Chronic Hypersensitivity Pneumonitis and Pulmonary Sarcoidosis: Differentiation From Usual Interstitial Pneumonia Using High-Resolution Computed Tomography Yeon Joo Jeong, MD*, Kyung Soo Lee, MD†, Man Pyo Chung, MD‡, Joungho Han, MD§, Takeshi Johkoh, MD, PhD║, and Kazuya Ichikado, MD, PhD¶ The distinction of chronic hypersensitivity pneumonitis (HP) or advanced-stage sarcoidosis from idiopathic pulmonary fibrosis or usual interstitial pneumonia is important because each disease is managed differently and may have a different prognosis. The analyses of pattern and distribution of lung parenchymal abnormalities on high-resolution computed tomography scans help differentiate among the 3 diseases. In chronic HP, the presence of lobular areas of decreased attenuation and centrilobular small nodules and the absence of lower lung zone predominance are characteristically observed. In advanced-stage sarcoidosis, patchy areas of reticulation, traction bronchiectasis, architectural distortion, honeycomblike cysts, bullae, and paracicatricial emphysema are observed in the upper and middle lung zones. Lung bases are usually spared. In idiopathic pulmonary fibrosis or usual interstitial pneumonia, however, the presence of honeycombing with lower lung zone predominance and the absence of centrilobular small nodules are important findings that allow us to differentiate the disease from chronic HP or advanced-stage sarcoidosis. In the 3 diseases, most important prognosispredicting factor is the extent of fibrotic score (the extent of honeycombing and reticulation) calculated on high-resolution computed tomography scans or fibrosis estimated on chest radiographs. Semin Ultrasound CT MRI 35:47-58 C 2014 Elsevier Inc. All rights reserved.

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hronic diffuse interstitial lung diseases, such as chronic hypersensitivity pneumonitis (HP), advanced-stage

*Department of Radiology, Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, Pusan, Republic of Korea. †Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. ‡Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. §Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. ║Department of Radiology, Kinki Central Hospital Mutual Add Association of Public School Teachers, Itami, Japan. ¶Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan. Address reprint requests to Kyung Soo Lee, MD, Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul 135-710, Korea. E-mail: [email protected]

0887-2171/$-see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.sult.2013.10.006

sarcoidosis, or Langerhans cell histiocytosis, are often difficult to diagnose because the clinical and functional manifestations are nonspecific and frequently mimic those of idiopathic pulmonary fibrosis (IPF). High-resolution computed tomography (HRCT) can play an important role in the diagnosis of chronic HP or advanced-stage sarcoidosis.1,2 Chronic HP is characterized on HRCT by the presence of reticulation and traction bronchiectasis and bronchiolectasis owing to fibrosis superimposed on findings of acute or subacute HP. Advancedstage sarcoidosis is characterized on HRCT by the presence of honeycomblike cysts, bullae, broad and coarse septal bands, architectural distortion, volume loss, and traction bronchiectasis. These CT findings may mimic those of usual interstitial pneumonia (UIP). Furthermore, although HP and sarcoidosis can have distinctive histologic appearances, recent studies have shown that chronic HP and advanced-stage sarcoidosis can manifest histologic patterns of UIP.3 The distinction of chronic HP or advanced-stage sarcoidosis from IPF is important because each disease is managed differently and may show a different prognosis. Removal of 47

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48 any potential causative antigen is the most important factor in the management of HP, and corticosteroid treatment is often effective in patients with sarcoidosis.4,5 However, the treatment of IPF usually includes corticosteroids and often other immunosuppressive agents, without environmental intervention (ie, usually ineffective).6 The prognosis of IPF is usually poor with median survival length between 2.5 and 3.5 years, even though with vigorous treatment. This review focuses on the HRCT findings of chronic HP and advanced-stage sarcoidosis based on histologic findings and explores how they can be differentiated from UIP on HRCT. The utility of clinical, HRCT, and histopathologic findings in predicting the prognosis of patients is described.

Chronic Hypersensitivity Pneumonia Clinical Features HP is an immunologically mediated inflammation of the lung parenchyma and airways in response to repeated inhalation of organic antigens or low-molecular-weight inorganic molecules. The prevalence and incidence of HP in the general population are unknown and are influenced by various factors, such as disease definition and geographic conditions. HP occurs only in a susceptible host and is avoidable if the offending antigen is identified. Episodes of acute and subacute HP usually resolve after cessation of antigen exposure. Chronic HP is thought to develop slowly after unrecognized persistent or intermittent exposure to very low level of antigen during months or years without discrete episodes of acute respiratory symptoms. It is separated from subacute HP by the presence of fibrosis on radiologic and histologic examinations. Patients with chronic HP present with slowly progressive shortness of breath, persistent cough, or constitutional symptoms, such as fatigue, malaise, anorexia, and weight loss. Fever, myalgia, and acute dyspnea, seen in acute and subacute forms of HP, are rare. Because of nonspecific clinical symptoms and the lack of discrete attacks of antigen exposure, clinical suspicion is the most important step for the diagnosis of chronic HP. Detailed history taking is essential. Pulmonary function test demonstrates restrictive lung function with a reduction in the carbon monoxide diffusion capacity (DLco). History of environmental and occupational exposure to a known inciting antigen, positive serum precipitating antibodies against offending antigens, chest HRCT findings suggestive of HP, a lymphocytosis with low CD4þ-CD8þ lymphocyte ratio in bronchoalveolar lavage (BAL) fluid, and granulomatous inflammation, especially around the bronchioles, on lung biopsies can help to diagnose HP. Identification of causative antigen and removal from exposure is the best treatment option. A trial of corticosteroid therapy is usually recommended for patients with severe or progressive chronic HP. As chronic HP is characterized by the development of pulmonary fibrosis, it may cause severe irreversible and progressive

physiological impairment.7 Some patients may eventually develop severe chronic hypoxemia requiring continuous oxygen therapy. Therefore, the prognosis of chronic HP largely depends on the extent of irreversible permanent lung fibrosis at the time of diagnosis. The overall prognosis of chronic HP appears to be better than that of UIP.8

Histopathologic Diagnosis Although the pathogenesis of HP is uncertain, both type III and type IV immune reactions play an important role.9 Inhaled antigens are probably deposited predominantly on bronchiolar and alveolar epithelium, typically resulting in both alveolitis and bronchiolitis. Therefore, histologic appearance of HP is characterized by alveolar interstitial thickening by mononuclear cell infiltration, cellular bronchiolitis, and poorly formed granulomas in the peribronchial interstitium (Fig. 1). However, the histologic appearance of chronic HP is complicated.10 Repeated or long-term exposure can result in parenchymal interstitial fibrosis. Foci of interstitial inflammation may be seen between areas of fibrosis. Alveolar walls may be thickened by alveolar cell hyperplasia. Constrictive bronchiolitis may be present. The classic poorly formed granulomas are seen in less than 50% of patients with chronic HP. Honeycombing and thickening of pulmonary arterioles are seen in the advanced stage of chronic HP (Fig. 2). Therefore, histologic features of chronic HP comprise overlapping UIP-like pattern, a nonspecific interstitial pneumonia (NSIP)-like pattern, organizing pneumonia pattern, centrilobular fibrosis or bridging fibrosis (continuous fibrosis between the centrilobular and subpleural location) with or without granuloma.3 Ohtani et al11 analyzed the histologic and clinical characteristics of chronic bird fancier's lung in 26 patients. The NSIP pattern was found in 13 patients, 8 of them having fibrotic NSIP-like lesions; the UIP-like pattern in 11 patients; and organizing pneumonia in 2 patients. Therefore, the diagnosis of HP can be confirmed by visualization of increased numbers of lymphocytes in BAL fluid and by histologic findings on lung biopsy in the presence of a history of exposure and consistent clinical and radiologic findings.

HRCT Findings The radiologic findings of HP are influenced by the stage of the disease. The most characteristic features of HP (subacute HP) on HRCT are bilateral patchy areas of ground-glass opacity, poorly defined centrilobular nodules, and lobular areas of mosaic attenuation on inspiratory images and of air trapping on expiratory CT images (Fig. 1).12,13 Sometimes, thin-walled cysts can be seen in a small percentage of patients.14 At histologic examination, centrilobular nodules correspond to cellular bronchiolitis, noncaseating granulomas, and bronchiolocentric interstitial pneumonitis (Fig. 1).1 The lobular areas of mosaic attenuation and air trapping are presumed to be secondary to small airway obstruction owing to cellular bronchiolitis or, less commonly, constrictive bronchiolitis. Thin-walled cysts are presumed to result from bronchiolitis and bronchiolar obstruction.

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Figure 1 Subacute hypersensitivity pneumonitis (summer type) in a 59-year-old man. Lung window images of thin-section (1.5-mm section thickness) CT scans obtained at levels of aortic arch (A) and cardiac ventricle (B) show patchy and extensive areas of ground-glass opacity in both the lungs. Also note poorly formed centrilobular small nodules (arrows in A) and lobular areas of mosaic attenuation (open arrows in B). (C) High-magnification (hematoxylin-eosin staining, 100) photomicrograph of biopsy specimen demonstrates centrilobular alveolitis (arrows) around respiratory bronchioles with dense chronic inflammatory cell infiltration. (Color version of figure is available online.)

The radiologic findings of chronic HP are characterized by the presence of fibrosis, although evidence of active disease is often present. HRCT findings of chronic HP include intralobular interstitial thickening, irregular interlobular septal thickening, traction bronchiectasis, and honeycombing superimposed on findings of subacute HP12 (Fig. 2). Chronic HP may closely mimic UIP and fibrotic NSIP (Figs. 2 and 3). The HRCT features that best differentiated chronic HP from UIP and NSIP are the presence of lobular areas of mosaic attenuation and centrilobular small nodules and the lack of lower zone predominance (Fig. 3). Silva et al15 assessed the accuracy of thin-section CT in distinguishing chronic HP from IPF and NSIP. Lobular areas of mosaic attenuation were seen in 80% of patients with chronic HP, whereas they were seen in 43% with IPF and in 34% with NSIP. Centrilobular nodules were seen in 56% of patients with chronic HP, whereas they were seen in 15% with IPF and in 14% with NSIP. Thin-walled cysts were also seen more commonly in patients with chronic HP (39%) than in those with IPF or UIP (0%) or NSIP (12%). No significant difference was observed in the frequency of honeycombing in patients with chronic HP (64%) and IPF

or UIP (67%). However, patients with IPF or UIP were more likely to have basal predominance of honeycombing and fibrosis than were those with chronic HP. Reported mortality rates ranges from 10%-21% in studies of patients with farmer lung, whereas chronic pigeon fancier lung has demonstrated a 5-year mortality of 29% and a median survival of 11.2 years.16 In a recent study of patients with HP who have fibrosis at biopsy, the median survival time was 7.1 years.8 In regression analysis, only the presence of histopathologic honeycomb fibrosis (hazard ratio ¼ 2.9) and the degree of fibrosis at surgical lung biopsy (hazard ratio ¼ 2.2) increased the risk of mortality. Hanak et al17 correlated HRCT evidence of pulmonary fibrosis with survival in patients with HP and concluded that the presence as well as the extent of fibrosis on CT was associated with increased mortality.

Chronic Sarcoidosis Clinical Features Sarcoidosis is a multisystem granulomatous disease of unknown etiology. It may occur at any age, but the disease is

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Figure 2 Chronic hypersensitivity pneumonitis in a 52-year-old man. Lung window images of thin-section (1.5-mm section thickness) CT scans obtained at levels of right basal trunk (A) and lower lobar subsegmental bronchi (B) show patchy areas of pulmonary fibrosis with interlobular septal and intralobular interstitial thickening and traction bronchiectasis in the right lung. Also note centrilobular small nodules (arrows in A). (C) High-magnification (hematoxylin-eosin staining, 100) photomicrograph of biopsy specimen demonstrates dense interstitial fibrosis with chronic inflammatory cell infiltration around distal airways (arrows). Also note large area of the normal lung (open arrows). Combination of fibrotic lesions and normal lung simulates usual interstitial pneumonia. (D) High-magnification (hematoxylin-eosin staining, 400) photomicrograph discloses small granuloma in interstitium adjacent to respiratory bronchiole. No necrosis is seen within granuloma. (Color version of figure is available online.)

recognized most commonly in patients between the ages of 20 and 40 years and is slightly more common in women. Thoracic involvement occurs in more than 90% of patients with sarcoidosis. It is characterized by a variable clinical presentation and course, ranging from an asymptomatic chest radiographic abnormality to severe onset of symptoms with spontaneous resolution and chronic progressive organ dysfunction. A severe variant of sarcoidosis (Löfgren syndrome), which presents with fever, erythema nodosum, and arthralgia with bilateral hilar lymphadenopathy, is more likely to resolve spontaneously. Up to one-third of patients with sarcoidosis develop chronic persistent or progressive disease.5 Chronic sarcoidosis is a

persistent or recurrent disease after treatment, without showing a spontaneous improvement. Insidious onset of disease is common in chronic sarcoidosis. Nonspecific constitutional symptoms, including fatigue, fever, anorexia, and weight loss, may be found. Organ-specific symptoms and signs are seen. The presence of skin lesion over the nose, cheeks, and ears (lupus pernio), and multiorgan involvement at the time of diagnosis are more common in chronic sarcoidosis. Pulmonary infiltrate and fibrosis, bone involvement, nephrocalcinosis, and pulmonary hypertension are also common. BAL shows lymphocytosis with increased CD4þ-CD8þ ratio. Most patients have restrictive lung

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Figure 3 Chronic hypersensitivity pneumonitis (bird breeder lung) in a 64-year-old man. (A) Lung window image of thinsection (1.5-mm section thickness) CT scan obtained at level of intrathoracic distal trachea shows patchy areas of subpleural ground-glass opacity in both the lungs. Also note poorly formed centrilobular small nodules (arrows). (B) CT scan obtained at level of bronchus intermedius demonstrates lobular areas of mosaic attenuation (open arrows) and subpleural groundglass opacity areas as well in both lungs. (C) CT scan obtained at level of liver dome shows patchy areas of subpleural ground-glass opacity and reticulation in both the lungs.

abnormalities with decreased DLco. Diagnosis of sarcoidosis is based on a compatible clinical or radiographic picture as well as histologic demonstration of noncaseating granulomas. In addition, exclusion of other granulomatous disease, such as HP, tuberculosis, and fungal infection, is required. Corticosteroids are the mainstay of treatment for sarcoidosis. As chronic granulomatous inflammation leads to significant functional impairment of the affected organ, patients with sarcoidosis often require long-term administration of systemic corticosteroids. Prolonged treatment with modest doses of corticosteroids inevitably results in disabling side effects. Therefore, treatment is usually limited to the symptomatic patients with progressive functional derangement of the lung and liver.18 It is also indicated to those involving vital organs, such as the heart and brain. Steroid-sparing agents often are administered. Less than 5% of patients die of sarcoidosis. Main causes of death are cardiac or brain involvement and respiratory failure due to pulmonary fibrosis.19

Histopathologic Diagnosis The pathologic hallmark of sarcoidosis is noncaseating granulomas composed of clusters of epithelioid histiocytes and multinucleated giant cells surrounded by lymphocytes20 (Fig. 4). Necrosis of granulomas is usually minimal in amount or may present in a minority of granulomas. Although the granulomatous inflammation may resolve completely, some residual fibrosis is common. Fibrotic changes usually begin at the periphery of a granuloma and extend centrally, leading to complete fibrosis, hyalinization, or both. Granulomatous inflammation in the lung parenchyma has a characteristic distribution in relation to lymphatics in the peribronchovascular interstitial space, subpleural interstitial space, and interlobular septa (Fig. 4). In early stages, granulomas in these sites are discrete, but as the disease progresses, they often become confluent and are associated with fibrous tissue. The upper lobes of the lungs are most severely affected. Rarely, parenchymal disease is more extensive, in which case individual granulomas can conglomerate with each other and

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Figure 4 Pulmonary sarcoidosis and Sjögren syndrome in a 57-year-old woman. (A) Lung window image of thin-section (2.5-mm section thickness) CT scan obtained at level of liver dome shows diffuse ground-glass opacity and nodular thickening (arrows) of interlobular septa in both the lungs. (B) Low-magnification (hematoxylin-eosin staining, 10) photomicrograph of biopsy specimen demonstrates noncaseating granulomas distributed along pleura, bronchovascular bundles, alveolar walls, and interlobular septa (arrows) as well. (C) High-magnification photomicrograph (hematoxylineosin staining, 100) discloses noncaseating granulomas located around terminal bronchioles and their accompanying arterioles. (Color version of figure is available online.)

with granulomas in the peribronchovascular and septal interstitium to form relatively discrete masses several centimeters or more in diameter (“nodular sarcoidosis”) (Fig. 5). Fibrosis in such areas may be associated with traction bronchiectasis, which sometimes results in the formation of cavities.

HRCT Findings The most common, typical parenchymal manifestation of pulmonary sarcoidosis seen on HRCT scan is small nodules with a perilymphatic distribution. HRCT shows sharply defined, small (2-4 mm in diameter), rounded nodules, usually with a bilateral and symmetric distribution.2 The nodules are most numerous along the bronchovascular bundles (connective tissue sheath around the pulmonary vessels and airways) and adjacent to the costal pleura (subpleural lung and visceral pleural involvement) and

interlobar fissures. They are also commonly seen along interlobular septa and in the centrilobular region (Fig. 4). Correlation of HRCT with pathologic findings has shown that they represent interstitial aggregates of granulomas and associated fibrous tissue.21 Although sarcoid granulomas arise as small nodular lesions, they may coalesce over time, forming larger lesions. On CT, they usually appear as ill-defined, irregular opacities measuring 1-4 cm in diameter (Fig. 5). They are typically multiple and bilateral, and they may be located in perihilar or peripheral regions. Small satellite nodules are often visible at the periphery of these masses, producing an appearance that has been termed the “galaxy sign”22 (Fig. 6). In most patients, sarcoid granulomas resolve with time. However, in an estimated 20% of patients, fibrosis becomes more prominent over time. Fibrosis is seen predominantly in the upper and middle zones, in a patchy distribution.23

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Figure 5 Pulmonary sarcoidosis in a 33-year-old man. Lung window images of thin-section (1.5-mm section thickness) CT scans obtained at levels of right upper lobar bronchus (A) and basal trunks (B) show variable-sized nodular lesions in both the lungs. Nodules are located along bronchovascular bundles, subpleural lungs, and pulmonary fissures. Also note nodular thickening of bronchovascular bundles (arrows). (C) Low-magnification (hematoxylin-eosin staining, 40) photomicrograph of transbronchial lung biopsy specimen demonstrates small noncaseating granulomas (arrows) in interstitium along pleura and interlobular septa (open arrows). vv, vessel. (Color version of figure is available online.)

On HRCT, linear opacities, traction bronchiectasis, architectural distortion, fibrotic cysts, bullae, and paracicatricial emphysema are observed24 (Fig. 7). Obstruction of lobar or segmental bronchi by either wall fibrosis or accumulation of granulomas may result in parenchymal distortion and cyst formation. Occasionally, honeycomblike cysts are seen, which are most commonly distributed in the subpleural regions of the middle and upper lungs, whereas the lung bases are usually spared.23 Distribution and location of fibrosis and honeycomblike cysts are the differential diagnostic points from UIP. The radiographic staging system is well correlated with patient prognosis of pulmonary sarcoidosis. Spontaneous remission occurs in 60%-90% of patients with stage 1 disease, in 40%-70% with stage 2 disease, in 10%-20% with stage 3 disease, and in 0% with stage 4 disease.25 Although the prognostic value of CT findings has not yet been extensively studied, it is known that fibrosis demonstrated on chest radiographs and a reduced vital capacity o 1.5 L are poor prognostic factors.24

IPF or UIP Clinical Features IPF is a chronic progressive fibrotic interstitial pneumonia of unknown cause. The disease is limited to the lungs, not accompanied by systemic involvement. It occurs primarily in adults older than 50 years, with male predominance. The onset of symptoms is insidious. Persistent cough and slowly progressive dyspnea on exertion over years are the main cardinal symptoms. Systemic symptoms, such as fever and malaise, are absent. Not uncommonly, acute deterioration of respiratory symptoms develops during its clinical course. Acute exacerbation of IPF is reported to occur in approximately 5%-10% of patients annually.26 Finger clubbing is observed in more than half of the patients. IPF results in restrictive lung function with a reduction in DLco. Fine inspiratory crackle is heard at the lower lung zone on chest auscultation. Neutrophil-rich cell count is detected on the analysis of BAL fluid.

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3.5 years from time of diagnosis. Baseline diffusing capacity for carbon monoxide, longitudinal change of lung function over 6 or 12 months, HRCT features on fibrosis and honeycombing, 6-minute-walk test indexes, histopathologic findings, and pulmonary hypertension are predictive of survival in IPF.

Histopathologic Diagnosis

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The main histologic feature of UIP is a heterogeneous appearance with foci of the normal lung alternating with areas that show a variable degree of interstitial inflammation and fibrosis (spatial heterogeneity).29 The inflammation is composed predominantly of lymphocytes, with variable numbers of plasma cells and eosinophils. Alveolar airspaces commonly contain an increased number of macrophages. Interstitial fibrosis is mainly composed of mature collagen, with small foci of loose (fibroblastic) connective tissue, reflecting temporal heterogeneity of process. Mild involvement is manifested as a slight degree of alveolar interstitial thickening with preservation of the parenchymal architecture. As disease becomes more severe, alveoli are replaced by fibrous tissue. Contraction of fibrous tissue results in dilatation of residual respiratory bronchioles and alveolar ducts, leading to the formation of cystic spaces (honeycombing)

A Figure 6 Pulmonary sarcoidosis showing CT-galaxy sign in a 74-yearold woman. (A) Lung window images of thin-section (1.0-mm section thickness) CT scan obtained at level of right upper lobar bronchus show multifocal areas of ill-defined irregular opacities (arrows) located along bronchovascular bundles in both lungs. Note small satellite nodules visible at periphery of these opacities. (B) High-magnification (hematoxylin-eosin staining, 100) photomicrograph of biopsy specimen demonstrates small noncaseating granulomas (open arrows) in interstitium. Also note large nodule (arrows), probably formed by confluence of small granulomas. (Color version of figure is available online.)

Diagnosis of IPF requires the following: (1) exclusion of other known causes of interstitial lung disease (eg, domestic and occupational environmental exposure, connective tissue disease, and drug toxicity), (2) the presence of a UIP pattern on chest HRCT scan in patients not subjected to surgical lung biopsy, and (3) specific combinations of chest HRCT and surgical lung biopsy pattern in patients subjected to surgical lung biopsy.27 Multidisciplinary discussion between the treating pulmonologists, radiologists, and pathologists can improve the diagnostic accuracy of IPF. At present, no medical therapy is proven to be effective for IPF. Corticosteroids and other immune modulatory agents are ineffective to improve the survival of the patents with IPF. Pirfenidone as an antifibrotic agent can be effective.28 Several clinical trials with novel drugs for IPF are ongoing. Oxygen supplementation is needed for the hypoxemic patients. Lung transplantation is the last option. The prognosis of IPF is dismal, with a median length of survival between 2.5 and

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Figure 7 Chronic pulmonary sarcoidosis in a 33-year-old man. Lung window images of thin-section (1.0-mm section thickness) CT scans obtained at levels of the great vessels (A) and aortic arch (B) show dense small nodules and reticulation in upper lung zones. Also note areas (arrows) of mosaic attenuation.

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Figure 8 Usual interstitial pneumonia in a 55-year-old woman. Lung window images of thin-section (1.0-mm section thickness) CT scans obtained at levels of lower lobar segmental bronchi (A) and lung base (B), and with patient in prone position, show patchy areas of pulmonary fibrosis with intralobular lines and ground-glass opacity. Note lower lung zone predominance and absence of honeycombing. (C and D) Low- and high-magnification (hematoxylin-eosin staining, 10 and 100, respectively) photomicrographs of biopsy specimen demonstrate end-stage pulmonary fibrosis and honeycombing involving entire specimen. Subpleural and interlobular septal fibrosis is clearly seen in (D). (Color version of figure is available online.)

(Fig. 8). The same process can occur adjacent to membranous bronchioles and bronchi, resulting in bronchiolectasis and bronchiectasis, respectively. These histologic changes are more prominent in the subpleural regions than in the central parenchyma and are usually more severe in the basal region of the lower lobes.

HRCT Findings The characteristic HRCT findings of UIP consist of intralobular lines and honeycombing involving mainly the subpleural regions and lung bases.29,30 The intralobular lines reflect the presence of interstitial fibrosis. The intralobular interstitial thickening also results in the presence of irregular interfaces between the lung and pulmonary vessels, bronchi, and pleural surfaces. The bronchioles and bronchi in areas of fibrosis are often dilated and tortuous (traction bronchiolectasis and bronchiectasis) (Fig. 9). As is seen histologically, parenchymal involvement is typically patchy on HRCT scans, with areas of

normal and markedly abnormal lung often present in the same lobe. Honeycombing is seen on HRCT scans in most cases and typically involves the subpleural regions and lung bases.31 Honeycombing is defined as clustered cystic airspaces, typically of comparable diameters on the order of 3-10 mm and having well-defined walls. The cysts typically appear to share walls on HRCT scan and usually occur in several layers. Other findings of UIP on HRCT include irregular thickening of interlobular septa and patchy areas of ground-glass attenuation. Interlobular septal thickening reflects the presence of fibrosis in the periphery of the secondary lobular, and patchy areas of ground-glass attenuation reflects areas of inflammation or fibrosis. HRCT criteria of UIP pattern proposed by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association are as follows: (1) subpleural and basal predominance, (2) reticular abnormality, (3) honeycombing with or without

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Figure 9 End-stage pulmonary fibrosis in a 57-year-old man with usual interstitial pneumonia. Lung window images of thin-section (1.0-mm section thickness) CT scans obtained at levels of bronchus intermedius (A) and liver dome (B) show bilateral patchy areas of subpleural pulmonary fibrosis with honeycombing predominance. Note lower lung zone predominance. (C) Low-magnification (hematoxylin-eosin staining, 10) photomicrograph of biopsy specimen shows end-stage pulmonary fibrosis consisting of parenchymal dense fibrosis, honeycombing, and smooth muscle hypertrophy (arrows) in bronchial walls. (Color version of figure is available online.)

traction bronchiectasis, and (4) absence of features listed as inconsistent with UIP pattern27 (Fig. 9). On HRCT, the overall extent of fibrosis (reticulation and honeycombing) has been consistently shown to correlate with disease severity parameters on pulmonary function tests and prognosis.32 The typical UIP pattern on HRCT scan also has been shown to indicate a worse prognosis in patients with IPF compared with those with atypical HRCT findings. Recently, the extent of honeycombing at baseline as well as its progression on sequential follow-up CT scan is demonstrated as an important prognostic determinant in patients of fibrotic interstitial pneumonia, including UIP and fibrotic NSIP.33

centrilobular small nodules, and the absence of lower lung zone predominance are characteristically observed. In IPF or UIP, however, the presence of lower lung zone predominance of honeycombing and absence of centrilobular small nodules are important findings that help differentiate the disease from chronic HP or end-stage sarcoidosis.15 In end-stage sarcoidosis, patchy areas of reticulation, traction bronchiectasis, architectural distortion, honeycomblike cysts, bullae, and paracicatricial emphysema are observed in the upper and middle lung zones. Lung bases are usually spared. Distribution and location of reticulation and traction bronchiectasis and honeycomblike cysts are the differential diagnostic points from UIP or chronic HP.

Differentiation From Each Other on HRCT

Conclusion

In chronic HP, the presence of lobular areas of decreased attenuation (the so-called mosaic attenuation) and

The distinction of chronic HP or advanced-stage sarcoidosis from IPF is important because each disease is managed differently and may show a different prognosis. Clinical

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Table Clinical, Pathologic, and Radiologic Features of Chronic Hypersensitivity Pneumonitis, Advanced-Stage Sarcoidosis, and Usual Interstitial Pneumonia Chronic HP Epidemiology Prevalence and incidence are influenced by various factors Pulmonary Restrictive defect with decreased Function DLco Test Clinical Progressive shortness of breath, features chronic cough, or constitutional symptoms Treatment Removal of any potential causative antigen and corticosteroids Pathologic Alveolar interstitial thickening by a findings mononuclear infiltrate, cellular bronchiolitis, and poorly formed granulomas in peribronchial interstitium and interstitial fibrosis Typical HRCT Intralobular interstitial thickening, findings irregular interlobular septal thickening, traction bronchiectasis, and honeycombing superimposed on findings of subacute HP

Pulmonary Sarcoidosis

UIP

Peak incidence, third decade

Onset age 4 50 years

Restrictive defect with decreased DLco

Restrictive defect with decreased DLco

Nonspecific constitutional symptoms Chronic cough and slowly progressive dyspnea on exertion Corticosteroids

Corticosteroids with immunosuppressive agents Noncaseating granulomatous Heterogeneous appearance with foci inflammation and interstitial fibrosis of normal lung alternating with areas that show a variable degree of interstitial inflammation and fibrosis

Intralobular lines and honeycombing Linear opacities, traction involving mainly the subpleural bronchiectasis, architectural regions and lung bases distortion, fibrotic cysts, bullae, paracicatrical emphysema, honeycomb cysts, and micronodules with perilymphatic distribution Presence of lobular areas of mosaic Honeycomblike cysts distributed in Differential the subpleural regions of the middle attenuation and centrilobular diagnostic and upper lungs, whereas the lung points from nodules and the lack of lower zone bases are usually spared predominance UIP

features overlap among the 3 diseases; therefore, differentiation among the 3 diseases is difficult, although not impossible. History of exposure to offending antigen in chronic HP, extrapulmonary manifestations in sarcoidosis, and, if feasible, BAL can help to make a differential diagnosis. The analyses of pattern and distribution of lung parenchymal abnormalities on HRCT scans help differentiate among the 3 diseases. In the 3 diseases, most important prognosis-predicting factor is the extent of fibrotic score (the extent of honeycombing and reticulation) calculated on HRCT scans (Table).

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Chronic hypersensitivity pneumonitis and pulmonary sarcoidosis: differentiation from usual interstitial pneumonia using high-resolution computed tomography.

The distinction of chronic hypersensitivity pneumonitis (HP) or advanced-stage sarcoidosis from idiopathic pulmonary fibrosis or usual interstitial pn...
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