Pursuing Clinical Predictors and Biomarkers for Progression in ILD: Analysis of the Pulmonary Fibrosis Foundation (PFF) Registry

Abstract

Introduction: Pulmonary fibrosis is a characteristic of various interstitial lung diseases (ILDs) with differing etiologies. Clinical trials in progressive pulmonary fibrosis (PPF) enroll patients based on previously described clinical criteria for past progression, which include a clinical practice guideline for PPF classification and inclusion criteria from the INBUILD trial. In this study, we compared the ability of past FVC (forced vital capacity) progression and baseline biomarker levels to predict future progression in a cohort of patients from the PFF Patient Registry.

Methods: Biomarkers previously associated with pathobiology and/or progression in pulmonary fibrosis were selected to reflect cellular senescence (telomere length), pulmonary epithelium (SP-D, RAGE), myeloid activation (CXCL13, YKL40, CCL18, OPN) and fibroblast activation (POSTN, COMP, PROC3).

Results: PFF or INBUILD-like clinical criteria was used to separate patients into past progressor and non-past progressor groups, and neither clinical criterion appeared to enrich for patients with greater future lung function decline. All baseline biomarkers measured were differentially expressed in patient groups compared to healthy controls. Baseline levels of SP-D and POSTN showed the highest correlations with FVC slope over one year, though correlations were low.

Conclusions: Our findings provide further evidence that prior decline in lung function may not predict future disease progression for ILD patients, and elevate the need for molecular definitions of a progressive phenotype. Across ILD subtypes, certain shared pathobiologies may be present based on the molecular profile of certain biomarker groups observed. In particular, SP-D may be a common marker of pulmonary injury and future lung function decline across ILDs.

Keywords: Biomarkers; Idiopathic Pulmonary Fibrosis (IPF); Interstitial Lung disease (ILD); Progressive Pulmonary Fibrosis (PPF).

Fig. 1

Characterization of disease progression and biomarker profiles across ILD subtypes (A) FVC slope for progressors and non-progressors were compared by unadjusted t-test according to either PPF or INBUILD-like criteria. Left side boxplots show comparisons for the ILD subcohort. Right side boxplots show patients from the subcohort with non-IPF ILDs (N = 67) where PPF criteria selected 14 (20.9%) patients and INBUILD criteria selected 12 (17.9%) patients as past progressors. (B) Baseline biomarker levels for Surfactant Protein D (SP-D) and Periostin as compared between progressors and non-progressors by unadjusted t-test according to INBUILD-like criteria. Comparisons for both the ILD subcohort and patients with non-IPF ILDs are shown. (C) Comparison of baseline biomarker levels for SP-D and CXCL13 between healthy controls and the full ILD cohort subgrouped by diagnosis using t-test adjusted for multiple comparisons and for age. *p-value < 0.05 **p-value < 0.01 ***p-value < 0.001 ****p < 0.0001. (D) Correlation between baseline biomarker level and FVC slope in the full cohort for SP-D and Periostin with Pearson correlation shown