Shaney Barratt - Academia.edu (original) (raw)

Papers by Shaney Barratt

Research paper thumbnail of Clinicoserological features of antisynthetase syndrome (ASyS)-associated interstitial lung disease presenting to respiratory services: comparison with idiopathic pulmonary fibrosis and ASyS diagnosed in rheumatology services

BMJ Open Respiratory Research, 2021

IntroductionAntisynthetase syndrome (ASyS) is a rare autoimmune connective tissue disease (CTD), ... more IntroductionAntisynthetase syndrome (ASyS) is a rare autoimmune connective tissue disease (CTD), associated with autoantibodies targeting tRNA synthetase enzymes, that can present to respiratory (interstitial lung disease (ILD)) or rheumatology (myositis, inflammatory arthritis and systemic features) services. The therapeutic management of CTD-associated ILD and idiopathic pulmonary fibrosis (IPF) differs widely, thus accurate diagnosis is essential.MethodsWe undertook a retrospective, multicentre observational cohort study designed to (1) evaluate differences between ASyS-associated ILD with IPF, (2) phenotypic differences in patients with ASyS-ILD presenting to respiratory versus rheumatology services, (3) differences in outcomes between ASySassociated with Jo-1 versus non-Jo-1 autoantibodies and (4) compare long-term outcomes between these groups.ResultsWe identified 76 patients with ASyS-ILD and 78 with IPF. Patients with ASyS were younger at presentation (57 vs 77 years, p<0...

Research paper thumbnail of The prognostic value of cardiopulmonary exercise testing in interstitial lung disease: a systematic review

ERJ Open Research, 2020

The heterogeneity of interstitial lung disease (ILD) results in prognostic uncertainty concerning... more The heterogeneity of interstitial lung disease (ILD) results in prognostic uncertainty concerning end-of-life discussions and optimal timing for transplantation. Effective prognostic markers and prediction models are needed. Cardiopulmonary exercise testing (CPET) provides a comprehensive assessment of the physiological changes in the respiratory, cardiovascular and musculoskeletal systems in a controlled laboratory environment. It has shown promise as a prognostic factor for other chronic respiratory conditions. We sought to evaluate the prognostic value of CPET in predicting outcomes in longitudinal studies of ILD. MEDLINE, Embase and the Cochrane Database of Systematic Reviews were used to identify studies reporting the prognostic value of CPET in predicting outcomes in longitudinal studies of ILD. Study quality was assessed using the Quality in Prognosis Study risk of bias tool. Thirteen studies were included that reported the prognostic value of CPET in ILD. All studies reporte...

Research paper thumbnail of Outcome of hospitalisation for COVID-19 in patients with Interstitial Lung Disease: An international multicentre study

RationaleThe impact of COVID-19 on patients with Interstitial Lung Disease (ILD) has not been est... more RationaleThe impact of COVID-19 on patients with Interstitial Lung Disease (ILD) has not been established.ObjectivesTo assess outcomes following COVID-19 in patients with ILD versus those without in a contemporaneous age, sex and comorbidity matched population.MethodsAn international multicentre audit of patients with a prior diagnosis of ILD admitted to hospital with COVID-19 between 1 March and 1 May 2020 was undertaken and compared with patients, without ILD obtained from the ISARIC 4C cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished IPF from non-IPF ILD and used lung function to determine the greatest risks of death.Measurements and Main ResultsData from 349 patients with ILD across Europe were included, of whom 161 were admitted to hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity-score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After ...

Research paper thumbnail of Understanding the burden of interstitial lung disease post-COVID-19: the UK Interstitial Lung Disease-Long COVID Study (UKILD-Long COVID)

BMJ Open Respiratory Research, 2021

IntroductionThe COVID-19 pandemic has led to over 100 million cases worldwide. The UK has had ove... more IntroductionThe COVID-19 pandemic has led to over 100 million cases worldwide. The UK has had over 4 million cases, 400 000 hospital admissions and 100 000 deaths. Many patients with COVID-19 suffer long-term symptoms, predominantly breathlessness and fatigue whether hospitalised or not. Early data suggest potentially severe long-term consequence of COVID-19 is development of long COVID-19-related interstitial lung disease (LC-ILD).Methods and analysisThe UK Interstitial Lung Disease Consortium (UKILD) will undertake longitudinal observational studies of patients with suspected ILD following COVID-19. The primary objective is to determine ILD prevalence at 12 months following infection and whether clinically severe infection correlates with severity of ILD. Secondary objectives will determine the clinical, genetic, epigenetic and biochemical factors that determine the trajectory of recovery or progression of ILD. Data will be obtained through linkage to the Post-Hospitalisation COVI...

Research paper thumbnail of Outcome of Hospitalization for COVID-19 in Patients with Interstitial Lung Disease. An International Multicenter Study

American Journal of Respiratory and Critical Care Medicine, 2020

Rationale: The impact of coronavirus disease (COVID-19) on patients with interstitial lung diseas... more Rationale: The impact of coronavirus disease (COVID-19) on patients with interstitial lung disease (ILD) has not been established. Objectives: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age-, sex-, and comorbidity-matched population. Methods: An international multicenter audit of patients with a prior diagnosis of ILD admitted to the hospital with COVID-19 between March 1 and May 1, 2020, was undertaken and compared with patients without ILD, obtained from the ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterisation Consortium) cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished idiopathic pulmonary fibrosis from non-idiopathic pulmonary fibrosis ILD and used lung function to determine the greatest risks of death. Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to the hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching, patients with ILD with COVID-19 had significantly poorer survival (hazard ratio [HR], 1.60; confidence interval, 1.17-2.18; P = 0.003) than age-, sex-, and comorbidity-matched controls without ILD. Patients with an FVC of ,80% had an increased risk of death versus patients with FVC >80% (HR, 1.72; 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR, 2.27; 1.3923.71). Conclusions: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.

Research paper thumbnail of The prognostic value of cardiopulmonary exercise testing in interstitial lung disease: a systematic review

ERJ Open Research, 2020

The heterogeneity of interstitial lung disease (ILD) results in prognostic uncertainty concerning... more The heterogeneity of interstitial lung disease (ILD) results in prognostic uncertainty concerning end-of-life discussions and optimal timing for transplantation. Effective prognostic markers and prediction models are needed. Cardiopulmonary exercise testing (CPET) provides a comprehensive assessment of the physiological changes in the respiratory, cardiovascular and musculoskeletal systems in a controlled laboratory environment. It has shown promise as a prognostic factor for other chronic respiratory conditions. We sought to evaluate the prognostic value of CPET in predicting outcomes in longitudinal studies of ILD.MEDLINE, Embase and the Cochrane Database of Systematic Reviews were used to identify studies reporting the prognostic value of CPET in predicting outcomes in longitudinal studies of ILD. Study quality was assessed using the Quality in Prognosis Study risk of bias tool.Thirteen studies were included that reported the prognostic value of CPET in ILD. All studies reported ...

Research paper thumbnail of Inhibitors of the Autotaxin-Lysophosphatidic Acid Axis and Their Potential in the Treatment of Interstitial Lung Disease: Current Perspectives

Clinical Pharmacology: Advances and Applications, 2020

Idiopathic pulmonary fibrosis is a progressive fibrosing interstitial lung disease for which ther... more Idiopathic pulmonary fibrosis is a progressive fibrosing interstitial lung disease for which there is no known cure. Currently available therapeutic options have been shown at best to slow the progression of the disease and thus there remains an urgent unmet need to identify new therapies. In this article, we will discuss the mechanisms of action, pre-clinical and clinical trial data surrounding inhibitors of the autotaxin-lysophosphatidic acid axis, which show promise as emerging novel therapies for fibrotic lung disease.

Research paper thumbnail of Prognostic factors in chronic hypersensitivity pneumonitis

European Respiratory Review, 2020

Hypersensitivity pneumonitis (HP) is an immunologically mediated lung disease resulting from expo... more Hypersensitivity pneumonitis (HP) is an immunologically mediated lung disease resulting from exposure to inhaled environmental antigens. Prognosis is variable, with a subset of patients developing progressive fibrosis leading to respiratory failure and death. Therefore, there is an urgent need to identify factors which predict prognosis and survival in patients with HP. We undertook a narrative review of existing evidence to identify prognostic factors in patients with chronic HP. Patient demographics, smoking history, extent of antigen exposure and comorbidities all have reported associations with disease outcome, and physiological, radiological and laboratory markers have been shown to predict overall survival. While no single marker has been demonstrated to accurately and reliably predict prognosis, older age, more severe impairment of pulmonary function at baseline and established fibrosis on either biopsy or high-resolution computed tomography are consistently associated with w...

Research paper thumbnail of Idiopathic Pulmonary Fibrosis (IPF): An Overview

Journal of Clinical Medicine, 2018

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterised by chronic, pro... more Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterised by chronic, progressive scarring of the lungs and the pathological hallmark of usual interstitial pneumonia. Current paradigms suggest alveolar epithelial cell damage is a key initiating factor. Globally, incidence of the disease is rising, with associated high morbidity, mortality, and economic healthcare burden. Diagnosis relies on a multidisciplinary team approach with exclusion of other causes of interstitial lung disease. Over recent years, two novel antifibrotic therapies, pirfenidone and nintedanib, have been developed, providing treatment options for many patients with IPF, with several other agents in early clinical trials. Current efforts are directed at identifying key biomarkers that may direct more customized patient-centred healthcare to improve outcomes for these patients in the future.

Research paper thumbnail of Effects of hypoxia and hyperoxia on the differential expression of VEGF-A isoforms and receptors in Idiopathic Pulmonary Fibrosis (IPF)

Respiratory research, Jan 15, 2018

Dysregulation of VEGF-A bioavailability has been implicated in the development of lung injury/fib... more Dysregulation of VEGF-A bioavailability has been implicated in the development of lung injury/fibrosis, exemplified by Idiopathic Pulmonary Fibrosis (IPF). VEGF-A is a target of the hypoxic response via its translational regulation by HIF-1α. The role of hypoxia and hyperoxia in the development and progression of IPF has not been explored. In normal lung (NF) and IPF-derived fibroblasts (FF) VEGF-Aa protein expression was upregulated by hypoxia, mediated through activation of VEGF-Aa gene transcription. VEGF-A receptors and co-receptors were differentially expressed by hypoxia and hyperoxia. Our data supports a potential role for hypoxia, hyperoxia and VEGF-Aa isoforms as drivers of fibrogenesis.

Research paper thumbnail of VEGF isoforms have differential effects on permeability of human pulmonary microvascular endothelial cells

Respiratory Research, 2017

Background: Alternative splicing of Vascular endothelial growth factor-A mRNA transcripts (common... more Background: Alternative splicing of Vascular endothelial growth factor-A mRNA transcripts (commonly referred as VEGF) leads to the generation of functionally differing isoforms, the relative amounts of which have potentially significant physiological outcomes in conditions such as acute respiratory distress syndrome (ARDS). The effect of such isoforms on pulmonary vascular permeability is unknown. We hypothesised that VEGF 165 a and VEGF 165 b isoforms would have differing effects on pulmonary vascular permeability caused by differential activation of intercellular signal transduction pathways. Method: To test this hypothesis we investigated the physiological effect of VEGF 165 a and VEGF 165 b on Human Pulmonary Microvascular Endothelial Cell (HPMEC) permeability using three different methods: trans-endothelial electrical resistance (TEER), Electric cell-substrate impedance sensing (ECIS) and FITC-BSA passage. In addition, potential downstream signalling pathways of the VEGF isoforms were investigated by Western blotting and the use of specific signalling inhibitors. Results: VEGF 165 a increased HPMEC permeability using all three methods (paracellular and transcellular) and led to associated VE-cadherin and actin stress fibre changes. In contrast, VEGF 165 b decreased paracellular permeability and did not induce changes in VE-cadherin cell distribution. Furthermore, VEGF 165 a and VEGF 165 b had differing effects on both the phosphorylation of VEGF receptors and downstream signalling proteins pMEK, p42/44MAPK, p38 MAPK, pAKT and peNOS. Interestingly specific inhibition of the pMEK, p38 MAPK, PI3 kinase and eNOS pathways blocked the effects of both VEGF 165 a and VEGF 165 b on paracellular permeability and the effect of VEGF 165 a on proliferation/migration, suggesting that this difference in cellular response is mediated by an as yet unidentified signalling pathway(s). Conclusion: This study demonstrates that the novel isoform VEGF 165 a and VEGF 165 b induce differing effects on permeability in pulmonary microvascular endothelial cells.

Research paper thumbnail of Differential Expression of VEGF-Axxx Isoforms is Critical for Development of Pulmonary Fibrosis

American journal of respiratory and critical care medicine, Aug 29, 2017

Fibrosis following lung injury is related to poor outcome and Idiopathic Pulmonary Fibrosis (IPF)... more Fibrosis following lung injury is related to poor outcome and Idiopathic Pulmonary Fibrosis (IPF) can be regarded as an exemplar. Vascular Endothelial Growth Factor-A (VEGF-A) has been implicated in this context but there are conflicting reports as to whether it is a contributory or protective factor. Differential splicing of the VEGF-A gene produces multiple functional isoforms including VEGF-A165a, and VEGF-A165b a member of the inhibitory family. To-date there is no clear information on the role of VEGF in IPF. To establish VEGF isoform expression and functional effects in IPF. We used tissue sections, plasma and lung fibroblasts from IPF patients and controls. In a bleomycin-induced lung fibrosis model we used wild type MMTV mice and a triple transgenic mouse SPC-rtTA+/-TetoCre+/-LoxP-VEGF-A+/+ to conditionally induce VEGF-A isoform deletion specifically in the ATII cells of adult mice. IPF and normal lung fibroblasts differentially expressed and responded to VEGF-A165a and VEGF...

Research paper thumbnail of T2 VEGF signalling:differences in isoforms?

Research paper thumbnail of Vascular Endothelial Growth Factor in Acute Lung Injury and Acute Respiratory Distress Syndrome

Respiration, 2014

Acute respiratory distress syndrome (ARDS) is the most severe form of lung injury, characterised ... more Acute respiratory distress syndrome (ARDS) is the most severe form of lung injury, characterised by alveolar oedema and vascular permeability, in part due to disruption of the alveolar capillary membrane integrity. Vascular endothelial growth factor (VEGF) was originally identified as a vascular permeability factor and has been implicated in the pathogenesis of acute lung injury/ARDS. This review describes our current knowledge of VEGF biology and summarises the literature investigating the potential role VEGF may play in normal lung maintenance and in the development of lung injury.

Research paper thumbnail of Vascular remodelling in the pathogenesis of idiopathic pulmonary fibrosis

QJM, 2014

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrosing interstitial pneu... more Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrosing interstitial pneumonia of unknown aetiology that usually leads to respiratory failure and death within 5 years of diagnosis. Alveolar epithelial cell injury, disruption of alveolar capillary membrane integrity and abnormal vascular repair and remodelling have all been proposed as possible pathogenic mechanisms. This review summarizes our current knowledge of the abnormalities in vascular remodelling observed in IPF and highlights several of the cytokines thought to play a pathogenic role, which may ultimately prove to be future therapeutic targets.

Research paper thumbnail of Detection of VEGF-Axxxb Isoforms in Human Tissues

PLoS ONE, 2013

Vascular Endothelial Growth Factor-A (VEGF-A) can be generated as multiple isoforms by alternativ... more Vascular Endothelial Growth Factor-A (VEGF-A) can be generated as multiple isoforms by alternative splicing. Two families of isoforms have been described in humans, pro-angiogenic isoforms typified by VEGF-A 165 a, and anti-angiogenic isoforms typified by VEGF-A 165 b. The practical determination of expression levels of alternative isoforms of the same gene may be complicated by experimental protocols that favour one isoform over another, and the use of specific positive and negative controls is essential for the interpretation of findings on expression of the isoforms. Here we address some of the difficulties in experimental design when investigating alternative splicing of VEGF isoforms, and discuss the use of appropriate control paradigms. We demonstrate why use of specific control experiments can prevent assumptions that VEGF-A 165 b is not present, when in fact it is. We reiterate, and confirm previously published experimental design protocols that demonstrate the importance of using positive controls. These include using known target sequences to show that the experimental conditions are suitable for PCR amplification of VEGF-A 165 b mRNA for both q-PCR and RT-PCR and to ensure that mispriming does not occur. We also provide evidence that demonstrates that detection of VEGF-A 165 b protein in mice needs to be tightly controlled to prevent detection of mouse IgG by a secondary antibody. We also show that human VEGF 165 b protein can be immunoprecipitated from cultured human cells and that immunoprecipitating VEGF-A results in protein that is detected by VEGF-A 165 b antibody. These findings support the conclusion that more information on the biology of VEGF-A 165 b isoforms is required, and confirm the importance of the experimental design in such investigations, including the use of specific positive and negative controls.

Research paper thumbnail of VEGF (Vascular Endothelial Growth Factor) and Fibrotic Lung Disease

International Journal of Molecular Sciences, 2018

Interstitial lung disease (ILD) encompasses a group of heterogeneous diseases characterised by va... more Interstitial lung disease (ILD) encompasses a group of heterogeneous diseases characterised by varying degrees of aberrant inflammation and fibrosis of the lung parenchyma. This may occur in isolation, such as in idiopathic pulmonary fibrosis (IPF) or as part of a wider disease process affecting multiple organs, such as in systemic sclerosis. Anti-Vascular Endothelial Growth Factor (anti-VEGF) therapy is one component of an existing broad-spectrum therapeutic option in IPF (nintedanib) and may become part of the emerging therapeutic strategy for other ILDs in the future. This article describes our current understanding of VEGF biology in normal lung homeostasis and how changes in its bioavailability may contribute the pathogenesis of ILD. The complexity of VEGF biology is particularly highlighted with an emphasis on the potential non-vascular, non-angiogenic roles for VEGF in the lung, in both health and disease.

Research paper thumbnail of Vascular endothelial growth factor (VEGF) in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS): paradox or paradigm?

Thorax, 2006

Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury (ALI), rema... more Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury (ALI), remains a devastating condition with a high mortality. It is characterised by alveolar injury and increased pulmonary vascular permeability. Vascular endothelial cell growth factor (VEGF) was identified by its properties to increase permeability and act as a cellular growth factor, hence its potential for a key role in the pathogenesis of ALI/ARDS. This review describes the basic biology of VEGF and its receptors as an essential prerequisite to discussing the available and sometimes paradoxical published data, before considering a paradigm for the role of VEGF in the human lung.

Research paper thumbnail of Clinicoserological features of antisynthetase syndrome (ASyS)-associated interstitial lung disease presenting to respiratory services: comparison with idiopathic pulmonary fibrosis and ASyS diagnosed in rheumatology services

BMJ Open Respiratory Research, 2021

IntroductionAntisynthetase syndrome (ASyS) is a rare autoimmune connective tissue disease (CTD), ... more IntroductionAntisynthetase syndrome (ASyS) is a rare autoimmune connective tissue disease (CTD), associated with autoantibodies targeting tRNA synthetase enzymes, that can present to respiratory (interstitial lung disease (ILD)) or rheumatology (myositis, inflammatory arthritis and systemic features) services. The therapeutic management of CTD-associated ILD and idiopathic pulmonary fibrosis (IPF) differs widely, thus accurate diagnosis is essential.MethodsWe undertook a retrospective, multicentre observational cohort study designed to (1) evaluate differences between ASyS-associated ILD with IPF, (2) phenotypic differences in patients with ASyS-ILD presenting to respiratory versus rheumatology services, (3) differences in outcomes between ASySassociated with Jo-1 versus non-Jo-1 autoantibodies and (4) compare long-term outcomes between these groups.ResultsWe identified 76 patients with ASyS-ILD and 78 with IPF. Patients with ASyS were younger at presentation (57 vs 77 years, p<0...

Research paper thumbnail of The prognostic value of cardiopulmonary exercise testing in interstitial lung disease: a systematic review

ERJ Open Research, 2020

The heterogeneity of interstitial lung disease (ILD) results in prognostic uncertainty concerning... more The heterogeneity of interstitial lung disease (ILD) results in prognostic uncertainty concerning end-of-life discussions and optimal timing for transplantation. Effective prognostic markers and prediction models are needed. Cardiopulmonary exercise testing (CPET) provides a comprehensive assessment of the physiological changes in the respiratory, cardiovascular and musculoskeletal systems in a controlled laboratory environment. It has shown promise as a prognostic factor for other chronic respiratory conditions. We sought to evaluate the prognostic value of CPET in predicting outcomes in longitudinal studies of ILD. MEDLINE, Embase and the Cochrane Database of Systematic Reviews were used to identify studies reporting the prognostic value of CPET in predicting outcomes in longitudinal studies of ILD. Study quality was assessed using the Quality in Prognosis Study risk of bias tool. Thirteen studies were included that reported the prognostic value of CPET in ILD. All studies reporte...

Research paper thumbnail of Outcome of hospitalisation for COVID-19 in patients with Interstitial Lung Disease: An international multicentre study

RationaleThe impact of COVID-19 on patients with Interstitial Lung Disease (ILD) has not been est... more RationaleThe impact of COVID-19 on patients with Interstitial Lung Disease (ILD) has not been established.ObjectivesTo assess outcomes following COVID-19 in patients with ILD versus those without in a contemporaneous age, sex and comorbidity matched population.MethodsAn international multicentre audit of patients with a prior diagnosis of ILD admitted to hospital with COVID-19 between 1 March and 1 May 2020 was undertaken and compared with patients, without ILD obtained from the ISARIC 4C cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished IPF from non-IPF ILD and used lung function to determine the greatest risks of death.Measurements and Main ResultsData from 349 patients with ILD across Europe were included, of whom 161 were admitted to hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity-score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After ...

Research paper thumbnail of Understanding the burden of interstitial lung disease post-COVID-19: the UK Interstitial Lung Disease-Long COVID Study (UKILD-Long COVID)

BMJ Open Respiratory Research, 2021

IntroductionThe COVID-19 pandemic has led to over 100 million cases worldwide. The UK has had ove... more IntroductionThe COVID-19 pandemic has led to over 100 million cases worldwide. The UK has had over 4 million cases, 400 000 hospital admissions and 100 000 deaths. Many patients with COVID-19 suffer long-term symptoms, predominantly breathlessness and fatigue whether hospitalised or not. Early data suggest potentially severe long-term consequence of COVID-19 is development of long COVID-19-related interstitial lung disease (LC-ILD).Methods and analysisThe UK Interstitial Lung Disease Consortium (UKILD) will undertake longitudinal observational studies of patients with suspected ILD following COVID-19. The primary objective is to determine ILD prevalence at 12 months following infection and whether clinically severe infection correlates with severity of ILD. Secondary objectives will determine the clinical, genetic, epigenetic and biochemical factors that determine the trajectory of recovery or progression of ILD. Data will be obtained through linkage to the Post-Hospitalisation COVI...

Research paper thumbnail of Outcome of Hospitalization for COVID-19 in Patients with Interstitial Lung Disease. An International Multicenter Study

American Journal of Respiratory and Critical Care Medicine, 2020

Rationale: The impact of coronavirus disease (COVID-19) on patients with interstitial lung diseas... more Rationale: The impact of coronavirus disease (COVID-19) on patients with interstitial lung disease (ILD) has not been established. Objectives: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age-, sex-, and comorbidity-matched population. Methods: An international multicenter audit of patients with a prior diagnosis of ILD admitted to the hospital with COVID-19 between March 1 and May 1, 2020, was undertaken and compared with patients without ILD, obtained from the ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterisation Consortium) cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished idiopathic pulmonary fibrosis from non-idiopathic pulmonary fibrosis ILD and used lung function to determine the greatest risks of death. Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to the hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching, patients with ILD with COVID-19 had significantly poorer survival (hazard ratio [HR], 1.60; confidence interval, 1.17-2.18; P = 0.003) than age-, sex-, and comorbidity-matched controls without ILD. Patients with an FVC of ,80% had an increased risk of death versus patients with FVC >80% (HR, 1.72; 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR, 2.27; 1.3923.71). Conclusions: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.

Research paper thumbnail of The prognostic value of cardiopulmonary exercise testing in interstitial lung disease: a systematic review

ERJ Open Research, 2020

The heterogeneity of interstitial lung disease (ILD) results in prognostic uncertainty concerning... more The heterogeneity of interstitial lung disease (ILD) results in prognostic uncertainty concerning end-of-life discussions and optimal timing for transplantation. Effective prognostic markers and prediction models are needed. Cardiopulmonary exercise testing (CPET) provides a comprehensive assessment of the physiological changes in the respiratory, cardiovascular and musculoskeletal systems in a controlled laboratory environment. It has shown promise as a prognostic factor for other chronic respiratory conditions. We sought to evaluate the prognostic value of CPET in predicting outcomes in longitudinal studies of ILD.MEDLINE, Embase and the Cochrane Database of Systematic Reviews were used to identify studies reporting the prognostic value of CPET in predicting outcomes in longitudinal studies of ILD. Study quality was assessed using the Quality in Prognosis Study risk of bias tool.Thirteen studies were included that reported the prognostic value of CPET in ILD. All studies reported ...

Research paper thumbnail of Inhibitors of the Autotaxin-Lysophosphatidic Acid Axis and Their Potential in the Treatment of Interstitial Lung Disease: Current Perspectives

Clinical Pharmacology: Advances and Applications, 2020

Idiopathic pulmonary fibrosis is a progressive fibrosing interstitial lung disease for which ther... more Idiopathic pulmonary fibrosis is a progressive fibrosing interstitial lung disease for which there is no known cure. Currently available therapeutic options have been shown at best to slow the progression of the disease and thus there remains an urgent unmet need to identify new therapies. In this article, we will discuss the mechanisms of action, pre-clinical and clinical trial data surrounding inhibitors of the autotaxin-lysophosphatidic acid axis, which show promise as emerging novel therapies for fibrotic lung disease.

Research paper thumbnail of Prognostic factors in chronic hypersensitivity pneumonitis

European Respiratory Review, 2020

Hypersensitivity pneumonitis (HP) is an immunologically mediated lung disease resulting from expo... more Hypersensitivity pneumonitis (HP) is an immunologically mediated lung disease resulting from exposure to inhaled environmental antigens. Prognosis is variable, with a subset of patients developing progressive fibrosis leading to respiratory failure and death. Therefore, there is an urgent need to identify factors which predict prognosis and survival in patients with HP. We undertook a narrative review of existing evidence to identify prognostic factors in patients with chronic HP. Patient demographics, smoking history, extent of antigen exposure and comorbidities all have reported associations with disease outcome, and physiological, radiological and laboratory markers have been shown to predict overall survival. While no single marker has been demonstrated to accurately and reliably predict prognosis, older age, more severe impairment of pulmonary function at baseline and established fibrosis on either biopsy or high-resolution computed tomography are consistently associated with w...

Research paper thumbnail of Idiopathic Pulmonary Fibrosis (IPF): An Overview

Journal of Clinical Medicine, 2018

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterised by chronic, pro... more Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterised by chronic, progressive scarring of the lungs and the pathological hallmark of usual interstitial pneumonia. Current paradigms suggest alveolar epithelial cell damage is a key initiating factor. Globally, incidence of the disease is rising, with associated high morbidity, mortality, and economic healthcare burden. Diagnosis relies on a multidisciplinary team approach with exclusion of other causes of interstitial lung disease. Over recent years, two novel antifibrotic therapies, pirfenidone and nintedanib, have been developed, providing treatment options for many patients with IPF, with several other agents in early clinical trials. Current efforts are directed at identifying key biomarkers that may direct more customized patient-centred healthcare to improve outcomes for these patients in the future.

Research paper thumbnail of Effects of hypoxia and hyperoxia on the differential expression of VEGF-A isoforms and receptors in Idiopathic Pulmonary Fibrosis (IPF)

Respiratory research, Jan 15, 2018

Dysregulation of VEGF-A bioavailability has been implicated in the development of lung injury/fib... more Dysregulation of VEGF-A bioavailability has been implicated in the development of lung injury/fibrosis, exemplified by Idiopathic Pulmonary Fibrosis (IPF). VEGF-A is a target of the hypoxic response via its translational regulation by HIF-1α. The role of hypoxia and hyperoxia in the development and progression of IPF has not been explored. In normal lung (NF) and IPF-derived fibroblasts (FF) VEGF-Aa protein expression was upregulated by hypoxia, mediated through activation of VEGF-Aa gene transcription. VEGF-A receptors and co-receptors were differentially expressed by hypoxia and hyperoxia. Our data supports a potential role for hypoxia, hyperoxia and VEGF-Aa isoforms as drivers of fibrogenesis.

Research paper thumbnail of VEGF isoforms have differential effects on permeability of human pulmonary microvascular endothelial cells

Respiratory Research, 2017

Background: Alternative splicing of Vascular endothelial growth factor-A mRNA transcripts (common... more Background: Alternative splicing of Vascular endothelial growth factor-A mRNA transcripts (commonly referred as VEGF) leads to the generation of functionally differing isoforms, the relative amounts of which have potentially significant physiological outcomes in conditions such as acute respiratory distress syndrome (ARDS). The effect of such isoforms on pulmonary vascular permeability is unknown. We hypothesised that VEGF 165 a and VEGF 165 b isoforms would have differing effects on pulmonary vascular permeability caused by differential activation of intercellular signal transduction pathways. Method: To test this hypothesis we investigated the physiological effect of VEGF 165 a and VEGF 165 b on Human Pulmonary Microvascular Endothelial Cell (HPMEC) permeability using three different methods: trans-endothelial electrical resistance (TEER), Electric cell-substrate impedance sensing (ECIS) and FITC-BSA passage. In addition, potential downstream signalling pathways of the VEGF isoforms were investigated by Western blotting and the use of specific signalling inhibitors. Results: VEGF 165 a increased HPMEC permeability using all three methods (paracellular and transcellular) and led to associated VE-cadherin and actin stress fibre changes. In contrast, VEGF 165 b decreased paracellular permeability and did not induce changes in VE-cadherin cell distribution. Furthermore, VEGF 165 a and VEGF 165 b had differing effects on both the phosphorylation of VEGF receptors and downstream signalling proteins pMEK, p42/44MAPK, p38 MAPK, pAKT and peNOS. Interestingly specific inhibition of the pMEK, p38 MAPK, PI3 kinase and eNOS pathways blocked the effects of both VEGF 165 a and VEGF 165 b on paracellular permeability and the effect of VEGF 165 a on proliferation/migration, suggesting that this difference in cellular response is mediated by an as yet unidentified signalling pathway(s). Conclusion: This study demonstrates that the novel isoform VEGF 165 a and VEGF 165 b induce differing effects on permeability in pulmonary microvascular endothelial cells.

Research paper thumbnail of Differential Expression of VEGF-Axxx Isoforms is Critical for Development of Pulmonary Fibrosis

American journal of respiratory and critical care medicine, Aug 29, 2017

Fibrosis following lung injury is related to poor outcome and Idiopathic Pulmonary Fibrosis (IPF)... more Fibrosis following lung injury is related to poor outcome and Idiopathic Pulmonary Fibrosis (IPF) can be regarded as an exemplar. Vascular Endothelial Growth Factor-A (VEGF-A) has been implicated in this context but there are conflicting reports as to whether it is a contributory or protective factor. Differential splicing of the VEGF-A gene produces multiple functional isoforms including VEGF-A165a, and VEGF-A165b a member of the inhibitory family. To-date there is no clear information on the role of VEGF in IPF. To establish VEGF isoform expression and functional effects in IPF. We used tissue sections, plasma and lung fibroblasts from IPF patients and controls. In a bleomycin-induced lung fibrosis model we used wild type MMTV mice and a triple transgenic mouse SPC-rtTA+/-TetoCre+/-LoxP-VEGF-A+/+ to conditionally induce VEGF-A isoform deletion specifically in the ATII cells of adult mice. IPF and normal lung fibroblasts differentially expressed and responded to VEGF-A165a and VEGF...

Research paper thumbnail of T2 VEGF signalling:differences in isoforms?

Research paper thumbnail of Vascular Endothelial Growth Factor in Acute Lung Injury and Acute Respiratory Distress Syndrome

Respiration, 2014

Acute respiratory distress syndrome (ARDS) is the most severe form of lung injury, characterised ... more Acute respiratory distress syndrome (ARDS) is the most severe form of lung injury, characterised by alveolar oedema and vascular permeability, in part due to disruption of the alveolar capillary membrane integrity. Vascular endothelial growth factor (VEGF) was originally identified as a vascular permeability factor and has been implicated in the pathogenesis of acute lung injury/ARDS. This review describes our current knowledge of VEGF biology and summarises the literature investigating the potential role VEGF may play in normal lung maintenance and in the development of lung injury.

Research paper thumbnail of Vascular remodelling in the pathogenesis of idiopathic pulmonary fibrosis

QJM, 2014

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrosing interstitial pneu... more Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrosing interstitial pneumonia of unknown aetiology that usually leads to respiratory failure and death within 5 years of diagnosis. Alveolar epithelial cell injury, disruption of alveolar capillary membrane integrity and abnormal vascular repair and remodelling have all been proposed as possible pathogenic mechanisms. This review summarizes our current knowledge of the abnormalities in vascular remodelling observed in IPF and highlights several of the cytokines thought to play a pathogenic role, which may ultimately prove to be future therapeutic targets.

Research paper thumbnail of Detection of VEGF-Axxxb Isoforms in Human Tissues

PLoS ONE, 2013

Vascular Endothelial Growth Factor-A (VEGF-A) can be generated as multiple isoforms by alternativ... more Vascular Endothelial Growth Factor-A (VEGF-A) can be generated as multiple isoforms by alternative splicing. Two families of isoforms have been described in humans, pro-angiogenic isoforms typified by VEGF-A 165 a, and anti-angiogenic isoforms typified by VEGF-A 165 b. The practical determination of expression levels of alternative isoforms of the same gene may be complicated by experimental protocols that favour one isoform over another, and the use of specific positive and negative controls is essential for the interpretation of findings on expression of the isoforms. Here we address some of the difficulties in experimental design when investigating alternative splicing of VEGF isoforms, and discuss the use of appropriate control paradigms. We demonstrate why use of specific control experiments can prevent assumptions that VEGF-A 165 b is not present, when in fact it is. We reiterate, and confirm previously published experimental design protocols that demonstrate the importance of using positive controls. These include using known target sequences to show that the experimental conditions are suitable for PCR amplification of VEGF-A 165 b mRNA for both q-PCR and RT-PCR and to ensure that mispriming does not occur. We also provide evidence that demonstrates that detection of VEGF-A 165 b protein in mice needs to be tightly controlled to prevent detection of mouse IgG by a secondary antibody. We also show that human VEGF 165 b protein can be immunoprecipitated from cultured human cells and that immunoprecipitating VEGF-A results in protein that is detected by VEGF-A 165 b antibody. These findings support the conclusion that more information on the biology of VEGF-A 165 b isoforms is required, and confirm the importance of the experimental design in such investigations, including the use of specific positive and negative controls.

Research paper thumbnail of VEGF (Vascular Endothelial Growth Factor) and Fibrotic Lung Disease

International Journal of Molecular Sciences, 2018

Interstitial lung disease (ILD) encompasses a group of heterogeneous diseases characterised by va... more Interstitial lung disease (ILD) encompasses a group of heterogeneous diseases characterised by varying degrees of aberrant inflammation and fibrosis of the lung parenchyma. This may occur in isolation, such as in idiopathic pulmonary fibrosis (IPF) or as part of a wider disease process affecting multiple organs, such as in systemic sclerosis. Anti-Vascular Endothelial Growth Factor (anti-VEGF) therapy is one component of an existing broad-spectrum therapeutic option in IPF (nintedanib) and may become part of the emerging therapeutic strategy for other ILDs in the future. This article describes our current understanding of VEGF biology in normal lung homeostasis and how changes in its bioavailability may contribute the pathogenesis of ILD. The complexity of VEGF biology is particularly highlighted with an emphasis on the potential non-vascular, non-angiogenic roles for VEGF in the lung, in both health and disease.

Research paper thumbnail of Vascular endothelial growth factor (VEGF) in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS): paradox or paradigm?

Thorax, 2006

Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury (ALI), rema... more Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury (ALI), remains a devastating condition with a high mortality. It is characterised by alveolar injury and increased pulmonary vascular permeability. Vascular endothelial cell growth factor (VEGF) was identified by its properties to increase permeability and act as a cellular growth factor, hence its potential for a key role in the pathogenesis of ALI/ARDS. This review describes the basic biology of VEGF and its receptors as an essential prerequisite to discussing the available and sometimes paradoxical published data, before considering a paradigm for the role of VEGF in the human lung.