Toby M Maher1, Eunice Oballa2, Juliet K Simpson2, Joanne Porte3, Anthony Habgood4, William A Fahy2, Aiden Flynn2, Philip L Molyneaux1, Rebecca Braybrooke5, Hrushikesh Divyateja6, Helen Parfrey7, Doris Rassl8, Anne-Marie Russell1, Gauri Saini3, Elisabetta A Renzoni1, Anne-Marie Duggan2, Richard Hubbard9, Athol U Wells1, Pauline T Lukey2, Richard P Marshall2, R Gisli Jenkins10. 1. NIHR Respiratory Biomedical Research Unit, Royal Brompton Hospital, London, UK; Fibrosis Research Group, National Heart and Lung Institute, Imperial College, London, UK. 2. Fibrosis Discovery Performance Unit, GlaxoSmithKline R&D, GlaxoSmithKline Medicines Research Centre, Stevenage, UK. 3. Respiratory Research Unit, Division of Respiratory Medicine, University of Nottingham, Nottingham, UK; Nottingham Molecular Pathology Node, University of Nottingham, Nottingham, UK; National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK. 4. Respiratory Research Unit, Division of Respiratory Medicine, University of Nottingham, Nottingham, UK. 5. Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK; Nottingham Molecular Pathology Node, University of Nottingham, Nottingham, UK; National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK. 6. Clinical Pathology, Nottingham University Hospitals NHS Trust, Nottingham, UK. 7. Department of Respiratory Medicine, Papworth Hospital, Cambridge, UK. 8. Department of Pathology, Papworth Hospital, Cambridge, UK. 9. Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK; National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK. 10. Respiratory Research Unit, Division of Respiratory Medicine, University of Nottingham, Nottingham, UK; Nottingham Molecular Pathology Node, University of Nottingham, Nottingham, UK; National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK. Electronic address: gisli.jenkins@nottingham.ac.uk.
Abstract
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease trajectory. The aim of this study was to assess potential biomarkers to predict outcomes for people with IPF. METHODS: PROFILE is a large prospective longitudinal cohort of treatment-naive patients with IPF. We adopted a two-stage discovery and validation design using patients from the PROFILE cohort. For the discovery analysis, we examined 106 patients and 50 age and sex matched healthy controls from Nottingham University Hospitals NHS Trust and the Royal Brompton Hospital. We did an unbiased, multiplex immunoassay assessment of 123 biomarkers. We further investigated promising novel markers by immunohistochemical assessment of IPF lung tissue. In the validation analysis, we examined samples from 206 people with IPF from among the remaining 212 patients recruited to PROFILE Central England. We used the samples to attempt to replicate the biomarkers identified from the discovery analysis by use of independent immunoassays for each biomarker. We investigated the predictive power of the selected biomarkers to identify individuals with IPF who were at risk of progression or death. The PROFILE studies are registered on ClinicalTrials.gov, numbers NCT01134822 (PROFILE Central England) and NCT01110694 (PROFILE Royal Brompton Hospital). FINDINGS: In the discovery analysis, we identified four serum biomarkers (surfactant protein D, matrix metalloproteinase 7, CA19-9, and CA-125) that were suitable for replication. Histological assessment of CA19-9 and CA-125 suggested that these proteins were markers of epithelial damage. Replication analysis showed that baseline values of surfactant protein D (46·6 ng/mL vs 34·6 ng/mL, p=0·0018) and CA19-9 (53·7 U/mL vs 22·2 U/mL; p<0·0001) were significantly higher in patients with progressive disease than in patients with stable disease, and rising concentrations of CA-125 over 3 months were associated with increased risk of mortality (HR 2·542, 95% CI 1·493-4·328, p=0·00059). INTERPRETATION: We have identified serum proteins secreted from metaplastic epithelium that can be used to predict disease progression and death in IPF. FUNDING: GlaxoSmithKline R&D and the UK Medical Research Council.
BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease trajectory. The aim of this study was to assess potential biomarkers to predict outcomes for people with IPF. METHODS: PROFILE is a large prospective longitudinal cohort of treatment-naive patients with IPF. We adopted a two-stage discovery and validation design using patients from the PROFILE cohort. For the discovery analysis, we examined 106 patients and 50 age and sex matched healthy controls from Nottingham University Hospitals NHS Trust and the Royal Brompton Hospital. We did an unbiased, multiplex immunoassay assessment of 123 biomarkers. We further investigated promising novel markers by immunohistochemical assessment of IPF lung tissue. In the validation analysis, we examined samples from 206 people with IPF from among the remaining 212 patients recruited to PROFILE Central England. We used the samples to attempt to replicate the biomarkers identified from the discovery analysis by use of independent immunoassays for each biomarker. We investigated the predictive power of the selected biomarkers to identify individuals with IPF who were at risk of progression or death. The PROFILE studies are registered on ClinicalTrials.gov, numbers NCT01134822 (PROFILE Central England) and NCT01110694 (PROFILE Royal Brompton Hospital). FINDINGS: In the discovery analysis, we identified four serum biomarkers (surfactant protein D, matrix metalloproteinase 7, CA19-9, and CA-125) that were suitable for replication. Histological assessment of CA19-9 and CA-125 suggested that these proteins were markers of epithelial damage. Replication analysis showed that baseline values of surfactant protein D (46·6 ng/mL vs 34·6 ng/mL, p=0·0018) and CA19-9 (53·7 U/mL vs 22·2 U/mL; p<0·0001) were significantly higher in patients with progressive disease than in patients with stable disease, and rising concentrations of CA-125 over 3 months were associated with increased risk of mortality (HR 2·542, 95% CI 1·493-4·328, p=0·00059). INTERPRETATION: We have identified serum proteins secreted from metaplastic epithelium that can be used to predict disease progression and death in IPF. FUNDING: GlaxoSmithKline R&D and the UK Medical Research Council.
Authors: Philip L Molyneaux; Jonathan J Smith; Peter Saunders; Felix Chua; Athol U Wells; Elisabetta A Renzoni; Andrew G Nicholson; William A Fahy; R Gisli Jenkins; Toby M Maher Journal: Am J Respir Crit Care Med Date: 2021-01-01 Impact factor: 21.405
Authors: Shehabaldin Alqalyoobi; Ayodeji Adegunsoye; Angela Linderholm; Cara Hrusch; Claire Cutting; Shwu-Fan Ma; Anne Sperling; Imre Noth; Mary E Strek; Justin M Oldham Journal: Am J Respir Crit Care Med Date: 2020-01-15 Impact factor: 21.405
Authors: John S Kim; Brian T Steffen; Anna J Podolanczuk; Steven M Kawut; Imre Noth; Ganesh Raghu; Erin D Michos; Eric A Hoffman; Gisli Thor Axelsson; Gunnar Gudmundsson; Vilmundur Gudnason; Elias F Gudmundsson; Rachel A Murphy; Josée Dupuis; Hanfei Xu; Ramachandran S Vasan; George T O'Connor; William S Harris; Gary M Hunninghake; R Graham Barr; Michael Y Tsai; David J Lederer Journal: Am J Epidemiol Date: 2021-01-04 Impact factor: 4.897
Authors: Anna Stainer; Paola Faverio; Sara Busnelli; Martina Catalano; Matteo Della Zoppa; Almerico Marruchella; Alberto Pesci; Fabrizio Luppi Journal: Int J Mol Sci Date: 2021-06-10 Impact factor: 5.923