Idiopathic pulmonary fibrosis
Authors: S. Harari, A. Caminati
Journal: Allergy (2005)

Idiopathic pulmonary fibrosis (IPF) is the most common of the interstitial pneumonias of unknown etiology and the most aggressive interstitial lung disease. IPF is confirmed by the identification of usual interstitial pneumonia (UIP) on surgical lung biopsy (1–5). The idiopathic interstitial pneumonias (IIPs) are a group of diffuse parenchymal lung diseases (DPLDs) also described as interstitial lung diseases1. The IIPs are a heterogeneous group of nonneoplastic disorders resulting from damage to the lung parenchyma by varying patterns of inflammation and fibrosis (1). The IIPs include the entities of IPF, nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP), acute interstitial pneumonia (AIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), desquamative interstitial pneumonia (DIP), and lymphocytic interstitial pneumonia (LIP). Original and new hypothesis for the pathogenesis of IPF [adapted from Ref. (7)]. It is important to emphasize that IPF is a progressive and irreversible illness and, until now, there has been no available drug that has been able to modify the progressive natural course of IPF and its usual terminal outcome (1, 2, 6). It is characterized by radiographically evident interstitial infiltrates predominantly affecting the lung bases and by progressive dyspnea and worsening of pulmonary function, pathologically by fibroblast proliferation and extracellular matrix accumulation resulting in irreversible distortion of the architecture of the lung (1). The current strict definition of IPF provides a new focus for basic and clinical research that will improve insight into the pathogenesis of this disorder and stimulate the development of novel therapies (7). IPF is defined as a specific form of chronic fibrosing interstitial pneumonia limited to the lung and associated with the histologic appearance of UIP on surgical (thoracoscopic or open) lung biopsy (1). Many older studies included several forms of IIP under the term 'IPF', but today the clinical label 'IPF' should be reserved for patients with a specific form of fibrosing interstitial pneumonia referred to as UIP (1, 2, 8). Historical grouping of disparate disorders under the heading of IPF makes it difficult to compare current and older studies. This observation also explains the discrepancies between older and newer investigations of IPF in reported natural history and response to therapy (7). The definite diagnosis of IPF in the presence of a surgical biopsy showing UIP includes the following: 1) exclusion of other known causes of interstitial lung disease such as drug toxicities, environmental exposures, and collagen vascular diseases; 2) abnormal pulmonary function studies that include evidence of restriction [reduced VC often with an increased forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio] and/or impaired gas exchange; and 3) abnormalities on conventional chest radiographs or high-resolution computed tomography (HRCT) scans (1). In the absence of a surgical lung biopsy, the diagnosis of IPF remains uncertain. However, in the immunocompetent adult, the presence of all of the following major diagnostic criteria as well as at least three of the four minor criteria increases the likelihood of a correct clinical diagnosis of IPF (1): Exclusion of other known causes of interstitial lung disease such as drug toxicities, environmental exposures, and collagen vascular diseases. Abnormal pulmonary function studies that include evidence of restriction (reduced VC often with an increased FEV1/FVC ratio) and/or impaired gas exchange. Bibasilar reticular abnormalities with minimal ground glass opacities on HRCT scans. Transbronchial lung biopsy (TBB) or bronchoalveolar lavage (BAL) showing no features to support an alternative diagnosis. Age >50 years. Insidious onset of otherwise unexplained dyspnea on exertion. Duration of illness ≥3 months. Bibasilar, inspiratory crackles (dry or 'velcro' type in quality). Idiopathic pulmonary fibrosis has been reported worldwide and does not have predilection by race or ethnicity. Incidence of IPF is estimated to be around seven cases per 100 000 per year in women and 10 cases per 100 000 per year in men (9), but it increases with older age (10). The disease occurs primarily in individuals between 50 and 70 years of age, and it appears to be infrequent in young people and extremely rare in children (1, 11, 12). The prevalence of IPF ranges from 13 cases per 100 000 for women to 20 cases per 100 000 for men (9), although these figures may underestimate the problem. The etiology is unknown. Recognition of IPF as a distinct entity with lesions that vary in age and location raised important questions about the established view that IPF was a disease in which parenchymal fibrosis was directly caused by chronic inflammation (6–8). Although the pathogenetic mechanisms remain to be determined, the prevailing hypothesis holds that fibrosis is preceded and provoked by a chronic inflammatory process that injures the lung and modulates lung fibrogenesis, leading to the end-stage fibrotic scar. An important assumption was that if the inflammatory cascade was interrupted before irreversible tissue injury occurred, fibrosis might be avoided. Thus, this theory explains the initial enthusiasm for corticosteroid and cytotoxic therapy for IPF (7). However, there is little evidence that inflammation is prominent in early disease, and it is unclear whether inflammation is relevant to the development of the fibrotic process. Evidence suggests that inflammation does not play a pivotal role. Inflammation is not a prominent histopathologic finding, and epithelial injury in the absence of ongoing inflammation is sufficient to stimulate the development of fibrosis (Fig. 1). In addition, the inflammatory response to a lung fibrogenic insult is not necessarily related to the fibrotic response (13). Clinical measurements of inflammation fail to correlate with stage or outcome and it is now clear that potent anti-inflammatory therapy does not improve outcome. A growing body of evidence suggesting that IPF involves abnormal wound healing in response to multiple, microscopic sites of ongoing alveolar epithelial injury and activation associated with the formation of patchy fibroblast–myofibroblast foci, which evolve to fibrosis (13). In addition to emerging evidence that inflammation is not more prominent in early stages of UIP (8), it is becoming clear that the primary sites of ongoing injury and repair are the regions of fibroblastic proliferation, so-called fibroblast foci (8, 13, 14). These small aggregates of actively proliferating myofibroblasts and fibroblasts constitute many microscopic sites of ongoing alveolar epithelial injury and activation associated with evolving fibrosis (8, 14, 15). After injury, the alveolar epithelium must initiate a wound healing process to restore its barrier integrity. One important step is the rapid reepithelialization of the denuded area through epithelial cell migration, proliferation, and differentiation. In IPF, this response seems slow and inadequate. The alveolar epithelium shows a marked loss of or damage to type I cells, hyperplasia of type II cells, and altered expression of adhesion molecules and MHC antigens (16–19). Where the basement membrane remains intact, type II cells attempt to recover the epithelial surface; these cells express several enzymes, cytokines, and growth factors (16). In UIP, the capacity of type II alveolar cells to restore damaged type I cells is seriously altered, resulting in epithelial cuboidalization and the presence of transitional reactive phenotypes (16), abnormalities in pulmonary surfactant (20, 21), and alveolar collapse (22). In IPF, epithelial cells express several cytokines and growth factors that may promote fibroblast migration and proliferation and extracellular matrix accumulation. Alveolar epithelial cells may initiate the pathologic process, producing most of the factors [e.g. transforming growth factor (TGF)-β1, tumor necrosis factor (TNF)-α] (23–25) inducing the phenotypic changes seen among fibroblasts during the progression to end-stage fibrosis. Present evidence suggests that the earliest, and possibly the only, morphologic change associated with subsequent progression to dense fibrosis is the presence and extent of fibroblastic foci in the injured lung (8, 14, 15). After an initial insult or injury, the normal physiologic response of inflammation leads to matrix stimulation with proliferation and altered phenotype of mesenchymal cells (fibrogenesis) to stop the injury and provide temporary repair. This is usually followed by matrix mobilization (fibrolysis) and apoptosis of repair cells, both mesenchymal and inflammatory, and return to normal organ function. In the case of IPF, this normal process is diverted, with retention of altered mesenchymal cell phenotype (fibroblasts and myofibroblasts) through avoidance of apoptosis, with continued matrix production and reduced matrix mobilization. In addition, the altered stromal cell population and activated epithelium release a series of profibrogenic factors, such as TGF-β and platelet-derived growth factor, which interact with the deposited matrix at the site of abnormal repair (26), thus creating a new microenvironment in patchy areas of the lung. Other areas remain in normal structure and environment. The ability of matrix to sequester many growth and differentiation factors to create a 'fibrogenic' microenvironment is well established (26, 27). Many of these factors act on inflammatory cells in normal passage through the tissue modulating susceptibility to normal apoptosis, resulting in accumulation of these cells and apparent 'inflammation.' Thus, 'inflammation' is a result of a new microenvironment caused by abnormal interaction between mesenchyme and epithelium (28, 29). Nevertheless, the centrality of fibroblasts/myofibroblasts in IPF/UIP still remains controversial and unproven (13, 30–32). However, the type of inflammatory response may modulate tissue injury, fibrosis or both during the evolution of IPF. The inflammatory response in IPF is thought to resemble closely a Th2-type immune response. There are eosinophils, mast cells and increased amounts of the Th2 cytokines interleukin-4 and interleukin-13 (33–37). In murine models of lung disease, animals whose response to tissue injury is predominantly of the Th2-type are more prone to pulmonary fibrosis after lung injury than those with a predominantly Th1 response (35). Although the Th2 and Th1 phenotypes are not as well defined in IPF as they are in asthma and animal models, their potential importance is one rationale for undertaking trials of immunomodulators such as interferon-γ in an attempt to switch the inflammatory response to a more Th1-like phenotype (38). IPF begins insidiously, with the gradual onset of dyspnea or nonproductive cough. Dyspnea is usually progressive and is the most prominent and disabling symptom (39–42). In general, patients have symptoms for >6 months before seeking medical attention and, unfortunately, most of them are assisted by lung specialists 1 or 2 years after the beginning of symptoms. The disorder generally presents in the fifth and sixth decades. Associated systemic symptoms, such as low-grade fever and myalgia, may be present but are not common. A detailed occupational history, with attention to exposure to asbestos, silica, or other respirable toxins, is critical to rule out a pneumoconiosis that may mimic IPF (7). The physical examination in most patients (more than 80%) reveals fine bibasilar inspiratory crackles (velcro rales). With progression of the disease, rales extend toward the upper lung zones. Clubbing is noted in 25–50% of patients (11, 40, 43). The rest of the physical examination is unremarkable until late in the course of the disease, when severe pulmonary hypertension and cor pulmonare may become apparent (11, 44). Franck findings of collagen vascular disease (such as rashes, inflammatory arthritis, myositis, dry eyes, dry mouth, Raynaud's phenomenon, etc.) suggest an alternative diagnosis (1). The routine laboratory evaluation is often not helpful except to 'rule out' other causes of DPLD. Mild anemia, increases in markers of systemic inflammation (erythrocyte sedimentation rate or C-reactive protein level), hypergammaglobulinemia and nonspecific increases in rheumatoid factor and antinuclear antibodies are observed in up to 30% of patients (39–41). In the absence of other findings of a systemic illness, the presence of autoantibodies does not imply an underlying collagen vascular disease. Elevation of lactate dehydrogenase (LDH) may be noted but is a nonspecific finding common to pulmonary disorders. The typical findings of pulmonary function test are consistent with restrictive impairment. The lung volumes [total lung capacity (TLC), functional residual capacity (FRC), and residual volume (RV)] are reduced at some point in the course of disease. Early on, or more commonly in patients with superimposed chronic obstructive pulmonary disease, the lung volumes may be normal (1, 45). Expiratory flow rates, FEV1, and FVC are often decreased because of the reduction in lung volume, but the FEV1-to-FVC ratio is maintained or increased in IPF. The DLCO is reduced and may actually precede the reduction of lung volume. The resting arterial blood gases may be normal initially or may reveal mild hypoxemia and respiratory alkalosis. With exercise the arterial O2 pressure and arterial O2 saturation fall. Importantly, the abnormalities identified at rest do not accurately predict the magnitude of the abnormalities that may be seen with exercise (1, 46). Virtually all patients with IPF have an abnormal chest radiograph at the time of presentation (11). Indeed, basal reticular opacities are often visible on previous chest radiographs in retrospect for several years before the development of symptoms. Conversely, a normal chest radiograph cannot be used to exclude microscopic evidence of UIP on lung biopsy (47, 48). Peripheral reticular opacities, most profuse at the lung bases, are characteristic findings on the chest radiograph of patients with IPF (Fig. 2) (49). These opacities are usually bilateral, often asymmetric, and are commonly associated with decreased lung volumes. When a 'confident' diagnosis of IPF is made on the basis of the chest radiograph (compared with an 'uncertain' or 'unlikely' diagnosis of IPF), it is correct in 48% (50) to 87% (51, 52) of cases. Radiographic evidence of pleural disease or lymphadenopathy is not usually found in IPF. UIP is characterized on HRCT by the presence of patchy, predominantly peripheral, subpleural, bibasal reticular opacities, often associated with traction bronchiectasis (Fig. 3). Honeycombing is common (Fig. 4) (53). Ground glass attenuation is common, but is usually less extensive than reticular abnormality (54, 55). Architectural distortion, reflecting lung fibrosis, is often prominent. Lobar volume loss is seen with more advanced fibrosis. The extent of disease on HRCT correlates with fibrosis on biopsy and with physiologic impairment (7, 56). On serial scans in treated patients, the areas of ground glass attenuation may regress, but more commonly progress to fibrosis with honeycombing (57–60). Honeycomb cysts usually enlarge slowly over time (53). The CT pattern of UIP due to IPF can be indistinguishable from that found in UIP due to asbestosis and to collagen vascular disease. Patients with chronic hypersensitivity pneumonitis or with end-stage sarcoidosis may uncommonly develop a CT pattern similar to that of UIP (1). The CT pattern of NSIP may be indistinguishable from UIP but ground glass attenuation is the predominant finding in the majority of cases of NSIP and is the sole abnormality in about one-third of cases (60). Chest radiograph of a patient with IPF. Chest radiograph reveals peripheral, subpleural reticular opacities, most profuse at the lung bases. Chest HRCT in a patient with IPF. HRCT shows patchy, predominantly peripheral, subpleural, bibasal reticular abnormalities, traction bronchiectasis and bronchiolectasis and irregular septal thickening. There is also ground glass. Chest HRCT in a patient with IPF. HRCT shows predominantly peripheral and subpleural fibrosis with honeycombing. Reticular abnormality on CT correlates with fibrosis on histopathologic examination (54, 55). Honeycombing on CT correlates with honeycombing on biopsy. When ground glass attenuation is associated with reticular lines, traction bronchiectasis, or bronchiolectasis, it usually indicates histologic fibrosis. Isolated ground glass attenuation may correlate with evidence of interstitial inflammation, airspace filling by macrophages, patchy fibrosis, or a combination of these (54, 61, 62). A study examined the ability of physicians expert in the diagnosis of interstitial lung diseases to identify correctly HRCT scans from patients with biopsy-proved IPF (63). When the expert group made a confident diagnosis of IPF from the CT scan and basic clinical data, they were correct in over 80% of the cases. However, over half the patients with proved IPF had an uncertain diagnosis on the basis of HRCT and clinical evaluation. Thus, experienced clinicians can make a confident diagnosis of IPF in many patients without the need for biopsy (63–65). When the diagnostic studies do not support a confident diagnosis of IPF or the clinician is less experienced, a lung biopsy is needed for diagnosis (65). BAL has been helpful in elucidating the key immune effector cells driving the inflammatory response in IPF (66, 67). Increases in polymorphonuclear leukocytes (PMNs), neutrophil products, eosinophils, eosinophil products, activated alveolar macrophages, alveolar macrophages products, cytokines, growth factors for fibroblasts, and immune complexes have been noted in BAL of patients with IPF (1). Despite its value as a research tool, the diagnostic usefulness of BAL in IPF is limited. Although it is important in excluding alternative causes (e.g. malignancy, infections, eosinophilic pneumonia, pulmonary histiocytosis X), there is little evidence that it provides practical information to support a diagnosis of IPF, to monitor disease activity, or to predict the response to therapy. The pattern of inflammatory cells identified may be helpful in narrowing the differential diagnosis of fibrosing interstitial pneumonias but is not diagnostic of IPF. An increase in neutrophils (levels >5%) is noted in 70–90% of patients, an associated increase in eosinophils (levels >5%) is apparent in 40–60% of patients, and an additional increase in lymphocytes is noted in 10–20% of patients (68). However, these findings are seen in a wide variety of fibrosing lung conditions other that IPF. A lone increase in lymphocytes is uncommon in IPF (<10% of patients), so when present, another disorder should be excluded (e.g. granulomatous infectious disease, sarcoidosis, hypersensitivity pneumonitis, COP, NSIP, LIP). Increases in the percentage of neutrophils or eosinophils (or both) in BAL fluid have been associated with a worse prognosis in some but not all studies (1, 69). BAL lymphocytosis, found in fewer than 20% of patients with IPF, has been associated with a more cellular lung biopsy, less honeycombing, and a greater responsiveness to corticosteroid therapy (70). However, these relationships are too inconsistent in individual patients for BAL to be used as a reliable prognostic guide (66, 70–76). Usual interstitial pneumonia is the histopathologic pattern that identifies patients with IPF. Surgical lung biopsy, either open thoracotomy or preferentially by video-assisted thoracoscopy, provides the best tissue samples to distinguish UIP from other forms of IIP and to exclude other processes that mimic IPF when identified in the setting of interstitial lung disease of unknown etiology (1). Biopsy specimens should be obtained from areas that reflect the entire gamut of gross disease patterns as guided by intraoperative inspection of the lung surface or correlation with HRCT abnormality (55, 77–79). Areas of gross honeycombing should be avoided, as they show end-stage disease, and areas that show intermediate or relatively preserved lung should specifically be selected for biopsy, as the lung specimen must have fibrotic lung adjacent to normal lung for the pathologist to identify the UIP pattern (60). It is also valuable to biopsy more than one lobe as fibrotic and inflammatory interstitial diseases often show heterogeneity in the histologic patterns and the additional specimen provides essential diagnostic information (80). Avoiding the tips of the lobes, including the lingula, has been recommended (81–83), as these sites may show nonspecific fibrotic or inflammatory lesions. Because the diagnosis relies on grading lesions that vary in both age and location, a large piece of lung parenchyma is required. Therefore, TBBs are used only to rule out other disorders that mimic IPF but are not helpful in making the diagnosis of UIP (1, 53, 84). Although TBBs are abnormal in many cases, they do not confirm UIP. In addition, because of the small sample size (2–5 mm), TBBs should not be used to assess the degree of fibrosis or inflammation. TBB may exclude UIP by identifying an alternative specific diagnosis in the right clinical setting or with the use of special histopathologic methods or stains (1). Surgical lung biopsy is recommended in patients with suspected IPF and without contraindications to surgery. This recommendation is important in any patients with clinical or radiologic features that are not typical for IPF. In the instances when atypical clinical, radiographical, or physiologic features of IPF are encountered, it has been shown that histopathologic patterns other than UIP are more likely to be found, thereby often defining a process with a differential prognosis or resulting in alternative approaches to management. However, despite recommendations that histologic examination be routinely performed in these patients, two studies from United Kingdom have shown that lung biopsies are obtained in only 28–33% and 8–12% of patients, respectively (11, 85), and in 11% of patients in one study from the United States (9), likely reflecting the pessimism that findings on lung biopsy will alter the proposed treatment plan (86). In the period 1998–2000, 1382 cases were submitted to the Italian Register on diffuse infiltrative lung disorders (RIPID); the most frequent disease registered was IPF (37.6%). HRCT was considered as the most important tool for final diagnosis in the majority of cases (74.4%); 39.4% of patients underwent TBB and 39.2% of patients underwent BAL; a surgical biopsy was performed in 20.5% of patients (87). Actually, a major purpose of morphologic assessment is to distinguish UIP from other histologic subsets of IIP that differ in a number of clinical features, particularly in the response to treatment and prognosis. The gross morphologic findings in IPF range from a normal appearance in early cases to diffuse honeycombing in the later stages of the disease process (Fig. 5). The pleural surface of the lungs has a cobble-stoned appearance due to the retraction of scars along the interlobular septa. The overall lung size tends to be small. Disease involvement is usually heterogeneous and worse in the lower lobes. A subpleural, peripheral, and paraseptal distribution of fibrosis is often seen. The histologic hallmark and chief diagnostic criterion is a heterogeneous appearance at low magnification with alternating areas of normal lung, interstitial inflammation, fibrosis, and honeycomb change (Fig. 6). This marked variation from field to field, both in the degree of lung involvement and in the nature and appearance of the interstitial infiltrate, reflects the temporal heterogeneity of the interstitial process and constitutes the essence of the diagnostic criteria for UIP (1, 88–90). The fibrosis, often in a subpleural and/or paraseptal distribution, is temporally heterogeneous, with two major types: 1) dense scarring and honeycombing and 2) fibroblastic foci scattered at the edges of the dense scars (Fig. 7). The fibroblast foci represent sites of acute lung injury, and they are likely the earliest lesion of UIP recognizable by light microscopy. The dense fibrosis causes remodeling of the lung architecture resulting in collapse of alveolar walls and formation of cystic spaces or honeycombing (Fig. 8). The fibrotic thickened alveolar septa tend to be lined by hyperplastic cuboidal epithelial cells or a bronchiolar type of epithelium. Occasionally, the pneumocytes lining the alveolar walls are hyperplastic, with abundant cytoplasm, large hyperchromatic nuclei, and prominent nucleoli. Bronchiolar or cuboidal epithelium usually lines areas of cystic remodeling or honeycomb fibrosis. Interstitial inflammation is usually mild to moderate, consisting mostly of lymphocytes and a few plasma cells (91). Patients who are biopsied during an accelerated phase of their illness may show a combination of UIP and diffuse alveolar damage (92–94). It is important to acknowledge histologic features that distinguish other IIP from IPF, as the clinical course and management is different. DIP/RB-ILD is characterized by a relatively uniform thickening or thickening centered on the bronchioles of the alveolar septa, accompanied by a striking accumulation of pigment-laden intra-alveolar macrophages (95). AIP involves a diffuse fibroproliferative response to synchronous alveolar injuries; histologic features are identical to those of the exudative, proliferative and/or fibrotic phases of DAD (96). NSIP is manifested as varying degrees of inflammation and fibrosis that are uniformly distributed within the interstitium of the lung (97). In COP, inflammation is centered on the peribronchial interstitium and alveolar ducts; characteristic plugs of granulation tissue occlude the distal air spaces (1, 7, 98). Gross morphologic findings in IPF. The pleural surface of the lung has a cobble-stoned appearance due to the retraction of scars along the interlobular septa. There is fibrotic areas and honeycomb cystic changes with predominantly subpleural distribution. Histopathologic features of IPF. The figure shows a preparation of an open-lung biopsy specimen from a patient with UIP. At low magnification the interstitium is altered by a strikingly heterogeneous and nonuniform inflammatory and fibrosing process with alternating zones of inflammation, fibrosis, honeycomb change, and intervening patches of normal lung (hematoxylin and eosin, ×100, histologic section kindly provided by Prof. A. Pesci). Histopathologic features of IPF. The figure shows a fibroblastic focus. The fibroblastic focus is visible as a nodule of spindle cells arranged in linear fashion against a pale-staining extracellular matrix. The dense collagenous scar is juxtaposed with fibroblastic focus; the adjacent alveolar septa show little histologic abnormality (hematoxylin and eosin, ×200, histologic section kindly provided by Prof. A. Pesci). Histopathologic features of IPF. The figure shows a preparation of an open-lung biopsy specimen with dense scarring and honeycombing: the dense fibrosis causes remodeling of the lung architecture resulting in collapse of alveolar walls and formation of cystic spaces or honeycombing. Areas of end-stage honeycomb lung are found in almost all biopsies of UIP and may be extensive (hematoxylin and eosin, ×200, histologic section kindly provided by Prof. A. Pesci). Radiographic findings in patients with IIP demonstrated lobar heterogeneity. Flaherty et al. (99) hypothesized that heterogeneity of histologic diagnosis might exist from lobe to lobe in patients with suspected IIP. This study showed that interlobar and intralobar histologic variability is present in IIP and the presence of a UIP pattern in any sample confers a poor prognosis. Given the poor prognosis associated with a UIP pattern on any biopsy, the most important goal of the biopsy is finding UIP. Patients with a UIP pattern in all lobes were categorized as having concordant UIP; those with a pattern of UIP in at least one lobe but an NSIP pattern in another lobe were categorized as having discordant UIP. Interlobar histologic variability is common in IIP. This complicates the histologic classification of the disease. The histologic classification in 26% of the patients in the study could have differed between UIP and NSIP if only one biopsy had been obtained. Histologic heterogeneity has received little attention in the literature (80, 100, 101). No previous studies have analyzed the frequency of coexistence of histologic patterns suggestive of NSIP and UIP in the same patient. Heterogeneity of histologic patterns among lobes documents that sampling errors may result from protocols that obtain only one biopsy specimen for IIP. The study of Flaherty et al. emphasizes the value of obtaining a biopsy specimen from multiple lobes during a diagnostic evaluation for IIP (99). A histologic pattern of UIP in any lobe, even if a pattern of NSIP is seen in other lobes, is associated with a poor prognosis; Flaherty et al. propose that these patients be classified as having UIP. This proposal is based largely on finding that UIP-concordant and UIP-discordant patients had similar relative risks of mortality, and that the mortality of these groups was poor as compared with that for patients with NSIP (99). At present, there are no proven therapies for IPF. Conventional management of IPF is primarily based on the concept that suppressing inflammation prevents progression to fibrosis (102). However, the use of aggressive immunosuppressive and cytotoxic treatment regimens has largely failed to reduce the death