Yamikani Chimalizeni

Blantyre Malaria Project Epilepsy Study (BMPES) of neurological outcomes in retinopathy-positive paediatric cerebral malaria survivors: a prospective cohort study

Summary Background Cerebral malaria, a disorder characterised by coma, parasitaemia, and no other evident cause of coma, is challenging to diagnose definitively in endemic regions that have high rates of asymptomatic parasitaemia and limited neurodiagnostic facilities. A recently described malaria retinopathy improves diagnostic specificity. We aimed to establish whether retinopathy-positive cerebral malaria is a risk factor for epilepsy or other neurodisabilities. Methods Between 2005 and 2007, we did a prospective cohort study of survivors of cerebral malaria with malaria retinopathy in Blantyre, Malawi. Children with cerebral malaria were identified at the time of their index admission and age-matched to concurrently admitted children without coma or nervous system infection. Initially matching of cases to controls was 1:1 but, in 2006, enrolment criteria for cerebral malaria survivors were revised to limit inclusion to children with cerebral malaria and retinopathy on the basis of indirect ophthalmoscopic examination; matching was then changed to 1:2 and the revised inclusion criteria were applied retrospectively for children enrolled previously. Clinical assessments at discharge and standardised nurse-led follow-up every 3 months thereafter were done to identify children with new seizure disorders or other neurodisabilities. A Kaplan-Meier survival analysis was done for incident epilepsy. Findings 132 children with retinopathy-positive cerebral malaria and 264 age-matched, non-comatose controls were followed up for a median of 495 days (IQR 195–819). 12 of 132 cerebral malaria survivors developed epilepsy versus none of 264 controls (odds ratio [OR] undefined; p<0·0001). 28 of 121 cerebral malaria survivors developed new neurodisabilities, characterised by gross motor, sensory, or language deficits, compared with two of 253 controls (OR 37·8, 95% CI 8·8–161·8; p<0·0001). The risk factors for epilepsy in children with cerebral malaria were a higher maximum temperature (39·4°C [SD 1·2] vs 38·5°C [1·1]; p=0·01) and acute seizures (11/12 vs 76/120; OR 6·37, 95% CI 1·02–141·2), and male sex was a risk factor for new neurodisabilities (20/28 vs 38/93; OR 3·62, 1·44–9·06). Interpretation Almost a third of retinopathy-positive cerebral malaria survivors developed epilepsy or other neurobehavioural sequelae. Neuroprotective clinical trials aimed at managing hyperpyrexia and optimising seizure control are warranted. Funding US National Institutes of Health and Wellcome Trust.

The Epidemiology and Management of Non Typhoidal Salmonella Infections

Non typhoidal salmonella (NTS) infections affect children all over the world. In well resourced countries they usually present as mild gastro-enteritis, which resolves in a few days without active treatment

Neurologic outcomes in retinopathy- negative cerebral malaria survivors

Objectives: Patients surviving retinopathy-positive cerebral malaria (CM) are at high risk for the development of epilepsy, developmental disabilities, and behavioral abnormalities. We aimed to establish whether retinopathy-negative CM is also a risk factor for these outcomes. Methods: Between 2005 and 2007, survivors of CM and concurrently hospitalized controls in Blantyre, Malawi, were followed to assess the development of neurologic abnormalities. At discharge and every 3 months thereafter, incident cases of epilepsy and developmental disabilities were ascertained using screening questionnaires and confirmatory neurologic examinations. Incident cases of epilepsy and developmental disabilities were compared in retinopathy-negative CM survivors to controls and retinopathy-positive CM survivors. Results: Thirty-five retinopathy-negative CM survivors were enrolled. Their neurologic outcomes were compared to 132 retinopathy-positive CM survivors and 272 controls. Compared to survivors of retinopathy-positive CM, children without malaria retinopathy have an equal odds of adverse neurologic outcome (odds ratio [OR] = 1.0, 95% confidence interval [CI] 0.4–2.2). Eleven of 35 survivors of retinopathy-negative CM had at least 1 adverse neurologic outcome compared to 2 of 272 controls (OR 61.9, 95% CI 13.0–295.5). In retinopathy-negative CM survivors, a Blantyre Coma Scale score ≤1 on admission was associated with an adverse outcome. Conclusions: Compared with controls, children surviving either retinopathy-negative or -positive CM are at similar high risk for adverse neurologic outcomes. Studies to evaluate preventive and therapeutic strategies in children with both retinopathy-negative and -positive CM are needed to improve mortality, morbidity, or both.

Glycerol and acetaminophen as adjuvant therapy did not affect the outcome of bacterial meningitis in Malawian children.

We investigated the benefit of 2 candidate adjunctive therapies in bacterial meningitis: glycerol, which has shown promise in earlier studies, and acetaminophen, which is reportedly beneficial in adult septicemia. In a hospital in Blantyre, Malawi, we enrolled 360 children aged ≥ 2 months with proven bacterial meningitis (36% HIV infected) in a double-blind, randomized, placebo-controlled trial of glycerol and acetaminophen in a 2 × 2 factorial design. Of 4 groups, first group received oral glycerol, second received rectal acetaminophen, third received both therapies and the fourth received placebos only. Adjuvant therapies were given for the first 48 hours of antibiotic therapy. Endpoints were mortality and neurological sequelae. Baseline findings were similar across all groups, except that many children had prior antibiotics in the acetaminophen group and many were anemic in the acetaminophen and glycerol group. Outcomes were similar for all groups. We found no benefit from oral glycerol or rectal acetaminophen in, mostly pneumococcal, meningitis in Malawian children.

Risk Factors for Death and Severe Sequelae in Malawian Children with Bacterial Meningitis, 1997--2010

Background: Acute bacterial meningitis (ABM) causes significant death and disability in children worldwide, with HIV recognized as an established risk factor for infection and negative outcomes. However, additional major risk factors for death and disability in pediatric ABM remain unclear. Methods: We conducted a retrospective analysis of case data from 3 departmental studies of ABM involving 1784 children <15 years old who attended Queen Elizabeth Central Hospital in Blantyre, Malawi during 1997 to 2010. Univariate and multivariate logistic regression models were used to estimate the effects of HIV seropositivity, impaired consciousness and causative organism on death and severe sequelae. Results: Impaired consciousness or coma at the time of admission was strongly associated with death (coma: odds ratio [OR] = 14.4, 95% confidence interval [CI]: 9.42, 22.1) and severe sequelae (Coma: OR = 3.27, 95% CI: 2.02, 5.29) in multivariate logistic regression models. HIV seropositivity was significantly associated with increased odds of death (OR = 1.65, 95% CI: 1.20, 2.26) but not with developing severe sequelae (OR = 0.88, 95% CI: 0.56, 1.38). After adjustment, infection with Salmonella spp. was associated with increased odds of death (OR = 2.11, 95% CI: 1.06, 4.08) and pneumococcal meningitis was associated with increased odds of severe sequelae (OR = 1.84, 95% CI: 1.03, 3.29). Conclusions: Impaired consciousness and HIV infection increased the odds of death from ABM in Malawian children. Use of pneumococcal conjugate vaccine could greatly reduce the burden of ABM in Malawi.

Intramuscular Artesunate for Severe Malaria in African Children: A Multicenter Randomized Controlled Trial

Background Current artesunate (ARS) regimens for severe malaria are complex. Once daily intramuscular (i.m.) injection for 3 d would be simpler and more appropriate for remote health facilities than the current WHO-recommended regimen of five intravenous (i.v.) or i.m. injections over 4 d. We compared both a three-dose i.m. and a three-dose i.v. parenteral ARS regimen with the standard five-dose regimen using a non-inferiority design (with non-inferiority margins of 10%). Methods and Findings This randomized controlled trial included children (0.5–10 y) with severe malaria at seven sites in five African countries to assess whether the efficacy of simplified three-dose regimens is non-inferior to a five-dose regimen. We randomly allocated 1,047 children to receive a total dose of 12 mg/kg ARS as either a control regimen of five i.m. injections of 2.4 mg/kg (at 0, 12, 24, 48, and 72 h) (n = 348) or three injections of 4 mg/kg (at 0, 24, and 48 h) either i.m. (n = 348) or i.v. (n = 351), both of which were the intervention arms. The primary endpoint was the proportion of children with ≥99% reduction in parasitemia at 24 h from admission values, measured by microscopists who were blinded to the group allocations. Primary analysis was performed on the per-protocol population, which was 96% of the intention-to-treat population. Secondary analyses included an analysis of host and parasite genotypes as risks for prolongation of parasite clearance kinetics, measured every 6 h, and a Kaplan–Meier analysis to compare parasite clearance kinetics between treatment groups. A post hoc analysis was performed for delayed anemia, defined as hemoglobin ≤ 7g/dl 7 d or more after admission. The per-protocol population was 1,002 children (five-dose i.m.: n = 331; three-dose i.m.: n = 338; three-dose i.v.: n = 333); 139 participants were lost to follow-up. In the three-dose i.m. arm, 265/338 (78%) children had a ≥99% reduction in parasitemia at 24 h compared to 263/331 (79%) receiving the five-dose i.m. regimen, showing non-inferiority of the simplified three-dose regimen to the conventional five-dose regimen (95% CI −7, 5; p = 0.02). In the three-dose i.v. arm, 246/333 (74%) children had ≥99% reduction in parasitemia at 24 h; hence, non-inferiority of this regimen to the five-dose control regimen was not shown (95% CI −12, 1; p = 0.24). Delayed parasite clearance was associated with the N86YPfmdr1 genotype. In a post hoc analysis, 192/885 (22%) children developed delayed anemia, an adverse event associated with increased leukocyte counts. There was no observed difference in delayed anemia between treatment arms. A potential limitation of the study is its open-label design, although the primary outcome measures were assessed in a blinded manner. Conclusions A simplified three-dose i.m. regimen for severe malaria in African children is non-inferior to the more complex WHO-recommended regimen. Parenteral ARS is associated with a risk of delayed anemia in African children. Trial registration Pan African Clinical Trials Registry PACTR201102000277177

The platelet count in cerebral malaria, is it useful to the clinician?

We conducted this study to determine the prognostic significance of the platelet count in children with cerebral malaria. We studied children with cerebral malaria admitted to the pediatric research ward at Queen Elizabeth Central Hospital, Malawi. We analyzed 1,811 children with cerebral malaria and compared them with 521 children with bacterial meningitis. There was a significant difference in platelet counts between children with cerebral malaria and those with meningitis. Among children with cerebral malaria, there was no relationship between the platelet count and either the admission coma score or the eventual outcome. Those with malarial retinopathy were more thrombocytopenic than those without. Our results suggest that the platelet count is not prognostic in Malawian children with cerebral malaria.

Knowledge, attitudes and practices towards malaria among primary school pupils in Ndirande, Blantyre, Malawi.

A qualitative cross-sectional study was conducted at Ndirande Primary School in the peri-urban area of Blantyre, Malawi in 2002. The aim was to describe the knowledge, attitudes and practices towards malaria among pupils. Forty pupils (20 boys and 20 girls) were recruited into four focus group discussions. There was very good knowledge about the role of the female Anopheles mosquito as an agent for transmission of malaria. Respondents were also aware of the clinical features of malaria and what measures could be taken to prevent the disease. However, the survey showed that many of the environmental modification measures were difficult to implement in the overcrowded peri-urban areas. Respondents did not believe that they could influence parents or other authorities in instituting environmental modification interventions. We conclude that children are unlikely to be effective change agents if the social environment does not offer them the opportunity to influence key community figures.

The effects of malnutrition on cardiac function in African children

Objective Cardiac dysfunction may contribute to high mortality in severely malnourished children. Our objective was to assess the effect of malnutrition on cardiac function in hospitalised African children. Design Prospective cross-sectional study. Setting Public referral hospital in Blantyre, Malawi. Patients We enrolled 272 stable, hospitalised children ages 6–59 months, with and without WHO-defined severe acute malnutrition. Main outcome measures Cardiac index, heart rate, mean arterial pressure, stroke volume index and systemic vascular resistance index were measured by the ultrasound cardiac output monitor (USCOM, New South Wales, Australia). We used linear regression with generalised estimating equations controlling for age, sex and anaemia. Results Our primary outcome, cardiac index, was similar between those with and without severe malnutrition: difference=0.22 L/min/m2 (95% CI −0.08 to 0.51). No difference was found in heart rate or stroke volume index. However, mean arterial pressure and systemic vascular resistance index were lower in children with severe malnutrition: difference=−8.6 mm Hg (95% CI −12.7 to −4.6) and difference=−200 dyne s/cm5/m2 (95% CI −320 to −80), respectively. Conclusions In this largest study to date, we found no significant difference in cardiac function between hospitalised children with and without severe acute malnutrition. Further study is needed to determine if cardiac function is diminished in unstable malnourished children.

Evidence behind the WHO guidelines: hospital care for children: what is the most appropriate anti-fungal treatment for acute cryptococcal meningitis in children with HIV?

The World Health Organization has produced guidelines for the management of common illnesses in hospitals with limited resources. This series reviews the scientific evidence behind WHO’s recommendations. The WHO guidelines and more reviews are available at: http://www.ichrc.org. The WHO Pocketbook of Hospital Care for Children [1] recommends treating children with cryptococcal meningitis with intravenous amphotericin B (0.5–1.5mgkg 1 day ) for 14 days followed by oral fluconazole (3–6mgkg 1 day ) for 8 weeks. Following the management of an acute episode, current recommendations advise ongoing prophylaxis with fluconazole. This review addresses the question: what is the most appropriate anti-fungal treatment for acute cryptococcal meningitis in children with HIV?