Our research focuses predominantly on the interactions between infection, immunity and malnutrition, particularly in the context of HIV infection. Undernutrition contributes to 45% of child deaths in developing countries, yet we do not fully understand the pathophysiology of malnutrition, or the best interventions for prevention and treatment. Stunting is the most prevalent form of undernutrition, affecting 165 million children under 5 years of age globally, and there are ambitious targets to reduce prevalence by 40% between 2010 and 2025. However, due to population growth, the absolute number of stunted children in sub-Saharan Africa is likely to increase and we lack understanding of the most tractable pathways to target for prevention. Severe acute malnutrition (wasting) affects an estimated 52 million children under 5 years of age and has particularly high mortality in the context of HIV infection. The pathophysiology of severe acute malnutrition in HIV-infected children is not well understood but urgent new interventions are needed to reduce the 30% mortality associated with this condition.
We are interested in better defining pathways that can be targeted, and evaluating interventions to reduce malnutrition. In particular, we are investigating the role of enteropathy in undernutrition. Children in developing countries almost universally have a condition called environmental enteric dysfunction (EED), which is characterized by reduced absorptive capacity, mucosal inflammation and increased intestinal permeability. Passage of normally innocuous gut organisms into the systemic circulation causes chronic inflammation, which leads to impaired growth. We are trying to better define markers of EED, investigate the effects of enteropathy on oral vaccine responses, and characterise immune function in children with malnutrition.
In Zimbabwe, we are undertaking a cluster-randomized trial of improved infant feeding and/or improved water, sanitation and hygiene (WASH) among 5200 infants in two rural districts, to reduce EED and improve growth and anaemia in early life (SHINE; https://clinicaltrials.gov/ct2/show/NCT01824940). We are characterising in detail the biomedical pathway linking WASH and impaired growth and development in infancy. In linked substudies we are evaluating the role of the microbiota in malnutrition; the impact of maternal infection and inflammation on adverse birth outcomes; the role of mycotoxins in enteropathy and stunting; and the impact of these interventions in HIV-exposed infants.
In Zimbabwe and Zambia (with Professor Paul Kelly, Centre for Immunobiology) we are undertaking the Health Outcomes, Pathogenesis and Epidemiology of Severe Acute Malnutrition (HOPE-SAM) study, investigating the role of enteropathy in children with HIV and severe acute malnutrition, and conducting long-term follow-up of a cohort of children following nutritional rehabilitation to characterise long-term outcomes and immune function.
We also collaborate on large, pragmatic HIV trials in Africa through the MRC Clinical Trials Unit at UCL, including the ARROW trial (www.arrowtrial.org), which evaluated HIV monitoring strategies in 1200 children starting antiretroviral therapy (ART) in Uganda and Zimbabwe, and REALITY (https://clinicaltrials.gov/ct2/show/NCT01825031), a randomised trial of nutritional and antimicrobial interventions to reduce the high early mortality among HIV-infected children and adults starting ART. Both of these trials have ongoing immunology substudies to define the predictors of mortality and the pathways that can be targeted to improve outcomes.
Our group has a particular interest in cotrimoxazole, which we have shown reduces morbidity and mortality (Bwakura-Dangarembizi, N Engl J Med 2014) and improves growth and anaemia (Prendergast, Clin Infect Dis 2011) in HIV-infected children. We are characterising the immunomodulatory properties of cotrimoxazole in the lab, which we believe may have broader benefits for prevention of prematurity, intrauterine growth restriction and malnutrition in sub-Saharan Africa.
In parallel laboratory work, we are investigating the causes and consequences of chronic inflammation in HIV-infected children, focusing particularly on the role of co-infections (such as CMV and EBV), malnutrition and microbial translocation; and the immunology of HIV-exposed uninfected (HEU) infants, who have increased morbidity and mortality and poorer growth than HIV-unexposed infants.
The Prendergast Group 