Delayed iron improves iron status without altering malaria risk in severe malarial anemia

Abstract

Background: WHO guidelines recommend concurrent iron and antimalarial treatment in children with malaria and iron deficiency, but iron may not be well absorbed or utilized during a malaria episode.

Objectives: We aimed to determine whether starting iron 28 d after antimalarial treatment in children with severe malaria and iron deficiency would improve iron status and lower malaria risk.

Methods: We conducted a randomized clinical trial on the effect of immediate compared with delayed iron treatment in Ugandan children 18 mo-5 y of age with 2 forms of severe malaria: cerebral malaria (CM; n = 79) or severe malarial anemia (SMA; n = 77). Asymptomatic community children (CC; n = 83) were enrolled as a comparison group. Children with iron deficiency, defined as zinc protoporphyrin (ZPP) ≥ 80 µmol/mol heme, were randomly assigned to receive a 3-mo course of daily oral ferrous sulfate (2 mg · kg-1 · d-1) either concurrently with antimalarial treatment (immediate arm) or 28 d after receiving antimalarial treatment (delayed arm). Children were followed for 12 mo.

Results: All children with CM or SMA, and 35 (42.2%) CC, were iron-deficient and were randomly assigned to immediate or delayed iron treatment. Immediate compared with delayed iron had no effect in any of the 3 study groups on the primary study outcomes (hemoglobin concentration and prevalence of ZPP ≥ 80 µmol/mol heme at 6 mo, malaria incidence over 12 mo). However, after 12 mo, children with SMA in the delayed compared with the immediate arm had a lower prevalence of iron deficiency defined by ZPP (29.4% compared with 65.6%, P = 0.006), a lower mean concentration of soluble transferrin receptor (6.1 compared with 7.8 mg/L, P = 0.03), and showed a trend toward fewer episodes of severe malaria (incidence rate ratio: 0.39; 95% CI: 0.14, 1.12).

Conclusions: In children with SMA, delayed iron treatment did not increase hemoglobin concentration, but did improve long-term iron status over 12 mo without affecting malaria incidence.This trial was registered at clinicaltrials.gov as NCT01093989.

Keywords: cerebral malaria; inflammation; iron and malaria; iron deficiency; malaria; severe malarial anemia; zinc protoporphyrin.

FIGURE 1

Study diagram. Children with severe malaria (CM or SMA) were enrolled from the Paediatric Acute Care Unit at Mulago Hospital, Kampala. Healthy CC from the same village or household compound as children with severe malaria were also enrolled. Any child with ZPP  ≥ 80 μmol/mol heme was randomly assigned to start a 3-mo course of daily oral ferrous sulfate (2 mg/kg) at baseline (immediate arm, standard of care) or 28 d later (delayed arm). Children with ZPP < 80 μmol/mol heme were not randomly assigned to receive iron. CC, community children; CM, cerebral malaria; D, delayed; I, immediate; LTF, lost to follow-up; SMA, severe malarial anemia; ZPP, zinc protoporphyrin.

FIGURE 2

Kaplan–Meier survival plots reflecting time to first malaria episodes in children with CM (n = 79) (A), SMA (n = 77) (B), and CC (n = 35) (C), who received immediate or 28-d delayed iron therapy after treatment of malaria and were followed for 12 mo (350 d). CC, community children; CM, cerebral malaria; SMA, severe malarial anemia.

FIGURE 3

Value of biomarkers or proportion by month and study group for all children who were randomly assigned to iron [all CM (n = 79), all SMA (n = 77), and CC who were iron-deficient at day 0 (n = 35)]. (A) Hemoglobin, (B) ZPP, (C) ferritin, (D) sTfR, (E) hepcidin, (F) CRP. Hemoglobin values are presented as the mean value at each time point; bars represent SD. Other biomarker values are the median value; bars represent IQR. Superscripts reflect significant differences (P < 0.05) at each time point as assessed by ANOVA for continuous outcomes, with Tukey's test for pairwise comparisons. All values aside from hemoglobin were log transformed before ANOVA. Differences in the proportion iron-deficient by ZPP (B) were determined by chi-square test. ^aDifference between SMA and CM; ^bdifference between SMA and CC; ^cdifference between CM and CC. CC, community children; CM, cerebral malaria; CRP, C-reactive protein; SMA, severe malarial anemia; sTfR, soluble transferrin receptor; ZPP, zinc protoporphyrin.