Investigating the inflammatory process of COVID-19

Plain English summary of protocol

Current plain English summary as of 14/02/2022:

Background and study aims
COVID-19 has caused widespread disruption to people's lives. Clinicians have, during the course of their encounters, recognised some key features of this disease. It is a viral respiratory illness, and as such, can present with catastrophic destruction of the lining (epithelium) of the lung, resulting in water in the lung. The disease can also precipitate the formation of clots in blood vessels, resulting in loss of blood supply to various organs, resulting in stroke, kidney failure, liver failure and cardiac arrest.
It is the hypothesis of this study that all these effects are due to the breakdown of the epithelium throughout the body. This would explain why water floods the lung in severe COVID-19, causing severe Acute Respiratory Distress Syndrome (ARDS), and why this disease predisposes to clot formation, since when the epithelium of blood vessels break down, clots naturally form.
Interleukin-18 (IL-18) has been found to play an important role in the breakdown of epithelium in some parts of the body, most notably, the gut. It is constitutively produced in all epithelial cells of the body and is the end-product of a process known as "inflammasome" activation, part of the body's normal, healthy response to fighting off an infection like COVID-19. When, however, IL-18 is produced in unregulated amounts, due to the failure of IL-18 Binding Protein (IL-18BP), which mops up excess IL-18 and regulates its production, then widespread epithelium breakdown throughout the body, is hypothesised to occur. This study therefore is investigating the levels of both IL-18 and its regulator, IL-18BP. The hope is that, if IL-18BP is not being produced in sufficient quantities, resulting in unregulated high "free" IL-18, perhaps this study could lay the groundwork for seeing an interventional study,
aimed at curbing "free" IL-18 by administration of IL-18BP in drug form, or other proteins, that may act in a similar way.

Who can participate?
Patients over the age of 18 years presenting with COVID-like symptoms

What does the study involve?
The study involves the sampling of excess blood from blood samples that are already taken for clinical purposes from patients with and without COVID-19 disease. The study does not require participants to have further blood tests or additional interventions.

What are the possible benefits and risks of participating?
Since the study does not intervene in the patient's care, even to the extent of not taking further blood samples beyond what is already clinically necessary, there are no risks to participating in the study. The benefit is of course, in contributing to research. All patient data is pseudo-anonymised, and when published, will be presented in fully anonymised form.

Where is the study run from?
Redhill Hospital, Surrey and Sussex NHS Healthcare Trust (UK)

When is the study starting and how long is it expected to run for?
May 2020 to January 2021

Who is funding the study?
1. Cambridge University Hospitals Research Fund (UK)
2. Charitable donations from Mr Sulaiman Mubashir, Mr Sabahat Mubashir, Mr Elyas Nasser and Mrs Asma Rafi

Who is the main contact?
Dr Syed Muhammad Tahir Nasser
sash.isaacstudy@nhs.net

____
Previous plain English summary from 24/08/2021 to 14/02/2022:

Background and study aims
COVID-19 has caused widespread disruption to people's lives. Clinicians have, during the course of their encounters, recognised some key features of this disease. It is a viral respiratory illness, and as such, can present with catastrophic destruction of the lining (the epithelium) of the lung, resulting in water in the lung. The disease can also precipitate the formation of clots in blood vessels, resulting in loss of blood supply to various organs, resulting in stroke, kidney failure, liver failure and cardiac arrest.
It is the hypothesis of this study that all these effects are due to the breakdown of the epithelium throughout the body. This would explain why water floods the lung in severe COVID-19, causing severe Acute Respiratory Distress Syndrome (ARDS) and why this disease predisposes to clot formation, since when the epithelium of blood vessels break down, clots naturally form.
Interleukin-18 (IL-18) has been found to play an important role in the breakdown of epithelium in some parts of the body, most notably, the gut. It is constitutively produced in all epithelial cells of the body and is the end-product of a process known as "inflammasome" activation, part of the body's normal, healthy response to fighting off an infection like COVID-19. When, however, IL-18 is produced in unregulated amounts, due to the failure of IL-18 Binding Protein (IL-18BP), which mops up excess IL-18 and regulates its production, then widespread epithelium breakdown throughout the body, is hypothesised to occur.
This study therefore is investigating the levels of both IL-18 and its regulator, IL-18BP, in addition to Granzyme B, to see whether this hypothesis is borne out in the data. The hope is that, if IL-18BP is not being produced, resulting in unregulated high "free" IL-18, perhaps this study could lay the groundwork for seeing an interventional study, aimed at curbing "free" IL-18 by administering IL-18BP in drug form, or other proteins that may act in a similar way.

Who can participate?
Patients over the age of 18 years presenting with COVID-like symptoms

What does the study involve?
The study involves the sampling of excess blood from blood samples that are already taken for clinical purposes from patients with and without COVID-19 disease. The study does not require patient participants to have further blood tests or additional interventions.

What are the possible benefits and risks of participating?
Since the study does not intervene in the patient's care, even to the extent of not taking further blood samples beyond what is already clinically necessary, there are no risks to participating in the study. The benefit is of course, in contributing to research. All patient data is pseudo-anonymised, and when published, will be presented in fully anonymised form.

Where is the study run from?
Redhill Hospital, Surrey and Sussex NHS Healthcare Trust (UK)

When is the study starting and how long is it expected to run for?
May 2020 to January 2021

Who is funding the study?
Self-funded by CI Syed Nasser;
Cambridge Addenbrooke's Research Fund of Dr Shuaib Nasser;
Private funding by Mr Sulaiman Mubashir; Mr Sabahat Mubashir

Who is the main contact?
Dr Syed Muhammad Tahir Nasser
sash.isaacstudy@nhs.net

_____

Previous plain English summary:

Background and Study Aims:
COVID-19 has caused widespread disruption to people's lives. Clinicians have, during the course of their encounters, recognised some key features of this disease. It is a viral respiratory illness, and as such, can present with catastrophic destruction of the lining (the epithelium) of the lung, resulting in water in the lung. The disease can also precipitate the formation of clots in blood vessels, resulting in loss of blood supply to various organs, resulting in stroke, kidney failure, liver failure and cardiac arrest.

It is the hypothesis of this study that all these effects are due to the breakdown of what is known as the "epithelium" throughout the body. This would explain why water floods the lung in severe COVID-19, causing severe Acute Respiratory Distress Syndrome (ARDS) and why this disease predisposes to clot formation, since when the epithelium of blood vessels break down, clots naturally form.

Interleukin-18 (IL-18) plays a fundamental role in the breakdown of epithelium in the body. It is the end-product of a process known as "inflammasome" activation, and is part of the body's normal, healthy response to fighting off an infection like COVID-19. When, however, IL-18 is produced in unregulated amounts, due to the failure of IL-18 Binding Protein (IL-18BP), which mops up excess IL-18 and regulates its production, then widespread epithelium breakdown throughout the body, is the consequence.

This study therefore is investigating the levels of both IL-18 and its regulator, IL-18BP, in addition to Granzyme B, to see whether this hypothesis is borne out in the data. The hope is that, if IL-18BP is not being produced, resulting in unregulated high "free" IL-18, perhaps this study could lay the groundwork for seeing an interventional study, aimed at curbing "free" IL-18 by administering of IL-18BP in drug form, or other proteins that may act in a similar way.

Who can participate?
Patients over the age of 18 presenting with COVID-like symptoms.

What does the study involve?
The study involves the sampling of excess blood from blood samples that are already taken for clinical purposes from patients with and without COVID-19 disease. The study does not require patient participants to have further blood tests or additional interventions.

What are the possible benefits and risks of participating?
Since the study does not intervene in the patient's care, even to the extent of not taking further blood samples beyond what is already clinically necessary, there are no risks to participating in the study. The benefit is of course, in contributing to research. All patient data is pseudo-anonymised, and when published, will be presented in fully anonymised form.

Where is the study run from?
Redhill Hospital, Surrey and Sussex NHS Healthcare Trust (UK)

When is the study starting and how long is it expected to run for?
May 2020 to January 2021

Who is funding the study?
True Intelligence Limited (UK)

Who is the main contact?
Dr Syed Muhammad Tahir Nasser
sash.isaacstudy@nhs.net

Contact information

Dr Syed Muhammad Tahir Nasser
Scientific

East Surrey Hospital
Canada Avenue
Redhill
RH1 5RH
United Kingdom

ORCID ID	0000-0002-4700-862X
Phone	+44 (0)7875603852
Email	syed.nasser1@nhs.net

Dr Syed Muhammad Tahir Nasser
Public

East Surrey Hospital
Canada Avenue
Redhill
RH1 5RH
United Kingdom

ORCID ID	0000-0002-4700-862X
Phone	+44 (0)7875603852
Email	syed.nasser1@nhs.net

Study information

Eligibility

Locations

Countries of recruitment

• United Kingdom
• England

Study participating centre

Results and Publications

Study outputs

Additional files

ISRCTN13450549_PIS_v2_19Nov2020.pdf

uploaded 04/02/2021

Editorial Notes

24/02/2023: Publication reference added.
10/08/2022: The intention to publish date has been changed from 28/02/2022 to 28/02/2023.
14/02/2022: The following changes were made to the trial record:
1. The scientific title was changed from 'Levels of free IL-18, IL-18 binding protein and granzyme B according to disease severity of COVID-19' to 'Levels of total IL-18, IL-18 binding protein and calculated free IL-18 according to disease severity and mortality in COVID-19'.
2. The study hypothesis, interventions, primary and secondary outcome measures, inclusion and exclusion criteria, and plain English summary were updated.
3. The funder was updated from 'True Intelligence Limited and Investigator initiated and funded' to 'Cambridge University Hospitals Research Fund and charitable donations from Mr Sulaiman Mubashir, Mr Sabahat Mubashir, Mr Elyas Nasser and Mrs Asma Rafi'.
02/02/2022: The study design was changed from "Observational trial comprising cross-sectional case-control and longitudinal cohort arms" to "Prospective longitudinal cohort study".
24/01/2022: The following changes have been made:
1. The intention to publish date has been changed from 14/01/2022 to 28/02/2022.
2. The total final enrolment number has been added.
24/08/2021: The following changes were made to the trial record:
1. The secondary study design was changed from "Two arms: a) cross-sectional case-control; b) longitudinal cohort" to "Two arms: a) Case-control; b) Longitudinal cohort".
2. The interventions were changed.
3. The primary outcome measure was changed.
4. The publication and dissemination plan was changed.
5. The participant-level data was changed from To be made available at a later date to Available on request.
6. The plain English summary was updated to reflect these changes.
04/02/2021: The participant information sheet was uploaded as an additional file.
07/01/2021: Trial’s existence confirmed by NHS HRA.