Erythropoietin in children with hemolytic uremic syndrome: a pilot randomized controlled trial
Pediatric nephrology (Berlin, Germany). 2022
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.
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
PloS one. 2021;16(9):e0255769
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.
Malaria Chemoprevention in the Postdischarge Management of Severe Anemia
The New England journal of medicine. 2020;383(23):2242-2254
BACKGROUND Children who have been hospitalized with severe anemia in areas of Africa in which malaria is endemic have a high risk of readmission and death within 6 months after discharge. No prevention strategy specifically addresses this period. METHODS We conducted a multicenter, two-group, randomized, placebo-controlled trial in nine hospitals in Kenya and Uganda to determine whether 3 months of malaria chemoprevention could reduce morbidity and mortality after hospital discharge in children younger than 5 years of age who had been admitted with severe anemia. All children received standard in-hospital care for severe anemia and a 3-day course of artemether-lumefantrine at discharge. Two weeks after discharge, children were randomly assigned to receive dihydroartemisinin-piperaquine (chemoprevention group) or placebo, administered as 3-day courses at 2, 6, and 10 weeks after discharge. Children were followed for 26 weeks after discharge. The primary outcome was one or more hospital readmissions for any reason or death from the time of randomization to 6 months after discharge. Conditional risk-set modeling for recurrent events was used to calculate hazard ratios with the use of the Prentice-Williams-Peterson total-time approach. RESULTS From May 2016 through May 2018, a total of 1049 children underwent randomization; 524 were assigned to the chemoprevention group and 525 to the placebo group. From week 3 through week 26, a total of 184 events of readmission or death occurred in the chemoprevention group and 316 occurred in the placebo group (hazard ratio, 0.65; 95% confidence interval [CI], 0.54 to 0.78; P<0.001). The lower incidence of readmission or death in the chemoprevention group than in the placebo group was restricted to the intervention period (week 3 through week 14) (hazard ratio, 0.30; 95% CI, 0.22 to 0.42) and was not sustained after that time (week 15 through week 26) (hazard ratio, 1.13; 95% CI, 0.87 to 1.47). No serious adverse events were attributed to dihydroartemisinin-piperaquine. CONCLUSIONS In areas with intense malaria transmission, 3 months of postdischarge malaria chemoprevention with monthly dihydroartemisinin-piperaquine in children who had recently received treatment for severe anemia prevented more deaths or readmissions for any reason after discharge than placebo. (Funded by the Research Council of Norway and the Centers for Disease Control and Prevention; ClinicalTrials.gov number, NCT02671175.).
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)
Current developments in nutrition. 2019;3(Suppl 1)
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.
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
The Journal of Nutrition. 2016;146((9):):1769-74
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.
Effects of ribavirin dose reduction vs erythropoietin for boceprevir-related anemia in patients with chronic hepatitis C virus genotype 1 infection - a randomized trial
BACKGROUND & AIMS Treatment of hepatitis C virus (HCV) infection with boceprevir, peginterferon, and ribavirin can lead to anemia, which has been managed by reducing ribavirin dose and/or erythropoietin therapy. We assessed the effects of these anemia management strategies on rates of sustained virologic response (SVR) and safety. METHODS Patients (n= 687) received 4 weeks of peginterferon and ribavirin followed by 24 or 44 weeks of boceprevir (800 mg, 3 times each day) plus peginterferon and ribavirin. Patients who became anemic (levels of hemoglobin approximately <=10 g/dL) during the study treatment period (n= 500) were assigned to groups that were managed by ribavirin dosage reduction (n= 249) or erythropoietin therapy (n= 251). RESULTS Rates of SVR were comparable between patients whose anemia was managed by ribavirin dosage reduction (71.5%) vs erythropoietin therapy (70.9%), regardless of the timing of the first intervention to manage anemia or the magnitude of ribavirin dosage reduction. There was a threshold for the effect on rate of SVR: patients who received <50% of the total milligrams of ribavirin assigned by the protocol had a significantly lower rate of SVR (P < .0001) than those who received >=50%. Among patients who did not develop anemia, the rate of SVR was 40.1%. Eleven thromboembolic adverse events were reported in 9 of 295 patients who received erythropoietin, compared with 1 of 392 patients who did not receive erythropoietin. CONCLUSIONS Reduction of ribavirin dosage can be the primary approach for management of anemia in patients receiving peginterferon, ribavirin, and boceprevir forHCV infection. Reduction in ribavirin dosage throughout the course of triple therapy does not affect rates of SVR. However, it is important that the patient receives at least 50% of the total amount (milligrams) of ribavirin assigned by response-guided therapy. ClinicalTrials.gov number, NCT01023035. Copyright 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.
Iron supplementation in HIV-infected Malawian children with anemia: a double-blind, randomized, controlled trial
Clinical Infectious Diseases. 2013;57((11):):1626-34.
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.
Treatment for anemia in people with AIDS
Cochrane Database of Systematic Reviews. 2011;((10):):CD004776.
BACKGROUND Anemia is common in persons with HIV infection and is associated with poor prognosis. There is a need to assess the effects of anemia treatments, and to determine whether these interventions are beneficial. OBJECTIVES To determine the efficacy and safety of treatments for anemia in people with HIV infection and AIDS. SEARCH STRATEGY The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 10, 2010), MEDLINE (1980-November 25, 2010), EMBASE (1980-November 25, 2010), LlLACS (1982 to November 25, 2010), Africa Index Medicus (up to November 9, 2010), ISI Web of Knowledge (2005 to October 9, 2010), Scirus (October 9, 2010) reference lists of relevant articles. We asked the Cochrane HIV/AIDS and Pregnancy and Childbirth Groups to check their Specialised Registers. We also checked the reference lists of all trials identified by the above methods. SELECTION CRITERIA Randomized trials assessing the effects of treatments for anemia in people diagnosed with HIV infection. There were no age restrictions. DATA COLLECTION AND ANALYSIS Two authors independently assessed relevant studies for inclusion. Data extraction and quality assessment of relevant studies was performed by two authors and checked by the other two authors. MAIN RESULTS Six trials with a high risk of bias, including 537 patients, met the inclusion criteria. These trials only covered recombinant Human erythropoietin alfa (rHuEPO). Two of them including adult and paediatric participants (84 participants and 4 events) comparing rHuEPO to placebo did not reduce the risk of mortality with a follow up to 12 weeks (pooled RR 0.56, 95% confidence interval (CI) 0.08 to 4.05, I(2) = 0%). Any trials that compared rHuEPO to placebo did not show any benefit on hematological values response, number of patients transfused, or number of packed red cell transfused. Two trial compared the effects of two rHuEPO dosing regimens on hemoglobin value and quality of life, but the effects are unclear. Three RCT reported high risk of attrition bias; therefore, were not included in a meta-analysis. AUTHORS' CONCLUSIONS This updated Cochrane review provides evidence that rHuEPO compared with placebo does not reduce mortality, does not reduce transfusion requirements, did not increase hemoglobin levels, and did not improve quality of life in HIV-infected patients with anemia. The results are based on six RCTs with high risk of bias. Therefore prescription of this intervention for treating anemia in patients with AIDS is not justified, unless new evidence from a large high quality trial alters this conclusion.
Use of epoetin beta during combination therapy of infection with hepatitis c virus with ribavirin improves a sustained viral response
Journal of Medical Virology. 2010;82((1):):49-56.
The aim of the study was to evaluate the effects of epoetin-beta on anemia and sustained viral response in patients with chronic hepatitis C receiving treatment with pegylated interferon and ribavirin. Forty-two Caucasian patients with chronic hepatitis C infection, treated with pegylated interferon alpha-2a or alpha-2b plus ribavirin, who experienced at least a 2 log decline in HCV-RNA in the first month of therapy and a > or =2. 5 g/dl hemoglobin drop from baseline, were recruited. They were divided into two groups: 22 patients received epoetin-beta 30,000 U administered s. c. q. w. (group A) and 20 patients received a reduced ribavirin dose of 600 mg daily (group B). The end-of-treatment response was 95. 4% (21/22) in group A and 80% (16/20) (P = 0. 2) in group B. Sustained viral response in group A was 81. 8% (18/22), statistically higher than in group B (45%, 9/20) (P = 0. 03). Mean corpuscular volume of erythrocytes was statistically lower in group A than in group B 4 weeks after starting epoetin-beta or reduced ribavirin dose (P < 0. 001), end-of-treatment (P < 0. 001) and after 6 months follow-up (P < 0. 001). A negative correlation between the levels of ferritin serum was found in group A at the baseline and mean corpuscular volume value after 1 month of combination antiviral therapy (r = -0. 45; P = 0. 35), 4 weeks after starting epoetin-beta (r = -0. 43; P = 0. 04) and after 6 months follow-up (r = -0. 45; P = 0. 03). Administration of epoetin-beta increases sustained viral response rates among patients developing anemia, because the standard dose of ribavirin is maintained, thereby reducing the side-effects of antiviral treatment.
Treatment of chronic hepatitis C virus genotype 1 with peginterferon, ribavirin, and epoetin alpha
Successful treatment of chronic HCV with peginterferon (PEGIFN) and ribavirin (RVN) is often limited by anemia. We performed the present study to determine if utilizing epoetin alpha (EPO) with or without a higher dose of RVN could enhance sustained virologic response (SVR). We randomized 150 treatment-naive patients with chronic HCV genotype 1 into 3 treatment groups: (1) PEGIFN alpha-2b (1. 5 microg/kg/week) + weight-based RVN (WBR) 13. 3 mg/kg/day (800 to 1400 mg/day); (2) PEGIFN alpha-2b + WBRVN + EPO (40,000 U/week); or (3) PEGIFN alpha-2b + higher dose WBR 15. 2 mg/kg/day (1000 to 1600 mg/day) + EPO. We initiated EPO at the onset of therapy to maintain the hemoglobin between 12 and 15 g/dL. When required, we reduced RVN by 200-mg steps. African Americans compose 36% of the population. A significantly smaller percentage of group 2 patients had a decline in hemoglobin to less than 10 g/dL (9% versus 34%; P < 0. 05) and required that the RVN dose be reduced (10% versus 40%; P < 0. 05) compared to group 1 patients. Despite this, SVR was similar in these groups (19% to 29%). SVR was significantly greater (P < 0. 05) in group 3 patients (49%). This resulted from a significant decline (P < 0. 05) in relapse rate; only 8% versus 38% for groups 1 and 2. CONCLUSION We conclude that using EPO in all subjects at the initiation of PEGIFN and RVN treatment will not enhance SVR given the same starting dose of RVN. In contrast, a higher starting dose of RVN was associated with a lower relapse rate and higher rate of SVR.