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Pharmacological Therapy for Idiopathic Pulmonary Fibrosis
Past, Present, and Future

NHLBI Workshop Summary

Published in the Am J Respir Crit Care Med Vol 160. pp 1771- 1777, 1999 Internet address: www. atsjournals. org

ROBERT J. MASON, MARVIN I. SCHWARZ, GARY W. HUNNINGHAKE, and ROBERT A. MUSSON
Department of Medicine, National Jewish Medical and Research Center, Denver; Division of Pulmonary and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado; Division of Pulmonary Medicine, University of Iowa Hospital and Clinic, Iowa City, Iowa; and Division of Lung Disease, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland

Idiopathic pulmonary fibrosis (IPF) is a devastating illness for which current therapy is minimally effective. If medical therapy for IPF is going to improve over the next decade, controlled clinical trials will be needed to evaluate new drugs and treatment regimens. To date, very few multicenter trials have been conducted in IPF compared with diseases with a similar mortality (Table 1). Current therapy, which usually includes corticosteroids with or without a cytotoxic agent, has evolved without the support of large, well-controlled clinical trials. One reason for the paucity of clinical trials is that the number of patients is limited and an adequate trial would require multiple centers in order to recruit sufficient numbers of patients. Until recently, it was thought that only 5/ 100,000 individuals in the United States develop IPF per year. However, more recent data indicate that the incidence is much higher (1). More importantly, multicenter trials require uniform diagnostic criteria and outcome variables. Although there have been concerns about diagnostic criteria, substantial progress has been made recently in our understanding of the pathogenesis, diagnostic criteria, and outcome variables that are necessary to support clinical trials in IPF and IPF-related interstitial lung diseases. Finally, there are candidate new therapies that are ready for critical evaluation.


TABLE 1
MORTALITY IN IPF AND OTHER DISEASES

Disease

Mortality
IPF 50% at 5 yr (13)
COPD FEV1.0 , 30% predicted 50% at 3 yr (60)
COPD and long-term oxygen therapy 50% at 5 yr (61)
Acute myocardial infarction (seen in emergency room) 25% at 5 yr (62)
Coronary bypass surgery (3 vessels) 30% at 4 yr (63)
Lung cancer 85% at 5 yr (64)
Breast cancer 20% at 5 yr (64)
Prostate cancer 15% at 5 yr (64)
Cirrhosis with variceal bleeding 50% at 4 yr (65)

Definition of abbreviation: COPD 5 chronic obstructive pulmonary disease.


This report summarizes a workshop sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and Office of Rare Diseases on September 9-10, 1998 to review current medical therapy and opportunities for future investigation of the pathogenesis and therapy for IPF and related diseases. This conference was built on the discussions and consensus achieved at prior NHLBI workshops in 1990 (2) and 1994 (3) and integrated more recent insights into diagnosis, pathogenesis, and therapy. Recently, there has been significant progress in case definition and our understanding of the pathologic spectrum of IPF and IPF-related interstitial lung diseases (4- 6). A great deal of effort has been put forward on case definition by international professional societies and will be published soon. The participants believe that a consensus can also be reached on the pathologic classification of IPF, the role of high-resolution computerized tomography (HRCT) lung scans, and clinical and physiological criteria for the diagnosis of these diseases. In addition, there is greater knowledge of the pathogenesis of these diseases (7-11). The participants also felt that studies on pathogenesis have pointed to several new independent potential avenues of therapy and classes of potentially therapeutic agents. However, there remains variability in the therapeutic response between IPF and IPF-related illnesses. To increase our understanding of this spectrum of diseases and their response to therapy, the participants indicated that specific diagnosis is required, and this can only be accomplished with a complete clinical, radiographic, and pathologic assessment of individual cases. This report draws on the presentations of the participants, using material they provided, and the recommendations as synthesized by the organizers and discussants.

Clinical research in pulmonary fibrosis may have additional benefits for other fibroproliferative diseases such as atherosclerosis, cirrhosis, and connective tissue diseases. Similarities between atherosclerosis and pulmonary fibrosis were discussed, and there were common themes concerning the importance of certain growth factors, cytokines, and cell-cell interactions. The biologic principles of pathogenesis and, therefore, the opportunities for therapy are similar for these diseases. Therefore, the total benefit from studies of pulmonary fibrosis may also impact other fibroproliferative diseases. However, pulmonary fibrosis occurs in the very special microenvironment of the lung. Although observations made in other fibroproliferative diseases can guide the design of studies and help prioritize agents for therapy, the ultimate test still requires specific evaluation in patients with pulmonary fibrosis. Ultimately, efficacy of therapy requires formal studies with sufficient numbers of patients in order to provide convincing results.


CASE DEFINITION OF IPF
IPF is a specific form of fibrosing interstitial pneumonia limited to the lung and has the histopathologic pattern of usual interstitial pneumonitis (UIP) upon analysis of a surgical lung biopsy. The definitive diagnosis of IPF requires a surgical lung biopsy. Because it remains a diagnosis of exclusion, a detailed clinical assessment is required to exclude other diffuse parenchymal diseases. Most patients are over 50 yr of age and report an insidious onset of progressive dyspnea and nonproductive cough over months to years. Inspiratory crackles are noted on examination of the chest and finger clubbing is present in approximately 25%. Chest radiographs show bilateral peripheral-based reticular opacities and honeycombing predominantly involving the lower lung zones. Physiology reveals reduced lung volumes with restrictive physiology, a diminished single-breath diffusing capacity, and hypoxemia with exercise.

A concern of the conference participants was that in most instances the diagnosis of IPF can not be reliably established without a surgical biopsy. A critical issue for therapeutic trials is that the investigators must be confident of the diagnosis of a particular interstitial lung disease, and this is best achieved by a review panel that should consider all available information. There are some cases of IPF with significant pleural based honeycombing on HRCT and without other significant radiographic abnormalities that can be reliably diagnosed as IPF with over 90% confidence (12). However, if there is any doubt in the diagnosis, a surgical biopsy is indicated. Interpretation of data on the responsiveness to corticosteroid therapy in earlier studies of IPF is difficult to evaluate because precise pathologic diagnoses were not established. For the purpose of future clinical trials, UIP must be differentiated from bronchiolitis obliterans with organizing pneumonia (BOOP), nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), acute interstitial pneumonia (AIP), lymphocytic interstitial pneumonia (LIP), respiratory bronchiolitis associated interstitial lung disease (RBILD), and chronic hypersensitivity pneumonitis (HP).


SUMMARY OF PAST THERAPEUTIC TRIALS
A number of prior studies have evaluated potential therapies for patients with IPF (5, 13-26). Most of these studies have evaluated the effects of corticosteroids, cytotoxic agents, or colchicine, although in a few studies other drugs were tested (27, 28). In most studies, the number of patients was too small to determine efficacy, and the design of the studies did not always include a parallel placebo-controlled group.

Corticosteroids are the mainstay of therapy in IPF. Many studies, especially early studies, reported that 10 to 30% of patients with IPF have an initial, objective improvement with this form of therapy (13-15, 24). Reevaluation of these studies has questioned whether most of the patients who responded to therapy truly had IPF (4). There are a number of reasons for this reevaluation. First, some of the patients in these studies had a collagen vascular disease and, therefore, did not have IPF. Second, there were few biopsies performed to establish a diagnosis of IPF. Thus, it is unlikely that all of the patients in these studies would be classified as IPF by our current criteria. Two additional observations suggest that the responsive patients had a disorder other than IPF. In general, the patients who responded to therapy were younger than 50 yr of age and were female. Most patients with these demographic characteristics do not have UIP on lung biopsy by our current criteria. Recent studies of well-defined patients with IPF suggest that few, if any, patients with IPF respond to corticosteroid therapy. No studies have determined that corticosteroids alter survival when compared with untreated patients.

Several studies have evaluated the effects of cytotoxic agents and noted beneficial effects in the treatment of patients with IPF. An early study from the Brompton Hospital suggested that therapy with cyclophosphamide and prednisone improves survival compared with therapy with prednisone alone (16). However, the same reservations regarding patient selection that were noted previously for clinical trials of corticosteroids apply to this study. Others have suggested that cyclophosphamide slows the decline in pulmonary function in patients with IPF but does not alter survival (22, 25). Similar observations and reservations exist regarding the clinical trials on the efficacy of azathioprine (18).

Two studies evaluated colchicine for the treatment of IPF (19, 29). One compared prednisone alone to prednisone plus colchicine and there was no additional benefit of colchicine (29). In another study, the effects of colchicine alone were similar to that of prednisone alone (19). None of the patients had an initial response to therapy, and pulmonary function continued to decline in all patients. The median survival was unchanged, suggesting little effect of the drugs. The only benefit of colchicine therapy was fewer side effects when compared with prednisone.

As an aggregate, these observations suggest that current therapy has minimal or no beneficial effect for patients with IPF. In addition, the two most commonly used agents (prednisone and cyclophosphamide) are associated with significant side effects. These observations provide impetus to identify new forms of therapy for this disease and to define the dose regimen for maximal benefit with minimal side effects from standard immunosuppressive therapy.

ETIOLOGY AND PATHOGENESIS
Etiology
The prior NHLBI-sponsored workshops stressed the need for genetic markers of susceptibility and for expanded studies on the genetics and pathogenesis of familial IPF (3). These issues were reaffirmed at the present meeting, and the development of new tools for molecular epidemiology and methodological advances provided by the Human Genome Project provide an opportunity for important advances. In future clinical trials of patients with IPF, samples of DNA should be collected for future investigation of genetic markers. A central repository of DNA samples and lung biopsies of patients with familial IPF would be useful and may provide the genetic material for defining this important subset of patients with IPF. The issue of environmental factors contributing to the pathogenesis of IPF remains open, and additional case control studies with matched, well-defined cases of IPF to define environmental associations would be informative. In addition, investigation of the potential role of DNA viruses in the pathogenesis of these diseases is warranted. Although no viral particles are observed in electron micrographs of biopsies of patients with IPF, a systematic evaluation for viral DNA has not been reported.

Pathogenesis
Several plausible schemes for the pathogenesis of IPF have been proposed (7-9, 30). These schemes are not mutually exclusive. For simplicity and focusing research questions and new therapeutic options, these diagrams commonly depict inflammatory cells acting directly on fibroblasts through a variety of inflammatory mediators, cytokines, and growth factors (Figure 1). However, the interaction of the inflammatory cascade with parenchymal lung cells is also important. Because this pathologic process occurs within the microenvironment of the distal gas exchange units of the lung, i.e., alveoli and terminal bronchioles, there are also important interactions of inflammatory cells with pulmonary epithelial cells and endothelial cells. It should be noted that not only inflammatory and parenchymal cells affect fibroblasts, but fibroblasts also alter inflammatory and parenchymal cells. Hypotheses about specific cell types and mediators in pulmonary fibrosis have been reviewed previously and will not be presented in this report because it was not a major focus of this workshop.

 

Inflammatory cells and mediators, effects on  fibroblasts

Figure 1. Pathogenesis of pulmonary fibrosis. There are numerous pathways that can lead to pulmonary fibrosis and none are mutually exclusive. In this diagram, important cell-cell interactions that do not involve fibroblasts are not shown in order to focus attention on the role of fibroblasts. This scheme poses a problem in that specific targeted therapy would be ineffective because of the redundancy of pathways toward fibrosis. However, it is highly likely that only a few of these pathways are critical in human IPF. Studies with KGF in rats and gene deletion studies in mice indicate that a single growth factor or receptor might be highly effective. Therapy need not be directed at the whole inflammatory response as is the current rationale for corticosteroids and cytotoxic agents. Abbreviations: IL-4 5 interleukin-4; FGF-2 5 fibroblast growth factor-2, basic FGF; TGF-b 5 transforming growth factor-beta; TNF-a 5 tumor necrosis factor; PDGF 5 platelet-derived growth factor; IL-1 5 interleukin-1; IGF-1 5 insulin-like growth factor-1; HB-EGF 5 heparin binding epidermal-like growth factor; gIFN 5 gamma interferon; PGE2 5 prostaglandin E2.

In the normal lung, the interstitium of the alveolar wall is thin and the number of fibroblasts is limited. Most fibroblasts and collagen fibers occur along blood vessels and conducting airways. The balance of fibrogenic and antifibrogenic factors must be toward suppression of fibroblast proliferation and matrix production. However, we know little about the antifibrogenic factors that are present in the normal lung. The identification of these antifibrogenic factors as well as those that occur in the late-term fetal lung when the mesenchyme decreases might provide new insight and novel approaches to the treatment of pulmonary fibrosis.

The major targets of therapy have focused on the inflammatory cells, and this has led to the use of anti-inflammatory agents. However, corticosteroids and cytotoxic drugs are minimally effective in IPF. Newer approaches should include agents that directly affect fibroblasts, agents that alter specific classes of inflammatory cells such as macrophages or T cells and their inflammatory products, and agents that alter epithelial/ fibroblast or endothelial/ fibroblast interactions. The regulation of the fibrotic process in the lung will be enhanced by the development of transgenic mice with genetic deletions of specific
growth factors, mediators, or cytokine and their cognate receptors. In addition, current molecular techniques afford the opportunity of producing recombinant soluble growth factors and cytokine receptors for treatment protocols.

One important pathologic feature of UIP, the underlying histopathology of IPF, is the fibroproliferative plaque which is the focal area of active fibrogenesis (31-33). The cell-cell interactions, inflammatory mediators, and growth factors in these foci need to be defined and may provide important avenues for therapy. Many investigators believe that regulation of injury, repair, and fibrogenesis in these specific areas might hold the clue to new treatments for IPF. Pulmonary hypertension is a complication of pulmonary fibrosis that merits additional attention and might benefit from more aggressive therapy. Pulmonary hypertension is one of the rate-limiting factors in the dyspnea and exercise limitation of patients with IPF and a contributor to mortality. In addition to supplemental oxygen, patients may benefit from vasodilators such as prostacyclin and treatment directed at vascular remodeling.

POTENTIAL THERAPEUTIC INTERVENTIONS
As noted previously, current therapy has minimal beneficial effects on patients with IPF. Thus, future studies should focus on newer forms of therapy and, if possible, early in the course of the disease. The selection of agents for treatment trials should be guided by our current knowledge of the pathogenesis of IPF and preclinical data on experimental pulmonary fibrosis in rodents and in vitro experiments. The following list contains agents that the participants discussed and recommended for consideration in clinical trials. Some of the agents are ready to be examined now in a Phase II or Phase III clinical trial. However, others on the list, while promising, will require additional evaluation prior to a trial.

Pirfenidone
Pirfenidone, an antifibrotic agent, showed promise in IPF patients in an open label study (34). There was limited toxicity and improvement in some patients, but a larger prospective double-blind study is required to establish efficacy. In this study most patients had failed immunosuppressive and cyto-toxic therapy and had advanced disease. Pirfenidone ameliorates bleomycin-induced pulmonary fibrosis in hamsters (35). In vitro, pirfenidone decreases IPF lung fibroblast proliferation, extracellular matrix production, transforming growth factor-beta (TGF-b)-stimulated collagen synthesis, and mitogenic effects of platelet-derived growth factor (PDGF) (36).

Interferon Gamma (IFN-g)
IFN-g is an attractive therapeutic candidate because it regulates both macrophage and fibroblast functions. The theoretical benefits would include diminished expression of insulin-like growth factor 1 (IGF-1), a profibrogenic growth factor produced by macrophages, and suppression of fibroblast proliferation and collagen synthesis. In addition, IFN-g inhibits a fibrogenic growth factor produced by mast cells, fibroblast growth factor-2 (FGF-2, basic FGF) (37), and a variety of neutrophil- derived cytokines (38).

Interferon Beta (IFN-b)
IFN-b is widely used for the treatment of chronic hepatitis C and multiple sclerosis and has anti-inflammatory properties. In mice, IFN-b inhibits irradiation-induced pulmonary fibrosis (39). There is currently an ongoing prospective clinical trial on the effect of IFN-b in the treatment of patients with IPF.

Suramin
Suramin is a sulfonated naphthylurea that has been used clinically for many years to treat onchocerciasis. It also has been shown to have in vitro antiretroviral activity and was used in some clinical trials in acquired immunodeficiency syndrome (AIDS) in the 1980s. The main clinical use of suramin has been in the treatment of prostate cancer. Suramin has the unusual in vitro property of antagonizing the effects of a number of growth factors including TGF-b, IGF-1, PDGF, epidermal-like growth factor (EGF), and FGF. The mechanism has not been completely identified, but there appears to be inhibition at the level of ligand binding. The attractive property of suramin is the relatively promiscuous nature of its growth factor binding. It is likely that a number of growth factors mediate fibroblast proliferation and collagen deposition and that the potential effect against many different growth factors is

appealing. Suramin has been shown to delay wound healing. A less attractive quality is that suramin must be administered intravenously. One reversible toxic effect of suramin is the inhibition of mineralocorticoid release. For this reason, low doses of prednisone are required with the administration. Suramin offers a novel approach to treating IPF by targeting some of the effector molecules, namely growth factors.

Relaxin
Relaxin is a secreted protein thought to be responsible for structural remodeling of the interpubic ligament and cervix during the later phases of pregnancy. Relaxin inhibits TGF-b-induced collagen and fibronectin production by human lung fibroblasts and increases expression of matrix metalloproteinase 1 (procollagenase) and decreases the production of a tissue inhibitor of metalloproteinases (40). In vivo, relaxin inhibits pulmonary fibrosis produced by bleomycin and fibrosis associated with implanted polyvinyl sponges (41).

Eicosanoids
The prostaglandin PGE2 is a potent inhibitor of fibroblast proliferation and matrix production in vitro, and, therefore, administration of PGE2 may ameliorate the fibrotic process. An oral analogue of PGE2 is a potential candidate for therapeutic intervention. Exogenous PGE2 has not been evaluated in vivo in animal models of pulmonary fibrosis to our knowledge. However, in an animal model of pulmonary fibrosis produced by bleomycin, indomethacin, an inhibitor of cyclooxygenase, decreased pulmonary fibrosis (42) Leukotriene B4 (LTB4 ), a potent chemotactic factor for neutrophils, is increased in lavage and lung homogenates of patients with IPF, and macrophages from IPF patients secrete more LTB4 than control macrophages (43, 44). There are high concentrations of constitutive 5-lipoxygenase activation in IPF lungs (44). Leukotrienes have a broad spectrum of biologic responses and in general are proinflammatory. Leukotrienes also stimulate collagen synthesis and fibroblast chemotaxis, proliferation, and collagen synthesis. Inhibition of leukotriene production may be an effective adjuvant therapy, and drugs are now available to block leukotriene synthesis.

Angiotensin-converting Enzyme Inhibitors/ Angiotensin II Receptor Antagonists
The angiotensin-converting enzyme inhibitor, captopril, has been shown to reduce fibroblast proliferation and pulmonary fibrosis due to irradiation in rats (45, 46). Angiotensin II stimulates matrix production by fibroblasts, and angiotensin II receptor blockers have been reported to inhibit pulmonary fibrosis resulting from irradiation and bleomycin. Because these drugs are available for human studies and can be given orally, further evaluation seems warranted.

Keratinocyte Growth Factor
Keratinocyte growth factor (KGF) greatly stimulates type II cell proliferation in vivo and in vitro (47, 48). KGF represents a class of growth factors that stimulate epithelial cells but have no direct effect on mesenchymal cells and fibroblasts. The KGF receptor is expressed only on epithelial cells. In addition, KGF causes a pleotropic cytoprotective effect on pulmonary epithelial cells and increases surfactant protein gene expression and sodium/ potassium ATPase (49, 50). These properties would be beneficial in altering the response to lung injury. Animals pretreated with KGF are protected from injury and the subsequent development of fibrosis caused by bleomycin, irradiation, acid instillation, oxygen toxicity, and a-naphthylthio-urea (51-55). Because IPF is thought to be a chronic fibrotic disease resulting from focal active inflammation and fibrogen-esis, administration of KGF might be very beneficial. However, although animal studies with KGF are impressive and reproducible, in most studies KGF must be given before injury and long-term therapy would require systemic administration. Many investigators believe that type II cell hyperplasia is an important response to limit fibroblast migration, proliferation, and matrix production. However, as shown in Figure 1, type II cells are also candidates for production of fibrogenic cytokines and growth factors and could contribute to the fibroproliferative response.

Other Potential Therapeutic Agents
Other potential agents discussed include cyclosporin, N-acetyl cysteine and other antioxidants, thalidomide (56, 57), endothelin receptor antagonists (58, 59), the human soluble tumor necrosis factor (TNF) receptor fusion protein interleukin-10 (IL-10), and anticoagulants. In addition, it is highly likely that other promising agents will emerge in the next few years.

The workshop did not attempt to rank potential interventions and the aforementioned list should not be considered any attempt at prioritization. The consensus of the conference was that the time was right to evaluate the efficacy of new agents in the treatment of IPF.

RECOMMENDATIONS
The current availability of several novel therapeutic agents and the emergence of additional agents from laboratory and clinical studies of pulmonary fibrosis indicate that it is appropriate to begin systemic evaluation of different treatment regimens in IPF.

Improvement in the treatment of patients with IPF will require rigorous controlled clinical trials to compare different treatment options. Although the incidence of IPF is greater than previously thought, multicenter trials will still be required, because it is very unlikely that any single center will have sufficient numbers of suitable patients to provide results in a timely manner.

Prospective studies should be designed to provide valuable information on causes, genetic predisposition, and pathogenesis of IPF. This is especially true for providing DNA samples for genetic studies, e. g., genetic markers of susceptibility. There is also a need for additional prospective case-controlled epidemiologic studies to identify potential contributing environmental factors.

Additional surrogate markers of disease activity are needed. Because the duration of disease is long and progression is slow, current outcomes need to be based on mortality or significant changes in physiology or HRCT scores. It would be useful to develop surrogate markers of disease activity such that if a particular marker changed within 1 to 2 mo of therapy, one could predict a long-term favorable response or failure of therapy.

The diagnosis of IPF and IPF-related diseases must be made with a very high level of confidence so that the results can be readily interpreted. It is anticipated that there will be some responders and some nonresponders to therapy. The future care of patients with IPF and IPF-related diseases requires
precise identification of the responders for interpretation of results and for designing subsequent prospective studies. In general, diagnosis usually requires a surgical biopsy usually provided by video-assisted thorascopic surgery (VATS) in order to provide sufficient tissue for pathologic diagnosis. Assessment should be made by an expert panel of pathologists who communicate regularly to provide consistent interpretations.

Clinical trials would benefit from broad inclusion criteria so that patients with IPF-related diseases, who are more likely to respond to therapy are included. However, the diagnosis of individual cases must be as specific and definite as possible so that the anticipated responders can be defined as precisely as possible. For example, there may be separate parallel studies for patients with the pathologic diagnosis of BOOP, NSIP, UIP, and those with connective tissue disease.

Additional studies of the reproducibility of HRCT scoring systems and pathology interpretations are warranted.

Measurement of quality of life is an important outcome variable and the current questionnaires should be made as disease-specific as possible and validated for use in future studies.

There is a need for animal models of lung inflammation and fibrosis. Studies of transonic and knockout mice with targeted alterations in cytokines, growth factors, and their receptors are important and will be critical for defining the role of certain inflammatory and fibrogenic factors in the response to injury and the development of pulmonary fibrosis.

There is a pressing need to continue research to investigate the regulation of injury, repair, and fibrogenesis in the unique microenvironment of the lung. These studies will provide insight for development of the next generation of therapeutic options for IPF.

Conference Participants
The authors wish to thank the participants of the conference who provided important ideas embodied in this report. These participants included:

Robert Baughman, Cincinnati, OH; Reuben Cherniack, Denver, CO; Thomas V. Colby, Scottsdale, AZ; Bernadette Gochuico, Bethesda, MD; Jeffrey Golden, San Francisco, CA; Ronald Gold-stein, Boston, MA; Gary W. Hunninghake, Iowa City, IA; Anna Katzenstein, Syracuse, NY; Talmadge E. King, San Francisco, CA; Charles Kuhn, Bethesda, MD; David Lynch, Denver, CO; Robert J. Mason, Denver, CO, Chair; Robert A. Musson, Bethesda, MD; Paul W. Nobel, New Haven, CT; Ganesh Raghu, Seattle, WA; Marvin I. Schwarz, Denver, CO; Cecilia M. Smith, San Diego, CA.

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(Received in original form March 1, 1999 and in revised form June 1, 1999)
Workshop sponsored by the National Heart, Lung, and Blood Institute and the Office of Rare Diseases, National Institutes of Health, Bethesda, Maryland and held in Bethesda, Maryland on September 9-10, 1998.

Correspondence and requests for reprints should be addressed to Robert A. Musson, Ph. D., Division of Lung Diseases, National Heart, Lung, and Blood Institute, 2 Rockledge Centre, Suite 10018, 6701 Rockledge Drive, MSC 7952, Bethesda, MD 20892.

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