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American Journal of Respiratory and Critical Care Medicine Vol 173. pp. 1066-1071, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.2601011

Pulmonary and Critical Care Updates

Update in Diffuse Parenchymal Lung Diseases 2005

Fernando J. Martinez and Michael P. Keane

Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan; and Division of Pulmonary and Critical Care Medicine, University of California, Los Angeles, Los Angeles, California

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

CLINICAL ADVANCES

A number of publications have shed light on important clinical concepts surrounding the clinical evaluation and management of diffuse parenchymal lung diseases (DPLDs). These include approaches to idiopathic interstitial pneumonias (IIPs), including nonspecific interstitial pneumonia (NSIP) and idiopathic pulmonary fibrosis (IPF; idiopathic usual interstitial pneumonia [UIP]), connective tissue–associated DPLD, hypersensitivity pneumonitis (HP), and lymphangioleiomyomatosis (LAM).

IIPs
A series of sentinel observations have addressed diagnostic issues, staging approaches, unique phenotypes, and management strategies for IIPs.

Diagnostic approach.
The approach to diagnosis in patients with DPLDs has continued to evolve over the past decade. A recent centennial review described the major impact of high-resolution computed tomography (HRCT) in guiding the diagnostic approach to patients with suspected IIP (1). It is evident that stereotypical imaging features have been described for many DPLDs, including some of the IIPs (2). The diagnostic accuracy of the radiological features of UIP has been demonstrated in well-designed clinical studies (3–5). Despite these data, there remains diagnostic confusion regarding the separation of UIP from other IIPs, particularly NSIP (6). On the other hand, increasing data have suggested that predominance of ground-glass opacity with no honeycombing is more common in NSIP. In a recent series, such a pattern was seen in 96% of patients with NSIP and 59% of patients with UIP (7). Unfortunately, the overall diagnostic accuracy of HRCT for separating these two disorders was 70% in this series.

The contrast between expert and less experienced radiologists in applying HRCT criteria to the diagnosis of IPF has recently been reported in data from a landmark clinical therapeutic trial (8). As part of this trial, HRCT scans were interpreted by clinical site radiologists and an expert radiology core using predefined criteria. The core radiologists agreed with a diagnosis of IPF in 99% of those diagnosed by site radiologists; little difference was found if the clinical site was an "academic" center or a community-based practice. A survey of American College of Chest Physician members (52.6% responses to the survey) suggested that 67% of respondents accepted HRCT diagnosis for IPF (9). Interestingly, one investigative group has demonstrated that interaction between expert clinicians and radiologists improves the interobserver agreement of the former in evaluating patients with IIPs (10). It is evident that a consensus is developing that typical features of UIP in the appropriate clinical setting can be used to accurately diagnose IPF. In other IIPs, particularly NSIP, the data may be more variable and a surgical lung biopsy remains an important part of the diagnostic approach.

Concurrent emphysema and IPF on HRCT may identify a varying phenotype in IPF. Two groups have recently described such a picture. In one cohort, 47% of patients exhibited pulmonary hypertension at presentation and 55% during a mean of 2.1 yr of follow-up (11). Survival was 87.5% at 2 yr and 54.6% at 5 yr, with a median survival of 6.1 yr. In a smaller cohort of eight patients with upper lobe predominant emphysema and basilar fibrotic changes consistent with UIP, seven of eight patients exhibited echocardiographic pulmonary hypertension (12).

The role of histopathologic evaluation has similarly evolved over the past several decades (1). The histologic criteria for DPLDs, including the IIPs, have become better accepted. Unfortunately, significant interobserver disagreement remains among expert pathologists (13). The majority of the variability relates to distinguishing NSIP from UIP. This has been highlighted by a retrospective study comparing local, general pathologist interpretation with that of an expert pathologist (14). The histopathologic interpretation by the specialist differed from the general pathologist in 52% of cases. It is evident that additional work is required to standardize pathologic interpretation.

Staging.
Several investigators have continued to highlight the prognostic value of pulmonary function studies in both IPF and NSIP (8, 15). Two recent studies have confirmed that a baseline decrease in DLCO is highly predictive of mortality in IPF and NSIP (8, 15). The work of Jegal and colleagues is particularly germane because they examined a large cohort of patients with IPF (n = 131) and NSIP (n = 48). Multivariate modeling confirmed that a very low baseline DLCO seems to predict impaired survival, independent of histologic diagnosis, confirming the previous findings of another group (16). Based partly on these results, one group has proposed classifying patients with IPF and NSIP as exhibiting advanced disease if the baseline DLCO is less than 39% predicted and limited if the DLCO is greater than 40% predicted (17). The prognostic value of serial changes in physiologic parameters has been further supported by the finding that a 6-mo decrease in FVC of greater than 10% was predictive of survival (15), confirming the findings of other groups (18, 19). On the other hand, in the placebo-treated arm of a large therapeutic trial in IPF, a decrease in FVC of more than 10% predicted exhibited a sensitivity of 60%, specificity of 75%, positive predictive value of 31%, and negative predictive value of 91% in predicting survival (20).

Several groups have confirmed the prognostic value of a simple 6-min walk study in IPF (21–23). Two of these groups confirmed a remarkably similar mortality in patients with IPF who demonstrated a trough saturation of less than 88% during a room-air 6-min walk study (21, 23). One of these groups examined a cohort of patients with fibrotic IIP serially and confirmed an excellent reproducibility in 6-min walk distance but poor reproducibility in the amplitude of oxygen desaturation (23). On the other hand, they confirmed that a trough saturation of less than 88% was highly reproducible in the short term. It is evident that baseline and longitudinal changes in pulmonary physiologic parameters have a clear role in the clinical assessment and management of patients with IIP.

Unique phenotypes.
The importance of a family history of fibrosing lung disease was demonstrated by a report characterizing 111 families with two or more cases of IIPs among first-degree family members (24). Within these families were 309 affected and 360 unaffected individuals (237 members, 25%, refused to participate). A thorough review confirmed that older age, male sex, and a history of smoking cigarettes were associated with the development of fibrosing interstitial pneumonia (IP). Importantly, 45% of the pedigrees demonstrated phenotypic variability with various subtypes of IPs present within the families. A smaller, retrospective analysis of 15 families with familial IPF suggested that the clinical, radiologic, and pathologic findings were more similar in familial IPF cases than those with nonfamilial disease (25). Importantly, outcome was similar between familial and nonfamilial IPF.

The natural history of IPF has been further defined by the identification that acute exacerbations of disease occur with a greater frequency than previously suspected. Examination of the natural history and pace of death in a carefully evaluated cohort of patients with IPF enrolled in the placebo arm of a multicenter therapeutic trial suggested that 47% of patients who died during a median follow-up of 72 wk died with an abrupt (occurring within minutes to hours) or acute (<= 4 wk) pace of deterioration before death (26). Overall, approximately 8.9% of deaths in this cohort died after abrupt or acute deterioration. A small retrospective study presented details in seven patients who presented with an acute deterioration in dyspnea (< 28 d; median, 14 d) (27). CT scans in all patients demonstrated ground-glass opacities and airspace consolidation, whereas surgical lung biopsies (in five patients) or autopsies (in two patients) demonstrated underlying UIP and superimposed diffuse alveolar damage. Further prospective data are required to define the incidence, natural history, and the optimal diagnostic and therapeutic approach to acute exacerbations of IPF.

Management strategies.
Therapeutic options for the IIPs have evolved over the past decade (1). In the case of IPF, this has been particularly evident given the lack of definitive data supporting efficacy for currently available therapies. The standard paradigm of disease pathogenesis, which suggested a predominantly inflammatory process, has been challenged by an aberrant host response to epithelial cell injury with resulting fibroproliferation.

Several groups have provided additional controlled data that have shed further light, and raised new questions, regarding therapeutic options in IPF. Azuma and colleagues reported the results of a prospective, double-blind, placebo-controlled trial of pirfenidone, a novel compound with pleiotropic antifibrotic effects (28). One hundred and seven patients with IPF were randomized to pirfenidone or placebo in a study with a novel primary endpoint, the change in lowest SpO2 during a steady-state 6-min exercise test. The primary endpoint did not reach significance in the overall group. However, in the 80 of 107 patients who were able to complete the exercise test at baseline, improvement favoring pirfenidone was noted. Change in VC at 9 mo favored pirfenidone but not TLC, DLCO, or resting PaO2. The study was terminated early by the data safety monitoring board after 14% of the patients in the placebo group met predetermined criteria for an acute exacerbation compared with none in the pirfenidone group. Additional therapeutic trials are ongoing to better define the therapeutic effect, optimal dose, and risk–benefit of pirfenidone in IPF.

A multicenter European group applied concepts of increased oxidative stress in IPF (described below) by performing an elegant controlled trial of azathioprine/prednisone/placebo versus azathioprine/prednisone/N-acetyl cysteine (NAC) in 182 patients with IPF (29). The study was powered to detect a treatment difference of 15% for VC and 20% for DLCO after 1 yr. Using last-observation-carried-forward methodology, there was a statistically significant difference between the two treatment groups favoring the NAC arm (relative difference of 9% in VC and 24% in DLCO). In addition, the NAC-treated group experienced significantly lesser bone marrow toxicity. These data clearly support that NAC provides beneficial clinical and physiologic effects when added to azathioprine and prednisone in IPF. A thoughtful editorial highlighted the inherent difficulty in extrapolating that such "triple combination" therapy should be considered standard therapy in patients with IPF given the absence of placebo control for the azathioprine/prednisone combination (30). It is interesting to note that the longitudinal change in FVC and DLCO with the triple combination was remarkably similar to that noted in the placebo arm of two recent trials (26, 28).

An additional interesting study examined the role of modulating the prothrombotic state in patients with IPF by completing an open-labeled, placebo-controlled trial of anticoagulation in addition to prednisone (31). Unfortunately, there was differential dropout, with 8 of 31 patients in the anticoagulation not participating compared with none of 33 patients in the anticoagulant arm. There was no dramatic difference in survival time or hospitalization-free survival, the primary endpoints, although overall mortality was worse without anticoagulation (hazard ratio, 2.9; 95% confidence interval, 1.0–8.0). The major difference appeared to relate to the mortality from acute exacerbations of IPF. The dropouts and open-label nature of the study limit the interpretation of its results, but certainly suggests that additional investigation into this novel therapeutic approach is warranted.

Miscellaneous DPLDs
Several investigative groups provided important insight into the characteristics and complications of LAM. Ryu and colleagues presented preliminary results of a 3-yr, multicenter registry of patients with LAM (32). With aggressive recruitment, the six centers recruited and characterized 243 patients (both incident and prevalent cases) with both sporadic and tuberous sclerosis complex (TSC)–associated LAM. From this well-characterized cohort, numerous important observations flowed, including that spontaneous pneumothorax was the sentinel event leading to diagnosis in about one-third of cases. In contrast to previous reports, the age range was relatively broad (18–76 yr), with more than one-third of patients being postmenopausal. Comparison between sporadic (n = 196) and TSC-associated disease (n = 34) yielded important information, including similar symptoms but a greater prevalence of renal angiomyolipomas and nephrectomy in patients with TSC. Overall for the cohort there was significant impairment in health-related quality of life. Additional clinically relevant information was provided by Taveira-DaSilva and colleagues who examined bone mineral density (BMD) in a large cohort (n = 211) of patients with LAM (33). Importantly, 70% of patients had abnormal BMD, with greater abnormality associated with greater severity of lung disease, menopause, and oophorectomy. After adjusting for baseline lung function and baseline BMD, biphosphonate therapy but not progesterone therapy was associated with lower rate of bone loss. These data highlight an important comorbid condition in patients with LAM.

HP remains a challenging diagnostic and therapeutic dilemma. Fink and colleagues reported the results of a National Heart, Lung, and Blood Institute and the Office of Rare Diseases workshop exploring needs and opportunities for HP research (34). The authors of this workshop summary highlighted recent advances, and continuing limitations of diagnosis in HP, suggesting the need to consider revising diagnostic criteria to include a presumptive diagnosis in the absence of a clear-cut source of exposure. The wide variety of exposures resulting in HP was briefly reviewed as were concepts in radiologic, physiologic, and histopathologic assessment. In conclusion, a series of recommendations were made to advance future research in this area, including the need for the following: (1) establishing a multicenter, collaborative network; (2) defining risk factors affecting occurrence and natural history of disease; (3) establishing reasonable and validated case definitions; (4) exploring the use of biomarkers; (5) developing and supporting population-based studies; (6) better defining the natural history of disease; (7) developing a standardized battery of antigens known to cause HP; and (8) using quantitative CT and HRCT in prospective studies of well-defined HP cases.

Several groups provided important data in connective tissue–associated DPLD. Ito and colleagues reported clinical, physiologic, and histopathologic results in 33 consecutive cases of lung disease complicating primary Sjögren's syndrome culled from multiple centers (35). NSIP was the most frequently seen histopathologic pattern (61% of cases, all but one fibrosing). In the majority of patients, steroids were administered (85% of cases); the 5-yr survival in the entire cohort was 84%, and in those patients with NSIP, 83%. A low PaO2 and microscopic honeycombing were associated with impaired survival. Several of these same investigators also reported results of a retrospective study of 18 patients with well-defined rheumatoid arthritis who underwent surgical lung biopsy for lung disease (36). Ten patients had a UIP pattern on biopsy whereas six exhibited an NSIP pattern; five patients with UIP died, whereas none with NSIP died during a median follow-up of approximately 4 yr in both groups.

PATHOBIOLOGICAL CONCEPTS

Oxidative Stress
There has been significant interest in the role of cellular redox state in the progression of IPF. The lung has a number of antioxidant defense mechanisms to deal with both reactive oxygen species and reactive nitrogen species. Kinnula and coworkers (37) reviewed the role of oxidative stress in the progression of IPF and suggested that cellular oxidative stress may have a critical role in the gene expression of a variety of profibrotic factors. The recently published European multicenter study of NAC in IPF described above lends further support to this concept of oxidative stress (29). However, despite the salutary effect on lung function, there was no effect on survival (29).

The Alveolar Macrophage
The importance of inflammation in the progression of pulmonary fibrosis has been debated over the last few years. Reynolds reviewed the role of the alveolar macrophage in the elaboration of a variety of inflammatory mediators that have been implicated in the pathogenesis of pulmonary fibrosis (38). His perspective nicely delineates the evolution and revision of hypotheses over time and makes interesting reading for all about to embark on a career in investigative pulmonary medicine.

The alveolar macrophage is believed to have a pivotal role in the development of idiopathic pulmonary alveolar proteinosis because antibodies to granulocyte-macrophage colony–stimulating factor (GM-CSF) impair alveolar macrophage differentiation. The study by Tazawa and colleagues showed that treatment of patients with inhaled GM-CSF restored alveolar macrophage function and underscores the importance of normal alveolar macrophage function to the maintenance of homeostasis in the lung (39).

Discoidin domain receptor-1 (DDR1) is a receptor-associated tyrosine kinase that is activated by collagen and expressed on macrophages. Matsuyama and colleagues have shown that DDR1 expression was higher on CD14-positive cells from the bronchoalveolar lavage fluid (BALF) of patients with IPF as compared with patients with chronic obstructive pulmonary disease or healthy control subjects (40). These findings were confirmed using immunohistochemistry of IPF tissue specimens where DDR1 was found on interstitial inflammatory cells (40). Activation of DDR1 led to the expression of a variety of inflammatory mediators from isolated macrophages (40). These findings suggest that collagen itself, through its interaction with macrophages, may be an important stimulus for progressive fibrosis.

Transforming Growth Factor-beta and Fibrosis
Activins are members of the transforming growth factor (TGF)-beta family that enhance proliferation and differentiation of fibroblasts and that have been implicated in the pathophysiology of pulmonary fibrosis. Aoki and colleagues demonstrated the expression of activin protein in macrophages and fibroblasts in rat lung after bleomycin administration (41). They then administered the activin binding protein follistatin and were able to attenuate the development of fibrosis after bleomycin administration (41). Bonniaud and colleagues demonstrated that inhibition of the TGF-beta1 receptor (also known as the activin receptor–like kinase-5 [ALK5]) can attenuate the development of fibrosis in rats after the overexpression of TGF-beta1 (42). The most interesting aspect of this study was the fact that the inhibitor is an orally active small-molecular-weight drug that has therapeutic potential for human diseases such as IPF. The role of the TGF-beta pathway in the development of fibrosis was further highlighted in another study from Bonniaud and colleagues demonstrating the importance of the Smad3 pathway in the development of fibrosis after overexpression of interleukin 1 (IL-1) (43). Furthermore, TGF-beta1 has been recently shown to induce proliferation of interstitial fibroblasts through the induction of fibroblast growth factor (FGF)-2 (44). However, TGF-beta1 is not the only path to fibrosis as it has been demonstrated that IL-13 can induce fibrosis in the absence of TGF-beta1 (45). Interestingly, IL-13 also induces fibrosis in a TGF-beta1–dependent manner, and this has recently been demonstrated to occur through the IL-13{alpha}2 receptor, which was previously believed to be a nonsignaling receptor (46).

Imatinib and Platelet-derived Growth Factor
Imatinib mesylate (also known as Gleevac in the United States and Glivec in Europe) is a potent inhibitor of tyrosine kinase, which has been shown to be highly active against chronic myeloid leukemia and gastrointestinal stromal tumors. It is also a specific inhibitor of platelet-derived growth factor receptor tyrosine kinase. Aono and coworkers demonstrated the efficacy of imatinib mesylate in the inhibition of bleomycin-induced pulmonary fibrosis in mice (47). The major effect was on the proliferation of mesenchymal cells, with little effect on inflammation (47). In a similar study of radiation-induced fibrosis, Abdollahi and colleagues found that three different receptor tyrosine kinase inhibitors (including imatinib) attenuated the development of fibrosis after radiation (48). These studies suggest that imatinib or other receptor tyrosine kinase inhibitors may have therapeutic benefit in the treatment of pulmonary fibrosis.

Fibroblasts, Bone Marrow–derived Precursor Cells, and Epithelial-to-Mesenchymal Transition
There is increasing interest in the role of circulating mesenchymal precursor cells in the pathogenesis of pulmonary fibrosis. One of the challenges has been the identification of specific markers for fibroblasts and mesenchymal cells in the lung. Lawson and colleagues demonstrated that fibroblast specific protein-1 (FSP-1) might be a useful marker in vivo (49). They showed that FSP-1 was present in fibroblasts but not macrophages or type II cells and colocalized to collagen-producing cells in the bleomycin model of pulmonary fibrosis (49).

The role of bone marrow–derived or circulating mesenchymal precursor cells in the pathophysiology of fibrosis remains an area of intense investigation. Rojas and coworkers demonstrated the importance of an intact bone marrow in the repair of the injured lung, whereas Moore and colleagues showed an important role for CCR2 in the recruitment and activation of bone marrow–derived fibrocytes in the promotion of fibrosis (50, 51). The specific conditions that stimulate the release and recruitment of reparative cells as opposed to fibrosis promoting myofibroblast precursors remain to be determined.

An alternative hypothesis as to the source of myofibroblasts in IPF is the concept of epithelial-to-mesenchymal transition (EMT). This had previously been shown to occur in the kidney but until recently had not been demonstrated in the lung. Willis and colleagues showed that alveolar epithelial cells undergo EMT when chronically exposed to TGF-beta1 (52). They also found that, in tissue samples from patients with IPF, there were cells that coexpressed epithelial and mesenchymal markers, suggesting that the in vitro observations are relevant in vivo (52). Kasai and colleagues confirmed the in vitro findings and showed that TGF-beta1 induced EMT through Smad2 (53).

A third possibility for the accumulation of fibroblasts and myofibroblasts in the lung is local proliferation or resistance of fibroblasts to apoptosis. Frankel and colleagues demonstrated that tumor necrosis factor-{alpha} sensitizes both normal and IPF pulmonary fibroblasts to Fas-induced apoptosis (54). They suggested that the relative lack of inflammation in IPF favors fibroblast accumulation by reducing the sensitivity to apoptosis (54). The findings would also suggest that inhibition of tumor necrosis factor might favor fibroblast accumulation in IPF.

Vascular Remodeling
The role of vascular remodeling in pulmonary fibrosis has received attention over the last few years. This was further highlighted in the study by Burdick and colleagues demonstrating that CXCL11 could inhibit bleomycin-induced pulmonary fibrosis in mice through the inhibition of new vessel formation (55). CXCL11 is highly induced by interferon and has an important role in innate immunity. Further support for a role of vascular remodeling in pulmonary fibrosis was seen in the study by Hamada and coworkers (56). They transfected the gene for the soluble vascular endothelial growth factor (VEGF) receptor (sflt-1) into the skeletal muscle of mice that received intratracheal bleomycin (56). This expression of the soluble receptor and the subsequent inhibition of VEGF activity were associated with a decrease in vascular remodeling as assessed by the expression of von Willebrand factor (56). Furthermore, there was an associated reduction in fibrosis (56).

Pediatric Interstitial Lung Disease
Mutations in the surfactant genes are associated with severe neonatal lung disease and interstitial lung disease in children. Mice that are deficient in surfactant protein C develop increased and prolonged pulmonary fibrosis with enhanced epithelial cell apoptosis after treatment with bleomycin (57). ABCA3 is a member of the ATP-binding cassette family of proteins that mediate translocation of a variety of substrates across membranes. Mutations in the ABAC3 gene have been associated with fatal neonatal lung disease due to surfactant deficiency (58). Bullard and colleagues found that three of four patients with desquamative interstitial pneumonitis had ABAC3 mutations on both alleles (59).

Sarcoidosis
Sarcoidosis has been considered a Th1-mediated disease and the chemokine receptors CXCR3 and CXCR6 are expressed on Th1 cells. Agostini and colleagues investigated the role of CXCL16 and its receptor CXCR6 in sarcoidosis (60). In keeping with the Th1 hypothesis, they found that 98% of BALF lymphocytes from patients with sarcoid expressed CXCR3 (60). The mean percentage of lymphocytes expressing CXCR6 was approximately 50% in active sarcoid and 20% in inactive disease (60). The predominant cellular source of CXCL16, as assessed by immunohistochemistry, appeared to be monocytes/macrophages and epithelial cells (60). The regulation of CXCR6 expression on peripheral T cells was similar to the regulation of CXCR3 with both IL-15 and IL-18 leading to up-regulation of CXCR6 receptor expression, although in a more delayed fashion than with CXCR3 (60).

Further support for IL-18 in sarcoidosis is seen in the study of Kelly and colleagues who described a role for endotoxin in the up-regulation of IL-18, which they found to be elevated in BALF of patients with sarcoidosis (61). They show that endotoxin is responsible for the up-regulation of IL-18 in THP-1 cells in response to epithelial lining fluid from patients with active sarcoidosis (61). The authors found increased levels of endotoxin in BALF of patients with active sarcoid as compared with recovered patients (61). There was also evidence of bacterial DNA (Moraxella catarrhalis and Haemophilus influenzae) in 19 of 26 patients with sarcoid (61). In contrast, patients who had recovered from sarcoid had no evidence of bacterial DNA (61). They also found increased incidence of the –607 C/C genotype of the IL-18 promoter in a population of 97 Irish patients with sarcoidosis (61). However, there was no difference in promoter activity between the C/C and C/A genotypes in response to LPS, and they therefore propose that this single nucleotide polymorphism may be in linkage disequilibrium for another functional mutation (61).

CCR2 and CCR5 are additional chemokine receptors that are expressed on Th1 cells and associated with Th1 profiles. Valentonyte and coworkers studied three CCR2 gene polymorphisms in 1,203 patients with sarcoidosis and their families (62). Case-control comparisons and family-based genetic analyses did not support previous findings of a relationship between CCR2 polymorphism and sarcoidosis, although they did confirm linkage disequilibrium, suggesting that there is a susceptibility gene in proximity to the CCR2 gene (62). Spagnolo and colleagues studied several CCR5 polymorphisms in two cohorts of British and Dutch patients with sarcoidosis and two cohorts of British and Dutch control subjects (63). They found one of the haplotypes was associated with the presence of parenchymal disease, although there was no association with susceptibility to sarcoidosis, suggesting that this gene polymorphism was acting after disease induction (63).

FOOTNOTES

DOI: 10.1164/rccm.2601011

Conflict of Interest Statement: F.J.M. was a consultant and a speaker for Intermune dating to the last calendar year. He was a coinvestigator in the GIPF-007 study by Intermune. The total compensation with Intermune has been less than $10,000. He was the principal investigator of the BUILD 1 at the University of Michigan, which was sponsored by Actelion. The personal total compensation was less than $10,000. He was a member of the Encysive steering committee of a selective endothelin antagonist being investigated in scleroderma-related pulmonary parenchymal disease. Given the potential conflict with IPF NET studies, he has relinquished his role on this steering committee. He has been a member of the Co-Therix steering committee for an inhaled vasodilator (Iloprost) in IPF-related pulmonary hypertension. This relationship has ended. He has been a member of several Pfizer advisory boards, CME committees, and Speaker's Bureau relating exclusively to COPD. His total compensation from Pfizer was greater than $10,000 but less than $20,000. He has been a member of several Boehringer Ingelheim advisory boards, CME committees, and Speaker's Bureau relating exclusively to COPD. His total compensation from Boehringer Ingelheim was greater then $10,000 but less than $20,000 and he has not been involved with any IPF-related compounds. M.P.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form January 9, 2006; accepted in final form January 17, 2006

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