In vivo models of Drug Induced ILD; tools to study

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In vivo models of Drug Induced ILD; tools to study and improve drug safety (Conference Abstract)

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Conference Abstract: DIILD in vivo models

In vivo models of Drug Induced ILD; tools to study and improve drug safety (Conference Abstract)

Irma Mahmutovic Persson, Hanna Falk Håkansson, Per-Ola Önnervik, Janne Persson, Karin von Wachenfeldt, Lars E. Olsson - on behalf of the TRISTAN Consortium


ERS Lung Science Conference (LSC), 8-11 March 2018, Estoril, Portugal

 

Background

Drug safety is extremely important, yet many drugs on the market have the possibility to induce interstitial lung injury, also known as drug induced interstitial lung disease (DIILD), although they are not administered locally into the lung. Once DIILD starts to develop, patients are normally taken off the drug, and in more severe cases treated with glucocorticoids. As a result, the induced lung injury resolve in many patients while others continue to develop progressive disease. In order to improve drug development in the future, and also to understand how to better treat patients with progressive DIILD, additional studies are required to investigate the underlying mechanisms of e.g. cell and matrix interactions. Well characterized models are needed for evaluation and development of biomarkers in order to better understand and accordingly prevent the progression of DIILD. The work presented here is part of a larger effort supported by IMI aiming at developing and validating pre-clinical imaging biomarkers for DIILD (TRISTAN). As a first step, a robust Bleomycin model is developed by testing various doses of Bleomycin from different manufacturers, along with imaging-monitoring of disease progression correlating this to cell- and histology analyses.

CONFERENCE ABSTRACT: DIILD IN VIVO MODELS
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Systematic review: In vivo imaging in animal models

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Systematic review: In vivo imaging in animal models relevant to drug-induced Interstitial lung disease (DIILD) (Conference Abstract)

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Conference Abstract: DIILD Animal Models

Systematic review: In vivo imaging in animal models relevant to drug-induced Interstitial lung disease (DIILD) (Conference Abstract)

Irma Mahmutovic Persson, Karin von Wachenfeldt, Kashmira Pindoria, Michael Haase, Simon Campbell, Juan X. Delgado, Mark Wright, John C. Waterton and Lars E. Olsson - on behalf of the TRISTAN Consortium


European Respiratory Society, International Congress 2018, 15-19 September 2018, Paris, France

 

Abstract

Translational Imaging Biomarkers (IB) are needed to avoid or manage drug-toxicity, resulting in drug-induced interstitial lung disease (DIILD). We reviewed the literature on in vivo imaging to detect and assess lung lesions in animal models with relevance to DIILD and with pathological changes resembling clinical DIILD.

CONFERENCE ABSTRACT: DIILD ANIMAL MODELS
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Imaging biomarkers of oedema and fibrosis in a rat

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Imaging biomarkers of oedema and fibrosis in a rat model of Drug-Induced Interstitial Lung Disease (DIILD) (Conference Abstract)

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Conference Abstract: Imaging of DIILD in rats

Imaging biomarkers of oedema and fibrosis in a rat model of Drug-Induced Interstitial Lung Disease (DIILD) (Conference Abstract)

Irma Mahmutovic Persson, Anders Örbom, Per-Ola Önnervik, Karin von Wachenfeldt and Lars E. Olsson- on behalf of the TRISTAN Consortium


European Respiratory Society, International Congress 2018, 15-19 Septembr 2018, Paris, France

 

Background

Drugs used to treat various diseases may induce lung injury known as drug induced interstitial lung disease (DIILD). Clinical and pre-clinical studies within the TRISTAN-consortium are aimed at finding translational Imaging Biomarkers (IB) that can indicate progression of DIILD at an early stage. In the present in vivo study, magnetic resonance imaging (MRI) was applied along with analyses of lavage and lung tissue.

CONFERENCE ABSTRACT: IMAGING OF DIILD IN RATS
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Drug-Induced Interstitial Lung Disease: A Systematic Review

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Drug-Induced Interstitial Lung Disease: A Systematic Review

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DIILD Review

Drug-Induced Interstitial Lung Disease: A Systematic Review

Sarah Skeoch, Nicholas Weatherley , Andrew J. Swift, Alexander Oldroyd, Christopher Johns, Conal Hayton, Alessandro Giollo, James M. Wild, John C. Waterton, Maya Buch, Kim Linton, Ian N. Bruce, Colm Leonard, Stephen Bianchi and Nazia Chaudhuri


J. Clin. Med. 2018, 7(10), 356 doi: 10.3390/jcm7100356.

 

Background

Drug-induced interstitial lung disease (DIILD) occurs as a result of numerous agents, but the risk often only becomes apparent after the marketing authorisation of such agents. Methods: In this PRISMA-compliant systematic review, we aimed to evaluate and synthesise the current literature on DIILD. Results: Following a quality assessment, 156 full-text papers describing more than 6000 DIILD cases were included in the review. However, the majority of the papers were of low or very low quality in relation to the review question (78%). Thus, it was not possible to perform a meta-analysis, and descriptive review was undertaken instead. DIILD incidence rates varied between 4.1 and 12.4 cases/million/year. DIILD accounted for 3–5% of prevalent ILD cases. Cancer drugs, followed by rheumatology drugs, amiodarone and antibiotics, were the most common causes of DIILD. The radiopathological phenotype of DIILD varied between and within agents, and no typical radiological pattern specific to DIILD was identified. Mortality rates of over 50% were reported in some studies. Severity at presentation was the most reliable predictor of mortality. Glucocorticoids (GCs) were commonly used to treat DIILD, but no prospective studies examined their effect on outcome. Conclusions: Overall high-quality evidence in DIILD is lacking, and the current review will inform larger prospective studies to investigate the diagnosis and management of DIILD.

DIILD REVIEW
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Hyperpolarised 129xenon MR spectroscopy and diffusion-weighted

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Hyperpolarised 129xenon MR spectroscopy and diffusion-weighted MRI at baseline in patients with interstitial lung disease (Conference Abstract)

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Conference Abstract: Hyperpolarised 129xenon MRS in ILD

Hyperpolarised 129xenon MR spectroscopy and diffusion-weighted MRI at baseline in patients with interstitial lung disease (Conference Abstract)

James Eaden, Paul Hughes, Ho-Fung Chan, Guilhem Collier, Oliver Rodgers, Graham Norquay, Matthew Austin, Laurie Smith, Steve Renshaw, Colm Leonard, Sarah Skeoch, Nazia Chaudhuri, Geoff Parker, Stephen Bianchi, and Jim Wild


Proceedings of the International Society of Magnetic Resonance in Medicine 27th Scientific Meeting and Exhibition, Montréal, Canada 11th-16th May 2019

CONFERENCE ABSTRACT: HYPERPOLARISED 129XENON MRS IN ILD
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Evaluation of automatic methods for arterial input function extraction

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Evaluation of automatic methods for arterial input function extraction for perfusion quantification in the lung (Conference Abstract)

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Conference Abstract: Automated AIF extraction

Evaluation of automatic methods for arterial input function extraction for perfusion quantification in the lung (Conference Abstract)

Marta Tibiletti, Josephine H Naish, Paul J.C. Hughes, Helen Marshall, Colm Leonard, Sarah Skeoch, Nazia Chaudhuri, Ian Bruce, James Eaden, Stephen Bianchi, Jim M Wild, Geoff JM Parker


Proceedings of the International Society of Magnetic Resonance in Medicine 27th Scientific Meeting and Exhibition, Montréal, Canada 11th-16th May 2019

 

CONFERENCE ABSTRACT: AUTOMATED AIF EXTRACTION
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Comparison of algorithm to determine Ventilated Volume Fraction

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Comparison of algorithm to determine Ventilated Volume Fraction from Oxygen-Enhanced MRI in Cystic Fibrosis (Conference Abstract)

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Conference Abstract: Determine ventilated volume fraction

Comparison of algorithm to determine Ventilated Volume Fraction from Oxygen-Enhanced MRI in Cystic Fibrosis (Conference Abstract)

Marta Tibiletti, Josephine H Naish, Katharina Martini, Thomas Frauenfelder, Geoff JM Parker


Proceedings of the International Society of Magnetic Resonance in Medicine 27th Scientific Meeting and Exhibition, Montréal, Canada 11th-16th May 2019

 

CONFERENCE ABSTRACT: DETERMINE VENTILATED VOLUME FRACTION
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Experimental and quantitative imaging techniques

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Experimental and quantitative imaging techniques in interstitial lung disease

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Imaging Techniques in ILD

Experimental and quantitative imaging techniques in interstitial lung disease

Nicholas D Weatherley, James A Eaden, Neil J Stewart, Brian J Bartholmai, Andrew J Swift, Stephen Mark Bianchi, Jim M Wild


Thorax 2019;74:611-619. doi:10.1136/thoraxjnl-2018-211779.

 

Abstract

Interstitial lung diseases (ILDs) are a heterogeneous group of conditions, with a wide and complex variety of imaging features. Difficulty in monitoring, treating and exploring novel therapies for these conditions is in part due to the lack of robust, readily available biomarkers. Radiological studies are vital in the assessment and follow-up of ILD, but currently CT analysis in clinical practice is qualitative and therefore somewhat subjective. In this article, we report on the role of novel and quantitative imaging techniques across a range of imaging modalities in ILD and consider how they may be applied in the assessment and understanding of ILD. We critically appraised evidence found from searches of Ovid online, PubMed and the TRIP database for novel and quantitative imaging studies in ILD. Recent studies have explored the capability of texture-based lung parenchymal analysis in accurately quantifying several ILD features. Newer techniques are helping to overcome the challenges inherent to such approaches, in particular distinguishing peripheral reticulation of lung parenchyma from pleura and accurately identifying the complex density patterns that accompany honeycombing. Robust and validated texture-based analysis may remove the subjectivity that is inherent to qualitative reporting and allow greater objective measurements of change over time. In addition to lung parenchymal feature quantification, pulmonary vessel volume analysis on CT has demonstrated prognostic value in two retrospective analyses and may be a sign of vascular changes in ILD which, to date, have been difficult to quantify in the absence of overt pulmonary hypertension. Novel applications of existing imaging techniques, such as hyperpolarised gas MRI and positron emission tomography (PET), show promise in combining structural and functional information. Although structural imaging of lung tissue is inherently challenging in terms of conventional proton MRI techniques, inroads are being made with ultrashort echo time, and dynamic contrast-enhanced MRI may be used for lung perfusion assessment. In addition, inhaled hyperpolarised 129Xenon gas MRI may provide multifunctional imaging metrics, including assessment of ventilation, intra-acinar gas diffusion and alveolar-capillary diffusion. PET has demonstrated high standard uptake values (SUVs) of 18F-fluorodeoxyglucose in fibrosed lung tissue, challenging the assumption that these are ‘burned out’ and metabolically inactive regions. Regions that appear structurally normal also appear to have higher SUV, warranting further exploration with future longitudinal studies to assess if this precedes future regions of macroscopic structural change. Given the subtleties involved in diagnosing, assessing and predicting future deterioration in many forms of ILD, multimodal quantitative lung structure-function imaging may provide the means of identifying novel, sensitive and clinically applicable imaging markers of disease. Such imaging metrics may provide mechanistic and phenotypic information that can help direct appropriate personalised therapy, can be used to predict outcomes and could potentially be more sensitive and specific than global pulmonary function testing. Quantitative assessment may objectively assess subtle change in character or extent of disease that can assist in efficacy of antifibrotic therapy or detecting early changes of potentially pneumotoxic drugs involved in early intervention studies.

IMAGING TECHNIQUES IN ILD
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Biological- and imaging biomarkers of oedema and fibrosis

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Biological- and imaging biomarkers of oedema and fibrosis in a rat model of Drug-Induced Interstitial Lung Disease (DIILD) (Conference Abstract)

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IBs of oedema and fibrosis in rat DIILD

Biological- and imaging biomarkers of oedema and fibrosis in a rat model of Drug-Induced Interstitial Lung Disease (DIILD) (Conference Abstract)

Irma Mahmutovic Persson, Hanna Falk Håkansson, Anders Örbom, Per-Ola Önnervik, Janne Persson, Karin Von Wachenfeldt, Lars E. Olsson.


European Respiratory Journal 2019 54: PA2417. doi: 10.1183/13993003.congress-2019.PA2417.

Abstract

A large number of systemically administered drugs have the potential to cause DIILD. We aim to characterize a model of DIILD in the rat and develop imaging biomarkers for detection and quantification of DIILD.

Methods: Sprague-Dawley rats received one single dose of intratracheal bleomycin and were longitudinally imaged at day 0, 3, 7, 14, 21 and 28 post dosing, applying imaging techniques MRI and PET/CT. Bronchoalveolar lavage fluid (BALF) was analyzed for total protein and inflammatory cells. Lungs were taken for further analyses by histology, and stained for inflammation and collagen deposition.

Results: Bleomycin induced significant increase in total protein concentration and total cell count in BALF, peaking at day3 (p>0.001) and day7 (p>0.001) compared to control, respectively. The lesion measured by MRI and the FDG-PET signal in the lungs of bleomycin challenged rats was significantly increased during day3-14, peaking at day7. Two subgroups of animals were identified as low- and high responders to bleomycin challenge, by their different change in total lung volume. Both groups showed signs of inflammation initially, while at later time points the low-responder group recovered towards control, and the high-responder group showed progressive fibrosis with significant increase of lesion volume (p<0.001), compared to control.

Conclusion: Bleomycin-induced lung injury with MRI and PET readout in rats, is an adequate and translational animal model for DIILD studies. The scenario comprised different disease responses, with different fractions of inflammation and fibrosis. Thereby, this study improved the understanding biological- and imaging biomarkers in DIILD.

IBS OF OEDEMA AND FIBROSIS IN RAT DIILD
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Hyperpolarised 129-xenon diffusion-weighted MRI

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Hyperpolarised 129-xenon diffusion-weighted MRI in interstitial lung disease (Conference Abstract)

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Conference Abstract: Hyperpolarised 129Xe diffusion-weighted MRI in ILD

Hyperpolarised 129-xenon diffusion-weighted MRI in interstitial lung disease (Conference Abstract)

James Eaden, Ho-Fung Chan, Paul Hughes, Nicholas Weatherly, Matthew Austin, Laurie Smith, Jim Lithgow, Andrew Swift, Stephen Renshaw, Maya Buch, Colm Leonard, Sarah Skeoch, Nazia Chaudhuri, Geoff Parker, Stephen Bianchi, Jim Wild


European Respiratory Journal 2019 54: PA3157. doi: 10.1183/13993003.congress-2019.PA3157.

Abstract

Introduction: Apparent diffusion coefficient (ADC) is a measure of gas diffusion in the airspaces, where restrictions by tissue boundaries provide information about lung microstructure down to the alveolar level. Diffusion-weighted (DW) MRI of the lung with hyperpolarised helium in idiopathic pulmonary fibrosis (IPF) has shown that ADC correlates with DLCO, KCO and CT fibrosis score (Chan, H-F. et al. Radiology 2019; doi:10.1148/radiol.2019181714) but to date no data are available on the utility of 129-xenon (129Xe) diffusion in interstitial lung disease (ILD). Aim: To evaluate the ability of 129Xe DW-MRI to distinguish between ILD subtypes.

Methods: A prospective, multicentre study of patients with ILD including drug induced ILD (DI-ILD), hypersensitivity pneumonitis (HP), IPF and connective tissue disease ILD (CTD-ILD). Hyperpolarised 129Xe DW-MRI was performed on a 1.5 T scanner and mean ADC was calculated. Results: To date, 33 patients (6 DI-ILD, 7 HP, 15 IPF, 5 CTD-ILD) have undergone baseline 129Xe DW-MRI. There was a significant difference in mean ADC between the ILD subtypes (p=0.011), with the significant difference occuring between the HP (median: 0.038cm2/s) and IPF (median: 0.048cm2/s) groups (p<0.01). Median FVC% predicted in the HP and IPF groups was 75.6% and 84.7% respectively. There was a correlation between mean ADC and DLCO (r=-0.39; p=0.03) as well as KCO (r=-0.58; p<0.01) but not FVC (r=0.24; p=0.19).

Conclusions: We demonstrate a correlation between mean 129Xe ADC and DLCO but not FVC. Our findings suggest significant differences in mean ADC between IPF and HP. Therefore, 129Xe DW-MRI could potentially have a role in differentiating changes in the airway microstructure in ILD subtypes.

CONFERENCE ABSTRACT: HYPERPOLARISED 129XE DIFFUSION-WEIGHTED MRI IN ILD
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