Syndromic infections
Lead Research Organisation:
University College London
Department Name: UNLISTED
Abstract
When children who are very unwell arrive at hospitals in Africa and other low-income countries, it is often hard to work out what is causing the illness. Malaria and other common infections in these settings can give the same symptoms. These symptoms may include fever or low levels of haemoglobin in the blood. It is often impossible to find out exactly what is making them sick. This is a big problem, as it makes it hard to know how best to treat them. In this programme we will design and run studies to work out the best ways to treat these children. We aim to reduce their chance of dying and make sure that guidelines recommend the best approaches. We will also design and run studies to work out the best ways of managing serious infections caused by bacteria more generally. In particular we want to reduce the threat posed by antimicrobial (drug) resistance. We will particularly look at infants (less than 30 days old) and children to work out the antibiotic doses they should be getting. The antibiotic doses children get vary hugely. This is because doses for children are mostly based on past practice, rather than evidence.
Technical Summary
Infectious diseases remain major causes of mortality and morbidity worldwide, but their effects are particularly prominent in low and middle-income countries. Some infectious diseases often present acutely as a collection of symptoms without any specific infectious agent ever being identified (termed “syndromic infections” here); such presentations are particularly common in low-income settings and in children, place large burdens on healthcare resources and lead to unacceptably high rates of death, often occurring rapidly after admission. A major challenge is the weak evidence base underpinning relevant guidelines, which consequently may be in conflict (eg between guidelines for managing malaria and anaemia, even though these conditions commonly co-exist).
This programme aims firstly to develop and test generic strategic approaches to manage acutely sick children presenting to hospital services in Africa, in order to improve outcomes and ensure that harms do not outweigh benefits, and ensure guidelines are evidence-based. This will be achieved through designing, conducting and analysing large mortality-endpoint randomised trials to inform definitive management guidelines in this challenging and relatively under-researched area. We will also develop and conduct underpinning early phase trials to ensure that the design of these Phase III trials is optimised. We will address questions in severe malaria, diarrhoeal disease and bacterial infections, and their common presentations (e.g. anaemia) as these are major global contributors to childhood morbidity and mortality.
Second, antimicrobial resistance is a key priority for the MRC and many organisations worldwide. It represents an enormous global threat; again infecting organisms are commonly not identified meaning antibiotics are widely used empirically, potentially accelerating spread of resistance. Other major challenges include the generally lack of a single standard-of-care, and difficulties in defining, and ascertaining objectively, non-mortality endpoints. The overall goal of this part of the programme is to improve the treatment and management of serious bacterial infections, particularly bacterial sepsis, in neonates, children and adults across the world; and to address the threats posed by increasing levels of antimicrobial resistance. This will be achieved through conducting large randomised trials and developing novel trial designs to optimise the assessment of different approaches to reducing the morbidity and mortality burden associated with serious bacterial infections, particularly considering drugs and course durations. We will particularly focus on conducting trials in neonates and children that can lead to licensing of appropriate antibiotic doses, since most use is based on historical precedent rather than evidence.
This programme aims firstly to develop and test generic strategic approaches to manage acutely sick children presenting to hospital services in Africa, in order to improve outcomes and ensure that harms do not outweigh benefits, and ensure guidelines are evidence-based. This will be achieved through designing, conducting and analysing large mortality-endpoint randomised trials to inform definitive management guidelines in this challenging and relatively under-researched area. We will also develop and conduct underpinning early phase trials to ensure that the design of these Phase III trials is optimised. We will address questions in severe malaria, diarrhoeal disease and bacterial infections, and their common presentations (e.g. anaemia) as these are major global contributors to childhood morbidity and mortality.
Second, antimicrobial resistance is a key priority for the MRC and many organisations worldwide. It represents an enormous global threat; again infecting organisms are commonly not identified meaning antibiotics are widely used empirically, potentially accelerating spread of resistance. Other major challenges include the generally lack of a single standard-of-care, and difficulties in defining, and ascertaining objectively, non-mortality endpoints. The overall goal of this part of the programme is to improve the treatment and management of serious bacterial infections, particularly bacterial sepsis, in neonates, children and adults across the world; and to address the threats posed by increasing levels of antimicrobial resistance. This will be achieved through conducting large randomised trials and developing novel trial designs to optimise the assessment of different approaches to reducing the morbidity and mortality burden associated with serious bacterial infections, particularly considering drugs and course durations. We will particularly focus on conducting trials in neonates and children that can lead to licensing of appropriate antibiotic doses, since most use is based on historical precedent rather than evidence.
Organisations
- University College London (Lead Research Organisation)
- Manhiça Health Research Centre (CISM) (Collaboration)
- Kwame Nkrumah University of Science and Technology (KNUST) (Collaboration)
- Liverpool School of Tropical Medicine (Collaboration)
- ST GEORGE'S UNIVERSITY OF LONDON (Collaboration)
- Tropical Disease Research Centre (Collaboration)
- Mahidol Oxford Tropical Medicine Research Unit (Collaboration)
- The Wellcome Trust Sanger Institute (Collaboration)
- University of Sussex (Collaboration)
- Kenyan Institute for Medical Research (KEMRI) (Collaboration)
- University of Melbourne (Collaboration)
- Mbale Hospital (Collaboration)
- KING'S COLLEGE LONDON (Collaboration)
- Global Antibiotic Research and Development Partnership (Collaboration)
Publications
Abouyannis M
(2023)
A global core outcome measurement set for snakebite clinical trials.
in The Lancet. Global health
Adler H
(2022)
Clinical features and management of human monkeypox: a retrospective observational study in the UK.
in The Lancet. Infectious diseases
Ahmed S
(2021)
Development and internal validation of clinical prediction models for outcomes of complicated intra-abdominal infection.
in The British journal of surgery
Brehm R
(2024)
Use of point-of-care haemoglobin tests to diagnose childhood anaemia in low- and middle-income countries: A systematic review.
in Tropical medicine & international health : TM & IH
Brown N
(2021)
Treatment of methicillin-resistant Staphylococcus aureus (MRSA): updated guidelines from the UK
in JAC-Antimicrobial Resistance
Brown NM
(2021)
Treatment of methicillin-resistant Staphylococcus aureus (MRSA): updated guidelines from the UK.
in The Journal of antimicrobial chemotherapy
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00004/01 | 01/04/2021 | 31/03/2026 | £5,186,000 | ||
MC_UU_00004/02 | Transfer | MC_UU_00004/01 | 01/04/2021 | 31/03/2026 | £4,446,000 |
MC_UU_00004/03 | Transfer | MC_UU_00004/02 | 01/04/2021 | 31/03/2026 | £4,999,000 |
MC_UU_00004/04 | Transfer | MC_UU_00004/03 | 01/04/2021 | 31/03/2026 | £5,315,000 |
MC_UU_00004/05 | Transfer | MC_UU_00004/04 | 01/04/2021 | 31/03/2026 | £3,107,000 |
MC_UU_00004/06 | Transfer | MC_UU_00004/05 | 01/04/2021 | 31/03/2026 | £2,889,000 |
MC_UU_00004/07 | Transfer | MC_UU_00004/06 | 01/04/2021 | 31/03/2026 | £2,369,000 |
MC_UU_00004/08 | Transfer | MC_UU_00004/07 | 01/04/2021 | 31/03/2026 | £2,270,000 |
MC_UU_00004/09 | Transfer | MC_UU_00004/08 | 01/04/2021 | 31/03/2026 | £2,160,000 |
Description | Membership of the WHO Expert Panel for a technical consultation |
Geographic Reach | Africa |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | Joint Global Health Trials (H-PRIME trial) |
Amount | £4,375,063 (GBP) |
Funding ID | MR/P74363/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 07/2020 |
End | 06/2025 |
Description | KD-CAAP - corticosteroids for Kawasaki disease |
Amount | € 5,337,956 (EUR) |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 04/2019 |
End | 11/2023 |
Description | NeoCHG |
Amount | £133,000 (GBP) |
Organisation | Global Antibiotic Research and Development Partnership |
Sector | Charity/Non Profit |
Country | Switzerland |
Start | 04/2021 |
End | 09/2022 |
Description | NeoSep1 trial |
Amount | £209,329 (GBP) |
Organisation | Global Antibiotic Research and Development Partnership |
Sector | Charity/Non Profit |
Country | Switzerland |
Start | 07/2021 |
End | 06/2022 |
Description | PedPOLY-B polymyxins for children and neonates |
Amount | € 395,559 (EUR) |
Organisation | Global Antibiotic Research and Development Partnership |
Sector | Charity/Non Profit |
Country | Switzerland |
Start | 06/2019 |
End | 06/2022 |
Description | SNIP-Africa Severe neonatal infection adaptive platform trials in Africa |
Amount | € 7,999,329 (EUR) |
Organisation | Sixth Framework Programme (FP6) |
Department | European and Developing Countries Clinical Trials Partnership |
Sector | Public |
Country | Netherlands |
Start | 07/2023 |
End | 06/2028 |
Description | Severe Malaria Africa - A consortium for Research and Trials (SMAART) |
Amount | £4,028,013 (GBP) |
Funding ID | 209265/Z/17/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2019 |
End | 06/2025 |
Description | neoAMR neonatal sepsis programme |
Amount | € 2,500,000 (EUR) |
Organisation | Global Antibiotic Research and Development Partnership |
Sector | Charity/Non Profit |
Country | Switzerland |
Start | 06/2018 |
End | 05/2023 |
Description | neoVT-AMR - strategies to reduce vertical transmission of multi-drug resistant pathogens to neonates |
Amount | £233,411 (GBP) |
Funding ID | MR/T039035/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 04/2021 |
End | 03/2022 |
Description | GARDP |
Organisation | Global Antibiotic Research and Development Partnership |
Country | Switzerland |
Sector | Charity/Non Profit |
PI Contribution | MRC CTU at UCL is leading on statistics and trial management for randomised trials in the fields of antibiotic treatment/antimicrobial resistance in children. |
Collaborator Contribution | GARDP mobilizes partners to develop new and improved antibiotics through partnerships with governments, the private sector, academia and civil society. |
Impact | Grants to run large-scale observational studies and trials in neonatal sepsis, leading to peer-reviewed publications and ongoing studies. Multidiscplinary, including clinical medicine, statistics, trial management, laboratory management. |
Start Year | 2018 |
Description | KEMRI |
Organisation | Kenyan Institute for Medical Research (KEMRI) |
Department | Severe Malaria Cohort in Kilifi Kenya |
Country | Kenya |
Sector | Academic/University |
PI Contribution | MRC CTU at UCL is leading on statistics and trial/study design for a programme of randomised trials for the "acutely sick child in Africa". |
Collaborator Contribution | KEMRI provides clinical leadership and leads on trial/study management for a programme of randomised trials for the "acutely sick child in Africa". |
Impact | Multiple grants, peer-reviewed publications, incorporate into guidelines. Multidiscplinary, including clinical medicine, statistics, trial management, laboratory management. |
Start Year | 2008 |
Description | Kwame Nkrumah University of Science and Technology, Kumasi, Ghana |
Organisation | Kwame Nkrumah University of Science and Technology (KNUST) |
Country | Ghana |
Sector | Academic/University |
PI Contribution | MRC CTU at UCL is leading on statistics and trial/study design for a programme of randomised trials for the "acutely sick child in Africa", including severe malaria. |
Collaborator Contribution | Clinical and scientific expertise, and recruitment to the studies. |
Impact | Multidiscplinary, including clinical medicine, statistics, trial/study management, laboratory management. |
Start Year | 2017 |
Description | Laboratory S. aureus |
Organisation | The Wellcome Trust Sanger Institute |
Department | Human Genetics |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This collaboration has benefitted both sides as linking laboratory (AUREUS) and therapeutic (SNAP) trials- it led to other linkage and collaborations such as Ruth Massey, University of Bristol |
Collaborator Contribution | Our partner is going to provide WGS to our samples and is likely to improve our overall collaborations |
Impact | Recent development- multidisciplinary- infectious diseases, microbiology & laboratory |
Start Year | 2022 |
Description | MORU |
Organisation | Mahidol Oxford Tropical Medicine Research Unit |
Country | Thailand |
Sector | Public |
PI Contribution | MRC CTU at UCL is leading on statistics and trial/study design for a programme of randomised trials for the "acutely sick child in Africa", including severe malaria. |
Collaborator Contribution | MORU are world leaders in malaria, and are providing clinical and scientific expertise. |
Impact | Peer reviewed publications, leading to incorporation in guidelines. Multidiscplinary, including clinical medicine, statistics, trial/study management, laboratory management. |
Start Year | 2017 |
Description | Manhica Health Research Centre (CISM) (Mozambique) |
Organisation | Manhiça Health Research Centre (CISM) |
Country | Mozambique |
Sector | Public |
PI Contribution | MRC CTU at UCL is leading on statistics and trial/study design for a programme of randomised trials for the "acutely sick child in Africa", including severe malaria. |
Collaborator Contribution | Clinical and scientific expertise, and recruitment to the studies. |
Impact | Multidiscplinary, including clinical medicine, statistics, trial/study management, laboratory management. |
Start Year | 2017 |
Description | Mbale Clinical Research Institute and Mbale and Soroti Regional Referral Hospitals |
Organisation | Mbale Clinical Research Institute |
Country | Uganda |
Sector | Hospitals |
PI Contribution | MRC CTU at UCL is leading on statistics and trial/study design for a programme of randomised trials for the "acutely sick child in Africa". |
Collaborator Contribution | Mbale Clinical Research Institute provides trial management and Mbale and Soroti Regional Referral Hospitals provide clinical expertise and are recruiting sites. |
Impact | Multiple randomised trials leading to peer reviewed publications and incorporation in guidelines Multidiscplinary, including clinical medicine, statistics, trial management, laboratory management. |
Start Year | 2009 |
Description | PET collaboration for nuclear imaging |
Organisation | King's College London |
Department | Division of Imaging Sciences and Biomedical Engineering |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have collaborated on the development of reviews and future grants |
Collaborator Contribution | The partners have helped write grants and reviews |
Impact | Multi-disciplinary - nuclear medicine, radiology & infection |
Start Year | 2021 |
Description | Pharmaceuticals in S. aureus |
Organisation | Liverpool School of Tropical Medicine |
Department | Liverpool Insect Testing Establishment |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | A linkage to understand pharmaceuticals together |
Collaborator Contribution | We have linked research clinical trials with those understanding pharmaceuticals |
Impact | too early- multi-disciplinary pharmacy & medical/trials |
Start Year | 2023 |
Description | SNAP |
Organisation | University of Melbourne |
Country | Australia |
Sector | Academic/University |
PI Contribution | We have set up a collaboration and applied for national funding for this international trial |
Collaborator Contribution | They have set up SNAP trial internationally |
Impact | collaboration and systems being developed- new grants being written |
Start Year | 2021 |
Description | SNAP UK collaboration |
Organisation | University of Sussex |
Department | Brighton and Sussex Medical School |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This is a new link to deliver trials |
Collaborator Contribution | The partners have contributed to trial design and future planning |
Impact | Another outcome of this partnership has been a trial called the DURATION trial. Although we are not a partner on the trial I am on the DSMB |
Start Year | 2021 |
Description | St George's University of London |
Organisation | St George's University of London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | MRC CTU at UCL is leading on design and statistical aspects of randomised trials in the fields of antibiotic treatment/antimicrobial resistance in children and neonates. |
Collaborator Contribution | The team at SGUL provide clinical leadership to the programme of trials. |
Impact | Multiple grants to conduct trials and observational studies, leading to peer reviewed publications, with further impacts to come. Multidiscplinary, including clinical medicine, statistics, trial management, laboratory management. |
Start Year | 2015 |
Description | Tropical Diseases Research Centre, Ndola, Zambia |
Organisation | Tropical Disease Research Centre |
Country | Zambia |
Sector | Academic/University |
PI Contribution | MRC CTU at UCL is leading on statistics and trial/study design for a programme of randomised trials for the "acutely sick child in Africa", including severe malaria. |
Collaborator Contribution | Clinical and scientific expertise, and recruitment to the studies. |
Impact | Multidiscplinary, including clinical medicine, statistics, trial/study management, laboratory management. |
Start Year | 2019 |
Title | Azithromycin |
Description | Azithromycin could potentially reduce mortality associated with bacterial co-infection in severe malaria. Doses for this indication are being tested in a Phase I/II evaluation funded by an MRC trial development grant. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Trial ongoing |
Title | Biphasic cuirass ventilation (BCV) |
Description | Non-invasive ventilation support which could potentially reduce mortality in children with cerebral malaria. Phase I trial ongoing, funded by the Wellcome Trust. |
Type | Therapeutic Intervention - Physical |
Current Stage Of Development | Initial development |
Year Development Stage Completed | 2022 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Trial ongoing |
Title | Chlorhexidine |
Description | Chlorhexidine antiseptic, initial pilot phase, funded by MRC trial development grant. |
Type | Preventative Intervention - Physical/Biological risk modification |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2022 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | None to date |
Title | Cotrimoxazole |
Description | Drug which could potentially reduce morbidity in children with sickle cell anaemia, being evaluated in a large pragmatic trial funded by the MRC. The system won't let me add the same trial twice even though it is a factorial trial testing multiple different interventions. ISRCTN15724013 |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Development Status | Under active development/distribution |
Impact | Trial ongoing |
Title | Dihydroartemisinin-piperaquine |
Description | Drug which could potentially reduce morbidity in children with sickle cell anaemia, being evaluated in a large pragmatic trial funded by the MRC. The system won't let me add the same trial twice even though it is a factorial trial testing multiple different interventions. ISRCTN15724013 |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2022 |
Development Status | Under active development/distribution |
Impact | Trial ongoing |
Title | Fosfomycin, flomoxef |
Description | Fosfomycin and flomoxef are old antibiotics which could potentially improve outcomes from neonatal sepsis. They will initially be tested in a Phase I pharmacokinetic study before a large scale clinical evaluation, both funded by GARDP. ISRCTN48721236 is not available in the list above (but is on the ISRCTN website). |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2022 |
Development Status | Under active development/distribution |
Impact | Trial ongoing |
Title | Hydroxyurea |
Description | Drug which could potentially reduce mortality in children with sickle cell anaemia, being evaluated in a large pragmatic trial funded by the MRC. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2022 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Trial ongoing |
Title | Levetiracetam |
Description | The NOVICE trial is testing the potential benefits of a special type of ventilation that applies suction or negative pressure to the chest (meaning keeping children breathing by pushing air in and out of their lungs) in combination with Levetiracetam given before children have had any fits, as a way to prevent them stopping breathing completely and/or preventing or reducing the amount of pressure that builds up in their brains which can lead to death, or brain damage and disability over the long-term. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Trial ongoing |
URL | https://www.isrctn.com/ISRCTN76942974 |
Title | Oral and IV fluids for rehydration in gastroenteritis |
Description | There are many questions regarding the optimal use of rehydration fluids in gastroenteritis in acutely sick children in Africa. This Phase II trial funded by an MRC trial development grant is designed to identify promising strategies for a future large Phase III trial. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
UKCRN/ISCTN Identifier | PACTR202103852542919 |
Impact | Trial ongoing |
Title | Sevuparin |
Description | Sevuparin is a drug which could potentially reduce mortality in children with severe malaria. It is currently being evaluated in a dose-finding study funded by the Wellcome Trust. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Initial development |
Year Development Stage Completed | 2022 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Trial ongoing |
Description | Briefing paper: Should children with severe anaemia be transfused with whole blood or red cell concentrates? |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | This briefing paper explores new data from the TRACT trial on outcomes for children with anaemia receiving transfusion with whole blood vs red cell concentrates. It is available in English, French and Portuguese. |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.mrcctu.ucl.ac.uk/studies/all-studies/t/tract/briefing-papers-about-blood-transfusion-for... |
Description | TRACT algorithm briefing paper |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | This briefing paper summarises recommendations and the clinical management algorithm developed at a stakeholder meeting held in 2020, based on the evidence from the TRACT trial. The consensus algorithm is designed to help health workers deliver evidence-based care to children with severe anaemia within the context of resource-limited settings. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.mrcctu.ucl.ac.uk/media/1972/tract-algorithm-briefing.pdf |
Description | Webinar for Africa Blood Transfusion Services |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | New research from secondary analysis of the TRACT trial was presented to representatives from 6 different national Blood Transfusion Services from across Africa, as well as to the President of the African Blood Transfusion services which sparked questions and discussions afterwards and several Transfusion services expressed interest in further research in this particular area (the impact of different types of blood preparation on clinical outcomes in children with severe anaemia). |
Year(s) Of Engagement Activity | 2021 |