Published: 18 January 2022
Authors: Willis S Bowman, MD Chad A Newton, MD Angela L Linderholm, PhD Megan L Neely, PhD Janelle Vu Pugashetti, MD Bhavika Kaul, MD et al.
Source: This abstract has been sourced from NZ Respiratory Research Review Issue 201
Progressive fibrosing interstitial lung disease (ILD) is characterised by parenchymal
scar formation, leading to high morbidity and mortality. The ability to predict this
phenotype remains elusive. We conducted a proteomic analysis to identify novel plasma
biomarkers of progressive fibrosing ILD and developed a proteomic signature to predict
this phenotype.
Relative plasma concentrations for 368 biomarkers were determined with use of a semi-quantitative,
targeted proteomic platform in patients with connective tissue disease-associated
ILD, chronic hypersensitivity pneumonitis, or unclassifiable ILD who provided research
blood draws at the University of California (discovery cohort) and the University
of Texas (validation cohort). Univariable logistic regression was used to identify
individual biomarkers associated with 1-year ILD progression, defined as death, lung
transplant, or 10% or greater relative forced vital capacity (FVC) decline. A proteomic
signature of progressive fibrosing ILD was then derived with use of machine learning
in the University of California cohort and validated in the University of Texas cohort.
The discovery cohort comprised 385 patients (mean age 63·6 years, 59% female) and
the validation cohort comprised 204 patients (mean age 60·7 years, 61% female). 31
biomarkers were associated with progressive fibrosing ILD in the discovery cohort,
with 17 maintaining an association in the validation cohort. Validated biomarkers
showed a consistent association with progressive fibrosing ILD irrespective of ILD
clinical diagnosis. A proteomic signature comprising 12 biomarkers was derived by
machine learning and validated in the University of Texas cohort, in which it had
a sensitivity of 0·90 and corresponding negative predictive value of 0·91, suggesting
that approximately 10% of patients with a low-risk proteomic signature would experience
ILD progression in the year after blood draw. Those with a low-risk proteomic signature
experienced an FVC change of +85·7 mL (95% CI 6·9 to 164·4) and those with a high-risk
signature experienced an FVC change of −227·1 mL (−286·7 to −167·5). A theoretical
clinical trial restricted to patients with a high-risk proteomic signature would require
80% fewer patients than one designed without regard to proteomic signature.
17 plasma biomarkers of progressive fibrosing ILD were identified and showed consistent
associations across ILD subtypes. A proteomic signature of progressive fibrosing ILD
could enrich clinical trial cohorts and avoid the need for antecedent progression
when defining progressive fibrosing ILD for clinical trial enrolment.
Link to abstract
