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.

A Competing-Risk Approach for Modeling Length of Stay in Severe Malaria Patients in South-East Asia and the Implications for Planning of Hospital Services.

Background: Management of severe malaria with limited resources requires comprehensive planning. Expected length of stay (LOS) and the factors influencing it are useful in the planning and optimisation of service delivery. Methods: A secondary, competing-risk approach to survival analysis was performed for 1217 adult severe malaria patients from the South-East Asia Quinine Artesunate Malaria Trial. Results: Twenty percent of patients died; 95.4% within 7 days compared to 70.3% of those who were discharged. Median time to discharge was 6 days. Compared to quinine, artesunate increased discharge incidence (subdistribution-Hazard ratio, 1.24; [95% confidence interval 1.09-1.40]; P = .001) and decreased incidence of death (0.60; [0.46-0.80]; P < .001). Low Glasgow coma scale (discharge, 1.08 [1.06-1.11], P < .001; death, 0.85 [0.82-0.89], P < .001), high blood urea-nitrogen (discharge, 0.99 [0.99-0.995], P < .001; death, 1.00 [1.00-1.01], P = .012), acidotic base-excess (discharge, 1.05 [1.03-1.06], P < .001; death, 0.90 [0.88-0.93], P < .001), and development of shock (discharge, 0.25 [0.13-0.47], P < .001; death, 2.14 [1.46-3.12], P < .001), or coma (discharge, 0.46 [0.32-0.65], P < .001; death, 2.30 [1.58-3.36], P < .001) decreased cumulative incidence of discharge and increased incidence of death. Conventional Kaplan-Meier survival analysis overestimated cumulative incidence compared to competing-risk model. Conclusions: Clinical factors on admission and during hospitalisation influence LOS in severe malaria, presenting targets to improve health and service efficiency. Artesunate has the potential to increase LOS, which should be accounted for when planning services. In-hospital death is a competing risk for discharge; an important consideration in LOS models to reduce overestimation of risk and misrepresentation of associations.

Early neonatal mortality and neurological outcomes of neonatal resuscitation in a resource-limited setting on the Thailand-Myanmar border: A descriptive study.

BACKGROUND: Of the 4 million neonatal deaths worldwide yearly, 98% occur in low and middle-income countries. Effective resuscitation reduces mortality and morbidity but long-term outcomes in resource-limited settings are poorly described. This study reports on newborn neurological outcomes following resuscitation at birth in a resource-limited setting where intensive newborn care including intubation is unavailable. METHODS: Retrospective analysis of births records from 2008 to 2015 at Shoklo Malaria Research Unit (SMRU) on the Thailand-Myanmar border. FINDINGS: From 21,225 newbonrs delivered, 15,073 (71%) met the inclusion criteria (liveborn, singleton, ≥28 weeks' gestation, delivered in SMRU). Neonatal resuscitation was performed in 460 (3%; 422 basic, 38 advanced) cases. Overall early neonatal mortality was 6.6 deaths per 1000 live births (95% CI 5.40-8.06). Newborns receiving basic and advanced resuscitation presented an adjusted rate for death of 1.30 (95%CI 0.66-2.55; p = 0.442), and 6.32 (95%CI 3.01-13.26; p<0.001) respectively, compared to newborns given routine care. Main factors related to increased need for resuscitation were breech delivery, meconium, and fetal distress (p<0.001). Neurodevelopmental follow-up to one year was performed in 1,608 (10.5%) of the 15,073 newborns; median neurodevelopmental scores of non-resuscitated newborns and those receiving basic resuscitation were similar (64 (n = 1565) versus 63 (n = 41); p = 0.732), while advanced resuscitation scores were significantly lower (56 (n = 5); p = 0.017). INTERPRETATIONS: Newborns requiring basic resuscitation at birth have normal neuro-developmental outcomes at one year of age compared to low-risk newborns. Identification of risk factors (e.g., breech delivery) associated with increased need for neonatal resuscitation may facilitate allocation of staff to high-risk deliveries. This work endorses the use of basic resuscitation in low-resource settings, and supports on-going staff training to maintain bag-and-mask ventilation skills.

Standardization of Clinical Assessment and Sample Collection Across All PERCH Study Sites.

BACKGROUND.: Variable adherence to standardized case definitions, clinical procedures, specimen collection techniques, and laboratory methods has complicated the interpretation of previous multicenter pneumonia etiology studies. To circumvent these problems, a program of clinical standardization was embedded in the Pneumonia Etiology Research for Child Health (PERCH) study. METHODS.: Between March 2011 and August 2013, standardized training on the PERCH case definition, clinical procedures, and collection of laboratory specimens was delivered to 331 clinical staff at 9 study sites in 7 countries (The Gambia, Kenya, Mali, South Africa, Zambia, Thailand, and Bangladesh), through 32 on-site courses and a training website. Staff competency was assessed throughout 24 months of enrollment with multiple-choice question (MCQ) examinations, a video quiz, and checklist evaluations of practical skills. RESULTS.: MCQ evaluation was confined to 158 clinical staff members who enrolled PERCH cases and controls, with scores obtained for >86% of eligible staff at each time-point. Median scores after baseline training were ≥80%, and improved by 10 percentage points with refresher training, with no significant intersite differences. Percentage agreement with the clinical trainer on the presence or absence of clinical signs on video clips was high (≥89%), with interobserver concordance being substantial to high (AC1 statistic, 0.62-0.82) for 5 of 6 signs assessed. Staff attained median scores of >90% in checklist evaluations of practical skills. CONCLUSIONS.: Satisfactory clinical standardization was achieved within and across all PERCH sites, providing reassurance that any etiological or clinical differences observed across the study sites are true differences, and not attributable to differences in application of the clinical case definition, interpretation of clinical signs, or in techniques used for clinical measurements or specimen collection.

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.

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.

Fosphenytoin for seizure prevention in childhood coma in Africa: a randomized clinical trial.

PURPOSE: We conducted a double-blind trial to determine whether a single intramuscular injection of fosphenytoin prevents seizures and neurologic sequelae in children with acute coma. METHODS: We conducted this study at Kilifi District Hospital in coastal Kenya and Kondele Children's Hospital in western Kenya. We recruited children (age, 9 months to 13 years) with acute nontraumatic coma. We administered fosphenytoin (20 phenytoin equivalents/kg) or placebo and examined the prevalence and frequency of clinical seizures and occurrence of neurocognitive sequelae. RESULTS: We recruited 173 children (median age, 2.6 [interquartile range, 1.7-3.7] years) into the study; 110 had cerebral malaria, 8 had bacterial meningitis, and 55 had encephalopathies of unknown etiology. Eighty-five children received fosphenytoin and 88 received placebo. Thirty-three (38%) children who received fosphenytoin had at least 1 seizure compared with 32 (36%) who received placebo (P = .733). Eighteen (21%) and 15 (17%) children died in the fosphenytoin and placebo arms, respectively (P = .489). At 3 months after discharge, 6 (10%) children in the fosphenytoin arm had neurologic sequelae compared with 6 (10%) in the placebo arm (P = .952). CONCLUSION: A single intramuscular injection of fosphenytoin (20 phenytoin equivalents/kg) does not prevent seizures or neurologic deficits in childhood acute nontraumatic coma.

Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial.

BACKGROUND: Early rapid fluid resuscitation (boluses) in African children with severe febrile illnesses increases the 48-hour mortality by 3.3% compared with controls (no bolus). We explored the effect of boluses on 48-hour all-cause mortality by clinical presentation at enrolment, hemodynamic changes over the first hour, and on different modes of death, according to terminal clinical events. We hypothesize that boluses may cause excess deaths from neurological or respiratory events relating to fluid overload. METHODS: Pre-defined presentation syndromes (PS; severe acidosis or severe shock, respiratory, neurological) and predominant terminal clinical events (cardiovascular collapse, respiratory, neurological) were described by randomized arm (bolus versus control) in 3,141 severely ill febrile children with shock enrolled in the Fluid Expansion as Supportive Therapy (FEAST) trial. Landmark analyses were used to compare early mortality in treatment groups, conditional on changes in shock and hypoxia parameters. Competing risks methods were used to estimate cumulative incidence curves and sub-hazard ratios to compare treatment groups in terms of terminal clinical events. RESULTS: Of 2,396 out of 3,141 (76%) classifiable participants, 1,647 (69%) had a severe metabolic acidosis or severe shock PS, 625 (26%) had a respiratory PS and 976 (41%) had a neurological PS, either alone or in combination. Mortality was greatest among children fulfilling criteria for all three PS (28% bolus, 21% control) and lowest for lone respiratory (2% bolus, 5% control) or neurological (3% bolus, 0% control) presentations. Excess mortality in bolus arms versus control was apparent for all three PS, including all their component features. By one hour, shock had resolved (responders) more frequently in bolus versus control groups (43% versus 32%, P <0.001), but excess mortality with boluses was evident in responders (relative risk 1.98, 95% confidence interval 0.94 to 4.17, P = 0.06) and 'non-responders' (relative risk 1.67, 95% confidence interval 1.23 to 2.28, P = 0.001), with no evidence of heterogeneity (P = 0.68). The major difference between bolus and control arms was the higher proportion of cardiogenic or shock terminal clinical events in bolus arms (n = 123; 4.6% versus 2.6%, P = 0.008) rather than respiratory (n = 61; 2.2% versus 1.3%, P = 0.09) or neurological (n = 63, 2.1% versus 1.8%, P = 0.6) terminal clinical events. CONCLUSIONS: Excess mortality from boluses occurred in all subgroups of children. Contrary to expectation, cardiovascular collapse rather than fluid overload appeared to contribute most to excess deaths with rapid fluid resuscitation. These results should prompt a re-evaluation of evidence on fluid resuscitation for shock and a re-appraisal of the rate, composition and volume of resuscitation fluids. TRIAL REGISTRATION: ISRCTN69856593.

Effect of intermittent preventive treatment for malaria during infancy on serological responses to measles and other vaccines used in the Expanded Programme on Immunization: results from five randomised controlled trials.

BACKGROUND: Intermittent preventive treatment for malaria during infancy (IPTi) is the administration of a full therapeutic course of antimalarial drugs to infants living in settings where malaria is endemic, at the time of routine vaccination in the first year of life. We investigated whether IPTi with sulfadoxine-pyrimethamine or other antimalarial drug combinations adversely affected serological responses to vaccines used in the Expanded Programme on Immunization (EPI). METHODS: The study was done in a subset of children enrolled in five randomised controlled trials in Navrongo, Ghana; Kilimanjaro, Tanzania; Manhica, Mozambique; Kisumu, Kenya; and Bungoma, Kenya. All infants presenting for the second dose of the diphtheria-tetanus-pertussis vaccination (given at 8-10 weeks of age) were eligible, and analyses included all children who had received measles vaccination (at 9 months of age) and at least one dose of IPTi or placebo. Blood samples were collected before and after vaccination, and antibody titres were measured by plaque reduction neutralisation (measles, yellow fever), microneutralisation (polio serotypes 1 and 3), and ELISA (all other EPI antigens). Laboratory personnel were unaware of the randomisation groups. We compared the proportion of infants in the IPTi and placebo groups who did not attain protective antibody titres after vaccination, using a one-sided significance non-inferiority margin of 5% for measles (the primary endpoint) and 10% for other EPI antigens. FINDINGS: Between September, 2000, and May, 2008, 8416 children were enrolled in the five studies. Paired samples from 2368 children from sites where sulfadoxine-pyrimethamine was compared with placebo were analysed for measles antibodies. 464 children with detectable measles antibody in their sample before vaccination were excluded, leaving 1904 individuals (934 placebo and 970 sulfadoxine-pyrimethamine) in the study. IPTi with sulfadoxine-pyrimethamine did not have a clinically significant effect on immune responses to measles vaccine; 61 of 970 (6·3%) children who received IPTi did not develop a protective antibody response after measles vaccination compared with 60 of 934 (6·4%) who received placebo, a difference of -0·14% (95% CI -2·3 to 2·1). When other antimalarial drugs were used for IPTi the results were much the same. Among 2396 children from whom serological response data for other EPI antigens were available, we identified no evidence of an adverse effect of IPTi with sulfadoxine-pyrimethamine or other antimalarial drugs on the proportion achieving protective antibody concentrations. INTERPRETATION: IPTi with sulfadoxine-pyrimethamine does not affect serological responses to EPI vaccines. This analysis, therefore, supports the WHO recommendation for coadministration of IPTi with sulfadoxine-pyrimethamine to infants at the time of the second and third doses of DTP and measles vaccination, in areas of sub-Saharan Africa with moderate to high malaria transmission and where malaria parasites are sensitive to these drugs. It also suggests that treatment of clinical malaria at or around the time of vaccination does not compromise vaccine responsiveness. FUNDING: Bill & Melinda Gates Foundation.

The definition of pneumonia, the assessment of severity, and clinical standardization in the Pneumonia Etiology Research for Child Health study.

To develop a case definition for the Pneumonia Etiology Research for Child Health (PERCH) project, we sought a widely acceptable classification that was linked to existing pneumonia research and focused on very severe cases. We began with the World Health Organization's classification of severe/very severe pneumonia and refined it through literature reviews and a 2-stage process of expert consultation. PERCH will study hospitalized children, aged 1-59 months, with pneumonia who present with cough or difficulty breathing and have either severe pneumonia (lower chest wall indrawing) or very severe pneumonia (central cyanosis, difficulty breastfeeding/drinking, vomiting everything, convulsions, lethargy, unconsciousness, or head nodding). It will exclude patients with recent hospitalization and children with wheeze whose indrawing resolves after bronchodilator therapy. The PERCH investigators agreed upon standard interpretations of the symptoms and signs. These will be maintained by a clinical standardization monitor who conducts repeated instruction at each site and by recurrent local training and testing.

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.).

Low incidence of abacavir hypersensitivity reaction among African children initiating antiretroviral therapy.

Hypersensitivity reactions are reported in approximately 5% of adults receiving abacavir, but there are few published data in children. Among 1150 African children receiving antiretroviral therapy in a randomized trial, suspected hypersensitivity reactions to abacavir were rare (0.3%; 95% CI, 0.01-0.9). Patients were managed successfully through the provision of clear guidelines and education of clinical staff, children, and their caregivers.

Malaria in children.

The past decade has seen an unprecedented surge in political commitment and international funding for malaria control. Coverage with existing control methods (ie, vector control and artemisinin-based combination therapy) is increasing, and, in some Asian and African countries, childhood morbidity and mortality from malaria caused by Plasmodium falciparum are starting to decline. Consequently, there is now renewed interest in the possibility of malaria elimination. But the ability of the parasite to develop resistance to antimalarial drugs and increasing insecticide resistance of the vector threaten to reduce and even reverse current gains. Plasmodium vivax, with its dormant liver stage, will be particularly difficult to eliminate, and access to effective and affordable treatment at community level is a key challenge. New drugs and insecticides are needed urgently, while use of an effective vaccine as part of national malaria control programmes remains an elusive goal. This Seminar, which is aimed at clinicians who manage children with malaria, especially in resource-poor settings, discusses present knowledge and controversies in relation to the epidemiology, pathophysiology, diagnosis, treatment, and prevention of malaria in children.

Burden, features, and outcome of neurological involvement in acute falciparum malaria in Kenyan children.

CONTEXT: Plasmodium falciparum appears to have a particular propensity to involve the brain but the burden, risk factors, and full extent of neurological involvement have not been systematically described. OBJECTIVES: To determine the incidence and describe the clinical phenotypes and outcomes of neurological involvement in African children with acute falciparum malaria. DESIGN, SETTING, AND PATIENTS: A review of records of all children younger than 14 years admitted to a Kenyan district hospital with malaria from January 1992 through December 2004. Neurological involvement was defined as convulsive seizures, agitation, prostration, or impaired consciousness or coma. MAIN OUTCOME MEASURES: The incidence, pattern, and outcome of neurological involvement. RESULTS: Of 58,239 children admitted, 19,560 (33.6%) had malaria as the primary clinical diagnosis. Neurological involvement was observed in 9313 children (47.6%) and manifested as seizures (6563/17,517 [37.5%]), agitation (316/11,193 [2.8%]), prostration (3223/15,643 [20.6%]), and impaired consciousness or coma (2129/16,080 [13.2%]). In children younger than 5 years, the mean annual incidence of admissions with malaria was 2694 per 100,000 persons and the incidence of malaria with neurological involvement was 1156 per 100,000 persons. However, readmissions may have led to a 10% overestimate in incidence. Children with neurological involvement were older (median, 26 [interquartile range {IQR}, 15-41] vs 21 [IQR, 10-40] months; P<.001), had a shorter duration of illness (median, 2 [IQR, 1-3] vs 3 [IQR, 2-3] days; P<.001), and a higher geometric mean parasite density (42.0 [95% confidence interval {CI}, 40.0-44.1] vs 30.4 [95% CI, 29.0-31.8] x 10(3)/microL; P<.001). Factors independently associated with neurological involvement included past history of seizures (adjusted odds ratio [AOR], 3.50; 95% CI, 2.78-4.42), fever lasting 2 days or less (AOR, 2.02; 95% CI, 1.64-2.49), delayed capillary refill time (AOR, 3.66; 95% CI, 2.40-5.56), metabolic acidosis (AOR, 1.55; 95% CI, 1.29-1.87), and hypoglycemia (AOR, 2.11; 95% CI, 1.31-3.37). Mortality was higher in patients with neurological involvement (4.4% [95% CI, 4.2%-5.1%] vs 1.3% [95% CI, 1.1%-1.5%]; P<.001). At discharge, 159 (2.2%) of 7281 patients had neurological deficits. CONCLUSIONS: Neurological involvement is common in children in Kenya with acute falciparum malaria, and is associated with metabolic derangements, impaired perfusion, parasitemia, and increased mortality and neurological sequelae. This study suggests that falciparum malaria exposes many African children to brain insults.

From evidence to action? Challenges to policy change and programme delivery for malaria in pregnancy.

This paper discusses the factors that influence whether strategies for preventing and treating malaria in pregnancy are successfully translated into national policy and programme implementation, and identifies key operational research issues. Countries require guidance on how to assess the effectiveness of intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine in the context of increasing sulfadoxine-pyrimethamine resistance. At the same time, data on the safety and efficacy of alternatives to sulfadoxine-pyrimethamine for prevention and treatment are urgently needed. Systematic examination of the cultural and operational constraints to delivery and uptake of IPTp with sulfadoxine-pyrimethamine and use of insecticide-treated nets would provide a rational basis for strategies aimed at improving coverage. Standardised methodology must be used to monitor IPTp coverage and to compare different approaches for scaling-up the delivery of insecticide-treated nets to pregnant women. Adequate budgetary provision for the implementation of policy and for operational research to improve programme delivery should be included in national applications to the Global Fund to Fight AIDS, Tuberculosis and Malaria. The provision of clear policy guidance on malaria in pregnancy and its translation into evidence-based guidelines that are made widely available at a country level are central to improving malaria control in this particularly vulnerable group.