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  • Journal article
    Dawes TJW, McCabe C, Dimopoulos K, Stewart I, Bax S, Harries C, Samaranayake CB, Kempny A, Molyneaux PL, Seitler S, Semple T, Li W, George PM, Kouranos V, Chua F, Renzoni EA, Kokosi M, Jenkins G, Wells AU, Wort SJ, Price LCet al., 2023,

    Phosphodiesterase 5 inhibitor treatment and survival in interstitial lung disease pulmonary hypertension: A Bayesian retrospective observational cohort study

    , Respirology, Vol: 28, Pages: 262-272, ISSN: 1323-7799

    Background and ObjectivePulmonary hypertension is a life-limiting complication of interstitial lung disease (ILD-PH). We investigated whether treatment with phosphodiesterase 5 inhibitors (PDE5i) in patients with ILD-PH was associated with improved survival.MethodsConsecutive incident patients with ILD-PH and right heart catheterisation, echocardiography and spirometry data were followed from diagnosis to death, transplantation or censoring with all follow-up and survival data modelled by Bayesian methods.ResultsThe diagnoses in 128 patients were idiopathic pulmonary fibrosis (n = 74, 58%), hypersensitivity pneumonitis (n = 17, 13%), non-specific interstitial pneumonia (n = 12, 9%), undifferentiated ILD (n = 8, 6%) and other lung diseases (n = 17, 13%). Final outcomes were death (n = 106, 83%), transplantation (n = 9, 7%) and censoring (n = 13, 10%). Patients treated with PDE5i (n = 50, 39%) had higher mean pulmonary artery pressure (median 38 mm Hg [interquartile range, IQR: 34, 43] vs. 35 mm Hg [IQR: 31, 38], p = 0.07) and percentage predicted forced vital capacity (FVC; median 57% [IQR: 51, 73] vs. 52% [IQR: 45, 66], p=0.08) though differences did not reach significance. Patients treated with PDE5i survived longer than untreated patients (median 2.18 years [95% CI: 1.43, 3.04] vs. 0.94 years [0.69, 1.51], p = 0.003) independent of all other prognostic markers by Bayesian joint-modelling (HR 0.39, 95% CI: 0.23, 0.59, p < 0.001) and propensity-matched analyses (HR 0.38, 95% CI: 0.22, 0.58, p < 0.001). Survival difference with treatment was significantly larger if right ventricular function was normal, rather than abnormal, at presentation (+2.55 years, 95% CI: −0.03, +3.97 vs. +0.98 years, 95% CI: +0.47, +2.00, p = 0.04).ConclusionPDE5i treatment in ILD-PH should be investigated by a prospective randomized trial.

  • Journal article
    Fabbri L, Moss S, Khan FA, Chi W, Xia J, Robinson K, Smyth AR, Jenkins G, Stewart Iet al., 2023,

    Parenchymal lung abnormalities following hospitalisation for COVID-19 and viral pneumonitis: a systematic review and meta-analysis

    , Thorax, Vol: 78, Pages: 191-201, ISSN: 0040-6376

    Introduction Persisting respiratory symptoms in COVID-19 survivors may be related to development of pulmonary fibrosis. We assessed the proportion of chest CT scans and pulmonary function tests consistent with parenchymal lung disease in the follow-up of people hospitalised with COVID-19 and viral pneumonitis.Methods Systematic review and random effects meta-analysis of proportions using studies of adults hospitalised with SARS-CoV-2, SARS-CoV, MERS-CoV or influenza pneumonia and followed up within 12 months. Searches performed in MEDLINE and Embase. Primary outcomes were proportion of radiological sequelae on CT scans; restrictive impairment; impaired gas transfer. Heterogeneity was explored in meta-regression.Results Ninety-five studies (98.9% observational) were included in qualitative synthesis, 70 were suitable for meta-analysis including 60 SARS-CoV-2 studies with a median follow-up of 3 months. In SARS-CoV-2, the overall estimated proportion of inflammatory sequelae was 50% during follow-up (0.50; 95% CI 0.41 to 0.58; I2=95%), fibrotic sequelae were estimated in 29% (0.29; 95% CI 0.22 to 0.37; I2=94.1%). Follow-up time was significantly associated with estimates of inflammatory sequelae (−0.036; 95% CI −0.068 to –0.004; p=0.029), associations with fibrotic sequelae did not reach significance (−0.021; 95% CI −0.051 to 0.009; p=0.176). Impaired gas transfer was estimated at 38% of lung function tests (0.38 95% CI 0.32 to 0.44; I2=92.1%), which was greater than restrictive impairment (0.17; 95% CI 0.13 to 0.23; I2=92.5%), neither were associated with follow-up time (p=0.207; p=0.864).Discussion Sequelae consistent with parenchymal lung disease were observed following COVID-19 and other viral pneumonitis. Estimates should be interpreted with caution due to high heterogeneity, differences in study casemix and initial severity.

  • Journal article
    Hewitt RJ, Bartlett EC, Ganatra R, Butt H, Kouranos V, Chua F, Kokosi M, Molyneaux PL, Desai SR, Wells AU, Jenkins RG, Renzoni EA, Kemp S, Devaraj A, George PMet al., 2022,

    Lung cancer screening provides an opportunity for early diagnosis and treatment of interstitial lung disease

    , Thorax, Vol: 77, Pages: 1149-1151, ISSN: 0040-6376

    Interstitial lung abnormalities (ILA) can be incidentally detected in patients undergoing low-dose CT screening for lung cancer. In this retrospective study, we explore the downstream impact of ILA detection on interstitial lung disease (ILD) diagnosis and treatment. Using a targeted approach in a lung cancer screening programme, the rate of de novo ILD diagnosis was 1.5%. The extent of abnormality on CT and severity of lung function impairment, but not symptoms were the most important factors in differentiating ILA from ILD. Disease modifying therapies were commenced in 39% of ILD cases, the majority being antifibrotic therapy for idiopathic pulmonary fibrosis.

  • Journal article
    Allen RJ, Stockwell A, Oldham JM, Guillen-Guio B, Schwartz DA, Maher TM, Flores C, Noth I, Yaspan BL, Jenkins RG, Wain Let al., 2022,

    Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis

    , THORAX, Vol: 77, Pages: 829-833, ISSN: 0040-6376
  • Journal article
    Molyneaux PL, Fahy WA, Byrne AJ, Braybrooke R, Saunders P, Toshner R, Albers G, Chua F, Renzoni EA, Wells AU, Karkera Y, Oballa E, Saini G, Nicholson AG, Jenkins G, Maher TMet al., 2022,

    CYFRA 21-1 predicts progression in IPF: a prospective longitudinal analysis of the PROFILE cohort

    , American Journal of Respiratory and Critical Care Medicine, Vol: 205, Pages: 1440-1448, ISSN: 1073-449X

    OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a progressive and inevitably fatal condition for which there are a lack of effective biomarkers to guide therapeutic decision making. RATIONALE: To determine the relationship between serum levels of the cytokeratin fragment CYFRA 21-1 and disease progression and mortality in individuals with IPF enrolled in the PROFILE study. METHODS: CYFRA 21-1 was identified by immunohistochemistry in samples of human lung. Concentrations of CYFRA 21-1 were measured using an Elisa-based assay in serum, collected at baseline, 1- and 3-months, from 491 individuals with an incident diagnosis of IPF enrolled in the PROFILE study and from 100 control subjects. Study subjects were followed for a minimum of 3 years. MEASUREMENTS AND MAIN RESULTS: CYFRA 21-1 localises to hyperplastic epithelium in IPF lung. CYFRA 21-1 levels were significantly higher in IPF subjects compared to healthy controls in both discovery (n=132) (control 0.96±0.81 ng/mL versus IPF; 2.34±2.15 ng/mL, p < 0.0001) and validation (n=359) (control; 2.21±1.54 ng/mL and IPF; 4.13±2.77 ng/mL, p<0.0001) cohorts. Baseline levels of CYFRA 21-1 distinguished individuals at risk of 12-month disease progression (C-statistic 0.70 (95% CI 0.61-0.79), p < 0.0001) and were predictive of overall-mortality (HR 1.12 (1.06-1.19) per 1 ng/mL increase in CYFRA 21-1, p=0.0001). Furthermore, 3-month change in levels of CYFRA 21-1 separately predicted 12-month and overall survival in both the discovery and validation cohorts. CONCLUSIONS: CYFRA 21-1, a marker of epithelial damage and turnover, has the potential to be an important prognostic and therapeutic biomarker in individuals with IPF.

  • Journal article
    Kraven LM, Taylor AR, Molyneaux PL, Maher T, McDonough J, Mura M, Yang I, Schwartz DA, Huang Y, Noth I, Ma SF, Yeo AJ, Fahy WA, Jenkins G, Wain Let al., 2022,

    Cluster analysis of transcriptomic datasets to identify endotypes of idiopathic pulmonary fibrosis

    , Thorax, Vol: 78, Pages: 551-558, ISSN: 0040-6376

    Background Considerable clinical heterogeneity in idiopathic pulmonary fibrosis (IPF) suggests the existence of multiple disease endotypes. Identifying these endotypes would improve our understanding of the pathogenesis of IPF and could allow for a biomarker-driven personalised medicine approach. We aimed to identify clinically distinct groups of patients with IPF that could represent distinct disease endotypes.Methods We co-normalised, pooled and clustered three publicly available blood transcriptomic datasets (total 220 IPF cases). We compared clinical traits across clusters and used gene enrichment analysis to identify biological pathways and processes that were over-represented among the genes that were differentially expressed across clusters. A gene-based classifier was developed and validated using three additional independent datasets (total 194 IPF cases).Findings We identified three clusters of patients with IPF with statistically significant differences in lung function (p=0.009) and mortality (p=0.009) between groups. Gene enrichment analysis implicated mitochondrial homeostasis, apoptosis, cell cycle and innate and adaptive immunity in the pathogenesis underlying these groups. We developed and validated a 13-gene cluster classifier that predicted mortality in IPF (high-risk clusters vs low-risk cluster: HR 4.25, 95% CI 2.14 to 8.46, p=3.7×10−5).Interpretation We have identified blood gene expression signatures capable of discerning groups of patients with IPF with significant differences in survival. These clusters could be representative of distinct pathophysiological states, which would support the theory of multiple endotypes of IPF. Although more work must be done to confirm the existence of these endotypes, our classifier could be a useful tool in patient stratification and outcome prediction in IPF.

  • Journal article
    Khan FA, Stewart I, Moss S, Fabbri L, Robinson KA, Johnson SR, Jenkins RGet al., 2022,

    Three-Month FVC Change: A Trial Endpoint for Idiopathic Pulmonary Fibrosis Based on Individual Participant Data Meta-analysis

    , AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 205, Pages: 936-948, ISSN: 1073-449X
  • Journal article
    Khan F, Howard L, Hearson G, Edwards C, Barber C, Jones S, Wilson AM, Maher TM, Saini G, Stewart I, Jenkins Get al., 2022,

    Clinical utility of home versus hospital spirometry in fibrotic ILD: evaluation following INJUSTIS interim analysis

    , Annals of the American Thoracic Society, Vol: 19, Pages: 506-510, ISSN: 1546-3222
  • Journal article
    Nakanishi T, Cerani A, Forgetta V, Zhou S, Allen RJ, Leavy OC, Koido M, Assayag D, Jenkins RG, Wain L, Yang I, Lathrop GM, Wolters PJ, Schwartz DA, Richards JBet al., 2022,

    Genetically increased circulating FUT3 level leads to reduced risk of idiopathic pulmonary fibrosis: a Mendelian randomisation study

    , EUROPEAN RESPIRATORY JOURNAL, Vol: 59, ISSN: 0903-1936
  • Journal article
    Ramis J, Middlewick R, Pappalardo F, Cairns JT, Stewart ID, John AE, Naveed S-U-N, Krishnan R, Miller S, Shaw DE, Brightling CE, Buttery L, Rose F, Jenkins G, Johnson SR, Tatler ALet al., 2022,

    Lysyl oxidase-like 2 is increased in asthma and contributes to asthmatic airway remodelling

    , European Respiratory Journal, Vol: 60, Pages: 1-13, ISSN: 0903-1936

    Airway smooth muscle cells (ASM) are fundamental to asthma pathogenesis, influencing bronchoconstriction, airway hyper-responsiveness, and airway remodelling. Extracellular matrix (ECM) can influence tissue remodelling pathways, however, to date no study has investigated the effect of ASM ECM stiffness and crosslinking on the development of asthmatic airway remodelling. We hypothesised that TGFβ activation by ASM is influenced by ECM in asthma and sought to investigate the mechanisms involved. This study combines in vitro and in vivo approaches: human ASM cells were used in vitro to investigate basal TGFβ activation and expression of ECM crosslinking enzymes. Human bronchial biopsies from asthmatic and non-asthmatic donors were used to confirm LOXL2 expression ASM. A chronic ovalbumin model of asthma was used to study the effect of LOXL2 inhibition on airway remodelling. We found that ASM cells from asthmatics activated more TGFβ basally than non-asthmatic controls and that diseased cell-derived ECM influences levels of TGFβ activated. Our data demonstrate that the ECM crosslinking enzyme LOXL2 is increased in asthmatic ASM cells and in bronchial biopsies. Crucially, we show that LOXL2 inhibition reduces ECM stiffness and TGFβ activation in vitro, and can reduce subepithelial collagen deposition and ASM thickness, two features of airway remodelling, in an ovalbumin mouse model of asthma. These data are the first to highlight a role for LOXL2 in the development of asthmatic airway remodelling and suggest that LOXL2 inhibition warrants further investigation as a potential therapy to reduce remodelling of the airways in severe asthma.

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