The Burden and Spectrum of Paediatric Severe Malaria and Aetiology of Dark Urine Syndrome in Eastern Uganda

From May 2011 - April 2012, I prospectively conducted paediatric ward admissions surveillance (WSS) and described both the in-patient burden and clinical spectrum of severe P. falciparum malaria (SM) in children admitted to Mbale Regional Referral Hospital (Mbale RRH). Furthermore, epidemiology, clinical features and the outcomes of dark urine syndrome (DUS) were described using both retrospective dark urine epidemiological study (REDUES); (FEAST trial ISRCTN 69856593) and the prospective dark urine epidemiological study (PRODUES) nested in the WSS. Overall 10,208/23,217 (44.0%) children were enrolled in the WSS, a majority 87% were under 5 years of age. Malaria 6,714/10,208 (65. 8%) and DUS 1,087/10,208 (10.6%) were among the common diagnoses. Neonatal conditions accounted for 947/9,551 (10.0%) admissions. The in-hospital mortality was high 655 (6.4%); with higher case fatality rate (CFR) 13.2% in neonates compared to 3.7% in older children, P=0.0001. The WHO criteria for surveillance of severe malaria were fulfilled in 662 admissions or 10% of all malaria cases. The common clinical presentations included respiratory distress 554/662 (83.7%), shock 411/662 (62.1%), clinical jaundice 177/662 (26.7%), severe anaemia 169/662 (25.5%), hyperlactataemia 134/662 (20. 3%) and DUS 93/662 (14.0%); features similar to, but also varying from those reported from other settings. The mortality in SM was high 63/662 (9.5%) but consistent with other reports, with higher CFR in patients with multiple features. In the REDUES, 394/3,170 (12.4%) had DUS with a majority 318/394 (81.0%) presenting to Eastern Uganda. Complications of DUS included clinical jaundice in 256/318 (80.5%) and severe anaemia (Hb P=0.211) was similar in children with and without DUS respectively. PRODUES enrolled 268 strictly defined cases in whom use of antimalarials 129/268 (48.1%) and herbs 52/268 (19.4%) were common. Haemoglobinuria 92/165 (55.8%) and myoglobinuria 59/165 (36.0%), markers of massive haemolysis and muscle cell injury respectively were found; possibly related to the pathophysiology of malaria. In conclusion, the spectrum of SM in children at Mbale RRH was similar to, but also varied from current descriptions from other sites. The DUS was linked to malaria with innate characteristics and drugs being risk factors

Evaluation of antiretroviral therapy information system in Mbale Regional Referral Hospital, Uganda

Magister Public Health - MPHHIV/AIDS is the largest and most serious global epidemic in the recent times. To date, the epidemic has affected approximately 40 million people (range 33 - 46 million) of whom 67%, that is, an estimated 27 million people are in the Sub Saharan Africa. The Sub Saharan Africa is also reported to have the highest regional prevalence of 7.2% compared to an average of 2% in other regions. A medical cure for HIV/AIDS remains elusive but use of antiretroviral therapy (ART) has resulted in improvement of quality and quantity of life as evidenced by the reduction of mortality and morbidity associated with the infection, hence longer and good quality life for HIV/AIDS patients on ART.South Afric

Increased adhesion of Plasmodium falciparum infected erythrocytes to ICAM-1 in children with acute intestinal injury

Background Children with severe malaria are at increased risk of invasive bacterial disease particularly infection with enteric gram-negative organisms. These organisms are likely to originate from the gut, however, how and why they breach the intestinal interface in the context of malaria infection remains unclear. One explanation is that accumulation of infected red blood cells (iRBCs) in the intestinal microvasculature contributes to tissue damage and subsequent microbial translocation which can be addressed through investigation of the impact of cytoadhesion in patients with malaria and intestinal damage. Methods Using a static adhesion assay, cytoadhesion of iRBCs was quantified in 48 children with malaria to recombinant proteins constitutively expressed on endothelial cell surfaces. Cytoadhesive phenotypes between children with and without biochemical evidence of intestinal damage [defined as endotoxemia or elevated plasma intestinal fatty acid binding protein (I-FABP)] was compared. Results The majority of parasites demonstrated binding to the endothelial receptors CD36 and to a lesser extent to ICAM-1. Reduced adhesion to CD36 but not adhesion to ICAM-1 or rosetting was associated with malarial anaemia (p = 0.004). Increased adhesion of iRBCs to ICAM-1 in children who had evidence of elevated I-FABP (p = 0.022), a marker of intestinal ischaemia was observed. There was no correlation between the presence of endotoxemia and increased adhesion to any of the recombinant proteins. Conclusion Increased parasite adhesion to ICAM-1 in children with evidence of intestinal ischaemia lends further evidence to a link between the cytoadherence of iRBCs in gut microvasculature and intestinal damage

Inhibition of an erythrocyte tyrosine kinase with imatinib prevents Plasmodium falciparum egress and terminates parasitemia

With half of the world's population at risk for malaria infection and with drug resistance on the rise, the search for mutation-resistant therapies has intensified. We report here a therapy for Plasmodium falciparum malaria that acts by inhibiting the phosphorylation of erythrocyte membrane band 3 by an erythrocyte tyrosine kinase. Because tyrosine phosphorylation of band 3 causes a destabilization of the erythrocyte membrane required for parasite egress, inhibition of the erythrocyte tyrosine kinase leads to parasite entrapment and termination of the infection. Moreover, because one of the kinase inhibitors to demonstrate antimalarial activity is imatinib, i.e. an FDA-approved drug authorized for use in children, translation of the therapy into the clinic will be facilitated. At a time when drug resistant strains of P. falciparum are emerging, a strategy that targets a host enzyme that cannot be mutated by the parasite should constitute a therapeutic mechanism that will retard evolution of resistance

Inhibition of an erythrocyte tyrosine kinase with imatinib prevents <i>Plasmodium falciparum</i> egress and terminates parasitemia

With half of the world’s population at risk for malaria infection and with drug resistance on the rise, the search for mutation-resistant therapies has intensified. We report here a therapy for Plasmodium falciparum malaria that acts by inhibiting the phosphorylation of erythrocyte membrane band 3 by an erythrocyte tyrosine kinase. Because tyrosine phosphorylation of band 3 causes a destabilization of the erythrocyte membrane required for parasite egress, inhibition of the erythrocyte tyrosine kinase leads to parasite entrapment and termination of the infection. Moreover, because one of the kinase inhibitors to demonstrate antimalarial activity is imatinib, i.e. an FDA-approved drug authorized for use in children, translation of the therapy into the clinic will be facilitated. At a time when drug resistant strains of P. falciparum are emerging, a strategy that targets a host enzyme that cannot be mutated by the parasite should constitute a therapeutic mechanism that will retard evolution of resistance

Children’s Oxygen Administration Strategies Trial (COAST): A randomised controlled trial of high flow versus oxygen versus control in African children with severe pneumonia.

Background: In Africa, the clinical syndrome of pneumonia remains the leading cause of morbidity and mortality in children in the post-neonatal period. This represents a significant burden on in-patient services. The targeted use of oxygen and simple, non-invasive methods of respiratory support may be a highly cost-effective means of improving outcome, but the optimal oxygen saturation threshold that results in benefit and the best strategy for delivery are yet to be tested in adequately powered randomised controlled trials. There is, however, an accumulating literature about the harms of oxygen therapy across a range of acute and emergency situations that have stimulated a number of trials investigating permissive hypoxia. Methods: In 4200 African children, aged 2 months to 12 years, presenting to 5 hospitals in East Africa with respiratory distress and hypoxia (oxygen saturation \u3c 92%), the COAST trial will simultaneously evaluate two related interventions (targeted use of oxygen with respect to the optimal oxygen saturation threshold for treatment and mode of delivery) to reduce shorter-term mortality at 48-hours (primary endpoint), and longer-term morbidity and mortality to 28 days in a fractional factorial design, that compares: Liberal oxygenation (recommended care) compared with a strategy that permits hypoxia to SpO2 \u3e or = 80% (permissive hypoxia); and High flow using AIrVO2TM compared with low flow delivery (routine care). Discussion: The overarching objective is to address the key research gaps in the therapeutic use of oxygen in resource-limited setting in order to provide a better evidence base for future management guidelines. The trial has been designed to address the poor outcomes of children in sub-Saharan Africa, which are associated with high rates of in-hospital mortality, 9-10% (for those with oxygen saturations of 80-92%) and 26-30% case fatality for those with oxygen saturations \u3c80%

Nutritional supplementation in children with severe pneumonia in Uganda and Kenya (COAST-Nutrition): a phase 2 randomised controlled trial

Background Severe pneumonia in African children results in poor long-term outcomes (deaths/readmissions) with undernutrition as a key risk factor. We hypothesised additional energy/protein-rich Ready-to-Use Therapeutic Foods (RUTF) would meet additional nutritional requirements and improve outcomes. Methods COAST-Nutrition was an open-label Phase 2 randomised controlled trial in children (aged 6 months-12 years) hospitalised with severe pneumonia (and hypoxaemia, SpO2 \u3c92%) in Mbale, Soroti, Jinja, Masaka Regional Referral Hospitals, Uganda and Kilifi County Hospital, Kenya (ISRCTN10829073 (registered 6th June 2018) PACTR202106635355751 (registered 2nd June 2021)). Children were randomised (ratio 1:1) to enhanced nutritional supplementation with RUTF (plus usual diet) for 56 days vs usual diet (control). The primary outcome was change in mid-upper arm circumference (MUAC) at 90 days as a composite with mortality. Secondary outcomes include anthropometric status, mortality, and readmissions at Days 28, 90 and 180. Findings Between 12 August 2018 and 22 April 2022, 846 eligible children were randomised, 424 to RUTF and 422 to usual diet, and followed for 180-days [12 (1%) lost-to-follow-up]. RUTF supplement was initiated in 417/419 (\u3e99%). By Day 90, there was no significant difference in the composite endpoint (probabilistic index 0.49, 95% CI 0.45–0.53, p = 0.74). Respective 90-day mortality (13/420 3.1% vs 14/421 3.3%) and MUAC increment (0.54 (SD 0.85) vs 0.55 (SD 0.81)) were similar between arms. There was no difference in any anthropometric secondary endpoints to Day 28, 90 or 180 except skinfold thickness at Day 28 and Day 90 was greater in the RUTF arm. Serious adverse events were higher in the RUTF arm (n = 164 vs 108), mainly due to hospital readmission for acute illness (54/387 (14%) vs 37/375 (10%). Interpretation Our study suggested that nutritional supplementation with RUTF did not improve outcomes to 180 days in children with severe pneumonia. Funding This trial is part of the EDCTP2 programme (grant number RIA-2016S-1636-COAST-Nutrition) supported by the European Union, and UK Joint Global Health Trials scheme: Medical Research Council, Department for International Development, Wellcome Trust (grant number MR/L004364/1, UK)

Children’s oxygen administration strategies trial (COAST): A randomised controlled trial of high flow versus oxygen versus control in African children with severe pneumonia

Background: In Africa, the clinical syndrome of pneumonia remains the leading cause of morbidity and mortality in children in the post-neonatal period. This represents a significant burden on in-patient services. The targeted use of oxygen and simple, non-invasive methods of respiratory support may be a highly cost-effective means of improving outcome, but the optimal oxygen saturation threshold that results in benefit and the best strategy for delivery are yet to be tested in adequately powered randomised controlled trials. There is, however, an accumulating literature about the harms of oxygen therapy across a range of acute and emergency situations that have stimulated a number of trials investigating permissive hypoxia.Methods: In 4200 African children, aged 2 months to 12 years, presenting to 5 hospitals in East Africa with respiratory distress and hypoxia (oxygen saturation \u3c 92%), the COAST trial will simultaneously evaluate two related interventions (targeted use of oxygen with respect to the optimal oxygen saturation threshold for treatment and mode of delivery) to reduce shorter-term mortality at 48-hours (primary endpoint), and longer-term morbidity and mortality to 28 days in a fractional factorial design, that compares: Liberal oxygenation (recommended care) compared with a strategy that permits hypoxia to SpO2 \u3e or = 80% (permissive hypoxia); and High flow using AIrVO2TM compared with low flow delivery (routine care)

Immediate Versus Triggered Transfusion for Children with Uncomplicated Severe Anaemia

Background: The World Health Organization recommends a haemoglobin transfusion threshold of 0.2) nor evidence of differences between groups in re-admissions (p=0.36), serious adverse events (p=0.36) nor in haemoglobin recovery at 180-days (p=0.08). Length-of-stay was mean 0.9 days longer in the triggered group. Conclusions: There was no evidence of differences in clinical outcomes over 6 months with triggered vs immediate transfusion. Triggered transfusion reduced blood-volume requirements by 60% but increased length-of-stay by 20% and required repeated haemoglobin monitoring and surveillance