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Khan, Fasihul (2022) Biomarkers of progressive lung fibrosis. PhD thesis, University of Nottingham.

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Abstract

Interstitial lung diseases (ILD) encompass a heterogeneous group of immuno-inflammatory and fibrotic diseases of the lung parenchyma. The most common and severe ILD is idiopathic pulmonary fibrosis (IPF), a chronic progressive fibrotic lung disease of unknown aetiology associated with poor prognosis. A substantial proportion of individuals with ILDs other than IPF also develop progressive fibrosis with clinical, radiological, and genetic similarities, suggesting a shared final common pathway across progressive fibrotic ILDs irrespective of aetiology. Study of shared mechanisms of progression has the potential to aid prognostication, enable a precise approach to therapeutic strategies and allow stratification into clinical trials. Biomarkers are objectively measured and reproducible characteristics that enable stratification of disease phenotypes. The aim of this thesis was to examine and characterise the role of clinical biomarkers in fibrotic lung diseases to enable early identification of progressive fibrotic phenotypes.

An evidence synthesis of blood biomarkers as prognosticators in IPF highlighted several biomarkers with prognostic potential and identified priorities for future blood biomarker research. The first individual participant data (IPD) meta-analysis in IPF of matrix metalloproteinase-7 demonstrated baseline measurements were independently associated with disease outcomes. To evaluate the role of physiological variables as prognostic biomarkers and as surrogate trial endpoints, the largest analysis of interventional trial placebo arms in IPF was performed using robust IPD methodology. Baseline and three-month change in physiological variables, particularly FVC were independently associated with disease outcomes, supporting their role as prognostic biomarkers. The association between short-term change in FVC and disease outcomes were replicated in individuals receiving anti-fibrotics using pooled analysis of pirfenidone and nintedanib treatment arms. Moreover, a difference in FVC change over three-months between treatment and placebo arms was observed, supporting three-month FVC as a surrogate endpoint in future IPF trials.

An ongoing prospective multi-centre observational cohort study (INJUSTIS) to assess longitudinal disease behaviour and the role of biomarkers in other fibrotic lung diseases was established. Interim analysis suggested a significant proportion of individuals with non-IPF fibrotic ILD had progressive phenotypes that were comparable with disease behaviour in IPF. Lung function, particularly FVC change over three-months was independently associated with poorer outcomes. The role of home spirometry in fibrotic ILD was assessed, and though measurements were accurate and reliable when compared with hospital spirometry, daily FVC measurements were unable to predict mortality at earlier timepoints. An exploratory blood biomarker analysis performed in individuals with extremes of IPF offered further support for the role of CA-125 as a prognostic biomarker and identified several biomarkers and biological pathways for more focussed assessment in the complete INJUSTIS cohort.

Taken collectively, the data presented in this thesis strongly support an important role for biomarkers in fibrotic ILD to identify progressive fibrotic phenotypes and enable personalised approaches to patient management. Whilst the COVID-19 pandemic was severely disruptive, the work presented forms the basis for further study of biomarkers in progressive pulmonary fibrosis.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Jenkins, Gisli Johnson, Simon Stewart, Iain Saini, Gauri
Keywords:	Interstitial lung diseases; Progressive fibrosis; Clinical biomarkers; Fibrotic phenotypes
Subjects:	W Medicine and related subjects (NLM Classification) > WF Respiratory system
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID:	67514
Depositing User:	Khan, Fasihul
Date Deposited:	31 Jul 2022 04:41
Last Modified:	31 Jul 2022 04:41
URI:	https://eprints.nottingham.ac.uk/id/eprint/67514

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