Provision of sufficient iron for brain development in children living in malaria-endemic
areas while also protecting them from infection is an unachieved public health goal for
>10 years. The 2006 landmark study on malaria-endemic Pemba Island brought the
complicated relationship between iron and malaria to the world stage by reporting
universal prophylactic iron supplementation increases the risk of child hospitalization
and death. Treating iron deficiency in children who have malaria is also an unsolved
challenge. In sub-Saharan Africa, iron deficiency and malaria coexist, frequently causing
a multifactorial anemia that is a primary cause of hospitalization and mortality in
children <5 y. The current World Health Organization standard-of-care regimen of
concurrent treatment with antimalarial medication and iron therapy has been unsuccessful,
with frequent reports of subsequent infection, including malaria, persistent iron
deficiency, and unresolved anemia.
One solution to effectively treat coexisting malaria and iron deficiency is to stagger
interventions, treating malaria first and delaying iron. The inflammatory response
against malaria induces high levels of the protein hepcidin, which reduces intestinal
iron absorption and prohibits release of iron from reticulo-endothelial cells. Iron given
orally during or shortly after a malaria episode is thus not well absorbed or distributed
to red blood cells or the brain. Moreover, unabsorbed iron in the gut may promote the
growth of pathogenic bacteria, potentially leading to subsequent infectious morbidity. A
pilot study was recently completed in Ugandan children with malaria and iron deficiency
that used iron stable isotopes to test whether iron given 28 days after (delayed group)
or concurrently with (immediate group) antimalarial treatment was better incorporated
into red blood cells (1R03HD074262). It was found that delayed iron was incorporated
twice as well as immediate iron and that iron status at 56 days was similar between
groups. An important finding was that children in the immediate group had a higher
incidence of infections in the 56-day follow-up period. In this application, the team
proposes a large-scale, randomized clinical trial with 12 months follow up powered to
capture long-term differences in iron status, morbidity, and neurobehavioral development
as a function of immediate or delayed iron following treatment for malaria and iron
deficiency. The gut microbiome will be analyzed to elucidate a mechanism of any
differences in incidence of infections.
One long-term goal is to develop safe and effective strategies for managing concurrent
malaria and iron deficiency in children, with reduction of infections and optimization of
neurobehavioral development representing successful outcomes. The objective of this
application is to conduct a placebo-controlled, randomized clinical trial to determine
whether iron therapy begun with vs. 28 days after antimalarial treatment in Ugandan
children 6-48 months with malaria and iron deficiency leads to better iron status, fewer
infections, and better neurobehavioral development after 12 months. The central
hypothesis is that better iron incorporation and lower incidence of infectious illness
observed with delayed iron in our short-term, physiology-focused R03 study will translate
into better long-term iron status, fewer episodes of infection, and better
neurobehavioral outcomes after 12 months. The rationale is that this study will determine
if staggering antimalarial treatment and iron therapy protects against immediate
morbidity while also optimizing long-term neurobehavioral development. The Specific Aims
are:
Aim 1: Establish the effect of immediate vs. delayed iron treatment on long-term iron
status.
It is hypothesized that delayed iron will result in better iron status 6 and 12 months
after treatment for malaria due to better initial iron absorption and utilization as
compared to the immediate iron group.
Aim 2: Determine the effect of delayed iron treatment on the incidence of infectious
illness.
It is hypothesized that the better absorbed delayed iron will result in fewer infections
in the 6 and 12 months after treatment for malaria due, in part, to a less pathogenic
intestinal microbiome profile.
Aim 3: Establish the effect of delayed iron treatment on neurobehavioral development.
It is hypothesized that delayed iron will result in better neurobehavioral outcomes (as
assessed by standardized cognitive and behavioral tests) due to better iron absorption
and utilization.
Anticipated Impact: Untreated iron deficiency may protect a child from malaria and other
infections, but the consequent potentially permanent damage to the developing brain is an
unacceptable alternative. Establishment of methods to effectively ensure brain iron
health while protecting the child from infection will promote attainment of full
cognitive and behavioral development for tens of millions of children worldwide suffering
from malaria and iron deficiency.