Abdoulaye Traoré

Epilepsy as a Consequence of Cerebral Malaria in Area in Which Malaria Is Endemic in Mali, West Africa

Summary:  Purpose: Cerebral malaria (CM) is suspected to be a potential cause of epilepsy in tropical areas, but little information is available. The purpose of this study was to evaluate the role of CM in epilepsy among children in Mali.

Evidence That Interferon-γ Plays a Protective Role during Cerebral Malaria

BACKGROUND The pathogenic mechanisms of cerebral malaria (CM) are unclear but are thought to involve cytokine-mediated inflammation enhanced by parasite sequestration in the brain microcirculation. The role that interferon (IFN)-gamma could play that would enhance inflammation but also reduce parasitemia is unclear. METHODS Plasma IFN-gamma concentrations were measured by enzyme-linked immunosorbent assay in 96 children with CM and 40 children with uncomplicated malaria (UM) who had been recruited from Gabriel Toure Hospital (Bamako, Mali). We investigated the relationship between IFN- gamma concentrations and disease by nonparametric analysis. Polymorphisms in IFNG were characterized by restriction enzyme analysis or size-determination electrophoresis. Associations between polymorphisms and CM were evaluated by the family-based association test on 240 families. RESULTS During episodes of malaria, IFN-gamma concentrations were lower in children with CM than in children with UM (P = .007). IFNG-183T (P = .009) and IFNG-183G/T (P = .013) were found to be less frequent than expected in children with CM. A trend toward association was also observed between IFNG(CA)14/(CA)14 (P = .073) and CM. The IFNG-183G/T and IFNG(CA)14/(CA)14 genotypes were more frequent in children with UM than in children with CM (odds ratio, 0.30 and 0.34, respectively). CONCLUSIONS The low plasma IFN- gamma concentrations in children with CM and the associations between a reduced risk of CM and (1) the IFNG-183T allele (which increases gene transcription) and (2) the IFNG-183G/T genotype are consistent with the concept that IFN-gamma protects against CM.

Safety and immunogenicity of the malaria vaccine candidate MSP3 long synthetic peptide in 12-24 months-old Burkinabe children.

Background A Phase Ia trial in European volunteers of the candidate vaccine merozoite surface protein 3 (MSP3), a Plasmodium falciparum blood stage membrane, showed that it induces biologically active antibodies able to achieve parasite killing in vitro, while a phase Ib trial in semi-immune adult volunteers in Burkina Faso confirmed that the vaccine was safe. The aim of this study was to assess the safety and immunogenicity of this vaccine candidate in children aged 12–24 months living in malaria endemic area of Burkina Faso. Methods The study was a double-blind, randomized, controlled, dose escalation phase Ib trial, designed to assess the safety, reactogenicity and immunogenicity of three doses of either 15 or 30 µg of MSP3-LSP adsorbed on aluminum hydroxide in 45 children 12 to 24 months of age randomized into three equal groups. Each group received 3 vaccine doses (on days 0, 28 and 56) of either 15 µg of MSP3-LSP, 30 µg of MSP3-LSP or of the Engerix B hepatitis B vaccine. Children were visited at home daily for the 6 days following each vaccination to solicit symptoms which might be related to vaccination. Serious adverse events occurring during the study period (1 year) were recorded. Antibody responses to MSP3-LSP were measured on days 0, 28, 56 and 84. Results All 45 enrolled children received three MSP3 vaccine doses. No serious adverse events were reported. Most of the adverse events reported were mild to moderate in severity. The only reported local symptoms with grade 3 severity were swelling and induration, with an apparently dose related response. All grade 3 adverse events resolved without any sequelae. Both MSP3 doses regimens were able to elicit high levels of anti-MSP3 specific IgG1 and IgG3 antibodies in the volunteers with very little or no increase in IgG2, IgG4 and IgM classes: i.e. vaccination induced predominantly the isotypes involved in the monocyte-dependent mechanism of P. falciparum parasite-killing. Conclusion Our results support the promise of MSP3-LSP as a malaria vaccine candidate, both in terms of tolerability and of immunogenicity. Further assessment of the efficacy of this vaccine is recommended. Trial Registration ClinicalTrials.gov NCT00452088

A functional promoter variant in IL12B predisposes to cerebral malaria

The role of the Th1 pathway in the pathogenesis of severe malaria is unclear. We recently reported that a polymorphism with increasing IFNG transcription is associated with protection against cerebral malaria (CM). Interleukin-12 is required for Th1 cell differentiation, which is characterized by the production of interferon-gamma. We investigated 21 markers in IL12-related genes, including IL12A and IL12B encoding the two IL-12 (IL12p70) subunits, IL12p35 and IL12p40. We performed a family-based association study using a total sample set of 240 nuclear families. The IL12Bpro polymorphism was associated with susceptibility to CM. The CTCTAA allele and the GC/CTCTAA genotype are over-transmitted to children with CM (P = 0.0002 and 0.00002, respectively). We estimated the odds ratio to be 2.11 for risk of CM in heterozygous children [(95% confidence interval, 1.49-2.99); P < 0.0001]. Although the CTCTAA allele had a dominant effect on CM susceptibility, this effect is much stronger in heterozygous children, consistent with the functional effects of this allele in a heterozygous form. Heterozygosity for this polymorphism has been associated with reduced expression of the gene encoding IL12p40 and a low level of IL12p70 production. These results, together with the findings from immunological studies of low interferon-gamma and IL-12 levels in CM, support a protective role for the Th1 pathway in CM.

Implementation of Home based management of malaria in children reduces the work load for peripheral health facilities in a rural district of Burkina Faso

BackgroundHome Management of Malaria (HMM) is one of the key strategies to reduce the burden of malaria for vulnerable population in endemic countries. It is based on the evidence that well-trained communities health workers can provide prompt and adequate care to patients close to their homes. The strategy has been shown to reduce malaria mortality and severe morbidity and has been adopted by the World Health Organization as a cornerstone of malaria control in Africa. However, the potential fall-out of this community-based strategy on the work burden at the peripheral health facilities level has never been investigated.MethodsA two-arm interventional study was conducted in a rural health district of Burkina Faso. The HMM strategy has been implemented in seven community clinics catchments area (intervention arm). For the other seven community clinics in the control arm, no HMM intervention was implemented. In each of the study arms, presumptive treatment was provided for episodes of fevers/malaria (defined operationally as malaria).The study drug was artemether-lumefantrine, which was sold at a subsidized price by community health workers/Key opinion leaders at the community level and by the pharmacists at the health facility level.The outcome measured was the proportion of malaria cases among all health facility attendance (all causes diseases) in both arms throughout the high transmission season.ResultsA total of 7,621 children were enrolled in the intervention arm and 7,605 in the control arm. During the study period, the proportions of malaria cases among all health facility attendance (all causes diseases) were 21.0%, (445/2,111, 95% CI [19.3%–22.7%]) and 70.7% (2,595/3,671, 95% CI 68.5%–71.5%), respectively in the intervention and control arms (p << 0.0001). The relative risk ratio for a fever/malaria episode to be treated at the HF level was 30% (0.30 < RR < 0.32).The number of malaria episodes treated in the intervention arm was much higher than in the control arm (6,661 vs. 2,595), with malaria accounting for 87.4% of all disease episodes recorded in the intervention area and for 34.1% in the control area (P < 0.0001). Of all the malaria cases treated in the intervention arm, only 6.7% were treated at the health facility level.ConclusionThese findings suggest that implementation of HMM, by reducing the workload in health facilities, might contributes to an overall increase of the performance of the peripheral health facilities.

Life-threatening malaria in African children: a prospective study in a mesoendemic urban setting.

Background: The population exposed to malaria within African cities has steadily increased. However, comprehensive data on life-threatening malaria features and risk factors in children from urban areas with seasonal malaria transmission, such as in Bamako (Mali), are lacking. Methods: Children admitted to the Gabriel Touré Hospital in Bamako with severe malarial anemia (SMA) and/or cerebral malaria (CM) were prospectively included in the study. Indicators of either SMA or CM were analyzed using logistic regression; and death hazard ratios (HRs) were estimated through survival analysis. Results: The study included 455 children: 66% presented with CM, 34% with SMA, 3% with hypoglycemia (HG); 5% with dehydration; 17% with respiratory distress (RD); 25% with splenomegaly; and 92% with hepatomegaly. The children with CM were older than those with SMA. CM was more often associated with dehydration, HG, and RD, whereas SMA was more often associated with splenomegaly. The overall case fatality rate was 16%, and 94% of the children who died had CM. HG [HR: 2.37; 95% confidence interval (CI): 1.04–5.39; P = 0.040], RD (HR: 4.23; 95% CI: 2.46–7.30; P < 10−6) and a deep coma with a Blantyre score of less than 3 (HR: 6.78, 95% CI: 2.43–18.91; P < 10−3), were all independent predictors of death. Conclusions: These findings delineate the patterns of severe malaria in children in a West African mesoendemic urban setting. They validate practicable prognostic indicators of life-threatening malaria for use in the limited facilities available in African health centers and provide a frame of reference for further research addressing life-threatening malaria in this setting.

In vitro antiplasmodial and cytotoxic properties of some medicinal plants from western Burkina Faso

Background Resistance of malaria parasites to existing drugs complicates treatment, but an antimalarial vaccine that could protect against this disease is not yet available. It is therefore necessary to find new effective and affordable medicines. Medicinal plants could be a potential source of antimalarial agents. Some medicinal plants from Burkina Faso were evaluated for their antiplasmodial and cytotoxic properties in vitro. Methods Crude dichloromethane, methanol, water-methanol, aqueous and alkaloids extracts were prepared for 12 parts of 10 plants. Chloroquine-resistant malaria strain K1 was used for the in vitro sensibility assay. The Plasmodium lactacte dehydrogenase technique was used to determine the 50% inhibitory concentration of parasites activity (IC50). The cytotoxic effects were determined with HepG2 cells, using the tetrazolium-based colorimetric technique, and the selectivity index (SI) was calculated. Results Sixty crude extracts were prepared. Seven extracts from Terminalia avicenoides showed IC50 < 5 µg/mL. The IC50 of dichloromethane, methanol, aqueous and alkaloids extracts ranged between 1.6 µg/mL and 4.5 µg/mL. Three crude extracts from Combretum collinum and three from Ficus capraefolia had an IC50 ranging between 0.2 µg/mL and 2.5 µg/mL. Crude extracts from these three plants had no cytotoxic effect, with SI > 1. The other plants have mostly moderate or no antimalarial effects. Some extracts from Cordia myxa, Ficus capraefolia and Opilia celtidifolia showed cytotoxicity, with an SI ranging between 0.4 and 0.9. Conclusion Our study showed a good antiplasmodial in vitro activity of Terminalia avicenoides, Combretum collinum and Ficus capraefolia. These three plants may contain antiplasmodial molecules that could be isolated by bio-guided phytochemical studies.

Familial Aggregation of Cerebral Malaria and Severe Malarial Anemia

BACKGROUND The predominant manifestations of severe malaria in African children are cerebral malaria (CM) and severe malarial anemia (SMA). As a first step toward a family-based approach to identify the environmental and genetic pathways that contribute to severe malaria, we tested whether it aggregates within families. METHODS Family history of severe malaria was explored during face-to-face interviews with parents. Logistic regression was used to determine whether CM and SMA aggregate within individuals and within families. The pattern of familial aggregation was then expressed as familial odds ratios that were adjusted for relevant risk factors. RESULTS This study was of 2811 inhabitants of Bamako, Mali, clustered in 407 nuclear families. The probands were 136 children with severe malaria and 271 healthy children from the community. Within-person association of CM and SMA was significant (odds ratio, 6.15 [95% confidence interval (CI), 2.62-14.41]). Over a lifetime, with each additional affected relative, the odds of a person contracting CM increased by 1.98 times (95% CI, 1.59-2.45), and the odds of having SMA increased by 1.91 times (95% CI, 1.05-3.47). Over a lifetime, for a child whose sibling had a history of CM, the odds of having CM were 2.49 times greater (95% CI, 1.51-4.10) than the odds for a child whose sibling had no such history; for a child whose sibling had a history of SMA, the odds of having SMA were 4.92 times greater (95% CI, 1.21-19.9) than the odds for a child whose sibling had no such history. CONCLUSION Our data suggest strong familial aggregation of CM and SMA.

Health providers' perceptions of clinical trials: lessons from Ghana, Kenya and Burkina Faso.

Background Clinical trials conducted in Africa often require substantial investments to support trial centres and public health facilities. Trial resources could potentially generate benefits for routine health service delivery but may have unintended consequences. Strengthening ethical practice requires understanding the potential effects of trial inputs on the perceptions and practices of routine health care providers. This study explores the influence of malaria vaccine trials on health service delivery in Ghana, Kenya and Burkina Faso. Methods We conducted: audits of trial inputs in 10 trial facilities and among 144 health workers; individual interviews with frontline providers (n=99) and health managers (n=14); and group discussions with fieldworkers (n=9 discussions). Descriptive summaries were generated from audit data. Qualitative data were analysed using a framework approach. Results Facilities involved in trials benefited from infrastructure and equipment upgrades, support with essential drugs, access to trial vehicles, and placement of additional qualified trial staff. Qualified trial staff in facilities were often seen as role models by their colleagues; assisting with supportive supervision and reducing facility workload. Some facility staff in place before the trial also received formal training and salary top-ups from the trials. However, differential access to support caused dissatisfaction, and some interviewees expressed concerns about what would happen at the end of the trial once financial and supervisory support was removed. Conclusion Clinical trials function as short-term complex health service delivery interventions in the facilities in which they are based. They have the potential to both benefit facilities, staff and communities through providing the supportive environment required for improvements in routine care, but they can also generate dissatisfaction, relationship challenges and demoralisation among staff. Minimising trial related harm and maximising benefits requires careful planning and engagement of key actors at the outset of trials, throughout the trial and on its’ completion.

Epilepsy as a Consequence of Cerebral Malaria in Area in Which Malaria Is Endemic in Mali, West Africa: CEREBRAL MALARIA AND EPILEPSY IN MALI

Summary:  Purpose: Cerebral malaria (CM) is suspected to be a potential cause of epilepsy in tropical areas, but little information is available. The purpose of this study was to evaluate the role of CM in epilepsy among children in Mali.