ISARIC Clinical Characterisation Protocol for H5N1 Research Response
Overview
- ISARIC has peer-reviewed, open-access tools that make outbreak research easier, faster and better.
- The tools have been adapted for H5N1 patient recruitment (and can be used for any human infection with a novel zoonotic influenza virus).
- To prepare and activate a research response to H5N1: (1) define your research objectives, (2) tailor the tools to your context, (3) obtain necessary approval, (4) enrol participants, (5) collect and analyse data, (6) inform clinical care, public health response, and clinical trial design.
Rationale
In response to the global threat of H5N1, a highly pathogenic avian influenza virus causing human infection in several countries, ISARIC has adapted its outbreak research response tools to support a standardised, coordinated action by health care and research centres.
Rapid clinical characterisation of human cases of H5N1 infection is critical to calibrate public health interventions and improve patient outcomes through providing reliable and actionable clinical evidence. ISARIC’s Clinical Characterisation Protocol and Clinical Epidemiology Platform are openly available to facilitate rapid standardised data and sample collection and analysis for independent or collaborative research.
Tools
The Clinical Characterisation Protocol (CCP) provides a standardised method for the rapid, coordinated clinical investigation of emerging health threats including H5N1. Researchers may customise the investigations according to their research objectives and available resources. The table below links research objectives to the different modules outlined in the CCP. A toolkit to guide the process of launching CCP at your site is also available. The Clinical Epidemiology Platform is a suite of integrated tools to facilitate collection and analysis of clinical data. The platform is designed to support research and collaboration. It includes:
- H5N1 case report form (CRF) , a template CRF that can be used as is or tailored to your context using our BRIDGE tool.
- BRIDGE , a web-based application where you can edit the H5N1 CRF to your needs, then autogenerate a paper CRF, a CRF completion guide and database files (xml and csv data dictionary) to launch a REDCap database that matches your CRF.
- VERTEX , a program that automates analysis of the clinical data in your database to generate tables and visualisations using reproducible analytic pipelines for essential medical statistics. All analytics can be tailored to fit the needs of your data. Click here to view a demo version featuring a synthetic H5N1 dataset.
The Clinical Epidemiology Platform can be used to collect, process and analyse data for the CCP or for any other study that is active at your site.
Objectives
Research objectives should be determined based on their potential to deliver impact in the context of other initiatives, including public health response. The proposed strategy below begins with a broad scope then de-escalates as research questions are answered. The decision on what data variables to include or exclude in the de- escalation phase lies with the PI at network or site level.
Table of research objectives that can be addressed using ISARIC tools.
Several objectives may be achieved simultaneously by combining processes.
| Research Objectives | Data / Data & Bio-sample * | Recruitment Goals |
|---|---|---|
| CCP Module 0 - Sites with data capacity only, no biological sampling | ||
| Clinical characterisation of presentations, risk factors, disease progression and outcomes | Data only - all variables | Up to 1000 hospitalised cases |
| Clinical characterisation of prognosis and burden of disease | Data only - data that PI deems necessary and feasible | Unlimited number of hospitalised cases |
| CCP Modules 1& 2 - Sites with data and sampling capacity (and resources to fund testing or storage) | ||
| Virology: Phenotypic assays | Fresh samples containing live virus | Up to 100 hospitalised cases |
| Virology: Test diagnostics | Fresh samples containing live virus | Up to 100 hospitalised cases |
| Virology: Viral sequencing | Virus inactivated by guanidine thiocyanate | Unlimited number of hospitalised cases |
| Host genetics: Characterise mechanisms, prioritise new treatments | Whole blood; virus inactivated by guanidine thiocyanate | Up to 10,000 hospitalised cases; scaling down to critically ill only (through GenOMICC) in a large outbreak |
| Transcriptome: Characterise response, predictors, mechanisms | Virus inactivated by guanidine thiocyanate | Up to 1000 hospitalised cases |
| Proteome: Characterise response, predictors, mechanisms | Serum/plasma with virus inactivated by gamma irradiation | Up to 1000 hospitalised cases |
| Serology: Impact of prior exposure, evolution of antibody response | Serum/plasma with virus inactivated by gamma irradiation | Up to 500 cases of any severity, or up to 500 hospitalised cases in a large outbreak |
| CCP Module 3 - Only in sites with advanced research infrastructure | ||
| Cell mediated immunity; B cells for antibody production | Fresh whole blood, no viral inactivation | Up to 100 cases of any severity |
| Pharmacokinetics | Multiple body fluids | Up to 100 cases of any severity |
*Sampling and laboratory procedures are detailed in the Annex 2 of the ISARIC-WHO Clinical Characterisation Protocol v3.3 (.docx)
Steps to prepare and activate your research response to H5N1
STEP 1: Define the research objectives
Using the list above, or others you have prioritised, define which research objectives will be met by your response.
STEP 2: Tailor the tools to your context
- Protocol:Download the ISARIC-WHO Clinical Characterisation Protocol. Adapt the contents to meet your selected objectives and your context. Develop other study documents needed to activate the study, e.g., informed consent form.
- CRF:Use the BRIDGE website to add/remove variables on the H5N1 CRF to fit your needs. When complete, BRIDGE will generate your tailored CRF, completion guide, and database files. Upload the database files to REDCap to launch your database – or use a data management software of your choice. (If you do not have access to REDCap or other data management software, you can use ISARIC’s REDCap and data management services – email data@isaric.org to request access.)
STEP 3: Obtain necessary approvals
Submit your study documents and liaise with the responsible committees / authorities to gain approval.
STEP 4: Enrol participants
Invite eligible individuals to participate, provide information, and obtain necessary consent.
STEP 5: Collect and analyse your data
Use your tailored database to collect participant data. Implement the VERTEX pipeline to auto-generate a dashboard of analytic outputs. ISARIC can support your implementation of these tools which may be downloaded at your site and/or used for aggregate analysis of multi-site datasets using ISARIC’s data governance framework.
Links:
STEP 6: Inform clinical care, public health response, and clinical trial design
Share your evidence widely, including with those who are making clinical and public health decisions, and those undertaking further research.
Acknowledge the use of ISARIC as ISARIC tools are licensed under Creative Commons. See guidance here
For more information or support, contact ISARIC's Global Support Centre at the Pandemic Sciences Institute, University of Oxford: data@isaric.org.