Patient-specific tracheal deformation, predicted toxicant uptake and histopathology in lung fibrosis

Background: Our simulations previously predicted focal areas of gaseous pollutant dose delivered to the airway mucosa of a patient with idiopathic pulmonary fibrosis (IPF). We hypothesize a relation between these dose predictions and clinically meaningful endpoints in IPF which link toxicant-driven epithelial injury and disrepair to IPF etiology and pathogenesis. Objective: To determine associations between patient-specific modeling of tracheal geometry, computer simulations of toxicant dose, and lung histopathology in patients with IPF. Methods: The first three conducting airway generations of ten patients diagnosed with IPF were reconstructed from their high-resolution CT chest scans. We quantified geometric abnormalities of the reconstructed tracheas based on their curvature and eccentricity (cross-sectional flattening), and performed three-dimensional computer simulations to predict the average and upper values (i.e. hotspots) of reactive toxicant dose to the underlying mucosa. Distal biopsy tissue samples were characterized by epithelial cell phenotype, extent of fibrosis, and histopathologic severity scores. Non-parametric correlation analysis examined associations between these descriptors. Results: Computed values for curvature and eccentricity of IPF-deformed trachea varied widely among patients and correlated with more subjective rankings of tracheal deformation, and with predicted toxicant dose. Overall histopathologic severity was positively correlated with tracheal deformation and upper decile toxicant uptake. Tracheal curvature was significantly correlated with fibroblastic foci. Conclusions: These results demonstrate an association of tracheal curvature with predicted toxicant dose and with histopathologic indicators in distal tissue. This suggests that these measures may be predictors of risk for acute IPF exacerbations, subsequent clinical deterioration, and disease progression.