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Idiopathic Interstitial Pneumonias

Usual Interstitial Pneumonia versus Nonspecific Interstitial Pneumonia

University of Michigan Health System, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Fernando J. Martinez, M.D., M.S., University of Michigan Health System, 1500 East Medical Center Drive, 3916 Taubman Center, Ann Arbor, MI 48109–0360. E-mail: fmartine{at}umich.edu

ABSTRACT

Diffuse parenchymal lung diseases (DPLDs) are a group of disorders that involve the space between the epithelial and endothelial basement membranes. Recent guidelines for the classification of DPLDs recommended separating patients into several categories, including (1) DPLDs of known cause, (2) granulomatous DPLDs, (3) rare DPLDs with well-defined clinicopathologic features, and (4) the idiopathic interstitial pneumonias (IIPs). The IIPs are further subdivided into categories that include usual interstitial pneumonia (idiopathic pulmonary fibrosis [IPF] if the usual interstitial pneumonia is idiopathic in origin) and nonspecific interstitial pneumonia. In numerous cohorts, IPF has been associated with impaired prognosis compared with nonspecific interstitial pneumonia, except in the setting of markedly impaired physiology at presentation. It is therefore imperative for the health care provider to rapidly assess the likelihood of a patient having IPF. The diagnostic approach has been refined over the past several years, with much clearer recommendations addressing the optimal clinical, radiologic, and laboratory assessments of patients with IIPs. Similarly, therapeutic interventions have rapidly evolved, with less emphasis on standard immunosuppression and increasing focus on interventions targeting fibroproliferation. Numerous therapeutic trials have recently been completed, are ongoing, or are soon to begin patient recruitment. A multicenter, National Institutes of Health–funded clinical research network has been convened to target novel therapeutic approaches in well-designed controlled trials. The next few years will be an exciting time in the evaluation and treatment of DPLDs as increasing clinically relevant biological information is translated to novel diagnostic and therapeutic approaches.

Key Words: idiopathic interstitial pneumonia • usual interstitial pneumonia • nonspecific interstitial pneumonia • idiopathic pulmonary fibrosis

Diffuse parenchymal lung diseases (DPLDs) are a group of disorders that involve the space between the epithelial and endothelial basement membranes (1). Although over 200 diseases can result in such a syndrome, the resulting clinical, physiologic, and radiographic manifestations are often similar. Recent guidelines for the classification of DPLDs recommended the use of four categories: (1) DPLD of known cause (e.g., drugs, associated with a connective tissue disease, environmental exposure, etc.), (2) granulomatous DPLD (e.g., sarcoidosis), (3) rare DPLD with well-defined clinicopathologic features (e.g., lymphangioleiomyomatosis, pulmonary Langerhans' cell histiocytosis, pulmonary alveolar proteinosis, and eosinophilic pneumonia), and (4) the idiopathic interstitial pneumonias (IIPs; Figure 1) (1). The IIPs are further subdivided into usual interstitial pneumonia (UIP; idiopathic pulmonary fibrosis [IPF] if the UIP is idiopathic), desquamative interstitial pneumonia, respiratory bronchiolitis interstitial lung disease, acute interstitial pneumonia, cryptogenic organizing pneumonia, nonspecific interstitial pneumonia (NSIP), and lymphocytic interstitial pneumonia (Figure 1) (1). This article presents a "standard of care" approach to the diagnosis and management of UIP and NSIP.

View larger version (12K): [in this window] [in a new window]   Figure 1. Diffuse parenchymal lung diseases (DPLDs) consist of disorders of known causes (e.g., collagen vascular disease or environmental- or drug-related causes) and disorders of unknown cause. The latter include idiopathic interstitial pneumonias (IIPs), granulomatous lung disorders, and other forms of interstitial lung disease, including lymphangioleiomyomatosis, pulmonary Langerhans' cell histiocytosis/histiocytosis X, and eosinophilic pneumonia. The most important distinction among the IIPs is that between idiopathic pulmonary fibrosis (IPF) and the other interstitial pneumonias, which include nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis–associated interstitial lung disease (RBILD), acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia (COP), and lymphocytic interstitial pneumonia (LIP). Reprinted by permission from Reference 1. BOOP = bronchiolitis obliterans organizing pneumonia.

The general approach to a patient with DPLD is to identify the most likely diagnosis in an expeditious fashion. The American Thoracic Society (ATS) and European Respiratory Society (ERS) have recommended an integrated clinical, radiologic, and pathologic approach to the diagnosis of diffuse parenchymal lung diseases (1). A suggested approach includes a comprehensive assessment of clinical history, physical examination findings, selected laboratory studies, imaging studies, and, in selected patients, transbronchial or surgical lung biopsy (Figure 2). Numerous investigators have highlighted the guarded prognosis of patients with idiopathic UIP. One such comparison among differing IIP groups is highlighted in Figure 3 (2). In this series, the histologic picture of idiopathic UIP (i.e., a diagnosis of IPF) among a large cohort of patients with IIPs was associated with the worst hazard ratio for long-term mortality (hazard ratio, 28.46; 95% confidence interval [CI], 5.5–147). It is therefore imperative for the health care provider to rapidly assess the likelihood of a patient having IPF. This may be particularly difficult in the separation of IPF from idiopathic NSIP (3–5).

View larger version (21K): [in this window] [in a new window]   Figure 2. Algorithm outlining an approach for evaluating a patient with suspected interstitial lung disease (ILD). Bronch = bronchoscopy; DAD = diffuse alveolar damage; DIP = desquamative interstitial pneumonia; Dx = diagnosis; Hx = history; LIP = lymphocytic interstitial pneumonia; NSIP = nonspecific interstitial pneumonia; OP = organizing pneumonia; PE = physical examination; PFT = pulmonary function tests; RBILD = respiratory bronchiolitis interstitial lung disease; UIP = usual interstitial pneumonia; VATS = video-assisted thoracoscopy. Reprinted by permission from Reference 110.

View larger version (17K): [in this window] [in a new window]   Figure 3. Kaplan-Meier survival curves in patients with UIP (solid line, n = 106), NSIP (dotted line, n = 33), and RBILD/DIP(dashed line, n = 22) grouped by histologic classification (p < 0.00001). Reprinted by permission from Reference 2.

General Characteristics
A careful history is required in the initial evaluation of patients with DPLD. Important features include sex, age, comorbidities, drug exposures, and assessment of living and work conditions. Age is important because some DPLDs are more common in younger individuals (e.g., sarcoidosis, eosinophilic granuloma, familial IPF, and Gaucher disease), whereas others are more common in older patients (e.g., IPF). Similarly, sex may affect predisposition to certain DPLDs; lymphangioleiomyomatosis and pulmonary involvement in tuberous sclerosis are seen predominantly in premenopausal females, whereas women with IPF have an improved prognosis compared with men (2). The identification of a connective tissue disorder is particularly important. Although the histologic picture of NSIP is most frequently seen in this clinical setting (6–13), the prognosis of UIP is markedly improved if connective tissue disease is present compared with IPF (Figure 4) (14). The clinical features and natural history of idiopathic and connective tissue associated NSIP seem to be similar (13, 15).

View larger version (11K): [in this window] [in a new window]   Figure 4. Kaplan-Meier survival curves in patients with connective tissue–associated UIP (dashed line) and idiopathic UIP (solid line; log-rank test, p = 0.005). Reprinted by permission from Reference 14.

A patient's home environment may be an important source of exposure to new antigens and can result in DPLD, especially hypersensitivity pneumonitis (HP) (19). These points were highlighted by a multicenter study of 661 patients (400 in a derivation cohort, 261 in a validation cohort) evaluated for potential HP (20). A clinical prediction rule was generated with logistic modeling that demonstrated an excellent predictive ability (area under the curve of 0.93). The six predictors incorporated in the clinical rule included exposure to a known offending antigen (OR, 38.8; 95% CI, 11.6–129.6), positive precipitating antibodies to the offending antigen (OR, 5.3; 95% CI, 2.7–10.4), recurrent episodes of symptoms (OR, 1.20; 95% CI, 1.5–7.5), inspiratory crackles (OR, 4.5; 95% CI, 1.8–11.7), symptoms 4 to 8 h after exposure to an offending antigen (OR, 7.2; 95% CI, 1.8–28.6), and weight loss (OR, 2.0; 95% CI, 1.8–28.6). An appropriate exposure history is the most vital component suggesting a diagnosis of acute HP. These concepts may be more difficult (but more relevant) in the chronically symptomatic patient. For example, one group reported six cases with a histologic pattern on lung biopsy of NSIP but a well-defined clinical syndrome consistent with HP (21). In addition, chronic antigen exposure can be associated with a clinico-radiologic-pathologic picture that may be difficult to separate from IPF (22–27). One investigative group has used novel methodology to establish a unique gene expression pattern from lung tissue of patients with well-defined UIP in contrast to HP (28). Additional study is required to place this diagnostic approach in a clinical setting.

Patients with DPLD typically present with cough and dyspnea; this is true for IPF and NSIP. Table 1 enumerates summary results from numerous published studies. A longer duration of symptoms is generally noted in IPF, although overlap is present. A detailed account of current and previous medication use should be obtained because numerous prescription medications have been associated with the development of DPLD, including NSIP (29). An excellent Web-based resource is available to query for specific drugs and recent reports of pulmonary disease (www.pneumotox.com). Smoking can alter the development of DPLD and can affect the course of disease. Some DPLDs are seen almost exclusively in smokers (30, 31). Cigarette smoking has also been implicated in the development of IPF (32). In a multicenter study examining familial IIPs, a smoking history was strongly associated with DPLD in siblings (33). Furthermore, smoking may influence disease course. Two recent large series have suggested an improved survival in patients with IPF who are smokers (2, 34); this protective effect persisted after adjustment for other confounding factors and remains biologically unexplained.

PHYSICAL EXAMINATION

The physical examination is generally nonspecific. The characteristic finding is bibasilar crackles, which is seen with similar frequency in IPF and NSIP. Clubbing may be a bit more common in IPF, although it can be seen with NSIP (see Table 1). The physical examination may be helpful in identifying signs of underlying connective tissue disorders, which may make NSIP more likely or modify the natural history of UIP. Careful attention should be given to extrapulmonary manifestations of disease.

LABORATORY FEATURES

Routine laboratory tests and specific serologic studies may be useful in the evaluation of patients with DPLD. This is evident in the diagnosis of HP, where the presence of precipitating antibodies to an offending antigen has proven useful in a recent multicenter study (20). Similarly, laboratory studies may aid in the diagnosis of connective tissue–associated diseases. A minimum panel of initial laboratory investigations includes a complete blood count with differential, electrolytes, renal function studies, liver function studies, antinuclear antibodies, rheumatoid factor, and a urinalysis (16).

PHYSIOLOGY

Most DPLDs share a common pattern of physiologic abnormalities characterized by reduced lung volumes and impaired carbon monoxide diffusing capacity (DL_CO) (41). These abnormalities are not specific for an individual disorder, particularly when NSIP is contrasted with IPF. Atypical, physiologic presentations in patients with IPF who presented with preserved lung volumes have been described (42–44). These investigative groups implicated a positive smoking history in these patients. In the best-characterized cohorts, radiographic imaging confirmed the presence of concomitant emphysema. These patients with mixed IPF and emphysema seem to exhibit a high proportion of pulmonary vascular abnormality (44). Characteristic arterial blood gas abnormalities in DPLD include resting hypoxemia and increased alveolar–arterial difference in partial pressure (P[A-a]O₂); gas exchange abnormalities are more evident during exercise (41). This abnormality can be identified with simple testing, such as the 6-min walk study. One group has contrasted 6-min walk test results in IPF and NSIP (45). Table 2 enumerates the differences in exertional desaturation between the two groups. Both groups experience a similar degree of exertional desaturation.

Two groups have confirmed the prognostic value of resting and exercise-induced hypoxemia in IIP (55, 56). Several groups have extended this concept to the simpler 6-min walk study (45, 57, 58). Two of these groups have demonstrated a remarkably similar mortality in patients with IPF who exhibit a trough saturation of less than 88% during a room-air 6-min walk study, which is worse than patients without such level of desaturation (Figure 5). In addition, one of these groups has confirmed that a trough saturation of less than 88% is highly reproducible in the short term (58). The prognostic value of serial 6-min walk measurements requires further study.

View larger version (26K): [in this window] [in a new window]   Figure 5. (A) Kaplan-Meier survival curve for patients with UIP grouped by desaturation (oxygen saturation of 88% or less) on 6-min walk test (desaturators, dashed line; nondesaturators, solid line; p = 0.0018). Reprinted by permission from Reference 45. (B) Mortality in a small group of patients with IPF was higher in patients desaturating to 88% or lower during the 6-min walk test than in those without desaturation (p = 0.04). Desaturators (solid circles); nondesaturators (open circles). Reprinted by permission from Reference 58.

Radiographic studies are usually abnormal in patients with DPLD, although chest X-rays (CXR) and HRCT scans can be normal in approximately 10% of patients (59, 60). Although some CXR features may be helpful, the chest radiographic pattern is not specific, with studies demonstrating that a correct diagnosis is made in only 50% of cases (16). HRCT has dramatically altered the diagnostic evaluation of patients with DPLD. The technique allows a detailed evaluation of the lung parenchyma by using 1- to 2-mm-thick slices reconstructed with an algorithm that maximizes spatial resolution (61, 62). Several studies have confirmed that abnormalities can be identified when they are not visible on CXR (63). Furthermore, observer variability is decreased with HRCT compared with CXR, and a confident diagnosis is more likely to be made with HRCT (64).

HRCT is helpful in providing a diagnosis in some of the DPLDs, including IPF, lymphangitic carcinoma, sarcoidosis, silicosis, subacute HP, and pulmonary alveolar proteinosis (see Figure 2) (1, 16). Over the years, the diagnostic features of IPF have become better defined. In a sentinel study, Hunninghake and colleagues examined the diagnostic value of a clinical, radiologic, and pathologic diagnosis in 91 patients evaluated at multiple centers for suspected IPF (65). Using pathologic diagnosis as the gold standard, the PPV of an UIP diagnosis was high for the diagnosis by a core of expert radiologists (85%) and a core of expert clinicians (87%), in contrast to individual investigators at the referring institution (69%). When confined to patients in whom radiologists felt confident in the HRCT diagnosis ( 60% of the cases), the PPV of an IPF diagnosis improved (96%). These investigators noted that lower lobe honeycombing and upper lung irregular lines (Figure 6) were predictive of a HRCT diagnosis of UIP (66). Similar data have been reported from other single-center studies (51, 67, 68). Flaherty and colleagues extended these findings by assessing the prognostic value of a HRCT diagnosis in contrast to a pathologic diagnosis of UIP (51). Patients with typical HRCT features of UIP exhibited the worst survival (Figure 7).

View larger version (818K): [in this window] [in a new window]   Figure 6. (A, B) High-resolution images from patient with biopsy-proven UIP. Note the upper lobe septal thickening and basilar predominant, subpleural honeycomb change. (C, D) High-resolution images from patient with biopsy-proven fibrosing NSIP. Note the basilar predominant ground glass opacity with traction bronchiectasis. (E, F) High-resolution images from patient with biopsy-proven cellular NSIP. Note the basilar predominant ground glass opacity.

View larger version (16K): [in this window] [in a new window]   Figure 7. Kaplan-Meier survival curves for patients grouped by combining high-resolution computed tomography (HRCT) and histopathologic features as follows: histopathologic pattern showing NSIP and HRCT interpreted as indeterminate or NSIP (n = 23, dotted line), histopathologic pattern showing UIP and HRCT interpreted as indeterminate or NSIP (n = 46, dashed line), and histopathologic pattern showing UIP and HRCT interpreted as UIP (n = 27, solid line), p = 0.001. + = last follow-up visit; circle = death. Reprinted by permission from Reference 111.

The radiographic picture of NSIP has been evolving, although this remains somewhat controversial. Hartman and colleagues described the findings in 50 patients from multiple centers with biopsy-proven NSIP (70). Eleven of these patients had CT findings that were compatible with previous descriptions of NSIP, although 16 (32%) exhibited findings more compatible with UIP. In contrast, MacDonald and colleagues contrasted CT findings identified by four expert radiologists in 21 patients with NSIP with those of 32 patients with UIP (71). The only CT feature independently associated with NSIP was ground-glass attenuation. This finding is the salient HRCT feature of NSIP; in fibrotic variants, lobar volume loss, reticulation, and/or traction bronchiectasis can be seen (62) (see Figure 6). The distribution may be subpleural, peribronchovascular, or both; a basilar predominance is most frequently noted (62). Flaherty and colleagues noted that a radiologic diagnosis of probable or definite NSIP was confirmed pathologically in only 41% of cases; the remainder of cases exhibited histologic findings of UIP on surgical lung biopsy. These data suggest that a radiologic diagnosis of NSIP must be made with caution (72).

The accuracy of these diagnostic features has proven variable. Johkoh and colleagues presented HRCT images from 129 patients with various interstitial disorders (35 with UIP, 24 with bronchiolitis obliterans organizing pneumonia, 23 with desquamative interstitial pneumonia, 20 with acute interstitial pneumonia, and 27 with NSIP) in a blinded fashion to two observers (73). The two observers made an accurate diagnosis in 57% of the cases; a correct diagnosis was more likely with UIP (71%) than with NSIP (9%). These investigators have subsequently confirmed a high degree of accuracy in the HRCT diagnosis of UIP (100%) in 92 patients with cystic lung disease (74). Elliott and colleagues presented HRCT images from 25 patients with NSIP (five with connective tissue disease) and 22 patients with IPF to two thoracic radiologists (68). The overall accuracy of CT for IPF versus NSIP was 70%, with PPVs of 88% for IPF and 73% for NSIP. Varying results were noted by Aziz and colleagues, who presented 131 HRCT images of patients with DPLD (36 with NSIP, 24 with IPF) to 11 thoracic radiologists (5). Overall, observer agreement was modest ( = 0.48), with NSIP proving the most difficult diagnosis. Preliminary data suggest that the level of radiologist expertise may affect interobserver agreement (75). These data suggest that typical features of UIP are highly accurate in the hands of experienced radiologists. In an appropriate clinical setting, the diagnosis of IPF may be assured without the need for a surgical lung biopsy (see Figure 2). On the other hand, the diagnosis of NSIP generally requires a surgical lung biopsy (SLB; see below).

BRONCHOSCOPY/BRONCHOALVEOLAR LAVAGE/SLB

The role of bronchoscopy, bronchoalveolar lavage (BAL), and SLB for the diagnosis of DPLD continues to be debated. BAL is straightforward to perform, confers little risk, and can be diagnostic in certain cases (16). One group created a discriminant diagnostic model from BAL counts in a population of patients with sarcoidosis, HP, and IPF; this model was validated in a second group of patients with a similar distribution of DPLDs (76). A correct diagnosis was made in 94.5% of the patients. A second group examined BAL cell differential counts in a large group of patients (710 with interstitial lung diseases, 583 with inflammatory lung diseases, 455 with lung tumor mimicking interstitial diseases) (77). The absence of lymphocytes modestly improved diagnostic ability in IPF. On the other hand, the limited diagnostic value of BAL differential counts in separating fibrotic NSIP from IPF was highlighted by Veeraraghavan and colleagues, who noted remarkable overlap between the two disorders (78). In summary, BAL provides limited diagnostic value in separating NSIP from IPF, although it may provide diagnostic value if HP is in the differential.

Transbronchial biopsy adds a slight additional risk of bleeding and pneumothorax and can provide useful in the diagnosis of some DPLDs, including sarcoidosis (79). Transbronchial biopsy is of limited value in the diagnosis of IPF or NSIP due to the small amount of tissue that is obtained. One group retrospectively recorded the results of therapy based on transbronchial biopsies demonstrating inflammatory infiltration in the setting of a CT demonstrating diffuse parenchymal lung disease but without typical findings of UIP (honeycomb change) (80). These patients experienced physiologic improvement after steroid therapy. Additional prospective study is required to better define the role of such bronchoscopic sampling in the evaluation of patients with NSIP or IPF.

The role of SLB has become better defined and more straightforward given the advent of video-assisted thoracoscopy, a surgical procedure that can be performed in the outpatient setting (81). The diagnostic findings of SLB in IIPs have become better standardized with the recent consensus statement (1). The cardinal feature of UIP is bilateral, heterogeneous involvement, with a predilection for the lower lobes and peripheral (subpleural) regions (69, 82). The heterogeneity is visualized at low magnification and is characterized by areas of normal lung, interstitial inflammation, fibrosis, and honeycomb change observed concomitantly. Alveolar walls are thickened by collagen, extracellular matrix, and mild to moderate infiltration by lymphocytes, plasma cells, and histocytes. Hyperplasia of type II pneumocytes is also noted. Honeycomb cysts are composed of cystic, fibrotic airspaces that are frequently lined by bronchiolar epithelium and filled with mucin. Fibroblastic foci, aggregates of proliferating fibroblasts, and myofibroblasts are additional cardinal features of UIP.

The histologic findings of NSIP have been described in detail (1, 82, 83). Temporal homogeneity is a fundamental histologic feature in NSIP (82). There is a broad range of alveolar wall inflammation or fibrosis. At the cellular end of the spectrum, the abnormality consists predominantly of mild to moderate interstitial chronic inflammation (1). At the fibrosing end of the spectrum, the NSIP pattern is characterized by dense or loose interstitial fibrosis. Alveolar remodeling with honeycomb cyst formation and fibroblastic foci are absent or inconspicuous (1). The difficulty in histologic assessment of NSIP was highlighted by an ATS/ERS committee of expert pathologists, clinicians, and radiologists who examined the clinical, radiologic, and histologic findings in 305 cases of suspected NSIP (72). Only 67 of these cases were considered as compatible with NSIP; 17 satisfied criteria for a definite diagnosis. Histologic diagnosis of NSIP remains challenging.

Significant interobserver disagreement remains among expert pathologists (3, 4, 84, 85). Nicholson and colleagues presented biopsy findings in 83 patients (133 lobar biopsies) with DPLDs to 10 thoracic pathologists (4). The overall was modest (0.38), with more than 50% of the variability related to the presence of NSIP, particularly in its distinction from UIP. Preliminary data have suggested even greater interobserver discrepancy between pathologists with differing expertise (86). In part, this discrepancy reflects histologic variability within patients. Several groups have documented that histologic findings of NSIP and UIP are frequently noted in multiple lobes (and even in the same lobe) of patients undergoing SLB (85, 87, 88). Two of these groups have confirmed that the presence of UIP in any lobe from a patient with IIP was associated with impaired survival (Figure 8).

View larger version (34K): [in this window] [in a new window]   Figure 8. (A) Kaplan-Meier survival curves for patients with concordant UIP (n = 51, dashed line), discordant UIP (n = 28, solid line), and NSIP (n = 30, dotted line), grouped by histologic classification (p < 0.0003). + = last follow-up visit; circle = death. Reprinted by permission from Reference 85. (B) Kaplan-Meier survival curves for patients with concordant UIP (n = 25), discordant UIP-NSIP (n = 8), and concordant NSIP-NSIP (n = 31), grouped by histologic patterns. Patients with concordant NSIP-NSIP had a significantly better survival than discordant UIP-NSIP and concordant UIP (p = 0.02 and p = 0.04, respectively), but there was no significant difference between the concordant UIP-UIP and discordant UIP-NSIP groups (p = 0.48). Reprinted by permission from Reference 88.

The diagnosis of DPLD remains challenging. The variability in HRCT features, SLB findings, and interobserver agreement among expert interpreters complicates the situation significantly. Furthermore, the presence of a typical radiologic or histologic picture does not ensure a correct diagnosis without an appropriate clinical setting. The ATS and ERS have suggested an iterative approach to diagnosis that incorporates all available data in reaching a final diagnosis (1). One group has recently tested the effects of such a diagnostic approach. Figure 9 illustrates the approach taken to assess the impact of incorporating clinical, radiologic, and histologic information in achieving a final diagnosis by expert clinicians, radiologists, and pathologists (3). Table 3 demonstrates increasing interobserver agreement as additional data are added and interaction between the participants is allowed. These data strongly support an interactive approach between clinicians, radiologists, and pathologists in the diagnosis of an IIP. Table 4 illustrates that the greatest change in intraobserver agreement between the three clinicians and two radiologists occurs at the stage when histologic information becomes available. These data support the value of SLB in achieving a final diagnosis in many IIPs.

View larger version (34K): [in this window] [in a new window]   Figure 9. Schematic representation of the information presented to each of the participants at each step of a study assessing the role of an iterative approach to diagnosing IIP. SLB = surgical lung biopsy. Individuals made their diagnostic decisions without conferring in steps 1 and 2 and individually after conferring in steps 3–5. Reprinted by permission from Reference 3.

THERAPEUTIC APPROACHES

The therapeutic approach to IPF and NSIP has been rapidly evolving. A detailed description is beyond the scope of this article. The interested reader is referred to recent detailed reviews (72, 89–91). In large part, the evolving nature of therapeutic approaches reflects evolution of the concepts regarding the biological processes resulting in NSIP and IPF (92, 93).

The approach to therapy in NSIP has generally emphasized the use of antiinflammatory therapies, although no prospective, randomized, controlled trials exist to allow firm conclusions to be drawn. The impact of therapy is difficult to ascertain. Published data are generally limited to retrospective studies, with variable treatment regimens and follow-up (91). In general, improvement or stability has been reported, although relapses have been described; cellular NSIP seems to respond better than fibrosing NSIP. We prospectively studied 10 patients with NSIP and 29 patients with IPF treated with high-dose prednisone (1 mg/kg/d for 1–3 mo, with a subsequent taper) (2). Figure 10A demonstrates that 4 of 10 (40%) patients with NSIP improved (based on clinical-radiologic-physiologic [CRP] scores), five remained stable, and one deteriorated. Some investigators have reported improvement in HRCT scans with therapy (94, 95).

View larger version (25K): [in this window] [in a new window]   Figure 10. (A) Results of high-dose steroid therapy for 3 mo in 29 patients with UIP and 10 patients with NSIP. Response to therapy was assessed by change in clinical-radiologic-physiologic (CRP) score after 3 mo of therapy. Responders were defined as having a > 10-point drop in CRP score and a stable ± 10 change in CRP score; nonresponders were defined as having a > 10-point rise in CRP score. A difference in the distribution of response was seen between patients with UIP and patients with NSIP (p = 0.05, Fisher's exact test). Reprinted by permission from Reference 2. (B) Kaplan-Meier survival curves by response status in a cohort of patients with IPF treated with 3 mo of high-dose steroids. Response to therapy was assessed by change in CRP score after 3 mo of therapy. Responders were defined as having a > 10-point drop in CRP score and a stable ± 10 change in CRP score; nonresponders were defined as having a > 10-point rise in CRP score. A difference was seen between the groups, with the best survival seen in patients remaining stable during the initial 3 mo of steroid therapy (p < 0.001). Solid line = stable; dotted line = responder; nonresponder = dashed line; o = death; + = last follow-up visit. Reprinted by permission from Reference 96.

Given these unimpressive results, numerous small studies have combined cytotoxic agents with corticosteroids in patients with IPF. The majority of the data come from retrospective or uncontrolled studies (90). The most widely cited study was the small, prospective, controlled trial of Raghu and colleagues, who evaluated the effects of prednisone alone with prednisone plus azathioprine (98). Although most patients deteriorated, patients treated with combination therapy seemed to experience an age-adjusted survival benefit after 4 yr of follow-up. Collard and colleagues reported a case-control study of patients with IPF treated with combined cyclophosphamide and prednisone at one institution compared with untreated patients from a second institution (99). No survival differences were seen. Despite the limited available data, combined immunomodulatory therapy has been considered a standard therapeutic option by international recommendations (69).

As increasing insight has been accumulated into the pathogenesis of UIP (92, 93), therapy targeted at pathways involved in the fibroproliferative response have been studied in IPF. Recently completed or ongoing trials are enumerated in Table 5. The most noteworthy include the GIPF-001 study of IFN-1b in IPF (100). This large, controlled trial noted no difference in primary endpoint (progression-free survival) or most secondary endpoints. In patients defined as having milder disease (defined post hoc) or treatment-adherent (defined a priori), there was a suggestion of potential survival benefit. A much larger controlled trial is ongoing, with survival as the primary endpoint. A multicenter consortium has recently reported the results of a trial combining the antioxidant N-acetyl cysteine (NAC) with prednisone and azathioprine versus prednisone/azathioprine plus placebo (124). The group treated with combined immunosuppression and NAC (600 mg three times daily) demonstrated lower declines in FVC (9%) and DL_CO (24%) after 1 yr. Tolerability was similar in both groups, although significantly less bone marrow toxicity was seen with the addition of NAC to the combined immunosuppressive regimen. The longitudinal change in FVC and DL_CO in NAC/immunosuppressive-treated patients in this trial was remarkably similar to the placebo-treated patients in the GIPF-001 study (101), despite similar baseline characteristics among the cohorts (Figure 11). The role of such combination therapy can only be clearly defined with a placebo-controlled trial (125).

View larger version (61K): [in this window] [in a new window]   Figure 11. (A) Vital capacity as a percentage of predicted in azathioprine/prednisone/placebo- treated patients (dashed line) and N-acetylcysteine (NAC)–treated patients (solid line). Over 12 mo of follow-up, the NAC-treated patients experienced lesser decrease. Reprinted by permission from Reference 124. (B) DLCO as a percentage of predicted in azathioprine/prednisone/placebo-treated patients (dashed line) and NAC-treated patients (solid line). Over 12 mo of follow-up, the NAC-treated patients experienced lesser decrease. Reprinted by permission from Reference 124. (C) FVC, University of California–San Diego Shortness of Breath Questionnaire (UCSD SOBQ), DLCO, alveolar-arterial gradient (A-a gradient), and transitional dyspnea index (TDI) followed longitudinally over 72 mo in an IPF cohort treated with placebo. Solid circles = FVC, %predicted; solid squares = UCSD SOBQ score; solid triangles = DLCO, %predicted; solid diamonds = A-a gradient, mm Hg; asterisks = TDI score. Reprinted by permission from Reference 101.

CONCLUSIONS

A systematic, iterative approach to the patient with a DPLD should focus on a rapid and accurate diagnostic process. Assurance of an IPF diagnosis is the most important factor from a prognostic standpoint. From a prognostic standpoint, the accuracy of the IPF diagnosis is the most important factor. Therapeutic options include immunosuppressive therapy for NSIP and a series of therapeutic trials in patients with IPF. Early consideration for lung transplantation in IPF also seems to be a wise consideration.

FOOTNOTES

Conflict of Interest Statement: F.J.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form November 23, 2005; accepted in final form December 1, 2005)

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