Jeffrey J Swigris Assistant Professor of Medicine, Interstitial Lung Disease Program, National Jewish Medical and Research Center, Denver , Kevin K Brown, MD Vice Chair, Department of Medicine, and Director, Interstitial Lung Disease Program, National Jewish Medical and Research Center, Denver

Originally printed in:
» US Respiratory Disease 2007 - October 2007

Idiopathic pulmonary fibrosis (IPF) is a devastating disease. Marked by progressive breathlessness, impaired quality of life and functional status, and a median survival of 2.5–5 years,¹ IPF remains resistant to currently available medical therapy. However, recent advances suggest a more promising future: the recognition of its clinical impact and increasing prevalence,^2,3 the successful completion of multiple controlled, multicenter trials, and fresh basic scientific discoveries have led to a better understanding of IPF’s natural history and molecular underpinnings. The results of a number of currently active clinical studies and basic investigation are hastening the day of at least disease control, if not cure.

Pathogenesis
Recent studies have highlighted three themes in the pathogenesis of IPF: the role of alveolar epithelial cells (AECs); the potential involvement of bonemarrow- derived mesenchymal cells; and the composition of the fibrotic architecture of the IPF lung. While the fibroblast is recognized as a central player in the pathogenesis of IPF, the AEC is believed to actively participate in fibrogenesis by locally releasing multiple pro-fibrotic cytokines after injury.⁴ Beyond these cytokines, AECs may participate in epithelial–mesenchymal transformation (EMT).⁵ In EMT, driven by as yet not fully characterized forces, AECs transform into fibroblasts and myofibroblasts. This mechanism, if shown to be clinically relevant in IPF, provides a potential therapeutic target. It was previously thought that fibroblasts and myofibroblasts in IPF were predominantly resident cells; however, new information suggests that circulating bone-marrow-derived cells—‘fibrocytes’⁶—traffic to the lungs in response to injury and participate in the evolution of fibrosis.^7,8 Whether and how fibrocytes might be inhibited from making their way to the lung is unknown, and is a source of ongoing investigation. In the usual interstitial pneumonia (UIP) pattern of lung injury (see Figure 1), subepithelial aggregations of fibroblasts and myofibroblasts, termed fibroblast foci, are believed to represent the leading edge of fibroproliferation.⁹ On 2D histological section, these foci appear isolated and randomly distributed throughout the interstitium. However, when the UIP lung is reconstructed in 3D, individual foci actually form a complex, interconnected reticulum.¹⁰ More investigation will be necessary to explore the implications of this finding and to clarify whether molecular cross-talk occurs between the elements composing this fibrotic framework.

Prognosis in Idiopathic Pulmonary Fibrosis
Several important recent studies have advanced our understanding of prognosis and IPF disease activity. A number of these are summarized below.

Baseline Predictors of Outcome
Several baseline (at the time of diagnosis) clinical variables are known to predict survival in patients with IPF. These include symptom severity, radiographic features, pulmonary physiology, and the presence of pulmonary arterial hypertension (PAH). Thus, mortality is associated with higher levels of dyspnea¹¹ and a greater extent of fibrosis on high-resolution computed tomography (HRCT)¹² at baseline. Several studies have demonstrated that baseline physiological measures such as dynamic or static lung volumes and diffusing capacity—either alone^13–18 or combined in predictive models¹⁹—correlate tightly with survival. Gas exchange also provides prognostic information. Early studies suggested that gas exchange with exercise was the most sensitive measure of disease severity,²⁰ and new data suggest that the presence and severity of desaturation during a timed walk test provide important prognostic information.^21,22 IPF patients whose peripheral oxygen saturation (SpO₂) falls to 88% or less during a room-air 6-minute walk test (6MWT) at sea level have a significantly shortened survival compared with those who do not desaturate.²¹ These data must be tempered by the finding that the lowest SpO2 during a 6MWT is not particularly reproducible (r=0.61).²³ However, the distance walked during the 6MWD has excellent reproducibility, correlates well with maximal oxygen uptake as measured during symptom-limited treadmill exercise test,²³ and correlates with mortality. Lederer and colleagues found that among 454 lung fibrosis subjects listed for lung transplantation, those with a 6MWD of <207m had a mortality rate four times that of IPF subjects able to walk >207m. The prevalence of PAH is reported to occur in up to 85% of subjects with IPF,²⁴ and its presence is associated with significantly shortened survival.^25,26 Early information also suggests that treating pulmonary hypertension in the setting of IPF results in at least functional improvement.²⁷ Whether medications that have demonstrated survival benefit for subjects with primary PAH in previous studies will have the same beneficial effects in patients with IPF-related PAH is unknown, but is an area of active clinical investigation.

Longitudinal Changes and Outcomes
Longitudinal changes in several easily measured clinical variables correlate well with mortality (see Table 1). Multiple studies have confirmed the reliability of a change in forced vital capacity (FVC) over periods of 3–12 months as a potent predictor of survival.^18,28–30 A 12-month change in percent predicted diffusing capacity of the lung for carbon monoxide (ppDLCO) has been shown to be predictive in some^,18 but not all,²⁹ studies. Also, while changes over time in alveolar–arterial (A-a) O₂ have been shown to be associated with survival in at least one study,²⁹ within the context of a controlled treatment trial King and co-investigators found that a dichotomized change in A-a O₂ (≥5mmHg versus <5mmHg change over three to six months) was unreliable and not associated with mortality. Acute exacerbation of IPF (AEIPF) is a recognized aspect of the disease that has drawn the attention of investigators.³¹ It is now appreciated that, in a significant minority of IPF patients, acute exacerbations occur that can be of varying severity and are independent of physiological stage.³⁰ In a recent retrospective analysis, of 36 deaths in patients with IPF 89% were considered to be IPF-related, and nearly half of these were due to AEIPF.³⁰ More work is needed to identify etiologies and effective therapy for AEIPF.

Biomarkers
Japanese clinicians and researchers have used circulating levels of kit ligand (KL)-6 to identify subjects with various interstitial lung diseases, and more recent work suggests that serum levels of this high-molecular-weight glycoprotein are strongly associated with survival in IPF.³² Investigators are intensively searching for other reliable and robust biomarkers useful in IPF.³³