© 2003 American Thoracic Society DOI: 10.1165/rcmb.2003-0159SU
Idiopathic Pulmonary FibrosisCONTENTS Introduction. Augustine M.K. Choi S3 To the Pittsburgh International Lung Conference with Love. Thomas L. Petty S4 Histologic Classification of Idiopathic Chronic Interstitial Pneumonias. Sanja Dacic and Samuel A. Yousem S5 Imaging of the Idiopathic Interstitial Lung Diseases: Concepts and Conundrums. Diane C. Strollo S10 The Prognosis of Idiopathic Pulmonary Fibrosis. Andrew Perez, Robert M. Rogers, and James H. Dauber S19 Idiopathic Pulmonary Fibrosis: New Insights into Classification and Pathogenesis Usher in a New Era in Therapeutic Approaches. Paul W. Noble S27 Microarray Analysis of Idiopathic Pulmonary Fibrosis. Naftali Kaminski S32 Pulmonary Fibrosis of Sarcoidosis: New Approaches, Old Ideas. David R. Moller S37 Proteomic and Inducible Transgenic Approaches to Study Disease Processes. Prabir Ray, Li Chen, Vladimir A. Tyurin, Valerian E. Kagan, and Frank A. Witzmann S42 Pulmonary Fibrosis in Families. James E. Loyd S47 Gene Profiling and Kinase Screening in Asbestos-Exposed Epithelial Cells and Lungs. Maria E. Ramos-Nino, Nicolas Heintz, Luca Scapoli, Marcella Martinelli, Susan Land, Norma Nowak, Astrid Haegens, Brian Manning, Nicole Manning, Maximilian MacPherson, Maria Stern, and Brooke Mossmann S51 The Importance of Sarcoidosis Genotype to Lung Phenotype. Jan C. Grutters, Hiroe Sato, Kenneth I. Welsh, and Roland M. du Bois S59 Cytokine Phenotypes Serve as a Paradigm for Experimental Immune-Mediated Lung Diseases and Remodeling. Steven L. Kunkel, Stephen W. Chensue, Nicholas Lukacs, and Cory Hogaboam S63 CXC Chemokines in Vascular Remodeling Related to Pulmonary Fibrosis. Robert M. Strieter, John A. Belperio, and Michael P. Keane S67 Possible Roles for Apoptosis and Apoptotic Cell Recognition in Inflammation and Fibrosis. Peter M. Henson S70 Regulation of Receptor for Advanced Glycation End Products during Belomycin-Induced Lung Injury. Lana E. Hanford, Cheryl L. Fattman, Lisa M. Schaefer, Jan J. Enghild, Zuzana Valnickova, and Tim D. Oury S77 The Role of Heme Oxygenase-1 in Pulmonary Fibrosis. Danielle Morse S82 Fibroblast Phenotypes in Pulmonary Fibrosis. Sem H. Phan S87 The Epithelial/Fibroblastic Pathway in the Pathogenesis of Idiopathic Pulmonary Fibrosis: Tying Loose Ends. Moisés Selman and Annie Pardo S93 Molecular Targets for Drug Discovery in Idiopathic Pulmonary Fibrosis: Work in Progress. Peter B. Bitterman S98 Pittsburgh International Lung Conference at Nemacolin: Summary. Robert M. Strieter S102
IntroductionThe discipline of respiratory medicine is experiencing an era of unprecedented advance in our understanding of the fundamental basis of human lung disease. Exponential growth in basic lung biology, fueled by the elucidation of the human genome sequence, is successfully coupled with unique human disease applications of this knowledge. This fusion of basic genetics and clinical medicine promises to change our understanding of lung disease diagnosis and treatment. With this promise come major challenges. Our brightest investigators are faced with significant pressures related to academic and clinical productivity, financial stability, and competition. In this backdrop, we have created the Pittsburgh International Lung conference. Our goal is to establish a forum for junior and senior lung investigators to isolate themselves, focus on "state of the art" investigation in a selected area of lung disease, and foster collaborative, collegial, and productive interactions.In proposing this conference, we have turned to the gold standard. For over 40 years, the Aspen Lung Conference has served, with great distinction, a unique role for lung investigators. Inaugurated in 1958 as a conference to understand emphysema and chronic bronchitis, this annual meeting has evolved as a premier forum for basic scientists, physician investigators, and clinicians, to consider progress in the full range of lung diseases. Conference topics have included chronic obstructive and interstitial lung disorders, the acute respiratory distress syndrome (ARDS), genetically determined lung diseases such as cystic fibrosis, and environmental lung disease. The Aspen conference provides a unique level of focus, scientific leadership, and collegiality not traditionally available at other major pulmonary conferences. We believe the dramatic growth in lung investigation warrants a second annual conference with aligned goals and spirit. We are truly indebted to Drs. Thomas Petty and Marvin Schwarz for their guidance and direction in the development of the Pittsburgh International Lung Conference. The Pittsburgh Conference planning committee will maintain a close dialog with the Aspen Conference organizers to avoid redundancy and promote synergy of the selected topics for these two lung conferences on an annual basis. The topic chosen for the inaugural year of the Pittsburgh International Lung Conference was Idiopathic Pulmonary Fibrosis. Few lung disorders have seen a renewed investigative focus like IPF. A historical paradigm of lung inflammation leading to fibrosis is being rapidly revised, incorporating an expanding knowledge base in the topic areas of genetics, lung fibrosis, injury, and repair. National clinical trials, often considered impossible in this disorder, now rapidly explore promising yet unproven therapies. Advancing techniques in lung imaging and noninvasive assessment provide clinicians exciting new tools to diagnose and monitor disease progression. We were honored to assemble an international group of leading investigators to focus on the current and future state of our knowledge in IPF. Our motivation for the topic of IPF is also personal. In 2002, the Simmons family of Pittsburgh provided financial support to the University of Pittsburgh to establish the Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease. This family grew to appreciate the terrible difficulties of IPF from Dorothy's viewpoint during her entirely too brief course with this disease. Recognizing the existing limitations in our treatments, the family has focused their resources on the promotion of investigation and education in IPF. The initial event of the Pittsburgh International Lung Conference this year was the appointment of Dr. Naftali Kaminski to the Simmons Chair for ILD at the University Of Pittsburgh School Of Medicine. Each year we hope to provide a summary of the conference proceedings in the AJRCMB. The presenters for this year's conference were truly outstanding, and we are indebted to their commitment and collegiality in this inaugural year. We were inspired by your scientific creativity, and motivated by your vibrant and selfless interactions. AUGUSTINE M. K. CHOI, M.D. Division of Pulmonary, Allergy, and Critical Care Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania
To the Pittsburgh International Lung Conference with LoveAn important new International Lung Conference was inaugurated in October by Professor Augustine Choi (Head of the Division of Pulmonary, Allergy and Critical Care Medicine) and his colleagues at the University of Pittsburgh Medical Center. Its goal is to provide a research forum to focus on the challenging problem of idiopathic pulmonary fibrosis (IPF)-related disorders.A major driving stimulus for this new program was the generosity of Mr. Richard Simmons, who lost his dear wife, Dorothy, to IPF recently. It was my deep honor to be asked by Augustine to offer some remarks about the Aspen Lung Conferences, which began as a series of emphysema conferences in 1958. At that time, the goal was to begin to understand emphysema and chronic bronchitis. Considerable progress has been made since then. The Aspen Lung Conferences, as they were later named, evolved as a forum with the purpose of bringing together basic and applied scientists, as well as clinicians, to consider progress in COPD, asthma, and later the acute respiratory distress syndrome (ARDS). Also, interstitial lung diseases, genetically determined lung diseases such as cystic fibrosis, and less focused topics, such as the environment and the lung, were tackled in the resort atmosphere of Aspen, Colorado. The Aspen conferences were successful, and offered something unique and beyond what was available at major pulmonary conferences in North America and Europe. The newly inaugurated Pittsburgh Conference offers to do similar things that will help bridge the gap between known clinical challenges in lung disease, and ultimately help to provide solutions to diseases such as IPF. This is how we may emerge from a bewildering wilderness. Only by understanding genetically determined and other risk factors, and the impact of environmental exposures that conspire to inflict both acute and chronic lung injuries resulting in progressive fibrosis, will we make significant progress. We must discover the basic molecular and biochemical process involved in IPF as the foundation for developing new therapeutic targets. Armed with much-needed facts about mechanisms of lung damage and destruction, the pharmaceutical industry will be able to design and develop new pharmacologic agents that will prevent or forestall the progress of IPF. Thus, new progress can be made and solutions found. On behalf of the Aspen Lung Conference Steering Committee and as its official historian, I welcome Pittsburgh International Lung Conference into the arena of struggle and discovery. "Fac –et spera" means work and hope. It is with this spirit and my personal optimism that I wish this new conference God speed. THOMAS L. PETTY, M.D. University of Colorado Medical Center and Rush-Presbyterian Medical Center
Histologic Classification of Idiopathic Chronic Interstitial PneumoniasHistorical PerspectivesThe diagnosis and management of idiopathic interstitial pneumonia (IIP) have challenged physicians since their description more than a century ago. Significant progress in the understanding of interstitial lung diseases was made in the mid-1960s with recognition of collagen vascular diseases (CVD), drugs, and occupational exposures as potential causes. However, a large group of entities still remained idiopathic, and in 1968 Liebow and Carrington were first to classify chronic IIPs into the following five histopathologic subgroups: usual interstitial pneumonia (UIP), bronchiolitis interstitial pneumonia (BIP), desquamative interstitial pneumonia (DIP), giant cell interstitial pneumonia (GIP), and lymphoid interstitial pneumonia (LIP) (1). In the ensuing twenty years, new entities were described and the original IIPs studied in greater depth. The results were then codified in the classification schema described in 1998 by Katzenstein and Myers (2). Their classification scheme recognized five entities: usual interstitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis–associated interstitial lung disease (RB-ILD), nonspecific interstitial pneumonia (NSIP), and acute interstitial lung disease (AIP) (former Hamman-Rich syndrome). The most recent classification by the American Thoracic Society and European Respiratory Society (ATS/ERS) emphasizes the importance of an integrated clinical, radiologic, and pathologic approach to the diagnosis of IIP (3). In particular, it is vitally important that biopsy findings are correlated with high-resolution computed tomography (HRCT), as heterogeneity of lung injury patterns are common in IIP (4–6). This classification expands on the histopathologic terms defined by Katzenstein and Myers, but more precisely defines the relationship between clinico-radiographic findings and histopathology. Fundamental Rules for Pathologic Classification Although the clinical and radiographic diagnosis of IIP can be made in some cases, many patients still require open lung biopsy to determine their underlying histopathologic pattern. Pathologic classification is a very dynamic process requiring close clinico-radiographic correlation. For most practicing pulmonary pathologists, the diagnosis of chronic interstitial lung disease is made at low magnification. Several questions relating to the histologic review of the lung biopsies need to be answered to make a correct diagnosis (Figure 1) .
The first question is whether the disease process is diffuse or patchy. The process is patchy if there are alternating zones of normal and inflammatory/fibrosing lung parenchyma. In contrast, if the entire pulmonary parenchyma appears affected by the inflammatory process and there is very little or no normal lung parenchyma associated with the disease, the process is classified as diffuse. The second important issue is to identify the primary anatomic sites of the lobule/acinus affected by the inflammatory or fibrosing process. The anatomic locations affected by the common chronic inflammatory lung diseases are summarized in the Table 1. Subpleural or paraseptal distribution reflects injury in the distal portion of the lobule and acinus, and is defined by the extension of the inflammation and fibrosis from the subpleural region centripetally into the pulmonary parenchyma. With a bronchiolocentric distribution, the periphery of the pulmonary lobule is relatively spared and the inflammatory process is primarily localized to the bronchovascular bundle with extension into the contiguous peribronchiolar alveolar septa. Alveolar septal distribution is defined by thickened alveolar septa, either by inflammation or fibrosis, throughout the lobule. The process is lymphangitic if the inflammation tracks along the visceral pleura, interlobular septa, and bronchovascular bundles with relative sparing of the septa.
The third basic concept in the understanding of interstitial lung disease is the concept of temporal homogeneity and temporal heterogeneity. Temporal homogeneity indicates that the age of lung injury is approximately the same (acute, subacute, or chronic), and there are no mixtures of all three injury patterns in the same biopsy. In contrast, in temporally heterogenous lung injury one can identify areas of honeycombing (chronic), interstitial or air space fibromyxoid connective tissue (subacute), and alveolar epithelial cell necrosis and hyaline membranes (acute). Finally, one needs to define the overall phase of interstitial injury that may play an important role in predicting responsiveness to therapy: acute, interstitial edema with alveolar pneumocyte necrosis, fibrin, and hyaline membranes; subacute, airspace or interstitial loose fibromyxoid granulation tissue; or scar, remodeled or densely fibrotic lung where architecture is often destroyed, remodeled, or thickened by dense eosinophilic collagen. Once the above described features are identified, histologic classification of IIP should be relatively straightforward in most cases, particularly when correlated with radiographic and clinical findings (Table 2). It is important to emphasize that subclassification of IIP requires exclusion of known causes of these patterns of injury. This mandates close communication between clinicians, radiologists, and pathologists, and could result in reclassification of an interstitial pneumonia if additional information becomes available.
Usual Interstitial Pneumonia/Idiopathic Pulmonary Fibrosis UIP is characterized by patchy subpleural and paraseptal distribution of parenchymal injury. Temporal heterogeneity is seen at low magnification, with alternating areas of normal lung parenchyma, interstitial mononuclear infiltrates, septal fibromyxoid tissue (fibroblastic foci), and honeycomb lung (Figure 2) . Secondary changes, such as pulmonary hypertension and mucous plugs, are frequently present (2, 7, 8).
Open lung biopsies may occasionally show a combination of UIP pattern and subacute (cryptogenic organizing pneumonitis [COP]) or acute diffuse alveolar damage (DAD) lesions (9, 10). If no underlying cause can be determined for such presentation, this histology reflects an accelerated phase or acute exacerbation of UIP (6, 7). Occasionally, moderate number of interstitial or airspace eosinophils may be seen, but they are typically focal, and eosinophilic pneumonia can be excluded (11). It is important to remember that the pattern of interstitial inflammation and fibrosis in patients with CVD, drug-induced interstitial disease, chronic hypersensitivity pneumonitis or asbestosis can be histologically indistinguishable from the idiopathic pulmonary fibrosis (IPF), and the clinico-radiologic–pathologic correlation is essential in such instances. Nonspecific Interstitial Pneumonia NSIP is an idiopathic interstitial pneumonia that does not meet the diagnostic criteria for UIP, DIP, RB-ILD, AIP, or COP. The lung injury is typically diffuse, but may be patchy, and has an alveolar septal pattern. It is characterized by temporally homogenous mild to moderate interstitial mononuclear inflammation (cellular pattern) with dense interstitial fibrosis (fibrosing pattern) (Figure 3) . Some cases may show mixed cellular and fibrosing pattern (12–15). Lymphoid aggregates are common. Fibroblastic foci and honeycombing are absent or inconspicuous.
Histologic patterns of NSIP can be associated with CVD, hypersensitivity pneumonitis, drug reactions, and infections including HIV, and those clinical conditions should be clinically excluded. Desquamative Interstitial Pneumonia DIP is characterized by diffuse, temporally homogenous alveolar septal inflammation and fibrosis with uniform airspace filling by smokers' macrophages (16). The alveolar septa are lined by reactive pneumocytes and are thickened by mononuclear infiltrate and mild increase in septal collagen (Figure 4) . It has the appearance of NSIP with all airspaces filled with alveolar macrophages, often of the smokers type.
Because many patients with other IIP are often current or former smokers, DIP-like pattern can be seen focally in UIP, RB-ILD, NSIP, eosinophilic pneumonia, chronic hemorrhage, and veno-occlusive disease. Respiratory Bronchiolitis-Associated Interstitial Lung Disease The histologic changes of RB-ILD are patchy and bronchiolocentric in distribution. It is characterized by a temporally homogenous peribronchiolar mononuclear infiltrate with rare eosinophils, inconspicuous septal mononuclear cells, and irregular, centrilobular airspace filling by finely pigmented macrophages (Figure 5) . Mild peribronchiolar fibrosis is also seen (17–20).
DIP and RB-ILD, once considered distinct entities, are related lesions which differ only in the severity, distribution, and extent of the histopathologic abnormality. Cryptogenic Organizing Pneumonia COP is a patchy bronchiolocentric temporally homogenous process characterized by fibromyxoid connective tissue plugs in lumens of airways and airspaces (Figure 6) . There is a mild peribronchiolar and interstitial mononuclear inflammatory infiltrate. The lung architecture is relatively preserved (21–29).
The presence of airspace neutrophils, acute bronchiolitis, granulomas, necrosis, hyaline membranes, and prominent eosinophilic inflammatory infiltrate strongly argues against the diagnosis of primary COP. Lymphoid Interstitial Pneumonia LIP is characterized by a dense diffuse temporally homogenous lymphoid infiltration predominantly alveolar septal in distribution (Figure 7) . The lymphoid infiltrate is comprised mostly of T lymphocytes, plasma cells, and macrophages. Some architectural distortion, including honeycombing, nonnecrotizing granulomas, and small foci of organizing pneumonia, may be present. Lymphoid hyperplasia (MALT hyperplasia) is a frequently associated finding (30–34).
The major differential diagnosis from a clinical standpoint is the separation of LIP from low-grade lymphoma, particularly extranodal marginal zone B-cell lymphoma of MALT. Malignant lymphoma usually show a monomorphous lymphoid infiltrate distributed along lymphatic routes, often associated with destruction of alveolar architecture, Dutcher bodies, and pleural infiltration. Immunohistochemical and molecular gene rearrangement studies may be necessary to exclude lymphoproliferative disorder (3). LIP also must be differentiated histologically from follicular bronchiolitis, nodular lymphoid hyperplasia, infection (especially Pneumocystis carinii pneumonia), and other interstitial lung disorders such as NSIP, organizing pneumonia, and UIP. The cited references provide a very detailed description of lymphoid hyperplasia of the lung that is beyond the scope of this very brief summary. Role of Surgical Lung Biopsy ATS/ERS recently published a consensus statement describing major and minor criteria for the clinical diagnosis of IPF. The panel noted that in the absence of surgical lung biopsy findings, the diagnosis of IPF remains unproven, and that a definitive diagnosis of IIP can be established only with the aid of a surgical lung biopsy (3). In addition, the role of HRCT as an integral part of the evaluation of the patient with suspected IIP has been emphasized. The primary role of HRCT is to separate patients with UIP from those with other IIP such as NSIP, RB-ILD, DIP etc. HRCT may also be helpful in identifying patients with other diseases such as sarcoidosis, lymphangioleiomyomatosis, eosinophilic granuloma and hypersensitivity pneumonitis (3). The role of transbronchial biopsy in the diagnosis of IIP in most cases is to exclude sarcoidosis, lymphangitic carcinoma, infections, DAD, and some rare conditions such as alveolar proteinosis, lymphangioleiomyomatosis, and Langerhans' cell histiocytosis (35–41). Most pulmonary pathologists would agree that the assessment of IIP requires a surgical (open or thoracoscopic) lung biopsy. It is important for the surgeon not to biopsy the radiologically or grossly palpable "worst" areas. This is often nondiagnostic and most times shows nonspecific end-stage honeycomb lung. The open lung biopsy should be taken from more than one lobe of the lung. It is still controversial whether to biopsy lingula and right middle lobe, as both of these sites frequently show nonspecific fibrosis (39–44). The biopsy should be large in the size, and in our experience at least 5 cm in greatest dimension. It should be obtained at the edge of the grossly abnormal areas of the lung to include grossly normal lung parenchyma. Most important is that the biopsy must be deep, extending well into the "medulla" of the subpleural lung parenchyma. Shallow subpleural biopsies are frequently nondiagnostic. This allows one to escape nonspecific subpleural scarring and obtain actively injured lung parenchyma to assess the features that are important in making a diagnosis of IIP. Footnotes This section was written by Sanja Dacic and Samuel A. Yousem (Department of Pathology, Division of Anatomic Pathology, University of Pittsburgh Medical Center, Presbyterian University Hospital, Pittsburgh, Pennsylvania). References
Imaging of the Idiopathic Interstitial Lung DiseasesConcepts and ConundrumsThe interstitial lung diseases (ILD) are a diverse group of inflammatory-fibrosing disorders that affect predominantly the pulmonary interstitium rather than the airspaces. The etiology of most ILD is known, such as collagen vascular diseases, drug-induced lung diseases, infectious and noninfectious granulomatous diseases, inhalation of organic and inorganic materials and noxious gases, and proliferative and malignant neoplastic processes (1). The diagnosis of ILD, in some instances, may be established from clinical, laboratory, and radiologic data, without lung biopsy (2). The insult that produces idiopathic ILD remains unknown, and the disease is limited to the lungs and is typically immune mediated. Despite the variety of insults that may induce the initial injury of ILD, the pathogenesis and end-stage morphologic changes may be similar, although the rate of disease progression may vary considerably (1).The current clinico-pathologic classification of idiopathic nongranulomatous ILD includes a disparate group of lung diseases that have at least some degree of interstitial cellular inflammation and may culminate in pulmonary fibrosis (3) (Table 1). This grouping of diseases includes idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonitis (NSIP), respiratory bronchiolitis–interstitial lung disease (RB-ILD), desquamative interstitial pneumonitis (DIP), cryptogenic organizing pneumonia (COP), and acute interstitial pneumonitis (AIP). The etiology is not always idiopathic. Whereas IPF and NSIP are predominantly diseases of the interstitium, RB-ILD and DIP represent a continuum of smoking-related diseases of the small airways, interstitium, and alveoli. COP is an idiopathic inflammation of the small airways and airspaces with minor involvement of the interstitium. AIP is an idiopathic form of diffuse alveolar damage and involves the alveoli and the interstitium. NSIP is a relatively new histologic category, and like DIP, may not represent a distinct clinicopathologic syndrome (4). In some instances, when an ILD may not be easily or concisely characterized, it may be labeled as "unclassifiable ILD."
Imaging of Idiopathic ILD The primary role of imaging is to identify the presence and extent of pulmonary fibrosis, as this portends a less favorable prognosis regardless of etiology. In addition, certain patterns of lung involvement may suggest a specific disease category (5). Diseases that involve the interstitium (IPF, NSIP) may result in pulmonary fibrosis and manifest with reticulations (innumerable interlacing linear opacities typically due to intralobular interstitial thickening), "honeycomb" change (cystic dilatation of distal bronchioles and airspaces that share common thickened walls), and traction bronchiectasis or bronchiolectasis (irregular dilatation of bronchi and bronchioles, typically associated with reticulations or honeycomb cysts) (6). Processes that affect the airspaces (DIP, COP, AIP) may exhibit consolidation, defined as a homogeneous increase of lung attenuation that obscures the margins of vessels and airways. Bronchiolocentric diseases (RB-ILD, COP) may exhibit dilated and/or thickened bronchioles. Any process with active inflammation or fibrosis may exhibit "ground glass" attenuation, defined as hazy increased lung attenuation that does not obscure or distort the underlying lung architecture. Ground glass attenuation may precede the development of pulmonary fibrosis (7, 8). When pulmonary fibrosis is the predominant pattern, associated ground glass attenuation typically reflects microscopic changes of fibrosis (9). Computed tomography (CT) and high-resolution CT (HRCT) are the mainstays of the noninvasive evaluation of ILD and play a critical role in its early detection, characterization, and differentiation from other lung diseases. A normal HRCT does not always exclude early and clinically significant ILD, especially when physiologic testing is abnormal (10). The radiologic findings of pulmonary fibrosis on HRCT correlate strongly with fibrosis on histology (P = 0.0001), and pure ground-glass attenuation in patients with suspected ILD correlates well with interstitial inflammation (P = 0.03) (5, 11). CT may be used to select an optimal site of lung biopsy and to exclude patients with severe end-stage fibrosis who may not benefit from biopsy (5, 12). Radiologic and pathologic features of idiopathic ILD may be identical to those of ILD of known etiology (13).
Idiopathic Pulmonary Fibrosis
On CT, IPF typically exhibits features of pulmonary fibrosis with little active inflammation (Figure 4) . Honeycomb cysts (96%), distorted intralobular reticulations (80%), and traction bronchiolectasis (50%) have a striking predilection for the lung periphery and bases, and may involve all lobes in advanced disease (14, 19). Ground-glass attenuation (75%) is typically admixed with fibrosis and is rarely the dominant pattern (Figures 5 and 6) . Mildly enlarged reactive mediastinal lymph nodes are common, and correlate with greater disease severity (20, 21). Following single lung transplantation of patients with IPF, the native lung may exhibit progressive fibrosis (22).
It has been reported that  10% of patients with IPF, typically older male smokers, may develop lung cancer (23). Squamous cell carcinoma is the most common histologic type. Lung cancer typically arises within areas of fibrosis and manifests as a peripheral pulmonary nodule or mass or as a subtle, poorly defined area of consolidation or asymmetric fibrosis, which may make early detection difficult (23, 24) (Figure 7)
.
Nonspecific Interstitial Pneumonitis NSIP has varying amounts of subacute interstitial inflammation (cellular NSIP) and fibrosis (fibrotic NSIP) that do not meet the histologic criteria of UIP or other ILD (25–27). The histopathologic pattern of NSIP exhibits temporal homogeneity that results from a single lung insult, with all areas of reparation at the same stage of healing. Compared with IPF, patients with NSIP pattern tend to be younger and have milder symptoms of shorter duration, with a more favorable prognosis. The radiologic features of NSIP reflect the varied amounts of inflammation and fibrosis. NSIP has a predilection for the basilar and peripheral portions of the lungs, similar to IPF, but tends to have a greater component of inflammation and potentially reversible disease (14). Chest radiography may be normal, but characteristically reflects decreased lung volumes (70%) and symmetric bibasilar peripheral ground glass attenuation, consolidation, and/or fibrosis (28) (Figure 8) .
CT features of NSIP may have significant overlap with those of IPF/UIP, DIP, and COP, and cases of NSIP are commonly misdiagnosed on CT (25, 29). Cellular NSIP typically exhibits prominent ground glass attenuation (70–100%). Fibrotic NSIP may show fine reticulations, thickened septal and pleural lines, traction bronchiolectasis, and honeycomb cysts, which may be identical to those of IPF (25, 29–31). Bronchocentric consolidation, similar to that of COP, is occasionally detected (32). Radiologic and clinical features of NSIP may improve following corticosteroid therapy (33).
Respiratory Bronchiolitis–Interstitial Lung Disease and Desquamative Interstitial Pneumonitis Imaging features of RB and RB-ILD typically overlap, and may be normal or show subtle areas of ground glass attenuation, fine linear reticulations, and/or emphysematous changes (Figure 9) . CT may also reveal small airways disease with mildly thickened and dilated bronchioles, "soft" centrilobular nodules, and ground glass attenuation that may be centrilobular or diffuse (Figures 10 and 11) . These abnormalities are typically greatest in the upper aspects of the lungs and may improve or resolve following smoking cessation (35). Honeycomb change and traction bronchiectasis are uncommon.
Imaging of patients with DIP may be normal or demonstrate predominantly ground glass attenuation and/or consolidation that may be bibasilar and peripheral, or less commonly, diffuse (36) (Figure 12) . A smaller component of reticulations and honeycomb change reflect pulmonary fibrosis. Emphysematous changes may also be present.
Cryptogenic Organizing Pneumonia COP is a subacute febrile noninfectious disease of the small airways and airspaces that may mimic pneumonia. Patients typically present in the 5th to 6th decades of life with cough and dyspnea of approximately three months duration. COP typically improves dramatically following corticosteroid therapy, but may quickly relapse when the dosage is reduced or discontinued (37, 38). COP is the preferred nomenclature, but is still used interchangeably with the older term of bronchiolitis obliterans organizing pneumonia (BOOP) (37). Injury of the small airways results in mucosal ulcerations that heal with granulation tissue plugs (proliferative "bronchiolitis obliterans") that extend into the alveoli ("organizing pneumonia"), with a smaller component of interstitial inflammation. Proliferative bronchiolitis of COP is a distinct entity from constrictive bronchiolitis obliterans, which is a common injury of lung and bone marrow transplant recipients and results in irreversible scarring of the bronchiolar walls with secondary air trapping. On chest radiography, COP typically manifests as decreased lung volumes and multifocal subsegmental patchy consolidations with a juxta-pleural or bronchocentric distribution (38) (Figure 13) . On CT, COP typically exhibits mixed consolidations and areas of ground glass attenuation that may be triangular, patchy, and peripheral in distribution or extend centrifugally from plugged airways (37, 38). A nodular component, defined by the secondary pulmonary lobule, may have a patent bronchus or feeding vessel (39, 40). Both unilateral and migratory lung involvement have been reported (38). In addition, a subset of patients with COP may exhibit a fulminant clinical course that culminates in severe pulmonary fibrosis and/or death (41). Bibasilar juxta-pleural reticulations are uncommon, and generally correlate with fibrosis and a less favorable outcome (37, 38, 42). Reactive mediastinal lymph nodes may be mildly enlarged.
Acute Interstitial Pneumonitis (formerly Hammon Rich Syndrome) AIP is an acute fulminant lung injury due to idiopathic diffuse alveolar damage (43). Patients typically develop rapidly progressive hypoxemia and respiratory failure that require mechanical ventilation. At least 50% of patients die in the weeks following disease onset. Hamman and Rich originally described AIP as a rapidly progressive and typically fatal form of pulmonary fibrosis (44). AIP is now recognized as a distinct entity from IPF. AIP is characterized acutely by alveolar hyaline membrane formation and mild interstitial inflammation, followed by type 2 pneumocyte proliferation, and typically culminates in interstitial and alveolar fibrosis (14, 44). The histopathologic pattern of AIP is identical to that of adult respiratory distress syndrome due to sepsis, shock, multi-system trauma, and multiple other insults. Chest radiographic abnormalities typically lag behind signs and symptoms of respiratory failure by 24–48 h, then manifest with decreased lung volumes and mild diffuse ground glass attenuation that may rapidly progress to symmetric and diffuse or bibasilar air space consolidation (45) (Figure 14) . On CT, AIP is characterized by random extensive ground glass attenuation (100%) and consolidation (67%), with focal sparing of scattered second pulmonary lobules (43, 46). Interlobular septal thickening and traction bronchiolectasis may also be present, but honeycomb change is uncommon (44). In the infrequent survivor, AIP may heal with no residua or with variable degrees of fibrosis (45, 46).
Differential Diagnoses The radiologic features of the idiopathic ILD overlap and may be identical to ILD of known etiology. UIP secondary to connective tissue diseases (Figure 15) and asbestosis (Figure 16) may mimic IPF. Chronic aspiration may be a common cause of limited bibasilar fibrosis (Figure 17) . Granulomatous ILD typically manifests as small nodules, which are "hard" and of lymphatic distribution in sarcoidosis (Figure 18) , versus "soft" and centrilobular in patients with hypersensitivity pneumonitis (Figure 19) . In addition, hypersensitivity pneumonitis may exhibit patchy consolidation and air trapping that mimics RB-ILD or COP. The drug-induced and neoplastic ILD (lymphocytic interstitial pneumonitis and lymphangetic metastases) may also exhibit reticulations and ground glass attenuation. Secondary findings may provide important clues to the etiology of ILD, such as a dilated esophagus with scleroderma, pleural plaques with asbestos exposure, lymphadenopathy with sarcoidosis or lymphangetic metastases, and increased liver attenuation with amiodarone drug-induced lung disease.
Conclusions The primary role of imaging of ILD is to identify the presence and extent of fibrosis, to detect secondary findings characteristic of ILD of known etiology, and to direct the optimal sites of lung biopsy. The diagnosis of idiopathic ILD requires a multidisciplinary approach and integration of the clinical features, to include disease duration and prevalence, with the radiologic pattern and distribution (47). In the clinical setting of progressive chronic ILD, the diagnosis of UIP/IPF can be made with confidence on HRCT. However, in many instances, the clinical and radiologic features of the various ILD overlap, and surgical lung biopsies may be needed. The temporal heterogeneity of UIP pattern is the defining histopathologic feature of IPF; all other ILD have temporal homogeneity. NSIP and DIP may have a similar peripheral and basilar distribution as IPF, but typically have more cellular inflammation on histopathology and ground glass attenuation on CT. RB-ILD is characterized by small airways disease in the upper aspects of the lungs, and smoking cessation with follow-up CT to document disease resolution may pre-empt a lung biopsy. COP clinically may mimic pneumonia of several months duration, is a diagnosis of exclusion, and typically manifests on CT as patchy peripheral nodular consolidations that resolve following corticosteroid therapy. AIP is a rare explosive lung disease that rapidly progresses to respiratory failure and death. Lung biopsy is usually needed to confirm the diagnosis and exclude infectious or other treatable entities. Footnotes This section was written by Diane C. Strollo, M.D. (Dorothy P. and Richard P. Simmons Center for Research and Education in Interstitial Lung Disease, Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania). References
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