Transfusion management of severe anaemia in African children: a consensus algorithm

The phase III Transfusion and Treatment of severe anaemia in African Children Trial (TRACT) found that conservative management of uncomplicated severe anaemia [haemoglobin (Hb) 40–60 g/l] was safe, and that transfusion volume (20 vs. 30 ml/kg whole blood equivalent) for children with severe anaemia (Hb 37·5°C). In 2020 a stakeholder meeting of paediatric and blood transfusion groups from Africa reviewed the results and additional analyses. Among all 3196 children receiving an initial transfusion there was no evidence that nutritional status, presence of shock, malaria parasite burden or sickle cell disease status influenced outcomes or modified the interaction with fever status on volume required. Fever status at the time of ordering blood was a reliable determinant of volume required for optimal outcome. Elevated heart and respiratory rates normalised irrespective of transfusion volume and without diuretics. By consensus, a transfusion management algorithm was developed, incorporating three additional measurements of Hb post-admission, alongside clinical monitoring. The proposed algorithm should help clinicians safely implement findings from TRACT. Further research should assess its implementation in routine clinical practice

Mechanisms of Transcranial Doppler Ultrasound phenotypes in paediatric cerebral malaria remain elusive.

BACKGROUND: Cerebral malaria (CM) results in significant paediatric death and neurodisability in sub-Saharan Africa. Several different alterations to typical Transcranial Doppler Ultrasound (TCD) flow velocities and waveforms in CM have been described, but mechanistic contributors to these abnormalities are unknown. If identified, targeted, TCD-guided adjunctive therapy in CM may improve outcomes. METHODS: This was a prospective, observational study of children 6 months to 12 years with CM in Blantyre, Malawi recruited between January 2018 and June 2021. Medical history, physical examination, laboratory analysis, electroencephalogram, and magnetic resonance imaging were undertaken on presentation. Admission TCD results determined phenotypic grouping following a priori definitions. Evaluation of the relationship between haemodynamic, metabolic, or intracranial perturbations that lead to these observed phenotypes in other diseases was undertaken. Neurological outcomes at hospital discharge were evaluated using the Paediatric Cerebral Performance Categorization (PCPC) score. RESULTS: One hundred seventy-four patients were enrolled. Seven (4%) had a normal TCD examination, 57 (33%) met criteria for hyperaemia, 50 (29%) for low flow, 14 (8%) for microvascular obstruction, 11 (6%) for vasospasm, and 35 (20%) for isolated posterior circulation high flow. A lower cardiac index (CI) and higher systemic vascular resistive index (SVRI) were present in those with low flow than other groups (p \u3c 0.003), though these values are normal for age (CI 4.4 [3.7,5] l/min/m2, SVRI 1552 [1197,1961] dscm-5m2). Other parameters were largely not significantly different between phenotypes. Overall, 118 children (68%) had a good neurological outcome. Twenty-three (13%) died, and 33 (19%) had neurological deficits. Outcomes were best for participants with hyperaemia and isolated posterior high flow (PCPC 1-2 in 77 and 89% respectively). Participants with low flow had the least likelihood of a good outcome (PCPC 1-2 in 42%) (p \u3c 0.001). Cerebral autoregulation was significantly better in children with good outcome (transient hyperemic response ratio (THRR) 1.12 [1.04,1.2]) compared to a poor outcome (THRR 1.05 [0.98,1.02], p = 0.05). CONCLUSIONS: Common pathophysiological mechanisms leading to TCD phenotypes in non-malarial illness are not causative in children with CM. Alternative mechanistic contributors, including mechanical factors of the cerebrovasculature and biologically active regulators of vascular tone should be explored

Transfusion management of severe anaemia in African children: a consensus algorithm

The phase III Transfusion and Treatment of severe anaemia in African Children Trial(TRACT) found that conservative management of uncomplicated severe anaemia (haemoglobin(Hb)4-6g/dl) was safe and that transfusion volume(20 versus30 mls/kg whole blood equivalent)for children with severe anaemia (Hb37.5oC). In 2020 a stakeholder meeting of paediatric and blood transfusion groups from Africa reviewed the results and additional analyses. Among all children (3196) receiving an initial transfusion, there was no evidence that nutritional status, presence of shock, malaria parasite burden, or sickle cell disease status influenced outcomes, or modified the interaction with fever status on volume required. Fever status at the time of ordering blood was a reliable determinant of volume required for optimal outcome. Elevated heart and respiratory rates normalised irrespective of transfusion volume and without diuretics. By consensus, a transfusion management algorithm was developed, incorporating 3 additional measurements of Hb post-admission, alongside clinical monitoring. The proposed algorithm should help clinicians safely implement findings from TRACT. Further research should assess its implementation in routine clinical practic

Identifying critically ill children in Malawi: A modified qSOFA score for low-resource settings.

In low-resource settings, a reliable bedside score for timely identification of children at risk of dying, could help focus resources and improve survival. The rapid bedside Liverpool quick Sequential Organ Failure Assessment (LqSOFA) uses clinical parameters only and performed well in United Kingdom cohorts. A similarly quick clinical assessment-only score has however not yet been developed for paediatric populations in sub-Saharan Africa. In a development cohort of critically ill children in Malawi, we calculated the LqSOFA scores using age-adjusted heart rate and respiratory rate, capillary refill time and Blantyre Coma Scale, and evaluated its prognostic performance for mortality. An improved score, the Blantyre qSOFA (BqSOFA), was developed (omitting heart rate, adjusting respiratory rate cut-off values and adding pallor), subsequently validated in a second cohort of Malawian children, and compared with an existing score (FEAST-PET). Prognostic performance for mortality was evaluated using area under the receiver operating characteristic curve (AUC). Mortality was 15.4% in the development (N = 493) and 22.0% in the validation cohort (N = 377). In the development cohort, discriminative ability (AUC) of the LqSOFA to predict mortality was 0.68 (95%-CI: 0.60-0.76). The BqSOFA and FEAST-PET yielded AUCs of 0.84 (95%-CI:0.79-0.89) and 0.83 (95%-CI:0.77-0.89) in the development cohort, and 0.74 (95%-CI:0.68-0.79) and 0.76 (95%-CI:0.70-0.82) in the validation cohort, respectively. We developed a simple prognostic score for Malawian children based on four clinical parameters which performed as well as a more complex score. The BqSOFA might be used to promptly identify critically ill children at risk of dying and prioritize hospital care in low-resource settings

Intramuscular Artesunate for Severe Malaria in African Children: A Multicenter Randomized Controlled Trial.

BACKGROUND: Current artesunate (ARS) regimens for severe malaria are complex. Once daily intramuscular (i.m.) injection for 3 d would be simpler and more appropriate for remote health facilities than the current WHO-recommended regimen of five intravenous (i.v.) or i.m. injections over 4 d. We compared both a three-dose i.m. and a three-dose i.v. parenteral ARS regimen with the standard five-dose regimen using a non-inferiority design (with non-inferiority margins of 10%). METHODS AND FINDINGS: This randomized controlled trial included children (0.5-10 y) with severe malaria at seven sites in five African countries to assess whether the efficacy of simplified three-dose regimens is non-inferior to a five-dose regimen. We randomly allocated 1,047 children to receive a total dose of 12 mg/kg ARS as either a control regimen of five i.m. injections of 2.4 mg/kg (at 0, 12, 24, 48, and 72 h) (n = 348) or three injections of 4 mg/kg (at 0, 24, and 48 h) either i.m. (n = 348) or i.v. (n = 351), both of which were the intervention arms. The primary endpoint was the proportion of children with ≥ 99% reduction in parasitemia at 24 h from admission values, measured by microscopists who were blinded to the group allocations. Primary analysis was performed on the per-protocol population, which was 96% of the intention-to-treat population. Secondary analyses included an analysis of host and parasite genotypes as risks for prolongation of parasite clearance kinetics, measured every 6 h, and a Kaplan-Meier analysis to compare parasite clearance kinetics between treatment groups. A post hoc analysis was performed for delayed anemia, defined as hemoglobin ≤ 7 g/dl 7 d or more after admission. The per-protocol population was 1,002 children (five-dose i.m.: n = 331; three-dose i.m.: n = 338; three-dose i.v.: n = 333); 139 participants were lost to follow-up. In the three-dose i.m. arm, 265/338 (78%) children had a ≥ 99% reduction in parasitemia at 24 h compared to 263/331 (79%) receiving the five-dose i.m. regimen, showing non-inferiority of the simplified three-dose regimen to the conventional five-dose regimen (95% CI -7, 5; p = 0.02). In the three-dose i.v. arm, 246/333 (74%) children had ≥ 99% reduction in parasitemia at 24 h; hence, non-inferiority of this regimen to the five-dose control regimen was not shown (95% CI -12, 1; p = 0.24). Delayed parasite clearance was associated with the N86YPfmdr1 genotype. In a post hoc analysis, 192/885 (22%) children developed delayed anemia, an adverse event associated with increased leukocyte counts. There was no observed difference in delayed anemia between treatment arms. A potential limitation of the study is its open-label design, although the primary outcome measures were assessed in a blinded manner. CONCLUSIONS: A simplified three-dose i.m. regimen for severe malaria in African children is non-inferior to the more complex WHO-recommended regimen. Parenteral ARS is associated with a risk of delayed anemia in African children. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201102000277177

Incidence and predictors of hospital readmission in children presenting with severe anaemia in Uganda and Malawi: a secondary analysis of TRACT trial data

Background: Severe anaemia (haemoglobin < 6 g/dL) is a leading cause of recurrent hospitalisation in African children. We investigated predictors of readmission in children hospitalised with severe anaemia in the TRACT trial (ISRCTN84086586) in order to identify potential future interventions. Methods: Secondary analyses of the trial examined 3894 children from Uganda and Malawi surviving a hospital episode of severe anaemia. Predictors of all-cause readmission within 180 days of discharge were identified using multivariable regression with death as a competing risk. Groups of children with similar characteristics were identified using hierarchical clustering. Results: Of the 3894 survivors 682 (18%) were readmitted; 403 (10%) had ≥2 re-admissions over 180 days. Three main causes of readmission were identified: severe anaemia (n = 456), malaria (n = 252) and haemoglobinuria/dark urine syndrome (n = 165). Overall, factors increasing risk of readmission included HIV-infection (hazard ratio 2.48 (95% CI 1.63–3.78), p < 0.001); ≥2 hospital admissions in the preceding 12 months (1.44(1.19–1.74), p < 0.001); history of transfusion (1.48(1.13–1.93), p = 0.005); and missing ≥1 trial medication dose (proxy for care quality) (1.43 (1.21–1.69), p < 0.001). Children with uncomplicated severe anaemia (Hb 4-6 g/dL and no severity features), who never received a transfusion (per trial protocol) during the initial admission had a substantially lower risk of readmission (0.67(0.47–0.96), p = 0.04). Malaria (among children with no prior history of transfusion) (0.60(0.47–0.76), p < 0.001); younger-age (1.07 (1.03–1.10) per 1 year younger, p < 0.001) and known sickle cell disease (0.62(0.46–0.82), p = 0.001) also decreased risk of readmission. For anaemia re-admissions, gross splenomegaly and enlarged spleen increased risk by 1.73(1.23–2.44) and 1.46(1.18–1.82) respectively compared to no splenomegaly. Clustering identified four groups of children with readmission rates from 14 to 20%. The cluster with the highest readmission rate was characterised by very low haemoglobin (mean 3.6 g/dL). Sickle Cell Disease (SCD) predominated in two clusters associated with chronic repeated admissions or severe, acute presentations in largely undiagnosed SCD. The final cluster had high rates of malaria (78%), severity signs and very low platelet count, consistent with acute severe malaria. Conclusions: Younger age, HIV infection and history of previous hospital admissions predicted increased risk of readmission. However, no obvious clinical factors for intervention were identified. As missing medication doses was highly predictive, attention to care related factors may be important. Trial registration: ISRCTN ISRCTN84086586. Keywords: Severe anaemia, Readmissio

Digital innovation for food security: a case study of the TEEAL programme and its contribution to agricultural research output in African institutions

This article looks at The Essential Electronic Agricultural Library (TEEAL), an innovative offline database, and its impact on research output in agricultural institutions in Africa. The article also examines some lessons gathered from 10 years of training and outreach on the system in Sub-Saharan Africa. TEEAL, a project of Cornell University’s R. Mann Library, in cooperation with over 50 major scientific publishers, societies, and index providers, is a digital collection of research journals for agriculture and related sciences. Researchers, students, academic staff and librarians can discover and access thousands of full-text PDF articles without the use of the Internet. Through TEEAL, scientists in developing countries now have access to current research; but has this access translated into effective research and teaching? Several studies have been carried out to evaluate whether TEEAL was meeting its objective of contributing to the enhancement of the quality and effectiveness of agricultural research and teaching through improving students’ and researchers’ access to relevant literature. The studies took various approaches in collecting data including a questionnaire, interviews and a bibliometric analysis of publications from institutions that have acquired and are using TEEAL. Results generally show that TEEAL is successfully meeting its objective. Recommendations are made for extending the use of TEEAL sets, particularly the inclusion of more journals from developing countries as a way of further enhancing its appeal to a wider audience.Innovation, No,44, June 201