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Idiopathic Pulmonary Fibrosis: Evolving Concepts Jay H. Ryu, MD; Teng Moua, MD; Craig E. Daniels, MD; Thomas E. Hartman, MD; Eunhee S. Yi, MD; James P. Utz, MD; and Andrew H. Limper, MD Abstract Idiopathic pulmonary fibrosis (IPF) occurs predominantly in middle-aged and older adults and accounts for 20% to 30% of interstitial lung diseases. It is usually progressive, resulting in respiratory failure and death. Diagnostic criteria for IPF have evolved over the years, and IPF is currently defined as a disease characterized by the histopathologic pattern of usual interstitial pneumonia occurring in the absence of an identifiable cause of lung injury. Understanding of the pathogenesis of IPF has shifted away from chronic inflammation and toward dysregulated fibroproliferative repair in response to alveolar epithelial injury. Idiopathic pulmonary fibrosis is likely a heterogeneous disorder caused by various interactions between genetic components and environmental exposures. High-resolution computed tomography can be diagnostic in the presence of typical findings such as bilateral reticular opacities associated with traction bronchiectasis/bronchiolectasis in a predominantly basal and subpleural distribution, along with subpleural honeycombing. In other circumstances, a surgical lung biopsy may be needed. The clinical course of IPF can be unpredictable and may be punctuated by acute deteriorations (acute exacerbation). Although progress continues in unraveling the mechanisms of IPF, effective therapy has remained elusive. Thus, clinicians and patients need to reach informed decisions regarding management options including lung transplant. The findings in this review were based on a literature search of PubMed using the search terms idiopathic pulmonary fibrosis and usual interstitial pneumonia, limited to human studies in the English language published from January 1, 2000, through December 31, 2013, and supplemented by key references published before the year 2000. ª 2014 Mayo Foundation for Medical Education and Research

diopathic pulmonary fibrosis (IPF) is a common form of interstitial lung disease (ILD) and occurs predominantly in middle-aged and older adults.1-3 It accounts for 20% to 30% of ILDs and is usually progressive, resulting in respiratory failure and death. Idiopathic pulmonary fibrosis is included under the rubric of idiopathic interstitial pneumonias, among which it is the most common type.4-7 The findings in this review were based on a literature search of PubMed using the search terms idiopathic pulmonary fibrosis and usual interstitial pneumonia, limited to human studies in the English language published from January 1, 2000, through December 31, 2013, and supplemented by key references published before the year 2000.

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EVOLUTION OF DISEASE DEFINITION Diagnostic criteria for IPF have evolved over the years. Initial descriptions of the disease that is now called IPF date back nearly 80 years.8 Over many of the intervening years, IPF (also previously called cryptogenic fibrosing alveolitis) was defined somewhat broadly as a progressive,

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fibrosing inflammatory disease of the lung parenchyma of unknown cause and comprised several clinicopathologic entities that are now considered distinct disease entities.1 The advent of high-resolution computed tomography (HRCT), which allowed more detailed imaging of the lung parenchyma and refinements in the histopathologic classification, allowed differentiation of distinctive ILDs and led to the current, more restrictive, definition of IPF. In the late 1990s, several studies identified prognostic implications associated with distinctive histopathologic patterns of idiopathic interstitial pneumonias.9-11 The histopathologic pattern of usual interstitial pneumonia (UIP) was associated with a considerably worse prognosis compared with other forms of chronic interstitial pneumonias, including nonspecific interstitial pneumonia and desquamative interstitial pneumonia. Usual interstitial pneumonia is a morphological type of lung injury with a variegated pattern and alternating areas of normal or near-normal lung, temporal heterogeneity of fibrosis consisting of scattered fibroblastic foci

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From the Division of Pulmonary and Critical Care Medicine (J.H.R., T.M., C.E.D., J.P.U., A.H.L.), Department of Radiology (T.E.H.), and Division of Anatomic Pathology (E.S.Y.), Mayo Clinic, Rochester, MN.

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In 2000, an international consensus statement was published defining IPF as a disease characterized by the histopathologic pattern of UIP of unknown cause, ie, absence of an identifiable cause of lung injury such as drug toxicity, inhalational or occupational exposures, radiation therapy, and connective tissue disease.2 This is the definition used at the present time.3

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Idiopathic pulmonary fibrosis (IPF) occurs predominantly in middle-aged and older adults and accounts for 20% to 30 % of interstitial lung diseases. The pathogenesis of IPF involves dysregulated fibroproliferative repair in response to alveolar epithelial injury. Diagnosis of IPF can be achieved noninvasively when characteristic computed tomographic findings are encountered in the appropriate clinical context. Bronchoscopy or surgical lung biopsy may be needed in some patients to confirm the diagnosis.

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Idiopathic pulmonary fibrosis is usually progressive, but the clinical course varies widely among individual patients.

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Antifibrotic agents show promise in the treatment of IPF. As currently defined, IPF is likely a heterogeneous disorder caused by various interactions between genetic components and environmental exposures.

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in the background of dense acellular collagen, and architectural distortion due to chronic fibrosis and honeycombing3,7 (Figure 1). These features are most prominent in the subpleural and paraseptal zones of the lung. Fibroblast foci are usually seen at the interface between chronic fibrotic and relatively normal-appearing lung parenchyma.

PATHOGENESIS The cause of IPF remains unknown. The lack of efficacy of anti-inflammatory therapy, eg, highdose corticosteroids, in the treatment of IPF has cast doubt on the major role of chronic inflammation in the development of parenchymal fibrosis in this disease. Recurrent or persistent alveolar epithelial injury with dysregulated repair is currently thought to be the major mechanism leading to progressive pulmonary fibrosis.12-14 Cells responsible for the fibrotic architectural distortion in the lung include myofibroblasts and fibrosis progenitor cells.15-17 Mechanisms underlying the recruitment and proliferation of these cells as well as their pathologic differentiation remain to be clarified, but there appears to be a large number of mediators involved including cytokines, chemokines, fibrogenic factors, coagulant proteins, oxidants, and regulators of apoptosis.18,19 It is likely that deposition of extracellular matrix components including collagen is integral to this fibrotic

FIGURE 1. Histopathologic features of usual interstitial pneumonia. A, Low-power view shows marked fibrosis with architectural distortion, honeycombing in a predominantly subpleural distribution with absence of features inconsistent with usual interstitial pneumonia, eg, granulomas, marked inflammation, organizing pneumonia (hematoxylin-eosin, original magnification 40). B, High-power view shows fibroblast foci, focal pale areas of active fibroblast proliferation at the edge of dense fibrosis (hematoxylineosin, original magnification 100).

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process.20 Given that IPF generally affects middle-aged to older persons, age-related biological changes including telomeric function probably play an important role as well.21 These processes may lead to premature cellular senescence in alveolar cells and exhaustion of precursor cells needed in alveolar regeneration, thus resulting in aberrant repair via fibrosis.22 Some have invoked the role of mechanical stress such as recurrent tractional forces on the periphery of the aging lung as a major factor in the development of pulmonary fibrosis.23 Progress has been made in identifying genetic determinants of pulmonary fibrosis. For example, recent genome-wide association studies have identified the association of IPF with a single-nucleotide allelic variant in the promoter of the MUC5B gene, which is present in 38% of patients with IPF.24 Interestingly, the presence of the MUC5B promotor allelic variant appears to impart overall better survival prognosis in these patients.25 In addition, variants in genes for telomerase components have been implicated in familial pulmonary fibrosis as well as IPF.26-28 Other genes implicated in familial pulmonary fibrosis include genes for surfactant protein C and surfactant protein A2.29,30 EPIDEMIOLOGY In the United States, the incidence of IPF is estimated to be 7 to 17 per 100,000 person-years, while the prevalence appears to be between 20 to 60 per 100,000 persons.31,32 The age at diagnosis of IPF is usually between 50 and 85 years.1-3,33,34 Idiopathic pulmonary fibrosis is uncommon in patients aged less than 50 years, who account for 2% to 15% of those diagnosed as having this disorder.31,32,35 More men than women have been reported with IPF, with a male to female ratio of approximately 1.5:1.12,13 Approximately 1% to 4% of all patients with IPF have a family history of the disease.36-39 The familial form of pulmonary fibrosis tends to present at younger age when compared with the more common sporadic form.37,38,40 Idiopathic pulmonary fibrosis has been associated with cigarette smoking, a variety of environmental exposures such as organic and inorganic dusts, pharmacological therapies, other medical disorders, and microbial agents such as Epstein-Barr virus.41 Despite numerous studies reporting these associations, the role of these agents in the etiology of IPF remains unclear. Mayo Clin Proc. n XXX 2014;nn(n):1-13 www.mayoclinicproceedings.org

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CLINICAL FEATURES Most patients with IPF present with progressively worsening breathlessness and cough, which is usually dry.1,2,33,34 Less common symptoms may include chest discomfort or constitutional features such as fatigue, lowgrade fever, or weight loss. Some patients with IPF may present with abnormal radiologic findings or pulmonary function abnormalities in the absence of respiratory symptoms. Nearly all patients with IPF have bibasilar inspiratory crackles that are qualitatively described as “Velcro-like,” and approximately one-half to two-thirds of patients manifest digital clubbing.1,2,33,34 Physical signs of pulmonary hypertension (PH) and cor pulmonale such as increased pulmonic component of the second heart sound, right ventricular lift, and tricuspid regurgitation may be observed in patients with advanced disease.42,43 Cyanosis is a late manifestation. LABORATORY TESTING Screening blood tests may reveal an elevated erythrocyte sedimentation rate, but the hemoglobin level along with leukocyte and differential counts are usually normal.1-3 Some patients may have elevated titers of antinuclear antibody, rheumatoid factor, or other autoantibodies in the absence of an identifiable connective tissue disorder.1-3 In recent years, several potential diagnostic and prognostic biomarkers have been identified in the peripheral blood. These biomarkers include matrix metalloproteinases MMP-1 and MMP-7, chemokine CCL-18, surfactant protein A, chitinase-like protein YKL-40, free circulating DNA, periostin, and osteopontin.44,45 Krebs von den Lungen 6 (KL-6) is a mucinous high-molecular-weight glycoprotein that is expressed mainly on type II pneumocytes but also on epithelial cells of the respiratory bronchioles and some extrapulmonary sites. The serum 6 KL-6 level appears to be a marker of alveolar epithelial cell injury and may be useful in staging of ILDs, including IPF, but testing is not widely available.46,47 RADIOLOGIC FEATURES On chest radiography, the most common abnormalities are bilateral interstitial opacities with a predilection for the peripheral and lower lung zones. However, chest radiographs

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may look normal in 2% to 10% of patients with IPF at presentation.1-3 As the disease advances, the reticular opacities become coarser, lung volume decreases, and peripheral honeycombing becomes apparent along with radiographic signs of PH and cor pulmonale, including pulmonary artery enlargement and cardiomegaly. High-resolution computed tomography is essential in the evaluation of a patient with suspected ILD, including IPF. It provides a more detailed depiction of intrathoracic structures and often allows a presumptive diagnosis of a specific ILD based on characteristic findings.3,48,49 High-resolution computed tomography is more sensitive than chest radiography in the detection of UIP and more accurate in discriminating between various ILDs. A confident radiologic diagnosis of UIP can be achieved in the presence of bilateral reticular opacities associated with traction bronchiectasis/ bronchiolectasis in a predominantly basal and subpleural distribution, along with subpleural honeycombing3,48,49 (Figure 2). It should be noted, however, that honeycombing can sometimes be difficult to distinguish from traction bronchiolectasis, subpleural cysts, and paraseptal emphysema.50 Ground-glass opacities, if present, should be less extensive than reticular abnormalities. Mild enlargement of mediastinal lymph nodes can be seen, but pleural abnormalities are typically absent. When the radiologic

diagnosis of UIP is based on these findings, it is correct in more than 90% of cases.3,6,48,49 PULMONARY FUNCTION TESTING Pulmonary function testing usually reveals restrictive impairment with reduced lung volumes and decreased diffusing capacity in patients with IPF.1-3,51 In early stages, an isolated reduction in diffusing capacity may be seen with normal lung volumes. Gas exchange is impaired with an increased alveolar-arterial gradient for partial pressure of oxygen. Even when the resting partial arterial pressure of oxygen is normal, an exercise-induced decrease in arterial oxygen saturation is commonly observed. In patients with IPF who have preexisting obstructive lung disease such as emphysema, relative normalization of lung volumes and flows occurs.1,52 Thus, the lung volumes and flows may appear normal or near normal in the presence of severe exertional dyspnea. In such situations, the diffusing capacity will be severely reduced and HRCT will reveal the presence of a combined pathologic process, typified by upper lung emphysema and lower lung fibrosis.53,54 DIAGNOSIS A definitive diagnosis of IPF requires evidence of UIP as documented by characteristic HRCT features or a surgical lung biopsy (in the absence of

FIGURE 2. High-resolution computed tomographic features of usual interstitial pneumonia. A, Axial view shows subpleural predominance of reticular opacities and honeycombing with absence of features inconsistent with a usual interstitial pneumonia pattern, eg, extensive ground-glass opacities, consolidation, micronodules, mosaic pattern (air trapping). B, Sagittal view shows subpleural and basilar predominance of reticular opacities and honeycombing.

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HRCT features inconsistent with UIP, eg, upper lung predominance, diffuse micronodules, or mosaic attenuation) and exclusion of identifiable causes such as drugs, inhalational exposures (eg, chronic hypersensitivity pneumonitis and asbestosis), and connective tissue diseases1-3,6,55 (Table). A confident HRCT diagnosis of UIP can be made in one-half to two-thirds of patients with IPF.3,56 In patients with nondiagnostic HRCT imaging, additional evaluation is needed to establish the diagnosis of IPF or another ILD. Although transbronchial lung biopsy is generally inadequate for confirming the diagnosis of UIP, bronchoscopic biopsy and bronchoalveolar lavage may yield findings of another ILD such as sarcoidosis, hypersensitivity pneumonitis, eosinophilic pneumonia, pulmonary Langerhans cell histiocytosis, and pulmonary alveolar proteinosis.3,6,57,58 For example, lymphocytosis (30% lymphocytes) identified on analysis of bronchoalveolar lavage fluid in a patient with suspected IPF suggests the alternative diagnosis of either nonspecific interstitial pneumonia or hypersensitivity pneumonitis.59 With the advent of transbronchial cryobiopsy, which yields larger and less distorted specimens of lung parenchyma compared with traditional forceps biopsy, bronchoscopic biopsy may take on a more prominent role in the diagnosis of IPF.60 When needed, surgical lung biopsy is usually obtained by video-assisted thoracoscopic surgery rather than thoracotomy. For procurement of optimal representative samples, surgical lung biopsy is obtained from multiple lobes. Surgical lung biopsy is generally considered the definitive procedure in defining the underlying histopathologic pattern but is associated with risks, particularly for patients with severe respiratory impairment, acute worsening, or other comorbidities.61-65 Thus, the decision regarding surgical lung biopsy needs to be individualized, considering the clinical context, diagnostic possibilities, potential benefits of establishing a definitive diagnosis vs the risks associated with the procedure, and patient preferences. Because the diagnosis of IPF incorporates clinical, radiologic, and histopathologic findings, multidisciplinary correlation of these findings enhances diagnostic accuracy.3,66 A recent international consensus statement on the diagnosis and management of IPF provides criteria used in the HRCT and histopathologic diagnosis of UIP, along with multidisciplinary Mayo Clin Proc. n XXX 2014;nn(n):1-13 www.mayoclinicproceedings.org

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correlation that results in the diagnosis of IPF.3 Any HRCT findings that are unusual for IPF should cause one to question the diagnosis of IPF, even when the surgical lung biopsy reveals UIP. For example, chronic hypersensitivity pneumonitis, drug-induced lung disease, connective tissue diseaseeassociated ILD, and asbestosis can be associated with a UIP pattern on lung biopsy.3,55,67 CLINICAL COURSE AND COMORBIDITIES Median survival for patients with IPF is estimated to be approximately 3 years.2,3,6,9,34 Although many patients with IPF experience gradual progression of their lung disease associated with increasing exertional dyspnea and functional limitation, the clinical course of individual patients is often unpredictable.68 Some patients may experience no physiologic or clinical worsening over a course of months to years, while others encounter unexpected acute deteriorations or complications related to progressive respiratory insufficiency and coexisting medical conditions. Furthermore, distinct patterns of disease progression, “slow” and “rapid,” have been described with detectable differences in biological phenotype as assessed by gene expression profiles.69 Several staging systems have been proposed to improve the accuracy of prognostication, but none have yet gained wide clinical acceptance.70-72 The immediate cause of death is IPF itself in approximately one-half of patients, while others die of pneumonia, aspiration, myocardial infarction, stroke, and other nonpulmonary causes.73,74 Acute Exacerbation The clinical course of IPF may be punctuated by single or multiple acute deteriorations resulting in periods of rapid clinical decline and sometimes death. Some of these episodes represent acute exacerbation of IPF, which is defined as acute worsening of dyspnea within TABLE. Diagnostic Criteria for Idiopathic Pulmonary Fibrosis 1. Exclude identifiable causes of interstitial lung disease (eg, occupational or environmental exposures to fibrogenic agents, connective tissue diseases, drugs and radiation) 2. Usual interstitial pneumonia pattern shown by: (a) High-resolution computed tomographic findings or (b) Surgical lung biopsy, in the absence of high-resolution computed tomographic features inconsistent with usual interstitial pneumonia

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a 30-day period with evidence of abnormal gas exchange and new radiologic infiltrates in the absence of an identifiable cause such as infection, heart failure, or pulmonary embolism.75 The HRCT features associated with acute exacerbations commonly consist of ground-glass opacities superimposed on pulmonary fibrosis (peripheral honeycombing and reticular opacities) (Figure 3). This phenomenon is poorly understood, may be observed at any time during the course of disease, and may occasionally be the presenting manifestation of IPF.73,75,76 In general, bronchoalveolar lavage is recommended to exclude an infectious process. Surgical lung biopsy reveals diffuse alveolar damage superimposed on UIP but is generally not indicated in the management of these patients.76 The mortality rate associated with acute exacerbation in IPF is 70% to 80% despite high-dose corticosteroid therapy and antimicrobial therapies that are commonly used.75,77,78 Combined Pulmonary Fibrosis and Emphysema Some patients with IPF may have preexisting emphysema resulting in a condition that has been termed combined pulmonary fibrosis and emphysema.52-54 Debate continues as to whether this condition represents a distinct entity with unique susceptibility to both fibrosis and emphysema or merely a coincidence of pulmonary

FIGURE 3. High-resolution computed tomographic features of acute exacerbation in idiopathic pulmonary fibrosis. Diffuse ground-glass opacities are seen bilaterally, greater on the right, superimposed on underlying usual interstitial pneumonia characterized by reticular opacities and honeycombing in the subpleural tissues.

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fibrosis occurring in patients with preexisting emphysema related to smoking. Affected patients are predominantly male, and nearly all have a smoking history.52,53,79 High-resolution computed tomography reveals emphysema in the upper lobes and fibrosis in the lower lobes.53,79 Some studies suggest that this combined process may be associated with a high incidence of PH and a worse prognosis.53,54,80 Pulmonary Hypertension Pulmonary hypertension appears to be relatively common in IPF, being detected in approximately 30% to 40% of patients overall and nearly 85% of patients with end-stage or advanced disease.42,43,81 The presence of PH may be overlooked in patients with IPF given the similarities in clinical presentation. Pulmonary hypertension in patients with IPF is generally associated with worse pulmonary function and hypoxemia but can sometimes be seen in patients with mild lung disease. The latter observation has raised the possibility of pulmonary vascular remodeling beyond hypoxic vasoconstriction associated with the progressive parenchymal fibrotic process. Pulmonary hypertension in patients with combined pulmonary fibrosis and emphysema may relate to reduction in the total alveolar capillary area by fibrotic and emphysematous destruction of the pulmonary vascular bed.82,83 Sleep-related oxygen desaturation may contribute to the development of PH in some patients with IPF.84 The presence of PH in patients with IPF is associated with decreased exercise capacity and worse survival.42,43,85 Supplemental oxygen therapy is used for patients with PH and hypoxemia, although there has been no evidence proving a beneficial effect on survival. A clinical trial assessing the effect of sildenafil therapy in patients with advanced IPF (diffusing capacity