Seminars in Roentgenology
Volume 45, Issue 1 , Pages 29-35, January 2010

Smoking-Related Interstitial Lung Diseases

  • Jonathan H. Chung, MD

      Affiliations

    • Division of Thoracic Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA
    • ,
  • Jeffrey P. Kanne, MD

      Affiliations

    • Division of Cardiothoracic Imaging, Department of Radiology, University of Wisconsin-Madison, MC
    • Corresponding Author InformationAddress 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

Article Outline

 

Cigarette 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 one-fifth of total annual deaths).1 The most common smoking-related 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, 3, 4, 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 high-resolution computed tomography (HRCT).

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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 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

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 (Figure 2, Figure 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 Ground-glass 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.

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  • Figure 2. 

    Transverse (A) and coronal (B) HRCT images of a 55-year-old male smoker with PLCH show scattered thin-wall cysts (arrows) in the upper lobes with a few scattered small nodules.

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  • Figure 4. 

    Transverse (A) and coronal (B) HRCT images of a 48-year-old female smoker with PLCH show multiple cysts, some of which have irregular shapes, predominating in the upper lobes. Scattered small nodules are also present.

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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 ground-glass opacity present, more so on the right, likely a manifestation of a DIP-like reaction.

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  • 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.

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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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 bronchioles 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 obstructive-restrictive 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 hypersensitivity pneumonitis, although clinical history is often adequate to distinguish these 2 entities. Moreover, cigarette smoking may be somewhat protective against developing hypersensitivity pneumonitis.28

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  • 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).

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  • 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.

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 However, 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 RB-ILD usually persist.21 Corticosteroids are often administered in cases of moderate or severe respiratory impairment though their effectiveness in RB-ILD is questionable.4

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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 intra-alveolar 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 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

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  • 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.

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 (Fig. 12). The nature of these cysts is unknown, but they may represent dilation of small airways or mild centrilobular emphysema.2

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  • 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.

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.

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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 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, 39, 40, 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

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  • 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)

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.

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Conclusion 

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. 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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PII: S0037-198X(09)00070-4

doi:10.1053/j.ro.2009.07.006

Seminars in Roentgenology
Volume 45, Issue 1 , Pages 29-35, January 2010

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