Does a short term nutritional supplementation prevent
malnutrition in ill children?
Effectiveness of nutritional supplementation (ready-to-use therapeutic food
and multi micronutrients) of 2 weeks in preventing malnutrition in children
6-59 months with infection (malaria, pneumonia, diarrhoea)
PhD Dissertation
Ecole de Santé Publique - Université Libre de Bruxelles
Saskia van der Kam
10
thJanuary 2017
Promotor
Prof. Dr. P. Donnen
Does a short term nutritional supplementation prevent
malnutrition in ill children?
Effectiveness of nutritional supplementation (ready-to-use therapeutic food
and multi micronutrients) of 2 weeks in preventing malnutrition in children
6-59 months with infection (malaria, pneumonia, diarrhoea)
PhD Dissertation
Ir. Saskia van der Kam
Ecole de Santé Publique - Université Libre de Bruxelles
Dissertation committee:
Prof. P. Donnen – Promotor
Prof. M. Dramaix-Wilmet – President
Prof. K. Castetbon – Member
Dr. P. Bahwere – Member
Prof. J. Berger – Member
Prof. A. Briend – Member
Prof. P. Goyens – Member
Prof. W. Zhang – Member
Summary
It has been generally recognised that sick children have an increased risk on malnutrition. An activated immune system requires more nutrients while illness is often associated with a lower absorption and decreased consumption because of lack of appetite. When these increased needs are not balanced with an adequate availability of nutrients, the sick child is at higher risk of developing malnutrition.
Médecins Sans Frontières investigated the question whether this process is mitigated by simple short term nutritional supplementation given to sick children alongside medical treatment. Three Randomised Controlled Trials (RCT’s) were conducted. The first, in Democratic Republic of Congo, was a pilot; 180 children with malaria were randomised in 2 arms: 1 group receiving 2 weeks of ready to use therapeutic food (RUTF) and a control group. The children were followed for a period of 4 weeks. Children in the RUTF group showed a higher weight gain in the first 14 days compared to the control group, at day 28 the weight gain in both groups was similar.
Thereafter, 2 RCT’s were implemented in Uganda and Nigeria using a similar methodology. Children with malaria, lower respiratory tract infection or diarrhoea (sample size of 2202) were randomised in three groups: supplemented with 2 weeks of RUTF, supplemented with 2 weeks of micronutrient powder (MNP), and not receiving supplementation after each disease episode. The incidence of malnutrition was compared after an observation period of 6 months.
The trial in Uganda showed a reduction in malnutrition in the RUITF group with 31%, while in Nigeria, there was no significant reduction in the RUTF group. The MNP group did not show reduction in malnutrition in any site. In the group of moderate malnourished children the RUTF and MNP supplementations were not effective in preventing deterioration to severe malnutrition. However, when the studies were combined the RUTF group showed a lower mortality compared to the MNP group.
mixed; it was associated with a higher incidence of malnutrition in Kaabong, but in Goronyo a higher frequency of malaria decreased the incidence of malnutrition. In addition, a more frequent monitoring of the children and treatment of their illnesses was associated with a decreased incidence of malnutrition.
The difference in effectiveness of supplementation between the sites can be explained by differences in food security and level of morbidity. It is argued that the fragile food security in Kaabong limits the supply of nutrients, and therefore supplementation with RUTF was effective. In Goronyo the high frequency of morbidity limits convalescence and therefore supplementation was not effective.
It is likely that malnutrition is more effectively prevented when several interventions are combined like water and sanitation to prevent diarrhoea, malaria chemoprophylaxis and preventative and curative health and nutrition interventions.
Table of contents
Summary ... v
1. INTRODUCTION ... 1
1.1
Background ... 1
1.2
Aim of the research project ... 2
1.3
Hypothesis and objectives ... 5
1.4
Methodology... 5
1.5
Thesis outline ... 6
2. INTERACTION NUTRITION AND INFECTION ...11
2.1
Introduction ...11
2.2
Historical perspective ...11
2.3
Role of nutrients in the immune system ...12
2.3.1 Barrier functions of the gut mucosa ...13
2.3.2 The role of nutrients in the immune response ...13
2.4
Effect of infection on nutritional status ...15
2.4.1 Background ...15
2.4.2 Weight loss associated with infection ...16
2.5
Effect of supplementation on nutritional state of ill children...17
2.6
Effect of supplementation on infection ...19
2.7
Conclusion ...20
3. STUDY DESCRIPTION ...27
3.1
Introduction ...27
3.2
Study design ...27
3.3
Settings ...29
3.4
Objectives and Hypothesis ...31
3.5
Outcome indicators ...33
3.6
Participants ...33
3.7
Supplementation ...34
3.8
Procedures ...37
3.10 Analysis and reporting ...42
4. RESULTS...51
4.1
Overview ...51
4.2
Summary of results ...51
4.3
Pilot randomised controlled trial Dubié (DRC) ...54
4.3.1 Summary results Dubié ...54
4.3.2 Publication RCT Dubié (DRC) ...54
4.4
Randomised controlled trial Kaabong (Uganda) ...55
4.4.1 Summary results Kaabong ...55
4.4.2 Publication RCT Kaabong (Uganda) ...55
4.5
Randomised controlled trial Goronyo (Nigeria) ...56
4.5.1 Summary results Goronyo ...56
4.5.2 Publication RCT Goronyo (Nigeria)...56
4.6
Combined data Kaabong and Goronyo ...57
4.6.1 Summary ...57
4.6.2 Methods ...57
4.6.3 Result incidence NNO merged data set ...59
4.6.4 Number of allocations and NNO ...60
4.6.5 Variables associated with NNO ...62
4.6.6 Mortality ...67
4.6.7 Discussion merged data Kaabong and Goronyo ...68
4.6.8 Conclusion merged data Goronyo and Kaabong ...71
5. DISCUSSION ...74
5.1
Recapitulation ...74
5.2
Context and baseline ...75
5.2.1 Context ...75
5.2.2 Baseline Incidence of malnutrition ...75
5.3
Effectiveness of supplementation ...78
5.3.1 Incidence of malnutrition ...78
5.3.2 Duration of supplementation ...79
5.3.3 Effectiveness in moderately malnourished participants ...79
5.3.4 Specific vulnerable groups ...80
5.3.5 Other anthropometric indicators ...81
5.3.6 Association between incidence of malnutrition and morbidity ...83
5.3.7 Effect of supplementation on morbidity ...87
5.4
Methodological considerations ...92
5.4.1 RCT ...92
5.4.2 Outcome measures ...92
5.4.3 Confounding factors ...93
5.4.4 MAM exclusion Kaabong ...93
5.4.5 Study group of ill children ...94
5.4.6 Multivariable analysis ...94
5.4.7 Overall conclusion ...94
6. CONCLUSIONS AND IMPLICATIONS ... 100
6.1
Conclusion ... 100
6.2
Implications for nutritional strategies ... 101
6.3
Further research ... 102
7. BIBLIOGRAPHY DISSERTATION... 108
8. ACKNOWLEDGEMENTS AND BACKGROUND AUTHOR ... 121
Acknowledgements ... 121
About the author ... 123
Abbreviation
Description
AOR
Adjusted Odds RatioCu
Cupper
DRC Democratic Republic of Congo
EDTA
Ethylenediaminetetraacetic acidEED
Environmental Enteric Dysfunction
ESP
Ecole Santé Publique
Fe
Iron
HAZ
Height-for-Age z-scoreHR-adj
adjusted Hazard RatioIPTi
Intermittent Preventive Treatment in infants
IRR
Incidence Rate Ratio
LGA
Local Government Area
LNS
Lipid based Nutrition SupplementLNS-LQ
LNS Large QuantityLNS-MQ
LNS Medium QuantityLNS-SQ
LNS Small QuantityLRTI
Lower Respiratory Tract InfectionMAM
Moderate Malnutrition
Mg
Magnesium
Mn
Manganese
MNP
Micro-Nutrient Powder
MSF
Médecins Sans Frontières
MSF-OCA
Médecins sans Frontières-Operational Centre AmsterdamMUAC
Mid Upper Arm Circumference
NNO
Negative Nutritional Outcome
P.f
Plasmodium falciparumPI
Principle InvestigatorPUFA
Poly Unsaturated Fatty Acid
RCT
Randomised Controlled Trial
resp.
respectivelyRUTF
Ready to Use Therapeutic Food
SAM
Severe Malnutrition
SAP
Statistical Analysis Plansd
standard deviation
Se
Selenium
SMC
Seasonal Malaria Chemo ProphylaxisSMD
Standard Mean DifferenceTFC
Therapeutic Feeding CentreTNF
Tumor Necrosis FactorULB
Universié libre de Bruxelles
UNICEF
United Nations Children FundWASH
Water And Sanitation and HygieneWAZ
Weight-for-Age z-score
WFP
World Food ProgramWHO
World Health Organisation
WHZ
Weight-for-Height z-score
Acronyms:
NNO: Negative Nutritional Outcome:
NNO is defined depending nutritional status
For non-malnourished children at enrolment NNO is defined as: weight-for-height z-score <−2, MUAC <115 mm, or nutritional oedema, whichever occurred first.
For moderately malnourished children at enrolment, NNO was defined as weight-for-height z-score <−3, MUAC <115 mm, nutritional oedema (SAM), or weight loss >10% from baseline, whichever occurred first.
SAM: Severe Acute Malnutrition
Defined as:
weight-for-height z-score <−3, MUAC <115 mm, nutritional oedemaMAM: Moderate Acute Malnutrition
Defined as: weight-for-height z-score between – and -2 and MUAC ≥ 11.5
NAM: Non-Malnourished:
1
1. INTRODUCTION
1.1 Background
Malnutrition is one of the single greatest threats to child survival, associated with 3.1 million child deaths each year – of which half a million from wasting as a result of malnutrition– or 45% of all child deaths worldwide (1). The global burden of malnutrition is staggering, with an estimated 8% prevalence of moderate acute malnutrition among children (51.5 million children) and 2.9% prevalence of severe acute malnutrition (18.7 million children) in 2011 (1). These malnourished children have a higher risk of mortality, ranging from a three-fold increased risk for the moderately malnourished to a nearly ten-fold increase for the severely malnourished (2).
Initiatives to prevent severe malnutrition and related deaths have evolved during the last few decades. In the 1970s, the combination of growth monitoring and nutrition education was implemented in many parts of Africa. This was later combined with the distribution of protein-rich porridges. However, the effectiveness of these programmes was not extensively evaluated so no proof of effectiveness can be given (3).
Other ways of prevention were also researched. Promotion of breastfeeding, promotion of appropriate complementary feeding including supplementation in food-insecure populations, and micronutrient supplementation (Zinc and vitamin A) were identified as the most cost-effective measures (4).
2
1.2 Aim of the research project
The relationship between infection and malnutrition is thought to be bidirectional voiced as early as in 1968 in a of the WHO on interactions of nutrition and infection(11). In summary the conclusion is that malnutrition increases the risk of and worsens the course of infectious disease; and infection leads to malnutrition (12,13).
Figure 1: Relationship between nutrition and infection; source K. Brown 2003
Infection adversely affects nutritional status through reductions in dietary intake and intestinal absorption, and through increased catabolism and sequestration of nutrients that are required for tissue synthesis and growth. On the other hand, malnutrition can predispose to infection due to its negative impact on the barrier protection provided by the skin and mucous membranes and by inducing alterations in host immune function (12).
This process can become more chronic, eg. the Environmental Enteric Dysfunction (EED), previously called tropical enteropathy, refers to an syndrome of inflammation and reduced barrier function in the small intestine, resulting in chronic inflammation, poor appetite, reduced absorptive capacity, and growth impairment. It is associated with poor sanitation, chronic gut infections, and micronutrient deficiencies (14,15).
3
Although the presentation of the vicious circle between infection and malnutrition is schematic and very general, it orders information and helps to direct investigations of associations. The general nature of the presentation implies that the associations might differ in strength which is dependent on the specific diseases and contextual factors like food security, culture and health environment.Many interventions focus on treating malnutrition, which is rather labour-intensive and cost-intensive while trying to reach an acceptable coverage of the treatment programs (17). Besides food security activities malnutrition could be prevented mitigating the process of weight loss during and after an infection and strengthening the immunity by an improved diet during and after illness.
Therefore, in order to prevent malnutrition after an infection, the World Health Organisation (WHO) recommends that caretakers give children additional healthy food daily during the two weeks after the onset of illness (18–20).
This recommendation is likely to be ineffective in resource-poor settings, as poverty might prevent caregivers to implement it. A more effective strategy to reduce disease-related malnutrition in resource-poor areas may be to provide an ill child with a high quality nutritional supplement.
4
However, there is limited evidence on the effectiveness of nutritional supplementation to limit weight loss while recovery from illness. Despite the commonly shared intuitive reasoning, its effectiveness should be proven before an organisation will set up a large-scale supplementation to ill children. Therefore, the aim of this research project is to investigate whether a nutritional supplementation to ill children will prevent malnutrition.Whether and the nature of supplementation required to prevent malnutrition in non-seriously ill children is undecided. Micronutrients play a part in the immune function and if one or more are lacking, immunity will reduce. Micronutrients also play a role in regulating appetite; in case of reduced availability of micronutrients, appetite will also reduce. However, it is also possible that macronutrients are not only essential to provide energy, but also to provide essential fatty acids and amino acids, needed for the immune function which might specifically be important in marginally nourished children in food-insecure populations. The question remains whether it is essential to include the macronutrient components such as essential fatty acids and high quality as in Ready to Use Therapeutic Food (RUTF) or whether micronutrients alone are enough to mitigate weight loss after illness.
It is important to investigate the effectiveness of complete foods and micronutrients alone, as there are huge financial and logistical advantages to using micronutrients alone. The price of products has consequences for the feasibility and sustainability of such a supplementation program.
For this reason, two commonly used supplements were investigated: 1. a RUTF with both macro- and micro-nutrients
2. a powder with only the multi-micronutrient component.
5
Children younger than 5 years with a non-serious illness were selected as the target group, as they are the most vulnerable for malnutrition and morbidity. The diseases investigated in the study are the three childhood diseases with the highest contribution to mortality in this age group and of which the outcome is exacerbated by malnutrition: diarrhoea, malaria and lower respiratory tract infection (LRTI) (22). The nutritional supplementation given alongside medical treatment is meant to limit and mitigate weight loss associated with the illness in order to enhance recovery from the illness and weight loss. The usual maximum recovery time of these illnesses is 2 weeks, therefore the duration of supplementation is chosen to be 2 weeks (23–25).1.3 Hypothesis and objectives
The objective of the study is to assess the effectiveness of a nutritional supplement for non-severely ill children on the incidence of malnutrition.
This leads to the Primary Hypothesis: Supplementation for 14 days with RUTF, concurrently with appropriate medical treatment for malaria, and/or LRTI, and/or diarrhoea reduces the incidence of acute malnutrition compared to a control group during 6 months follow-up, amongst children 6-59 months of age (excluding severely malnourished) with malaria and/or, LRTI and/or diarrhoea at time of recruitment.
A secondary objective is to determine the effectiveness of 14 days MNP supplementation versus a control group and versus RUTF on the incidence of acute malnutrition during 6 months follow-up,
Other secondary objectives are to determine the effect on frequency of morbidity, mean weight change, frequency of ‘no weight gain and/or weight loss’, and the effectiveness in specific subgroups such as moderately malnourished, children under 2 years of age and breastfed children:
1.4 Methodology
6
The first was a pilot in order to assess whether the reasoning of supplementing ill children in prevention of malnutrition was a valid concept. The pilot RCT was conducted in in the Katanga province of the Democratic Republic of Congo (DRC). Through an open randomised controlled trial, we investigated to what extent ready-to-use therapeutic food (RUTF) promotes catch-up growth in children after an acute, uncomplicated episode of Plasmodium falciparum malaria. At day 14, the RUTF group had a significant higher mean weight gain compared to the control group, but after 28 days there was no difference shown.This study showed that children receiving RUTF for 14 days reduces the period that children are at risk of malnutrition. These results seemed promising, but as this pilot was limited in scope, sample size and follow-up period, the result should be confirmed by studies with more power, longer follow-up time and studying the outcome of incidence of malnutrition as opposed to mean weight changes.
We therefore planned two other RCT’s in two different settings. One RCT was conducted in Kaabong (Karamoja region), Uganda, a poor agro-pastoral community. The other RCT was conducted in Goronyo, Nigeria, a richer trading community which faces high malnutrition and morbidity burdens. In both RCT’s, children with at least one of the three study diseases (malaria, LRTI and diarrhoea) were targeted. Two supplements were compared: RUTF and micronutrients and a sample size of over 2000 children in total in each study, close to 700 per study arm. As the settings and outcomes were quite different, the RCT’s were analysed and presented separately.
1.5 Thesis outline
The following chapter contains a review of the relevant literature. It starts with a historical overview of research in this field, and is followed by current insights into the role of supplementation (micronutrients or high quality food) in literature.
7
The used methodology, and interpretation of results and are discussed in chapter 5.8
Key messages - Introduction
Malnutrition is a global problem and is often associated with disease.
The risk to develop malnutrition during an illness is increased because an activated
immune system increases the demand for nutrients, while malabsorption and
decreased consumption decreases the availability of nutrients.
3 Randomized Controlled Trials (RCT’s) in 3 countries were implemented to
investigate the effectiveness of nutritional supplementation of ill children in
preventing malnutrition.
9
References
1. Black RE, Victora CG, Walker SP, Bhutta Z a, Christian P, de Onis M, et al. Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet. 2013 Aug 3;382(9890):427–51.
2. Black RE, Allen LH, Bhutta ZA, Caulfield LE, de Onis M, Ezzati M, et al. Maternal and child undernutrition: global and regional exposures and health consequences. Lancet. 2008 Jan 19;371(9608):243–60.
3. Garner P. Is routine growth monitoring effective? A systematic review of trials. Arch Dis Child. 2000 Mar 1;82(3):197–201.
4. Bhutta ZA, Das JK, Rizvi A, Gaffey MF, Walker N, Horton S, et al. Evidence-based
interventions for improvement of maternal and child nutrition: what can be done and at what cost? Lancet. 2013 Aug 3;382(9890):452–77.
5. Isanaka S, Nombela N, Djibo A, Poupard M, Van Beckhoven D, Gaboulaud V, et al. Effect of preventive supplementation with ready-to-use therapeutic food on the nutritional status, mortality, and morbidity of children aged 6 to 60 months in Niger: a cluster randomized trial. JAMA. 2009 Jan 21;301(3):277.
6. Hess S, Abbeddou S, Yakes E, Some J, Prado E, Ouedraogo Z, et al. Small-quantity lipid-based nutrient supplements together with malaria and diarrhea treatment improve growth and neurobehavioral development in young Burkinabe children. In: International Congres of Nutrition 2013. p. 2013.
7. Huybregts L, Houngbé F, Salpéteur C, Brown R, Roberfroid D, Ait-Aissa M, et al. The Effect of Adding Ready-to-Use Supplementary Food to a General Food Distribution on Child Nutritional Status and Morbidity: A Cluster-Randomized Controlled Trial. PLoS Med. 2012
Sep;9(9):e1001313.
8. Soofi S, Cousens S, Iqbal SP, Akhund T, Khan J, Ahmed I, et al. Effect of provision of daily zinc and iron with several micronutrients on growth and morbidity among young children in Pakistan: a cluster-randomised trial. Lancet. 2013 Jul 6;382(9886):29–40.
9. Goulet O, Lebenthal E, Branski D, Jones PJH. Nutritional solutions to major public health problems of preschool children: how to optimise growth and development. J Pediatr Gastroenterol Nutr. 2006;43(Supplement 3):S1–3.
10. Rowland MG, Rowland SG, Cole TJ. Impact of infection on the growth of children from 0 to 2 years in an urban West African community. Am J Clin Nutr. Am Soc Nutrition; 1988;47(1):134– 8.
11. Scrimshaw NS, Tailor CE, Gordon JE. Interactions of nutrition and infection. WHO monograph series. Geneva: WHO; 1968. 461-472 p.
12. Brown KH. Diarrhea and Malnutrition. J Nutr. 2003;133:328–32.
13. Calder PC. Feeding the immune system. In: Proc Nutr Soc. 2013. p. 299–309.
14. Crane RJ, Jones KDJ, Berkley J a. Environmental Enteric Dysfunction: An Overview. Food Nutr Bull. 2015 Mar 24;36(1 suppl1):S76–87.
15. Humphrey JH. Child undernutrition, tropical enteropathy, toilets, and handwashing. Lancet. Elsevier Ltd; 2009;374(9694):1032–5.
16. Rytter MJH, Kolte L, Briend A, Friis H, Christensen VB. The Immune System in Children with Malnutrition—A Systematic Review. Akiyama T, editor. PLoS One. 2014 Aug 25;9(8):e105017. 17. IFPRI. Global nutrition report; Actions and accountability; to accelerate the world’s progress on
nutrition. Washington DC.; 2014.
18. WHO. Food , Water and Family Health : A Manual for Community Educators [Internet]. Geneva: WHO, UNDP; 1994. Available from:
http://apps.who.int/iris/bitstream/10665/62963/1/WHO_HEP_94.2.pdf?ua=1
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20. Dewey KG. Guiding Principles for Feeding non-Breastfed children 6-24 months of age[Internet]. WHO; 2005. Available from:
http://apps.who.int/iris/bitstream/10665/43281/1/9241593431.pdf?ua=1&ua=1
21. Unicef Supply Division. Multiple Micronutrient Powder Supply & Outlook [Internet]. 2016. Available from:
http://www.unicef.org/supply/files/Micro_Nutrient_Powder_-_September_2016(1).pdf
22. UNICEF. The state of worlds children 2008; Child survival [Internet]. 2008. Available from: http://www.unicef.org/sowc08/docs/sowc08.pdf
23. Hoare S, Poppitt SD, Prentice AM, Weaver LT. Dietary supplementation and rapid catch-up growth after acute diarrhoea in childhood. Br J Nutr. 1996 Oct 9;76(4):479.
24. Sowunmi A, Gbotosho GO, Adedeji A a, Fateye B a, Sabitu MF, Happi CT, et al. Effects of acute Plasmodium falciparum malaria on body weight in children in an endemic area. Parasitol Res. 2007 Jul;101(2):343–9.
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2. INTERACTION NUTRITION AND INFECTION
2.1 Introduction
It has been suggested that nutritional status and infection are interrelated, but the scientific search to discover the nature of this relationship did only increase until the 1960’s. The first paragraph of this chapter details the historical perspective, followed by an overview on the role of nutrients in immunity and the role of infections on nutritional status. Finally the effect of supplementation on prevention of malnutrition and morbidity in ill children status is explored.
2.2 Historical perspective
It has long been observed that malnourished children have a higher risk on severe outcome of morbidity and that ill children have a higher risk on malnutrition. In 1968, almost half a century ago, the World Health Organisation (WHO) published a monograph on the influence of infections on nutritional state and vice versa. This paper was the first to suggest a synergistic relation between malnutrition and infection, but not much was known about its mechanisms (1).
About a decade later, in 1976, scientists further discussed this relationship (2). In this workshop, participants discussed prevention by nutrition-related interventions such as fortification of the diet with proteins and related improvements in agriculture (3). Prof. Whitehead presented clear correlations between weight loss and gastroenteritis and malaria. The participants of the workshop observed that a child’s protein requirement was large during the catch-up growth period after an infection (higher protein-energy ratio), but when given enough food, the children could reach a catch-up growth rate up to 4 times the normal growth rate (4). It was also recognised that infections increase nutritional needs through increased metabolism and that these needs should be met in order to reduce the risk on malnutrition. In addition, the crucial importance of health care coverage in preventing malnutrition was recognised.
12
Not all researchers found a negative relation between diarrhoea and weight loss. In Bangladesh in 1989, Briend et al. did see weight loss after diarrhoea episodes, though this was temporary as it was not apparent a few weeks later (7),In 1989, Tomkins and Watson published a review of the synergistic relationship between nutritional status and infectious disease. Protein-energy malnutrition has a depressing effect on the immune system; even mild degrees of malnutrition begin to adversely affect immune-competence, hence morbidity and mortality. On the other hand, infections anorexia, changes in metabolism, mal-absorption, as well as behavioural changes affecting feeding practices; and lead to malnutrition in the context of limited nutritional reserves. This review also discussed micronutrients, such as zinc supplementation, and the dilemma of iron deficiency and supplementation. It further emphasised the twin goals of nutrition improvement and control of infection in primary health care programmes (8).
Later research showed that food enriched with proteins increased weight gain in children who had shigellosis (9). Furthermore, fortified porridge was found to increase weight gain in children with diarrhoea (10).
In 1997, Scrimshaw et al. gave an overview on synergism of nutrition, infection, and immunity (11). Since then, research advanced on the mechanisms of immune systems in general, which led to an update of the overview in 2003 (12). In the years after, research focused on the role of individual micronutrient deficiencies – such as zinc and vitamin A – in decreased immunity, and how supplementation with these micronutrients could prevent illness, reduce the severity of illness or decrease morbidity and mortality (13–15).
2.3 Role of nutrients in the immune system
13
2.3.1 Barrier functions of the gut mucosa
The epithelial layers, mucosa, are the first barrier against unwanted particles like in the respiratory system and the guts; the integrity of these should be maintained, and if necessary repaired.
One of the most important barriers is the gut mucosa. The barrier formed by the skin and mucosal surfaces is considered the first-line defence of the immune system, upheld by the physical integrity of the epithelia, anti-microbial factors in secretions (e.g. lysozyme, secretory IgA and gastric acidity) and the commensal bacterial flora (16,17). The gut mucosa also regulates important functions such as intestinal digestion, secretion and absorption of electrolytes, water, and nutrients.
The gut barriers integrity is enforced by antioxidants and a lack of anti-oxidants and other nutrients like vitamin A, zinc, glutamine and arginine are associated with intestinal inflammation, barrier disruption and malabsorption (18–20).
An impaired barrier function reduces not only absorption but it also triggers chronic inflammation reaction as luminal contents (not necessarily pathogens) crossing the gut wall activates the immune system (16,18).
Therefore chronic and repeated infection high frequency of intestinal infection can trigger chronic inflammation reaction and reduction of nutrient absorption and appetite. This refers to the syndrome of environmental enteric dysfunction (EED). EED is an incompletely defined inflammatory disorder in the gut, as a result of recurring infections in the small intestine via the oral-faecal ingestion route. A constant exposure to pathogenic bacteria in the small intestine induces inflammatory processes, degeneration of the intestinal mucosa layers and a constantly activated immune system. It is associated with poor appetite, a reduced absorptive capacity and growth failure. The exact mechanisms are not known, but a lack of certain micronutrients (zinc, vitamin A, essential fatty acids) and poor sanitation seem to play a role (18,21).
2.3.2 The role of nutrients in the immune response
14
The immune system needs to be activated by signalling proteins, cytokines, enzymes and hormones that need proteins and other mediators such as prostaglandins and leukotrienes.This leads to acute replication and multiplication of cells needed for the immune system, for maintaining the barrier function, and for regulatory systems. This requires many nutrients such as nucleotides, amino acids fatty acids, phosphate, Fe, Folic Acid, Mg, cholesterol, vitamins A, B’s and D. Some of these can be retrieved from body stores and some should come from the diet such as essential fatty acids (PUFA’s) and essential amino acids (17).
A part of acute immune response is the oxidative burst that refers to the release of highly reactive oxidative particles that should damage the pathogen. However, this highly reactive particles can also be damaging to host tissue as well, therefore nutrients are needed to neutralise this mechanism including anti-oxidants but also glucose, oxygen, vitamins E and C, glutathione, enzymes like glutathione peroxidases and co-factors like Mn, Cu, Zn, Fe, Se (17).
Finally an activated immune system leads to high metabolic activity needing energy. Nutrients are needed as energy source (glucose, amino-acids, and fatty acids), as co-enzymes (vitamins) and as electron carriers (Fe and Cu) (17).
Several studies show that there are a number of other nutrients whose availability at an appropriate level is essential for the immune response to operate effectively. These nutrients include essential amino acids, the essential fatty acid linoleic acid, vitamin A, folic acid, vitamin B6, vitamin B12, vitamin C, vitamins E, Zn, Cu, Fe and Se.
15
Zinc deficiency in animals is associated with a wide range of immune system impairments, e.g. decreasing the number of nucleated cells and the number and proportion of cells which are lymphoid precursors. Low plasma zinc levels have shown to predict the subsequent development of lower respiratory tract infections (LRTI) and diarrhoea. Correspondingly there are now a number of studies showing that zinc supplementation decreases the incidence of childhood diarrhoea and respiratory illness (23).Several macronutrients, such as lipids, carbohydrates and proteins, have also shown to be important; either as a building block for immune cells, or by delivering energy (11). For example, n-3
Polyunsaturated fatty acids (PUFA) are key components due to their anti-inflammatory properties and their role in maintaining the integrity of cell walls (22).
2.4 Effect of infection on nutritional status
2.4.1 BackgroundInfections increase the demand for many nutrients for the immune system, increased metabolism and losses while supply is limited by anorexia and malabsorption (24,25). An adequate and balanced availability of a mix of nutrients is essential for a well-functioning immune system. As the external supply of nutrients is compromised (anorexia), nutrient stores are used and supply of nutrients for the immune system often receive priority above the needs for normal growth and metabolism (11) (26). When these systems are not adequate, catabolism of tissues is the last option to supply nutrients for the immune system, resulting in weight loss.
The key of weight loss is anorexia and decreased appetite as this is hampering mitigation of the losses and increased demands. Anorexia is caused by the products of the immune system like microbial products cytokines and tumour necrosis factor (TNF) (27,28). Possibly nutrients that play a role in regulating appetite could mitigate anorexia during convalesce (29).
16
infection is cured. Moreover, it is not clear whether increased feeding alters or hampers the recovery of infection as food deprivation may have a function in recovery (30).Nevertheless the period of anorexia should be as short as possible, in order to limit weight loss. Prompt treatment of infection could also mitigate anorexia. Lack of proper recovery after an infectious disease (convalescence) makes a child also more susceptible to weight loss and also to infections such as diarrhoea and malaria (6,31,32).
2.4.2 Weight loss associated with infection
Infections are associated with weight loss on the short term but the extent can vary extensively and also there are some inconsistencies in the literature.
Several authors report that diarrhoea is associated with weight loss (5,6,8,33–35). Research in Bangladesh showed that children with diarrhoea suffered from immediate weight loss;
but this was mostly is temporary weight loss; most children regained their previous weight within a couple of weeks(36). Moreover, it has been reported that after improvement of the burden of diarrhoea in Gambia over a period 15 years, there was no improvement of growth (37).It is also observed that the weight loss after an diarrhoea is caught up after recovery, also without any supplementation although the period needed for recovery was longer when not supplemented (10,35,36).
Jones et al. state that catch up growth might be seen between infectious episodes, provided adequate nutritional intake is maintained and the interval between infections is long enough (38). This underlines that convalescence and weight gain after an illness is complex and depends on several variables such as other illnesses, incidence of morbidity, health care and diet.
17
Depending on the illness, the period between illnesses and the nutritional supply of ill children catch up growth can be seen. But children who have frequently infections and their nutrition supply is not adequate might lack this catch up growth. As most studies report on the average changes in weight, these children might be overlooked. Children with weight loss are averaged with children with high catch up growth while the proportion of children that is not showing sufficient catch up growth and who develop malnutrition is more of concern.2.5 Effect of supplementation on nutritional state of ill children
Infection predisposes for malnutrition, while malnutrition increases the risk of a severe outcome of infection. A review shows that the risk of mortality related to diarrhoea, pneumonia, malaria and measles is increased with a factor 3 to 5 when a child is moderately malnourished; the factor doubles for severe malnutrition (42).
Nutritional deficiencies should be corrected. However, it is not clear whether supplementation during convalescence of illness enhances recovery from weight loss and infection for non-malnourished children. Of specific interest are moderately malnourished children who have also low nutrient stores which will be depleted during an infection. Nutritional deficiencies have a negative influence on immunity, as shown in several studies, and these deficiencies should be corrected. In children with a marginal nutritional state, a sub-clinical deficiency of particular nutrients can be induced by infections. A well-known example is measles inducing Vitamin A deficiency, which results in xeropthalmia (11).
18
Although there is potential for a dietary intervention with polyunsaturated fatty acids to combat the anorexia during infection, this may be difficult as dependent observations show different effects of polyunsaturated fatty acids on cytokine production (27).The other potential route to enhanced weight gain and improved nutritional state is by shortening the period of infection and strengthening immunity. A shortened period of convalescence after an illness, - when appetite returns and metabolism returns to a normal - state could result in an overall improved nutritional status, as weight loss is limited and returning to a previous weight takes less time. A shortened convalescence period also means that the period in which immunity is reduced is shorter; this could lead to a lower frequency of illnesses and thus a lower frequency of weight loss episodes. This reasoning has not yet been extensively tested, but there is some research indicating that supplementation during illness potentially reduces the convalescence time and increases weight gain. As reported by Scrimshaw, Martorell et al. found a decrease in the duration of diarrhoea when supplemented with a high protein supplement (12). Hoare et al. found that weight loss after acute diarrhoea was corrected by providing a supplement enriched with vitamins and minerals for two weeks after an episode of diarrhoea, while no significant weight gain occurred during non-intervention periods (10).
These investigations show mixed results; possibly the effect of supplementation to ill children (and children in general) is dependent on environmental factors as food availability and level of morbidity and thus the effect will differ between areas.
Weight loss during infections is caused primarily by anorexia related to the infection. The infection can create shortages of the micronutrients that regulate anorexia, which may induce anorexia or ensure that it persists over time, as micronutrients play also a role in regulation of appetite. Therefore, supplementation with micronutrients alone after an infection might increase appetite and might mitigate weight loss in ill children.
19
ranging from 8 to 52 weeks (47). However, a more recent meta-analysis only should an increase in height, and the change was small (48). In addition, supplementation with micronutrients in ill children alone has hardly been studied.A deficiency in a few micronutrients or even in one nutrient could be the limiting factor for resuming appetite and growth after an infection, as many micronutrients play a role in the immune system, growth, and recovery. Therefore, nutritional fortification with multiple micronutrients were tried out and were found to reduce the incidence of diarrhoea (49). Multi-micronutrients in general had some effect on linear growth, but the effect was small (48,50,51). Veenemans et al. studied the effect of multi- micronutrients with various quantities of zinc on the incidence of malaria, but no effect on the incidence of malaria or other diseases was found (52,53).
Several programmes have distributed lipid-based supplements (LNS), but the reports on effects on morbidity or weight gain are mixed (54–57). However, there is a strong trend observed that LNS supplementation decreases mortality (54).
One can conclude that supplementation with a combination of micronutrients or multi-micronutrients with or without food is promising, but results of research is mixed and foremost lacking.
2.6 Effect of supplementation on infection
Nutrients can help decrease the duration and severity of infections, and therefore improve nutritional outcomes. Several micronutrients have been proven to reduce the severity and frequency of illness. Studies have shown that zinc supplementation during diarrhoea episodes reduces the severity and frequency of both diarrhoea and lower respiratory tract infections (14). Vitamin A supplementation has been shown to reduce mortality in general (58).
20
In the aforementioned DRC study (46), the children who received 2 weeks of RUTF were significantly less likely to report coughing at 14 days after beginning the supplementation with RUTF (AOR: 2.85, P=0.005), suggesting disease can be reduced with supplementation. Most studies are not seeing an effect of supplementation with LNS to a general population of children on the incidence of illnesses (54,57). However, an supplementation in Chad saw a decrease in morbidity (55). Also, there is a strong trend observed that LNS supplementation decreases mortality (54).There is no clear evidence of the effect of supplementation with multi-micronutrients or LNS on morbidity to children from a general population. There is no evidence of the effect of supplementation on morbidity to ill children.
2.7 Conclusion
Although the science of immunology has advanced rapidly, there is not much insight yet into the role of nutrition in recovery from an infection. A relationship exists and, regardless of the exact mechanisms, the effect of supplementation in the vicious cycle of malnutrition and diseases could be two-fold: reducing weight loss during illness and reducing the frequency of illness.
To date, there has been no evidence to show the impact of nutritional supplementation on incidence of malnutrition or morbidity amongst routine users of outpatient clinics. In addition, there is limited information on how to roll out such an intervention, including which populations to target, the composition suitable for ill children and the preferred form of delivering such supplements.
Above all, these studies are implemented in the general population of children, not specifically in ill children to prevent further decrease of the nutritional state. Yet it is still the general expectation that good food during convalescence of an illness improves recovery. The lack of evidence of the effectiveness of nutritional supplementation in ill children warrants further investigation before launching large supplementation programmes.
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Key messages – Interaction Nutrition and Infection
In the 60’s it was recognised that infection increases the risk on malnutrition and
malnutrition increases the risk on morbidity and worse outcome of disease.
Initially malnutrition in ill children was considered to be related to a lack of proteins; later
more attention was given to the relationship between individual micronutrients like
vitamin A, zinc and selenium and the immune system.
Nutrients are needed to maintain integrity of barriers against pathogens, specifically the
mucosa of the intestines.
An activated immune system requires higher quantities of nutrients, eg. glutamine, vitamin
B, zinc, for maintaining cell integrity, immune cell production and normal metabolic
processes.
Infections are associated with malabsorption and decreased appetite what hampers to
meeting the increased needs of nutrients.
22
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3. STUDY DESCRIPTION
3.1 Introduction
The previous chapter gives an overview of how infection and malnutrition are related. A low nutritional status impairs the integrity of barriers in the body against pathogens, it lowers immunity by lack of building stones and regulators, and a low nutritional status can impair the energy metabolism that is activated during an immune response. An infection increases the demand for nutrients needed for the immune reaction while the supply is decreased by anorexia associated with infections.
Literature reporting on the effect on malnutrition and morbidity of supplementation with micronutrients or Lipid Based Nutrients (LNS) to children in a general population gave mixed results. Little is known about the effectiveness of supplementation on malnutrition and morbidity in non-severe ill (and not malnourished) children. The objective of the underlying study is to inform program strategies whether nutritional supplementation of non-severely ill children presenting at the medical outpatient clinic can prevent malnutrition.
3.2 Study design
The aim of the study is to determine whether 14 days nutritional supplementation with Ready to Use Therapeutic Food (RUTF) or multi-micronutrient powder (MNP) reduces the incidence of acute malnutrition at 6 months of follow-up among children with a non-severe illness. Diarrhoea, lower respiratory tract infections (LRTI), and malaria were chosen as the study diseases as these are the three main causes of death in the age group six months to five years (1).
To move away of observational reports Médecins Sans Frontières (MSF) conducted three randomised controlled trials; one pilot and two similar larger studies.
non-28
random assignment), which limit confidence in the conclusions (2–5). Also, there are hardly any studies published on supplementation of ill children; those available had small samples sizes (6–8). In order to move away from descriptive studies which produce limited evidence, we conducted three randomised controlled trials; one pilot and two similar larger studies.We studied the effectiveness of a nutritional supplementation in circumstances where the treatment usually would be given following routine and standard care and usual outcomes, as the intention is that, if supplementation to ill children was found to be effective in preventing malnutrition, to implement nutritional supplementation in the usual routine outpatient clinics. We did not intent to study the efficacy (the result of supplementation under ideal conditions) nor the efficiency (cost in resources, or time) of supplementation in relation to malnutrition (9,10).
The first trial in Dubié, DRC, was a pilot trial to test the design and feasibility of the study and to find out whether such a study gives meaningful results.
Children with non-severe malaria were assigned to two arms of 80 participants each: one group receiving 1 RUTF per day for 2 weeks and a control group. The follow-up period was one month (11). Building on this experience, two other studies were implemented in very different settings: the resource-poor Kaabong (Uganda) and Goronyo (Nigeria), a generally wealthier area yet facing a high morbidity (12,13). In these two studies, two supplements were tested with children having one of three diseases.
Children presenting at the clinic with non-severe malaria, LRTI, and/or diarrhoea were included in the study. The participants were randomly assigned to one of the three study arms: control, RUTF, or multi-micronutrients. The participants received 1 sachet of RUTF (92 grams) per day for 14 days, 2 sachets multi-micronutrients per day for 14 days or no supplement. The participants had six monthly follow-up appointments after inclusion.
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Table 1: Summary of the three Randomised Controlled TrialsLocation Study arms Disease Target group < 5 years
Sample size Duration observation Study period Dubié, DRC RUTF Control Malaria Non-malnourished 160 28 days January – February 2009 Kaabong, Uganda RUTF MNP Control Malaria LRTI Diarrhoea Non-malnourished 2202 168 days April 2011 - September 2012 Goronyo, Nigeria RUTF MNP Control Malaria LRTI Diarrhoea Non-malnourished and moderately malnourished 2213 168 days February 2012 - February 2013
An overview of the methods used in the pilot trial in Dubié and in the two large trials in Kaabong and Goronyo are presented below. The studies are described in detail in chapter 4 of this thesis, which includes the full publications (11–13). Further details can be accessed in the research protocols (14– 16), research reports (17–19) and the Statistical Analysis Plans (20,21).
3.3 Settings
Dubié
The pilot study was implemented in Dubié, a village in the Katanga region of the Democratic Republic of the Congo (DRC) that shortly before the trial gave home to displaced people. At the time of the trial, the conflict had been resolved, the displaced had returned home and Dubié was once again a peaceful and quiet small town in a rather inaccessible part of DRC. Dubié is situated in a rural area in a forest, where people make their living from fishing, agriculture, small trade and what the forest brings. The diet generally consists of porridge made from maize, sorghum or cassava; beans or dried fish with vegetable sauce; and sometimes (bush) meat. One of the prevailing morbidities is malaria, an illness that is generally associated with malnutrition.
Kaabong
30
assistance (22,23). Food security is fragile as a result of poverty and cycles of drought and floods. In 2009, 58.4% of the Kaabong population was considered to be food insecure (23). The food insecurity was exacerbated by ongoing conflict that ended during the implementation of the study in May 2011. During the study period, overall household food security showed improvement in the entire region that resulted in a prevalence of acute malnutrition among children was 8.5%; of this, 2% was severe acute malnutrition in May 2011 in Kaabong (24). In 2014, the UN World Food Program concluded that the poor nutritional status of children in Karamoja was not necessarily the result of a lack of food, but rather the result of a combination of high incidence of illness (fever, malaria, and diarrhoea), poor sanitation facilities, lack of vitamin A supplementation, and a poor dietary diversity (25).Kaabong was chosen as a research area because of its combination of poor food security, morbidity as a cause of malnutrition, and a low dietary quality. The involvement of MSF in Kaabong started in 2007 with support to mother and child care, including a nutrition treatment programme. In the period of the study, these activities were phased out as the internal conflict was over and the Ministry of Health could provide the health care. In the study period a supplementary feeding programme to treat moderately malnourished children (supported by World Vision International) and a therapeutic feeding programme to treat severely malnourished children (supported by Action Contre le Faim) were present.
Goronyo
Goronyo is a regional town in Goronyo Local Government Area (LGA; comparable with district) in Sokoto State, in the northwest of Nigeria. Goronyo LGA is primarily dependent on agriculture (including irrigated agriculture) and animal husbandry, with also income derived from trade and small-scale manufacturing. A variety of crops are grown, including millet, sorghum, rice, maize, groundnuts, cowpeas, okra, onions, spinach, and tomatoes (26). The climate has one rainy season from May to October, which is also the traditional hunger season and malaria season, while from January to June it can be very hot.
31
supply, hygiene, and sanitation; inadequate (health) education; and a poor understanding of the importance of food quality, quantity, and diversity (27). A high proportion of children under 5 years were not consuming protein-rich and nutrient-dense foods on a daily basis; for example, only 35% of diets included milk and dairy products, and only 8% of diets included fish and poultry (28).In March 2009 (during the hot, dry season), there was a global acute malnutrition (GAM) prevalence of 14.8% and a SAM prevalence of 4.9%; while in March 2010, the GAM and SAM prevalence was 11.5% and 2.6% respectively (28,29). This chronic existence of malnutrition is linked to a marginal economic situation and under-resourced health care system, combined with gender inequality and poor weaning practices in northern Nigeria (30).
The 2009 survey found that 51% of the children reported having an illness (including fever, diarrhoea, and cough) at some time during the previous 14 days, suggesting a high burden of disease that likely exacerbates an already precarious problem of malnutrition. The prevalence of malnutrition among those children who reported an illness in the previous 14 days was 23%, compared with 7% among non-sick children (p < 0.001), illustrating a relation between malnutrition and disease (28).
Because of the high frequency of severe malnutrition among children and its contribution to high morbidity, this site was chosen to investigate whether nutritional supplementation to ill children would significantly decrease the incidence of malnutrition.
Médecins sans Frontières-Operational Centre Amsterdam (MSF-OCA) has provided medical support to Sokoto State Hospital Goronyo since 2008. The activities included outpatient clinics and hospital-based medical care for children, including a therapeutic feeding programme with an inpatient clinic and four outpatient facilities. In 2012, MSF treated 9,505 children for severe malnutrition in Goronyo. MSF withdrew from Goronyo in February 2013 due to security-related reasons.
