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.
Transfusion transmitted babesiosis: A systematic review of reported cases
Transfus Apher Sci. 2020;:102843
BACKGROUND Transfusion transmitted babesiosis (TTB) has a high mortality rate but may go unrecognized, particularly in non-endemic areas. We therefore conducted a systematic review to better characterize clinical aspects of TTB. METHODS A literature search was conducted in PubMed and CINAHL databases, from which 25 eligible articles describing 60 TTB patients met criteria for data extraction. RESULTS Symptom evaluation was provided for 25 implicated donors: 18/25 (72%) were asymptomatic while 7/25 (28%) had mild flu-like symptoms but were asymptomatic at time of donation. It was common for a single donor or donation to infect multiple patients. Where reported, species included B. microti - 54/60 (90%), B. duncani - 3/60 (5%), and B. divergens-like MO-1 - 1/60 (2%). Most TTB patients (44/60, 73%) resided in endemic states, while most TTB deaths 6/9 (67%) occurred in non-endemic states. Severity of hemolysis was proportional to degree of parasitemia. Mortality in our series was 9/60 (15%); most deaths occurred at extremes of the age spectrum: 6/9 non-survivors were aged >55 years, 2/9 were <1 year, only 1/9 was 2-54 years. Number of comorbidities was higher among non-survivors (median = 4) compared to survivors (median = 1). CONCLUSIONS All implicated donors (for which symptoms data were reported) resulting in TTB infections were asymptomatic at the time of donation, and it was common for a single donor or donation to infect multiple patients. Mortality of TTB appeared highest among those with more comorbidities and in non-endemic states. Heightened awareness of this diagnosis is key in its recognition.
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.
Safety and effectiveness of apheresis in the treatment of infectious diseases: a systematic review
The Journal of infection. 2019
OBJECTIVES Apheresis has been used as adjunctive treatment of severe falciparum malaria, loiasis and babesiosis. This systematic review aimed to investigate the safety and efficacy of apheresis in the treatment of these conditions. METHODS MEDLINE, PUBMED, EMBASE and CINAHL databases were searched to identify studies published between January 1969 and March 2018 involving patients treated using apheresis for severe falciparum malaria, loiasis or babesiosis. Data extracted included details about the apheresis intervention, populations, study methods and outcomes relating to efficacy and safety. RESULTS A total of 67 publications met the inclusion criteria and were included in the data synthesis, 36 for malaria (70 cases), 17 for babesiosis (22 cases) and 14 for loiasis (34 cases). Publications were case reports, case series, and cohort studies; there were no randomised controlled trials identified. Potential publication bias was considered to be high. CONCLUSIONS Systematic review of the literature suggests that apheresis may be a useful adjunct in the treatment of patients hospitalised for babesiosis, and prior to chemotherapy in loiasis with microfilarial count >8000 parasites/mL. Data does not support the use of apheresis in patients with severe falciparum malaria.
A systematic review of transfusion-transmitted malaria in non-endemic areas
Malaria Journal. 2018;17((1)):36.
BACKGROUND Transfusion-transmitted malaria (TTM) is an accidental Plasmodium infection caused by whole blood or a blood component transfusion from a malaria infected donor to a recipient. Infected blood transfusions directly release malaria parasites in the recipient's bloodstream triggering the development of high risk complications, and potentially leading to a fatal outcome especially in individuals with no previous exposure to malaria or in immuno-compromised patients. A systematic review was conducted on TTM case reports in non-endemic areas to describe the epidemiological characteristics of blood donors and recipients. METHODS Relevant articles were retrieved from Pubmed, EMBASE, Scopus, and LILACS. From each selected study the following data were extracted: study area, gender and age of blood donor and recipient, blood component associated with TTM, Plasmodium species, malaria diagnostic method employed, blood donor screening method, incubation period between the infected transfusion and the onset of clinical symptoms in the recipient, time elapsed between the clinical symptoms and the diagnosis of malaria, infection outcome, country of origin of the blood donor and time of the last potential malaria exposure. RESULTS Plasmodium species were detected in 100 TTM case reports with a different frequency: 45% Plasmodium falciparum, 30% Plasmodium malariae, 16% Plasmodium vivax, 4% Plasmodium ovale, 2% Plasmodium knowlesi, 1% mixed infection P. falciparum/P. malariae. The majority of fatal outcomes (11/45) was caused by P. falciparum whilst the other fatalities occurred in individuals infected by P. malariae (2/30) and P. ovale (1/4). However, non P. falciparum fatalities were not attributed directly to malaria. The incubation time for all Plasmodium species TTM case reports was longer than what expected in natural infections. This difference was statistically significant for P. malariae (p = 0.006). A longer incubation time in the recipient together with a chronic infection at low parasite density of the donor makes P. malariae a subtle but not negligible risk for blood safety aside from P. falciparum. CONCLUSIONS TTM risk needs to be taken into account in order to enhance the safety of the blood supply chain from donors to recipients by means of appropriate diagnostic tools.
Role of Plasmapheresis and Extracorporeal Membrane Oxygenation in the Treatment of Leptospirosis Complicated with Pulmonary Hemorrhages
Journal of tropical medicine. 2018;2018:4520185
Introduction: Leptospirosis is an emerging infectious disease associated with multiorgan involvement and significant morbidity and mortality. Although pulmonary hemorrhage due to leptospirosis has a high fatality, specific treatment options are limited and their efficacy is not adequately proven. We opted to find out the current evidence on plasmapheresis and extracorporeal membrane oxygenation (ECMO) in pulmonary hemorrhages due to leptospirosis. Methods: The first search was conducted in PubMed, OVID, Google Scholar, and Cochrane clinical trial registry using keywords "leptospirosis" OR "Leptospira" OR "Weil's disease" AND "plasmapheresis" OR "plasma exchange" AND "pulmonary hemorrhage" OR "alveolar hemorrhage" OR "lung hemorrhage" and the second search was done using keyword "leptospirosis" OR "Leptospira" OR "Weil's disease" AND "ECMO" OR "Extracorporeal membrane oxygenation." The searches were not limited by study design or the date of publication. Only articles written in English were reviewed. Although we intended to include only clinical trials, it was decided later to include other information such as case reports and case series which addressed these treatment modalities. Two authors selected articles independently in a blinded manner using a set of inclusion and exclusion criteria and discrepancies were solved after discussions. Results: The information found was very limited. This included one clinical trial which showed a significant survival benefit with plasmapheresis but the study design had many limitations. Two case reports described the benefit of plasmapheresis in severe leptospirosis with pulmonary hemorrhages. There were eight case reports where ECMO was performed and out of all only one patient has died. One retrospective study on patients with severe leptospirosis mentioned that four out of five patients with pulmonary hemorrhages survived after being treated with ECMO. Conclusions: Current evidence is insufficient to recommend the routine use of plasmapheresis or ECMO for patients presenting with pulmonary hemorrhages due to leptospirosis. ECMO may be a promising mode of treatment in acute respiratory failure in leptospirosis related pulmonary hemorrhages. These treatment modalities, however, can be applied based on the availability of resources and expertise at the discretion of the clinician in charge, considering patient related factors such as cardiovascular stability and derangement of coagulation profile. Clinical trials conducted adhering to standard procedures are urgently required to establish the efficacy of these treatment modalities.
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.