Objectives

To identify and validate circulating protein biomarkers of idiopathic pulmonary fibrosis survival.

Background

Idiopathic Pulmonary Fibrosis (IPF) is a devastating parenchymal lung disease characterized by progressive lung scarring, high healthcare utilization and poor survival. Lung transplantation remains the sole curative option in IPF, but donor lungs are scarce, and many patients die awaiting transplant. To improve IPF outcomes, new therapies are urgently needed.

Biomarkers associated with clinically relevant outcomes represent potential targets for therapeutic intervention and promising tools for prognostication. To date, a host of blood-based proteins associated with differential IPF survival have been identified through targeted investigation. While these findings shed important light on IPF pathobiology, most have relied on presumed mediators or molecular markers of fibrogenesis. To overcome limitations inherent to targeted analysis, unbiased investigation is needed. The IPF Survival Proteomics study was initiated to identify and validate protein biomarkers associated with differential transplant-free survival (TFS) in participants with IPF.

Participants

Consecutive patients with IPF who provided a research blood draw for prospective biorepositories administered by the Pulmonary Fibrosis Foundation (PFF) Patient Registry (March 2016–June 2018); University of California, Davis (July 2016–April 2021); University of Chicago (March 2007–July 2017); and University of Virginia (September 2018–November 2021) were eligible for inclusion. Patients from the PFF Patient Registry constituted the discovery cohort, while those from the University of California, Davis; University of Chicago; and University of Virginia comprised the validation cohort.

Proteomic data were generated for 871 participants in the discovery cohort and 355 participants in the validation cohort.

Design

The IPF Survival Proteomics study conducted a multicenter cohort analysis. Peripheral blood was collected from participants and then plasma was isolated according to center-specific protocols. Plasma samples were processed as a single batch. At the time of plating, samples were randomized according to center, age, sex, and race to mitigate batch effects. Proteins associated with three-year TFS were identified using multivariable Cox proportional hazards regression. Those associated with TFS after adjustment for false discovery in the discovery cohort were advanced for testing in the validation cohort, with proteins maintaining TFS association with consistent effect direction considered validated. After combining cohorts, functional analyses were performed, and machine learning was used to derive a proteomic signature of TFS.

Demographics, smoking history, percent predicted forced vital capacity (FVC), percent predicted diffusion capacity of the lung for carbon monoxide (DLCO), anti-fibrotic (pirfenidone or nintedanib) exposure and immunosuppressant (mycophenolate mofetil, azathioprine or prednisone ≥20mg) were collected at the time of blood draw.

The primary endpoint assessed was 3-year TFS, which was defined as the time from blood draw to death, lung transplant, or censoring at 36 months or earlier if lost to follow-up.

Conclusions

140 circulating plasma proteins associated with differential TFS across two independent IPF cohorts were identified. These proteins represent diverse pathobiological pathways, with many being known contributors to IPF pathobiology and others representing novel associations. A proteomic signature of TFS accurately discriminated TFS and outperformed a clinical prediction model, highlighting the potential for composite protein biomarkers to provide valuable clinical information.

Oldham JM, Huang Y, Bose S, et al. Proteomic Biomarkers of Survival in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2024;209(9):1111-1120. doi:10.1164/rccm.202301-0117OC

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