Syndromic infections

Lead Research Organisation: University College London

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.

Publications

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