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Erythropoietin in children with hemolytic uremic syndrome: a pilot randomized controlled trial
Balestracci A, Capone MA, Meni Battaglia L, Toledo I, Martin SM, Beaudoin L, Balbaryski J, Gómez L
Pediatric nephrology (Berlin, Germany). 2022
Abstract
BACKGROUND The efficacy of recombinant human erythropoietin (rHuEPO) in sparing red blood cell (RBC) transfusions in children with hemolytic uremic syndrome related to Shiga toxin-producing Escherichia coli (STEC-HUS) is uncertain. METHODS We conducted a pilot randomized controlled open trial between December 2018 and January 2021. Children were randomized to the intervention (subcutaneous rHuEPO 50 U/kg three times weekly until discharge + RBC transfusion if hemoglobin ≤ 7 g/dL and/or hemodynamic instability) or to the control arm (RBC transfusion if hemoglobin ≤ 7 g/dL and/or hemodynamic instability). Primary outcome was the number of RBC transfusions received during hospitalization. Secondary outcomes were to explore whether baseline EPO levels were adequate to the degree of anemia, to correlate selected acute phase parameters with the number of RBC transfusions, and to assess possible adverse events. RESULTS Twelve patients per arm were included; they were comparable at recruitment and throughout the disease course. Median number of RBC transfusions was similar between groups (1.5, p = 0.76). Most patients had baseline EPO levels adequate to the degree of anemia, which did not correlate with the number of transfusions (r = 0.19, p = 0.44). Conversely, baseline (r = 0.73, p = 0.032) and maximum lactic dehydrogenase levels (r = 0.78, p = 0.003), creatinine peak (r = 0.71, p = 0.03) and dialysis duration (r = 0.7, p = 0.04) correlated significantly with RBC requirements. No side effects were recorded. CONCLUSION In children with STEC-HUS, the administration of rHuEPO did not reduce the number of RBC transfusions. Larger studies addressing higher doses and similar severity of kidney failure at rHuEPO initiation (e.g. at start of dialysis) are warranted. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT03776851. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Adherence to community versus facility-based delivery of monthly malaria chemoprevention with dihydroartemisinin-piperaquine for the post-discharge management of severe anemia in Malawian children: A cluster randomized trial
Nkosi-Gondwe T, Robberstad B, Mukaka M, Idro R, Opoka RO, Banda S, Kühl MJ, O Ter Kuile F, Blomberg B, Phiri KS
PloS one. 2021;16(9):e0255769
Abstract
BACKGROUND The provision of post-discharge malaria chemoprevention (PMC) in children recently admitted with severe anemia reduces the risk of death and re-admissions in malaria endemic countries. The main objective of this trial was to identify the most effective method of delivering dihydroartemesinin-piperaquine to children recovering from severe anemia. METHODS This was a 5-arm, cluster-randomized trial among under-5 children hospitalized with severe anemia at Zomba Central Hospital in Southern Malawi. Children were randomized to receive three day treatment doses of dihydroartemesinin-piperaquine monthly either; 1) in the community without a short text reminder; 2) in the community with a short message reminder; 3) in the community with a community health worker reminder; 4) at the facility without a short text reminder; or 5) at the facility with a short message reminder. The primary outcome measure was adherence to all treatment doses of dihydroartemesinin-piperaquine and this was assessed by pill-counts done by field workers during home visits. Poisson regression was utilized for analysis. RESULTS Between March 2016 and October 2018, 1460 clusters were randomized. A total of 667 children were screened and 375 from 329 clusters were eligible and enrolled from the hospital. Adherence was higher in all three community-based compared to the two facility-based delivery (156/221 [70·6%] vs. 78/150 [52·0%], IRR = 1·24,95%CI 1·06-1·44, p = 0·006). This was observed in both the SMS group (IRR = 1·41,1·21-1·64, p<0·001) and in the non-SMS group (IRR = 1·37,1·18-1·61, p<0·001). Although adherence was higher among SMS recipients (98/148 66·2%] vs. non-SMS 82/144 (56·9%), there was no statistical evidence that SMS reminders resulted in greater adherence ([IRR = 1·03,0·88-1·21, p = 0·68). When compared to the facility-based non-SMS arm (control arm), community-based delivery utilizing CHWs resulted in higher adherence [39/76 (51·3%) vs. 54/79 (68·4%), IRR = 1·32, 1·14-1·54, p<0·001]. INTERPRETATION Community-based delivery of dihydroartemesinin-piperaquine for post-discharge malaria chemoprevention in children recovering from severe anemia resulted in higher adherence compared to facility-based methods. TRIAL REGISTRATION NCT02721420; ClinicalTrials.gov.
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Malaria Incidence Does Not Differ with Immediate Compared to 28-day Delayed Iron Treatment in Children with Severe Malaria and Iron Deficiency (OR10-04-19)
Cusick S, Opoka R, Ssemata A, Georgieff M, John C
Current developments in nutrition. 2019;3(Suppl 1)
Abstract
Objectives: We aimed to determine if delaying iron until 28 days after antimalarial treatment in children with severe malaria and iron deficiency leads to fewer subsequent clinical malaria episodes as compared to concurrent iron therapy. Methods: The randomized controlled trial was conducted Ugandan children 18 mo-5 y with severe malaria [cerebral malaria (CM), n = 79; severe malarial anemia (SMA), n = 77] and healthy community children (CC, n = 83) at Mulago Hospital in Kampala, Uganda. All children with malaria received antimalarial treatment. Children with iron deficiency (defined by zinc protoporphyrin (ZPP) >= 80 micromol/mol heme) were randomized to start a 90-day course of ferrous sulfate (2 mg/kg/day) concurrently with antimalarial treatment on Day 0 (immediate group, I) or on Day 28 (delayed group, D). Incidence of malaria episodes over the 12-month follow-up period was assessed by sick-child visits to the study clinic. Malaria was defined as measured fever (T >37.5 degrees C) plus Plasmodium falciparum on blood smear. Negative binomial regression was used to model counts of malaria episodes as a function of treatment group (I or D), controlling for age. Hazard ratios compared time to event between the I and D groups. Results: All children with CM and SMA and 35 CC had high ZPP and were randomized to I or D iron. There were no differences in malaria incidence (defined with either measured fever or history of fever) with I vs. D treatment in any study group. The incidence of inpatient malaria episodes defined with history of fever was marginally statistically significant lower with D iron in the SMA group [incidence rate ratio (IRR) D/I (95% CI) = 0.38 (0.14, 1.1), P = 0.07). In the SMA group, children who received D iron tended to have a longer time to first inpatient event than children in the I group [Hazard ratio (95% CI) D/I: 0.37 (0.13, 1.1), P = 0.07]. Conclusions: Delaying iron in children with severe malaria had no clear risk or benefit on subsequent malaria incidence or time-to-first episode as compared to immediate treatment. Given that previous analysis revealed that iron status was improved with delayed iron among children with SMA, the lack of difference in malaria incidence suggests that delaying iron therapy may be a safe way to improve iron status in this group. Funding Sources: NIH/NICHD.
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Delaying Iron Therapy until 28 Days after Antimalarial Treatment Is Associated with Greater Iron Incorporation and Equivalent Hematologic Recovery after 56 Days in Children: A Randomized Controlled Trial
Cusick SE, Opoka RO, Abrams SA, John CC, Georgieff MK, Mupere E
The Journal of Nutrition. 2016;146((9):):1769-74
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Abstract
BACKGROUND Iron therapy begun concurrently with antimalarial treatment may not be well absorbed because of malaria-induced inflammation. Delaying the start of iron therapy may permit better iron absorption and distribution. OBJECTIVE We compared erythrocyte iron incorporation in children who started iron supplementation concurrently with antimalarial treatment or 28 d later. We hypothesized that delayed iron supplementation would be associated with greater incorporation and better hematologic recovery. METHODS We enrolled 100 children aged 6-59 mo with malaria and hemoglobin concentrations of 50.0-99.9 g/L who presented to Mulago Hospital, Kampala, into a randomized trial of iron therapy. All children were administered antimalarial treatment. Children with zinc protoporphyrin (ZPP) ≥80 mumol/mol heme were randomly assigned to start iron supplementation concurrently with the antimalarial treatment [immediate iron (I) group] or 28 d later [delayed iron (D) group]. All children were administered iron-stable isotope 57Fe on day 0 and 58Fe on day 28. We compared the percentage of iron incorporation at the start of supplementation (I group at day 0 compared with D group at day 28, aim 1) and hematologic recovery at day 56 (aim 2). RESULTS The percentage of iron incorporation (mean +/- SE) was greater at day 28 in the D group (16.5% +/- 1.7%) than at day 0 in the I group (7.9% +/- 0.5%; P < 0.001). On day 56, concentrations of hemoglobin and ZPP and plasma ferritin, soluble transferrin receptor (sTfR), hepcidin, and C-reactive protein did not differ between the groups. On day 28, the hemoglobin (mean +/- SD) and plasma iron markers (geometric mean; 95% CI) reflected poorer iron status in the D group than in the I group at this intervening time as follows: hemoglobin (105 +/- 15.9 compared with 112 +/- 12.4 g/L; P = 0.04), ferritin (39.3 mug/L; 23.5, 65.7 mug/L compared with 79.9 mug/L; 58.3, 110 mug/L; P = 0.02), sTfR (8.9 mg/L; 7.4, 10.7 mg/L compared with 6.7 mg/L; 6.1, 7.5 mg/L; P = 0.01), and hepcidin (13.3 ng/mL; 8.3, 21.2 ng/mL compared with 38.8 ng/mL; 28.3, 53.3 ng/mL; P < 0.001). CONCLUSIONS Delaying the start of iron improves incorporation but leads to equivalent hematologic recovery at day 56 in Ugandan children with malaria and anemia. These results do not demonstrate a clear, short-term benefit of delaying iron. This trial was registered at clinicaltrials.gov as NCT01754701.
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Iron supplementation in HIV-infected Malawian children with anemia: a double-blind, randomized, controlled trial
Esan MO, van Hensbroek MB, Nkhoma E, Musicha C, White SA, Ter Kuile FO, Phiri KS
Clinical Infectious Diseases. 2013;57((11):):1626-34.
Abstract
Background.It is unknown whether iron supplementation in human immunodeficiency virus (HIV)-infected children living in regions with high infection pressure is safe or beneficial. A 2-arm, double-blind, randomized, controlled trial was conducted to examine the effects of iron supplementation on hemoglobin, HIV disease progression, and morbidity. Methods.HIV-infected Malawian children aged 6-59 months with moderate anemia (hemoglobin level, 7.0-9.9 g/dL) were randomly assigned to receive 3 mg/kg/day of elemental iron and multivitamins (vitamins A, C, and D) or multivitamins alone for 3 months. Participants were followed for 6 months. Results.A total of 209 children were randomly assigned to treatment, and 196 (93.8%) completed 6 months of follow-up. Iron supplementation was associated with greater increases in hemoglobin concentrations (adjusted mean difference [aMD], 0.60; 95% confidence interval [CI], .06-1.13; P = .03) and reduced the risk of anemia persisting for up to 6 months follow-up (adjusted prevalence ratio, 0.59; 95% CI, .38-.92; P = .02). Children who received iron had a better CD4 percentage response at 3 months (aMD, 6.00; 95% CI, 1.84-10.16; P = .005) but an increased incidence of malaria at 6 months (incidence rate, 120.2 vs 71.7; adjusted incidence rate ratio [aIRR], 1.81 [95% CI, 1.04-3.16]; P = .04), especially during the first 3 months (incidence rate, 78.1 vs 36.0; aIRR, 2.68 [95% CI, 1.08-6.63]; P = .03). Conclusions.Iron supplementation in anemic HIV-infected children has beneficial effects on hemoglobin, anemia, and immunity but increases the risk of malaria. Thus, iron supplementation in HIV-infected children living in malaria-endemic areas should only be provided in combination with adequate protection from malaria. Clinical Trials Registration.ISRCTN-62947977.
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Control of bleeding in children with Dengue hemorrhagic fever using recombinant activated factor VII: a randomized, double-blind, placebo-controlled study
Chuansumrit A, Wangruangsatid S, Lektrakul Y, Chua MN, Zeta Capeding MR, Bech OM, Dengue Study Group
Blood Coagulation & Fibrinolysis. 2005;16((8):):549-55.
Abstract
OBJECTIVES We evaluated the efficacy and safety of recombinant activated factor VII (rFVIIa) in children aged < 18 years old with grade II or grade III Dengue hemorrhagic fever (DHF) who required blood component therapy for controlling bleeding episodes. STUDY DESIGN Patients were randomized to the rFVIIa group or placebo group in a ratio of 2:1. rFVIIa or placebo (100 microg/kg body weight) was given by intravenous bolus injection. When bleeding was not effectively controlled, a second dose of rFVIIa or placebo (100 microg/kg) was given 30 min after the first dose. RESULTS Nine and 16 patients received placebo and rFVIIa, respectively. The demographics, bleeding manifestations and grade of DHF were similar for the rFVIIa and placebo groups. Apart from petechiae and ecchymosis, one to four additional bleeding sites were found in each patient, including hematemesis (n = 15), epistaxis (n = 14), gum bleeding (n = 12), melena (n = 7), hypermenorrhea (n = 4), hematochezia (n = 2) and hematuria (n = 2). The mean total dose of rFVIIa (138. 4 +/- 50. 9 microg/kg) and placebo (145. 4 +/- 53. 7 microg/kg) were comparable. The efficacy of bleeding control at 2 h after the first dose was completely ceased (rFVIIa 75. 0% versus placebo 44. 4%), decreased (rFVIIa 18. 7% versus placebo 11. 2%), and unchanged or worsened (rFVIIa 6. 3% versus placebo 44. 4%). Some patients with active bleeding received platelet concentrates 3-12 h after the first dose of rFVIIa or placebo. The subsequent efficacy of bleeding control at 6, 12 and 24 h was comparable between the two groups. The cumulative use of red blood cells (rFVIIa 31. 3% versus placebo 33. 3%) and plasma (rFVIIa 25% versus placebo 22%) during the 24-h period was not significantly different between the two groups. In contrast, platelet concentrate requirement in the rFVIIa group (6. 3%) was lower than the placebo (33. 3%). No clinical evidence of thromboembolic complications or mortality as a result of bleeding was observed. CONCLUSION rFVIIa appears to be a useful adjunctive treatment to blood component transfusion for controlling active bleeding in children with DHF especially when platelet concentrate is not readily available.
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Randomised placebo-controlled trial of iron supplementation and malaria chemoprophylaxis for prevention of severe anaemia and malaria in Tanzanian infants
Menendez C, Kahigwa E, Hirt R, Vounatsou P, Aponte JJ, Font F, Acosta CJ, Schellenberg DM, Galindo CM, Kimario J, et al
Lancet. 1997;350((9081):):844-50.
Abstract
BACKGROUND Malaria and anaemia, especially that due to iron deficiency, are two leading causes of morbidity worldwide. Little is known about the relative contribution of Plasmodium falciparum infection and iron deficiency to the aetiology of anaemia in malaria-endemic areas. We undertook a randomised comparison of different strategies for control of anaemia and malaria in infants, including an assessment of the effect of iron supplementation on malaria susceptibility. METHODS 832 infants born at one hospital in a malaria-hyperendemic area of Tanzania between January and October, 1995, were randomly assigned to group DI, receiving daily oral iron (2 mg/kg daily) plus weekly Deltaprim (3.125 mg pyrimethamine plus 25 mg dapsone); group IP, receiving iron plus weekly placebo; group DP, receiving daily placebo plus weekly Deltaprim; or group PP. supplementation was given from 8 to 24 weeks of age, and the weekly chemoprophylaxis from 8 to 48 weeks. The frequency of severe anaemia (packed-cell volume < 25%) and malaria episodes was assessed through a combination of passive case detection and cross-sectional surveys. FINDINGS The groups that received iron supplementation had a lower frequency of severe anaemia than those that did not receive iron (0.62 vs 0.87 cases per person-year; protective efficacy 28.8% [95% CI 6.3-45.8). Iron supplementation had no effect on the frequency of malaria (0.87 vs 1.00 cases per person-year; protective efficacy 12.8% [-12.8 to 32.5]). The groups that received malaria prophylaxis had lower frequencies of both severe anaemia (0.45 vs 1.04 episodes per person-year; protective efficacy 57.3% [43.0-67.9]) and malaria (0.53 vs 1.34 episodes per person-year; protective efficacy 60.5% [48.2-69.9]) than the groups that did not receive prophylaxis. After the end of the intervention period, children who had received malaria chemoprophylaxis had higher rates of severe anaemia and malaria than non-chemoprophylaxis groups (relative risks 2.2 [1.3-3.7] and 1.8 [1.3-2.6]). INTERPRETATION Malaria chemoprophylaxis during the first year of life was effective in prevention of malaria and anaemia but apparently impaired the development of natural immunity. Iron supplementation was effective in preventing severe anaemia without increasing susceptibility to malaria. Our findings support iron supplementation of infants to prevent iron-deficiency anaemia, even in malaria-endemic areas.
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The effect of oral iron therapy during treatment for Plasmodium falciparum malaria with sulphadoxine-pyrimethamine on Malawian children under 5 years of age
Nwanyanwu OC, Ziba C, Kazembe PN, Gamadzi G, Gandwe J, Redd SC
Annals of Tropical Medicine & Parasitology. 1996;90((6):):589-95.
Abstract
In sub-Saharan countries, although malaria and malaria-associated anaemia are major public health problems, the usefulness of supplementary iron treatment for children with malaria-associated anaemia is unknown. In a 6-week period during the 1995 rainy season, 222 Malawian children aged < 5 years, who sought treatment for malaria, had > or = 500 parasites/microliter blood and at least 5 g haemoglobin (HB)/dl blood and whose parents gave consent, were randomized into a prospective study comparing the efficacy of sulphadoxine- pyrimethamine only (SP), SP plus daily iron (SPD) and SP plus weekly iron (SPW) as treatment for malaria-associated anaemia. The patients had their HB concentrations measured on enrollment (day 0), just before antimalarial treatment, and on days 3, 7, 14, 21 and 28; 215 (96.8%) completed the 28-day study. Among the children with 5-8 g HB/dl on enrolment, HB gain by the end of the study was significantly greater than in the children with > 8 g HB/dl initially (4.1 v. 2.2 g/dl; P < 0.05), and those in the SPD group gained significantly more HB by days 21 and 28 (3.6 and 4.9 g/dl, respectively) than those in either the SPW (2.7 and 3.7 g/dl, respectively) or the S2 groups (2.6 and 3.5 g/dl, respectively); there was no difference in HB gain between the SP and SPW groups. Type of treatment had no apparent effect, at any time during the study, on HB gains in those patients who had > 8 g HB/dl on enrolment. Thus the children with 5-8 g HB/dl on enrolment benefited from daily iron therapy whereas those with > 8 g HB/dl derived no significant benefit; improvement in HB depended most on whether enrolment HB was < or = 8.0 g/dl. As treatment with an effective antimalarial drug resulted in HB gains, irrespective of treatment group or HB concentration at enrolment, the anaemia observed may be mostly related to malaria. However, as a larger proportion of the iron-treated patients failed to clear their parasitaemias than of those given SP alone, oral iron may inhibit SP action. It is therefore recommended that, for children with both malaria and malaria-associated anaemia, the malaria should first be cleared with an effective antimalarial drug, such as SP, before the anaemia, if it still persists, is treated with iron.
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Does iron therapy benefit children with severe malaria-associated anaemia? A clinical trial with 12 weeks supplementation of oral iron in young children from the Turiani Division, Tanzania
van den Hombergh J, Dalderop E, Smit Y
Journal of Tropical Pediatrics. 1996;42((4):):220-7.
Abstract
Oral iron supplementation is often routinely given to children with malaria-associated anaemia, but its contribution to recovery is controversial. A randomized clinical trial, evaluating such routine, was carried out among 100 children, who had a haemoglobin of < or = 5 g/dl and a positive blood smear for malaria parasites. All children received malaria therapy (chloroquin + fansidar) and were randomly allocated to two groups, one receiving additional oral iron treatment, the other being the control. In the 12-week follow-up period the haemoglobin level and malaria indices were measured at 2, 4, 8, and 12 weeks. There was a 100 per cent compliance during the follow-up period. In each group 20 children (40 per cent) required a blood transfusion. In the remaining 60 children, after 2 weeks the haemoglobin had risen 3.7 g/dl in the ferrous-supplemented group compared to 3.5 g/dl in the non-ferrous group. Thereafter, the increase in haemoglobin in both groups was steady. At follow-up measurements, the groups did not differ for haemoglobin levels. The mean haemoglobin at 12 weeks was 9.2 and 9.0 g/dl, respectively. It was concluded that iron supplementation did not have any effect on the rate of parasitaemia and on parasite density during the 12 weeks. However, the iron-supplemented group had a significantly increased morbidity from other causes than malaria. It appears that iron does not have an effect on the recovery of haemoglobin level in children with malaria-associated anaemia. This study provides no evidence supporting routine iron supplementation to these children.