Evaluating Tissue Heterogeneity in the Radiologically Normal-Appearing Tissue in IPF Compared to Healthy Controls

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a progressive interstitial lung disease characterised by heterogeneously distributed fibrotic lesions. The inter- and intra-patient heterogeneity of the disease has meant that useful biomarkers of severity and progression have been elusive. Previous quantitative computed tomography (CT) based studies have focussed on characterising the pathological tissue. However, we hypothesised that the remaining lung tissue, which appears radiologically normal, may show important differences from controls in tissue characteristics. Quantitative metrics were derived from CT scans in IPF patients (N=20) and healthy controls with a similar age (N=59). An automated quantitative software (CALIPER, Computer-Aided Lung Informatics for Pathology Evaluation and Rating) was used to classify tissue as normal-appearing, fibrosis, or low attenuation area. Densitometry metrics were calculated for all lung tissue and for only the normal-appearing tissue. Heterogeneity of lung tissue density was quantified as coefficient of variation and by quadtree. Associations between measured lung function and quantitative metrics were assessed and compared between the two cohorts. All metrics were significantly different between controls and IPF (p<0.05), including when only the normal tissue was evaluated (p<0.04). Density in the normal tissue was 14% higher in the IPF participants than controls (p<0.001). The normal-appearing tissue in IPF had heterogeneity metrics that exhibited significant positive relationships with the percent predicted diffusion capacity for carbon monoxide. We provide quantitative assessment of IPF lung tissue characteristics compared toa healthy control group of similar age. Tissue that appears visually normal in IPF exhibits subtle but quantifiable differences that are associated with lung function and gas exchange.