Profiling the Inflammatory Cascade of COVID-19 (CASCADE)

CASCADE: Profiling the Inflammatory Cascade of COVID-19

COVID-19 is a new and poorly understood virus. It is imperative that the scientific community develops an understanding of the viral mechanisms and human immunological response in order to develop effective therapies and assess their efficacy.

This research study is being initiated in response to the ongoing COVID-19 pandemic and will provide much needed insight into the temporal immune response which can lead to rapid respiratory failure in infected patients.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Other: Blood sample

Detailed Description

The immuno-inflammatory cascade is essential to define in COVID-19 patients to develop an intervention strategy to abrogate respiratory failure. For this study, four groups of patients have been identified to inform disease characterisation:

• Patients in the community
• Patients at hospital admission
• Rapidly deteriorating patients
• Ventilated, critically ill patients There is an urgent need to elucidate the dynamic peripheral blood signature including neutrophil, monocyte, lymphocyte and soluble mediators. Indeed recent data suggest that activation and subsequent exhaustion of cytotoxic T cells and emergence of GM-CSF+ CD4+ T cells and inflammatory monocytes and macrophages (in blood and BAL(1,2,3)) are associated with severe pathology in COVID-19 patients, however the fine kinetics of changes in these populations relative to disease progression are unknown.

In this study, samples will be obtained from NHS Lothian patients (in both primary care and hospital settings) who have tested positive for COVID-19 infection. Once consented, blood samples and (where possible) surplus clinical samples will be obtained from participants at defined time-points through the duration of their disease. Participants who rapidly deteriorate during their hospital admission will provide smaller, more frequent blood samples to permit profiling of the immunological/inflammatory response during deterioration.

Patients without COVID-19 but of comparable age and comorbid status will act as controls.

In-house assays will be used to measure and phenotype circulating immune cells, their activation status and cytokine production (focusing primarily on polymorphonuclear leukocytes, mononuclear phagocytes and lymphocytes) from peripheral blood samples obtained from participants at different stages of COVID-19 disease.

Blood and other clinical samples (including but not limited to Bronchoalveolar Lavage (BAL), bronchoabsorption) will undergo laboratory analysis, including but not limited to; whole blood cytokine release assays, inflammatory biomarkers and cell numbers, measurement of cytokines, flow cytometric cell analysis and staining of cells for markers.

Results will inform the identification of optimized biomarkers, timing of interventions and lead prioritisation of pharmaceutical assets for experimental medicine studies or assays for use in high throughput automated screens of compound libraries to modulate observed phenotypes and profile the inflammatory pathway. It will build from and complement emerging data from other national or international studies e.g. ISARIC 4C but will be distinct since it informs a specific translational study platform which requires greater depth of phenotyping and more precise kinetic analysis to inform design of early clinical studies of repurposed immunomodulating therapeutics. It is intended this will accelerate the linking of basic mechanistic information with drug targets for development and assessment of COVID-19 therapies. Research materials and results will be also be used to develop novel diagnostics and prognostic approaches that can help identify high risk patients who need higher level of monitoring or care and more fully define susceptibility and risk.

• Study Type: Observational
• Enrollment (Actual): 41

Contacts and Locations

Study Locations

• United Kingdom
  • Edinburgh, United Kingdom, EH16 4SA
    • Royal Infirmary of Edinburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Cohort 1 COVID-19 Patients with confirmed COVID-19 infection (n=200) Cohort 2 Control Patients who have not tested positive for COVID-19 infection (n=20)

Description

Inclusion Criteria:

All participants:

• Aged over 16 years
• Provision of consent (either from the patient or by a personal legal representative)

COVID-19 Cohort only:

• Confirmed COVID-19 infection

Control Cohort only:

• No clinical suspicion of COVID-19

Exclusion Criteria:

All participants:

• Deemed unsuitable for participation by attending clinician

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
COVID-19; Patients in the community; Patients at hospital admission; Rapidly deteriorating patients; Ventilated, critically ill patients With confirmed COVID-19 infection	Other: Blood sample; Serial blood sampling to monitor immune cells in patient with COVID 19 infection and compare with control group who have no evidence of COVID-19 infection
Control; No clinical suspicion of COVID-19 infection	Other: Blood sample; Serial blood sampling to monitor immune cells in patient with COVID 19 infection and compare with control group who have no evidence of COVID-19 infection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine levels of cytokines and chemokines to elucidate the temporal inflammatory cascade in COVID-19	We will determine levels of select cytokines and chemokines in plasma and serum samples from patients and control subjects.	Up to 20 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Identification, quantification and phenotyping of inflammatory cells and biomarkers.	Up to 20 days

Collaborators and Investigators

• Sponsor: University of Edinburgh
• Collaborators: NHS Lothian

Study record dates

Study Major Dates

• Study Start (Actual): May 12, 2020
• Primary Completion (Actual): April 10, 2021
• Study Completion (Actual): August 10, 2022

Study Registration Dates

• First Submitted: April 16, 2020
• First Submitted That Met QC Criteria: July 17, 2024
• First Posted (Actual): July 19, 2024

Study Record Updates

• Last Update Posted (Actual): October 16, 2024
• Last Update Submitted That Met QC Criteria: October 14, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: AC20054

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No