Feasibility, safety, and impact of the RTS,S/AS01E malaria vaccine when implemented through national immunisation programmes: evaluation of cluster-randomised introduction of the vaccine in Ghana, Kenya, and Malawi.

BACKGROUND: The RTS,S/AS01E malaria vaccine (RTS,S) was introduced by national immunisation programmes in Ghana, Kenya, and Malawi in 2019 in large-scale pilot schemes. We aimed to address questions about feasibility and impact, and to assess safety signals that had been observed in the phase 3 trial that included an excess of meningitis and cerebral malaria cases in RTS,S recipients, and the possibility of an excess of deaths among girls who received RTS,S than in controls, to inform decisions about wider use. METHODS: In this prospective evaluation, 158 geographical clusters (66 districts in Ghana; 46 sub-counties in Kenya; and 46 groups of immunisation clinic catchment areas in Malawi) were randomly assigned to early or delayed introduction of RTS,S, with three doses to be administered between the ages of 5 months and 9 months and a fourth dose at the age of approximately 2 years. Primary outcomes of the evaluation, planned over 4 years, were mortality from all causes except injury (impact), hospital admission with severe malaria (impact), hospital admission with meningitis or cerebral malaria (safety), deaths in girls compared with boys (safety), and vaccination coverage (feasibility). Mortality was monitored in children aged 1-59 months throughout the pilot areas. Surveillance for meningitis and severe malaria was established in eight sentinel hospitals in Ghana, six in Kenya, and four in Malawi. Vaccine uptake was measured in surveys of children aged 12-23 months about 18 months after vaccine introduction. We estimated that sufficient data would have accrued after 24 months to evaluate each of the safety signals and the impact on severe malaria in a pooled analysis of the data from the three countries. We estimated incidence rate ratios (IRRs) by comparing the ratio of the number of events in children age-eligible to have received at least one dose of the vaccine (for safety outcomes), or age-eligible to have received three doses (for impact outcomes), to that in non-eligible age groups in implementation areas with the equivalent ratio in comparison areas. To establish whether there was evidence of a difference between girls and boys in the vaccine's impact on mortality, the female-to-male mortality ratio in age groups eligible to receive the vaccine (relative to the ratio in non-eligible children) was compared between implementation and comparison areas. Preliminary findings contributed to WHO's recommendation in 2021 for widespread use of RTS,S in areas of moderate-to-high malaria transmission. FINDINGS: By April 30, 2021, 652 673 children had received at least one dose of RTS,S and 494 745 children had received three doses. Coverage of the first dose was 76% in Ghana, 79% in Kenya, and 73% in Malawi, and coverage of the third dose was 66% in Ghana, 62% in Kenya, and 62% in Malawi. 26 285 children aged 1-59 months were admitted to sentinel hospitals and 13 198 deaths were reported through mortality surveillance. Among children eligible to have received at least one dose of RTS,S, there was no evidence of an excess of meningitis or cerebral malaria cases in implementation areas compared with comparison areas (hospital admission with meningitis: IRR 0·63 [95% CI 0·22-1·79]; hospital admission with cerebral malaria: IRR 1·03 [95% CI 0·61-1·74]). The impact of RTS,S introduction on mortality was similar for girls and boys (relative mortality ratio 1·03 [95% CI 0·88-1·21]). Among children eligible for three vaccine doses, RTS,S introduction was associated with a 32% reduction (95% CI 5-51%) in hospital admission with severe malaria, and a 9% reduction (95% CI 0-18%) in all-cause mortality (excluding injury). INTERPRETATION: In the first 2 years of implementation of RTS,S, the three primary doses were effectively deployed through national immunisation programmes. There was no evidence of the safety signals that had been observed in the phase 3 trial, and introduction of the vaccine was associated with substantial reductions in hospital admission with severe malaria. Evaluation continues to assess the impact of four doses of RTS,S. FUNDING: Gavi, the Vaccine Alliance; the Global Fund to Fight AIDS, Tuberculosis and Malaria; and Unitaid.

International Consensus Criteria for Pediatric Sepsis and Septic Shock.

Importance: Sepsis is a leading cause of death among children worldwide. Current pediatric-specific criteria for sepsis were published in 2005 based on expert opinion. In 2016, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, but it excluded children. Objective: To update and evaluate criteria for sepsis and septic shock in children. Evidence Review: The Society of Critical Care Medicine (SCCM) convened a task force of 35 pediatric experts in critical care, emergency medicine, infectious diseases, general pediatrics, nursing, public health, and neonatology from 6 continents. Using evidence from an international survey, systematic review and meta-analysis, and a new organ dysfunction score developed based on more than 3 million electronic health record encounters from 10 sites on 4 continents, a modified Delphi consensus process was employed to develop criteria. Findings: Based on survey data, most pediatric clinicians used sepsis to refer to infection with life-threatening organ dysfunction, which differed from prior pediatric sepsis criteria that used systemic inflammatory response syndrome (SIRS) criteria, which have poor predictive properties, and included the redundant term, severe sepsis. The SCCM task force recommends that sepsis in children be identified by a Phoenix Sepsis Score of at least 2 points in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems. Children with a Phoenix Sepsis Score of at least 2 points had in-hospital mortality of 7.1% in higher-resource settings and 28.5% in lower-resource settings, more than 8 times that of children with suspected infection not meeting these criteria. Mortality was higher in children who had organ dysfunction in at least 1 of 4-respiratory, cardiovascular, coagulation, and/or neurological-organ systems that was not the primary site of infection. Septic shock was defined as children with sepsis who had cardiovascular dysfunction, indicated by at least 1 cardiovascular point in the Phoenix Sepsis Score, which included severe hypotension for age, blood lactate exceeding 5 mmol/L, or need for vasoactive medication. Children with septic shock had an in-hospital mortality rate of 10.8% and 33.5% in higher- and lower-resource settings, respectively. Conclusions and Relevance: The Phoenix sepsis criteria for sepsis and septic shock in children were derived and validated by the international SCCM Pediatric Sepsis Definition Task Force using a large international database and survey, systematic review and meta-analysis, and modified Delphi consensus approach. A Phoenix Sepsis Score of at least 2 identified potentially life-threatening organ dysfunction in children younger than 18 years with infection, and its use has the potential to improve clinical care, epidemiological assessment, and research in pediatric sepsis and septic shock around the world.

Development and Validation of the Phoenix Criteria for Pediatric Sepsis and Septic Shock.

Importance: The Society of Critical Care Medicine Pediatric Sepsis Definition Task Force sought to develop and validate new clinical criteria for pediatric sepsis and septic shock using measures of organ dysfunction through a data-driven approach. Objective: To derive and validate novel criteria for pediatric sepsis and septic shock across differently resourced settings. Design, Setting, and Participants: Multicenter, international, retrospective cohort study in 10 health systems in the US, Colombia, Bangladesh, China, and Kenya, 3 of which were used as external validation sites. Data were collected from emergency and inpatient encounters for children (aged <18 years) from 2010 to 2019: 3 049 699 in the development (including derivation and internal validation) set and 581 317 in the external validation set. Exposure: Stacked regression models to predict mortality in children with suspected infection were derived and validated using the best-performing organ dysfunction subscores from 8 existing scores. The final model was then translated into an integer-based score used to establish binary criteria for sepsis and septic shock. Main Outcomes and Measures: The primary outcome for all analyses was in-hospital mortality. Model- and integer-based score performance measures included the area under the precision recall curve (AUPRC; primary) and area under the receiver operating characteristic curve (AUROC; secondary). For binary criteria, primary performance measures were positive predictive value and sensitivity. Results: Among the 172 984 children with suspected infection in the first 24 hours (development set; 1.2% mortality), a 4-organ-system model performed best. The integer version of that model, the Phoenix Sepsis Score, had AUPRCs of 0.23 to 0.38 (95% CI range, 0.20-0.39) and AUROCs of 0.71 to 0.92 (95% CI range, 0.70-0.92) to predict mortality in the validation sets. Using a Phoenix Sepsis Score of 2 points or higher in children with suspected infection as criteria for sepsis and sepsis plus 1 or more cardiovascular point as criteria for septic shock resulted in a higher positive predictive value and higher or similar sensitivity compared with the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) criteria across differently resourced settings. Conclusions and Relevance: The novel Phoenix sepsis criteria, which were derived and validated using data from higher- and lower-resource settings, had improved performance for the diagnosis of pediatric sepsis and septic shock compared with the existing IPSCC criteria.

Recalibrating prognostic models to improve predictions of in-hospital child mortality in resource-limited settings.

BACKGROUND: In an external validation study, model recalibration is suggested once there is evidence of poor model calibration but with acceptable discriminatory abilities. We identified four models, namely RISC-Malawi (Respiratory Index of Severity in Children) developed in Malawi, and three other predictive models developed in Uganda by Lowlaavar et al. (2016). These prognostic models exhibited poor calibration performance in the recent external validation study, hence the need for recalibration. OBJECTIVE: In this study, we aim to recalibrate these models using regression coefficients updating strategy and determine how much their performances improve. METHODS: We used data collected by the Clinical Information Network from paediatric wards of 20 public county referral hospitals. Missing data were multiply imputed using chained equations. Model updating entailed adjustment of the model's calibration performance while the discriminatory ability remained unaltered. We used two strategies to adjust the model: intercept-only and the logistic recalibration method. RESULTS: Eligibility criteria for the RISC-Malawi model were met in 50,669 patients, split into two sets: a model-recalibrating set (n = 30,343) and a test set (n = 20,326). For the Lowlaavar models, 10,782 patients met the eligibility criteria, of whom 6175 were used to recalibrate the models and 4607 were used to test the performance of the adjusted model. The intercept of the recalibrated RISC-Malawi model was 0.12 (95% CI 0.07, 0.17), while the slope of the same model was 1.08 (95% CI 1.03, 1.13). The performance of the recalibrated models on the test set suggested that no model met the threshold of a perfectly calibrated model, which includes a calibration slope of 1 and a calibration-in-the-large/intercept of 0. CONCLUSIONS: Even after model adjustment, the calibration performances of the 4 models did not meet the recommended threshold for perfect calibration. This finding is suggestive of models over/underestimating the predicted risk of in-hospital mortality, potentially harmful clinically. Therefore, researchers may consider other alternatives, such as ensemble techniques to combine these models into a meta-model to improve out-of-sample predictive performance.

Malaria hospitalisation in East Africa: age, phenotype and transmission intensity.

BACKGROUND: Understanding the age patterns of disease is necessary to target interventions to maximise cost-effective impact. New malaria chemoprevention and vaccine initiatives target young children attending routine immunisation services. Here we explore the relationships between age and severity of malaria hospitalisation versus malaria transmission intensity. METHODS: Clinical data from 21 surveillance hospitals in East Africa were reviewed. Malaria admissions aged 1 month to 14 years from discrete administrative areas since 2006 were identified. Each site-time period was matched to a model estimated community-based age-corrected parasite prevalence to provide predictions of prevalence in childhood (PfPR2-10). Admission with all-cause malaria, severe malaria anaemia (SMA), respiratory distress (RD) and cerebral malaria (CM) were analysed as means and predicted probabilities from Bayesian generalised mixed models. RESULTS: 52,684 malaria admissions aged 1 month to 14 years were described at 21 hospitals from 49 site-time locations where PfPR2-10 varied from < 1 to 48.7%. Twelve site-time periods were described as low transmission (PfPR2-10 < 5%), five low-moderate transmission (PfPR2-10 5-9%), 20 moderate transmission (PfPR2-10 10-29%) and 12 high transmission (PfPR2-10 ≥ 30%). The majority of malaria admissions were below 5 years of age (69-85%) and rare among children aged 10-14 years (0.7-5.4%) across all transmission settings. The mean age of all-cause malaria hospitalisation was 49.5 months (95% CI 45.1, 55.4) under low transmission compared with 34.1 months (95% CI 30.4, 38.3) at high transmission, with similar trends for each severe malaria phenotype. CM presented among older children at a mean of 48.7 months compared with 39.0 months and 33.7 months for SMA and RD, respectively. In moderate and high transmission settings, 34% and 42% of the children were aged between 2 and 23 months and so within the age range targeted by chemoprevention or vaccines. CONCLUSIONS: Targeting chemoprevention or vaccination programmes to areas where community-based parasite prevalence is ≥10% is likely to match the age ranges covered by interventions (e.g. intermittent presumptive treatment in infancy to children aged 2-23 months and current vaccine age eligibility and duration of efficacy) and the age ranges of highest disease burden.

Criteria for Pediatric Sepsis-A Systematic Review and Meta-Analysis by the Pediatric Sepsis Definition Taskforce.

OBJECTIVE: To determine the associations of demographic, clinical, laboratory, organ dysfunction, and illness severity variable values with: 1) sepsis, severe sepsis, or septic shock in children with infection and 2) multiple organ dysfunction or death in children with sepsis, severe sepsis, or septic shock. DATA SOURCES: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from January 1, 2004, and November 16, 2020. STUDY SELECTION: Case-control studies, cohort studies, and randomized controlled trials in children greater than or equal to 37-week-old postconception to 18 years with suspected or confirmed infection, which included the terms "sepsis," "septicemia," or "septic shock" in the title or abstract. DATA EXTRACTION: Study characteristics, patient demographics, clinical signs or interventions, laboratory values, organ dysfunction measures, and illness severity scores were extracted from eligible articles. Random-effects meta-analysis was performed. DATA SYNTHESIS: One hundred and six studies met eligibility criteria of which 81 were included in the meta-analysis. Sixteen studies (9,629 patients) provided data for the sepsis, severe sepsis, or septic shock outcome and 71 studies (154,674 patients) for the mortality outcome. In children with infection, decreased level of consciousness and higher Pediatric Risk of Mortality scores were associated with sepsis/severe sepsis. In children with sepsis/severe sepsis/septic shock, chronic conditions, oncologic diagnosis, use of vasoactive/inotropic agents, mechanical ventilation, serum lactate, platelet count, fibrinogen, procalcitonin, multi-organ dysfunction syndrome, Pediatric Logistic Organ Dysfunction score, Pediatric Index of Mortality-3, and Pediatric Risk of Mortality score each demonstrated significant and consistent associations with mortality. Pooled mortality rates varied among high-, upper middle-, and lower middle-income countries for patients with sepsis, severe sepsis, and septic shock (p < 0.0001). CONCLUSIONS: Strong associations of several markers of organ dysfunction with the outcomes of interest among infected and septic children support their inclusion in the data validation phase of the Pediatric Sepsis Definition Taskforce.

The Clinical Profile of Severe Pediatric Malaria in an Area Targeted for Routine RTS,S/AS01 Malaria Vaccination in Western Kenya.

BACKGROUND: The malaria prevalence has declined in western Kenya, resulting in the risk of neurological phenotypes in older children. This study investigates the clinical profile of pediatric malaria admissions ahead of the introduction of the RTS,S/AS01 vaccine. METHODS: Malaria admissions in children aged 1 month to 15 years were identified from routine, standardized, inpatient clinical surveillance data collected between 2015 and 2018 from 4 hospitals in western Kenya. Malaria phenotypes were defined based on available data. RESULTS: There were 5766 malaria admissions documented. The median age was 36 months (interquartile range, 18-60): 15% were aged between 1-11 months of age, 33% were aged 1-23 months of age, and 70% were aged 1 month to 5 years. At admission, 2340 (40.6%) children had severe malaria: 421/2208 (19.1%) had impaired consciousness, 665/2240 (29.7%) had an inability to drink or breastfeed, 317/2340 (13.6%) had experienced 2 or more convulsions, 1057/2340 (45.2%) had severe anemia, and 441/2239 (19.7%) had severe respiratory distress. Overall, 211 (3.7%) children admitted with malaria died; 163/211 (77% deaths, case fatality rate 7.0%) and 48/211 (23% deaths, case fatality rate 1.4%) met the criteria for severe malaria and nonsevere malaria at admission, respectively. The median age for fatal cases was 33 months (interquartile range, 12-72) and the case fatality rate was highest in those unconscious (44.4%). CONCLUSIONS: Severe malaria in western Kenya is still predominantly seen among the younger pediatric age group and current interventions targeted for those <5 years are appropriate. However, there are increasing numbers of children older than 5 years admitted with malaria, and ongoing hospital surveillance would identify when interventions should target older children.

Smart triage: triage and management of sepsis in children using the point-of-care Pediatric Rapid Sepsis Trigger (PRST) tool.

BACKGROUND: Sepsis is the leading cause of death and disability in children. Every hour of delay in treatment is associated with an escalating risk of morbidity and mortality. The burden of sepsis is greatest in low- and middle-income countries where timely treatment may not occur due to delays in diagnosis and prioritization of critically ill children. To circumvent these challenges, we propose the development and clinical evaluation of a digital triage tool that will identify high risk children and reduce time to treatment. We will also implement and clinically validate a Radio-Frequency Identification system to automate tracking of patients. The mobile platform (mobile device and dashboard) and automated patient tracking system will create a low cost, highly scalable solution for critically ill children, including those with sepsis. METHODS: This is pre-post intervention study consisting of three phases. Phase I will be a baseline period where data is collected on key predictors and outcomes before implementation of the digital triage tool. In Phase I, there will be no changes to healthcare delivery processes in place at the study hospitals. Phase II will involve model derivation, technology development, and usability testing. Phase III will be the intervention period where data is collected on key predictors and outcomes after implementation of the digital triage tool. The primary outcome, time to treatment initiation, will be compared to assess effectiveness of the digital health intervention. DISCUSSION: Smart technology has the potential to overcome the barrier of limited clinical expertise in the identification of the child at risk. This mobile health platform, with sensors and data-driven applications, will provide real-time individualized risk prediction to rapidly triage patients and facilitate timely access to life-saving treatments for children in low- and middle-income countries, where specialists are not regularly available and deaths from sepsis are common. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT04304235, Registered 11 March 2020.

Serum Procalcitonin Levels in Children with Clinical Syndromes for Targeting Antibiotic Use at an Emergency Department of a Kenyan Hospital.

Serum procalcitonin (PCT) was measured in 228 children aged 1 month to 15 years at an emergency department of a hospital located in an area without local malaria transmission in children with suspected infections; 21% (49) children had a clinical syndrome for suspected bacterial infections (Syndrome+ve). In children with Syndrome+ve criteria, 27/49 (55.1%) had PCT ≥0.5 µg/l but only 59/179 (32.9%) of those Syndrome-ve had abnormal PCT, χ2 = 8.0, p = 0.005; positive likelihood ratio = 2.0 [95% confidence interval (CI) 1.2-3.3]; negative likelihood ratio = 0.8 (95% CI 0.7-1.0). In patients with pneumonia, 9/15 (60%) with severe pneumonia had PCT ≥0.5 µg/l compared to 11/21 (52.4%) with non-severe pneumonia, χ2 = 0.2, p = 0.65. Children with clinical signs of pneumonia or clinical signs suggestive of bacterial infections fulfilling clinical syndromic definitions for suspected bacterial infections commonly have elevated PCT level. PCT levels are associated with disease severity and antibiotic trials guided by PCT levels may be needed where cultures are not available.

Magnitude and pattern of improvement in processes of care for hospitalised children with diarrhoea and dehydration in Kenyan hospitals participating in a clinical network.

OBJECTIVE: WHO recommends optimisation of available interventions to reduce deaths of under-five children with diarrhoea and dehydration (DD). Clinical networks may help improve practice across many hospitals but experience with such networks is scarce. We describe magnitude and patterns of changes in processes of care for children with DD over the first 3 years of a clinical network. METHODS: Observational study involving children aged 2-59 months with DD admitted to 13 hospitals participating in the clinical network. Processes of individual patient care including agreement of assessment, diagnosis and treatment according to WHO guidelines were combined using the composite Paediatric Admission Quality of Care (PAQC) score (range 0-6). RESULTS: Data from 7657 children were analysed and improvements in PAQC scores were observed. Predicted mean PAQC score for all the hospitals at enrolment was 59.8% (95% CI: 54.7, 64.9) but showed a wide variation (variance 10.7%, 95% CI: 5.8, 19.6). Overall mean PAQC score increased by 13.8% (95% CI: 8.7-18.9, SD between hospitals: ±8.2) in the first 12 months, with an average 0.9% (95% CI: 0.3-1.5, SD ± 1.0) increase per month and plateaued thereafter, and changes were similar in two groups of hospitals joining the network at different times. CONCLUSION: Adherence to guidelines for children admitted with DD can be improved through participation in a clinical network but improvement is limited, not uniform for all aspects of care and contexts and occurs early. Future research should address these issues.

Mortality risk over time after early fluid resuscitation in African children.

BACKGROUND: African children hospitalised with severe febrile illness have a high risk of mortality. The Fluid Expansion As Supportive Therapy (FEAST) trial (ISCRTN 69856593) demonstrated increased mortality risk associated with fluid boluses, but the temporal relationship to bolus therapy and underlying mechanism remains unclear. METHODS: In a post hoc retrospective analysis, flexible parametric models were used to compare change in mortality risk post-randomisation in children allocated to bolus therapy with 20-40 ml/kg 5% albumin or 0.9% saline over 1-2 h or no bolus (control, 4 ml/kg/hour maintenance), overall and for different terminal clinical events (cardiogenic, neurological, respiratory, or unknown/other). RESULTS: Two thousand ninety-seven and 1041 children were randomised to bolus vs no bolus, of whom 254 (12%) and 91 (9%) respectively died within 28 days. Median (IQR) bolus fluid in the bolus groups received by 4 h was 20 (20, 40) ml/kg and was the same at 8 h; total fluids received in bolus groups at 4 h and 8 h were 38 (28, 43) ml/kg and 40 (30, 50) ml/kg, respectively. Total fluid volumes received in the control group by 4 h and 8 h were median (IQR) 10 (6, 15) ml/kg and 10 (10, 26) ml/kg, respectively. Mortality risk was greatest 30 min post-randomisation in both groups, declining sharply to 4 h and then more slowly to 28 days. Maximum mortality risk was similar in bolus and no bolus groups; however, the risk declined more slowly in the bolus group, with significantly higher mortality risk compared to the no bolus group from 1.6 to 101 h (4 days) post-randomisation. The delay in decline in mortality risk in the bolus groups was most pronounced for cardiogenic modes of death. CONCLUSIONS: The increased risk from bolus therapy was not due to a mechanism occurring immediately after bolus administration. Excess mortality risk in the bolus group resulted from slower decrease in mortality risk over the ensuing 4 days. Thus, administration of modest bolus volumes appeared to prevent mortality risk declining at the same rate that it would have done without a bolus, rather than harm associated with bolus resulting from a concurrent increased risk of death peri-bolus administration. TRIAL REGISTRATION: ISRCTN69856593. Date of registration 15 December 2008.

Lactate clearance as a prognostic marker of mortality in severely ill febrile children in East Africa.

BACKGROUND: Hyperlactataemia (HL) is a biomarker of disease severity that predicts mortality in patients with sepsis and malaria. Lactate clearance (LC) during resuscitation has been shown to be a prognostic factor of survival in critically ill adults, but little data exist for African children living in malaria-endemic areas. METHODS: In a secondary data analysis of severely ill febrile children included in the Fluid Expansion as Supportive Therapy (FEAST) resuscitation trial, we assessed the association between lactate levels at admission and LC at 8 h with all-cause mortality at 72 h (d72). LC was defined as a relative lactate decline ≥ 40% and/or lactate normalisation (lactate < 2.5 mmol/L). RESULTS: Of 3170 children in the FEAST trial, including 1719 children (57%) with Plasmodium falciparum malaria, 3008 (95%) had a baseline lactate measurement, 2127 (71%) had HL (lactate ≥ 2.5 mmol/L), and 1179 (39%) had severe HL (≥ 5 mmol/L). Within 72 h, 309 children (10.3%) died, of whom 284 (92%) had baseline HL. After adjustment for potential confounders, severe HL was strongly associated with mortality (Odds Ratio (OR) 6.96; 95% CI 3.52, 13.76, p < 0.001). This association was not modified by malaria status, despite children with malaria having a higher baseline lactate (median 4.6 mmol/L vs 3 mmol/L; p < 0.001) and a lower mortality rate (OR = 0.42; p < 0.001) compared to non-malarial cases. Sensitivity and specificity analysis identified a higher lactate on admission cut-off value predictive of d72 for children with malaria (5.2 mmol/L) than for those with other febrile illnesses (3.4 mmol/L). At 8 h, 2748/3008 survivors (91%) had a lactate measured, 1906 (63%) of whom had HL on admission, of whom 1014 (53%) fulfilled pre-defined LC criteria. After adjustment for confounders, LC independently predicted survival after 8 h (OR 0.24; 95% CI 0.14, 0.42; p < 0.001). Absence of LC (< 10%) at 8 h was strongly associated with death at 72 h (OR 4.62; 95% CI 2.7, 8.0; p < 0.001). CONCLUSIONS: Independently of the underlying diagnosis, HL is a strong risk factor for death at 72 h in children admitted with severe febrile illnesses in Africa. Children able to clear lactate within 8 h had an improved chance of survival. These findings prompt the more widespread use of lactate and LC to identify children with severe disease and monitor response to treatment. TRIAL REGISTRATION: ISRCTN69856593 Registered 21 January 2009.

Assessment of Myocardial Function and Injury by Echocardiography and Cardiac Biomarkers in African Children With Severe Plasmodium falciparum Malaria.

OBJECTIVES: Perturbed hemodynamic function complicates severe malaria. The Fluid Expansion as Supportive Therapy trial demonstrated that fluid resuscitation, involving children with severe malaria, was associated with increased mortality, primarily due to cardiovascular collapse, suggesting that myocardial dysfunction may have a role. The aim of this study was to characterize cardiac function in children with severe malaria. DESIGN: A prospective observational study with clinical, laboratory, and echocardiographic data collected at presentation (T0) and 24 hours (T1) in children with severe malaria. Cardiac index and ejection fraction were calculated at T0 and T1. Cardiac troponin I and brain natriuretic peptide were measured at T0. We compared clinical and echocardiographic variables in children with and without severe malarial anemia (hemoglobin < 5 mg/dL) at T0 and T1. SETTING: Mbale Regional Referral Hospital. PATIENTS: Children 3 months to 12 years old with severe falciparum malaria. INTERVENTIONS: Usual care. MEASUREMENTS AND MAIN RESULTS: We enrolled 104 children, median age 23.3 months, including 61 children with severe malarial anemia. Cardiac troponin I levels were elevated (> 0.1 ng/mL) in n equals to 50, (48%), and median brain natriuretic peptide was within normal range (69.1 pg/mL; interquartile range, 48.4-90.8). At T0, median Cardiac index was significantly higher in the severe malarial anemia versus nonsevere malarial anemia group (6.89 vs 5.28 L/min/m) (p = 0.001), which normalized in both groups at T1 (5.60 vs 5.13 L/min/m) (p = 0.452). Cardiac index negatively correlated with hemoglobin, r equals to -0.380 (p < 0.001). Four patients (3.8%) had evidence of depressed cardiac systolic function (ejection fraction < 45%). Overall, six children died, none developed pulmonary edema, biventricular failure, or required diuretic treatment. CONCLUSIONS: Elevation of cardiac index, due to increased stroke volume, in severe malaria is a physiologic response to circulatory compromise and correlates with anemia. Following whole blood transfusion and antimalarial therapy, cardiac index in severe malarial anemia returns to normal. The majority (> 96%) of children with severe malaria have preserved myocardial systolic function. Although there is evidence for myocardial injury (elevated cardiac troponin I), this does not correlate with cardiac dysfunction.

The Prevalence and Management of Dehydration amongst Neonatal Admissions to General Paediatric Wards in Kenya-A Clinical Audit.

An audit of randomly selected case records of 810 patients admitted to 13 hospitals between December 2015 and November 2016 was done. Prevalence of dehydration was 19.7% (2293 of 11 636) [95% CI: 17.1-22.6%], range across hospitals was 9.4% to 27.0%. Most cases with dehydration were clinically diagnosed (82 of 153; 53.6%), followed by excessive weight loss (54 of 153; 35.3%) and abnormal urea/electrolytes/creatinine (23 of 153; 15.0%). Documentation of fluids prescribed was poor but, where data were available, Ringers lactate (30 of 153; 19.6%) and 10% dextrose (18 of 153; 11.8%) were mostly used. Only 17 of 153 (11.1%) children had bolus fluid prescription, and Ringer's lactate was most commonly used for bolus at a median volume per kilogram body weight of 20 ml/kg (interquartile range, 12-30 ml/kg). Neonatal dehydration is common, but current documentation may underestimate the burden. Heterogeneity in practice likely reflects the absence of guidelines that in turn reflects a lack of research informing practical treatment guidelines.

High Frequency of Blackwater Fever Among Children Presenting to Hospital With Severe Febrile Illnesses in Eastern Uganda.

BACKGROUND: In the Fluid Expansion as a Supportive Treatment (FEAST) trial, an unexpectedly high proportion of participants from eastern Uganda presented with blackwater fever (BWF). METHODS: We describe the prevalence and outcome of BWF among trial participants and compare the prevalence of 3 malaria-protective red blood cell polymorphisms in BWF cases vs both trial (non-BWF) and population controls. RESULTS: Of 3170 trial participants, 394 (12.4%) had BWF. The majority (318 [81.0%]) presented in eastern Uganda and were the subjects of further analysis. BWF cases typically presented with both clinical jaundice (254/318 [80%]) and severe anemia (hemoglobin level <5 g/dL) (238/310 [77%]). Plasmodium falciparum parasitemia was less frequent than in non-BWF controls, but a higher proportion were positive for P. falciparum histidine rich protein 2 (192/246 [78.0%]) vs 811/1154 [70.3%]; P = .014), suggesting recent antimalarial treatment. Overall, 282 of 318 (88.7%) received transfusions, with 94 of 282 (33.3%) and 9 of 282 (3.4%) receiving 2 or 3 transfusions, respectively. By day 28, 39 of 318 (12.3%) BWF cases and 154 of 1554 (9.9%) non-BWF controls had died (P = .21), and 7 of 255 (3.0%) vs 13/1212 (1%), respectively, had severe anemia (P = .036). We found no association with G6PD deficiency. The prevalence of both the sickle cell trait (10/218 [4.6%]) and homozygous α+thalassemia (8/216 [3.7%]) were significantly lower among cases than among population controls (334/2123 [15.7%] and 141/2114 [6.6%], respectively), providing further support for the role of malaria. CONCLUSIONS: We report the emergence of BWF in eastern Uganda, a condition that, according to local investigators, was rare until the last 7 years. We speculate that this might relate to the introduction of artemisinin-based combination therapies. Further studies investigating this possibility are urgently required.

Inappropriate prescription of cough remedies among children hospitalised with respiratory illness over the period 2002-2015 in Kenya.

OBJECTIVE: To examine trends in prescription of cough medicines over the period 2002-2015 in children aged 1 month to 12 years admitted to Kenyan hospitals with cough, difficulty breathing or diagnosed with a respiratory tract infection. METHODS: We reviewed hospitalisation records of children included in four studies providing cross-sectional prevalence estimates from government hospitals for six time periods between 2002 and 2015. Children with an atopic illness were excluded. Amongst eligible children, we determined the proportion prescribed any adjuvant medication for cough. Active ingredients in these medicines were often multiple and were classified into five categories: antihistamines, antitussives, mucolytics/expectorants, decongestants and bronchodilators. From late 2006, guidelines discouraging cough medicine use have been widely disseminated and in 2009 national directives to decrease cough medicine use were issued. RESULTS: Across the studies, 17 963 children were eligible. Their median age and length of hospital stay were comparable. The proportion of children who received cough medicines shrank across the surveys: approximately 6% [95% CI: 5.4, 6.6] of children had a prescription in 2015 vs. 40% [95% CI: 35.5, 45.6] in 2002. The most common active ingredients were antihistamines and bronchodilators. The relative proportion that included antihistamines has increased over time. CONCLUSIONS: There has been an overall decline in the use of cough medicines among hospitalised children over time. This decline has been associated with educational, policy and mass media interventions.

Prevalence, aetiology, treatment and outcomes of shock in children admitted to Kenyan hospitals.

BACKGROUND: Shock may complicate several acute childhood illnesses in hospitals within low-income countries and has a high case fatality. Hypovolemic shock secondary to diarrhoea/dehydration and septic shock are thought to be common, but there are few reliable data on prevalence or treatment that differ for the two major forms of shock. Examining prevalence and treatment practices has become important since reports suggest high risks from liberal use of fluid boluses in African children. The present study aims to estimate the prevalence, fluid management practices and outcomes of shock among hospitalised children. METHODS: We analysed paediatric in-patient data collected using discharge case record review between October 2013 and February 2016 from 14 hospitals in Kenya which are part of a network (referred to as the Clinical Information Network) using similar tools for standardised clinical records with care directed by the local clinical team leaders. Data are from a period after dissemination of national guidance seeking to limit use of bolus fluids. RESULTS: A total of 74,402 children were admitted between October 2013 and February 2016. Children aged < 30 days or > 5 years, with severe acute malnutrition, surgical/burns, or cases with pre-defined minimum data sets were excluded from analysis. This resulted in 42,937 patients meeting the inclusion criteria. Prevalence of clinically diagnosed shock was 1.5 % (n = 622) and overall bolus use was 0.9 % (n = 366); 41 % (256/622) of children with clinically diagnosed shock did not receive a fluid bolus (but had a fluid plan for management of dehydration). Identified cases appeared mostly to be hypovolaemic shock secondary to dehydration/diarrhoea (94 %, 582/622), with a high case fatality (34 %, 211/622). Overall mortality for all admitted children was 5 % (2115/42,937) and was 7.9 % (798/10,096) in children with dehydration/diarrhoea. The diagnosis of hypovolaemic shock was nearly always accompanied by additional clinical diagnosis (99 %), most often pneumonia or malaria. Where bolus fluids were used, they were prescribed in accordance with guidelines (isotonic fluid at correct volume) in 92 % of cases. Inappropriate use of bolus fluids to treat milder forms of impaired circulation appeared very rarely. CONCLUSION: A diagnosis of shock is uncommon at admission and use of fluid bolus is rare in admissions to Kenyan hospitals. A fluid bolus, when prescribed, is mostly used in children with hypovolemic shock secondary to dehydration and case fatality in these cases is high. We found little evidence of liberal use of fluid bolus that might cause harm in a period following dissemination of national guidelines suggesting very strict criteria for fluid bolus use.

Anaemia and blood transfusion in African children presenting to hospital with severe febrile illness.

BACKGROUND: Severe anaemia in children is a leading cause of hospital admission and a major cause of mortality in sub-Saharan Africa, yet there are limited published data on blood transfusion in this vulnerable group. METHODS: We present data from a large controlled trial of fluid resuscitation (Fluid Expansion As Supportive Therapy (FEAST) trial) on the prevalence, clinical features, and transfusion management of anaemia in children presenting to hospitals in three East African countries with serious febrile illness (predominantly malaria and/or sepsis) and impaired peripheral perfusion. RESULTS: Of 3,170 children in the FEAST trial, 3,082 (97%) had baseline haemoglobin (Hb) measurement, 2,346/3,082 (76%) were anaemic (Hb <10 g/dL), and 33% severely anaemic (Hb <5 g/dL). Prevalence of severe anaemia varied from 12% in Kenya to 41% in eastern Uganda. 1,387/3,082 (45%) children were transfused (81% within 8 hours). Adherence to WHO transfusion guidelines was poor. Among severely anaemic children who were not transfused, 52% (54/103) died within 8 hours, and 90% of these deaths occurred within 2.5 hours of randomisation. By 24 hours, 128/1,002 (13%) severely anaemic children had died, compared to 36/501 (7%) and 71/843 (8%) of those with moderate and mild anaemia, respectively. Among children without severe hypotension who were randomised to receive fluid boluses of 0.9% saline or albumin, mortality was increased (10.6% and 10.5%, respectively) compared to controls (7.2%), regardless of admission Hb level. Repeat transfusion varied from ≤2% in Kenya/Tanzania to 6 to 13% at the four Ugandan centres. Adverse reactions to blood were rare (0.4%). CONCLUSIONS: Severe anaemia complicates one third of childhood admissions with serious febrile illness to hospitals in East Africa, and is associated with increased mortality. A high proportion of deaths occurred within 2.5 hours of admission, emphasizing the need for rapid recognition and prompt blood transfusion. Adherence to current WHO transfusion guidelines was poor. The high rates of re-transfusion suggest that 20 mL/kg whole blood or 10 mL/kg packed cells may undertreat a significant proportion of anaemic children. Future evaluation of the impact of a larger volume of transfused blood and optimum transfusion management of children with Hb of <6 g/dL is warranted.

Predicting mortality in sick African children: the FEAST Paediatric Emergency Triage (PET) Score.

BACKGROUND: Mortality in paediatric emergency care units in Africa often occurs within the first 24 h of admission and remains high. Alongside effective triage systems, a practical clinical bedside risk score to identify those at greatest risk could contribute to reducing mortality. METHODS: Data collected during the Fluid As Expansive Supportive Therapy (FEAST) trial, a multi-centre trial involving 3,170 severely ill African children, were analysed to identify clinical and laboratory prognostic factors for mortality. Multivariable Cox regression was used to build a model in this derivation dataset based on clinical parameters that could be quickly and easily assessed at the bedside. A score developed from the model coefficients was externally validated in two admissions datasets from Kilifi District Hospital, Kenya, and compared to published risk scores using Area Under the Receiver Operating Curve (AUROC) and Hosmer-Lemeshow tests. The Net Reclassification Index (NRI) was used to identify additional laboratory prognostic factors. RESULTS: A risk score using 8 clinical variables (temperature, heart rate, capillary refill time, conscious level, severe pallor, respiratory distress, lung crepitations, and weak pulse volume) was developed. The score ranged from 0-10 and had an AUROC of 0.82 (95 % CI, 0.77-0.87) in the FEAST trial derivation set. In the independent validation datasets, the score had an AUROC of 0.77 (95 % CI, 0.72-0.82) amongst admissions to a paediatric high dependency ward and 0.86 (95 % CI, 0.82-0.89) amongst general paediatric admissions. This discriminative ability was similar to, or better than other risk scores in the validation datasets. NRI identified lactate, blood urea nitrogen, and pH to be important prognostic laboratory variables that could add information to the clinical score. CONCLUSIONS: Eight clinical prognostic factors that could be rapidly assessed by healthcare staff for triage were combined to create the FEAST Paediatric Emergency Triage (PET) score and externally validated. The score discriminated those at highest risk of fatal outcome at the point of hospital admission and compared well to other published risk scores. Further laboratory tests were also identified as prognostic factors which could be added if resources were available or as indices of severity for comparison between centres in future research studies.

Mortality after fluid bolus in African children with severe infection.

BACKGROUND: The role of fluid resuscitation in the treatment of children with shock and life-threatening infections who live in resource-limited settings is not established. METHODS: We randomly assigned children with severe febrile illness and impaired perfusion to receive boluses of 20 to 40 ml of 5% albumin solution (albumin-bolus group) or 0.9% saline solution (saline-bolus group) per kilogram of body weight or no bolus (control group) at the time of admission to a hospital in Uganda, Kenya, or Tanzania (stratum A); children with severe hypotension were randomly assigned to one of the bolus groups only (stratum B). All children received appropriate antimicrobial treatment, intravenous maintenance fluids, and supportive care, according to guidelines. Children with malnutrition or gastroenteritis were excluded. The primary end point was 48-hour mortality; secondary end points included pulmonary edema, increased intracranial pressure, and mortality or neurologic sequelae at 4 weeks. RESULTS: The data and safety monitoring committee recommended halting recruitment after 3141 of the projected 3600 children in stratum A were enrolled. Malaria status (57% overall) and clinical severity were similar across groups. The 48-hour mortality was 10.6% (111 of 1050 children), 10.5% (110 of 1047 children), and 7.3% (76 of 1044 children) in the albumin-bolus, saline-bolus, and control groups, respectively (relative risk for saline bolus vs. control, 1.44; 95% confidence interval [CI], 1.09 to 1.90; P=0.01; relative risk for albumin bolus vs. saline bolus, 1.01; 95% CI, 0.78 to 1.29; P=0.96; and relative risk for any bolus vs. control, 1.45; 95% CI, 1.13 to 1.86; P=0.003). The 4-week mortality was 12.2%, 12.0%, and 8.7% in the three groups, respectively (P=0.004 for the comparison of bolus with control). Neurologic sequelae occurred in 2.2%, 1.9%, and 2.0% of the children in the respective groups (P=0.92), and pulmonary edema or increased intracranial pressure occurred in 2.6%, 2.2%, and 1.7% (P=0.17), respectively. In stratum B, 69% of the children (9 of 13) in the albumin-bolus group and 56% (9 of 16) in the saline-bolus group died (P=0.45). The results were consistent across centers and across subgroups according to the severity of shock and status with respect to malaria, coma, sepsis, acidosis, and severe anemia. CONCLUSIONS: Fluid boluses significantly increased 48-hour mortality in critically ill children with impaired perfusion in these resource-limited settings in Africa. (Funded by the Medical Research Council, United Kingdom; FEAST Current Controlled Trials number, ISRCTN69856593.).