Browsing by Author "Cusick, Sarah E."

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    Delayed iron does not alter cognition or behavior among children with severe malaria and iron deficiency
    (Nature, 2020-09) Ssemata, Andrew S.; Hickson, Meredith; Ssenkusu, John M.; Cusick, Sarah E.; Nakasujja, Noeline; Opoka, Robert O.; Kroupina, Maria; Georgieff, Michael K.; Bangirana, Paul; John, Chandy C.; Pediatrics, School of Medicine
    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.
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    Delayed iron improves iron status without altering malaria risk in severe malarial anemia
    (Oxford University Press, 2020-05) Cusick, Sarah E.; Opoka, Robert O.; Ssemata, Andrew S.; Georgieff, Michael K.; John, Chandy C.; Pediatrics, School of Medicine
    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.
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    Impact of Oxidative Stress on Risk of Death and Readmission in African Children With Severe Malaria: A Prospective Observational Study
    (Oxford University Press, 2022) Blatt, Daniel B.; Hanisch, Benjamin; Co, Katrina; Datta, Dibyadyuti; Bond, Caitlin; Opoka, Robert O.; Cusick, Sarah E.; Michelow, Ian C.; John, Chandy C.; Pediatrics, School of Medicine
    Background: We hypothesized that oxidative stress in Ugandan children with severe malaria is associated with mortality. Methods: We evaluated biomarkers of oxidative stress in children with cerebral malaria (CM, n = 77) or severe malarial anemia (SMA, n = 79), who were enrolled in a randomized clinical trial of immediate vs delayed iron therapy, compared with community children (CC, n = 83). Associations between admission biomarkers and risk of death during hospitalization or risk of readmission within 6 months were analyzed. Results: Nine children with CM and none with SMA died during hospitalization. Children with CM or SMA had higher levels of heme oxygenase-1 (HO-1) (P < .001) and lower superoxide dismutase (SOD) activity than CC (P < .02). Children with CM had a higher risk of death with increasing HO-1 concentration (odds ratio [OR], 6.07 [95% confidence interval {CI}, 1.17-31.31]; P = .03) but a lower risk of death with increasing SOD activity (OR, 0.02 [95% CI, .001-.70]; P = .03). There were no associations between oxidative stress biomarkers on admission and risk of readmission within 6 months of enrollment. Conclusions: Children with CM or SMA develop oxidative stress in response to severe malaria. Oxidative stress is associated with higher mortality in children with CM but not with SMA.
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    The Impact of Undernutrition on Cognition in Children with Severe Malaria and Community Children: A Prospective 2-Year Cohort Study
    (Oxford University Press, 2021) Mburu, Waruiru; Conroy, Andrea L.; Cusick, Sarah E.; Bangirana, Paul; Bond, Caitlin; Zhao, Yi; Opoka, Robert O.; John, Chandy C.; Pediatrics, School of Medicine
    Background: The frequency of recovery from undernutrition after an episode of severe malaria, and the relationship between undernutrition during severe malaria and clinical and cognitive outcomes are not well characterized. Methods: We evaluated undernutrition and cognition in children in Kampala, Uganda 18 months to 5 years of age with cerebral malaria (CM), severe malarial anemia (SMA) or community children (CC). The Mullen Scales of Early Learning was used to measure cognition. Undernutrition, defined as 2 SDs below median for weight-for-age (underweight), height-for-age (stunting) or weight-for-height (wasting), was compared with mortality, hospital readmission and cognition over 24-month follow-up. Results: At enrollment, wasting was more common in CM (16.7%) or SMA (15.9%) than CC (4.7%) (both p < 0.0001), and being underweight was more common in SMA (27.0%) than CC (12.8%; p = 0.001), while prevalence of stunting was similar in all three groups. By 6-month follow-up, prevalence of wasting or being underweight did not differ significantly between children with severe malaria and CC. Undernutrition at enrollment was not associated with mortality or hospital readmission, but children who were underweight or stunted at baseline had lower cognitive z-scores than those who were not {underweight, mean difference [95% confidence interval (CI)] -0.98 (-1.66, -0.31), -0.72 (-1.16, -0.27) and -0.61 (-1.08, -0.13); and stunted, -0.70 (-1.25, -0.15), -0.73 (-1.16, -0.31) and -0.61 (-0.96, -0.27), for CM, SMA and CC, respectively}. Conclusion: In children with severe malaria, wasting and being underweight return to population levels after treatment. However, being stunted or underweight at enrollment was associated with worse long-term cognition in both CC and children with severe malaria.
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    Zinc for infection prevention in children with sickle cell anemia: a randomized double-blind placebo-controlled trial
    (American Society of Hematology, 2023) Namazzi, Ruth; Opoka, Robert; Conroy, Andrea L.; Datta, Dibyadyuti; Tagoola, Abner; Bond, Caitlin; Goings, Michael J.; Ryu, Moon-Suhn; Cusick, Sarah E.; Krebs, Nancy F.; Jang, Jeong Hoon; Tu, Wanzhu; Ware, Russell E.; John, Chandy C.; Biostatistics and Health Data Science, School of Medicine
    Data from small clinical trials in the United States and India suggest zinc supplementation reduces infection in adolescents and adults with sickle cell anemia (SCA), but no studies of zinc supplementation for infection prevention have been conducted in children with SCA living in Africa. We conducted a randomized double-blind placebo-controlled trial to assess zinc supplementation for prevention of severe or invasive infections in Ugandan children 1.00-4.99 years with SCA. Of 252 enrolled participants, 124 were assigned zinc (10 mg) and 126 assigned placebo once daily for 12 months. The primary outcome was incidence of protocol-defined severe or invasive infections. Infection incidence did not differ between treatment arms (282 vs. 270 severe or invasive infections per 100 person-years, respectively, incidence rate ratio of 1.04 [95% confidence interval (CI), 0.81, 1.32, p=0.78]), adjusting for hydroxyurea treatment. There was also no difference between treatment arms in incidence of serious adverse events or SCA-related events. Children receiving zinc had increased serum levels after 12-months, but at study exit, 41% remained zinc deficient (<65 μg/dL). In post-hoc analysis, occurrence of stroke or death was lower in the zinc treatment arm (adjusted hazard ratio (95% CI), 0.22 (0.05, 1.00); p=0.05). Daily 10 mg zinc supplementation for 12 months did not prevent severe or invasive infections in Ugandan children with SCA, but many supplemented children remained zinc deficient. Optimal zinc dosing and the role of zinc in preventing stroke or death in SCA warrant further investigation.
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    Zinc for Infection Prevention in Sickle Cell Anemia (ZIPS): study protocol for a randomized placebo-controlled trial in Ugandan children with sickle cell anemia
    (BioMed Central, 2019-07-26) Datta, Dibyadyuti; Namazzi, Ruth; Conroy, Andrea L.; Cusick, Sarah E.; Hume, Heather A.; Tagoola, Abner; Ware, Russell E.; Opoka, Robert O.; John, Chandy C.; Pediatrics, School of Medicine
    BACKGROUND: Sickle cell anemia (SCA) is the most common inherited hemoglobinopathy worldwide. Infection is a major cause of illness and death in children with SCA, especially in sub-Saharan Africa where an estimated 50-90% of affected children die before their fifth birthday. Interventions to reduce the incidence and severity of infections are needed urgently. A high proportion of adults and children with SCA are zinc-deficient, and zinc deficiency leads to impaired immunity and an increased risk of infection. Zinc supplementation has been shown to decrease the risk of infection in adolescents and adults, but there are no data on the effectiveness of zinc for prevention of infection in children < 5 years of age with SCA. METHODS/DESIGN: The study will be a randomized, placebo-controlled, double-blind clinical trial in which 250 Ugandan children 1.00-4.99 years of age with SCA will receive daily zinc supplementation (10 mg oral dispersible tablet) or identical placebo for 12 months. DISCUSSION: If this trial shows a reduction in severe or invasive infection incidence, it would be the basis for a multi-site, multi-country clinical trial to assess real-world safety and efficacy of zinc in African children with SCA. Since zinc is safe, inexpensive, and easy to administer, this trial has the potential to improve the health of hundreds of thousands of African children with SCA through reduction of infection-related morbidity and mortality.