Acute vs. Delayed Iron: Effect on Red Cell Iron Incorporation in Severe Malaria
Condition: Iron Deficiency; Malaria; Nutrition; Global Health
MeSH terms: Malaria; Iron Deficiencies
Study type: Interventional

Summary: 
      The purpose of this study is to determine whether iron therapy given to iron-deficient
      Ugandan children with moderate-to-severe anemia and clinical malaria is better absorbed and
      incorporated into red blood cells if it is given concurrently with antimalarial treatment on
      Day 0 (immediate group) or 4 weeks after antimalarial treatment on Day 28 (delayed group).
      Use of iron stable isotopes 57Fe and 58Fe will permit measurement of red blood cell iron
      incorporation on Day 0 and Day 28 in all children. The investigators hypothesize that red
      cell iron incorporation at the time of initial supplement administration will be greater in
      children receiving delayed vs. immediate iron (Aim 1), and children in the delayed group will
      also have greater hematological recovery on Day 56 than children in the immediate group (Aim
      2).
    

Detailed description: 
      Approximately 1 million children < 5 y living in sub-Saharan Africa die from severe anemia
      annually. This severe anemia frequently results from coexisting iron deficiency and malaria
      infection, but the standard of care, concurrent iron therapy and antimalarial treatment, has
      proven ineffective at curing the profound anemia and has promoted proliferation of the
      parasite in some studies. The pro-inflammatory immune response mounted against malaria
      down-regulates iron absorption in the gut, making provision of oral iron supplements during
      malarial infection of questionable utility. The present study proposes to use iron stable
      isotopes and a randomized design to test whether starting 4 weeks of iron therapy immediately
      after antimalarial treatment or 4 weeks later is associated with greater iron incorporation
      into red blood cells at the time of initial administration of iron therapy and improved
      long-term hematological recovery. One hundred severely anemic (hemoglobin 5-9.9 g/dL) Ugandan
      children 6-59 mos with clinical signs of malaria who present to the Pediatric Acute Care Ward
      of Mulago Hospital in Kampala, Uganda, will be randomized to start iron immediately after
      antimalarial treatment on Day 0 (immediate group) or 4 weeks later on Day 28 (delayed group).
      Children will be assessed at the hospital on Day 0, Day 28 and Day 56 and will receive
      bi-weekly home visits for the 56-day study duration. The specific aims and corresponding
      hypotheses of the proposed study are:

      Aim 1: Identify the sequencing of antimalarial treatment and iron therapy that results in the
      greatest red cell iron incorporation at the time of initial iron supplement administration.
      The working hypothesis is that red cell iron incorporation will be greater at the time of
      initial supplement administration in children starting iron 4 weeks after antimalarial
      treatment (delayed group) compared to children starting iron concurrently with antimalarial
      treatment (immediate group), due to more complete parasite clearance and resolution of
      inflammation, permitting better iron uptake, distribution, and utilization.

      Aim 2: Determine whether long-term hematological recovery is impacted by immediate vs.
      delayed iron. The working hypothesis is that delayed iron treatment will be associated with
      greater hemoglobin and improved iron status at Day 56 compared to immediate treatment due to
      more complete parasite clearance and consequent improved iron absorption and use in the
      delayed group.

      The results of this study will establish a physiologically-based framework for the optimal
      timing of antimalarial treatment and iron therapy upon which future interventions aimed at
      improving iron status in malaria-endemic regions can be built, thus helping to reduce the
      morbidity and mortality and ensure the full neurobehavioral development of the millions of
      severely anemic children suffering from iron-deficiency and malaria.
    

Intervention name(s): Immediate iron; Delayed iron
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Children who start 4 weeks of iron therapy on Day 0; Children who start 4 weeks of iron therapy on Day 28
Other intervention name(s): Ferrous sulfate syrup
Intervention MeSH terms: Iron
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment