathol 17:971-986, 1993 12. Hidalgo A, Franquet T, Giménez A, et al: Smoking-related interstitial lung diseases: radiologic-pathologic correlation. Eur Radiol 16:24632470, 2006 13. Flaherty K, Martinez F: Cigarette smoking in interstitial lung disease: concepts for the internist. Med Clin North Am 88:1643-1653:xiii, 2004 14. Lacronique J: [Smoking. Epidemiology and pathology related to tobacco.] Rev Prat 44:2781-2783, 1994 15. Kanne J, Bilawich A, Lee C, et al: Smoking-related emphysema and interstitial lung diseases. J Thorac Imaging 22:286-291, 2007 16. Chaowalit N, Pellikka P, Decker P, et al: Echocardiographic and clinical characteristics of pulmonary hypertension complicating pulmonary Langerhans cell histiocytosis. Mayo Clin Proc 79:1269-1275, 2004 17. Vassallo R, Ryu J: Pulmonary Langerhans’ cell histiocytosis. Clin Chest Med 25:561-571:vii, 2004 18. Dauriat G, Mal H, Thabut G, et al: Lung transplantation for pulmonary Langerhans’ cell histiocytosis: a multicenter analysis. Transplantation 81:746-750, 2006 19. Niewoehner D, Kleinerman J, Rice D: Pathologic changes in the peripheral airways of young cigarette smokers. N Engl J Med 291:755-758, 1974 20. Moon J, du Bois R, Colby T, 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 21. Fraig M, Shreesha U, Savici D, et al: Respiratory bronchiolitis: a clinicopathologic study in current smokers, ex-smokers, and never-smokers. Am J Surg Pathol 26:647-653, 2002 22. Davies G, Wells A, du Bois R: Respiratory bronchiolitis associated with interstitial lung disease and desquamative interstitial pneumonia. Clin Chest Med 25:717-726:vi, 2004 23. Ryu J, Myers J, Capizzi S, et al: Desquamative interstitial pneumonia
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and respiratory bronchiolitis-associated interstitial lung disease. Chest 127:178-184, 2005 Portnoy J, Veraldi K, Schwarz M, et al: Respiratory bronchiolitis-interstitial lung disease: long-term outcome. Chest 131:664-671, 2007 Yousem S, Colby T, Gaensler E: Respiratory bronchiolitis-associated interstitial lung disease and its relationship to desquamative interstitial pneumonia. Mayo Clin Proc 64:1373-1380, 1989 Park J, Brown K, Tuder R, et al: Respiratory bronchiolitis-associated interstitial lung disease: radiologic features with clinical and pathologic correlation. J Comput Assist Tomogr 26:13-20, 2002 Mueller-Mang C, Grosse C, Schmid K, et al: What every radiologist should know about idiopathic interstitial pneumonias. Radiographics 27:595-615, 2007 Blanchet M, Israël-Assayag E, Cormier Y: Inhibitory effect of nicotine on experimental hypersensitivity pneumonitis in vivo and in vitro. Am J Respir Crit Care Med 169:903-909, 2004 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 Wells A, Nicholson A, Hansell D, et al: Respiratory bronchiolitis-associated interstitial lung disease. Semin Respir Crit Care Med 24:585-594, 2003 Craig P, Wells A, Doffman S, et al: Desquamative interstitial pneumonia, respiratory bronchiolitis and their relationship to smoking. Histopathology 45:275-282, 2004 Vassallo R, Jensen E, Colby T, 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 Kern D, Kuhn Cr, Ely E, et al: Flock worker’s lung: broadening the spectrum of clinicopathology, narrowing the spectrum of suspected etiologies. Chest 117:251-259, 2000 Akira M, Yamamoto S, Hara H, et al: Serial computed tomographic evaluation in desquamative interstitial pneumonia. Thorax 52:333-337, 1997 Carrington C, Gaensler E, Coutu R, et al: Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med 298:801-809, 1978 Allen J: Acute eosinophilic pneumonia. Semin Respir Crit Care Med 27:142-147, 2006 Takizawa H: Acute eosinophilic pneumonia: possible role of hyperreactivity of airway epithelial cells. Intern Med 41:917, 2002 Shiota Y, Kawai T, Matsumoto H, et al: Acute eosinophilic pneumonia following cigarette smoking. Intern Med 39:830-833, 2000 Nakamura H, Kashiwabara K, Narushima K, et al: [Bilateral hilar and mediastinal lymphadenopathy accompanying pulmonary infiltration with eosinophilia]. Nihon Kyobu Shikkan Gakkai Zasshi 35:447-450, 1997 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 Miki K, Miki M, Nakamura Y, et al: Early-phase neutrophilia in cigarette smoke-induced acute eosinophilic pneumonia. Intern Med 42: 839-845, 2003 Shorr A, Scoville S, Cersovsky S, et al: Acute eosinophilic pneumonia among US military personnel deployed in or near Iraq. J Am Med Assoc 292:2997-3005, 2004 King M, Pope-Harman A, Allen J, et al: Acute eosinophilic pneumonia: radiologic and clinical features. Radiology 203:715-719, 1997 Johkoh T, Müller N, Akira M, et al: Eosinophilic lung diseases: diagnostic accuracy of thin-section CT in 111 patients. Radiology 216:773780, 2000 Cheon J, Lee K, Jung G, et al: Acute eosinophilic pneumonia: radiographic and CT findings in six patients. AJR Am J Roentgenol 167: 1195-1199, 1996 Philit F, Etienne-Mastroïanni B, Parrot A, et al: Idiopathic acute eosinophilic pneumonia: a study of 22 patients. Am J Respir Crit Care Med 166:1235-1239, 2002
C
igarette smoke contains a mixture of over 4000 chemicals, many of which are toxic. Smoking-related illnesses are the leading cause of preventable deaths in the United States accounting of 440,000 deaths per year (nearly onefifth of total annual deaths).1 The most common smokingrelated illnesses include chronic obstructive pulmonary disease, bronchogenic carcinoma, and ischemic heart disease. However, the role of cigarette smoking in the pathogenesis of interstitial lung diseases is becoming increasingly apparent. The relationship between cigarette smoking and pulmonary Langerhans cell histiocytosis (PLCH), respiratory bronchiolitis (RB), respiratory bronchiolitis–associated interstitial lung disease (RB-ILD), and desquamative interstitial pneumonia (DIP) is well described.2-5 Data suggesting an association between cigarette smoking and acute eosinophilic pneumonia (AEP) are emerging. The relationship between cigarette smoking and idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia remains uncertain.6,7 Given how common smoking is and how uncommon these conditions are, other unknown factors presumably play a role in the pathogenesis of smoking-related interstitial lung disease.5 Patients afflicted with smoking-related interstitial lung disease tend to be younger with fewer comorbidities; hence, early diagnosis and treatment (primarily with smoking cessation) are paramount.5 This article discusses the clinical and histopathologic features of PLCH, RB, RB-ILD, DIP, and AEP and illustrates their respective imaging appearances, focusing primarily on highresolution computed tomography (HRCT).
monoclonal or polyclonal. PLCH, the term used when LCH is limited to the lungs, occurs almost exclusively in smokers.8,9 Initially, a very strong male predominance was reported. However, more recent studies demonstrate no definite sex predilection, which may reflect recent changes in smoking habits.10 The exact mechanism by which cigarette smoking leads to the development of PLCH has yet to be elucidated. However, the low incidence of PLCH relative to the high prevalence of smoking implies that host-related factors predispose patients to developing PLCH.10 Patients most often present with nonspecific cough or dyspnea, which are often attributed to smoking. Hence, a delay in diagnosis is common.10 Patients may also be asymptomatic in up to a quarter of cases.11 A small minority of patients may present with spontaneous pneumothorax.12 Physical examination is usually noncontributory except in cases of the pneumothorax. Definitive diagnosis is made by transbronchial or surgical lung biopsy. However, tissue diagnosis is often unnecessary in a smoker with characteristic findings on HRCT. Chest radiographs are abnormal in most patients with PLCH.13 The most common findings are reticular opacities, nodules, and cysts.14 Relative sparing of the lower lung zones and costophrenic sulci is typical. Lung volumes are usually normal or may be increased. Less common radiographic manifestations of PLCH include pleural effusions, hilar lymphadenopathy, and pneumothorax.7
PLCH PLCH belongs to the group of diseases comprising Langerhans cell histiocytosis (LCH) diseases characterized by the abnormal accumulation of CD1⫹ histiocytes (Langerhans cells) in any organ. Langerhans cell proliferation can be *Division of Thoracic Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA. †Division of Cardiothoracic Imaging, Department of Radiology, University of Wisconsin-Madison, MC. Address reprint requests to Jeffrey P. Kanne, MD, Division of Cardiothoracic Imaging, Department of Radiology, University of Wisconsin-Madison, MC 3235, 600 Highland Ave., Madison, WI 53572. E-mail: jkanne@ uwhealth.org
0037-198X/10/$-see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1053/j.ro.2009.07.006
Figure 1 A 44-year-old male smoker with PLCH. HRCT image through the upper lungs shows multiple small nodules, many of which are poorly defined and bronchocentric.
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Figure 2 Transverse (A) and coronal (B) HRCT images of a 55-yearold male smoker with PLCH show scattered thin-wall cysts (arrows) in the upper lobes with a few scattered small nodules.
Figure 3 A 52-year-old female smoker with PLCH. HRCT image through the upper lungs shows numerous small cysts.
J.H. Chung and J.P. Kanne
Figure 4 Transverse (A) and coronal (B) HRCT images of a 48-yearold female smoker with PLCH show multiple cysts, some of which have irregular shapes, predominating in the upper lobes. Scattered small nodules are also present.
HRCT is accurate in both diagnosis and follow-up of PLCH. Small, poorly defined nodules (1-10 mm) are present early in the disease course15 (Fig. 1). The nodules tend to be centrilobular, reflecting a bronchiolocentric distribution of the disease. Nodules in PLCH may enlarge and cavitate, resulting in development of lung cysts (Figs. 2 and 3). With progression, these cysts can coalesce and develop irregular shapes (Fig. 4). In prolonged, severe disease, the large cysts may progress to diffuse emphysema with fibrobullous destruction of the lung2 (Fig. 5). The combination of nodules and cysts in the upper and mid lung zones with relative sparing of the costophrenic sulci is highly suggestive of PLCH.15 Less commonly, interlobular septal thickening, micronodules, and ground-glass opacities may be present (Fig. 6). The ground-glass opacities may represent a DIP-like reaction, related to smoking (see DIP discussion).2 Groundglass opacities and thick-walled cysts may regress after smoking cessation (Fig. 7); however, linear opacities, thin-walled cysts, and emphysema usually persist.7 Spontaneous and recurrent pneumothorax may also occur.
Smoking-related interstitial lung disease When considering all cases of PLCH, prognosis is good with smoking cessation. Five- and 10-year survival rates are 74.6% and 63.9%, respectively.16 However, a subset of patients has progressive disease despite smoking cessation. In patients who are severely symptomatic, corticosteroid therapy may be considered in combination with smoking cessation, although the effectiveness of corticosteroids for PLCH is controversial.4 Therapy with other immunosuppressive agents, such as methotrexate, cyclophosphamide, and vinblastine4,17 has been reported, but their effectiveness for treating PLCH remains unclear. Development of pulmonary hypertension portends a poor prognosis in PLCH.4 In end-stage fibrosis, lung transplant may be an option.18 Pneumothorax may require tube thoracostomy; pleurodesis is often required because of the high rate of recurrence.
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Figure 6 HRCT image of a 39-year-old female smoker with PLCH shows small thin-wall cysts (arrows). Additionally, patchy groundglass opacity present, more so on the right, likely a manifestation of a DIP-like reaction.
Respiratory Bronchiolitis and RB-ILD RB is an extremely common finding in smokers, originally described by Niewoehner in 1974,19 and, by definition, patients are asymptomatic. Histologically, alveolar macrophages accumulate in the respiratory bronchioles. Interstitial inflammation is limited primarily to the respiratory bronchi-
Figure 5 A 59-year-old man with end-stage PLCH. HRCT images (A, B) demonstrate diffuse emphysema in both lungs. The patient ultimately underwent lung transplant.
Figure 7 HRCT image of a 53-year-old male smoker with PLCH (A) demonstrates diffuse ground-glass opacity, scattered small poorly defined lung nodules. Paraseptal emphysema is also present. HRCT image 1 year later after smoking cessation (B) shows resolution of nodules and ground-glass opacity. Paraseptal emphysema is unchanged.
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oles with minimal involvement of adjacent airspaces. RB-ILD shares the same histologic features as RB. However, in contrast with RB, patients with RB-ILD demonstrate clinical and physiological abnormalities. RB-ILD occurs almost exclusively in smokers or former smokers.3 Only a small minority of smokers develop RB-ILD, suggesting that other factors may also play a role. Moreover, RB-ILD may occasionally develop even with limited cigarette exposure. RB-ILD has been reported to develop after exposure to solder fumes, fiber glass, and diesel smoke, although this occurrence is very uncommon.20,21 Patients with RB-ILD usually present in the fourth or fifth decade of life with mild chronic cough or dyspnea.20 An acute presentation is less common. Inspiratory crackles are present in about half of patients.3 A mixed obstructiverestrictive pattern (though mostly restrictive) with decreased diffusion capacity is typical on pulmonary function tests.22 However, a substantial number of patients may have normal pulmonary function tests (20% in 1 series).23 Interestingly, up to 10% of patients respond favorably to bronchodilator therapy.24 Chest radiographs are normal in up to 20%-30% of cases; however, in cases of overt clinical RB-ILD, diffuse or basilar reticular or nodular opacities are present in most patients.20,25 Lung volumes are generally preserved. RB is characterized on HRCT by small, poorly defined centrilobular nodules in the upper lobes (Fig. 8). HRCT findings of RB-ILD include minute, poorly defined centrilobular nodules often superimposed on a background of patchy ground-glass opacity (Fig. 9). The upper lung zones are more often and more extensively involved than the lower zones. Bronchial wall thickening is common.26 Scattered secondary pulmonary lobules may have decreased attenuation and attenuated pulmonary vessels, reflecting air trapping from small airways disease (Fig. 10). Smoking-related emphysema may be present in a centrilobular or paraseptal distribution, but is usually not the major finding.27 On occasion, mild subpleural reticulation may be present, indicating interstitial fibrosis. The HRCT findings of RB-ILD are similar to those of subacute hypersen-
Figure 9 A 50-year-old male smoker with RB-ILD. Transverse (A, B) and coronal (C) HRCT images demonstrate diffuse ground-glass opacity with some lobular sparing in the lower lung zones. Mild paraseptal emphysema is also present (arrowheads).
Figure 8 A 47-year-old asymptomatic female smoker with RB. HRCT image through the upper lobes shows numerous small, poorly defined centrilobular nodules.
sitivity pneumonitis, although clinical history is often adequate to distinguish these 2 entities. Moreover, cigarette smoking may be somewhat protective against developing hypersensitivity pneumonitis.28 Prognosis is believed to be relatively good after smoking cessation with or without steroid administration.3,24,26,29 One study estimated that ⬎75% of patients survived for ⬎7 years after diagnosis.24 In mild disease, smoking cessation may result in radiographic and clinical improvement.24,30 How-
Smoking-related interstitial lung disease
33 Most but not all cases of DIP are related to smoking.31 DIP or DIP-like histology has also been associated with PLCH, dust inhalation, drug reaction, usual interstitial pneumonia, nonspecific interstitial pneumonia, collagen vascular disease, and infection.27,32,33 Patients commonly present with dyspnea or nonproductive cough in the fourth and fifth decades of life (Fig. 11).12 As in RB-ILD, chest auscultation usually reveals crackles. Clubbing of digits may be present in up to half of patients.23 Pulmonary function tests are often abnormal and may show restrictive, obstructive, mixed, or nonspecific patterns.5 Radiographic features of DIP include reticular or nodular opacities with a basal predominance.2,15 However, patients with active DIP may have normal chest radiographs.7 On HRCT, ground-glass opacity is typically present in the periphery and bases of the lungs, although this distribution is not always present.2,34 Mild reticulation may be present within basal foci of ground-glass opacity. Honeycombing is unusual and indicates advanced disease.27 Small, well-defined cysts may develop in areas of ground-glass opacity34
Figure 10 A 47-year-old female smoker with RB-ILD. HRCT image through the upper lungs (A) shows diffuse poorly defined centrilobular nodules similar but more profuse than those in Figure 8. HRCT image more caudad (B) demonstrates extensive ground-glass opacity with sparing some secondary lobules.
ever, a significant percentage of patients may not improve even with smoking cessation. In 1 series, 25% of patients had little symptomatic improvement despite smoking cessation; in fact, a larger proportion of patients had subjective worsening of their symptoms (44%).24 Similarly, although smoking cessation often results in normalization of histology in patients with RB, pathologic abnormalities in those with RBILD usually persist.21 Corticosteroids are often administered in cases of moderate or severe respiratory impairment though their effectiveness in RB-ILD is questionable.4
DIP DIP is a very rare interstitial pneumonia, which shares a similar histopathology to RB-ILD. In fact, some investigators propose that these 2 entities represent different spectrums of the same pathologic process. On histopathology, the cardinal feature of DIP is diffuse acinar collections of pigmented intraalveolar macrophages, which contrast with the bronchocentric distribution of macrophages in RB-ILD.31 Interstitial fibrosis, lymphoid follicles, and eosinophilic infiltration are also more common in DIP than in RB-ILD.31 Nevertheless, pathologists often struggle differentiating these 2 entities.15
Figure 11 A 55-year-old female smoker with DIP. Transverse (A) and coronal (B) HRCT images show patchy, ground-glass opacity with a basal and peribronchial predominance.
J.H. Chung and J.P. Kanne
34 (Fig. 12). The nature of these cysts is unknown, but they may represent dilation of small airways or mild centrilobular emphysema.2 Prognosis is generally good, with a considerably better outcome than in idiopathic pulmonary fibrosis. Survival at 10 years is approximately 70%.35 However, evidence suggests that DIP may have a worse prognosis than RB-ILD.25 In addition, with continual smoking, DIP tends to progress.23 Standard therapy, as in RB-ILD, includes smoking cessation and corticosteroids.
AEP AEP is a severe acute febrile illness; patients are usually very dyspneic and hypoxemic. AEP is more common in younger adults, although patients of any age can be affected.36 Acutely, abundant eosinophils are present on bronchoalveolar lavage in the absence of blood eosinophilia. Histologically, diffuse alveolar damage develops in association with tissue eosinophilia. Although the pathogenesis of AEP is unknown, helper T-cell (Th2) activation may play a role.37 Most cases of AEP are idiopathic. However, AEP associated with infection, drug reaction, toxin exposure, and cigarette smoking have been reported.4 The link between cigarette smoking and AEP is
Figure 13 A 19-year-old female smoker with AEP. HRCT image of the right lung shows septal thickening (arrowheads), ground-glass opacity, and nodular consolidation (arrows). (Courtesy of Dr Kiminori Fujimoto, Department of Radiology Kurume University School of Medicine, Kurume, Japan.) (Reprinted with permission.15)
less clear than between smoking and PLCH, RB-ILD, and DIP. However, multiple case reports and small case series from Japan suggest some link between smoking and AEP.38-41 One recent case series of US military personnel demonstrated a strong relationship between cigarette smoking and the development of AEP.42 All patients in this series were smokers. Furthermore, 14 of the 18 afflicted had recently started smoking. AEP mimics pulmonary edema on chest radiographs. Reticular opacities and interlobular septal thickening are present early in the disease process. Lower-lung predominant airspace consolidation may develop with disease progression, and most patients have small bilateral pleural effusions.43 On HRCT, patchy ground-glass opacity, smooth interlobular septal thickening, and pleural effusions are common (Fig. 13). Lung consolidation may develop as the disease evolves.44,45 Spontaneous resolution of AEP is uncommon. Most patients with AEP require respiratory support or mechanical ventilation.46 Rapid response after corticosteroid administration is typical, with clinical improvement occurring within hours or a couple of days. Prognosis is excellent, and most patients recover completely or with only mild residual dyspnea.36 Relapse after corticosteroid therapy is extremely rare.
Conclusion Figure 12 A 60-year-old male smoker with DIP. HRCT images (A, B) show basal predominant ground-glass opacity, mild reticulation, and a few scattered cysts (arrows). There is mild paraseptal emphysema.
Smoking has long been associated with chronic obstructive pulmonary disease, bronchogenic carcinoma, and ischemic heart disease. There are now ample data suggesting a strong association between smoking and PLCH, RB-ILD, and DIP.
Smoking-related interstitial lung disease Although not as definitive, smoking may also be associated with AEP. Correlation of HRCT findings and clinical presentation in smoking-related interstitial lung disease may preclude the need for histologic diagnosis. Additionally, HRCT is a useful tool to assess the response to smoking cessation— the primary treatment for these diseases.
35
24. 25.
26.
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