Defining the biologic and physiologic trajectory of presymptomatic through advanced pulmonary fibrosis

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PROJECT SUMMARY/ABSTRACT Pulmonary fibrosis (PF) is prevalent among 200,000 persons in the USA, a figure that is increasing. Most individuals present with progressive dyspnea and/or cough, and have moderately advanced disease with irreversible fibrosis at the time of diagnosis. Treatment of PF at an earlier (pre-clinical) stage would result in a greater reduction in the overall burden of morbidity, but limited understanding of the early natural history, including the biological and clinical progression, remains a barrier to accomplishing this goal. To improve the understanding of the earliest stages of PF, >450 asymptomatic relatives of persons with familial PF have undergone serial screening high resolution CT (HRCT) scans to detect pre-clinical PF, as part of an ongoing prospective cohort study. When defined by the new development or progression of abnormal changes of the pulmonary parenchyma (“interstitial lung abnormalities” [ILA]), pre-clinical PF is observed in approximately 20% of participants. While having ILA on the first screening HRCT is a major risk factor for progression, almost half of pre-clinical PF comprised new development of ILA, underscoring the need for additional biomarkers of early disease. Altered gene expression in the peripheral blood precedes pre-clinical progression in this cohort, and may represent a promising biomarker. Clinically, among those participants progressing through pre-clinical PF (toward clinically-diagnosed PF), the observed pattern of progressive physiologic decay appears to be disease stage-specific and occurs in a manner that may be shared across individuals with PF. Importantly, the forced vital capacity (FVC) undergoes very little change during pre-clinical PF. The FVC is used to monitor for PF progression and has been the primary endpoint in successful trials of disease modifying therapy for PF. Therefore, alternative endpoints/outcome measures are needed in order to study disease modification in pre- clinical PF. The overall hypothesis is that PF follows a sequenced progression, including blood biomarkers (transcriptomic and/or proteins) indicative of early pathobiology and predictive of pre-clinical progression, and a stage-specific, sequenced decay in key physiologic parameters. The following Specific Aims are proposed: (1) Define a blood biomarker signature to predict progressive pre-clinical PF; and (2) Develop a disease progression model (DPM) to describe the physiologic decay across all stages of PF. Disease-specific DPMs have been used to measure disease modification such that detection of a treatment effect is subject-specific, a more powerful alternative to analysis without regard to stage-specific progression expectations. The working hypotheses will be tested during continued observation of the prospective pre-clinical PF cohort and several cohorts of patients with established PF. Completion of these Aims is an important step toward a long-term programmatic goal (of the investigators and the NHLBI) to speed development of new disease modifying therapy for PF, particularly those capable of preventing or delaying symptom onset.