Showing papers on "Malaria published in 1998"

Dengue and Dengue Hemorrhagic Fever

Abstract: Dengue fever, a very old disease, has reemerged in the past 20 years with an expanded geographic distribution of both the viruses and the mosquito vectors, increased epidemic activity, the development of hyperendemicity (the cocirculation of multiple serotypes), and the emergence of dengue hemorrhagic fever in new geographic regions. In 1998 this mosquito-borne disease is the most important tropical infectious disease after malaria, with an estimated 100 million cases of dengue fever, 500,000 cases of dengue hemorrhagic fever, and 25,000 deaths annually. The reasons for this resurgence and emergence of dengue hemorrhagic fever in the waning years of the 20th century are complex and not fully understood, but demographic, societal, and public health infrastructure changes in the past 30 years have contributed greatly. This paper reviews the changing epidemiology of dengue and dengue hemorrhagic fever by geographic region, the natural history and transmission cycles, clinical diagnosis of both dengue fever and dengue hemorrhagic fever, serologic and virologic laboratory diagnoses, pathogenesis, surveillance, prevention, and control. A major challenge for public health officials in all tropical areas of the world is to devleop and implement sustainable prevention and control programs that will reverse the trend of emergent dengue hemorrhagic fever.

Molecular characterization of pyrethroid knockdown resistance (kdr) in the major malaria vector Anopheles gambiae s. s.

Abstract: Pyrethroid-impregnated bednets are playing an increasing role for combating malaria, especially in stable malaria areas. More than 90% of the current annual malaria incidence (c. 500 million clinical cases with up to 2 million deaths) is in Africa where the major vector is Anopheles gambiae s.s. As pyrethroid resistance has been reported in this mosquito, reliable and simple techniques are urgently needed to characterize and monitor this resistance in the field. In insects, an important mechanism of pyrethroid resistance is due to a modification of the voltage-gated sodium channel protein recently shown to be associated with mutations of the para-type sodium channel gene. We demonstrate here that one of these mutations is present in certain strains of pyrethroid resistant A. gambiae s.s. and describe a PCR-based diagnostic test allowing its detection in the genome of single mosquitoes. Using this test, we found this mutation in six out of seven field samples from West Africa, its frequency being closely correlated with survival to pyrethroid exposure. This diagnostic test should bring major improvement for field monitoring of pyrethroid resistance, within the framework of malaria control programmes.

Malaria : parasite biology, pathogenesis, and protection

Abstract: A Brief History of Malaria and Discovery of the Parasite's Life Cycle The Current Global Malaria Situation Gametocytes and Sexual Development Sporogonic Development in the Mosquito Engineering Resistance to Malaria Parasite Development in Mosquitoes Invasion of Vertebrate Cells: Hepatocytes Invasion of Vertebrate Cells: Erythrocytes Ultrastructure of Asexual Stages Carbohydrate Metabolism of Asexual Stages Hemoglobin Processing and the Metabolism of Amino Acids, Heme and Iron Malarial Lipids Purine and Pyrimidine Metabolism of Asexual Stages Malaria Parasite DNA The Plasmodium rRNA Genes Membrane Transport in the Malaria-Infected Erythrocyte The Genetic Structure of Malaria Parasite Populations Genome Discovery and Malaria Research: Current Status and Promise Extrachromosomal DNA: the Mitochondrion Extrachromosomal DNA: Plastid DNA Evolutionary Relationships of Human Malaria Parasites Introduction to the Modes of Action of and Mechanisms of Resistance to Anitmalarials The Molecular Basis of Resistance to the Sulfones, Sulfamides, and Dihydrofolate Reductase Inhibitors Chloroquine: Modes of Actions and Resistance and the Activity of Chloroquine Analogs From Quinine to Qinghaosu: Historical Perspectives Mitochondrial Physiology as a Target for Atovaquone and Other Antimalarials Malaria Pathophysiology Rosetting of Malaria-Infected Erythrocytes Animal Models: Rodents Animal Models: Primates Host Genetic Factors in Resistance to Malaria Acquired Immunity to Sexual Stages Acquired Immunity to Asexual Blood Stages Acquired Immunity to Sporozoites Immunity to Liver Stages Using DNA-Based Vaccine Technology and the Malaria Genome Project to Overcome Obstacles to Malaria Vaccine Development.

Maternal antibodies block malaria.

Abstract: Women are at increased risk from malaria during pregnancy, and, for unknown reasons, this risk is greatest during the first pregnancy1. Plasmodium falciparum, the most virulent of the four malaria parasites of humans, adheres to a molecule called chondroitin sulphate A (CSA) on the surface of syncytiotrophoblasts (cells lining the intervillous space)2 and sequesters in the human placenta. Here we show that anti-adhesion antibodies, which limit the accumulation of parasites in the placenta, appear in pregnant women from Africa and Asia who have been pregnant on previous occasions (multigravidas), but not in those who are pregnant for the first time (primigravidas). Anti-adhesion antibodies against CSA-binding parasites are strain-independent and are associated with greatly reduced prevalence and density of infection. We conclude that malaria susceptibility in primigravidas is related to the lack of these anti-adhesion antibodies, and that an anti-adhesion vaccine for maternal malaria may be globally effective.

Impact of chloroquine resistance on malaria mortality

Abstract: Over 12 years, from 1984 to 1995, we conducted a prospective study of overall and malaria specific mortality among three rural populations in the Sahel, savanna and forest areas of Senegal. The emergence of chloroquine resistance has been associated with a dramatic increase in malaria mortality in each of the studied populations. After the emergence of chloroquine resistance, the risk of malaria death among children 0-9 years old in the three populations was multiplied by 2.1, 2.5 and 5.5, respectively. This is the first study to document malaria mortality at the community level in Africa before and after the emergence of chloroquine resistance. Findings suggest that the spread of chloroquine resistance has had a dramatic impact on the level of malaria mortality in most epidemiological contexts in tropical Africa.

Efficacy of sulfadoxine-pyrimethamine for prevention of placental malaria in an area of Kenya with a high prevalence of malaria and human immunodeficiency virus infection.

Abstract: A fever case management (CM) approach using sulfadoxine-pyrimethamine (SP) was compared with two presumptive intertmittent SP treatment regimens in the second and third trimesters in pregnant primigravidae and secundigravidae in an area of intense Plasmodium falciparum malaria transmission in western Kenya. The investigation evaluated efficacy of the antimalarial regimens for prevention of placental malaria and examined the effect of human immunodeficiency virus (HIV) infection on antimalarial drug efficacy and adverse drug reactions. Twenty-seven percent (93 of 343) of pregnant women in the CM group had placental malaria compared with 12% (38 of 330; P < 0.001) of women who received two doses of SP and compared with 9% (28 of 316; P < 0.001) of women who received monthly SP. Fourteen percent (49 of 341) of women in the CM group delivered low birth weight (LBW) infants compared with 8% (27 of 325; P=0.118) of women who received two doses of SP and compared with 8% (26 of 331; P=0.078) of women who received monthly SP. Seven percent (7 of 99) of the HIV-negative women on the two-dose SP regimen had placental malaria compared with 25% (10 of 39; P=0.007) of HIV-positive women on the same regimen; the rate of placental malaria in HIV-positive women was reduced to 7% (2 of 28; P=-0.051) for women on the monthly SP regimen. Less than 2% of women reported adverse drug reactions, with no statistically significant differences between HIV-positive and HIV-negative women. Intermittent treatment with SP is safe and efficacious for the prevention of placental malaria in pregnant primigravidae and secundigravidae in sub-Saharan Africa. While a two-dose SP regimen may be effective in areas with low HIV seroprevalence, administration of SP monthly during the second and third trimesters of pregnancy should be considered in areas of high HIV seroprevalence to prevent the effects of maternal malaria on the newborn.

Malaria parasite development in mosquitoes

Abstract: Mosquitoes of the genus Anopheles transmit malaria parasites to humans. Anopheles mosquito species vary in their vector potential because of environmental conditions and factors affecting their abundance, blood-feeding behavior, survival, and ability to support malaria parasite development. In the complex life cycle of the parasite in female mosquitoes, a process termed sporogony, mosquitoes acquire gametocyte-stage parasites from blood-feeding on an infected host. The parasites carry out fertilization in the midgut, transform to ookinetes, then oocysts, which produce sporozoites. Sporozoites invade the salivary glands and are transmitted when the mosquito feeds on another host. Most individual mosquitoes that ingest gametocytes do not support development to the sporozoite stage. Bottle-necks occur at every stage of the cycle in the mosquito. Powerful new techniques and approaches exist for evaluating malaria parasite development and for identifying mechanisms regulating malaria parasite-vector interactions. This review focuses on those interactions that are important for the development of new approaches for evaluating and blocking transmission in nature.

Drug resistance in malaria

Abstract: Drug resistance in malaria is now widespread and in many parts of the world is making treatment increasingly difficult. This article reviews current knowledge of the mechanisms and extent of resistance of Plasmodium falciparum and P. vivax to the available antimalarial drugs, and the recommendations for treating malaria in regions where resistance is prevalent. Nearly 300 million people have malaria parasites in their blood as you read this article, and 0.5-2 million (mainly African children) will die from this parasitic infection each year. Of the four human parasites only P. falciparum regularly kills. This parasite has developed resistance to nearly all available antimalarial drugs1*2. Most important of these is chloroquine, a cheap, simply administered and relatively well-tolerated antimalarial that had become the mainstay of antimalarial treatment throughout the tropical world. In recent years P. vivax, particularly from Oceania and some parts of south-east Asia, has also developed resistance to chloroquine. Antimalarial drugs Dihydrofolate reductase inhibitors Proguanil, chlorproguanil, and later pyrimethamine were developed shortly after the second world war. The antimalarial biguanides, proguanil and chlorproguanil, are metabolised to the active cyclic triazine correspondence to metabolites, cycloguanil and chlorcycloguanil, respectively. These two prof N J white. Faculty of metabolites, together with pyrimethamine, and the related antibacterial Tropical Medicine trimethoprim, all selectively inhibit plasmodial dihydrofolate reductase

Imported Malaria: Prospective Analysis of Problems in Diagnosis and Management

Abstract: Imported malaria is an increasing problem in many countries. The objective of this study was to prospectively evaluate the diagnosis and treatment of imported malaria cases identified by active surveillance. Microscopic diagnosis at the community level was also compared to reference microscopic and blinded molecular diagnostic methods. Most travelers who acquire malaria had sought pretravel advice from a physician; however, only 11% used recommended chemoprophylaxis and only 17% used insect protection measures. The diagnosis of malaria was initially missed in 59% of cases. Community-based microscopic diagnosis provided incorrect species identification in 64% of cases. After presentation, the average delay before treatment was 7.6 days for falciparum malaria and 5.1 days for vivax malaria. Overall, 7.5% of Plasmodium falciparum-infected patients developed severe malaria, and in 11% of all cases therapy failed. Patients who present to a center without expertise in tropical medicine receive suboptimal treatment. Improvements in recognition, diagnosis, and treatment of malaria are essential to prevent morbidity and death among travelers.

Ecologic observations on anopheline vectors of malaria in the Brazilian Amazon.

Abstract: Human intervention in the Brazilian Amazon region promotes contacts between humans and vectors that may favor the propagation of anopheline mosquitoes and the spread of malaria in the absence of planning and infrastructure to control this disease. Vector ecology studies were carried out to determine the risk areas. These data should help in designing appropriate malaria control measures. Data from 14 different regions are reported. Vectors are able to adapt to different environments, which made it necessary to study each area. The parameters studied were Anopheles breeding sites, species distribution, incidence, feeding preferences, hours of maximum activity of adult mosquitoes, seasonality, resting places, and the presence of Plasmodium. Species complexes were also studied. Anopheles darlingi may be responsible for maintaining malaria in human populations in this region. A reduction in the population density of A. darlingi in a particular geographic area can sometimes cause the disappearance of malaria. This species feeds at night but has a peak of activity at the beginning of the evening and another at dawn. Other species are mainly crepuscular and all anophelines demonstrated pronounced exophilia. The timing of feeding activities was found to vary in areas altered by human intervention and also depended on the time of the year and climatic conditions. The larvae were more abundant in the rivers with a less acidic pH and rural areas showed the highest larval index.

Malaria infection of the mosquito Anopheles gambiae activates immune-responsive genes during critical transition stages of the parasite life cycle.

Abstract: Six gene markers have been used to map the progress of the innate immune response of the mosquito vector, Anopheles gambiae, upon infection by the malaria parasite, Plasmodium berghei. In addition to four previously reported genes, the set of markers included NOS (a nitric oxide synthase gene fragment) and ICHIT (a gene encoding two putative chitin-binding domains separated by a polythreonine-rich mucin region). In the midgut, a robust response occurs at 24 h post-infection, at a time when malaria ookinetes traverse the midgut epithelium, but subsides at later phases of malaria development. In contrast, the salivary glands show no significant response at 24 h, but are activated in a prolonged late phase when sporozoites are released from the midgut into the haemolymph and invade the glands, between 10 and 25 days after blood feeding. Furthermore, the abdomen of the mosquito minus the midgut shows significant activation of immune markers, with complex kinetics that are distinct from those of both midgut and salivary glands. The parasite evidently elicits immune responses in multiple tissues of the mosquito, two of which are epithelia that the parasite must traverse to complete its development. The mechanisms of these responses and their significance for malaria transmission are discussed.

Glucose-6-phosphate dehydrogenase deficiency and malaria

Abstract: Glucose-6-phosphate dehydrogenase (G6PD) is a cytoplasmic enzyme that is essential for a cell's capacity to withstand oxidant stress. G6PD deficiency is the commonest enzymopathy of humans, affecting over 400 million persons worldwide. The geographical correlation of its distribution with the historical endemicity of malaria suggests that 66PD deficiency has risen in frequency through natural selection by malaria. This is supported by data from in vitro studies that demonstrate impaired growth of P. falciparum parasites in G6PD-deficient erythrocytes. Attempts to confirm that G6PD deficiency is protective in field studies of malaria have yielded conflicting results, but recent results from large case control studies conducted in East and West Africa provide strong evidence that the most common African G6PD deficiency variant, G6PD A-, is associated with a significant reduction in the risk of severe malaria for both G6PD female heterozygotes and male hemizygotes. The effect of female homozygotes on severe malaria remains unclear but can probably be assumed to be similar to that of comparably deficient male hemizygotes.

Evaluation of the OptiMAL Test for Rapid Diagnosis of Plasmodium vivax and Plasmodium falciparum Malaria

Abstract: The development of rapid and specific diagnostic tests to identify individuals infected with malaria is of paramount importance in efforts to control the severe public health impact of this disease. This study evaluated the ability of a newly developed rapid malaria diagnostic test, OptiMAL (Flow Inc., Portland, Oreg.), to detect Plasmodium vivax and Plasmodium falciparum malaria during an outbreak in Honduras. OptiMAL is a rapid (10-min) malaria detection test which utilizes a dipstick coated with monoclonal antibodies against the intracellular metabolic enzyme parasite lactate dehydrogenase (pLDH). Differentiation of malaria parasites is based on antigenic differences between the pLDH isoforms. Since pLDH is produced only by live Plasmodium parasites, this test has the ability to differentiate live from dead organisms. Results from the OptiMAL test were compared to those obtained by reading 100 fields of traditional Giemsa-stained thick-smear blood films. Whole-blood samples were obtained from 202 patients suspected of having malaria. A total of 96 samples (48%) were positive by blood films, while 91 (45%) were positive by the OptiMAL test. The blood films indicated that 82% (79 of 96) of the patients were positive for P. vivax and 18% (17 of 96) were infected with P. falciparum. The OptiMAL test showed that 81% (74 of 91) were positive for P. vivax and 19% (17 of 91) were positive for P. falciparum. These results demonstrated that the OptiMAL test had sensitivities of 94 and 88% and specificities of 100 and 99%, respectively, when compared to traditional blood films for the detection of P. vivax and P. falciparum malaria. Blood samples not identified by OptiMAL as malaria positive normally contained parasites at concentrations of less than 100/microl of blood. Samples found to contain P. falciparum were further tested by two other commercially available rapid malaria diagnostic tests, ParaSight-F (Becton Dickinson, Cockeysville, Md.) and ICT Malaria P.f. (ICT Diagnostics, Sydney, Australia), both of which detect only P. falciparum. Only 11 of the 17 (65%) P. falciparum-positive blood samples were identified by the ICT and ParaSight-F tests. Thus, OptiMAL correctly identified P. falciparum malaria parasites in patient blood samples more often than did the other two commercially available diagnostic tests and showed an excellent correlation with traditional blood films in the identification of both P. vivax malaria and P. falciparum malaria. We conclude that the OptiMAL test is an effective tool for the rapid diagnosis of malaria.

Phase I/IIa Safety, Immunogenicity, and Efficacy Trial of NYVAC-Pf7, a Pox-Vectored, Multiantigen, Multistage Vaccine Candidate for Plasmodium falciparum Malaria

Abstract: Candidate malaria vaccines have failed to elicit consistently protective immune responses against challenge with Plasmodium falciparum. NYVAC-Pf7, a highly attenuated vaccinia virus with 7 P. falciparum genes inserted into its genome, was tested in a phase I/IIa safety, immunogenicity, and efficacy vaccine trial in human volunteers. Malaria genes inserted into the NYVAC genome encoded proteins from all stages of the parasite's life cycle. Volunteers received three immunizations of two different dosages of NYVAC-Pf7. The vaccine was safe and well tolerated but variably immunogenic. While antibody responses were generally poor, cellular immune responses were detected in >90% of the volunteers. Of the 35 volunteers challenged with the bite of 5 P. falciparum - infected Anopheles mosquitoes, 1 was completely protected, and there was a significant delay in time to parasite patency in the groups of volunteers who received either the low or high dose of vaccine compared with control volunteers.

IgG3 antibodies to Plasmodium falciparum merozoite surface protein 2 (MSP2): increasing prevalence with age and association with clinical immunity to malaria.

Abstract: In a cross-sectional survey carried out in west Africa (The Gambia), where Plasmodium falciparum malaria is endemic with seasonal transmission, 178 individuals 1-75 years of age were assessed for their antibody response to the malaria vaccine candidate, merozoite surface protein 2 (MSP2). Total IgG to recombinant antigens representing full-length, repetitive, and group-specific domains of both allelic families of MSP2 was determined by ELISA. The IgG-subclass profile of IgG-positive sera was assessed. Antibody prevalence was age-dependent, reaching a peak during adolescence. In MSP2-seropositive individuals, there was a predominance of cytophilic antibodies (IgG1 and IgG3); IgG1 antibodies were prevalent in children less than 10 years of age, whereas in adolescents and adults MSP2-specific antibodies were predominantly IgG3. In parallel, we conducted a longitudinal study of children (3-8 years of age) from the same community; sera collected before the malaria transmission season were tested for the presence of anti-MSP2 antibodies. The subsequent susceptibility of these children to clinical malaria was monitored and the association between anti-MSP2 antibodies of different IgG subclasses and resistance to clinical malaria was tested. The presence of IgG3 antibodies to MSP2 serogroup A was negatively associated with the risk of clinical malaria whereas IgG1 antibodies to MSP2 serogroup B were associated with an increased risk of clinical infection. Our data suggest that age/exposure-related acquisition of IgG3 antibodies to MSP2 may contribute to the development of clinically protective immunity to malaria.

Evolution of malaria in Africa for the past 40 years : Impact of climatic and human factors

Abstract: Different malarial situations in Africa within the past 40 years are discussed in order to evaluate the impact of climatic and human factors on the disease. North of the equator, more droughts and lower rainfall have been recorded since 1972; and in eastern and southern Africa, there have been alternating dry and wet periods in relation to El Nino. Since 1955, the increase in human population from 125 to 450 million has resulted in both expansion of land cultivation and urbanization. In stable malaria areas of West and Central Africa and on the Madagascar coasts, the endemic situation has not changed since 1955. However, in unstable malaria areas such as the highlands and Sahel significant changes have occurred. In Madagascar, cessation of malaria control programs resulted in the deadly epidemic of 1987-88. The same situation was observed in Swaziland in 1984-85. In Uganda, malaria incidence has increased more than 30 times in the highlands (1,500-1,800 m), but its altitudinal limit has not overcome that of the beginning of the century. Cultivation of valley bottoms and extension of settlements are in large part responsible for this increase, along with abnormally heavy rainfall that favored the severe epidemic of 1994. A similar increase in malaria was observed in neighboring highlands of Rwanda and Burundi, and epidemics have been recorded in Ethiopia since 1958. In contrast, in the Sahel (Niayes region, Senegal), stricken by droughts since 1972, endemic malaria decreased drastically after the disappearance of the main vector, Anopheles funestus, due to the destruction of its larval sites by cultivation. Even during the very wet year of 1995. An funestus did not reinvade the region and malaria did not increase. The same situation was observed in the Sahelian zone of Niger. Therefore, the temperature increase of 0.5 degree C during the last 2 decades cannot be incriminated as a major cause for these malaria changes, which are mainly due to the combination of climatic, human, and operational factors.

Reemergence of Epidemic Malaria in the Highlands of Western Kenya

Abstract: Hospital records (1990-1997) of a tea company in the Kericho district, western Kenya, showed malaria epidemics almost annually from May to July, with an annual attack rate of 50%, 857 hospitalizations per 100,000 per year, and 42 deaths per 100,000 per year; 32% of deaths in hospitalized patients were caused by malaria. A questionnaire survey (June 1997) of 244 patients hospitalized for malaria showed that only 8% had traveled to an area with known malaria transmission 30 days before diagnosis. The increasing malaria incidence may be due to drug resistance.

A Longitudinal Study of Type-Specific Antibody Responses to Plasmodium falciparum Merozoite Surface Protein-1 in an Area of Unstable Malaria in Sudan

Abstract: Merozoite surface protein-1 (MSP-1) of Plasmodium falciparum is a malaria vaccine candidate Ag. Immunity to MSP-1 has been implicated in protection against infection in animal models. However, MSP-1 is a polymorphic protein and its immune recognition by humans following infection is not well understood. We have compared the immunogenicity of conserved and polymorphic regions of MSP-1, the specificity of Ab responses to a polymorphic region of the Ag, and the duration of these responses in Sudanese villagers intermittently exposed to P. falciparum infections. Recombinant Ags representing the conserved N terminus (Block 1), the conserved C terminus, and the three main types of the major polymorphic region (Block 2) of MSP-1 were used to determine the specificity and longitudinal patterns of IgG Ab responses to MSP-1 in individuals. Abs from 52 donors were assessed before, during, and after malaria transmission seasons for 4 yr. Ags from the Block 1 region were rarely recognized by any donor. Responses to the C-terminal Ag occurred in the majority of acutely infected individuals and thus were a reliable indicator of recent clinical infection. Ags from the polymorphic Block 2 region of MSP-1 were recognized by many, although not all individuals after clinical malaria infections. Responses to Block 2 were type specific and correlated with PCR typing of parasites present at the time of infection. Responses to all of these Ags declined within a few months of drug treatment and parasite clearance, indicating that naturally induced human Ab responses to MSP-1 are short lived.

Merozoite surface antigen 1 and 2 genotypes and rosetting of Plasmodium falciparum in severe and mild malaria in Lambaréné, Gabon

Abstract: We present a case-control study to investigate the distribution of Plasmodium falciparum genotypes in patients with severe and mild malaria. We compared clinical and parasitological data with the parasites' genotype and rosetting. The study group consisted of 100 children suffering severe malaria, defined as severe anaemia and hyperparasitaemia.These children were matched by age, sex and provenance with 100 children with mild malaria. For characterization of the parasites we used the polymerase chain reaction to determine merozoite surface antigen (MSA) 1 and 2 genotypes and the phenomenon of rosette formation. We found a significant association between rosette formation and disease severity, and a significant association of severe anaemia with the presence of the MSA-1 allele K1. Infections with 2 genotypes in the severely affected group were significantly associated with severe anaemia and the presence of MSA-1 allele K1. Comparison with the findings of other groups led to the conclusion that the occurrence of P. falciparum genotypes seems to differ geographically.

Pathways and strategies for developing a malaria blood-stage vaccine*

Abstract: ▪ Abstract In the past 10 years, our knowledge of the malaria parasite has increased enormously: identification and analysis of parasite antigens, demonstration of protection of monkeys and mice following immunization with these antigens, and better understanding of the mechanisms of immunity to malaria and the pathogenesis of disease in malaria. Powerful new adjuvants have been developed, some of which—it is hoped—will be suitable for human use. Recently, a successful human trial of a vaccine aimed at sporozoites (the stage inoculated by mosquitoes) was completed. However, it is the red blood cell stage of the parasite that causes disease, and it is against this stage—in which the parasite grows at an exponential rate—that it has proven very difficult to induce a protective immune response by vaccination. This review focuses on recent exciting developments toward a blood-stage vaccine. We analyze the major obstacles to vaccine development and outline a strategy involving public- and industry-funded resea...

Risk of Severe Malaria among African Infants: Direct Evidence of Clinical Protection during Early Infancy

Abstract: Little empirical evidence from field-based studies exists on the relative magnitude or duration of clinical protection from Plasmodium falciparum malaria in infancy. A prospective study was undertaken to examine the age distribution of hospital admissions in four geographically and demographically well-defined areas with differing intensities of P. falciparum transmission. Where transmission was perennial, significant clinical protection from severe morbidity was observed up to the third month of life; in the seasonal transmission area, disease rates rose after the sixth month of life. Infants exposed to the highest rates of P. falciparum exposure demonstrated significant declines in the risks of severe malaria from 6 months of age. These data provide direct evidence for the very early acquisition of clinical immunity and for the existence of a period of clinical protection, which together may explain why, in these communities, the cumulative risk of malarial disease throughout childhood appears to decline with increasing transmission intensity.

Randomized Comparison of Artemether-Benflumetol and Artesunate-Mefloquine in Treatment of MultidrugResistant Falciparum Malaria

Abstract: An open, randomized comparison of artemether-benflumetol (CGP 56 697; Novartis) with artesunate-mefloquine was conducted in 617 patients with acute uncomplicated multidrug-resistant falciparum malaria on the western border of Thailand. Both treatments rapidly and reliably cleared fever and parasitemia, and there was no significant difference in the initial therapeutic response parameters. Parasite genotyping was used to distinguish recrudescences from new infections. The 63-day cure rate for artesunate-mefloquine (94%) was significantly higher than the cure rate for artemether-benflumetol (81%) (P < 0.001). Both regimens were well tolerated. Nausea, vomiting, dizziness, sleep disorders, and other neurological side effects were between two and four times more common in the artesunate-mefloquine group than in the artemether-benflumetol group (P < 0.001). Artemether-benflumetol is effective and very well tolerated in the treatment of multidrug-resistant falciparum malaria. A higher dose than that used in the present study may improve efficacy.

Unstable malaria in Sudan: the influence of the dry season. Clone multiplicity of Plasmodium falciparum infections in individuals exposed to variable levels of disease transmission.

Abstract: Studies of infection and immunity to malaria often take little account of the fact that the amount of infectious challenge individuals receive is very variable. Classic studies in areas of holoendemic transmission showed that clinical immunity develops quite rapidly during childhood, although the processes through which increasing levels of resistance to infection are acquired are still not understood. However, holoendemic transmission is one end of the spectrum of malaria epidemiology and the development of clinical immunity is also affected by factors such as the infection rate and the local parasite species composition. An exceptionally simple type of malaria transmission occurs during the short, autumnal malaria outbreaks of the Sudanese sahel-savannah belt, where a sparse 200-500 mm of rain falls in 2-3 summer months, Plasmodium falciparum causes > 95% of malaria cases in most areas, and the entomological inoculation rate (EIR) is very low by African standards; thus the population dynamics of malaria parasites are less affected by super-infection. A comparison of certain features of parasite genetic diversity, particularly the average number of parasite clones present in infections in the Sudanese sahel and in malaria study sites with different levels of transmission, is presented. It is proposed that increasing EIRs are associated with progressively smaller increases in the average number of malaria parasite clones per host and the implications of this relationship for studies on malaria infection and immunity are discussed.

Clinical features cannot predict a diagnosis of malaria or differentiate the infecting species in children living in an area of low transmission

Abstract: The differentiation of malaria from other causes of fever in the absence of microscopy is notoriously difficult. Clinical predictors of malaria have been studied in an area of low and unstable transmission on the western border of Thailand. In 1527 children aged 2-15 years who were followed prospectively for 7 months, 82% (1254) had at least one febrile episode. Malaria caused 24% (301) of the first febrile episodes (Plasmodium falciparum 128, P. vivax 151, P. malariae 1, mixed infections with P. falciparum and P. vivax 21). Each malaria case was matched with the next child of similar age presenting to the dispensary with another cause of fever. Clinical symptoms or signs associated with a final diagnosis of malaria were: confirmed fever (> or = 38 degrees C) (odds ratio [OR] 1.6, 95% confidence interval [95% CI] 1.4-1.9), headache (OR 1.5, 95% CI 1.3-1.9), muscle and/or joint pain (OR 2.0, 95% CI 1.6-2.8), nausea (OR 1.7, 95% CI 1.4-2.3), clinical anaemia (OR 1.4, 95% CI 1.3-3.3), palpable spleen (OR 1.3, 95% CI 1.1-1.7), palpable liver (OR 1.4, 95% CI 1.1-2.1), absence of cough (OR 1.6, 95% CI 1.4-2.0), and absence of diarrhoea (OR 1.5, 95% CI 1.2-2.4). None of these signs alone or in combination proved a good predictor of malaria. The best diagnostic algorithms (history of fever and headache without cough, and history of fever with an oral temperature > or = 38 degrees C [sensitivity 51% for both, specificity 72 and 71%, respectively]) would result in prescription of antimalarial drugs in 28-29% of the non-malaria febrile episodes, and only 49% of the true malaria cases. Thus half of the potentially life-threatening P. falciparum infections would not be treated. Although multivariate analysis identified vomiting, confirmed fever, splenomegaly and hepatomegaly as independent risk factors for a diagnosis of falciparum malaria, use of these signs to differentiate falciparum from vivax malaria, and thus to determine antimalarial treatment, was insufficiently sensitive or specific. Malaria diagnosis should be confirmed by microscopical examination of a blood slide or the use of specific dipstick tests in areas of low transmission where highly drug-resistant P. falciparum coexists with P. vivax.

Pathophysiology of fatal falciparum malaria in African children.

Abstract: Children living in sub-Saharan Africa bear the brunt of the mortality from falciparum malaria, yet there is a dearth of relevant post-mortem data. Clinical studies from centers in Africa suggest that the pathophysiology of severe malaria is different in children and adults. Three overlapping clinical syndromes, metabolic acidosis manifesting as hyperpnea, cerebral malaria, and severe anemia, are responsible for nearly all the deaths in African children. Despite improvements in antimalarial treatment, there has not been a significant reduction in mortality. We review the pathology and pathophysiology of fatal falciparum malaria in African children. Many questions remain, the answers to which would facilitate the development and evaluation of new approaches to the management of this disease.