Showing papers in "Malaria Journal in 2012"

Malaria resurgence: a systematic review and assessment of its causes

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.

The complexities of malaria disease manifestations with a focus on asymptomatic malaria.

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.

A review of malaria vaccine clinical projects based on the WHO rainbow table

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.

Spatial repellents: from discovery and development to evidence-based validation.

Abstract: International public health workers are challenged by a burden of arthropod-borne disease that remains elevated despite best efforts in control programmes. With this challenge comes the opportunity to develop novel vector control paradigms to guide product development and programme implementation. The role of vector behaviour modification in disease control was first highlighted several decades ago but has received limited attention within the public health community. This paper presents current evidence highlighting the value of sub-lethal agents, specifically spatial repellents, and their use in global health, and identifies the primary challenges towards establishing a clearly defined and recommended role for spatial repellent products in disease control.

Prevalence and risk factors of malaria in Ethiopia.

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.

The anaemia of Plasmodium vivax malaria

Abstract: Plasmodium vivax threatens nearly half the world’s population and is a significant impediment to achievement of the millennium development goals. It is an important, but incompletely understood, cause of anaemia. This review synthesizes current evidence on the epidemiology, pathogenesis, treatment and consequences of vivax-associated anaemia. Young children are at high risk of clinically significant and potentially severe vivax-associated anaemia, particularly in countries where transmission is intense and relapses are frequent. Despite reaching lower densities than Plasmodium falciparum, Plasmodium vivax causes similar absolute reduction in red blood cell mass because it results in proportionately greater removal of uninfected red blood cells. Severe vivax anaemia is associated with substantial indirect mortality and morbidity through impaired resilience to co-morbidities, obstetric complications and requirement for blood transfusion. Anaemia can be averted by early and effective anti-malarial treatment.

Primaquine radical cure of Plasmodium vivax: a critical review of the literature

Abstract: Background: Primaquine has been the only widely available hypnozoitocidal anti-malarial drug for half a century. Despite this its clinical efficacy is poorly characterized resulting in a lack of consensus over the optimal regimen for the radical cure of Plasmodium vivax. Methods: Published studies since 1950 of the use of primaquine regimens for preventing P. vivax relapse were reviewed. Data were extracted systematically from available papers. Primaquine regimens were categorized according to the total dose administered: very low (≤2.5 mg/kg), low (>2.5 mg/kg-<5.0 mg/kg) and high (≥ 5.0 mg/kg). The risk of recurrent infection were summarized across geographical regions and the odds ratios between treatment regimens calculated after stratifying by total treatment dose and duration of study follow up. Results: Data could be retrieved from 87 clinical trials presenting data in 59,735 patients enrolled into 156 treatment arms, conducted in 20 countries. There was marked heterogeneity in study design, particularly primaquine dosing and duration of follow up. The median rate of recurrence following very low dose of primaquine (n=44) was 25% (range 0-90%) at 4–6 months, compared to 6.7 % (range 0-59%) following low dose primaquine (n=82). High dose primaquine regimens were assessed in 28 treatment arms, and were associated with a median recurrence rate of 0% (Range: 0-15%) at one month. In 18 studies with control arms, the effectiveness of a very low dose primaquine regimen was no different from patients who did not receive primaquine (OR=0.60, 95% CI 0.33-1.09, p=0.09), whereas for the low dose regimens a significant difference was reported in 50% (6/12) of studies (overall OR=0.14, 95%CI: 0.06-0.35, p<0.001). Two studies enrolling 171 patients demonstrated high effectiveness of high dose primaquine compared to a control arm (OR=0.03 (95%CI: 0.01-0.13); p<0.0001). Conclusions: Low dose regimens retain adequate efficacy in some areas, but this is not uniform. The efficacy and safety of pragmatic high dose primaquine regimens needs to be assessed in a range of endemic and geographical locations. Such studies will require a prolonged period of follow up and comparison with control arms to account for confounding factors. Background Over 40% of the world’s population is at risk of infection with Plasmodium vivax, with an annual global burden estimated to be between 71 to 391 million clinical cases [1-3]. Vivax malaria causes significant morbidity and associated mortality, much of which is attributable to the chronic relapsing nature of the infection. As malaria

Estimates of Child Deaths Prevented from Malaria Prevention Scale-up in Africa 2001-2010.

Abstract: Background Funding from external agencies for malaria control in Africa has increased dramatically over the past decade resulting in substantial increases in population coverage by effective malaria prevention interventions. This unprecedented effort to scale-up malaria interventions is likely improving child survival and will likely contribute to meeting Millennium Development Goal (MDG) 4 to reduce the < 5 mortality rate by two thirds between 1990 and 2015.

The global pipeline of new medicines for the control and elimination of malaria

Abstract: Over the past decade, there has been a transformation in the portfolio of medicines to combat malaria. New fixed-dose artemisinin combination therapy is available, with four different types having received approval from Stringent Regulatory Authorities or the World Health Organization (WHO). However, there is still scope for improvement. The Malaria Eradication Research agenda identified several gaps in the current portfolio. Simpler regimens, such as a single-dose cure are needed, compared with the current three-day treatment. In addition, new medicines that prevent transmission and also relapse are needed, but with better safety profiles than current medicines. There is also a big opportunity for new medicines to prevent reinfection and to provide chemoprotection. This study reviews the global portfolio of new medicines in development against malaria, as of the summer of 2012. Cell-based phenotypic screening, and ‘fast followers’ of clinically validated classes, mean that there are now many new classes of molecules starting in clinical development, especially for the blood stages of malaria. There remain significant gaps for medicines blocking transmission, preventing relapse, and long-duration molecules for chemoprotection. The nascent pipeline of new medicines is significantly stronger than five years ago. However, there are still risks ahead in clinical development and sustainable funding of clinical studies is vital if this early promise is going to be delivered.

Attractive toxic sugar bait (ATSB) methods decimate populations of Anopheles malaria vectors in arid environments regardless of the local availability of favoured sugar-source blossoms

Abstract: Attractive toxic sugar bait (ATSB) methods are a new and promising "attract and kill" strategy for mosquito control. Sugar-feeding female and male mosquitoes attracted to ATSB solutions, either sprayed on plants or in bait stations, ingest an incorporated low-risk toxin such as boric acid and are killed. This field study in the arid malaria-free oasis environment of Israel compares how the availability of a primary natural sugar source for Anopheles sergentii mosquitoes: flowering Acacia raddiana trees, affects the efficacy of ATSB methods for mosquito control. A 47-day field trial was conducted to compare impacts of a single application of ATSB treatment on mosquito densities and age structure in isolated uninhabited sugar-rich and sugar-poor oases relative to an untreated sugar-rich oasis that served as a control. ATSB spraying on patches of non-flowering vegetation around freshwater springs reduced densities of female An. sergentii by 95.2% in the sugar-rich oasis and 98.6% in the sugar-poor oasis; males in both oases were practically eliminated. It reduced daily survival rates of female An. sergentii from 0.77 to 0.35 in the sugar-poor oasis and from 0.85 to 0.51 in the sugar-rich oasis. ATSB treatment reduced the proportion of older more epidemiologically dangerous mosquitoes (three or more gonotrophic cycles) by 100% and 96.7%, respectively, in the sugar-poor and sugar-rich oases. Overall, malaria vectorial capacity was reduced from 11.2 to 0.0 in the sugar-poor oasis and from 79.0 to 0.03 in the sugar-rich oasis. Reduction in vector capacity to negligible levels days after ATSB application in the sugar-poor oasis, but not until after 2 weeks in the sugar-rich oasis, show that natural sugar sources compete with the applied ATSB solutions. While readily available natural sugar sources delay ATSB impact, they do not affect overall outcomes because the high frequency of sugar feeding by mosquitoes has an accumulating effect on the probability they will be attracted to and killed by ATSB methods. Operationally, ATSB methods for malaria vector control are highly effective in arid environments regardless of competitive, highly attractive natural sugar sources in their outdoor environment.

Human movement data for malaria control and elimination strategic planning

Abstract: Recent increases in funding for malaria control have led to the reduction in transmission in many malaria endemic countries, prompting the national control programmes of 36 malaria endemic countries to set elimination targets. Accounting for human population movement (HPM) in planning for control, elimination and post-elimination surveillance is important, as evidenced by previous elimination attempts that were undermined by the reintroduction of malaria through HPM. Strategic control and elimination planning, therefore, requires quantitative information on HPM patterns and the translation of these into parasite dispersion. HPM patterns and the risk of malaria vary substantially across spatial and temporal scales, demographic and socioeconomic sub-groups, and motivation for travel, so multiple data sets are likely required for quantification of movement. While existing studies based on mobile phone call record data combined with malaria transmission maps have begun to address within-country HPM patterns, other aspects remain poorly quantified despite their importance in accurately gauging malaria movement patterns and building control and detection strategies, such as cross-border HPM, demographic and socioeconomic stratification of HPM patterns, forms of transport, personal malaria protection and other factors that modify malaria risk. A wealth of data exist to aid filling these gaps, which, when combined with spatial data on transport infrastructure, traffic and malaria transmission, can answer relevant questions to guide strategic planning. This review aims to (i) discuss relevant types of HPM across spatial and temporal scales, (ii) document where datasets exist to quantify HPM, (iii) highlight where data gaps remain and (iv) briefly put forward methods for integrating these datasets in a Geographic Information System (GIS) framework for analysing and modelling human population and Plasmodium falciparum malaria infection movements.

Understanding the clinical spectrum of complicated Plasmodium vivax malaria: a systematic review on the contributions of the Brazilian literature

Abstract: The resurgence of the malaria eradication agenda and the increasing number of severe manifestation reports has contributed to a renewed interested in the Plasmodium vivax infection. It is the most geographically widespread parasite causing human malaria, with around 2.85 billion people living under risk of infection. The Brazilian Amazon region reports more than 50% of the malaria cases in Latin America and since 1990 there is a marked predominance of this species, responsible for 85% of cases in 2009. However, only a few complicated cases of P. vivax have been reported from this region. A systematic review of the Brazilian indexed and non-indexed literature on complicated cases of vivax malaria was performed including published articles, masters' dissertations, doctoral theses and national congresses' abstracts. The following information was retrieved: patient characteristics (demographic, presence of co-morbidities and, whenever possible, associated genetic disorders); description of each major clinical manifestation. As a result, 27 articles, 28 abstracts from scientific events' annals and 13 theses/dissertations were found, only after 1987. Most of the reported information was described in small case series and case reports of patients from all the Amazonian states, and also in travellers from Brazilian non-endemic areas. The more relevant clinical complications were anaemia, thrombocytopaenia, jaundice and acute respiratory distress syndrome, present in all age groups, in addition to other more rare clinical pictures. Complications in pregnant women were also reported. Acute and chronic co-morbidities were frequent, however death was occasional. Clinical atypical cases of malaria are more frequent than published in the indexed literature, probably due to a publication bias. In the Brazilian Amazon (considered to be a low to moderate intensity area of transmission), clinical data are in accordance with the recent findings of severity described in diverse P. vivax endemic areas (especially anaemia in Southeast Asia), however in this region both children and adults are affected. Finally, gaps of knowledge and areas for future research are opportunely pointed out.

In vivo susceptibility of Plasmodium falciparum to artesunate in Binh Phuoc Province, Vietnam

Abstract: Background: By 2009, there were worrying signs from western Cambodia that parasitological responses to artesunate-containing treatment regimens for uncomplicated Plasmodium falciparum malaria were slower than elsewhere which suggested the emergence of artemisinin resistance. Vietnam shares a long land border with Cambodia with a large number of migrants crossing it on a daily basis. Therefore, there is an urgent need to investigate whether there is any evidence of a change in the parasitological response to the artemisinin derivatives in Vietnam. Methods: From August 2010 to May 2011, a randomized controlled clinical trial in uncomplicated falciparum malaria was conducted to compare two doses of artesunate (AS) (2mg/kg/day versus 4 mg/kg/day for three days) followed by dihydroartemisinin-piperaquine (DHA-PPQ) and a control arm of DHA-PPQ. The goal was characterization of the current efficacy of artesunate in southern Vietnam. The primary endpoint of this study was the parasite clearance half-life; secondary endpoints included the parasite reduction ratios at 24 and 48 hours and the parasite clearance time. Results: 166 patients were recruited into the study. The median parasite clearance half-lives were 3.54 (AS 2mg/kg), 2.72 (AS 4mg/kg), and 2.98 hours (DHA-PPQ) (p=0.19). The median parasite-reduction ratio at 24 hours was 48 in the AS 2mg/kg group compared with 212 and 113 in the other two groups, respectively (p=0.02). The proportions of patients with a parasite clearance time of >72 hours for AS 2mg/kg, AS 4mg/kg and DHA-PPQ were 27%, 27%, and 22%, respectively. Early treatment failure occurred in two (4%) and late clinical failure occurred in one (2%) of the 55 patients in the AS 2mg/kg group, as compared with none in the other two study arms. The PCR-corrected adequate clinical and parasitological response (APCR) rates in the three groups were 94%, 100%, and 100% (p=0.04). Conclusions: This study demonstrated faster P. falciparum parasite clearance in southern Vietnam than in western Cambodia but slower clearance in comparison with historical data from Vietnam. Further studies to determine whether this represents the emergence of artemisinin resistance in this area are needed. Currently, the therapeutic response to DHA-PPQ remains satisfactory in southern Vietnam.

Management of imported malaria in Europe

Abstract: In this position paper, the European Society for Clinical Microbiology and Infectious Diseases, Study Group on Clinical Parasitology, summarizes main issues regarding the management of imported malaria cases. Malaria is a rare diagnosis in Europe, but it is a medical emergency. A travel history is the key to suspecting malaria and is mandatory in patients with fever. There are no specific clinical signs or symptoms of malaria although fever is seen in almost all non-immune patients. Migrants from malaria endemic areas may have few symptoms. Malaria diagnostics should be performed immediately on suspicion of malaria and the gold- standard is microscopy of Giemsa-stained thick and thin blood films. A Rapid Diagnostic Test (RDT) may be used as an initial screening tool, but does not replace urgent microscopy which should be done in parallel. Delays in microscopy, however, should not lead to delayed initiation of appropriate treatment. Patients diagnosed with malaria should usually be hospitalized. If outpatient management is preferred, as is the practice in some European centres, patients must usually be followed closely (at least daily) until clinical and parasitological cure. Treatment of uncomplicated Plasmodium falciparum malaria is either with oral artemisinin combination therapy (ACT) or with the combination atovaquone/proguanil. Two forms of ACT are available in Europe: artemether/lumefantrine and dihydroartemisinin/piperaquine. ACT is also effective against Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi, but these species can be treated with chloroquine. Treatment of persistent liver forms in P. vivax and P. ovale with primaquine is indicated after excluding glucose 6 phosphate dehydrogenase deficiency. There are modified schedules and drug options for the treatment of malaria in special patient groups, such as children and pregnant women. The potential for drug interactions and the role of food in the absorption of anti-malarials are important considerations in the choice of treatment. Complicated malaria is treated with intravenous artesunate resulting in a much more rapid decrease in parasite density compared to quinine. Patients treated with intravenous artesunate should be closely monitored for haemolysis for four weeks after treatment. There is a concern in some countries about the lack of artesunate produced according to Good Manufacturing Practice (GMP).

Change in composition of the Anopheles gambiae complex and its possible implications for the transmission of malaria and lymphatic filariasis in north-eastern Tanzania

Abstract: A dramatic decline in the incidence of malaria due to Plasmodium falciparum infection in coastal East Africa has recently been reported to be paralleled (or even preceded) by an equally dramatic decline in malaria vector density, despite absence of organized vector control. As part of investigations into possible causes for the change in vector population density, the present study analysed the Anopheles gambiae s.l. sibling species composition in north-eastern Tanzania. The study was in two parts. The first compared current species complex composition in freshly caught An. gambiae s.l. complex from three villages to the composition reported from previous studies carried out 2–4 decades ago in the same villages. The second took advantage of a sample of archived dried An. gambiae s.l. complex specimens collected regularly from a fourth study village since 2005. Both fresh and archived dried specimens were identified to sibling species of the An. gambiae s.l. complex by PCR. The same specimens were moreover examined for Plasmodium falciparum and Wuchereria bancrofti infection by PCR. As in earlier studies, An. gambiae s.s., Anopheles merus and Anopheles arabiensis were identified as sibling species found in the area. However, both study parts indicated a marked change in sibling species composition over time. From being by far the most abundant in the past An. gambiae s.s. was now the most rare, whereas An. arabiensis had changed from being the most rare to the most common. P. falciparum infection was rarely detected in the examined specimens (and only in An. arabiensis) whereas W. bancrofti infection was prevalent and detected in all three sibling species. The study indicates that a major shift in An. gambiae s.l. sibling species composition has taken place in the study area in recent years. Combined with the earlier reported decline in overall malaria vector density, the study suggests that this decline has been most marked for An. gambiae s.s., and least for An. arabiensis, leading to current predominance of the latter. Due to differences in biology and vectorial capacity of the An. gambiae s.l. complex the change in sibling species composition will have important implications for the epidemiology and control of malaria and lymphatic filariasis in the study area.

Rationale for recommending a lower dose of primaquine as a Plasmodium falciparum gametocytocide in populations where G6PD deficiency is common

Abstract: In areas of low malaria transmission, it is currently recommended that a single dose of primaquine (0.75 mg base/kg; 45 mg adult dose) be added to artemisinin combination treatment (ACT) in acute falciparum malaria to block malaria transmission. Review of studies of transmission-blocking activity based on the infectivity of patients or volunteers to anopheline mosquitoes, and of haemolytic toxicity in glucose 6-dehydrogenase (G6PD) deficient subjects, suggests that a lower primaquine dose (0.25 mg base/kg) would be safer and equally effective. This lower dose could be deployed together with ACTs without G6PD testing wherever use of a specific gametocytocide is indicated.

Review of pyronaridine anti-malarial properties and product characteristics.

Abstract: Pyronaridine was synthesized in 1970 at the Institute of Chinese Parasitic Disease and has been used in China for over 30 years for the treatment of malaria. Pyronaridine has high potency against Plasmodium falciparum, including chloroquine-resistant strains. Studies in various animal models have shown pyronaridine to be effective against strains resistant to other anti-malarials, including chloroquine. Resistance to pyronaridine appears to emerge slowly and is further retarded when pyronaridine is used in combination with other anti-malarials, in particular, artesunate. Pyronaridine toxicity is generally less than that of chloroquine, though evidence of embryotoxicity in rodents suggests use with caution in pregnancy. Clinical pharmacokinetic data for pyronaridine indicates an elimination T1/2 of 13.2 and 9.6 days, respectively, in adults and children with acute uncomplicated falciparum and vivax malaria in artemisinin-combination therapy. Clinical data for mono or combined pyronaridine therapy show excellent anti-malarial effects against P. falciparum and studies of combination therapy also show promise against Plasmodium vivax. Pyronaridine has been developed as a fixed dose combination therapy, in a 3:1 ratio, with artesunate for the treatment of acute uncomplicated P. falciparum malaria and blood stage P. vivax malaria with the name of Pyramax® and has received Positive Opinion by European Medicines Agency under the Article 58 procedure.

Trends in malaria cases, hospital admissions and deaths following scale-up of anti-malarial interventions, 2000–2010, Rwanda

Abstract: To control malaria, the Rwandan government and its partners distributed insecticide-treated nets (ITN) and made artemisinin-based combination therapy (ACT) widely available from 2005 onwards. The impact of these interventions on malaria cases, admissions and deaths was assessed using data from district hospitals and household surveys. District records of ITN and ACT distribution were reviewed. Malaria and non-malaria indictors in 30 district hospitals were ascertained from surveillance records. Trends in cases, admissions and deaths for 2000 to 2010 were assessed by segmented log-linear regression, adjusting the effect size for time trends during the pre-intervention period, 2000–2005. Changes were estimated by comparing trends in post-intervention (2006–2010) with that of pre-intervention (2000–2005) period. All-cause deaths in children under-five in household surveys of 2005 and 2010 were also reviewed to corroborate with the trends of deaths observed in hospitals. The proportion of the population potentially protected by ITN increased from nearly zero in 2005 to 38% in 2006, and 76% in 2010; no major health facility stock-outs of ACT were recorded following their introduction in 2006. In district hospitals, after falling during 2006–2008, confirmed malaria cases increased in 2009 coinciding with decreased potential ITN coverage and declined again in 2010 following an ITN distribution campaign. For all age groups, from the pre-intervention period, microscopically confirmed cases declined by 72%, (95% Confidence Interval [CI], 12-91%) in 2010, slide positivity rate declined 58%, (CI, 47%–68%), malaria inpatient cases declined 76% (CI, 49%–88%); and malaria deaths declined 47% (CI, 47%–81%). In children below five years of age, malaria inpatients decreased 82% (CI, 61%-92%) and malaria hospital deaths decreased 77% (CI, 40%–91%). Concurrently, outpatient cases, admissions and deaths due to non-malaria diseases in all age groups either increased or remained unchanged. Rainfall and temperature remained favourable for malaria transmission. The annual all-cause mortality in children under-five in household surveys declined from 152 per 1,000 live births during 2001–2005, to 76 per 1,000 live births in 2006–2010 (55% decline). The five-year cumulative number of all-cause deaths in hospital declined 28% (8,051 to 5,801) during the same period. A greater than 50% decline in confirmed malaria cases, admissions and deaths at district hospitals in Rwanda since 2005 followed a marked increase in ITN coverage and use of ACT. The decline occurred among both children under-five and in those five years and above, while hospital utilization increased and suitable conditions for malaria transmission persisted. Declines in malaria indicators in children under 5 years were more striking than in the older age groups. The resurgence in cases associated with decreased ITN coverage in 2009 highlights the need for sustained high levels of anti-malarial interventions in Rwanda and other malaria endemic countries.

Larval food quantity affects development time, survival and adult biological traits that influence the vectorial capacity of Anopheles darlingi under laboratory conditions

Abstract: The incidence of malaria in the Amazon is seasonal and mosquito vectorial capacity parameters, including abundance and longevity, depend on quantitative and qualitative aspects of the larval diet. Anopheles darlingi is a major malaria vector in the Amazon, representing >95% of total Anopheles population present in the Porto Velho region. Despite its importance in the transmission of the Plasmodium parasite, knowledge of the larval biology and ecology is limited. Studies regarding aspects of adult population ecology are more common than studies on larval ecology. However, in order develop effective control strategies and laboratory breeding conditions for this species, more data on the factors affecting vector biology is needed. The aim of the present study is to assess the effects of larval food quantity on the vectorial capacity of An. darling under laboratory conditions. Anopheles darlingi was maintained at 28°C, 80% humidity and exposed to a daily photoperiod of 12 h. Larvae were divided into three experimental groups that were fed either a low, medium, or high food supply (based on the food amounts consumed by other species of culicids). Each experiment was replicated for six times. A cohort of adults were also exposed to each type of diet and assessed for several biological characteristics (e.g. longevity, bite frequency and survivorship), which were used to estimate the vectorial capacity of each experimental group. The group supplied with higher food amounts observed a reduction in development time while larval survival increased. In addition to enhanced longevity, increasing larval food quantity was positively correlated with increasing frequency of bites, longer blood meal duration and wing length, resulting in greater vectorial capacity. However, females had greater longevity than males despite having smaller wings. Overall, several larval and adult biological traits were significantly affected by larval food availability. Greater larval food supply led to enhance larval and production and larger mosquitoes with longer longevity and higher biting frequency. Thus, larval food availability can alter important biological traits that influence the vectorial capacity of An. darlingi.

Remote sensing-based time series models for malaria early warning in the highlands of Ethiopia

Abstract: Malaria is one of the leading public health problems in most of sub-Saharan Africa, particularly in Ethiopia. Almost all demographic groups are at risk of malaria because of seasonal and unstable transmission of the disease. Therefore, there is a need to develop malaria early-warning systems to enhance public health decision making for control and prevention of malaria epidemics. Data from orbiting earth-observing sensors can monitor environmental risk factors that trigger malaria epidemics. Remotely sensed environmental indicators were used to examine the influences of climatic and environmental variability on temporal patterns of malaria cases in the Amhara region of Ethiopia. In this study seasonal autoregressive integrated moving average (SARIMA) models were used to quantify the relationship between malaria cases and remotely sensed environmental variables, including rainfall, land-surface temperature (LST), vegetation indices (NDVI and EVI), and actual evapotranspiration (ETa) with lags ranging from one to three months. Predictions from the best model with environmental variables were compared to the actual observations from the last 12 months of the time series. Malaria cases exhibited positive associations with LST at a lag of one month and positive associations with indicators of moisture (rainfall, EVI and ETa) at lags from one to three months. SARIMA models that included these environmental covariates had better fits and more accurate predictions, as evidenced by lower AIC and RMSE values, than models without environmental covariates. Malaria risk indicators such as satellite-based rainfall estimates, LST, EVI, and ETa exhibited significant lagged associations with malaria cases in the Amhara region and improved model fit and prediction accuracy. These variables can be monitored frequently and extensively across large geographic areas using data from earth-observing sensors to support public health decisions.

CYP450 phenotyping and accurate mass identification of metabolites of the 8-aminoquinoline, anti-malarial drug primaquine

Abstract: Background The 8-aminoquinoline (8AQ) drug primaquine (PQ) is currently the only approved drug effective against the persistent liver stage of the hypnozoite forming strains Plasmodium vivax and Plasmodium ovale as well as Stage V gametocytes of Plasmodium falciparum. To date, several groups have investigated the toxicity observed in the 8AQ class, however, exact mechanisms and/or metabolic species responsible for PQ’s haemotoxic and anti-malarial properties are not fully understood.

Performance of community health workers under integrated community case management of childhood illnesses in eastern Uganda

Abstract: Curative interventions delivered by community health workers (CHWs) were introduced to increase access to health services for children less than five years and have previously targeted single illnesses. However, CHWs in the integrated community case management of childhood illnesses strategy adopted in Uganda in 2010 will manage multiple illnesses. There is little documentation about the performance of CHWs in the management of multiple illnesses. This study compared the performance of CHWs managing malaria and pneumonia with performance of CHWs managing malaria alone in eastern Uganda and the factors influencing performance. A mixed methods study was conducted among 125 CHWs providing either dual malaria and pneumonia management or malaria management alone for children aged four to 59 months. Performance was assessed using knowledge tests, case scenarios of sick children, review of CHWs’ registers, and observation of CHWs in the dual management arm assessing respiratory symptoms. Four focus group discussions with CHWs were also conducted. CHWs in the dual- and single-illness management arms had similar performance with respect to: overall knowledge of malaria (dual 72%, single 70%); eliciting malaria signs and symptoms (50% in both groups); prescribing anti-malarials based on case scenarios (82% dual, 80% single); and correct prescription of anti-malarials from record reviews (dual 99%, single 100%). In the dual-illness arm, scores for malaria and pneumonia differed on overall knowledge (72% vs 40%, p < 0.001); and correct doses of medicines from records (100% vs 96%, p < 0.001). According to records, 82% of the children with fast breathing had received an antibiotic. From observations 49% of CHWs counted respiratory rates within five breaths of the physician (gold standard) and 75% correctly classified the children. The factors perceived to influence CHWs’ performance were: community support and confidence, continued training, availability of drugs and other necessary supplies, and cooperation from formal health workers. CHWs providing dual-illness management handled malaria cases as well as CHWs providing single-illness management, and also performed reasonably well in the management of pneumonia. With appropriate training that emphasizes pneumonia assessment, adequate supervision, and provision of drugs and necessary supplies, CHWs can provide integrated treatment for malaria and pneumonia.

Understanding the population genetics of Plasmodium vivax is essential for malaria control and elimination

Abstract: Traditionally, infection with Plasmodium vivax was thought to be benign and self-limiting, however, recent evidence has demonstrated that infection with P. vivax can also result in severe illness and death. Research into P. vivax has been relatively neglected and much remains unknown regarding the biology, pathogenesis and epidemiology of this parasite. One of the fundamental factors governing transmission and immunity is parasite diversity. An understanding of parasite population genetic structure is necessary to understand the epidemiology, diversity, distribution and dynamics of natural P. vivax populations. In addition, studying the population structure of genes under immune selection also enables investigation of the dynamic interplay between transmission and immunity, which is crucial for vaccine development. A lack of knowledge regarding the transmission and spread of P. vivax has been particularly highlighted in areas where malaria control and elimination programmes have made progress in reducing the burden of Plasmodium falciparum, yet P. vivax remains as a substantial obstacle. With malaria elimination back on the global agenda, mapping of global and local P. vivax population structure is essential prior to establishing goals for elimination and the roll-out of interventions. A detailed knowledge of the spatial distribution, transmission and clinical burden of P. vivax is required to act as a benchmark against which control targets can be set and measured. This paper presents an overview of what is known and what is yet to be fully understood regarding P. vivax population genetics, as well as the importance and application of P. vivax population genetics studies.

Is dengue and malaria co-infection more severe than single infections? A retrospective matched-pair study in French Guiana

Abstract: Dengue and malaria are two major arthropod-borne infections in tropical areas, but dual infections were only described for the first time in 2005. Reports of these concomitant infections are scarce and there is no evidence of more severe clinical and biological pictures than single infections. To compare co-infections to dengue alone and malaria alone, a retrospective matched-pair study was conducted between 2004 and 2010 among patients admitted in the emergency department of Cayenne hospital, French Guiana. 104 dengue and malaria co-infection cases were identified during the study period and 208 individuals were matched in two comparison groups: dengue alone and malaria alone. In bivariate analysis, co-infection clinical picture was more severe than separated infections, in particular using the severe malaria WHO criteria. In multivariate analysis, independent factors associated with co-infection versus dengue were: masculine gender, CRP level > 50 mg/L, thrombocytopaenia < 50 109/L, and low haematocrit <36% and independent factors significantly associated with co-infections versus malaria were red cells transfusion, low haematocrit < 36%, thrombocytopaenia < 50 109/L and low Plasmodium parasitic load < 0.001%. In the present study, dengue and malaria co-infection clinical picture seems to be more severe than single infections in French Guiana, with a greater risk of deep thrombocytopaenia and anaemia.

Deaths due to Plasmodium knowlesi malaria in Sabah, Malaysia: association with reporting as Plasmodium malariae and delayed parenteral artesunate

Abstract: Background: The simian parasite Plasmodium knowlesi is recognized as a common cause of severe and fatal human malaria in Sabah, Malaysia, but is morphologically indistinguishable from and still commonly reported as Plasmodium malariae, despite the paucity of this species in Sabah. Since December 2008 Sabah Department of Health has recommended intravenous artesunate and referral to a general hospital for all severe malaria cases of any species. This paper reviews all malaria deaths in Sabah subsequent to the introduction of these measures. Reporting of malaria deaths in Malaysia is mandatory. Methods: Details of reported malaria deaths during 2010-2011 were reviewed to determine the proportion of each Plasmodium species. Demographics, clinical presentations and management of severe malaria caused by each species were compared. Results: Fourteen malaria deaths were reported, comprising seven Plasmodium falciparum, six P. knowlesi and one Plasmodium vivax (all PCR-confirmed). Of the six P. knowlesi deaths, five were attributable to knowlesi malaria and one was attributable to P. knowlesi-associated enterobacter sepsis. Patients with directly attributable P. knowlesi deaths (N=5) were older than those with P. falciparum (median age 51 [IQR 50-65] vs 22 [IQR 9-55] years, p=0.06). Complications in fatal P. knowlesi included respiratory distress (N=5, 100%), hypotension (N=4, 80%), and renal failure (N=4, 80%). All patients with P. knowlesi were reported as P. malariae by microscopy. Only two of five patients with severe knowlesi malaria on presentation received immediate parenteral anti-malarial treatment. The patient with P. vivax-associated severe illness did not receive parenteral treatment. In contrast six of seven patients with severe falciparum malaria received immediate parenteral treatment. Conclusion: Plasmodium knowlesi was responsible, either directly or through gram-negative bacteraemia, for almost half of malaria deaths in Sabah. Patients with severe non-falciparum malaria were less likely to receive immediate parenteral therapy. This highlights the need in Sabah for microscopically diagnosed P. malariae to be reported as P. knowlesi to improve recognition and management of this potentially fatal species. Clinicians need to be better informed of the potential for severe and fatal malaria from non-falciparum species, and the need to treat all severe malaria with immediate intravenous artesunate.

The extravascular compartment of the bone marrow: a niche for Plasmodium falciparum gametocyte maturation?

Abstract: Background: Plasmodium falciparum immature gametocytes accumulate in the bone marrow, but their exact location in this tissue remains unclear. Methods: The stage and deposition pattern of gametocytes was analysed on histological sections of a bone marrow sample collected in a patient with subacute P. falciparum malaria. Results: A majority (89%) of immature stages II to IV gametocytes and a minority (29%) of mature stage V gametocytes were observed in extravascular spaces. Discussion and conclusion: These observations represent a valuable step towards understanding sequestration patterns of P. falciparum gametocytes and may ultimately lead to novel transmission-blocking interventions.

Population genetic structure of Plasmodium falciparum across a region of diverse endemicity in West Africa

Abstract: Malaria parasite population genetic structure varies among areas of differing endemicity, but this has not been systematically studied across Plasmodium falciparum populations in Africa where most infections occur. Ten polymorphic P. falciparum microsatellite loci were genotyped in 268 infections from eight locations in four West African countries (Republic of Guinea, Guinea Bissau, The Gambia and Senegal), spanning a highly endemic forested region in the south to a low endemic Sahelian region in the north. Analysis was performed on proportions of mixed genotype infections, genotypic diversity among isolates, multilocus standardized index of association, and inter-population differentiation. Each location had similar levels of pairwise genotypic diversity among isolates, although there were many more mixed parasite genotype infections in the south. Apart from a few isolates that were virtually identical, the multilocus index of association was not significant in any population. Genetic differentiation between populations was low (most pairwise FST values < 0.03), and an overall test for isolation by distance was not significant. Although proportions of mixed genotype infections varied with endemicity as expected, population genetic structure was similar across the diverse sites. Very substantial reduction in transmission would be needed to cause fragmented or epidemic sub-structure in this region.

Prevalence of malaria infection in Butajira area, south-central Ethiopia

Abstract: In 2005, the Ethiopian government launched a massive expansion of the malaria prevention and control programme. The programme was aimed mainly at the reduction of malaria in populations living below 2,000 m above sea level. Global warming has been implicated in the increase in the prevalence of malaria in the highlands. However, there is still a paucity of information on the occurrence of malaria at higher altitudes. The objective of this study was to estimate malaria prevalence in highland areas of south-central Ethiopia, designated as the Butajira area. Using a multi-stage sampling technique, 750 households were selected. All consenting family members were examined for malaria parasites in thick and thin blood smears. The assessment was repeated six times for two years (October 2008 to June 2010). In total, 19,207 persons were examined in the six surveys. From those tested, 178 slides were positive for malaria, of which 154 (86.5%) were positive for Plasmodium vivax and 22 (12.4%) for Plasmodium falciparum; the remaining two (1.1%) showed mixed infections of Plasmodium falciparum and Plasmodium vivax. The incidence of malaria was higher after the main rainy season, both in lower lying and in highland areas. The incidence in the highlands was low and similar for all age groups, whereas in the lowlands, malaria occurred mostly in those of one to nine years of age. This study documented a low prevalence of malaria that varied with season and altitudinal zone in a highland-fringe area of Ethiopia. Most of the malaria infections were attributable to Plasmodium vivax.

Treatment outcome of intravenous artesunate in patients with severe malaria in the Netherlands and Belgium

Abstract: Intravenous (IV) artesunate is the treatment of choice for severe malaria. In Europe, however, no GMP-manufactured product is available and treatment data in European travellers are scarce. Fortunately, artesunate became available in the Netherlands and Belgium through a named patient programme. This is the largest case series of artesunate treated patients with severe malaria in Europe. Hospitalized patients treated with IV artesunate between November 2007 and December 2010 in the Netherlands and Belgium were retrospectively evaluated. Patient characteristics, treatment and clinical outcome were recorded on a standardized form and mortality, parasite clearance times and the occurrence of adverse events were evaluated. Of the 68 treated patients, including 55 with severe malaria, two patients died (2/55 = 3.6%). The mean time to 50% parasite clearance (PCT50), 90% and 99% were 4.4 hours (3.9 - 5.2), 14.8 hours (13.0 - 17.2), and 29.5 hours (25.9 - 34.4) respectively. Artesunate was well tolerated. However, an unusual form of haemolytic anaemia was observed in seven patients. The relationship with artesunate remains uncertain. Data from the named patient programme demonstrate that IV artesunate is effective and well-tolerated in European travellers lacking immunity. However, increased attention needs to be paid to the possible development of haemolytic anaemia 2-3 weeks after start of treatment. Treatment of IV artesunate should be limited to the period that IV treatment is required and should be followed by a full oral course of an appropriate anti-malarial drug.

Increasing incidence of malaria in children despite insecticide-treated bed nets and prompt anti-malarial therapy in Tororo, Uganda

Abstract: Background The burden of malaria has decreased in parts of Africa following the scaling up of control interventions. However, similar data are limited from high transmission settings.