Inflammation in Covid-19: Exploration of Critical Aspects of Pathogenesis (ICECAP)

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Inflammation Research

Abstract

The current coronavirus pandemic is causing significant illness and death. Severe coronavirus disease 2019 (Covid-19) leads to acute lung damage and organ injury, often requiring intensive care admission and prolonged periods of time on a ventilator. As this disease is new, the way that the virus causes organ injury is not understood. It is therefore urgent and vital that the effects of severe Covid-19 are described to rapidly inform clinical management and identify new treatment approaches.

The ICECAP consortium was established as a rapid response to the Covid-19 pandemic. By assembling a team of expert clinicians and scientists we are studying key features of fatal Covid-19. Authorised hospital post-mortem examinations of those who have died from Covid-19 provides a unique opportunity to study the whole body in a level of detail that is not possible during life. By collecting and analysing tissue samples collected during post-mortem examinations this will yield crucial information on the presence of the coronavirus in multiple organs in the body and also understand in greater depth how the body's immune system is responding. This allows us to rapidly answer important clinical questions and help to rapidly inform the evaluation and development of therapeutic interventions for Covid-19.

Technical Summary

The morbidity and mortality of patients with severe Covid-19 is high: understanding disease pathogenesis is critical to prioritise therapeutic targets. To achieve this, ICECAP has established a unique programme of rapid and detailed tissue sampling at autopsy of fatal Covid-19, integrated with optimised pipelines for downstream scientific analyses. By combining clinical and scientific expertise ICECAP are uniquely placed to address critical knowledge gaps.

Core project deliverables:
1.Ongoing recruitment to ICECAP research autopsies, performing detailed tissue retrieval within hours of death to ensure key cellular and biological information is preserved. This activity complements and expands our established COVID-19 tissue bank.
2.Mapping SARS-CoV-2 organotropism and cellular distribution. Expanding our preliminary findings, viral presence at an organ and cellular level will be described in multiple tissues, with evidence of viral replication sought. The organ-specific consequences of viral presence will be investigated, with immediate implications for clinical management, treatment with antivirals and healthcare services.
3.Delineation of Pulmonary Immunopathology is critical to understand in terms of viral elimination, immune-mediated organ dysfunction and cytokine production. Building upon established pathways, quantification and phenotyping of immunopathology will be achieved by complementary approaches of flow cytometry, single cell RNA sequencing, spatial RNA analysis and proteomics.

Our multi-disciplinary approach harnesses national and international expertise to incisively and rapidly deliver new disease-specific insights. These deliverables will drive the understanding of organ-specific viral presence, tolerance and mechanisms of immunopathology with clear benefits on prioritising potential therapeutic targets and patient management.

Publications

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Bing R (2021) In Vivo Thrombosis Imaging in Patients Recovering from COVID-19 and Pulmonary Embolism. in American journal of respiratory and critical care medicine

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Dorward D (2021) Tissue-Specific Immunopathology in Fatal COVID-19 in American Journal of Respiratory and Critical Care Medicine

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Russell CD (2022) Tissue Proteomic Analysis Identifies Mechanisms and Stages of Immunopathology in Fatal COVID-19. in American journal of respiratory cell and molecular biology

 
Description NERVTAG
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
 
Description Procurator Fiscal post mortem diagnosis of SARS-CoV-2
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
Impact Guidance to Procurator Fiscal service on post mortem diagnosis of SARS-CoV-2, based on our research findings.
 
Description 2. MRC Programme Grant. 'Resolving innate inflammatory responses to tissue injury and apoptotic cell clearance to develop novel therapeutic strategies for pulmonary diseases'
Amount £1,990,000 (GBP)
Funding ID MR/W019264/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 05/2022 
End 06/2027
 
Description The Molecular Basis Of The Sex-linked Functional Differences In B Cells
Amount £104,856 (GBP)
Funding ID BB/W010747/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 06/2021 
End 07/2022
 
Title Determination of SARS-CoV-2 protein in human samples 
Description Development and validation of immunohistochemistry/IF methodology for analysis of SARS-CoV-2 spike glycoprotein within multiple tissues. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2020 
Provided To Others? Yes  
Impact Defining tissue presence of SARS-CoV-2 in fatal disease 
URL https://www.atsjournals.org/doi/full/10.1164/rccm.202008-3265OC
 
Description ISARIC4C 
Organisation The Global Health Network
Department International Severe Acute Respiratory Infection Consortium (ISARIC)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Results from ICECAP fed into ISARIC4C to allow extrapolation of post mortem tissue observations into clinical cohorts where appropriate.
Collaborator Contribution Dr J Kenneth Bailie and Dr Clark Russell are project partners and contribute time and intellectual input into ICECAP studies, including project management, laboratory time and results analyses.
Impact Collaboration is multi-disciplinary and covers Intensive Care, Infection Medicine, Pathology and Respiratory Medicine expertise.
Start Year 2020
 
Description Proteomic analysis of immune cells 
Organisation Newcastle University
Department Newcastle University Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution Isolation and purification of human immune cells for proteomic analyses. Intellectual input to study design
Collaborator Contribution Resources, methodology, equipment, intellectual contributions
Impact Multidisciplinary. Immunology, clinical and proteomics colleagues
Start Year 2021
 
Description Spatial transcriptomics of organ injury 
Organisation University of Edinburgh
Department Centre for Cardiovascular Science
Country United Kingdom 
Sector Academic/University 
PI Contribution Contribution of resources, tissue and intellectual capacity to project
Collaborator Contribution Expertise in methodology and bioinformatic analyses
Impact Multi-disciplinary. Pulmonary, cardiovascular and bioinformatics teams (both clinical and non-clinical)
Start Year 2021
 
Description UK Coronavirus Immunology Consortium Theme 3. Tissue immunopathology of COVID-19 
Organisation Newcastle University
Department Newcastle University Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution We are contributing multiple tissue blocks from all of the ICECAP COVID post mortems and annotating areas of interest in each of the sections for further analysis.
Collaborator Contribution Tissue sections are going to be analysed by a range of technologies to further describe the immune environment in various tissues in fatal COVID-19 which will complement our ongoing work.
Impact None as yet
Start Year 2020
 
Description University of Edinburgh STOPCOVID 
Organisation Centre for Inflammation Research
Country United Kingdom 
Sector Public 
PI Contribution Results from ICECAP tissue analyses fed back into STOPCOVID initiative. Shared tissue, equipment and staff across programmes
Collaborator Contribution STOPCOVID provides salary support of key ICECAP staff. Sharing of equipment & staff, intellectual input to study design and data analyses.
Impact Publication - Tissue-Specific Immunopathology in Fatal COVID-19
Start Year 2020
 
Description Grand Rounds hospital presentation - COVID Lung 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Presentation at hospital grand rounds - updates on COVID lung injury and post mortem studies
Year(s) Of Engagement Activity 2020,2021
 
Description ICECAP website 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact We have compiled a lay summary of our research so far and this appears under on our ICECAP specific website under the 'ICECAP findings' section. https://www.ed.ac.uk/inflammation-research/research/icecap/research-outputs
Year(s) Of Engagement Activity 2020
URL https://www.ed.ac.uk/inflammation-research/research/icecap/research-outputs
 
Description Post Mortem relative feedback 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Our individual post mortem findings are fed back to the patient relatives by our research team. This also provides an opportunity to gather feedback on the previous interactions with the research team, with questionnaires on these interactions routinely sent to relatives. This informs whether our research design is both practical and acceptable to participants, and also helps us to improve the language and accessibility of our family information leaflets and consent forms.
Year(s) Of Engagement Activity 2020
 
Description The Science Social 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact A lay summary of our research objectives and findings for the website 'the science social', a science communication platform aimed at a public audience.
Year(s) Of Engagement Activity 2020
URL https://www.thesciencesocial.com/category/blog/research-summaries/