Genetic diversity of Plasmodium falciparum infections in mild and severe malaria of children from Kampala, Uganda.

Diversity in parasite virulence is one of the factors that contribute to the clinical outcome of malaria infections. The association between the severity of Plasmodium falciparum malaria and the number of distinct parasite populations infecting the host (multiplicity of infection) or polymorphism within any of the specific antigen genes was investigated. The study included 164 children presenting with mild and severe malaria from central Uganda where malaria is meso-endemic. The polymorphic regions of the circumsporozoite protein (csp), merozoite surface proteins 1 and 2 (msp1 and msp2), and glutamate-rich protein (glurp) were genotyped by polymerase chain reaction methods and fragment analysis by gel electrophoresis. In a subset of samples fragment analysis was also performed by fluorescent PCR genotyping followed by capillary electrophoresis. The multiplicity of infection (MOI), determined as the highest number of alleles detected within any of the four genetic loci, was significantly higher in severe than in mild malaria cases (mean 3.7 and 3.0, respectively, P=0.002). No particular genotype or allelic family of msp1 or msp2 was associated with severity of malaria, and nor did the genotyping method reveal any significant difference in MOI when only assessed by msp2 genotyping. Severity of malaria was not linked to the predominance of any particular msp1 or msp2 allelic types, independent of methods used for genotyping. Monitoring the dynamics of multiple clone infections in relation to disease outcome, host immune status and genetic factors will provide more insight into parasite virulence mechanisms.

Elevated levels of high-mobility group box-1 (HMGB1) in patients with severe or uncomplicated Plasmodium falciparum malaria.

Severe malaria is characterized by a massive release of proinflammatory cytokines in the context of sequestration of parasitized and normal red cells (RBCs). High-mobility group box 1 (HMGB1) is a DNA- and heparin-binding protein that also acts as a cytokine when released from cells in the extracellular milieu after a proinflammatory stimulus. In this study, we have measured the circulating levels of HMGB1 in 76 children with severe or uncomplicated malaria. Sera from both severe (P = 0.0022) and uncomplicated (P = 0.0049) patients had significantly higher circulating HMGB1 levels compared with healthy controls. Elevated HMGB1 in patients with ongoing Plasmodium falciparum infections might prolong inflammation and the febrile state of malaria and could offer a potential target for therapeutic intervention.

Detection of copy number variation and single nucleotide polymorphisms in genes involved in drug resistance and other phenotypic traits in P. falciparum clinical isolates collected from Uganda.

There is an increasing interest in mapping the genes of pathogens which underlie important phenotypic traits such as virulence and drug resistance. The Plasmodium falciparum genome exhibits sequence variation that contributes to the pathogenic mechanisms of the parasite. Determining the prevalence of resistance markers could provide a prediction about drug efficacy. Copy number polymorphism (CNP) of genes has been shown to influence important parasite phenotypes. In this work, CNPs within genes involved in drug resistance and other phenotypic traits namely P. falciparum multidrug resistance 1 (pfmdr-1), GTP cyclo hydrolase (gch1), Ring infected erythrocyte surface antigen precursor (resa) and a hypothetical protein coding gene were analyzed by quantitative real time-polymerase reaction (qRT-PCR) among clinical isolates collected from Uganda. The pfmdr-1 codons 86 and 1246 and P. falciparum chloroquine resistance (pfcrt) codon 76 were genotyped for single nucleotide polymorphisms (SNPs) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and the proportion of resistance associated mutations were determined among mild and severe malaria cases using the chi-square test. Forty and 42 P. falciparum isolates collected from children with mild and severe malaria respectively were analyzed for CNPs. Seventy five and 81 P. falciparum isolates from children with mild or severe malaria were analyzed for SNPs. No pfmdr-1, gch1 or novel gene amplifications were identified among the P. falciparum clinical isolates. Although chloroquine was officially withdrawn from policy use since 7 years, all P. falciparum isolates presented the associated pfcrt K76T mutation, whatever the clinical status and no specific mutation in the pfmdr-1 gene was associated with disease type. In conclusion, this study provides baseline measures for continued surveillance for changes in copy number and SNP types among genes implicated in drug resistance and other important phenotypes that may have a potential role in parasite virulence mechanisms or drug treatment outcomes.

Human immunodeficiency virus infection and cerebral malaria in children in Uganda: a case-control study.

BACKGROUND: Human immunodeficiency virus (HIV)-1 infection increases the burden of malaria by increasing susceptibility to infection and decreasing the response to malarial treatment. HIV-1 has also been found to suppress the immune system and predispose to severe forms of malaria in adults. There is still a paucity of data on the association between HIV-1 infection and cerebral malaria in children. The aim of this study was to determine whether HIV-1 infection is a risk factor for cerebral malaria in children. METHOD: We conducted an unmatched case-control study, in which 100 children with cerebral malaria were compared with 132 with uncomplicated malaria and 120 with no malaria. In stratified analyses we estimated odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age. RESULTS: HIV-1 infection was present in 9% of children with cerebral malaria compared to 2.3% in uncomplicated malaria (age-adjusted odds ratio (aOR) 5.94 (95% confidence interval (CI) 1.36-25.94, p = 0.012); and 2.5% in children with no malaria (aOR 3.85 (95% CI0.99-14.93, p = 0.037). The age-adjusted odds of being HIV-positive among children with cerebral malaria compared to the control groups (children with uncomplicated malaria and no malaria) was 4.98 (95% CI 1.54-16.07), p-value = 0.003. CONCLUSIONS: HIV-1 infection is associated with clinical presentation of cerebral malaria in children. Clinicians should ensure that children diagnosed with HIV infection are initiated on cotrimoxazole prophylaxis as soon as the diagnosis is made and caretakers counselled on the importance of adherence to the cotrimoxazole towards reducing the risk of acquiring P.falciparum malaria and associated complications such as cerebral malaria. Other malaria preventive measures such as use of insecticide-treated mosquito nets should also be emphasized during counselling sessions.

Severe neurological sequelae and behaviour problems after cerebral malaria in Ugandan children.

BACKGROUND: Cerebral malaria is the most severe neurological complication of falciparum malaria and a leading cause of death and neuro-disability in sub-Saharan Africa. This study aimed to describe functional deficits and behaviour problems in children who survived cerebral malaria with severe neurological sequelae and identify patterns of brain injury. FINDINGS: Records of children attending a specialist child neurology clinic in Uganda with severe neurological sequelae following cerebral malaria between January 2007 and December 2008 were examined to describe deficits in gross motor function, speech, vision and hearing, behaviour problems or epilepsy. Deficits were classified according to the time of development and whether their distribution suggested a focal or generalized injury. Any resolution during the observation period was also documented.Thirty children with probable exposure to cerebral malaria attended the clinic. Referral information was inadequate to exclude other diagnoses in 7 children and these were excluded. In the remaining 23 patients, the commonest severe deficits were spastic motor weakness (14), loss of speech (14), hearing deficit (9), behaviour problems (11), epilepsy (12), blindness (12) and severe cognitive impairment (9). Behaviour problems included hyperactivity, impulsiveness and inattentiveness as in attention deficit hyperactivity disorder (ADHD) and conduct disorders with aggressive, self injurious or destructive behaviour. Two patterns were observed; a) immediate onset deficits present on discharge and b) late onset deficits. Some deficits e.g. blindness, resolved within 6 months while others e.g. speech, showed little improvement over the 6-months follow-up. CONCLUSIONS: In addition to previously described neurological and cognitive sequelae, severe behaviour problems may follow cerebral malaria in children. The observed differences in patterns of sequelae may be due to different pathogenic mechanisms, brain regions affected or extent of injury. Cerebral malaria may be used as a new model to study the pathogenesis of ADHD.

var gene transcription dynamics in Plasmodium falciparum patient isolates.

A major feature of Plasmodium falciparum parasitized red blood cells (pRBC) is their capacity to sequester in the microcirculation. The binding is mediated by PfEMP1 (P. falciparum erythrocyte membrane protein 1), a variable protein encoded by the var gene family. P. falciparum avoids the host antibody response generated against previously used variants by switching the expression of PfEMP1, which may affect the disease outcome. We have here studied var gene transcription over time within the life cycle of the parasite by semi-quantitative PCR and sequencing by employing three sets of degenerate primers to the 5-prime end of the var genes (corresponding to the DBL1alpha-domain). To accurately determine transcript levels, subsequent in-depth analysis was made by amplifying the 10 most frequently expressed var sequences identified in each developmental stage by quantitative PCR (Q-PCR). The maximum peak in var gene transcription seems to vary in time among parasites. In five out of seven parasites, var gene transcription was found to be higher or equal at 22-26h post-invasion compared to 4-10h post-invasion. Our data indicate that the intra-isolate var gene transcription dominance order may change between different developmental stages. The transcription of var genes in field isolates is more complex than in laboratory strains and often changes after in vitro adaption of the parasite. By using semi-quantitative PCR employing degenerate primers combined with quantitative-PCR using specific primers it is possible to monitor var gene transcription in detail during the life cycle of the parasite. The work presented here suggests that trophozoite pRBC is likely to be the optimal source of RNA for predicting the translated var gene species.

Socioeconomic predictors of cognition in Ugandan children: implications for community interventions.

BACKGROUND: Several interventions to improve cognition in at risk children have been suggested. Identification of key variables predicting cognition is necessary to guide these interventions. This study was conducted to identify these variables in Ugandan children and guide such interventions. METHODS: A cohort of 89 healthy children (45 females) aged 5 to 12 years old were followed over 24 months and had cognitive tests measuring visual spatial processing, memory, attention and spatial learning administered at baseline, 6 months and 24 months. Nutritional status, child's educational level, maternal education, socioeconomic status and quality of the home environment were also measured at baseline. A multivariate, longitudinal model was then used to identify predictors of cognition over the 24 months. RESULTS: A higher child's education level was associated with better memory (p = 0.03), attention (p = 0.005) and spatial learning scores over the 24 months (p = 0.05); higher nutrition scores predicted better visual spatial processing (p = 0.002) and spatial learning scores (p = 0.008); and a higher home environment score predicted a better memory score (p = 0.03). CONCLUSION: Cognition in Ugandan children is predicted by child's education, nutritional status and the home environment. Community interventions to improve cognition may be effective if they target multiple socioeconomic variables.

Seizure activity and neurological sequelae in Ugandan children who have survived an episode of cerebral malaria.

BACKGROUND: Seizures are a common presenting feature in children with cerebral malaria (CM) and neurologic deficits have been described in survivors of CM. However few prospective studies have described the frequency of seizure activity and neurologic deficits in survivors of CM over time. METHODS: Eighty-two children aged 3 to 12 years who survived an episode of CM were followed up and monitored for seizure activity and neurologic deficits at discharge, 3, 6 and 24 months. Seventy six children with uncomplicated malaria (UM) and 105 healthy community controls (CC) age 3 to 12 years were recruited as comparison groups and the frequency of seizures in the 6 to 24 month follow-up period was compared in the 3 groups. RESULTS: Cumulative incidence of seizures increased over time in children with CM, with a total of 2 of 76 children (2.6%) reporting seizures at 3 months, 3 of 74 children (4.1%) at 6 months and 11 of 68 children (16.2%) at 24 months (Chi square for trend = 9.36, P=0.002). In contrast, neurologic deficits almost completely resolved over time, occurring in 19 of 76 children with CM (25%) at discharge, 2 of 74 children (2.7%) at 6 months, and 1 of 68 (1.5%) children at 24 months. CONCLUSIONS: During the 24 months following a CM episode, neurologic deficits resolve but the cumulative incidence of seizures increases in children with CM. Neurologic impairment after an episode of CM may not be limited to the neurologic deficits seen at discharge.

Predictors of anti-convulsant treatment failure in children presenting with malaria and prolonged seizures in Kampala, Uganda.

BACKGROUND: In endemic areas, falciparum malaria remains the leading cause of seizures in children presenting to emergency departments. In addition, seizures in malaria have been shown to increase morbidity and mortality in these patients. The management of seizures in malaria is sometimes complicated by the refractory nature of these seizures to readily available anti-convulsants. The objective of this study was to determine predictors of anti-convulsant treatment failure and seizure recurrence after initial control among children with malaria. METHODS: In a previous study, the efficacy and safety of buccal midazolam was compared to that of rectal diazepam in the treatment of prolonged seizures in children aged three months to 12 years in Kampala, Uganda. For this study, predictive models were used to determine risk factors for anti-convulsant treatment failure and seizure recurrence among the 221 of these children with malaria. RESULTS: Using predictive models, focal seizures (OR 3.21; 95% CI 1.42-7.25, p = 0.005), cerebral malaria (OR 2.43; 95% CI 1.20-4.91, p = 0.01) and a blood sugar >or=200 mg/dl at presentation (OR 2.84; 95% CI 1.11-7.20, p = 0.02) were independent predictors of treatment failure (seizure persistence beyond 10 minutes or recurrence within one hour of treatment). Predictors of seizure recurrence included: 1) cerebral malaria (HR 3.32; 95% CI 1.94-5.66, p < 0.001), 2) presenting with multiple seizures (HR 2.45; 95% CI 1.42-4.23, p = 0.001), 3) focal seizures (HR 2.86; 95% CI 1.49-5.49, p = 0.002), 4) recent use of diazepam (HR 2.43; 95% CI 1.19-4.95, p = 0.01) and 5) initial control of the seizure with diazepam (HR 1.96; 95% CI 1.16-3.33, p = 0.01). CONCLUSION: Specific predictors, including cerebral malaria, can identify patients with malaria at risk of anti-convulsant treatment failure and seizure recurrence.

Enteric bacterial pathogens in HIV-infected children with acute diarrhea in Mulago referral and teaching hospital, Kampala, Uganda.

OBJECTIVE: HIV-infected children develop severe bacterial infections. We set out to determine the enteric bacterial pathogens in HIV-infected children and HIV-negative controls with acute diarrhea and their antimicrobial sensitivities. METHODS: Children below 5 years of age with acute diarrhea were screened for HIV and their stools were analyzed by culture and use of antisera and the sensitivities of the pathogens were determined using the Kirby Bauer disc diffusion method. RESULTS: Of the 190 children, 47 were HIV positive. The prevalence rates of the pathogens in HIV-infected and -uninfected children were 19% (9/47) and 27% (38/143), respectively; odds ratio = 0.64 (95% confidence interval 0.20-1.97), P value .396. The pathogens in HIV-infected and -uninfected children were Escherichia coli, Salmonella, and Shigella species. Most isolates were resistant to cotrimoxazole. CONCLUSIONS: Escherichia coli, Salmonella, and Shigella species significantly cause acute diarrhea in HIV-infected and -uninfected children and they are highly resistant to cotrimoxazole.

Cerebral malaria in children is associated with long-term cognitive impairment.

OBJECTIVE: Cerebral malaria affects >785000 African children every year. We previously documented an increased frequency of cognitive impairment in children with cerebral malaria 6 months after their initial malaria episode. This study was conducted to determine the long-term effects of cerebral malaria on the cognitive function of these children. METHODS: Children who were 5 to 12 years of age and presented to Mulago Hospital, Kampala, Uganda, with cerebral malaria (n = 44) or uncomplicated malaria (n = 54), along with healthy, asymptomatic community children (n = 89), were enrolled in a prospective cohort study of cognition. Cognitive testing was performed at enrollment and 2 years later. The primary outcome was presence of a deficit in >or=1 of 3 cognitive areas tested. RESULTS: At 2-year follow-up testing, 26.3% of children with cerebral malaria and 12.5% with uncomplicated malaria had cognitive deficits in >or=1 area, as compared with 7.6% of community children. Deficits in children with cerebral malaria were primarily in the area of attention (cerebral malaria, 18.4%, vs community children, 2.5%). After adjustment for age, gender, nutrition, home environment, and school level, children with cerebral malaria had a 3.67-fold increased risk for a cognitive deficit compared with community children. Cognitive impairment at 2-year follow-up was associated with hyporeflexia on admission and neurologic deficits 3 months after discharge. CONCLUSIONS: Cerebral malaria is associated with long-term cognitive impairments in 1 of 4 child survivors. Future studies should investigate the mechanisms involved so as to develop interventions aimed at prevention and rehabilitation.

Cerebrospinal fluid cytokine levels and cognitive impairment in cerebral malaria.

Cerebrospinal fluid (CSF) and serum levels of 12 cytokines or chemokines important in central nervous system (CNS) infections were measured in 76 Ugandan children with cerebral malaria (CM) and 8 control children. As compared with control children, children with cerebral malaria had higher cerebrospinal fluid levels of interleukin (IL)-6, CXCL-8/IL-8, granulocyte-colony stimulating factor (G-CSF), tumor necrosis factor-alpha (TNF-alpha), and IL-1 receptor antagonist. There was no correlation between cerebrospinal and serum cytokine levels for any cytokine except G-CSF. Elevated cerebrospinal fluid but not serum TNF-alpha levels on admission were associated with an increased risk of neurologic deficits 3 months later (odds ratio 1.55, 95% CI: 1.10, 2.18, P = 0.01) and correlated negatively with age-adjusted scores for attention (Spearman rho, -0.34, P = 0.04) and working memory (Spearman rho, -0.32, P = 0.06) 6 months later. In children with cerebral malaria, central nervous system TNF-alpha production is associated with subsequent neurologic and cognitive morbidity.

Comparison of buccal midazolam with rectal diazepam in the treatment of prolonged seizures in Ugandan children: a randomized clinical trial.

OBJECTIVE: Our goal was to compare the efficacy and safety of buccal midazolam with rectal diazepam in the treatment of prolonged seizures in Ugandan children. METHODS: This was a single-blind, randomized clinical trial in which 330 patients were randomly assigned to receive buccal midazolam or rectal diazepam. The trial was conducted in the pediatric emergency unit of the national referral hospital of Uganda. Consecutive patients who were aged 3 months to 12 years and presented while convulsing or who experienced a seizure that lasted >5 minutes were randomly assigned to receive buccal midazolam plus rectal placebo or rectal diazepam plus buccal placebo. The primary outcome of this study was cessation of visible seizure activity within 10 minutes without recurrence in the subsequent hour. RESULTS: Treatment failures occurred in 71 (43.0%) of 165 patients who received rectal diazepam compared with 50 (30.3%) of 165 patients who received buccal midazolam. Malaria was the most common underlying diagnosis (67.3%), although the risk for failure of treatment for malaria-related seizures was similar: 35.8% for rectal diazepam compared with 31.8% for buccal midazolam. For children without malaria, buccal midazolam was superior (55.9% vs 26.5%). Respiratory depression occurred uncommonly in both of the treatment arms. CONCLUSION: Buccal midazolam was as safe as and more effective than rectal diazepam for the treatment of seizures in Ugandan children, although benefits were limited to children without malaria.

Intravascular catheter related infections in children admitted on the paediatric wards of Mulago Hospital, Uganda.

INTRODUCTION: Worldwide use of intravascular catheters (IVC) has been associated with both local and systemic infections. No studies have been done in the sub-Saharan region on IVC related infections. OBJECTIVE: To determine the prevalence, causative organisms and their antimicrobial susceptibility pattern and the factors associated with infections related to short term peripheral venous catheters in children admitted to the general paediatric wards in Mulago Hospital, Uganda. METHODS: A cross-sectional study of 391 children aged one day to 12 years, on Jelliffe ward in Mulago Hospital, who had short peripheral venous intravascular catheters uncoated with no antibiotic or antiseptic, was done. Social demographic characteristics, anthropometry, clinical examination including the catheter site were determined at enrollment. The children had their blood, catheter tip and hub samples taken off for culture and sensitivity as well as complete blood counts. The data collected was entered using EPI-INFO and analysed with SPSS packages. RESULTS: Out of the 391 short term peripheral venous catheters collected, 20.7% catheter tips and 11.3% catheter hubs were colonised. Phlebitis was observed in 17.4%. Bacteria isolated from colonised catheter tips were Staphylococcus aureus (60.5%), Staphylococcus epidermidis (23.5%). The most common organism isolated from the hub was Staphylococcus aureus (56.8%) followed by Staphylococcus epidermidis (18.1%). Gram positive and negative organisms were sensitive to ciprofloxacin, gentamycin for gram-negative organisms and augmentin, cefuroxime, ceftriaxone for the gram-positive organisms. After logistic regression, factors such oedema, modified Glasgow coma score of <10/15, 6 hourly benzyl penicillin were significantly associated with colonisation of the tip while use of 25% dextrose, chloramphenicol 6 hourly and blood transfusion were significantly associated with colonisation of the hub. CONCLUSION: The study showed that infections related to short peripheral venous catheters in paediatric general wards in Mulago Hospital occurs and prevalence was 20.72% for tips and 11.3% for hubs.

Rectal versus intravenous quinine for the treatment of childhood cerebral malaria in Kampala, Uganda: a randomized, double-blind clinical trial.

BACKGROUND: Although artemesinin derivatives are promising for the treatment of severe Plasmodium falciparum malaria, intravenous quinine remains the most affordable treatment. However, administration of intravenous quinine is often not feasible in rural areas in Africa because of the lack of simple equipment or trained staff. We compared the efficacy and safety of intrarectal quinine with those of intravenous quinine in the treatment of childhood cerebral malaria. METHODS: In a randomized, double-blind clinical trial at Mulago Hospital (Kampala, Uganda), Uganda's national referral hospital, we studied 110 children aged 6 months to 5 years who had cerebral malaria. Patients were randomized to receive either intrarectal or intravenous quinine. Main outcome measures included parasite clearance time, fever clearance time, coma recovery time, time to sit unsupported, time to begin oral intake, time until oral quinine was tolerated, and death. RESULTS: Overall, there was no difference in the clinical and parasitological outcomes between the 2 groups (data are mean+/-standard deviation, intrarectal quinine group vs. intravenous quinine group): coma recovery time, 19.4+/-18.1 h versus 17.0+/-12.1 h; fever clearance time, 26.7+/-16.1 h versus 29.9+/-18.1 h; and parasite clearance time, 43.2+/-14.2 h versus 41.9+/-15.2 h. Mortality was similar in both groups; 4 of 56 patients in the intrarectal quinine group died, and 5 of 54 patients in the intravenous quinine group died (odds ratio, 1.3; 95% confidence interval, 0.3-5.2). Intrarectal quinine was well tolerated, and no major immediate adverse events occurred. CONCLUSIONS: Intrarectal quinine is efficacious and could be used as an alternative in the treatment of childhood cerebral malaria, especially in situations in which intravenous therapy is not feasible.

Mannitol as adjunct therapy for childhood cerebral malaria in Uganda: a randomized clinical trial.

BACKGROUND: Several reports have suggested that raised intracranial pressure (ICP) is a major contributor to death among children with cerebral malaria. Mannitol, an osmotic diuretic, effectively lowers ICP and is used to treat post-traumatic raised ICP. It is not clear whether intravenous mannitol given to children with cerebral malaria improves clinical outcome. The objective of this study was to determine the effect of mannitol as adjunct therapy on the clinical outcome of children with cerebral malaria. METHODS: This randomized double-blind placebo controlled clinical trial was carried out at the Emergency Paediatric ward of Mulago Hospital, Uganda's national referral and teaching hospital. One hundred and fifty six children aged 6 to 60 months with cerebral malaria were randomized to either one dose of mannitol 1 g/kg or placebo, in addition to intravenous quinine. Main outcome measures included coma recovery time; time to sit unsupported, begin oral intake; duration of hospitalization; death and adverse effects. RESULTS: Time to regain consciousness (p = 0.11), sit unsupported (p = 0.81), time to start oral intake (p = 0.13) and total coma duration (p = 0.07) were similar in both groups. There was no significant difference in the mortality between the placebo (13/80 or 16.3%) and mannitol (10/76 or 13.2%) groups: RR = 1.2 (CI 0.5-2.7). No adverse effects were observed after administration of mannitol. CONCLUSION: Mannitol had no significant impact on clinical outcome of cerebral malaria. It is difficult to recommend intravenous mannitol as adjunct therapy for childhood cerebral malaria.

Cognitive impairment after cerebral malaria in children: a prospective study.

OBJECTIVE: This study was conducted to assess prospectively the frequency of cognitive deficits in children with cerebral malaria. METHODS: Cognitive testing in the areas of working memory, attention, and learning was performed for Ugandan children 5 to 12 years of age with cerebral malaria (n = 44), children with uncomplicated malaria (n = 54), and healthy community children (n = 89) at admission and 3 and 6 months later. RESULTS: Six months after discharge, 21.4% of children with cerebral malaria had cognitive deficits, compared with 5.8% of community children. Deficits were seen in the areas of working memory (11.9% vs 2.3%) and attention (16.7% vs 2.3%). Children with cerebral malaria had a 3.7-fold increased risk of a cognitive deficit, compared with community children, after adjustment for age, gender, nutritional status, school level, and home environment. Among children with cerebral malaria, those with a cognitive deficit had more seizures before admission (mean: 4.1 vs 2.2) and a longer duration of coma (43.6 vs 30.5 hours), compared with those without a deficit. Children with uncomplicated malaria did not have an increased frequency of cognitive deficits. CONCLUSIONS: Cerebral malaria may be a major cause of cognitive impairment in children in sub-Saharan Africa. Cognitive deficits in children with cerebral malaria are more likely for those who have multiple seizures before effective treatment for cerebral malaria.

Low levels of RANTES are associated with mortality in children with cerebral malaria.

BACKGROUND: In children with cerebral malaria (CM), serum chemokine levels and associated morbidity and mortality have not been characterized. METHODS: Serum levels of the cytokines interleukin (IL)-1 beta , IL-6, IL-10, interferon (IFN)-gamma, and tumor necrosis factor-alpha and the chemokines macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, and regulated upon activation, normal T cell expressed and secreted (RANTES) were measured in Ugandan children with CM, in children with uncomplicated malaria (UM), and in healthy children from the community, as control subjects (CCs). RESULTS: Children with CM had lower levels of RANTES and higher levels of all other cytokines and chemokines than CCs (all P<.0001), and they had lower levels of RANTES (P=.004) and higher levels of IL-10 (P=.003), IFN-gamma (P=.007), and IL-1 beta (P=.05) than children with UM. Children with CM who died had lower levels of RANTES (P=.006) and higher of levels of IL-6 (P=.006), IL-10 (P=.01), IFN-gamma (P=.03), and MIP-1 beta (P=.008) than children who survived. After adjustment for other cytokine and chemokine levels, only low levels of RANTES were independently associated with mortality (P=.016). Levels of RANTES correlated with platelet count but were associated with mortality independently of platelet count. CONCLUSIONS: The serum cytokine and chemokine profile of children who die of CM is similar to that of individuals who die of sepsis. Levels of RANTES are significantly lower in children with CM, and very low levels of RANTES are associated with mortality, independently of other cytokine and chemokine levels.

Rectal artemether versus intravenous quinine for the treatment of cerebral malaria in children in Uganda: randomised clinical trial.

OBJECTIVE: To compare the efficacy and safety of rectal artemether with intravenous quinine in the treatment of cerebral malaria in children. DESIGN: Randomised, single blind, clinical trial. SETTING: Acute care unit at Mulago Hospital, Uganda's national referral and teaching hospital in Kampala. PARTICIPANTS: 103 children aged 6 months to 5 years with cerebral malaria. INTERVENTION: Patients were randomised to either intravenous quinine or rectal artemether for seven days. MAIN OUTCOME MEASURES: Time to clearance of parasites and fever; time to regaining consciousness, starting oral intake, and sitting unaided; and adverse effects. RESULTS: The difference in parasitological and clinical outcomes between rectal artemether and intravenous quinine did not reach significance (parasite clearance time 54.2 (SD 33.6) hours v 55.0 (SD 24.3) hours, P = 0.90; fever clearance time 33.2 (SD 21.9) hours v 24.1(SD 18.9 hours, P = 0.08; time to regaining consciousness 30.1 (SD 24.1) hours v 22.67 (SD 18.5) hours, P = 0.10; time to starting oral intake 37.9 (SD 27.0) hours v 30.3 (SD 21.1) hours, P = 0.14). Mortality was higher in the quinine group than in the artemether group (10/52 v 6/51; relative risk 1.29, 95% confidence interval 0.84 to 2.01). No serious immediate adverse effects occurred. CONCLUSION: Rectal artemether is effective and well tolerated and could be used as treatment for cerebral malaria.