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BackgroundWhile national malaria incidence has been declining in Myanmar, some subregions within the nation continue to have high burdens of malaria morbidity and mortality. This study assessed the malaria situation in one of these regions, Banmauk Township, located near the Myanmar-India border. Our goal was to provide a detailed description of the malaria epidemiology in this township and to provide some evidence-based recommendations to formulate a strategy for reaching the national malaria elimination plan. Banmauk consistently has one of the highest malaria burdens in Myanmar.MethodsWith the implementation of strengthened malaria control and surveillance activities after the endorsement of a national malaria elimination plan in 2015, detailed incidence data were obtained for 2016-2018 for Banmauk Township. The data include patient demographics, parasite species, disease severity, and disease outcome. Data were analyzed to identify characteristics, trends, distribution, and risk factors.ResultsDuring 2016-2018, 2,402 malaria cases were reported, with Plasmodium falciparum accounting for 83.4% of infections. Both P. falciparum and P. vivax were transmitted more frequently during the rainy season (May-October). Despite intensified control, the annual parasite incidence rate (API) in 2017 (11.0) almost doubled that in 2016 (6.5). In total, 2.5% (59/2042) of the cases, of which 54 P. falciparum and 5 P. vivax, were complicated cases, resulting in 5 deaths. Malaria morbidity was high in children < 15 years and accounted for 33.4% of all cases and about 47% of the complicated cases. Older age groups and males living with poor transportation conditions were more likely to test positive especially in rainy and cold seasons. Despite the clear seasonality of malaria, severe cases were found among young children even more common in the dry season, when malaria incidence was low.ConclusionsDespite the declining trend, the malaria burden remained high in Banmauk Township.

BackgroundWhile national malaria incidence has been declining in Myanmar, some subregions within the nation continue to have high burdens of malaria morbidity and mortality. This study assessed the malaria situation in one of these regions, Banmauk Township, located near the Myanmar-India border. Our goal was to provide a detailed description of the malaria epidemiology in this township and to provide some evidence-based recommendations to formulate a strategy for reaching the national malaria elimination plan. Banmauk consistently has one of the highest malaria burdens in Myanmar.MethodsWith the implementation of strengthened malaria control and surveillance activities after the endorsement of a national malaria elimination plan in 2015, detailed incidence data were obtained for 2016-2018 for Banmauk Township. The data include patient demographics, parasite species, disease severity, and disease outcome. Data were analyzed to identify characteristics, trends, distribution, and risk factors.ResultsDuring 2016-2018, 2,402 malaria cases were reported, with Plasmodium falciparum accounting for 83.4% of infections. Both P. falciparum and P. vivax were transmitted more frequently during the rainy season (May-October). Despite intensified control, the annual parasite incidence rate (API) in 2017 (11.0) almost doubled that in 2016 (6.5). In total, 2.5% (59/2042) of the cases, of which 54 P. falciparum and 5 P. vivax, were complicated cases, resulting in 5 deaths. Malaria morbidity was high in children < 15 years and accounted for 33.4% of all cases and about 47% of the complicated cases. Older age groups and males living with poor transportation conditions were more likely to test positive especially in rainy and cold seasons. Despite the clear seasonality of malaria, severe cases were found among young children even more common in the dry season, when malaria incidence was low.ConclusionsDespite the declining trend, the malaria burden remained high in Banmauk Township.

The repetitive interspersed family (RIFIN) and the subtelomeric variable open reading frame (STEVOR) family represent two of three major Plasmodium falciparum variant surface antigen families involved in malaria pathogenesis and immune evasion and are potential targets in the development of natural immunity. Protein and peptide microarrays populated with RIFINs and STEVORs associated with severe malaria vulnerability in Malian children were probed with adult and pediatric sera to identify epitopes that reflect malaria exposure. Adult sera recognized and reacted with greater intensity to all STEVOR proteins than pediatric sera did. Serorecognition of and seroreactivity to peptides within the semiconserved domain of STEVORs increased with age and seasonal malaria exposure, while serorecognition and seroreactivity increased for the semiconserved and second hypervariable domains of RIFINs only with age. Serologic responses to RIFIN and STEVOR peptides within the semiconserved domains may play a role in natural immunity to severe malaria.IMPORTANCE Malaria, an infectious disease caused by the parasite Plasmodium falciparum, causes nearly 435,000 deaths annually worldwide. RIFINs and STEVORs are two variant surface antigen families that are involved in malaria pathogenesis and immune evasion. Recent work has shown that a lack of humoral immunity to these proteins is associated with severe malaria vulnerability in Malian children. This is the first study to have compared serologic responses of children and adults to RIFINs and STEVORs in settings of malaria endemicity and to examine such serologic responses before and after a clinical malaria episode. Using microarrays, we determined that the semiconserved domains in these two parasite variant surface antigen families harbor peptides whose seroreactivity reflects malaria exposure. A similar approach has the potential to illuminate the role of variant surface antigens in the development of natural immunity to clinical malar

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) proteins are expressed on the surface of the infected erythrocyte (IE). These proteins mediate the adhesion of the parasite IE to host cells which could result in severe forms of malaria. PfEMP1 is a variable protein and consists of several domains. PfEMP1s are encoded by var genes and composed of multiple duffy binding-like (DBL) domains and cysteine-rich inter-domain region (CIDR) domains. PfEMP1s can be classified into groups based on the chromosomal location, transcriptional direction and upstream promotor regions of var genes, the DBL or CIDR domains expressed or the domain cassettes (DC) expressed. DCs are sets of PfEMP1 domains that usually occur together. Transcription of specific PfEMP1 subtypes and DCs have been associated with severe malaria. These proteins are important for anti-malarial immunity. Antibody immunity to the different PfEMP1 types can develop gradually with exposure with potential to protect from severe malaria. The current study investigated if antibody responses to different subsets of PfEMP1s or selections of their constituent domains differed between individuals with severe malaria and uncomplicated malaria as well as between individuals presenting with specific severe malaria syndromes. The study also investigated how such antibodies vary between disease presentation and convalescence, 1-2 months after the malaria episode. Three aims were investigated in the present study: 1) to determine if recombinant CIDR domains are targets of antibodies in children with severe or uncomplicated malaria, 2) to determine if levels of opsonising antibodies against four parasite IE lines differed between children with severe or uncomplicated malaria and 3) to determine if the various recombinant PfEMP1 domains (transcripts of which were previously shown to be associated with severe or uncomplicated malaria in adults) are targets of antibody immunity in the same adults with severe or uncompli

Background: Expression of group A and the A-like subset of group B Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is associated with severe malaria (SM). The diversity of var sequences combined with the challenges of distinct classification of patient pathologies has made studying the role of distinct PfEMP1 variants on malaria disease severity challenging. The application of retinopathy in the recent years has provided a further method to clinically evaluate children with cerebral malaria (CM). The question of whether children with clinical CM but no retinopathy represent a completely different disease process or a subgroup within the spectrum of CM remains an important question in malaria. In the current study, we use newly designed primer sets with the best coverage to date in a large cohort of children with SM to determine the role of var genes in malaria disease severity and especially CM as discriminated by retinopathy. Methods: We performed qRT-PCR targeting the different subsets of these var genes on samples from Ugandan children with CM (n = 98, of whom 50 had malarial retinopathy [RP] and 47 did not [RN]), severe malarial anemia (SMA, n = 47), and asymptomatic parasitemia (AP, n = 14). The primers used in this study were designed based on var sequences from 226 Illumina whole genome sequenced P. falciparum field isolates. Results: Increasing severity of illness was associated with increasing levels of endothelial protein C receptor (EPCR)-binding PfEMP1. EPCR-binding PfEMP1 transcript levels were highest in children with combined CM and SMA and then decreased by level of disease severity: RP CM > RN CM > SMA > AP. Conclusions: The study findings indicate that PfEMP1 binding to EPCR is important in the pathogenesis of SM, including RN CM, and suggest that increased expression of EPCR-binding PfEMP1 is associated with progressively more severe disease. Agents that block EPCR-binding of PfEMP1 could provide novel interventions to pr

Background: Expression of group A and the A-like subset of group B Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is associated with severe malaria (SM). The diversity of var sequences combined with the challenges of distinct classification of patient pathologies has made studying the role of distinct PfEMP1 variants on malaria disease severity challenging. The application of retinopathy in the recent years has provided a further method to clinically evaluate children with cerebral malaria (CM). The question of whether children with clinical CM but no retinopathy represent a completely different disease process or a subgroup within the spectrum of CM remains an important question in malaria. In the current study, we use newly designed primer sets with the best coverage to date in a large cohort of children with SM to determine the role of var genes in malaria disease severity and especially CM as discriminated by retinopathy. Methods: We performed qRT-PCR targeting the different subsets of these var genes on samples from Ugandan children with CM (n = 98, of whom 50 had malarial retinopathy [RP] and 47 did not [RN]), severe malarial anemia (SMA, n = 47), and asymptomatic parasitemia (AP, n = 14). The primers used in this study were designed based on var sequences from 226 Illumina whole genome sequenced P. falciparum field isolates. Results: Increasing severity of illness was associated with increasing levels of endothelial protein C receptor (EPCR)-binding PfEMP1. EPCR-binding PfEMP1 transcript levels were highest in children with combined CM and SMA and then decreased by level of disease severity: RP CM > RN CM > SMA > AP. Conclusions: The study findings indicate that PfEMP1 binding to EPCR is important in the pathogenesis of SM, including RN CM, and suggest that increased expression of EPCR-binding PfEMP1 is associated with progressively more severe disease. Agents that block EPCR-binding of PfEMP1 could provide novel interventions to pr

A retrospective longitudinal descriptive study was conducted with the aim of describing the behavior of severe malaria in patients under 14 who were attended in the Emergency Hospital Libolo, Kwansa Sul, Angola, from March to December 2014. The age group, sex, days between onset of symptoms and emergency assistance to the bank, forms of presentation and mortality by age. Males, from 0 to 4 years of age, most went to the bank's emergency 4 to 7 days of onset of symptoms and the most frequent forms of presentation were the severe anemia and cerebral malaria. The mortality occurred in 1.3%. It was concluded that the disease is a health problem with high morbidity, which needs control tools available for its eradication., Se realizó un estudio descriptivo longitudinal retrospectivo, con el objetivo de describir el comportamiento del paludismo grave en 450 pacientes menores de 14 años que acudieron al Banco de urgencias del Hospital de Libolo, Kwansa Sul, Angola, desde marzo a diciembre de 2014. Se investigó el grupo de edades, sexo, días entre inicio de los síntomas y asistencia al banco de urgencias, formas de presentación y la mortalidad por edades. El dato primario se obtuvo de los procesos de internamiento, hojas de cargo y del libro de registro de fallecidos. Predominó el sexo masculino, de0 a4 años de edad, la mayoría acudió al banco de urgencias de4 a7 días de iniciado los síntomas y las formas de presentación más frecuentes fueron la anemia severa y el paludismo cerebral. La mortalidad ocurrió en el 1.3 %. Se concluyó que la enfermedad es un problema de salud, con alta morbilidad, que necesita de accesibles herramientas de control para su erradicación.

Tumour necrosis factor (TNF) - alpha has been shown to play an important role in the pathogenesis of falciparum malaria. Two TNF promoter polymorphisms, TNF-308 and TNF-238 have been associated with differential activity and production of TNF. In order to investigate the association between TNF-308 and TNF-238 and the clinical outcome of malaria in a Nigerian population, the two TNF polymorphisms were analysed using Sequenom iPLEX Platform. A total of 782 children; 283 children with uncomplicated malaria, 255 children with severe malaria and 244 children with asymptomatic infection (controls) were studied. The distribution of TNF-308 and TNF-238 genotypes were consistent with the Hardy-Weinberg equilibrium. Distribution of both TNF polymorphisms differed significantly across all clinical groups (TNF-308: p = 0.007; TNF-238: p=0.001). Further tests for association with severe malaria using genotype models controlling for age, parasitaemia and HbAS showed a significant association of the TNF-238 polymorphism with susceptibility to severe malaria (95% CI = 1.43-6.02, OR= 2.94, p = 0.003237) The GG genotype of TNF-238 significantly increased the risk of developing cerebral malaria from asymptomatic malaria and uncomplicated malaria (95% CI = 1.99-18.17, OR= 6.02, p <0.001 and 95% CI= 1.78-8.23, OR= 3.84, p <0.001 respectively). No significant association was found between TNF-308 and malaria outcome. These results show thegenetic association of TNF-238 in the clinical outcome of malaria in Ibadan, southwest Nigeria. These findings add support to the role of TNF in the outcome of malaria infection. Further large scale studies across multiple malaria endemic populations will be required to determine the specific roles of TNF-308 and TNF-238 in the outcome of falciparum malaria infection.

Introduction: Malaria ranks third among the major infectious diseases in causing deaths- after pneumococcal acute respiratory infections and tuberculosis. It is expected that by the turn of the century malaria would be the number one infectious killer disease in the world. It is the most widely distributed and is responsible for up to 400 million infections every year. The aim of the study was to describe the laboratory parameters and their correlation with mortality in Malaria. Methods: This was a one year retrospective and one and half year prospective study. All patients diagnosed to have Malaria were included in this study. Results: Laboratory parameters were recorded carefully and the data was analyzed by the appropriate statistical methods. A total of 124 patients were studied 92 patients of Plasmodium vivax, 21 patients of Plasmodium falciparum and 11 patients of Mixed malaria. Complications observed were severe anemia(< 7 gm/dl), thrombocytopenia, renal dysfunction (S.creat > 1.2mg/dl), raised bilirubin > 3mg%, metabolic acidosis, and acute respiratory distress syndrome (ARDS). Thrombocytopenia and jaundice were the most frequent complications in the severe cases. 10/124 patients (8.06%) expired. 8/10 patients who expired had four or more organ dysfunction. Conclusion: ARDS had the most significant correlation with mortality. Other significant factors contributing to death were jaundice, severe anemia and renal failure.

Introduction: Malaria ranks third among the major infectious diseases in causing deaths- after pneumococcal acute respiratory infections and tuberculosis. It is expected that by the turn of the century malaria would be the number one infectious killer disease in the world. It is the most widely distributed and is responsible for up to 400 million infections every year. The aim of the study was to describe the laboratory parameters and their correlation with mortality in Malaria. Methods: This was a one year retrospective and one and half year prospective study. All patients diagnosed to have Malaria were included in this study. Results: Laboratory parameters were recorded carefully and the data was analyzed by the appropriate statistical methods. A total of 124 patients were studied 92 patients of Plasmodium vivax, 21 patients of Plasmodium falciparum and 11 patients of Mixed malaria. Complications observed were severe anemia(< 7 gm/dl), thrombocytopenia, renal dysfunction (S.creat > 1.2mg/dl), raised bilirubin > 3mg%, metabolic acidosis, and acute respiratory distress syndrome (ARDS). Thrombocytopenia and jaundice were the most frequent complications in the severe cases. 10/124 patients (8.06%) expired. 8/10 patients who expired had four or more organ dysfunction. Conclusion: ARDS had the most significant correlation with mortality. Other significant factors contributing to death were jaundice, severe anemia and renal failure.

Background: In the Democratic Republic of Congo (DRC), few studies have focused on treatment-seeking paths selected by caretakers for the management of severe childhood malaria in an urban environment. The present study aims at describing the treatment-seeking paths according to the characteristics of households, as well as the subsequent impact on pre-hospitalization delay and malarial fatality and on the main syndromes associated with severe childhood malaria. Methods: This descriptive study included data collected at nine hospitals in Kinshasa between January and November 2011. A total of 1,350 children, under 15 years of age and hospitalized for severe malaria, were included in the study. Results: Regarding the management of malaria, 31.5% of households went directly to the health centre or hospital while 68.5% opted for self-medication, church and/or traditional healing therapy. The most frequent first-line option was self-medication, adopted by more than 61.5% of households. Nevertheless, rational self-medication using antimalarial drugs recommended by the WHO (artemisinin-based combinations) was reported for only 5.5% of children. Only 12.5% of households combined 2 or 3 traditional options. The following criteria influenced the choice of a modern vs. traditional path: household socioeconomic level, residential environment, maternal education level and religious beliefs. When caretakers opted for traditional healing therapy, the pre-hospitalization delay was longer and the occurrence of respiratory distress, severe anaemia and mortality was higher. Conclusion: The implementation of a malaria action plan in the Democratic Republic of Congo should take into account the diversity and pluralistic character of treatment-seeking behaviors in order to promote the most appropriate options (hospital and rational self-medication) and to avoid detrimental outcomes., SCOPUS: ar.j, info:eu-repo/semantics/published

Despite many advances in malaria control and elimination, infection by Plasmodium remains a significantly widespread cause of morbidity and mortality worldwide. Naturally acquired immunity to the parasite plays an important role in protection against malaria infection and the development of symptomatic disease. However, no evidence exists of sterile immunity to the disease and the development of sustained clinically protective antibody responses has been shown to require repeated infections. While many studies have focused on the complex nature of these responses against the antigenically diverse parasite, few have addressed the effect of malaria infection on the generation of memory B cell responses. A study of children in areas of high seasonal malaria transmission revealed a delay in malaria-specific MBC generation despite continual exposure to the parasite. In contrast, in a low transmission setting, lasting memory B cell responses were detected in adults following a single exposure to the parasite. These data indicate clinical malaria infections may hinder the generation and maintenance of malaria-specific memory B cell populations. Long-lived populations of B cells, including memory B cells and long-lived plasma cells, are generated during the germinal centre (GC) reaction in secondary lymphoid organs, such as the spleen. In support of the notion that clinical malaria episodes hinder the induction of humoral memory, histological studies revealed that human fatal malaria infections are accompanied by dramatic changes in splenic architecture, including impaired GC formation. The bulk of studies examining the induction of GC responses following malaria infection have made use of self-resolving infection models in mice. To specifically address the impact of severe malaria infections on these processes, the development of GC responses was assessed using the P. berghei ANKA model of severe malaria in comparison to immunisation with an equivalent antigenic load of at

Background: Malaria is a major health problem in tropical Africa. In DRC, little is known about the characteristics of households of children with severe malaria or the factors associated with its lethality, especially relative to hospital status. Methods: This study of 9 hospitals of the cityprovince of Kinshasa studied 1350 children younger than 15 years and hospitalized for severe malaria from January to November 2011. Results: More than three quarters of children admitted to public (state) and church hospitals were from poor households and with uneducated mothers (P < 0.001). The case-fatality rate (5.9% of all children) differed according to hospital status: 5.3% in state hospitals, 8.4% in private hospitals, and 4.0% in the faithbased hospitals (P < 0.001). The risk of death was significantly associated with circulatory collapse (odds ratio, OR = 10.3), number of associated syndromes>2 (OR = 3.5), z-score of weight-for-age ≤-2 (OR = 3.5), delay in seeking medical care (OR = 4.9), body temperature ≥40°C (OR = 2.9), respiratory distress (OR = 1.9) and home rental (versus ownership) a tenant (OR = 2.8), and anorexia was a protective factor (odds ratio = 0.5). Conclusion: Severe cases of malaria are rife Epiin poor households and periurban residential areas. Orienting prevention, control, and care- according to the vulnerability of affected households and providing early treatment are imperative if we are to reduce mortality from malaria., SCOPUS: ar.j, info:eu-repo/semantics/published

BackgroundData collected in clinical trials have been used to develop scoring systems that identify adults with malaria at greatest risk of death. One of these, the RCAM score, can be simply determined by measuring a patient’s Glasgow Coma Score and respiratory rate on admission to hospital. However the safety of using the RCAM score to define high-risk patients has not been assessed outside of the clinical trial setting.MethodsA retrospective audit of medical records of all adults admitted with a diagnosis of malaria to two tertiary referral hospitals in Lower Myanmar in 2013 was undertaken. An RCAM score was calculated in all patients and related to their subsequent clinical course.ResultsThe recent decline in malaria hospitalizations at both sites continued in 2013. During the year 90 adults were hospitalized with malaria; 62 (69%) had Plasmodium falciparum mono-infection, 11 (12%) had Plasmodium vivax mono-infection, 17 (19%) had mixed infection. All seven (7.7%) deaths occurred in patients infected with P. falciparum. An admission RCAM score <2 identified all the patients that would survive to discharge (positive predictive value (95% confidence interval (CI)) 100% (94.9-100%) and also predicted a requirement for less supportive care: 9/70 (13%) patients with an admission RCAM score <2 required supportive care (blood transfusion, vasopressor support or oxygen supplementation) during their hospitalization compared with 12/20 (60%) patients with an admission RCAM score ≥2 (p < 0.0001). No patient with P. vivax mono-infection required supportive care during their hospitalization. Patients with an oxygen saturation ≤95% on room air on admission were more likely to die before discharge (odds ratio 17.3 (95% CI: 2.9-101.2) than patients with a higher oxygen saturation (p = 0.002).ConclusionsEven outside a clinical trial setting the RCAM score reliably identifies adults with malaria who are at greatest risk of death and

Background: In the Democratic Republic of Congo (DRC), few studies have focused on treatment-seeking paths selected by caretakers for the management of severe childhood malaria in an urban environment. The present study aims at describing the treatment-seeking paths according to the characteristics of households, as well as the subsequent impact on pre-hospitalization delay and malarial fatality and on the main syndromes associated with severe childhood malaria. Methods: This descriptive study included data collected at nine hospitals in Kinshasa between January and November 2011. A total of 1,350 children, under 15 years of age and hospitalized for severe malaria, were included in the study. Results: Regarding the management of malaria, 31.5% of households went directly to the health centre or hospital while 68.5% opted for self-medication, church and/or traditional healing therapy. The most frequent first-line option was self-medication, adopted by more than 61.5% of households. Nevertheless, rational self-medication using antimalarial drugs recommended by the WHO (artemisinin-based combinations) was reported for only 5.5% of children. Only 12.5% of households combined 2 or 3 traditional options. The following criteria influenced the choice of a modern vs. traditional path: household socioeconomic level, residential environment, maternal education level and religious beliefs. When caretakers opted for traditional healing therapy, the pre-hospitalization delay was longer and the occurrence of respiratory distress, severe anaemia and mortality was higher. Conclusion: The implementation of a malaria action plan in the Democratic Republic of Congo should take into account the diversity and pluralistic character of treatment-seeking behaviors in order to promote the most appropriate options (hospital and rational self-medication) and to avoid detrimental outcomes., SCOPUS: ar.j, info:eu-repo/semantics/published

This study aimed to estimate the incidence of catastrophic health expenditures faced by households in Kinshasa with children affected by severe malaria. A total of 1350 children below the age of 15 year who were hospitalized due to severe malaria were included in the study. We analyzed the incidence of households facing catastrophic expenditures according to two thresholds: 40% of the household's capacity to pay and 10% of the household's total consumption. Based on the '40% of the capacity to pay' threshold, the incidence of catastrophic health expenditures reached 81.1%, and this estimate reached 46.4% for the '10% above total consumption' threshold. Regarding the ≥40% capacity to pay threshold, the incidences of catastrophic expenditures was higher among households with children who were admitted to state hospitals (adjusted odds ratio [aOR] 3.7) and private hospitals (aOR 59.1), for poor households (aOR 13), for households with medium socioeconomic statuses (aOR 3.2), for female-headed households (aOR 2.9), for households with children affected by the neurological form (aOR 4.8) and respiratory distress (aOR 3.6), and for households who opted for a pre-hospital resort (aOR 2.7). Similar results were obtained when the 10% above the total consumption threshold was applied. Greater government financing of medical attention would lead to a reduction in the catastrophic health expenditures faced by the poorest households., SCOPUS: ar.j, info:eu-repo/semantics/published

Introduction: Malaria remains a real problem of public health. Its hospital care generates important expenditures for affected households. The present study aimed to estimate direct and indirect costs of severe child malaria in reference hospitals in Kinshasa., SCOPUS: ar.j, info:eu-repo/semantics/published

a study is done to understand the behavior of severe malaria in infants who were attended at the clinical office inside the Hospital Nianankoro Fomba Segou in the Republic of Mali, from November to September 2012. The universe was the following 1431 patients diagnosed with malaria, a sample of 817 patients had severe malaria. The group 1-4 years, male was the most affected. From the most common symptoms and signs: fever, convulsion, diarrhea, vomiting, abdominal pain and pallor of the skin and mucosa. The most frequent complications were cerebral malaria, severe anemia and severe dehydration., Se realiza un estudio para conocer el comportamiento del paludismo grave en infantes que asistieron a la consulta de Pediatría del Hospital Regional Nianankoro Fomba de Segou en la República de Mali, en el período comprendido desde septiembre a noviembre de 2012. En el universo estudiado de 1 431 pacientes con diagnóstico de paludismo, una muestra de 817 pacientes tuvo paludismo grave. Predominó el grupo de 1–4 años, sexo masculino. Dentro de los síntomas y signos más frecuentes encontrados se encuentran: fiebre, convulsión, diarreas, vómitos, dolor abdominal y palidez cutánea mucosa. Las complicaciones más frecuentes encontradas fueron paludismo cerebral, anemia severa y deshidratación grave.

Endothelial nitric oxide (NO) bioavailability, microvascular function, and host oxygen consumption have not been assessed in pediatric malaria. We measured NO-dependent endothelial function by using peripheral artery tonometry to determine the reactive hyperemia index (RHI), and microvascular function and oxygen consumption (VO2) using near infrared resonance spectroscopy in 13 Indonesian children with severe falciparum malaria and 15 with moderately severe falciparum malaria. Compared with 19 controls, children with severe malaria and those with moderately severe malaria had lower RHIs (P = .03); 12% and 8% lower microvascular function, respectively (P = .03); and 29% and 25% higher VO2, respectively. RHIs correlated with microvascular function in all children with malaria (P < .001) and all with severe malaria (P < .001). Children with malaria have decreased endothelial and microvascular function and increased oxygen consumption, likely contributing to the pathogenesis of the disease.

Introduction: Malaria remains a real problem of public health. Its hospital care generates important expenditures for affected households. The present study aimed to estimate direct and indirect costs of severe child malaria in reference hospitals in Kinshasa., SCOPUS: ar.j, info:eu-repo/semantics/published

This study aimed to estimate the incidence of catastrophic health expenditures faced by households in Kinshasa with children affected by severe malaria. A total of 1350 children below the age of 15 year who were hospitalized due to severe malaria were included in the study. We analyzed the incidence of households facing catastrophic expenditures according to two thresholds: 40% of the household's capacity to pay and 10% of the household's total consumption. Based on the '40% of the capacity to pay' threshold, the incidence of catastrophic health expenditures reached 81.1%, and this estimate reached 46.4% for the '10% above total consumption' threshold. Regarding the ≥40% capacity to pay threshold, the incidences of catastrophic expenditures was higher among households with children who were admitted to state hospitals (adjusted odds ratio [aOR] 3.7) and private hospitals (aOR 59.1), for poor households (aOR 13), for households with medium socioeconomic statuses (aOR 3.2), for female-headed households (aOR 2.9), for households with children affected by the neurological form (aOR 4.8) and respiratory distress (aOR 3.6), and for households who opted for a pre-hospital resort (aOR 2.7). Similar results were obtained when the 10% above the total consumption threshold was applied. Greater government financing of medical attention would lead to a reduction in the catastrophic health expenditures faced by the poorest households., SCOPUS: ar.j, info:eu-repo/semantics/published

Background The Fulani are known to have a lower parasitaemia and less clinical episodes of malaria as compared to the Dogon sympatric ethnic group, living in Mali. Higher circulating malaria-specific antibody titers and increased pro-inflammatory cytokine levels have been shown in Fulani individuals. Several studies have tried to link haptoglobin (Hp) phenotypes with susceptibility to malaria, but without consensus. This study investigated the role of Hp phenotypes and cytokine levels in Dogon and Fulani during asymptomatic Plasmodium falciparum infection. Methods Two different cohorts were combined in this study: a 2008 cohort with 77 children aged between two and ten years and a 2001 cohort, with 82 children and adults, aged between 11 and 68 years. Hp phenotypes in plasma were measured by Western Blot. Circulating levels of sCD163, IL-6, IL-10, IFN-¿ and TNF were measured by ELISA. Multiple regression analysis was performed to associate Hp phenotypes with cytokine profiles. In addition, in vitro stimulation of peripheral blood mononuclear cells (PBMCs) with Hp:Hb complexes was performed and cytokine release in corresponding supernatants were measured using cytometric bead array. Results The results revealed a higher Hp2-2 phenotype prevalence in the Fulani. The Hp2-2 phenotype was associated with a higher susceptibility to P. falciparum infection in Dogon, but not in Fulani. In concordance with previous studies, Fulani showed increased inflammatory mediators (IL-6, IFN-¿) and additionally also increased sCD163 levels compared to Dogon, irrespective of infection. Furthermore, infected individuals showed elevated sCD163 levels compared to uninfected individuals, in both Fulani and Dogon. Multiple regression analysis revealed that the Hp1-1 phenotype was associated with higher levels of TNF and IFN-¿, as compared to the Hp2-2 phenotype. In vitro stimulation of PBMCs with Hb:Hp1-1 complexes resulted in a pro-inflammatory cytokine profile, whilst stimulation with Hb:H

BackgroundAdults with severe malaria frequently require intravenous fluid therapy to restore their circulating volume. However, fluid must be delivered judiciously as both under- and over-hydration increase the risk of complications and, potentially, death. As most patients will be cared for in a resource-poor setting, management guidelines necessarily recommend that physical examination should guide fluid resuscitation. However, the reliability of this strategy is uncertain. MethodsTo determine the ability of physical examination to identify hypovolaemia, volume responsiveness, and pulmonary oedema, clinical signs and invasive measures of volume status were collected independently during an observational study of 28 adults with severe malaria. ResultsThe physical examination defined volume status poorly. Jugular venous pressure (JVP) did not correlate with intravascular volume as determined by global end diastolic volume index (GEDVI; rs = 0.07, p = 0.19), neither did dry mucous membranes (p = 0.85), or dry axillae (p = 0.09). GEDVI was actually higher in patients with decreased tissue turgor (p < 0.001). Poor capillary return correlated with GEDVI, but was present infrequently (7% of observations) and, therefore, insensitive. Mean arterial pressure (MAP) correlated with GEDVI (rs = 0.16, p = 0.002), but even before resuscitation patients with a low GEDVI had a preserved MAP. Anuria on admission was unrelated to GEDVI and although liberal fluid resuscitation led to a median hourly urine output of 100 ml in 19 patients who were not anuric on admission, four (21%) developed clinical pulmonary oedema subsequently. MAP was unrelated to volume responsiveness (p = 0.71), while a low JVP, dry mucous membranes, dry axillae, increased tissue turgor, prolonged capillary refill, and tachycardia all had a positive predictive value for volume responsiveness of &le

Deuxième pays le plus endémique pour le paludisme au monde, la république démocratique du Congo (RDC) a adopté officiellement l’initiative Faire Reculer le Paludisme en 2001 et depuis, aligne sa politique de lutte contre le paludisme sur les directives de l’OMS dont les orientations les plus récentes consistent en 3 stratégies :[1] assurer aux malades un accès rapide à un traitement efficace et abordable, [2] assurer aux personnes exposées au risque, notamment les jeunes enfants et les femmes enceintes, l’association la plus adaptée de mesures de protection au niveau personnel et communautaire et [3] donner l’accès, aux femmes enceintes exposées au risque, à des traitements préventifs.Afin de contribuer à l’amélioration de la lutte antipaludique en RDC, le travail a été réalisé en 3 parties :une portant sur la pertinence du traitement préventif intermittent à la Sulfadoxine-Pyriméthamine (TPI-SP) chez la femme enceinte en contexte d’augmentation de la résistance du parasite, une 2e sur les facteurs déterminants l’adhésion des prestataires de soins, des vendeurs des médicaments et des patients à association Artesunate-Amodiaquine (AS-AQ) et une 3e décrivant le paludisme sévère chez l’enfant.La 1ère partie du travail portant sur le TPI-SP a été réalisée en 2 temps. La première approche a consisté en une analyse rétrospective des poids de naissance des nouveau-nés en fonction de la prise du TPI-SP par les mères dans 3 maternités en 2007 où les niveaux de résistance à la SP étaient différents. La deuxième approche, comparait l’effet du traitement préventif intermittent à la Sulfadoxine-Pyriméthamine en 1998/1999 et en 2007 à la prophylaxie à base de chloroquine en 1998/1999 à l’Est de la RDC dans un milieu où la résistance à la Sulfadoxine-Pyriméthamine avait accru considérablement.Dans les régions où la résistance du parasite était de faible (Mikalayi: 1,6% d’échec thérapeutique chez l’enfant) à modéré (Kisangani: 21,7% d’échec thérapeutique chez l’enfant), le, Doctorat en Sciences de la santé publique, info:eu-repo/semantics/nonPublished

Objective: The authors had for aim to evaluate diagnosis and treatment practices applied to children with clinically suspected severe malaria, in two referral hospitals of Kisangani. Patients and methods: A prospective study was carried out between January 1, 2010 and February 28, 2011 including all children admitted for clinically suspected severe malaria, with at least one of the WHO severity criteria. Results: One thousand one hundred and fifty-four children were admitted in the two hospitals, 427 (37.0%, n=. 1.154) for clinically suspected severe malaria: 155 (36.3%, n=. 427) had a positive thick drop examination (TDE), 198 (46.4%, n=. 427) a negative one, and 74 (17.3%, n=. 427) without thick blood smear examination. Prostration (48.0%) and anemia (40.3%) were the most common severity criteria, while 14.5% and 9.8% presented with convulsions and impaired consciousness respectively. The etiological treatment was quinine infusion. The case specific fatality rate was 19.4% (. n=. 427), 7.7% (. n=. 155) in confirmed cases, 9.6% (. n=. 198) in patients with negative thick blood smear, and 70.3% (. n=. 74) in patients without any TDE (. P <. 0.001). Conclusion: Poor technical support and inadequate organization of the patient circuit can result in underestimating the metabolic complications of severe malaria and of other severe infections of early childhood. This is detrimental to the patients, even when effective drugs are available. © 2012 ., SCOPUS: ar.j, info:eu-repo/semantics/published

[Truncated abstract] In Papua New Guinea (PNG), nearly 10% of children will die before their 5th birthday. The absence of contemporary data and the lack of vital reporting mechanisms in PNG result in substantial uncertainty in the overall estimates of mortality. This uncertainty is compounded when cause- or pathogen-specific mortality is estimated. This thesis focuses on malaria, caused by the parasites Plasmodium falciparum and P. vivax that are endemic to many coastal areas of PNG, and its impact on severe childhood illness and mortality. Official estimates suggest that malaria accounts for 15% of deaths in children older than 1 month across the country. However, the studies on which mortality estimates are based were performed in areas without intense malaria transmission. Therefore they may not accurately reflect the true impact of malaria in coastal populations, where transmission is hyperendemic and P. vivax is co-transmitted with P. falciparum. As in African settings, where malaria transmission is also high, the burden of severe malarial disease and subsequent mortality in PNG's coastal populations is primarily borne by young children and pregnant women. In PNG, P. vivax is also transmitted intensely and is an important difference with malaria in Africa where P. falciparum accounts for the vast majority of malaria morbidity. P. vivax itself is recognised as a cause of severe illness and mortality, whilst published data on mixed infections with P. vivax are conflicting, with studies describing abrogated, or augmented clinical effects in patients with both species present., Another key difference between the spectrum of malaria disease in Africa when compared with PNG is that, although crude-mortality estimates and epidemiological data implicate malaria as an important factor in severe illness and mortality, previous community and hospital–based observational studies in PNG and elsewhere in Oceania have reported very low mortality rates in children suffering from severe malaria. These apparently low severe malaria mortality rates have led to a number of explanations. Local genetic polymorphisms and possible cross-protective immunity provided by exposure to P. vivax during infancy have been suggested in previous studies. Some of the total genetic variability to malaria may be accounted for by alpha-thalassaemia and other known red blood cell polymorphisms such as South Asian Ovalocytosis commonly found in coastal Melanesians. The presence of such polymorphisms suggests that malaria has exerted a strong selective genetic effect on these populations. Equally, variation in the methods of clinical assessment, the quality of parasitological diagnosis of malaria or the extent to which other infectious diseases are excluded could also account for differences in malaria mortality rates. Finally over- or mis-diagnosis may be other factors accounting for this variability. Bacterial meningitis, viral encephalitis, pneumonia, bacterial sepsis and non-malarial severe anaemia have similar clinical features that overlap those of malaria such as coma, seizures, breathlessness, circulatory compromise and pallor. Consequently, where good quality laboratory or radiographic facilities are not available, over-diagnosis of severe malaria is the rule rather than the exception and other conditions are overlooked, leading to inappropriate management..., Thesis (Ph.D.)--University of Western Australia, 2013

Deuxième pays le plus endémique pour le paludisme au monde, la république démocratique du Congo (RDC) a adopté officiellement l’initiative Faire Reculer le Paludisme en 2001 et depuis, aligne sa politique de lutte contre le paludisme sur les directives de l’OMS dont les orientations les plus récentes consistent en 3 stratégies :[1] assurer aux malades un accès rapide à un traitement efficace et abordable, [2] assurer aux personnes exposées au risque, notamment les jeunes enfants et les femmes enceintes, l’association la plus adaptée de mesures de protection au niveau personnel et communautaire et [3] donner l’accès, aux femmes enceintes exposées au risque, à des traitements préventifs.Afin de contribuer à l’amélioration de la lutte antipaludique en RDC, le travail a été réalisé en 3 parties :une portant sur la pertinence du traitement préventif intermittent à la Sulfadoxine-Pyriméthamine (TPI-SP) chez la femme enceinte en contexte d’augmentation de la résistance du parasite, une 2e sur les facteurs déterminants l’adhésion des prestataires de soins, des vendeurs des médicaments et des patients à association Artesunate-Amodiaquine (AS-AQ) et une 3e décrivant le paludisme sévère chez l’enfant.La 1ère partie du travail portant sur le TPI-SP a été réalisée en 2 temps. La première approche a consisté en une analyse rétrospective des poids de naissance des nouveau-nés en fonction de la prise du TPI-SP par les mères dans 3 maternités en 2007 où les niveaux de résistance à la SP étaient différents. La deuxième approche, comparait l’effet du traitement préventif intermittent à la Sulfadoxine-Pyriméthamine en 1998/1999 et en 2007 à la prophylaxie à base de chloroquine en 1998/1999 à l’Est de la RDC dans un milieu où la résistance à la Sulfadoxine-Pyriméthamine avait accru considérablement.Dans les régions où la résistance du parasite était de faible (Mikalayi: 1,6% d’échec thérapeutique chez l’enfant) à modéré (Kisangani: 21,7% d’échec thérapeutique chez l’enfant), le, Doctorat en Sciences de la santé publique, info:eu-repo/semantics/nonPublished

Objective: The authors had for aim to evaluate diagnosis and treatment practices applied to children with clinically suspected severe malaria, in two referral hospitals of Kisangani. Patients and methods: A prospective study was carried out between January 1, 2010 and February 28, 2011 including all children admitted for clinically suspected severe malaria, with at least one of the WHO severity criteria. Results: One thousand one hundred and fifty-four children were admitted in the two hospitals, 427 (37.0%, n=. 1.154) for clinically suspected severe malaria: 155 (36.3%, n=. 427) had a positive thick drop examination (TDE), 198 (46.4%, n=. 427) a negative one, and 74 (17.3%, n=. 427) without thick blood smear examination. Prostration (48.0%) and anemia (40.3%) were the most common severity criteria, while 14.5% and 9.8% presented with convulsions and impaired consciousness respectively. The etiological treatment was quinine infusion. The case specific fatality rate was 19.4% (. n=. 427), 7.7% (. n=. 155) in confirmed cases, 9.6% (. n=. 198) in patients with negative thick blood smear, and 70.3% (. n=. 74) in patients without any TDE (. P <. 0.001). Conclusion: Poor technical support and inadequate organization of the patient circuit can result in underestimating the metabolic complications of severe malaria and of other severe infections of early childhood. This is detrimental to the patients, even when effective drugs are available. © 2012 ., SCOPUS: ar.j, info:eu-repo/semantics/published

Malaria remains a major cause of morbidity and mortality throughout the tropical world. The emergence of parasite strains resistant to chloroquine and other commonly used anti-malarial drugs provides an urgent call for vaccine development and novel drug discovery. The clinical manifestations of a P. falciparum infection can range from a mild febrile illness to life-threatening severe malaria, however the determinants of disease severity are not well understood. Although the early, innate immune response to malaria serves to limit parasite growth and reduce clinical manifestations, endogenous mediators produced in response to bioactive parasite products may contribute to pathology associated with malaria. The P. falciparum glycosylphosphatidylinositol (GPI) anchor has been described as a malarial toxin, capable of stimulating pro-inflammatory cytokine responses in vitro and in vivo. Vaccination with a synthetic form of the GPI glycan protects mice from experimental cerebral malaria and death. However attempts to investigate the bioactivity of GPI have been hindered by a lack of suitable reagents for its study. Monoclonal antibodies were raised to P. falciparum GPI and used as probes to investigate the role of GPI in parasite cell biology. The expression of free GPI in late schizonts, dynamic localization of GPI during merozoite invasion, and growth inhibition in the presence of an anti-GPI monoclonal antibody suggest that GPI may have a role in invasion of erythrocytes. Furthermore, the pan-species and multiple life stage reactivity of anti-GPI antibodies have important implications for vaccine development. The second part of this thesis describes a study of cellular cytokine and chemokine responses in a severe malaria case control study in Papua New Guinean children. Cytokines and chemokines produced by convalescent peripheral blood mononuclear cells (PBMC) in response to stimulation with parasitized red blood cells or Toll-like receptor 2 (TLR2) and TLR4 agonists w

Background: Counts of malaria parasites in peripheral blood are important to assess severity of Plasmodium falciparum malaria. Thin and thick smears are routinely used for this purpose. Methods. In this study the Binax NOW® Malaria Test, an easy-to-perform rapid diagnostic test, with Histidine Rich Protein-2 (HRP-2) and aldolase as diagnostic markers, was used for semi-quantitative assessment of parasitaemia of P. faciparum. Results: In 257 patients with imported P. falciparum malaria, reactivity of aldolase increased with higher parasitaemia. In all patients with a parasitaemia above 50,000 asexual parasites/l (> 1%) co-reactivity of HRP-2 and aldolase was observed. Absence of aldolase reactivity in the presence of HRP-2 was a reliable predictive marker to exclude high (> 1%) parasitaemia in P. falciparum malaria. Conclusions: Assessment of HRP-2 and aldolase co-reactivity can be of help in clinical decision making in the acute care setting of returning travellers suspected of having malaria.

Background: Plasmodium vivax and Plasmodium falciparum are the major causative agents of malaria. While knowledge of the genetic structure of malaria parasites is useful for understanding the evolution of parasite virulence, designing anti-malarial vaccines and assessing the impact of malaria control measures, there is a paucity of information on genetic diversity of these two malaria parasites in Pakistan. This study sought to shed some light on the genetic structure of P. vivax and P. falciparum in this understudied region. Methods: The genetic diversities of P. vivax and P. falciparum populations from the densely populated, malaria-endemic Bannu district of Pakistan were evaluated by analysis of their merozoite surface protein (msp) genes by PCR-RFLP. Specifically, the Pvmsp-3 alpha and Pvmsp-3 beta genes of P. vivax and the Pfmsp-1 and Pfmsp-2 genes of P. falciparum were analysed. Results: In P. vivax, genotyping of Pvmsp-3 alpha and Pvmsp-3 beta genes showed a high level of diversity at these loci. Four distinct allele groups: A (1.9 kb), B (1.5 kb), C (1.2 kb), and D (0.3 kb) were detected for Pvmsp-3 alpha, type A being the most prevalent (82%). Conversely, amplification of the P. vivax msp-3 alpha locus produced two allele groups: A (1.7-2.2 kb, 62%) and B (1.4-1.5 kb, 33%), with 5% mixed-strain infections. Restriction analysis of Pvmsp-3 alpha and Pvmsp-3 beta yielded 12 and 8 distinct alleles, respectively, with a combined mixed genotype prevalence of 20%. In P. falciparum, all three known genotypes of Pfmsp-1 and two of Pfmsp-2 were observed, with MAD20 occurring in 67% and 3D7/IC in 65% of the isolates, respectively. Overall, 24% P. falciparum samples exhibited mixed-strain infections. Conclusion: These results indicate that both P. vivax and P. falciparum populations in Pakistan are highly diverse.

Background: Plasmodium vivax and Plasmodium falciparum are the major causative agents of malaria. While knowledge of the genetic structure of malaria parasites is useful for understanding the evolution of parasite virulence, designing anti-malarial vaccines and assessing the impact of malaria control measures, there is a paucity of information on genetic diversity of these two malaria parasites in Pakistan. This study sought to shed some light on the genetic structure of P. vivax and P. falciparum in this understudied region. Methods: The genetic diversities of P. vivax and P. falciparum populations from the densely populated, malaria-endemic Bannu district of Pakistan were evaluated by analysis of their merozoite surface protein (msp) genes by PCR-RFLP. Specifically, the Pvmsp-3 alpha and Pvmsp-3 beta genes of P. vivax and the Pfmsp-1 and Pfmsp-2 genes of P. falciparum were analysed. Results: In P. vivax, genotyping of Pvmsp-3 alpha and Pvmsp-3 beta genes showed a high level of diversity at these loci. Four distinct allele groups: A (1.9 kb), B (1.5 kb), C (1.2 kb), and D (0.3 kb) were detected for Pvmsp-3 alpha, type A being the most prevalent (82%). Conversely, amplification of the P. vivax msp-3 alpha locus produced two allele groups: A (1.7-2.2 kb, 62%) and B (1.4-1.5 kb, 33%), with 5% mixed-strain infections. Restriction analysis of Pvmsp-3 alpha and Pvmsp-3 beta yielded 12 and 8 distinct alleles, respectively, with a combined mixed genotype prevalence of 20%. In P. falciparum, all three known genotypes of Pfmsp-1 and two of Pfmsp-2 were observed, with MAD20 occurring in 67% and 3D7/IC in 65% of the isolates, respectively. Overall, 24% P. falciparum samples exhibited mixed-strain infections. Conclusion: These results indicate that both P. vivax and P. falciparum populations in Pakistan are highly diverse.

Severe Plasmodium falciparum malaria is a major cause of global mortality, yet the immunological factors underlying progression to severe disease remain unclear. CD4+CD25+ regulatory T cells (Treg cells) are associated with impaired T cell control of Plasmodium spp infection. We investigated the relationship between Treg cells, parasite biomass, and P. falciparum malaria disease severity in adults living in a malaria-endemic region of Indonesia. CD4+CD25+Foxp3+CD127lo Treg cells were significantly elevated in patients with uncomplicated (UM; n = 17) and severe malaria (SM; n = 16) relative to exposed asymptomatic controls (AC; n = 10). In patients with SM, Treg cell frequency correlated positively with parasitemia (r = 0.79, p = 0.0003) and total parasite biomass (r = 0.87, p<0.001), both major determinants for the development of severe and fatal malaria, and Treg cells were significantly increased in hyperparasitemia. There was a further significant correlation between Treg cell frequency and plasma concentrations of soluble tumor necrosis factor receptor II (TNFRII) in SM. A subset of TNFRII+ Treg cells with high expression of Foxp3 was increased in severe relative to uncomplicated malaria. In vitro, P. falciparum–infected red blood cells dose dependently induced TNFRII+Foxp3hi Treg cells in PBMC from malaria-unexposed donors which showed greater suppressive activity than TNFRII− Treg cells. The selective enrichment of the Treg cell compartment for a maximally suppressive TNFRII+Foxp3hi Treg subset in severe malaria provides a potential link between immune suppression, increased parasite biomass, and malaria disease severity. The findings caution against the induction of TNFRII+Foxp3hi Treg cells when developing effective malaria vaccines.

Background: During malaria infection the Toll-like receptor 9 (TLR9) is activated through induction with plasmodium DNA or another malaria motif not yet identified. Although TLR9 activation by malaria parasites is well reported, the implication to the susceptibility to severe malaria is not clear. The aim of this study was to assess the contribution of genetic variation at TLR9 to severe malaria.Methods: This study explores the contribution of TLR9 genetic variants to severe malaria using two approaches. First, an association study of four common single nucleotide polymorphisms was performed on both family- and population-based studies from Malawian and Gambian populations (n>6000 individual). Subsequently, it was assessed whether TLR9 expression is affected by cis-acting variants and if these variants could be mapped. For this work, an allele specific expression (ASE) assay on a panel of HapMap cell lines was carried out.Results: No convincing association was found with polymorphisms in TLR9 for malaria severity, in either Gambian or Malawian populations, using both case-control and family based study designs. Using an allele specific expression assay it was observed that TLR9 expression is affected by cis-acting variants, these results were replicated in a second experiment using biological replicates.Conclusion: By using the largest cohorts analysed to date, as well as a standardized phenotype definition and study design, no association of TLR9 genetic variants with severe malaria was found. This analysis considered all common variants in the region, but it is remains possible that there are rare variants with association signals. This report also shows that TLR9 expression is potentially modulated through cis-regulatory variants, which may lead to differential inflammatory responses to infection between individuals.

Malaria is the primary infectious disease threat facing the U.S. soldier, and is the leading cause of all causalities during tropical deployments. The long-term objective of this project is to identify and prepare the malaria parasite forms causing severe anemia, and then apply functional genomics and bioformatics tools to identify 15 to 30 proteins that could form the basis for an effective vaccine at both the pre-erythrocytic and blood stages of malaria infection. The project will then evaluate these lead candidates for their recognition by sera collected from immune individuals, in order to identify the leading 3 to 5 candidates for a blood stage vaccine that prevents severe malaria anemia., The original document contains color images.

Malaria is the primary infectious disease threat facing the U.S. soldier and is the leading cause of all causalities during tropical deployments. The long-term objective of this project is to identify and prepare the malaria parasite forms causing severe anemia and then apply functional genomics and bioformatics tools to identify 15 to 30 proteins that could form the basis for an effective vaccine at both the pre-erythrocytic and blood stages of malaria infection. The project will then evaluate these lead candidates for their recognition by sera collected from immune individuals in order to identify the leading 3 to 5 candidates for a blood stage vaccine that prevents severe malaria anemia.

Malaria is the primary infectious disease threat facing the U.S. solider and is the leading cause of all casualties during tropical deployments. The long-term objective of this project is to identify and prepare the malaria parasite forms causing severe anemia and then apply functional genomics and bioinformatics tools to identify 15 to 30 proteins that could form the basis for an effective vaccine at both the pre-erythrocytic and blood stages of malaria infection. The project will then evaluate these lead candidates for their recognition by sera collected from immune individuals in order to identify the leading 3 to 5 candidates for a blood stage vaccine that prevents severe malarial anemia., The original document contains color images.

Artemisinins are antimalarials derived from the Chinese herb, Artemisia annua. These compounds clear the parasites from the blood more rapidly than other antimalarial agents. Intravenous formulations of artemisinins have been used in much of the world and represent an improvement in efficacy and safety for severe malaria. There are currently no FDA-approved intravenous artemisinin products available in the U.S. The Walter Reed Army Institute of Research has a long history with the artemisinins which has culminated in an intravenous artemisinin product. Between 2000 and 2002, two derivatives were in consideration (artesunate and artelinate) for development to licensure. After intense scrutiny and eventual consideration in committee at the Division of Experimental Therapeutics, artesunate was selected as the compound to put forward into advanced development. Artesunate is currently in use in much of the malarial world as a non- International Conference on Harmonisation (ICH) current Good Manufacturing Practices (cGMP) intravenous formulation produced in China and therefore gives us a potential wealth of clinical data. We envision our formulation of an ICH compliant, cGMP-produced, and FDA-licensed intravenous artesunate being available for use in the very near future for US military and civilians as well as eventual use worldwide. We have successfully filed an Investigational New Drug Application for this product and clinical trials with this agent are well underway. Our presentation will update the progress that has been made in preclinical studies, data from early current Good Clinical Practices (cGCP) Phase 1 trials (the first regulated Phase 1 work ever done with artesunate), data from early cGCP Phase 2 trials in Kenya, future planned clinical work, and our overall strategy for gaining full licensure of this product in the United States by the end of 2007., See also ADM002075. Presented at the Army Science Conference (25th) held in Orlando, Florida on 27-30 November 2006. The original document contains color images.