Delayed iron does not alter cognition or behavior among children with severe malaria and iron deficiency.

BACKGROUND: Malaria and iron deficiency (ID) in childhood are both associated with cognitive and behavioral dysfunction. The current standard of care for children with malaria and ID is concurrent antimalarial and iron therapy. Delaying iron therapy until inflammation subsides could increase iron absorption but also impair cognition. METHODS: In this study, Ugandan children 18 months to 5 years old with cerebral malaria (CM, n = 79), severe malarial anemia (SMA, n = 77), or community children (CC, n = 83) were enrolled and tested for ID. Children with ID were randomized to immediate vs. 28-day delayed iron therapy. Cognitive and neurobehavioral outcomes were assessed at baseline and 6 and 12 months (primary endpoint) after enrollment. RESULTS: All children with CM or SMA and 35 CC had ID (zinc protoporphyrin concentration ≥80 µmol/mol heme). No significant differences were seen at 12-month follow-up in overall cognitive ability, attention, associative memory, or behavioral outcomes between immediate and delayed iron treatment (mean difference (standard error of mean) ranged from -0.2 (0.39) to 0.98 (0.5), all P ≥ 0.06). CONCLUSIONS: Children with CM or SMA and ID who received immediate vs. delayed iron therapy had similar cognitive and neurobehavioral outcomes at 12-month follow-up. IMPACT: The optimal time to provide iron therapy in children with severe malaria is not known. The present study shows that delay of iron treatment to 28 days after the malaria episode, does not lead to worse cognitive or behavioral outcomes at 12-month follow-up. The study contributes new data to the ongoing discussion of how best to treat ID in children with severe malaria.

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

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.

Perceived benefits and risks of participation in a clinical trial for Ugandan children with sickle cell anemia.

INTRODUCTION: Understanding factors that affect the decisions of caregivers of African children to enroll their children in clinical trials would lead to more fully informed consent. METHODS: During the NOHARM study (NCT01976416), a placebo-controlled clinical trial of hydroxyurea for Ugandan children with sickle cell anemia (SCA), 206 caregivers were given a semistructured questionnaire about factors that influenced participation in the study and their perceptions of study benefits and risks. Factors were further assessed with focus group discussions. RESULTS: Caregivers identified education provided during the recruitment process (44%), the child's current poor state of health (35%), and the possibility of improvement in the child's health (16%) as their primary initial reasons for deciding to participate in the NOHARM trial. Concerns regarding the drug or participation in a research study, including the stated concern of death by several caregivers, were outweighed by the possibility of improvement in the child's health. During the study, 72% of caregivers cited improved health as an advantage of study participation, while disadvantages cited included the potential side effects of hydroxyurea, most of which did not occur during the trial. DISCUSSION: Our study findings highlight the generally poor state of health of Ugandan children with SCA, the desperation by caregivers for anything that could improve the child's health, and the inevitable improvements in care that result from strict adherence to a study protocol, even a protocol based on local guidelines. Studies in this vulnerable population must be careful not to portray improved care as a primary incentive for participation.

Comparison of iron status 28 d after provision of antimalarial treatment with iron therapy compared with antimalarial treatment alone in Ugandan children with severe malaria.

BACKGROUND: The provision of iron with antimalarial treatment is the standard of care for concurrent iron deficiency and malaria. However, iron that is given during a malaria episode may not be well absorbed or used, particularly in children with severe malaria and profound inflammation. OBJECTIVES: We aimed to 1) determine baseline values of iron and inflammatory markers in children with severe malarial anemia (SMA), children with cerebral malaria (CM), and community children (CC) and 2) compare markers in iron-deficient children in each group who received 28 d of iron supplementation during antimalarial treatment with those in children who did not receive iron during treatment.. DESIGN: Seventy-nine children with CM, 77 children with SMA, and 83 CC who presented to Mulago Hospital, Kampala, Uganda, were enrolled in a 28-d iron-therapy study. Children with malaria received antimalarial treatment. All children with CM or SMA, as well as 35 CC, had zinc protoporphyrin (ZPP) concentrations ≥80 µmol/mol heme and were randomly assigned to receive a 28-d course of iron or no iron. We compared iron markers at day 0 among study groups (CM, SMA, and CC groups) and at day 28 between children in each group who were randomly assigned to receive iron or to not receive iron. RESULTS: At day 0, children with CM and SMA had greater values of C-reactive protein, ferritin, and hepcidin than those of CC. At day 28, interactions between study and treatment group were NS. Children in the no-iron compared with iron groups had similar mean values for hemoglobin (115 compared with 113 g/L, respectively; P = 0.73) and ZPP (124 compared with 124 µmol/mol heme, respectively; P = 0.96) but had lower median ferritin [101.0 µg/L (95% CI: 84.2, 121.0 µg/L) compared with 152.9 µg/L (128.8, 181.6 µg/L), respectively; P ≤ 0.001] and hepcidin [45.8 ng/mL (36.8, 56.9 ng/mL) compared with 83.1 ng/mL (67.6, 102.2 ng/mL), respectively; P < 0.011]. CONCLUSIONS: Severe inflammation is a characterization of children with CM and SMA. The withholding of iron from children with severe malaria is associated with lower ferritin and hepcidin at day 28 but not a lower hemoglobin concentration. This trial was registered at clinicaltrials.gov as NCT01093989.