BackgroundChildren presenting to hospital with recent or current Plasmodium falciparum malaria are at increased the risk of invasive bacterial disease, largely enteric gram-negative organisms (ENGO), which is associated with increased mortality and recurrent morbidity. Although incompletely understood, the most likely source of EGNO is the bowel. We hypothesised that as a result of impaired gut-barrier function endotoxin (lipopolysaccharide), present in the cell-wall of EGNO and in substantial quantities in the gut, is translocated into the bloodstream, and contributes to the pathophysiology of children with severe malaria.MethodsWe conducted a prospective study in 257 children presenting with malaria to two hospitals in Kenya and Uganda. We analysed the clinical presentation, endotoxin and cytokine concentration.ResultsEndotoxaemia (endotoxin activity ≥0.4 EAA Units) was observed in 71 (27.6%) children but its presence was independent of both disease severity and outcome. Endotoxaemia was more frequent in children with severe anaemia but not specifically associated with other complications of malaria. Endotoxaemia was associated with a depressed inflammatory and anti-inflammatory cytokine response. Plasma endotoxin levels in severe malaria negatively correlated with IL6, IL10 and TGFβ (Spearman rho: TNFα: r=−0.122, p=0.121; IL6: r=−0.330, p<0.0001; IL10: r=−0.461, p<0.0001; TGFβ: r=−0.173, p<0.027).ConclusionsEndotoxaemia is common in malaria and results in temporary immune paralysis, similar to that observed in patients with sepsis and experimentally-induced endotoxaemia. Intense sequestration of P. falciparum-infected erythrocytes within the endothelial bed of the gut has been observed in pathological studies and may lead to gut-barrier dysfuction. The association of endotoxaemia with the anaemia phenotype implies that it may contribute to the dyserythropoesis accompanying malaria through inflammation. Both of these factors feasibly underpin the susceptibility to EGNO co-infection. Further research is required to investigate this initial finding, with a view to future treatment trials targeting mechanism and appropriate antimicrobial treatment.

BackgroundSevere anemia (SA, hemoglobin <6 g/dl) is a leading cause of pediatric hospital admission in Africa, with significant in-hospital mortality. The underlying etiology is often infectious, but specific pathogens are rarely identified. Guidelines developed to encourage rational blood use recommend a standard volume of whole blood (20 ml/kg) for transfusion, but this is commonly associated with a frequent need for repeat transfusion and poor outcome. Evidence is lacking on what hemoglobin threshold criteria for intervention and volume are associated with the optimal survival outcomes.MethodsWe evaluated the safety and efficacy of a higher volume of whole blood (30 ml/kg; Tx30: n = 78) against the standard volume (20 ml/kg; Tx20: n = 82) in Ugandan children (median age 36 months (interquartile range (IQR) 13 to 53)) for 24-hour anemia correction (hemoglobin >6 g/dl: primary outcome) and 28-day survival.ResultsMedian admission hemoglobin was 4.2 g/dl (IQR 3.1 to 4.9). Initial volume received followed the randomization strategy in 155 (97%) patients. By 24-hours, 70 (90%) children in the Tx30 arm had corrected SA compared to 61 (74%) in the Tx20 arm; cause-specific hazard ratio = 1.54 (95% confidence interval 1.09 to 2.18, P = 0.01). From admission to day 28 there was a greater hemoglobin increase from enrollment in Tx30 (global P <0.0001). Serious adverse events included one non-fatal allergic reaction and one death in the Tx30 arm. There were six deaths in the Tx20 arm (P = 0.12); three deaths were adjudicated as possibly related to transfusion, but none secondary to volume overload.ConclusionA higher initial transfusion volume prescribed at hospital admission was safe and resulted in an accelerated hematological recovery in Ugandan children with SA. Future testing in a large, pragmatic clinical trial to establish the effect on short and longer-term survival is warranted.Trial registrationClinicalTrials.Gov identifier: NCT01461590 registered 26 October 2011.Please see related commentary article http://www.biomedcentral.com/1741-7015/12/68/abstract.

Background: Severe anaemia in children requiring hospital admission is a major public health problem in malaria-endemic Africa. Affordable methods for the assessment of haemoglobin have not been validated against gold standard measures for identifying those with severe anaemia requiring a blood transfusion, despite this resource being in short supply. Methods: We conducted a prospective descriptive study of hospitalized children aged 2 months – 12 years at Mbale and Soroti Regional Referral Hospitals, assessed to have pallor at triage by a nurse and two clinicians. Haemoglobin levels were measured using the HemoCue® Hb 301 system (gold standard); the Haemoglobin Colour Scale; calorimetric and Sahli’s methods. We report clinical assessments of the degree of pallor, clinicians’ intention to transfuse, inter-observer agreement, limits of agreement using the Bland-Altman method, and the sensitivity and specificity of each method in comparison to HemoCue® Results: We recruited 322 children assessed by the admitting nurse as having severe (164; 51.0%), moderate (99; 30.7%) or mild (57; 17.7%) pallor. Agreement between the clinicians and the nurse were good: Clinician A Kappa=0.68 (0.60–0.76) and Clinician B Kappa=0.62 (0.53–0.71) respectively (P<0.0001 for both). The nurse, clinicians A and B indicated that of 94/116 (81.0%), 83/121 (68.6%) and 93/120 (77.5%) respectively required transfusion. HemoCue® readings indicated anaemia as mild (Hb10.0–11.9g/dl) in 8/292 (2.7%), moderate (Hb5.0–9.9g/dl) in 132/292 (45.2%) and severe (Hb<5.0g/dl) in 152/292 (52.1%). Comparing to HemoCue® the Sahli’s method performed best in estimation of severe anaemia, with sensitivity 84.0% and specificity 87.9% and a Kappa score of  0.70 (0.64–0.80). Conclusions: Clinical assessment of severe pallor results has a low specificity for the diagnosis of severe anaemia. To target blood transfusion Hb measurement by either Hemocue® or Sahli’s method for the cost of USD 4 or and USD 0.25 per test, respectively would be more cost-effective.

Background: Severe anaemia in children requiring hospital admission is a major public health problem in malaria-endemic Africa. Affordable methods for the assessment of haemoglobin have not been validated against gold standard measures for identifying those with severe anaemia requiring a blood transfusion, despite this resource being in short supply. Methods: We conducted a prospective descriptive study of hospitalized children aged 2 months – 12 years at Mbale and Soroti Regional Referral Hospitals, assessed to have pallor at triage by a nurse and two clinicians. Haemoglobin levels were measured using the HemoCue ® Hb 301 system (gold standard); the Haemoglobin Colour Scale; Colorimetric and Sahli’s methods. We report clinical assessments of the degree of pallor, clinicians’ intention to transfuse, inter-observer agreement, limits of agreement using the Bland-Altman method, and the sensitivity and specificity of each method in comparison to HemoCue ® Results: We recruited 322 children, clinically-assessed by the admitting nurse (n=314) as having severe (166; 51.6%), moderate (97; 30.1%) or mild (51; 15.8%) pallor. Agreement between the clinicians and the nurse were good: Clinician A Kappa=0.68 (0.60–0.76) and Clinician B Kappa=0.62 (0.53–0.71) respectively ( P<0.0001 for both). The nurse, clinicians A and B indicated that of 94/116 (81.0%), 83/121 (68.6%) and 93/120 (77.5%) respectively required transfusion. HemoCue ® readings indicated anaemia as mild (Hb10.0–11.9g/dl) in 8/292 (2.7%), moderate (Hb5.0–9.9g/dl) in 132/292 (45.2%) and severe (Hb<5.0g/dl) in 152/292 (52.1%). Comparing to HemoCue® the Sahli’s method performed best in estimation of severe anaemia, with sensitivity 84.0% and specificity 87.9% and a Kappa score of  0.70 (0.64–0.80). Conclusions: Clinical assessment of severe pallor results has a low specificity for the diagnosis of severe anaemia. To target blood transfusion Hb measurement by either Hemocue® or Sahli’s method for the cost of USD 4 or and USD 0.25 per test, respectively would be more cost-effective.

Background In sub-Saharan Africa (SSA), malaria remains a public health problem despite recent reports of declining incidence. Severe malaria is a multiorgan disease with wide-ranging clinical spectra and outcomes that have been reported to vary by age, geographical location, transmission intensity over time. There are reports of recent malaria epidemics or resurgences, but few data, if any, focus on the clinical spectrum of severe malaria during epidemics. This describes the clinical spectrum and outcomes of childhood severe malaria during the disease epidemic in Eastern Uganda. Methods This prospective cohort study from October 1, 2021, to September 7, 2022, was nested within the ‘Malaria Epidemiological, Pathophysiological and Intervention studies in Highly Endemic Eastern Uganda’ (TMA2016SF-1514-MEPIE Study) at Mbale Regional Referral Hospital, Uganda. Children aged 60 days to 12 years who at admission tested positive for malaria and fulfilled the clinical WHO criteria for surveillance of severe malaria were enrolled on the study. Follow-up was performed until day 28. Data were collected using a customized proforma on social demographic characteristics, clinical presentation, treatment, and outcomes. Laboratory analyses included complete blood counts, malaria RDT (SD BIOLINE Malaria Ag P.f/Pan, Ref. 05FK60-40-1) and blood slide, lactate, glucose, blood gases and electrolytes. In addition, urinalysis using dipsticks (Multistix® 10 SG, SIEMENS, Ref.2300) at the bedside was done. Data were analysed using STATA V15.0. The study had prior ethical approval. Results A total of 300 participants were recruited. The median age was 4.6 years, mean of 57.2 months and IQR of 44.5 months. Many children, 164/300 (54.7%) were under 5 years, and 171/300 (57.0%) were males. The common clinical features were prostration 236/300 (78.7%), jaundice in 205/300 (68.3%), severe malarial anaemia in 158/300 (52.7%), black water fever 158/300 (52.7%) and multiple convulsions 51/300 (17.0%), impaired consciousness 50/300(16.0%), acidosis 41/300(13.7%), respiratory distress 26/300(6.7%) and coma in 18/300(6.0%). Prolonged hospitalization was found in 56/251 (22.3%) and was associated with acidosis, P = 0.041. The overall mortality was 19/300 (6.3%). Day 28 follow-up was achieved in 247/300 (82.3%). Conclusion During the malaria epidemic in Eastern Uganda, severe malaria affected much older children and the spectrum had more of prostration, jaundice severe malarial anaemia, black water fever and multiple convulsions with less of earlier reported respiratory distress and cerebral malaria.