Exploring the role and association of monocytes with progression of Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic fibroproliferative disease characterised by accumulation of scar tissue within the lung parenchyma. The clinical course of IPF is heterogenous and disease severity at presentation often varies among patients. Mortality and FVC decline may not accurately reflect progression of fibrosis. As such, there is an unmet need for biomarkers to prognosticate IPF. The pathogenic mechanisms underlying the disease remain incompletely understood but involve aberrations in repair pathways. The role of monocytes in IPF has gained interest due to their role in orchestrating repair. I hypothesised that monocytes, measured from standard full blood count analysis, are associated with adverse clinical outcomes in IPF. I performed three retrospective clinical studies. In Study 1, I explored association between blood leukocytes (monocytes, neutrophils, and lymphocytes) with (i) progression of the Indeterminate of Usual interstitial pneumonia (iUIP) CT pattern to IPF and (ii) progression of established IPF. In study 2, I explored blood leukocyte association with progression of early fibrotic-interstitial lung abnormalities (EF-ILA) and in Study 3, I explored leukocyte association with radiological progression of fibrosis per se quantified by automated CT (CALIPER). Patients were enrolled from the Oxford Interstitial lung disease (ILD) service or Oxford Radiology service. Analyses were conducted using multivariate Cox proportional hazard regression. In Study 1 monocyte and neutrophil counts were associated with progression of iUIP to IPF. In cases with established IPF neutrophils, lymphopaenia and neutrophil: lymphocyte ratio were associated with FVC decline; while both monocytes and neutrophil levels (and derived indexes) were associated with all-cause mortality. In Study 2 EF-ILA was significantly associated with all-cause mortality. Monocytes and neutrophils (and derived indexes) were significantly associated with progression of EF-ILA and mortality. In Study 3 neutrophil count demonstrated significant association with progression of total lung fibrosis, as did all leukocyte indexes, but not absolute monocyte and lymphocyte counts. The association between monocytes, neutrophils and lymphocytes with mortality and disease progression across these cohorts suggests a role for these cells in the pathogenesis of IPF and sub-clinical ILD.

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