Blood test predicts risk of death and suggests new treatment targets in acutely ill children in lower-income countries
An international study has identified a blood-based indicator of intestinal damage and inflammation that strongly predicts mortality in sick children. The new biomarker could help to identify those children at greatest risk of dying after hospitalisation in parts of the world with limited resources.
The collaborative study by the University of Oxford and the international CHAIN Network was carried out across nine sites in six countries in sub-Saharan Africa and South Asia. The research was supported by the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre (BRC) and the KEMRI-Wellcome Trust.
Childhood mortality remains unacceptably high in many low- and middle-income countries, where chronic gut inflammation and environmental enteric dysfunction (EED) are widespread.
The research team examined plasma lipopolysaccharide (LPS) —a molecule derived from groups of bacteria that colonise the human intestine.
They analysed blood samples from 638 acutely ill hospitalised children and compared them with 251 healthy peers from their communities. Their results revealed a striking pattern: higher plasma LPS levels were strongly associated with an increased risk of death within 90 days, even in those children who were not severely undernourished.
Children who did not survive and exhibited high LPS levels also showed signs of defective intestinal barrier function including increased harmful gut bacteria, and higher faecal and systemic markers of inflammation.
The findings were published in two papers in the journal Nature Communications.
Dr James Njunge of the KEMRI-Wellcome Trust Research Programme and a post-doctoral researcher with the CHAIN Network is one of the lead authors. He said: “In many low-resource settings, children have hidden damage to the gut lining – a kind of ‘leaky gut’ that routine clinic checks don’t detect. This allows bacteria and their toxins to seep into the bloodstream, driving chronic inflammation, poor growth and weaker responses to oral vaccines.
“Our study shows that when these vulnerable children then develop severe infections such as sepsis or serious gut infections, this constant leak can overwhelm and ‘shut down’ the immune system, sharply increasing the risk of death. The CHAIN Network provided a unique platform to work closely with affected families and international collaborators to uncover these mechanisms.”
Another author, Professor Holm Uhlig of the University of Oxford’s Centre for Human Genetics and Co-theme Lead of the NIHR Oxford BRC Inflammation Across Tissues Theme, added: “This excellent international collaboration identified a strong biomarker and provided mechanistic insight into how enteric dysfunction in low- and middle-income countries is associated with increased mortality. As part of the NIHR Biomedical Research Centre in Oxford and a newly funded Medical Research Council (MRC) Centre for Research Excellence in Exposome Immunology, we plan to further investigate how environmental factors drive enteric dysfunction.”
To better understand the biological pathways leading to mortality, the researchers integrated their findings with a dataset of genes expressed by individual intestinal cell types. This allowed them to model how different immune cells interact with each other and with the cells that line the gut, offering new insights into how intestinal damage and systemic inflammation work together to drive poor outcomes.
Implications for Global Child Health
By identifying plasma LPS as a strong and independent predictor of mortality in acutely ill children, the study opens new avenues for early risk assessment and targeted interventions in settings where EED and malnutrition are common. Understanding the biological pathways associated with LPS-driven inflammation may also reveal new therapeutic targets, potentially improving survival for millions of vulnerable children worldwide.
Professor James Berkley from the University of Oxford’s Nuffield Department of Medicine and the KEMRI-Wellcome Trust Research Programme in Kenya said: “Mortality rates among children with common illnesses in Africa and South Asia continue to be unacceptably high, including after discharge from hospital.
“The CHAIN Network of paediatricians and scientists in countries with a high burden of child mortality, working together with cutting-edge collaborating laboratories in the UK and North America, have generated a new understanding of important underlying biological mechanisms in acutely ill children which are different to those usually seen in higher-resource settings and can be targeted by new treatments.”
The authors note that future work should explore practical approaches for measuring LPS or related inflammatory markers in clinical settings and evaluate interventions that strengthen gut integrity or reduce harmful inflammation.
Ends
Notes to Editors
The two papers published in Nature Communications are:
The CHAIN cohort study was conducted between November 2016 and January 2019 at nine hospitals in six countries: Bangladesh, Burkina Faso, Kenya, Malawi, Pakistan and Uganda.
Find out more about the CHAIN Network (Childhood Acute Illness & Nutrition Network)
The National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre (BRC) is based at the Oxford University Hospitals NHS Foundation Trust and run in partnership with the University of Oxford.
The mission of the National Institute for Health and Care Research (NIHR) is to improve the health and wealth of the nation through research. We do this by:
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About the Kenya Medical Research Institute Wellcome Trust Research Programme (KWTRP), Kenya
The Kenya Medical Research Institute (KEMRI)-Wellcome Trust Research Programme which was formally established in 1989, is a partnership between KEMRI, University of Oxford and the Wellcome Trust. KWTRP conducts high quality, purposeful, and relevant research in molecular biology, epidemiological, and clinical research. This research feeds directly into local and international health policy, with a parallel aim of supporting and nurturing the next generation of African researchers www.kemri-wellcome.org.