Insufficient food intake combined with infectious disease often results in undernutrition, ranging from specific micronutrient insufficiencies to acute and chronic malnutrition. In children under the age of five, severe acute malnutrition is estimated to be fatal in anywhere from a third to a half of cases, according to the World Health Organization (WHO). Whilst nutritional rehabilitation can promote weight gain, immune system dysfunction can persist and contribute to such malnutrition-associated disorders as environmental enteric dysfunction (EED). James Berkley and Kelsey Jones from the KEMRI-Wellcome Trust Research Programme, Kenya, and colleagues took a novel approach of targeting the immune response to tackle EED in children with severe acute malnutrition in Kenya, as published in a recent BMC Medicine study. Here Berkley and Jones discuss some of the wider issues and challenges of treating acute malnutrition in children, and what needs to be done to reduce the resulting levels of morbidity and mortality.
How widespread acute malnutrition in children worldwide, and what are the health consequences?
Childhood malnutrition is usually defined on the basis of height, weight and arm circumference in relation to standard reference measurements for children by age and sex. Children with low weight for height (‘wasted’), or who have oedema (a condition called kwashiorkor) are considered to be acutely malnourished, and there are at least 70 million such children worldwide. Being short for age, (‘stunted’) is regarded as reflecting chronic malnutrition and is very common, affecting a quarter of the world’s children under five, around 165 million children.
Children with acute malnutrition are extremely vulnerable to very severe infection with common diseases such as pneumonia or diarrhoea. The potentiating effect of malnutrition on infection is so severe that it’s been estimated that all forms of malnutrition may underlie up to a half of all child deaths. For those who survive acute malnutrition or who have chronic malnutrition, failing to grow properly in childhood is associated with a whole range of serious long-term medical and social consequences, which ultimately lead to the entrenchment of poverty across generations.
How are malnourished children currently treated?
Ideally, malnourished children are detected and treated early in the community at a stage when the malnutrition is only moderately severe. However, by the time a malnourished child is brought to hospital or clinic, they are often very unwell and a significant proportion will require hospital-based care for at least a week or so. For those who are well enough to be managed in the community the mainstay of treatment is so-called ready-to-use therapeutic food (RUTF), which is a group of micronutrient enriched oil-based spreads designed to meet acutely malnourished children’s needs during nutritional rehabilitation. All children with acute malnutrition are treated with an antibiotic and an anti-helminthic drug as standard, partly to get rid of any microbial overgrowth in the bowel, and will need to be followed up weekly.
Are there specific co-morbidities that need to be considered when treating acutely malnourished children?
It is absolutely essential that HIV infection is considered because this can be a common comorbidity in some settings, and requires specific treatment. Tuberculosis is common in some settings as well, and can be very difficult to diagnose. Additionally, it’s important to look at the whole family unit, because if one child is acutely malnourished it might be that others are suffering too. Outcomes of treatment for acute malnutrition are better the earlier the cases are picked up, so an opportunity to screen siblings is really important to take up.
What are the limitations of current treatments?
It is clear that with the right treatment, many acutely malnourished children will put on weight really well with just a few weeks of ready-to-use therapeutic food (RUTF) treatment. However, in the weeks and months following enrolment for nutritional rehabilitation, these children appear to retain an extreme vulnerability to severe infection, and have a risk of severe infection and mortality rate that is much higher than that of other children in the community. Also, we know that while the treatments we give are very good at making children ‘fatter’ they are not necessarily successful in making them ‘taller, and because we know that stunting is particularly associated with long-term difficulties, there is a concern that we’re not fully helping these children to ‘turn the corner’ to healthy growth and development.
The best medical treatments, including therapeutic feeds, should ideally be determined by rigorous clinical trials, however for malnutrition very few have been conducted. The World Health Organization (WHO) acknowledge that the evidence underlying the guidelines that they produce is generally of very low quality. (More on the latest updates to the WHO guidelines, and the process by which these updates are made can be found here).
Can you describe the novel approach that your team are working on to tackle acute malnutrition in children?
The small trial that we performed was the first trial ever conducted that directly targeted modulating the immune system in malnutrition. People often think of malnourished children as immunodeficient because they are so susceptible to infections. However, the evidence points to the immune system of malnourished children being over- rather than under-activated.
There is increasing recognition that stunting, in particular, arises not just due to chronic malnutrition but as a result of a whole range of environmental challenges and difficulties. Many, many children where we work in Nairobi, Kenya, have evidence of chronic intestinal inflammation, a condition that is called environmental enteric dysfunction (EED). It is hypothesised that lack of access to clean water, facilities for sanitation, and safe disposal of waste is very important in driving that. We were struck by the similarities between EED and inflammatory bowel diseases that you might see in children living in Europe, like Crohn’s disease. These inflammatory bowel diseases are probably partly triggered by the environment as well, but we know that an inappropriately exuberant immune response by the child themselves is always present and is a really good target for drug treatment. We thought, “why shouldn’t the same be true for the children we see in Nairobi?”, and so we performed a very small, very careful trial of treating children with severe acute malnutrition and stunting with a drug designed to dampen down immune activation in the gut that is commonly used in children with inflammatory bowel disease, alongside all the regular nutritional and medical treatment we give malnourished children as standard.
We are also working on a number of other strategies to tackle inflammation and infections in malnourished children. These include prophylaxis with low dose antibiotics during the most vulnerable period, and altering the composition of therapeutic feeds in order to target inflammation and immunological recovery.
What further research needs to be done to determine how useful this approach is?
The early phase study that we conducted was encouraging. However it was deliberately small to assess safety. We still don’t actually have enough data to call this even a ‘promising’ treatment as yet! We need more of the same, with more trials in larger groups of malnourished children to generate a lot more data from where we can start to design trials where we are looking at outcomes that are really related to healthy growth and development.
How difficult would it be to implement your approach in clinical practice?
At the moment we are a very long way from seeing mesalazine (the drug treatment used in our small trial), or similar treatments, being used in anything but a clinical trial setting. However, it is important that mesalazine is a cheap drug with a very good safety profile, so there is no reason if there was evidence that it worked, that it couldn’t be used in routine clinical practice. Generating data on effectiveness will be a challenge and will take many years, but our group is focused on getting treatments that work for children as our main priority, and we do believe that mesalazine has potential to do that.
What are the major challenges in reducing morbidity and mortality from acute malnourishment in children?
There is no doubt that we know the recipe for healthy growth and development because in wealthy countries children are healthier than they have been at any other time in history. However, waiting for political and economic answers to sort out undernutrition is not an option because it will be decades before all children grow up in equal societies with proper access to nutritious food, a sanitary environment, and high quality education – all of which we know they need.
In the meantime, we need to develop a set of interventions that are affordable, practical and scalable, and demonstrate through research that these make a tangible difference to children in order to leverage funding for roll-out. That’s the way to prevent acute malnutrition even arising. In the short term, we need to maximise the impact of what we’re able to provide here and now. While this kind of approach of damping down children’s own inflammatory activation is never going to replace their need for proper nutritional rehabilitation and management of medical complications, it might form part of the answer.
Questions from Joanna Denyer, Senior Assistant Editor for BMC Medicine.