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Showing papers on "Malaria published in 2012"


Journal ArticleDOI
TL;DR: The findings show that the malaria mortality burden is larger than previously estimated, especially in adults, and there has been a rapid decrease in malaria mortality in Africa because of the scaling up of control activities supported by international donors.

1,440 citations


Journal ArticleDOI
TL;DR: Genetically determined artemisinin resistance in P falciparum emerged along the Thailand–Myanmar border at least 8 years ago and has since increased substantially, with experts predicting resistance will reach rates reported in western Cambodia in 2–6 years.

889 citations


Journal ArticleDOI
12 Oct 2012-Science
TL;DR: Spatially explicit mobile phone data and malaria prevalence information from Kenya are used to identify the dynamics of human carriers that drive parasite importation between regions and identifies importation routes that contribute to malaria epidemiology on regional spatial scales.
Abstract: Human movements contribute to the transmission of malaria on spatial scales that exceed the limits of mosquito dispersal. Identifying the sources and sinks of imported infections due to human travel and locating high-risk sites of parasite importation could greatly improve malaria control programs. Here, we use spatially explicit mobile phone data and malaria prevalence information from Kenya to identify the dynamics of human carriers that drive parasite importation between regions. Our analysis identifies importation routes that contribute to malaria epidemiology on regional spatial scales.

887 citations


Journal ArticleDOI
TL;DR: Invasive strains of non-typhoidal salmonellae have emerged as a prominent cause of bloodstream infection in African adults and children, with an associated case fatality of 20–25% and might have adapted to cause invasive disease in human beings.

823 citations


Journal ArticleDOI
Selidji T Agnandji1, Selidji T Agnandji2, Bertrand Lell2, Bertrand Lell1  +165 moreInstitutions (14)
TL;DR: The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants.
Abstract: BACKGROUND: The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial. METHODS: We administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed. RESULTS: The incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, -7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222). CONCLUSIONS: The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.).

700 citations


Journal ArticleDOI
TL;DR: It is shown that submicroscopic parasite carriage is common in adults, in low-endemic settings and in chronic infections, and challenge the idea that individuals with little previous malaria exposure have insufficient immunity to control parasitaemia and suggest a role for molecular screening.
Abstract: Malaria parasite prevalence in endemic populations is an essential indicator for monitoring the progress of malaria control, and has traditionally been assessed by microscopy. However, surveys increasingly use sensitive molecular methods that detect higher numbers of infected individuals, questioning our understanding of the true infection burden and resources required to reduce it. Here we analyse a series of data sets to characterize the distribution and epidemiological factors associated with low-density, submicroscopic infections. We show that submicroscopic parasite carriage is common in adults, in low-endemic settings and in chronic infections. We find a strong, non-linear relationship between microscopy and PCR prevalence in population surveys (n ¼ 106), and provide a tool to relate these measures. When transmission reaches very low levels, submicroscopic carriers are estimated to be the source of 20–50% of all human-to-mosquito transmissions. Our findings challenge the idea that individuals with little previous malaria exposure have insufficient immunity to control parasitaemia and suggest a role for molecular screening.

520 citations


Journal ArticleDOI
TL;DR: It is argued that targeting malaria “hotspots” is a highly efficient way to reduce malaria transmission at all levels of transmission intensity.
Abstract: Current malaria elimination guidelines are based on the concept that malaria transmission becomes heterogeneous in the later phases of malaria elimination [1]. In the pre-elimination and elimination phases, interventions have to be targeted to entire villages or towns with higher malaria incidence until only individual episodes of malaria remain and become the centre of attention [1]. With increasing evidence of clustering of malaria episodes within villages, we argue that there is an intermediate step. Heterogeneity in malaria transmission within villages is present long before areas enter the pre-elimination phase, and identifying and targeting hotspots of malaria transmission should form the cornerstone of both successful malaria control and malaria elimination.

503 citations


Journal ArticleDOI
TL;DR: There is an urgent need to develop practical solutions to the financial and operational threats to effectively sustaining today’s successful malaria control programmes.
Abstract: Background: Considerable declines in malaria have accompanied increased funding for control since the year 2000, but historical failures to maintain gains against the disease underscore the fragility of these successes. Although malaria transmission can be suppressed by effective control measures, in the absence of active intervention malaria will return to an intrinsic equilibrium determined by factors related to ecology, efficiency of mosquito vectors, and socioeconomic characteristics. Understanding where and why resurgence has occurred historically can help current and future malaria control programmes avoid the mistakes of the past. Methods: A systematic review of the literature was conducted to identify historical malaria resurgence events. All suggested causes of these events were categorized according to whether they were related to weakened malaria control programmes, increased potential for malaria transmission, or technical obstacles like resistance. Results: The review identified 75 resurgence events in 61 countries, occurring from the 1930s through the 2000s. Almost all resurgence events (68/75=91%) were attributed at least in part to the weakening of malaria control programmes for a variety of reasons, of which resource constraints were the most common (39/68=57%). Over half of the events (44/75=59%) were attributed in part to increases in the intrinsic potential for malaria transmission, while only 24/75 (32%) were attributed to vector or drug resistance.

446 citations


Journal ArticleDOI
TL;DR: A map of glucose-6-phosphate dehydrogenase deficiency prevalence and severity is presented and individuals with the deficiency are at risk of mild to severe hemolysis when taking the antimalarial primaquine.
Abstract: Background Primaquine is a key drug for malaria elimination. In addition to being the only drug active against the dormant relapsing forms of Plasmodium vivax, primaquine is the sole effective treatment of infectious P. falciparum gametocytes, and may interrupt transmission and help contain the spread of artemisinin resistance. However, primaquine can trigger haemolysis in patients with a deficiency in glucose-6-phosphate dehydrogenase (G6PDd). Poor information is available about the distribution of individuals at risk of primaquine-induced haemolysis. We present a continuous evidence-based prevalence map of G6PDd and estimates of affected populations, together with a national index of relative haemolytic risk. Methods and Findings Representative community surveys of phenotypic G6PDd prevalence were identified for 1,734 spatially unique sites. These surveys formed the evidence-base for a Bayesian geostatistical model adapted to the gene's X-linked inheritance, which predicted a G6PDd allele frequency map across malaria endemic countries (MECs) and generated population-weighted estimates of affected populations. Highest median prevalence (peaking at 32.5%) was predicted across sub-Saharan Africa and the Arabian Peninsula. Although G6PDd prevalence was generally lower across central and southeast Asia, rarely exceeding 20%, the majority of G6PDd individuals (67.5% median estimate) were from Asian countries. We estimated a G6PDd allele frequency of 8.0% (interquartile range: 7.4–8.8) across MECs, and 5.3% (4.4–6.7) within malaria-eliminating countries. The reliability of the map is contingent on the underlying data informing the model; population heterogeneity can only be represented by the available surveys, and important weaknesses exist in the map across data-sparse regions. Uncertainty metrics are used to quantify some aspects of these limitations in the map. Finally, we assembled a database of G6PDd variant occurrences to inform a national-level index of relative G6PDd haemolytic risk. Asian countries, where variants were most severe, had the highest relative risks from G6PDd. Conclusions G6PDd is widespread and spatially heterogeneous across most MECs where primaquine would be valuable for malaria control and elimination. The maps and population estimates presented here reflect potential risk of primaquine-associated harm. In the absence of non-toxic alternatives to primaquine, these results represent additional evidence to help inform safe use of this valuable, yet dangerous, component of the malaria-elimination toolkit. Please see later in the article for the Editors' Summary

421 citations


Journal ArticleDOI
06 Apr 2012-Science
TL;DR: In this article, the authors used a two-phase strategy to identify genome regions(s) underlying this ongoing selective event and identified a selective sweep on chromosome 13 that shows strong association (P = 10−6) to 10−12) with slow Artemisinin-resistant parasites.
Abstract: Evolving resistance to artemisinin-based compounds threatens to derail attempts to control malaria. Resistance has been confirmed in western Cambodia and has recently emerged in western Thailand, but is absent from neighboring Laos. Artemisinin resistance results in reduced parasite clearance rates (CRs) after treatment. We used a two-phase strategy to identify genome region(s) underlying this ongoing selective event. Geographical differentiation and haplotype structure at 6969 polymorphic single-nucleotide polymorphisms (SNPs) in 91 parasites from Cambodia, Thailand, and Laos identified 33 genome regions under strong selection. We screened SNPs and microsatellites within these regions in 715 parasites from Thailand, identifying a selective sweep on chromosome 13 that shows strong association (P = 10(-6) to 10(-12)) with slow CRs, illustrating the efficacy of targeted association for identifying the genetic basis of adaptive traits.

373 citations


Journal ArticleDOI
TL;DR: This work compares the activity of 50 current and experimental antimalarials against liver, sexual blood, and mosquito stages of selected human and nonhuman parasite species, including Plasmodium falciparum, PlAsmodium berghei, and PlasModium yoelii.
Abstract: Background: Malaria remains a disease of devastating global impact, killing more than 800,000 people every year—the vast majority being children under the age of 5. While effective therapies are available, if malaria is to be eradicated a broader range of small molecule therapeutics that are able to target the liver and the transmissible sexual stages are required. These new medicines are needed both to meet the challenge of malaria eradication and to circumvent resistance. Methods and Findings: Little is known about the wider stage-specific activities of current antimalarials that were primarily designed to alleviate symptoms of malaria in the blood stage. To overcome this critical gap, we developed assays to measure activity of antimalarials against all life stages of malaria parasites, using a diverse set of human and nonhuman parasite species, including male gamete production (exflagellation) in Plasmodium falciparum, ookinete development in P. berghei, oocyst development in P. berghei and P. falciparum, and the liver stage of P. yoelii. We then compared 50 current and experimental antimalarials in these assays. We show that endoperoxides such as OZ439, a stable synthetic molecule currently in clinical phase IIa trials, are strong inhibitors of gametocyte maturation/gamete formation and impact sporogony; lumefantrine impairs development in the vector; and NPC-1161B, a new 8-aminoquinoline, inhibits sporogony. Conclusions: These data enable objective comparisons of the strengths and weaknesses of each chemical class at targeting each stage of the lifecycle. Noting that the activities of many compounds lie within achievable blood concentrations, these results offer an invaluable guide to decisions regarding which drugs to combine in the next-generation of antimalarial drugs. This study might reveal the potential of life-cycle–wide analyses of drugs for other pathogens with complex life cycles. Please see later in the article for the Editors’ Summary.

Journal ArticleDOI
TL;DR: Heritable artemisinin resistance is established in a second Cambodian province and future studies should explore the effect of erythrocyte polymorphisms and specific immune responses on half-life variation.
Abstract: Summary Background Artemisinin-resistant Plasmodium falciparum has been reported in Pailin, western Cambodia, detected as a slow parasite clearance rate in vivo. Emergence of this phenotype in western Thailand and possibly elsewhere threatens to compromise the effectiveness of all artemisinin-based combination therapies. Parasite genetics is associated with parasite clearance rate but does not account for all variation. We investigated contributions of both parasite genetics and host factors to the artemisinin-resistance phenotype in Pursat, western Cambodia. Methods Between June 19 and Nov 28, 2009, and June 26 and Dec 6, 2010, we enrolled patients aged 10 years or older with uncomplicated falciparum malaria, a density of asexual parasites of at least 10 000 per μL of whole blood, no symptoms or signs of severe malaria, no other cause of febrile illness, and no chronic illness. We gave participants 4 mg/kg artesunate at 0, 24, and 48 h, 15 mg/kg mefloquine at 72 h, and 10 mg/kg mefloquine at 96 h. We assessed parasite density on thick blood films every 6 h until undetectable. The parasite clearance half-life was calculated from the parasite clearance curve. We genotyped parasites with 18 microsatellite markers and patients for haemoglobin E, α-thalassaemia, and a mutation of G6PD , which encodes glucose-6-phosphate dehydrogenase. To account for the possible effects of acquired immunity on half-life, we used three surrogates for increased likelihood of exposure to P falciparum : age, sex, and place of residence. This study is registered with ClinicalTrials.gov, number NCT00341003. Findings We assessed 3504 individuals from all six districts of Pursat province seeking treatment for malaria symptoms. We enrolled 168 patients with falciparum malaria who met inclusion criteria. The geometric mean half-life was 5·85 h (95% CI 5·54–6·18) in Pursat, similar to that reported in Pailin (p=0·109). We identified two genetically different parasite clone groups: parasite group 1 (PG1) and parasite group 2 (PG2). Non-significant increases in parasite clearance half-life were seen in patients with haemoglobin E (0·55 h; p=0·078), those of male sex (0·96 h; p=0·064), and in 2010 (0·68 h; p=0·068); PG1 was associated with a significant increase (0·79 h; p=0·033). The mean parasite heritability of half-life was 0·40 (SD 0·17). Interpretation Heritable artemisinin resistance is established in a second Cambodian province. To accurately identify parasites that are intrinsically susceptible or resistant to artemisinins, future studies should explore the effect of erythrocyte polymorphisms and specific immune responses on half-life variation. Funding Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Journal ArticleDOI
TL;DR: The potential benefits of antioxidant supplementation as an adjuvant antimalarial strategy are discussed and oxidative stress mechanisms involved in the disease are reviewed.
Abstract: Malaria is a significant public health problem in more than 100 countries and causes an estimated 200 million new infections every year. Despite the significant effort to eradicate this dangerous disease, lack of complete knowledge of its physiopathology compromises the success in this enterprise. In this paper we review oxidative stress mechanisms involved in the disease and discuss the potential benefits of antioxidant supplementation as an adjuvant antimalarial strategy.

Journal ArticleDOI
TL;DR: The problems and obstacles to the study and control of asymptomatic malaria are discussed, the human and parasite factors associated with differential clinical outcomes are described, and the management and treatment strategies for the control of the disease are outlined.
Abstract: Malaria is a serious parasitic disease in the developing world, causing high morbidity and mortality. The pathogenesis of malaria is complex, and the clinical presentation of disease ranges from severe and complicated, to mild and uncomplicated, to asymptomatic malaria. Despite a wealth of studies on the clinical severity of disease, asymptomatic malaria infections are still poorly understood. Asymptomatic malaria remains a challenge for malaria control programs as it significantly influences transmission dynamics. A thorough understanding of the interaction between hosts and parasites in the development of different clinical outcomes is required. In this review, the problems and obstacles to the study and control of asymptomatic malaria are discussed. The human and parasite factors associated with differential clinical outcomes are described and the management and treatment strategies for the control of the disease are outlined. Further, the crucial gaps in the knowledge of asymptomatic malaria that should be the focus of future research towards development of more effective malaria control strategies are highlighted.

Journal ArticleDOI
TL;DR: The most comprehensive review of malaria vaccine projects to be published in the last several years is provided, and some unpublished information available for each project on the rainbow table is provided.
Abstract: Development and Phase 3 testing of the most advanced malaria vaccine, RTS,S/AS01, indicates that malaria vaccine R&D is moving into a new phase. Field trials of several research malaria vaccines have also confirmed that it is possible to impact the host-parasite relationship through vaccine-induced immune responses to multiple antigenic targets using different platforms. Other approaches have been appropriately tested but turned out to be disappointing after clinical evaluation. As the malaria community considers the potential role of a first-generation malaria vaccine in malaria control efforts, it is an apposite time to carefully document terminated and ongoing malaria vaccine research projects so that lessons learned can be applied to increase the chances of success for second-generation malaria vaccines over the next 10 years. The most comprehensive resource of malaria vaccine projects is a spreadsheet compiled by WHO thanks to the input from funding agencies, sponsors and investigators worldwide. This spreadsheet, available from WHO's website, is known as "the rainbow table". By summarizing the published and some unpublished information available for each project on the rainbow table, the most comprehensive review of malaria vaccine projects to be published in the last several years is provided below.

Journal ArticleDOI
TL;DR: Haemoglobin AS, CC, and AC genotypes and homozygous and heterozygous α-thalassaemia provide significant protection from severe malaria syndromes, but these haemoglobinopathies differ substantially in the degree of protection provided and confer mild or no protection against uncomplicated malaria and asymptomatic parasitaemia.
Abstract: Summary Background Haemoglobinopathies can reduce the risk of malaria syndromes. We aimed to quantify the relation between different haemoglobin mutations and malaria protection to strengthen the foundation for translational studies of malaria pathogenesis and immunity. Methods We systematically searched the Medline and Embase databases for studies that estimated the risk of malaria in patients with and without haemoglobinopathies up to Sept 9, 2011, and identified additional studies from reference lists. We included studies that enrolled mainly children or pregnant women and had the following outcomes: Plasmodium falciparum severe malaria, uncomplicated malaria, asymptomatic parasitaemia, or pregnancy-associated malaria, and Plasmodium vivax malaria. Two reviewers identified studies independently, assessed quality of the studies, and extracted data. We produced odds ratios (ORs; 95% CIs) for case-control studies and incidence rate ratios (IRRs; 95% CIs) for prospective studies. We did the meta-analysis with a random-effects model when equivalent outcomes were reported in more than one study. Findings Of 62 identified studies, 44 reported data for haemoglobin AS, 19 for haemoglobin AC and CC, and 18 for α-thalassaemia. Meta-analysis of case-control studies showed a decreased risk of severe P falciparum malaria in individuals with haemoglobin AS (OR 0·09, 95% CI 0·06–0·12), haemoglobin CC (0·27, 0·11–0·63), haemoglobin AC (0·83, 0·67–0·96), homozygous α-thalassaemia (0·63, 0·48–0·83), and heterozygous α-thalassaemia (0·83, 0·74–0·92). In meta-analysis of prospective trials only haemoglobin AS was consistently associated with protection from uncomplicated malaria (IRR 0·69, 95% CI 0·61–0·79); no haemoglobinopathies led to consistent protection from asymptomatic parasitaemia. Few clinical studies have investigated β-thalassaemia, haemoglobin E, P vivax malaria, or pregnancy-associated malaria. Interpretation Haemoglobin AS, CC, and AC genotypes and homozygous and heterozygous α-thalassaemia provide significant protection from severe malaria syndromes, but these haemoglobinopathies differ substantially in the degree of protection provided and confer mild or no protection against uncomplicated malaria and asymptomatic parasitaemia. Through attenuation of severity of malaria, haemoglobinopathies could serve as a model for investigation of the mechanisms of malaria pathogenesis and immunity. Funding US National Institute of Allergy and Infectious Diseases.

Journal ArticleDOI
TL;DR: The combined analysis showed that severe malaria syndromes, including severe anemia and cerebral malaria, are associated with high transcript levels of PfEMP1 domain cassette 8-encoding var genes.
Abstract: The clinical outcome of Plasmodium falciparum infections ranges from asymptomatic parasitemia to severe malaria syndromes associated with high mortality. The virulence of P. falciparum infections is associated with the type of P. falciparum erythrocyte membrane protein 1 (PfEMP1) expressed on the surface of infected erythrocytes to anchor these to the vascular lining. Although var2csa, the var gene encoding the PfEMP1 associated with placental malaria, was discovered in 2003, the identification of the var/PfEMP1 variants associated with severe malaria in children has remained elusive. To identify var/PfEMP1 variants associated with severe disease outcome, we compared var transcript levels in parasites from 88 children with severe malaria and 40 children admitted to the hospital with uncomplicated malaria. Transcript analysis was performed by RT-quantitative PCR using a set of 42 primer pairs amplifying var subtype-specific loci covering most var/PfEMP1 subtypes. In addition, we characterized the near-full-length sequence of the most prominently expressed var genes in three patients diagnosed with severe anemia and/or cerebral malaria. The combined analysis showed that severe malaria syndromes, including severe anemia and cerebral malaria, are associated with high transcript levels of PfEMP1 domain cassette 8-encoding var genes. Transcript levels of group A var genes, including genes encoding domain cassette 13, were also significantly higher in patients with severe syndromes compared with those with uncomplicated malaria. This study specifies the var/PfEMP1 types expressed in severe malaria in children, and thereby provides unique targets for future efforts to prevent and treat severe malaria infections.


Journal ArticleDOI
20 Sep 2012-Nature
TL;DR: Two previously unknown loci associated with severe falciparum malaria in patients and controls from Ghana, West Africa are identified and underline the potential of the GWA approach to provide candidates for the development of control measures against infectious diseases in humans.
Abstract: A genome-wide association study in Ghana, West Africa, to identify genetic variants associated with malaria pathogenesis reveals two previously unknown loci on chromosomes 1 and 16. This genome-wide association study in 2,645 cases and 3,050 controls from Ghana in West Africa identifies genetic variants that might affect any one of the many steps in malaria pathogenesis. Two novel loci are described. The first is on chromosome 1, in the vicinity of the ATP2B4 gene, which encodes the main calcium pump of erythrocytes, the host cells of the pathogenic stage of the malaria parasite. The second is on chromosome 16, close to MARVELD3, which encodes a tight-junction protein that is expressed on endothelial cells. These genetic variants may confer resistance by affecting key steps in disease development that could generate possible antimalarial targets. Malaria causes approximately one million fatalities per year, mostly among African children1. Although highlighted by the strong protective effect of the sickle-cell trait2,3, the full impact of human genetics on resistance to the disease remains largely unexplored4. Genome-wide association (GWA) studies are designed to unravel relevant genetic variants comprehensively; however, in malaria, as in other infectious diseases, these studies have been only partly successful5. Here we identify two previously unknown loci associated with severe falciparum malaria in patients and controls from Ghana, West Africa. We applied the GWA approach to the diverse clinical syndromes of severe falciparum malaria, thereby targeting human genetic variants influencing any step in the complex pathogenesis of the disease. One of the loci was identified on chromosome 1q32 within the ATP2B4 gene, which encodes the main calcium pump of erythrocytes6, the host cells of the pathogenic stage of malaria parasites. The second was indicated by an intergenic single nucleotide polymorphism on chromosome 16q22.2, possibly linked to a neighbouring gene encoding the tight-junction protein MARVELD3. The protein is expressed on endothelial cells7 and might therefore have a role in microvascular damage caused by endothelial adherence of parasitized erythrocytes. We also confirmed previous reports on protective effects of the sickle-cell trait and blood group O5,8,9. Our findings underline the potential of the GWA approach to provide candidates for the development of control measures against infectious diseases in humans.

Journal ArticleDOI
TL;DR: In the primary African malaria vector, Anopheles gambiae sensu stricto, a single enzyme, CYP6M2, confers resistance to two classes of insecticide, which is unique evidence in a disease vector of cross-resistance associated with a single metabolic gene that simultaneously reduces the efficacy of two of the four classes of Insecticide routinely used for malaria control.
Abstract: In the last decade there have been marked reductions in malaria incidence in sub-Saharan Africa. Sustaining these reductions will rely upon insecticides to control the mosquito malaria vectors. We report that in the primary African malaria vector, Anopheles gambiae sensu stricto, a single enzyme, CYP6M2, confers resistance to two classes of insecticide. This is unique evidence in a disease vector of cross-resistance associated with a single metabolic gene that simultaneously reduces the efficacy of two of the four classes of insecticide routinely used for malaria control. The gene-expression profile of a highly DDT-resistant population of A. gambiae s.s. from Ghana was characterized using a unique whole-genome microarray. A number of genes were significantly overexpressed compared with two susceptible West African colonies, including genes from metabolic families previously linked to insecticide resistance. One of the most significantly overexpressed probe groups (false-discovery rate-adjusted P < 0.0001) belonged to the cytochrome P450 gene CYP6M2. This gene is associated with pyrethroid resistance in wild A. gambiae s.s. populations) and can metabolize both type I and type II pyrethroids in recombinant protein assays. Using in vitro assays we show that recombinant CYP6M2 is also capable of metabolizing the organochlorine insecticide DDT in the presence of solubilizing factor sodium cholate.

Journal ArticleDOI
TL;DR: Physicians should be aware that malaria is not a clinical diagnosis but must be diagnosed, or excluded, by performing microscopic examination of blood films, and prompt diagnosis and appropriate treatment are then crucial to prevent morbidity and fatal outcomes.
Abstract: The first symptoms of malaria, common to all the different malaria species, are nonspecific and mimic a flu-like syndrome Although fever represents the cardinal feature, clinical findings in malaria are extremely diverse and may range in severity from mild headache to serious complications leading to death, particularly in falciparum malaria As the progression to these complications can be rapid, any malaria patient must be assessed and treated rapidly, and frequent observations are needed to look for early signs of systemic complications In fact, severe malaria is a life threatening but treatable disease The protean and nonspecific clinical findings occurring in malaria (fever, malaise, headache, myalgias, jaundice and sometimes gastrointestinal symptoms of nausea, vomiting and diarrhoea) may lead physicians who see malaria infrequently to a wrong diagnosis, such as influenza (particularly during the seasonal epidemic flu), dengue, gastroenteritis, typhoid fever, viral hepatitis, encephalitis Physicians should be aware that malaria is not a clinical diagnosis but must be diagnosed, or excluded, by performing microscopic examination of blood films Prompt diagnosis and appropriate treatment are then crucial to prevent morbidity and fatal outcomes Although Plasmodium falciparum malaria is the major cause of severe malaria and death, increasing evidence has recently emerged that Plasmodium vivax and Plasmodium knowlesi can also be severe and even fatal

Journal ArticleDOI
TL;DR: Global warming is expected to increase the occurrence, distribution, and intensity of avian malaria across this elevational gradient and threaten high‐elevation refugia, which is the key to survival of many susceptible Hawaiian birds.
Abstract: Avian malaria is a worldwide mosquito-borne disease caused by Plasmodium parasites. These parasites occur in many avian species but primarily affect passerine birds that have not evolved with the parasite. Host pathogenicity, fitness, and population impacts are poorly understood. In contrast to continental species, introduced avian malaria poses a substantial threat to naive birds on Hawaii, the Galapagos, and other archipelagoes. In Hawaii, transmission is maintained by susceptible native birds, competence and abundance of mosquitoes, and a disease reservoir of chronically infected native birds. Although vector habitat and avian communities determine the geographic distribution of disease, climate drives transmission patterns ranging from continuous high infection in warm lowland forests, seasonal infection in midelevation forests, and disease-free refugia in cool high-elevation forests. Global warming is expected to increase the occurrence, distribution, and intensity of avian malaria across this elevational gradient and threaten high-elevation refugia, which is the key to survival of many susceptible Hawaiian birds. Increased temperatures may have already increased global avian malaria prevalence and contributed to an emergence of disease in New Zealand.

Journal ArticleDOI
TL;DR: Development of newer classes of insecticide is crucial because if resistance continues unchecked, the hard-earned progress in malaria control in Africa could be quickly reversed.
Abstract: Malaria control depends on mosquito susceptibility to insecticides. We tested Anopheles gambiae mosquitoes from Cote d'Ivoire for resistance and screened a subset for target site mutations. Mosquitoes were resistant to insecticides of all approved classes. Such complete resistance, which includes exceptionally strong phenotypes, presents a major threat to malaria control.

Journal ArticleDOI
TL;DR: The KEMRI/Centers for Disease Control and Prevention (CDC) Health and Demographic Surveillance System (HDSS) is located in Rarieda, Siaya and Gem Districts (Siaya County), lying northeast of Lake Victoria in Nyanza Province, western Kenya.
Abstract: The KEMRI/Centers for Disease Control and Prevention (CDC) Health and Demographic Surveillance System (HDSS) is located in Rarieda, Siaya and Gem Districts (Siaya County), lying northeast of Lake Victoria in Nyanza Province, western Kenya. The KEMRI/CDC HDSS, with approximately 220 000 inhabitants, has been the foundation for a variety of studies, including evaluations of insecticide-treated bed nets, burden of diarrhoeal disease and tuberculosis, malaria parasitaemia and anaemia, treatment strategies and immunological correlates of malaria infection, and numerous HIV, tuberculosis, malaria and diarrhoeal disease treatment and vaccine efficacy and effectiveness trials for more than a decade. Current studies include operations research to measure the uptake and effectiveness of the programmatic implementation of integrated malaria control strategies, HIV services, newly introduced vaccines and clinical trials. The HDSS provides general demographic and health information (such as population age structure and density, fertility rates, birth and death rates, in- and out-migrations, patterns of health care access and utilization and the local economics of health care) as well as disease- or intervention-specific information. The HDSS also collects verbal autopsy information on all deaths. Studies take advantage of the sampling frame inherent in the HDSS, whether at individual, household/compound or neighbourhood level.

Journal ArticleDOI
TL;DR: In this article, the authors tried to limit confounding bias through exact matching on potential confounding factors associated with both exposure to malaria prevention (IPTp or ITNs) in pregnancy and birth outcomes, including local malaria transmission, neonatal tetanus vaccination, maternal age and education, and household wealth.
Abstract: Summary Background Low birthweight is a significant risk factor for neonatal and infant death. A prominent cause of low birthweight is infection with Plasmodium falciparum during pregnancy. Antimalarial intermittent preventive therapy in pregnancy (IPTp) and insecticide-treated mosquito nets (ITNs) significantly reduce the risk of low birthweight in regions of stable malaria transmission. We aimed to assess the effectiveness of malaria prevention in pregnancy (IPTp or ITNs) at preventing low birthweight and neonatal mortality under routine programme conditions in malaria endemic countries of Africa. Methods We used a retrospective birth cohort from national cross-sectional datasets in 25 African countries from 2000–10. We used all available datasets from multiple indicator cluster surveys, demographic and health surveys, malaria indicator surveys, and AIDS indicator surveys that were publically available as of 2011. We tried to limit confounding bias through exact matching on potential confounding factors associated with both exposure to malaria prevention (ITNs or IPTp with sulfadoxine–pyrimethamine) in pregnancy and birth outcomes, including local malaria transmission, neonatal tetanus vaccination, maternal age and education, and household wealth. We used a logistic regression model to test for associations between malaria prevention in pregnancy and low birthweight, and a Poisson model for the outcome of neonatal mortality. Both models incorporated the matched strata as a random effect, while accounting for additional potential confounding factors with fixed effect covariates. Findings We analysed 32 national cross-sectional datasets. Exposure of women in their first or second pregnancy to full malaria prevention with IPTp or ITNs was significantly associated with decreased risk of neonatal mortality (protective efficacy [PE] 18%, 95% CI 4–30; incidence rate ratio [IRR] 0·820, 95% CI 0·698–0·962), compared with newborn babies of mothers with no protection, after exact matching and controlling for potential confounding factors. Compared with women with no protection, exposure of pregnant women during their first two pregnancies to full malaria prevention in pregnancy through IPTp or ITNs was significantly associated with reduced odds of low birthweight (PE 21%, 14–27; IRR 0·792, 0·732–0·857), as measured by a combination of weight and birth size perceived by the mother, after exact matching and controlling for potential confounding factors. Interpretation Malaria prevention in pregnancy is associated with substantial reductions in neonatal mortality and low birthweight under routine malaria control programme conditions. Malaria control programmes should strive to achieve full protection in pregnant women by both IPTp and ITNs to maximise their benefits. Despite an attempt to mitigate bias and potential confounding by matching women on factors thought to be associated with access to malaria prevention in pregnancy and birth outcomes, some level of confounding bias possibly remains. Funding Malaria Control and Evaluation Partnership in Africa (MACEPA), Bill & Melinda Gates Foundation.

Journal ArticleDOI
01 Aug 2012-Chest
TL;DR: Because early markers of ALI/ARDS are lacking, fluid resuscitation in severe malaria should follow the old adage to "keep them dry," and the best antimalarial treatment of severe malaria is IV artesunate.

Journal ArticleDOI
TL;DR: Assays using transgenic P. falciparum with modified PfEMP1 expression to quantify serum antibodies to VSAs among individuals exposed to malaria found that the majority of the human antibody response to the IE targets Pf EMP1, a key target of humoral immunity, is found.
Abstract: Plasmodium falciparum is the major cause of malaria globally and is transmitted by mosquitoes. During parasitic development, P. falciparum-infected erythrocytes (P. falciparum-IEs) express multiple polymorphic proteins known as variant surface antigens (VSAs), including the P. falciparum erythrocyte membrane protein 1 (PfEMP1). VSA-specific antibodies are associated with protection from symptomatic and severe malaria. However, the importance of the different VSA targets of immunity to malaria remains unclear, which has impeded an understanding of malaria immunity and vaccine development. In this study, we developed assays using transgenic P. falciparum with modified PfEMP1 expression to quantify serum antibodies to VSAs among individuals exposed to malaria. We found that the majority of the human antibody response to the IE targets PfEMP1. Furthermore, our longitudinal studies showed that individuals with PfEMP1-specific antibodies had a significantly reduced risk of developing symptomatic malaria, whereas antibodies to other surface antigens were not associated with protective immunity. Using assays that measure antibody-mediated phagocytosis of IEs, an important mechanism in parasite clearance, we identified PfEMP1 as the major target of these functional antibodies. Taken together, these data demonstrate that PfEMP1 is a key target of humoral immunity. These findings advance our understanding of the targets and mediators of human immunity to malaria and have major implications for malaria vaccine development.

Journal ArticleDOI
TL;DR: A single episode of falciparum or vivax malaria in the first trimester of pregnancy can cause miscarriage and the risk of miscarriage was similar for women treated with chloroquine, quinine, or artesunate combination treatments in early pregnancy.
Abstract: Summary Background The effects of malaria and its treatment in the first trimester of pregnancy remain an area of concern. We aimed to assess the outcome of malaria-exposed and malaria-unexposed first-trimester pregnancies of women from the Thai–Burmese border and compare outcomes after chloroquine-based, quinine-based, or artemisinin-based treatments. Methods We analysed all antenatal records of women in the first trimester of pregnancy attending Shoklo Malaria Research Unit antenatal clinics from May 12, 1986, to Oct 31, 2010. Women without malaria in pregnancy were compared with those who had a single episode of malaria in the first trimester. The association between malaria and miscarriage was estimated using multivariable logistic regression. Findings Of 48 426 pregnant women, 17 613 (36%) met the inclusion criteria: 16 668 (95%) had no malaria during the pregnancy and 945 (5%) had a single episode in the first trimester. The odds of miscarriage increased in women with asymptomatic malaria (adjusted odds ratio 2·70, 95% CI 2·04–3·59) and symptomatic malaria (3·99, 3·10–5·13), and were similar for Plasmodium falciparum and Plasmodium vivax . Other risk factors for miscarriage included smoking, maternal age, previous miscarriage, and non-malaria febrile illness. In women with malaria, additional risk factors for miscarriage included severe or hyperparasitaemic malaria (adjusted odds ratio 3·63, 95% CI 1·15–11·46) and parasitaemia (1·49, 1·25–1·78 for each ten-fold increase in parasitaemia). Higher gestational age at the time of infection was protective (adjusted odds ratio 0·86, 95% CI 0·81–0·91). The risk of miscarriage was similar for women treated with chloroquine (92 [26%] of 354), quinine (95 [27%) of 355), or artesunate (20 [31%] of 64; p=0·71). Adverse effects related to antimalarial treatment were not observed. Interpretation A single episode of falciparum or vivax malaria in the first trimester of pregnancy can cause miscarriage. No additional toxic effects associated with artesunate treatment occurred in early pregnancy. Prospective studies should now be done to assess the safety and efficacy of artemisinin combination treatments in early pregnancy. Funding Wellcome Trust and Bill & Melinda Gates Foundation.

Book ChapterDOI
TL;DR: Mechanisms underlying the pathogenesis of severe vivax syndromes remain incompletely understood and further studies are needed to investigate the role of bacterial and other co-infections in these syndrome.
Abstract: Vivax malaria was historically described as ‘benign tertian malaria’ because individual clinical episodes were less likely to cause severe illness than Plasmodium falciparum. Despite this, Plasmodium vivax was, and remains, responsible for major morbidity and significant mortality in vivax-endemic areas. Single infections causing febrile illness in otherwise healthy individuals rarely progress to severe disease. Nevertheless, in the presence of co-morbidities, P. vivax can cause severe illness and fatal outcomes. Recurrent or chronic infections in endemic areas can cause severe anaemia and malnutrition, particularly in early childhood. Other severe manifestations include acute lung injury, acute kidney injury and uncommonly, coma. Multiorgan failure and shock are described but further studies are needed to investigate the role of bacterial and other co-infections in these syndromes. In pregnancy, P. vivax infection can cause maternal anaemia, miscarriage, low birth weight and congenital malaria. Compared to P. falciparum, P. vivax has a greater capacity to elicit an inflammatory response, resulting in a lower pyrogenic threshold. Conversely, cytoadherence of P. vivax to endothelial cells is less frequent and parasite sequestration is not thought to be a significant cause of severe illness in vivax malaria. With a predilection for young red cells, P. vivax does not result in the high parasite biomass associated with severe disease in P. falciparum, but a four to fivefold greater removal of uninfected red cells from the circulation relative to P. falciparum is associated with a similar risk of severe anaemia. Mechanisms underlying the pathogenesis of severe vivax syndromes remain incompletely understood.

Journal ArticleDOI
TL;DR: Individuals with poor socio-economic conditions are positively associated with malaria infection and spraying anti-malaria to the house was found to be one means of reducing the risk of malaria.
Abstract: More than 75% of the total area of Ethiopia is malarious, making malaria the leading public health problem in Ethiopia. The aim of this study was to investigate the prevalence rate and the associated socio-economic, geographic and demographic factors of malaria based on the rapid diagnosis test (RDT) survey results. From December 2006 to January 2007, a baseline malaria indicator survey in Amhara, Oromiya and Southern Nation Nationalities and People (SNNP) regions of Ethiopia was conducted by The Carter Center. This study uses this data. The method of generalized linear model was used to analyse the data and the response variable was the presence or absence of malaria using the rapid diagnosis test (RDT). The analyses show that the RDT result was significantly associated with age and gender. Other significant covariates confounding variables are source of water, trip to obtain water, toilet facility, total number of rooms, material used for walls, and material used for roofing. The prevalence of malaria for households with clean water found to be less. Malaria rapid diagnosis found to be higher for thatch and stick/mud roof and earth/local dung plaster floor. Moreover, spraying anti-malaria to the house was found to be one means of reducing the risk of malaria. Furthermore, the housing condition, source of water and its distance, gender, and ages in the households were identified in order to have two-way interaction effects. Individuals with poor socio-economic conditions are positively associated with malaria infection. Improving the housing condition of the household is one of the means of reducing the risk of malaria. Children and female household members are the most vulnerable to the risk of malaria. Such information is essential to design improved strategic intervention for the reduction of malaria epidemic in Ethiopia.