Moderate acute malnutrition (MAM) is common among children worldwide, with a prevalence
of 50M and an annual incidence likely 3-5x this number. It is defined by mid-upper arm
circumference (MUAC) ≥ 11.5 cm and < 12.5 cm or weight-for-length (WLZ) z-score ≥ -3 and
< -2. MAM increases a child's risk of deterioration to severe acute malnutrition (SAM),
stunting, death, infectious illnesses, and impaired cognitive development. In Malawi, in
the year following MAM treatment, nearly one-third of children will face a repeat episode
of MAM, 7-10% will develop SAM, and 4% will die. There is much progress yet to be made
toward improving rates of recovery and preventing the worst outcomes for the millions of
children suffering from MAM each year.
One potential avenue for improving outcomes in MAM is modification of supplementary foods
used for its treatment. Choline is an essential nutrient for human health and
development, evidence for which is largely drawn from animal models of choline deficiency
in which various somatic and cognitive developmental abnormalities are found. Of the
trials that have evaluated choline supplementation in humans, many have focused on the
role of choline in brain development and, specifically, how it may help foster improved
cognitive development in the setting of various insults, such as fetal alcohol syndrome.
There is also a growing body of evidence describing the many roles choline plays outside
of the brain, including in the etiology of malnutrition. Recently, choline deficiency has
been implicated in the development of kwashiorkor, an enigmatic form of severe acute
malnutrition characterized by pitting edema, dermatitis, hair color changes, and fatty
liver disease with inflammation. Animal models of choline deficiency display a remarkably
similar phenotype to kwashiorkor. When choline has been given to mice, rats, and dogs
with kwashiorkor-like malnutrition, the hallmark features of the disease have resolved.
This line of evidence suggests a causal role for choline deficiency in kwashiorkor,
proposed mechanisms for which include choline's functions in 1-carbon metabolism, sulfur
amino acid recycling, and sparing of the essential amino acid methionine. Methionine is
the key deficient amino acid in maize-predominant diets, such as are consumed in Malawi.
Choline is most abundant in animal-source foods, precisely those which are lacking in the
diets of many rural Malawian children. Kwashiorkor accounts for more than one-third of
SAM in Malawi in children under 5 years of age and 80% of MAM deterioration to SAM. If
the addition of choline to supplementary foods were demonstrated to reduce deterioration
to SAM among children with MAM and thereby promote recovery, this would represent an
important advance in MAM treatment.
Despite the data supporting choline's essential role in human health and emerging data on
its potential therapeutic role in malnutrition, there are no specifications for choline
content in food aid products. Common MAM treatment options, such as corn-soy-blend plus
and RUSF contain 50-70mg choline, approximately one-third of the 150-200mg recommended
for well children 6mo-3y of age. This does not account for the likely increased demand
for choline in the setting of malnutrition.
This will be an individually randomized, investigator-blinded, controlled clinical trial.
This trial will be conducted at 10 rural sites in southern Malawi where the co-Principal
Investigator, Mark Manary, has run malnutrition treatment clinics for over 15 years. The
study will include 1500 children (750 per group) 6-59 months of age with uncomplicated
MAM, as defined by mid-upper arm circumference (MUAC) ≥ 11.5 cm and < 12.5 cm and/or
weight-for-length z-score (WLZ) ≥ -3 and < -2. Exclusion criteria will be presence of
nutritional edema, features of complicated MAM, such as mental status changes or
breathing issues, as well as participation in a separate feeding program, known allergy
to study food ingredient, intention to move away from catchment area within 3 months,
developmental delay, or presence of a chronic severe medical condition such as congenital
heart disease. Those who wish to take part will undergo randomization, wherein they will
remove a single small opaque envelope from a larger opaque envelope and open it,
revealing a colored sticker that will correspond to their study group. Caregivers will
receive nutrition counselling, complete questionnaires pertaining to demographic, health
history/symptoms, and socioeconomic information, and be provided with a two-week supply
of their allotted study food for their child. Participants will receive approximately 500
Kcal/day of either C-RUSF or RUSF until they reach a clinical outcome (i.e., graduate,
deteriorate to SAM, fail/remain MAM, transfer to hospital, death, default) or for a
maximum of 12 weeks. They will be asked to return to clinic fortnightly for re-assessment
of anthropometry, illness symptoms, and re-provision of supplementary food until they
reach a study outcome. Participants will undergo MDAT testing at time of MAM outcome as
well as 5-7 months after MAM outcome to undergo repeat MDAT testing. A randomly chosen
subset of participants will undergo blood spot collection at time of MAM outcome.