Microscopic EB-OCT imaging to predict progression in interstitial lung abnormalities

Project Summary

Progressive pulmonary fibrosis (PPF) is debilitating with poor prognosis. Antifibrotic therapies in PPF slow

progression but do not reverse or stabilize disease. Thus, timing of therapy is key to improving outcomes,

especially if started in presymptomatic stages prior to lung function decline. To prove the efficacy of early therapy,

clinical trials will require prognostic enrichment with biomarkers to accurately identify presymptomatic individuals

at high risk of developing PPF. Interstitial lung abnormalities (ILA) on CT are linked to increased risk of PPF, but

not all ILAs will progress (progression rate ~30-60%) and CT is unable to distinguish ILAs that will progress to

PPF from those that are of no clinical consequence. The main limitation of CT is its resolution, which is insufficient

to detect microscopic features. Surgical lung biopsy (SLB) provides tissue for microscopy, but has high

morbidity/mortality risks. Over the last 10 years, we have developed and validated endobronchial optical

coherence tomography (EB-OCT) as a safe, minimally-invasive imaging modality to assess lung disease, with

microscopic resolution 200x higher than CT in tissue volumes 100x larger than SLB. We have established that

the subpleural space of both lungs can be practically and rapidly (10 sites in 0.9, allowing for

broad implementation of this technology to define an individual patient’s risk for ILA progression to PPF. With

these major developments in EB-OCT, we finally can safely investigate microscopic disease features in ILA that

may predict progression to PPF. In a preliminary cohort of ILA subjects, we identified high-risk features of early

architectural distortion by EB-OCT that predicted progression of ILA to PPF. Our compelling premise and

preliminary data support our central hypothesis that individuals with ILA who will progress to PPF have high-risk

microscopic features, defined as destructive fibrosis with microscopic honeycombing or traction bronchiolectasis,

that are detectable by EB-OCT. We are uniquely positioned to test this hypothesis due to our expertise in EB-

OCT and access to two large ILA cohorts with annual follow-up (with CT and PFT) to assess long-term outcomes

through our lung nodule CT screening program (smokers with ILA; Cohort 1) and existing ILA cohort (subjects

with ILA and family history of PPF; Cohort 2). In Aim 1, we will determine the accuracy of microscopic features,

as detected by EB-OCT, to predict progression to PPF in two independent ILA cohorts. In Aim 2, we will define

and validate an integrative prediction model for progression of ILA to PPF that combines EB-OCT, CT and

plasma biomarkers associated with PPF disease progression. Cohort 1 will serve as the derivation cohort and

Cohort 2 as a separate, de novo validation cohort. These foundational studies will enable prognostic enrichment

for future clinical trials evaluating early therapy in presymptomatic PPF, with potential to impact disease mortality.