Delaying Iron Therapy by 28 Days Is Associated with Improved Long‐Term Iron Status and Equivalent Hemoglobin in Children with Severe Malaria and Iron Deficiency

Abstract

BackgroundIron therapy started concurrently with antimalarial treatment in children with severe malaria and iron deficiency may not be well absorbed due to inflammation‐induced impairment of iron absorption and trapping of iron in reticuloendothelial stores under the influence of the hepatic protein hepcidin. Malaria‐induced increases in hepcidin concentration normalize after approximately 4 weeks.ObjectiveWe aimed: 1) To determine if iron therapy started concurrently with vs. 28 days after antimalarial treatment is associated with improvements in long‐term hemoglobin and iron status in children with severe malaria and iron deficiency; and 2) To establish how delayed iron affects long‐term iron and inflammatory markers in children with severe malarial anemia (SMA) vs. cerebral malaria (CM).MethodsWe enrolled Ugandan children with severe malaria (CM, n=77; SMA, n=79) and healthy community children (CC, n=83) aged 6–18 mos into a 12‐mo iron therapy study in Kampala, Uganda. Children with zinc protoporphyrin (ZPP) ≥ 80 μmol/mol heme were randomized to start a 3‐month‐course of oral iron therapy (2 mg/kg/day as ferrous sulfate) concurrently with antimalarial treatment on Day 0 (immediate group, I) or 28 days after antimalarial treatment (delayed group, D). We compared markers of iron status [hemoglobin (Hb), ferritin, soluble transferrin receptor (sTfR), hepcidin] and inflammation [C‐reactive protein (CRP)] at 6 and 12 mos follow up between the treatment groups and also among the study groups using ANOVA.ResultsAll children with severe malaria and 35/83 CC had elevated ZPP. There was no interaction between study group and treatment group for any biomarker at 6 or 12 months. At both time points, children in the I and D groups had equivalent hemoglobin, but children in the D group had significantly lower adjusted geometric mean ZPP (95% CI) concentrations [I vs. D: 6 mos: 86.7 (79.1, 95.1) vs. 75.8 (68.8, 83.4) μmol/mol heme, p=0.02; 12 mos: 84.3 (78.0, 91.0) vs. 72.7 (67.3, 78.6), p<0.01]. Children in the D group also had lower mean sTFR (95% CI) concentrations at 6 months [I vs. D: 6.0 (5.4, 6.7) vs. 5.1 (4.6, 5.7) mg/L, p=0.01) and higher mean hepcidin (95% CI) concentrations at 12 months [I vs. D 10.1 (8.3, 12.2) vs. 14.5 (11.8, 17.8) ng/mL, p<0.01]. At 6 and 12 months, children with SMA had significantly lower hemoglobin concentrations than children in the CM or CC group (pooled group effect 6 mos p=0.03; 12 mos p=0.02), higher ferritin (pooled group effect 6 & 12 mos p<0.001), and marginally higher CRP concentrations (pooled group effect 6 mos p=0.07; 12 mos p=0.08).ConclusionsDelaying iron by 28 days in children with severe malaria may improve long‐term iron status, while causing no change in hemoglobin concentrations as compared to immediate iron. The aberrations to iron metabolism in children with SMA appear to be persistent and associated with chronic inflammation, while those in children with CM are acute and rapidly reversible.Support or Funding InformationFunded by 1U01HD064698 from NIH/NICHD