Improving blood transfusion safety in resource-poor countries: a case study of using leucocyte reduced blood in Uganda

Background: The majority of blood transfusion safety strategies recommended by the WHO for resource-poor countries focus mainly on reducing the risk of transfusion-transmitted infections (TTIs). Other technologies such as leucocyte reduction may represent complementary strategies for improving transfusion safety. Objective: To evaluate the role of using leucocyte reduced blood in a resource-poor country. Methods: Pre-storage leucocyte reduced (LR) red blood cells (RBCs) were specially prepared for the Tissue Oxygenation by Transfusion in severe Anaemia and Lactic acidosis (TOTAL) study, at the Uganda Blood Transfusion Services from February 2013 through May 2015. Quality control tests were performed to evaluate the procedure, and the incremental cost of an LR\u2013RBC unit was estimated. Results: A total of 608 RBCs units were leucocyte reduced. Quality control tests were performed on 55 random RBCs units. The median (IQR) residual leucocyte count was 4 (0\u20225-10) WBC/uL, equivalent to 1\u20228x106> WBC per unit. The estimated incremental unit cost of leucocyte reduction was $37 USD per LR RBC unit. Conclusion: Leucocyte reduction of blood in a resource-poor country is doable although relatively costly. As such, its value in resource-poor countries should be weighed against other transfusion safety propositions

Blood use in sub‐Saharan Africa: a systematic review of current data

Background: Data on the use of blood products in sub-Saharan Africa (SSA) are scarce. A systematic review of published data on blood utilization according to diagnosis in SSA was performed. Study design and methods: Studies published from January 2000 to June 2018 were searched in PubMed, Embase and African Index Medicus. Data were extracted and synthesized. The proportion of blood products used for different diagnostic categories is presented. Results: 37 studies representing 159,746 transfusions to 96,690 patients from 14 countries in SSA were included. Data from six of 37 studies were pooled to determine blood product use according to diagnosis. The primary diagnostic categories were pediatric malaria (20%), sickle cell anemia [SCA] (18%), obstetric hemorrhage (16%), and other causes of bleeding (16%). About 8%, 6% and 2% of products were used for other infections, cancer treatment, and surgery respectively. Overall, 58.5% of the products transfused were red blood cells, 31.7 % whole blood, 7.2% fresh frozen plasma, and 2.6% as platelets. Estimated blood product use per population in SSA was 5.3 transfusions per 1000 people, compared with 52 and 34 per thousand for Australia and United States respectively. Conclusion: This study provides a systematic attempt to quantify blood utilization for SSA. Blood products in SSA are used primarily for pediatric malaria, SCA, obstetric hemorrhage and other causes of bleeding. Studies such as this represent an important early step towards improving hemovigilance in SSA

Community perceptions of paediatric severe anaemia in Uganda

BACKGROUND: Severe anaemia remains a major cause of morbidity and mortality among children in sub-Saharan Africa. There is limited research on the beliefs and knowledge for paediatric severe anaemia in the region. The effect of these local beliefs and knowledge on the healthcare seeking of paediatric severe anaemia remains unknown. OBJECTIVE: To describe community perceptions of paediatric severe anaemia in Uganda. METHODS: Sixteen in-depth interviews of caregivers of children treated for severe anaemia and six focus group discussions of community members were conducted in three regions of Uganda between October and November 2017. RESULTS: There was no common local name used to describe paediatric severe anaemia, but the disease was understood in context as 'having no blood'. Severe anaemia was identified to be a serious disease and the majority felt blood transfusion was the ideal treatment, but concomitant use of traditional and home remedies was also widespread. Participants articulated signs of severe pediatric anemia, such as palmar, conjunctival, and tongue pallor. Other signs described included jaundice, splenomegaly, difficulty in breathing and poor appetite. Poor feeding, malaria, splenomegaly and evil spirits were perceived to be the common causes of severe anaemia. Other causes included: human immunodeficiency virus (HIV), haemoglobinuria, fever, witchcraft, mosquito bites, and sickle cell. Splenomegaly and jaundice were perceived to be both signs and causes of severe anaemia. Severe anaemia was interpreted to be caused by evil spirits if it was either recurrent, led to sudden death, or manifested with cold extremities. CONCLUSION: The community in Uganda perceived paediatric severe anaemia as a serious disease. Their understanding of the signs and perceived causes of severe anaemia to a large extent aligned with known clinical signs and biological causes. Belief in evil spirits persists and may be one obstacle to seeking timely medical care for paediatric severe anaemia

Caregivers and community perceptions of blood transfusion for children with severe anaemia in Uganda

Objective To describe local perceptions of blood transfusion for children with severe anaemia in Uganda. Background Blood transfusion is a common emergency treatment for children with severe anaemia and saves millions of lives of African children. However, the perceptions of transfusion recipients have not been well studied. A better understanding of the perceived risk may improve transfusion care. Methods A qualitative study based on 16 in‐depth interviews of caregivers of transfused children, and six focus group discussions with community members was conducted in three regions of Uganda between October and November 2017. Results Caregivers of children and community members held blood transfusion in high regard and valued it as life‐saving. However, there were widespread perceived transfusion risks, including: Human immunodeficiency virus (HIV) transmission, too rapid blood infusion and blood incompatibility. Other concerns were: fatality, changes in behaviour, donor blood being ‘too strong’ and use of animal blood. In contrast, recent transfusion, older age, knowledge of HIV screening of blood for transfusion, faith in God and having a critically ill child were associated with less fear about transfusion. Respondents also emphasised challenges to transfusion services access including distance to hospitals, scarcity of blood and health workers' attitudes. Conclusion Perceptions of the community and caregivers of transfused children in Uganda about blood transfusion were complex: transfusion is considered life‐saving but there were strong perceived transfusion risks of HIV transmission and blood incompatibility. Addressing community perceptions and facilitating access to blood transfusion represent important strategies to improve paediatric transfusion care

Cytoadherence in paediatric malaria: ABO blood group, CD36, and ICAM1 expression and severe Plasmodium falciparum infection

As a leading cause of childhood mortality worldwide, selection pressure by Plasmodium falciparum continues to shape the human genome. Severe disturbances within the microcirculation result from the adhesion of infected erythrocytes to host receptors on monocytes, platelets, and endothelium. In this prospective study, we compared expression of all major host cytoadhesion receptors among Ugandan children presenting with uncomplicated malaria (n = 1078) versus children with severe malaria (n = 855), including cerebral malaria (n = 174), severe anaemia (n = 522), and lactic acidosis (n = 154). We report a significant survival advantage attributed to blood group O and increased monocyte expression of CD36 and ICAM1 (CD54). The high case fatality rate syndromes of cerebral malaria and lactic acidosis were associated with high platelet CD36 expression and thrombocytopenia, and severe malaria anaemia was characterized by low ICAM1 expression. In a logistic regression model of disease severity, odds ratios for the mitigating effects of blood group O, CD36, and ICAM1 phenotypes were greater than that of sickle haemoglobin. Host genetic adaptations to Plasmodium falciparum suggest new potential malaria treatment strategies

Inter-Relationships of Cardinal Features and Outcomes of Symptomatic Pediatric Plasmodium falciparum Malaria in 1,933 Children in Kampala, Uganda

Malaria remains a challenging diagnosis with variable clinical presentation and a wide spectrum of disease severity. Using a structured case report form, we prospectively assessed 1,933 children at Mulago Hospital in Kampala, Uganda with acute Plasmodium falciparum malaria. Children with uncomplicated malaria significantly differed from those with severe disease for 17 features. Among 855 children with severe disease, the case-fatality rate increased as the number of severity features increased. Logistic regression identified five factors independently associated with death: cerebral malaria, hypoxia, severe thrombocytopenia, leukocytosis, and lactic acidosis. Cluster analysis identified two groups: one combining anemia, splenomegaly, and leukocytosis; and a second group centered on death, severe thrombocytopenia, and lactic acidosis, which included cerebral malaria, hypoxia, hypoglycemia, and hyper-parasitemia. Our report updates previous clinical descriptions of severe malaria, quantifies significant clinical and laboratory inter-relationships, and will assist clinicians treating malaria and those planning or assessing future research (NCT00707200) (www.clinicaltrials.gov)

Dysregulation of the haem-haemopexin axis is associated with severe malaria in a case-control study of Ugandan children.

BACKGROUND: Malaria is associated with haemolysis and the release of plasma haem. Plasma haem can cause endothelial injury and organ dysfunction, and is normally scavenged by haemopexin to limit toxicity. It was hypothesized that dysregulation of the haem-haemopexin pathway contributes to severe and fatal malaria infections. METHODS: Plasma levels of haemin (oxidized haem), haemopexin, haptoglobin, and haemoglobin were quantified in a case-control study of Ugandan children with Plasmodium falciparum malaria. Levels at presentation were compared in children with uncomplicated malaria (UM; n = 29), severe malarial anaemia (SMA; n = 27) or cerebral malaria (CM; n = 31), and evaluated for utility in predicting fatal (n = 19) vs non-fatal (n = 39) outcomes in severe disease. A causal role for haemopexin was assessed in a pre-clinical model of experimental cerebral malaria (ECM), following disruption of mouse haemopexin gene (hpx). Analysis was done using Kruskall Wallis tests, Mann-Whitney tests, log-rank tests for survival, and repeated measures ANOVA. RESULTS: In Ugandan children presenting with P. falciparum malaria, haemin levels were higher and haemopexin levels were lower in SMA and CM compared to children with UM (haemin, p \u3c 0.01; haemopexin, p \u3c 0.0001). Among all cases of severe malaria, elevated levels of haemin and cell-free haemoglobin at presentation were associated with subsequent mortality (p \u3c 0.05). Compared to ECM-resistant BALB/c mice, susceptible C57BL/6 mice had lower circulating levels of haemopexin (p \u3c 0.01), and targeted deletion of the haemopexin gene, hpx, resulted in increased mortality compared to their wild type littermates (p \u3c 0.05). CONCLUSIONS: These data indicate that plasma levels of haemin and haemopexin measured at presentation correlate with malaria severity and levels of haemin and cell-free haemoglobin predict outcome in paediatric severe malaria. Mechanistic studies in the ECM model support a causal role for the haem-haemopexin axis in ECM pathobiology

Economic evaluation of postdischarge malaria chemoprevention in preschool children treated for severe anaemia in Malawi, Kenya, and Uganda: A cost-effectiveness analysis

Background Children hospitalised with severe anaemia in malaria-endemic areas are at a high risk of dying or being readmitted within six months of discharge. A trial in Kenya and Uganda showed that three months of postdischarge malaria chemoprevention (PDMC) with monthly dihydroartemisinin-piperaquine (DP) substantially reduced this risk. The World Health Organization recently included PDMC in its malaria chemoprevention guidelines. We conducted a cost-effectiveness analysis of community-based PDMC delivery (supplying all three PDMC-DP courses to caregivers at discharge to administer at home), facility-based PDMC delivery (monthly dispensing of PDMC-DP at the hospital), and the standard of care (no PDMC). Methods We combined data from two recently completed trials; one placebo-controlled trial in Kenya and Uganda collecting efficacy data (May 6, 2016 until November 15, 2018; n=1049), and one delivery mechanism trial from Malawi collecting adherence data (March 24, 2016 until October 3, 2018; n=375). Cost data were collected alongside both trials. Three Markov decision models, one each for Malawi, Kenya, and Uganda, were used to compute incremental cost-effectiveness ratios expressed as costs per quality-adjusted life-year (QALY) gained. Deterministic and probabilistic sensitivity analyses were performed to account for uncertainty. Findings Both PDMC strategies were cost-saving in each country, meaning less costly and more effective in increasing health-adjusted life expectancy than the standard of care. The estimated incremental cost savings for community-based PDMC compared to the standard of care were US$ 22·10 (Malawi), 38·52 (Kenya), and 26·23 (Uganda) per child treated. The incremental effectiveness gain using either PDMC strategy varied between 0·3 and 0·4 QALYs. Community-based PDMC was less costly and more effective than facility-based PDMC. These results remained robust in sensitivity analyses. Interpretation PDMC under implementation conditions is cost-saving. Caregivers receiving PDMC at discharge is a cost-effective delivery strategy for implementation in malaria-endemic southeastern African settings

Post-discharge Malaria Chemoprevention in Children Admitted with Severe Anaemia in Malaria-Endemic Settings in Africa: A systematic review and Individual Patient Data meta-analysis of randomised controlled trials

Background: Severe anaemia is associated with high in-hospital mortality among young children. In malaria-endemic areas, surviving children also have an increased risk of mortality or readmission after hospital discharge. We conducted an individual patient data (IPD) meta-analysis to determine the efficacy of monthly post-discharge malaria chemoprevention (PDMC) in children recovering from severe anaemia. Methods: Following PRISMA-IPD guidelines, we searched multiple databases, without time or language restrictions, for randomised controlled trials comparing monthly PDMC with placebo or standard-of-care among children admitted with severe anaemia in malaria-endemic Africa. Trials using daily or weekly malaria prophylaxis were not eligible. Fixed-effects two-stage meta-analysis of risk ratios (RR) was used to generate pooled effect estimates for mortality. Recurrent time-to-event data were analysed using one-stage mixed-effects Prentice-Williams-Peterson Total-Time models to obtain hazard ratios (HRs). This study is registered with PROSPERO-CRD42022308791. Findings: Three double-blind placebo-controlled trials involving 3,663 children with severe anaemia fulfilled the eligibility criteria; 3,507 (95.7%) contributed to the modified intention-to-treat analysis. They received either monthly sulfadoxine-pyrimethamine until the end of the malaria transmission season (average 3.1 courses/child) (N=1,085, the Gambia), monthly artemether-lumefantrine given at the end of the 4th and 8th week post-discharge (N=1,373, Malawi), or monthly dihydroartemisinin-piperaquine given at the end of the 2nd, 6th, and 10th week post-discharge (N=1,049, Uganda and Kenya). During the period of chemoprevention, PDMC was associated with a 77% reduction in mortality (RR=0.23 [95% CI 0.08-0.70], p=0.0094, I2=0%) and a 55% reduction in all-cause readmissions (HR=0.45 [0.36-0.56], p<0.0001). The reductions were not sustained after protective drug levels had waned. The small number of trials limited our ability to assess heterogeneity, its sources and publication bias. Interpretation: In malaria-endemic Africa, PDMC reduces mortality and readmissions in recently discharged children recovering from severe anaemia. PDMC can be a valuable strategy for the post-discharge management of this high-risk group. Future research should focus on methods of PDMC delivery, options to prolong the protection duration, other hospitalised special risk groups, and interventions targeting non-malarial causes of post-discharge morbidity

Implementation of post-discharge malaria chemoprevention (PDMC) in Benin, Kenya, Malawi, and Uganda: stakeholder engagement meeting report

A Stakeholder engagement meeting on the implementation of post-discharge malaria chemoprevention (PDMC) in Benin, Kenya, Malawi, and Uganda was held in Nairobi, Kenya, on 27 September 2023. Representatives from the respective National Malaria Control Programmes, the World Health Organization (WHO) Geneva, Africa Regional and Kenya offices, research partners, non-governmental rganizations, and the Medicines for Malaria Venture participated. PDMC was recommended by the WHO in June 2022 and involves provision of a full anti-malarial treatment course at regular intervals during the post-discharge period in children hospitalized with severe anaemia in areas of moderate-to-high malaria transmission. The WHO recommendation followed evidence from a meta-analysis of three clinical trials and from acceptability, delivery, cost-ffectiveness, and modelling studies. The trials were conducted in The Gambia using monthly sulfadoxine-pyrimethamine during the transmission season, in Malawi using monthly artemether-lumefantrine, and in Kenya and Uganda using monthly dihydroartemisinin-piperaquine, showing a significant reduction in all-cause mortality by 77% (95% CI 30–98) and a 55% (95% CI 44–64) reduction in all-cause hospital readmissions 6 months post-discharge. The recommendation has not yet been implemented in sub-Saharan Africa. There is no established platform for PDMC delivery. The objectives of the meeting were for the participating countries to share country contexts, plans and experiences regarding the adoption and implementation of PDMC and to explore potential delivery platforms in each setting. The meeting served as the beginning of stakeholder engagement within the PDMC Saves Lives project and will be followed by formative and implementation research to evaluate alternative delivery strategies in selected countries. Meeting highlights included country consensus on use of dihydroartemisinin-piperaquine for PDMC and expansion of the target group to "severe anaemia or severe malaria", in addition to identifying country-specific options for PDMC delivery for evaluation in implementation research. Further exploration is needed on whether the age group should be extended to school-age children