Showing papers in "Malaria Journal in 2016"

The need for operational research and capacity-building in support of the Global Technical Strategy for Malaria 2016–2030

Abstract: The Global Technical Strategy for Malaria 2016–2030 was adopted by the 68th World Health Assembly in May 2015. It emphasizes the importance of scaling up malaria control responses and moving towards elimination [1]. It is anticipated that such scale-up will help countries reduce and, eventually, eliminate the human suffering caused by malaria as well as contribute more broadly to the achievement of the Sustainable Development Goals. The Global Technical Strategy consists of three main pillars, underpinned by two supporting elements (Fig. 1). The first of the supporting elements, harnessing innovation and expanding research, is also recognized as critical in the global control and elimination of other diseases, such as tuberculosis [2]. It is recognized that operational and implementation research are needed to ensure that existing interventions are applied effectively and efficiently in different contexts and, as new interventions become available, to ensure that innovation is deployed appropriately and to maximum effect. Fig. 1 The World Health Organization Global Technical Strategy for Malaria 2016–2030 In 2011, the malERA Consultative Group on Health Systems and Operational Research published a Research Agenda for Malaria Eradication: Health Systems and Operational Research [3]. The WHO Global Malaria Programme (GMP) has more recently published the report of a multi-partner meeting that discussed operational challenges for malaria elimination, identified priority operational research questions and recommended ways forward [4]. Other organizations have produced similar lists of operational research priorities [5]. There is no shortage of recommendations on the priorities for operational research and most authors consider operational research to be relatively straightforward and, if using routinely-collected data, inexpensive. However, a recent review of the literature on malaria control and elimination between 2008 and 2013 (15,886 articles) revealed that less than 4 % met the definition of operational research. Of these articles only 19 (3.8 %) were related to malaria surveillance [6]. It would seem that operational research, though recognized as critically important to the success of global strategies for malaria control and elimination, is not so commonly undertaken or at least not so commonly published. Indeed, it could be argued that the difference between these two is academic since unpublished research is unlikely to inform widespread scaling up of malaria activities. Why is so little operational research done when much of it would be straightforward and inexpensive and could be done within the context of routine malaria programme activities? It is a long-standing problem. In 2007, a report of the Global Fund’s Technical Review Panel noted that operational research was often absent or inadequately elaborated in proposals [7]. The report further stated that proposals clearly described bottlenecks to progress and that these provide the basis for operational research questions that seem obvious but were not proposed. How can operational research be promoted to support the new Global Technical Strategy for Malaria? A good start would be to look at the recent experiences of other disease control programmes. In 2011, the WHO listed its priorities in operational research to improve tuberculosis care and control. One of the five priority areas for operational research was capacity-building for operational research. Key questions included: what are the existing models of operational health research capacity? What is the impact of existing training models in terms of products, outputs and outcomes? How to ensure sustainable operational research capacity at the national level? 4 years later, its Global Action Framework for TB Research described some of the lessons from this exercise and has provided case studies of how operational research capacity has been built in public health programmes in low-income and middle-income countries [2]. One of these case studies was the Structured Operational Research and Training Initiative (SORT IT) a global partnership-based initiative led by the Special Programme for Research and Training in Tropical Diseases (TDR) based at WHO [8]. Started in 2012, SORT IT aims to support countries to: conduct operational research around their own priorities, build adequate and sustainable operational research capacity within public health programmes; and make evidence-informed improvements to programme implementation. More than 400 health workers in 80 countries have been trained through SORT IT to date. Over the course of 1 year, participating health workers learn the skills required to develop operational research questions, protocols, data capture and analysis instruments and to publish their work. Over 90 % of participants publish their research in the peer reviewed literature and many go on to become facilitators in further SORT IT training courses. The training is currently being delivered in English, Russian and Spanish, with the transition into French underway. The model has been recognized as a reliable way to build the much-needed research capacity in public health programmes in LMICs [9, 10]. Having its roots in a training course run by Medecins Sans Frontieres and the International Union Against Tuberculosis and Lung Diseases, that supported tuberculosis control, SORT IT is now delivering regional and national capacity-building for operational research in all WHO regions and in number of disease areas [11, 12]. In TDR-supported SORT IT Programmes, the core training course is embedded within broader capacity-building activities in knowledge management (research needs assessments and prioritization, dissemination of research findings and evidence-informed policy making). Efforts are also made to consolidate research capacity that has been built through SORT IT by providing participants with further research training and small research grants. In 2014, two research studies related to malaria elimination were supported by SORT IT [13, 14]. In 2015–16, in collaboration with the Global Malaria Programme and the WHO African Regional Office (AFRO), a SORT IT programme supported four malaria-eliminating countries in Southern Africa: Botswana, Namibia, South Africa and Swaziland. A Supplement of Malaria Journal is in preparation to feature research outputs of this SORT IT programme. It is hoped that this Supplement will encourage others to adopt approaches like SORT IT, conduct operational research while building research capacity in malaria programmes and make evidence-informed improvements to policy and practice. On the occasion of the 2016 World Malaria Day the authors would like to highlight both the need for, and the feasibility of, building operational research capacity in malaria programmes in low- and middle-income countries if the ambitions of the Global Technical Strategy for Malaria 2016–2030 are to be achieved.

Challenges for malaria elimination in Brazil

Abstract: Brazil currently contributes 42 % of all malaria cases reported in the Latin America and the Caribbean, a region where major progress towards malaria elimination has been achieved in recent years. In 2014, malaria burden in Brazil (143,910 microscopically confirmed cases and 41 malaria-related deaths) has reached its lowest levels in 35 years, Plasmodium falciparum is highly focal, and the geographic boundary of transmission has considerably shrunk. Transmission in Brazil remains entrenched in the Amazon Basin, which accounts for 99.5 % of the country’s malaria burden. This paper reviews major lessons learned from past and current malaria control policies in Brazil. A comprehensive discussion of the scientific and logistic challenges that may impact malaria elimination efforts in the country is presented in light of the launching of the Plan for Elimination of Malaria in Brazil in November 2015. Challenges for malaria elimination addressed include the high prevalence of symptomless and submicroscopic infections, emerging anti-malarial drug resistance in P. falciparum and Plasmodium vivax and the lack of safe anti-relapse drugs, the largely neglected burden of malaria in pregnancy, the need for better vector control strategies where Anopheles mosquitoes present a highly variable biting behaviour, human movement, the need for effective surveillance and tools to identify foci of infection in areas with low transmission, and the effects of environmental changes and climatic variability in transmission. Control actions launched in Brazil and results to come are likely to influence control programs in other countries in the Americas.

Spatially variable risk factors for malaria in a geographically heterogeneous landscape, western Kenya: an explorative study

Abstract: Large reductions in malaria transmission and mortality have been achieved over the last decade, and this has mainly been attributed to the scale-up of long-lasting insecticidal bed nets and indoor residual spraying with insecticides. Despite these gains considerable residual, spatially heterogeneous, transmission remains. To reduce transmission in these foci, researchers need to consider the local demographical, environmental and social context, and design an appropriate set of interventions. Exploring spatially variable risk factors for malaria can give insight into which human and environmental characteristics play important roles in sustaining malaria transmission. On Rusinga Island, western Kenya, malaria infection was tested by rapid diagnostic tests during two cross-sectional surveys conducted 3 months apart in 3632 individuals from 790 households. For all households demographic data were collected by means of questionnaires. Environmental variables were derived using Quickbird satellite images. Analyses were performed on 81 project clusters constructed by a traveling salesman algorithm, each containing 50–51 households. A standard linear regression model was fitted containing multiple variables to determine how much of the spatial variation in malaria prevalence could be explained by the demographic and environmental data. Subsequently, a geographically-weighted regression (GWR) was performed assuming non-stationarity of risk factors. Special attention was taken to investigate the effect of residual spatial autocorrelation and local multicollinearity. Combining the data from both surveys, overall malaria prevalence was 24 %. Scan statistics revealed two clusters which had significantly elevated numbers of malaria cases compared to the background prevalence across the rest of the study area. A multivariable linear model including environmental and household factors revealed that higher socioeconomic status, outdoor occupation and population density were associated with increased malaria risk. The local GWR model improved the model fit considerably and the relationship of malaria with risk factors was found to vary spatially over the island; in different areas of the island socio-economic status, outdoor occupation and population density were found to be positively or negatively associated with malaria prevalence. Identification of risk factors for malaria that vary geographically can provide insight into the local epidemiology of malaria. Examining spatially variable relationships can be a helpful tool in exploring which set of targeted interventions could locally be implemented. Supplementary malaria control may be directed at areas, which are identified as at risk. For instance, areas with many people that work outdoors at night may need more focus in terms of vector control. Trial registration: Trialregister.nl NTR3496—SolarMal, registered on 20 June 2012

Is Nigeria winning the battle against malaria? Prevalence, risk factors and KAP assessment among Hausa communities in Kano State

Abstract: Malaria is one of the most severe global public health problems worldwide, particularly in Africa, where Nigeria has the greatest number of malaria cases. This community-based study was designed to investigate the prevalence and risk factors of malaria and to evaluate the knowledge, attitudes, and practices (KAP) regarding malaria among rural Hausa communities in Kano State, Nigeria. A cross-sectional community-based study was conducted on 551 participants from five local government areas in Kano State. Blood samples were collected and examined for the presence of Plasmodium species by rapid diagnostic test (RDT), Giemsa-stained thin and thick blood films, and PCR. Moreover, demographic, socioeconomic, and environmental information as well as KAP data were collected using a pre-tested questionnaire. A total of 334 (60.6 %) participants were found positive for Plasmodium falciparum. The prevalence differed significantly by age group (p < 0.01), but not by gender or location. A multivariate analysis showed that malaria was associated significantly with being aged 12 years or older, having a low household family income, not using insecticide treated nets (ITNs), and having no toilets in the house. Overall, 95.6 % of the respondents had prior knowledge about malaria, and 79.7, 87.6 and 95.7 % of them knew about the transmission, symptoms, and prevention of malaria, respectively. The majority (93.4 %) of the respondents considered malaria a serious disease. Although 79.5 % of the respondents had at least one ITN in their household, utilization rate of ITNs was 49.5 %. Significant associations between the respondents’ knowledge concerning malaria and their age, gender, education, and household monthly income were reported. Malaria is still highly prevalent among rural Hausa communities in Nigeria. Despite high levels of knowledge and attitudes in the study area, significant gaps persist in appropriate preventive practices, particularly the use of ITNs. Innovative and Integrated control measures to reduce the burden of malaria should be identified and implemented in these communities. Community mobilization and health education regarding the importance of using ITNs to prevent malaria and save lives should be considered.

Whole genome sequencing of Plasmodium falciparum from dried blood spots using selective whole genome amplification

Abstract: Translating genomic technologies into healthcare applications for the malaria parasite Plasmodium falciparum has been limited by the technical and logistical difficulties of obtaining high quality clinical samples from the field. Sampling by dried blood spot (DBS) finger-pricks can be performed safely and efficiently with minimal resource and storage requirements compared with venous blood (VB). Here, the use of selective whole genome amplification (sWGA) to sequence the P. falciparum genome from clinical DBS samples was evaluated, and the results compared with current methods that use leucodepleted VB. Parasite DNA with high (>95%) human DNA contamination was selectively amplified by Phi29 polymerase using short oligonucleotide probes of 8–12 mers as primers. These primers were selected on the basis of their differential frequency of binding the desired (P. falciparum DNA) and contaminating (human) genomes. Using sWGA method, clinical samples from 156 malaria patients, including 120 paired samples for head-to-head comparison of DBS and leucodepleted VB were sequenced. Greater than 18-fold enrichment of P. falciparum DNA was achieved from DBS extracts. The parasitaemia threshold to achieve >5× coverage for 50% of the genome was 0.03% (40 parasites per 200 white blood cells). Over 99% SNP concordance between VB and DBS samples was achieved after excluding missing calls. The sWGA methods described here provide a reliable and scalable way of generating P. falciparum genome sequence data from DBS samples. The current data indicate that it will be possible to get good quality sequence on most if not all drug resistance loci from the majority of symptomatic malaria patients. This technique overcomes a major limiting factor in P. falciparum genome sequencing from field samples, and paves the way for large-scale epidemiological applications.

Spatially variable risk factors for malaria in a geographically heterogeneous landscape, western Kenya

Abstract: Background: Large reductions in malaria transmission and mortality have been achieved over the last decade, and this has mainly been attributed to the scale-up of long-lasting insecticidal bed nets and indoor residual spraying with insecticides Despite these gains considerable residual, spatially heterogeneous, transmission remains To reduce transmission in these foci, researchers need to consider the local demographical, environmental and social context, and design an appropriate set of interventions Exploring spatially variable risk factors for malaria can give insight into which human and environmental characteristics play important roles in sustaining malaria transmission Methods: On Rusinga Island, western Kenya, malaria infection was tested by rapid diagnostic tests during two cross-sectional surveys conducted 3 months apart in 3632 individuals from 790 households For all households demographic data were collected by means of questionnaires Environmental variables were derived using Quickbird satellite images Analyses were performed on 81 project clusters constructed by a traveling salesman algorithm, each containing 50-51 households A standard linear regression model was fitted containing multiple variables to determine how much of the spatial variation in malaria prevalence could be explained by the demographic and environmental data Subsequently, a geographically-weighted regression (GWR) was performed assuming non-stationarity of risk factors Special attention was taken to investigate the effect of residual spatial autocorrelation and local multicollinearity Results: Combining the data from both surveys, overall malaria prevalence was 24 % Scan statistics revealed two clusters which had significantly elevated numbers of malaria cases compared to the background prevalence across the rest of the study area A multivariable linear model including environmental and household factors revealed that higher socioeconomic status, outdoor occupation and population density were associated with increased malaria risk The local GWR model improved the model fit considerably and the relationship of malaria with risk factors was found to vary spatially over the island; in different areas of the island socio-economic status, outdoor occupation and population density were found to be positively or negatively associated with malaria prevalence Discussion: Identification of risk factors for malaria that vary geographically can provide insight into the local epidemiology of malaria Examining spatially variable relationships can be a helpful tool in exploring which set of targeted interventions could locally be implemented Supplementary malaria control may be directed at areas, which are identified as at risk For instance, areas with many people that work outdoors at night may need more focus in terms of vector control Trial registration: Trialregisternl NTR3496 - SolarMal, registered on 20 June 2012

The Contribution of Agricultural Insecticide use to Increasing Insecticide Resistance in African Malaria Vectors

Abstract: The fight against malaria is increasingly threatened by failures in vector control due to growing insecticide resistance. This review examines the recent primary research that addresses the putative relationship between agricultural insecticide use and trends in insecticide resistance. To do so, descriptive evidence offered by the new research was categorized, and additional factors that impact the relationship between agricultural insecticide use and observed insecticide resistance in malaria vectors were identified. In 23 of the 25 relevant recent publications from across Africa, higher resistance in mosquito populations was associated with agricultural insecticide use. This association appears to be affected by crop type, farm pest management strategy and urban development.

Most Outdoor Malaria Transmission by Behaviourally-resistant Anopheles Arabiensis is Mediated by Mosquitoes that have Previously been inside Houses.

Abstract: Anopheles arabiensis is stereotypical of diverse vectors that mediate residual malaria transmission globally, because it can feed outdoors upon humans or cattle, or enter but then rapidly exit houses without fatal exposure to insecticidal nets or sprays. Life histories of a well-characterized An. arabiensis population were simulated with a simple but process-explicit deterministic model and relevance to other vectors examined through sensitivity analysis. Where most humans use bed nets, two thirds of An. arabiensis blood feeds and half of malaria transmission events were estimated to occur outdoors. However, it was also estimated that most successful feeds and almost all (>98 %) transmission events are preceded by unsuccessful attempts to attack humans indoors. The estimated proportion of vector blood meals ultimately obtained from humans indoors is dramatically attenuated by availability of alternative hosts, or partial ability to attack humans outdoors. However, the estimated proportion of mosquitoes old enough to transmit malaria, and which have previously entered a house at least once, is far less sensitive to both variables. For vectors with similarly modest preference for cattle over humans and similar ability to evade fatal indoor insecticide exposure once indoors, >80 % of predicted feeding events by mosquitoes old enough to transmit malaria are preceded by at least one house entry event, so long as ≥40 % of attempts to attack humans occur indoors and humans outnumber cattle ≥4-fold. While the exact numerical results predicted by such a simple deterministic model should be considered only approximate and illustrative, the derived conclusions are remarkably insensitive to substantive deviations from the input parameter values measured for this particular An. arabiensis population. This life-history analysis, therefore, identifies a clear, broadly-important opportunity for more effective suppression of residual malaria transmission by An. arabiensis in Africa and other important vectors of residual transmission across the tropics. Improved control of predominantly outdoor residual transmission by An. arabiensis, and other modestly zoophagic vectors like Anopheles darlingi, which frequently enter but then rapidly exit from houses, may be readily achieved by improving existing technology for killing mosquitoes indoors.

Plasmodium falciparum: multifaceted resistance to artemisinins.

Abstract: Plasmodium falciparum resistance to artemisinins, the most potent and fastest acting anti-malarials, threatens malaria elimination strategies. Artemisinin resistance is due to mutation of the PfK13 propeller domain and involves an unconventional mechanism based on a quiescence state leading to parasite recrudescence as soon as drug pressure is removed. The enhanced P. falciparum quiescence capacity of artemisinin-resistant parasites results from an increased ability to manage oxidative damage and an altered cell cycle gene regulation within a complex network involving the unfolded protein response, the PI3K/PI3P/AKT pathway, the PfPK4/eIF2α cascade and yet unidentified transcription factor(s), with minimal energetic requirements and fatty acid metabolism maintained in the mitochondrion and apicoplast. The detailed study of these mechanisms offers a way forward for identifying future intervention targets to fend off established artemisinin resistance.

Novel molecular diagnostic tools for malaria elimination: a review of options from the point of view of high-throughput and applicability in resource limited settings

Abstract: As malaria transmission continues to decrease, an increasing number of countries will enter pre-elimination and elimination. To interrupt transmission, changes in control strategies are likely to require more accurate identification of all carriers of Plasmodium parasites, both symptomatic and asymptomatic, using diagnostic tools that are highly sensitive, high throughput and with fast turnaround times preferably performed in local health service settings. Currently available immunochromatographic lateral flow rapid diagnostic tests and field microscopy are unlikely to consistently detect infections at parasite densities less than 100 parasites/µL making them insufficiently sensitive for detecting all carriers. Molecular diagnostic platforms, such as PCR and LAMP, are currently available in reference laboratories, but at a cost both financially and in turnaround time. This review describes the recent progress in developing molecular diagnostic tools in terms of their capacity for high throughput and potential for performance in non-reference laboratories for malaria elimination.

Plasmodium falciparum histidine rich protein-2 diversity and the implications for PfHRP 2: based malaria rapid diagnostic tests in Ghana.

Abstract: Background Malaria rapid diagnostic tests (RDTs) play a key role in malaria management and control. The PfHRP-2 based RDT is the most widely used RDT for malaria diagnosis in Ghana. Deletion of pfhrp2 in Plasmodium falciparum parasites affect the diagnostic accuracy of PfHRP-2 based RDT kits. Identifying the prevalence and distribution of P. falciparum parasites with deleted pfhrp2 is important for malaria control.

Malaria risk factor assessment using active and passive surveillance data from Aceh Besar, Indonesia, a low endemic, malaria elimination setting with Plasmodium knowlesi, Plasmodium vivax, and Plasmodium falciparum.

Abstract: As malaria transmission declines, it becomes more geographically focused and more likely due to asymptomatic and non-falciparum infections. To inform malaria elimination planning in the context of this changing epidemiology, local assessments on the risk factors for malaria infection are necessary, yet challenging due to the low number of malaria cases. A population-based, cross-sectional study was performed using passive and active surveillance data collected in Aceh Besar District, Indonesia from 2014 to 2015. Malaria infection was defined as symptomatic polymerase chain reaction (PCR)-confirmed infection in index cases reported from health facilities, and asymptomatic or symptomatic PCR-confirmed infection identified in reactive case detection (RACD). Potential risk factors for any infection, species-specific infection, or secondary-case detection in RACD were assessed through questionnaires and evaluated for associations. Nineteen Plasmodium knowlesi, 12 Plasmodium vivax and six Plasmodium falciparum cases were identified passively, and 1495 community members screened in RACD, of which six secondary cases were detected (one P. knowlesi, three P. vivax, and two P. falciparum, with four being asymptomatic). Compared to non-infected subjects screened in RACD, cases identified through passive or active surveillance were more likely to be male (AOR 12.5, 95 % CI 3.0–52.1), adult (AOR 14.0, 95 % CI 2.2–89.6 for age 16–45 years compared to <15 years), have visited the forest in the previous month for any reason (AOR 5.6, 95 % CI 1.3–24.2), and have a workplace near or in the forest and requiring overnight stays (AOR 7.9, 95 % CI 1.6–39.7 compared to workplace not near or in the forest). Comparing subjects with infections of different species, differences were observed in sub-district of residence and other demographic and behavioural factors. Among subjects screened in RACD, cases compared to non-cases were more likely to be febrile and reside within 100 m of the index case. In this setting, risk of malaria infection in index and RACD identified cases was associated with forest exposure, particularly overnights in the forest for work. In low-transmission settings, utilization of data available through routine passive and active surveillance can support efforts to target individuals at high risk.

Risk factors of malaria in children under the age of five years old in Uganda

Abstract: Malaria is the leading cause of morbidity in Uganda with 90–95 % of the population at risk and it contributing to approximately 13 % of under-five mortality. The aim of this study was to investigate the relationship between the malaria status of children under the age of 5 years old in Uganda and selected socio-economic, demographic and environmental factors, as well as to identify significant risk factors associated with malaria. This study made use of data collected from the 2014 Malaria Indicator Survey conducted in Uganda. Two test procedures for malaria in children under the age of 5 years old were carried out. Due to the complex survey design, a generalized linear mixed model was used to test for associations between several independent variables and the response variable, which was whether a child tested positive or negative for malaria according to the microscopy test. The sample in this study was made up of 4939 children. Of those children, 974 tested positive for malaria, resulting in an observed malaria prevalence of 19.7 %. The socio-economic factors closely related to the risk of malaria were main floor material, main wall material and availability of electricity in the household. The event of indoor residual spraying (IRS) significantly reduced a child’s risk of malaria. An older child was associated with a higher risk of malaria, however their risk decreased with an increase in cluster altitude and an increase in their caregiver’s education level. Although there has been a significant increase in the use of mosquito nets since the previous Malaria Indicator Survey done in 2009, particularly in the use of insecticide-treated nets (ITNs) and long-lasting insecticidal nets (LLINs), these control measures alone may not be sufficient. IRS will be a key strategy in reaching the malaria goals set by the government of Uganda. Supplementing these control measures with education of appropriate and consistent use of ITNs and LLINs, as well as education of practicing safe living habits, such as reducing outdoor activities during peak biting hours of a mosquito, can go a long way in aiding the reduction of the burden of malaria in Uganda.

Trends in US President’s Malaria Initiative-funded indoor residual spray coverage and insecticide choice in sub-Saharan Africa (2008–2015): urgent need for affordable, long-lasting insecticides

Abstract: This article reports the changing pattern of US President’s Malaria Initiative-funded IRS in sub-Saharan Africa between 2008 and 2015. IRS coverage in sub-Saharan Africa increased from <2 % of the at-risk population in 2005, to 11 % or 78 million people in 2010, mainly as a result of increased funding from PMI. The scaling up of IRS coverage in sub-Saharan Africa has been successful in several epidemiological settings and contributed to reduced malaria transmission rates. However, the spread and intensification of pyrethroid resistance in malaria vectors led many control programmes to spray alternative insecticides. Between 2009 and 2013, pyrethroid spraying decreased from 87 % (13/15) of PMI-funded countries conducting IRS to 44 % (7/16), while bendiocarb use increased from 7 % (1/15) to 56 % (9/16). Long-lasting pirimiphos-methyl CS received WHOPES recommendation in 2013 and was scheduled to be sprayed in 85 % (11/13) of PMI-funded countries conducting IRS in 2015. The gradual replacement of relatively inexpensive pyrethroids, firstly with bendiocarb (carbamate) and subsequently with pirimiphos methyl CS (organophosphate), has contributed to the downscaling of most PMI-funded IRS programmes. Overall, there was a 53 % decrease in the number of structures sprayed between years of peak coverage and 2015, down from 9.04 million to 4.26 million structures. Sizeable reductions in the number of structures sprayed were reported in Madagascar (56 %, 576,320–254,986), Senegal (64 %, 306,916–111,201), Tanzania (68 %, 1,224,095–389,714) and Zambia (63 %, 1,300,000–482,077), while in Angola, Liberia and Malawi PMI-funded spraying was suspended. The most commonly cited reason was increased cost of pesticides, as vector resistance necessitated switching from pyrethroids to organophosphates. There are worrying preliminary reports of malaria resurgence following IRS withdrawal in parts of Benin, Tanzania and Uganda. The increase in malaria cases following the end of the Global Malaria Eradication Programme in 1969 highlights the fragility of such gains when control efforts are weakened. At present there are several countries reliant on organophosphates and carbamates for IRS, and increasing incipient resistance is a serious threat that could result in IRS no longer being viable. A portfolio of new cost-effective insecticides with different modes of action is urgently needed.

Modelling the influence of temperature and rainfall on the population dynamics of Anopheles arabiensis

Abstract: Malaria continues to be one of the most devastating diseases in the world, killing more humans than any other infectious disease. Malaria parasites are entirely dependent on Anopheles mosquitoes for transmission. For this reason, vector population dynamics is a crucial determinant of malaria risk. Consequently, it is important to understand the biology of malaria vector mosquitoes in the study of malaria transmission. Temperature and precipitation also play a significant role in both aquatic and adult stages of the Anopheles. In this study, a climate-based, ordinary-differential-equation model is developed to analyse how temperature and the availability of water affect mosquito population size. In the model, the influence of ambient temperature on the development and the mortality rate of Anopheles arabiensis is considered over a region in KwaZulu-Natal Province, South Africa. In particular, the model is used to examine the impact of climatic factors on the gonotrophic cycle and the dynamics of mosquito population over the study region. The results fairly accurately quantify the seasonality of the population of An. arabiensis over the region and also demonstrate the influence of climatic factors on the vector population dynamics. The model simulates the population dynamics of both immature and adult An. arabiensis. The simulated larval density produces a curve which is similar to observed data obtained from another study. The model is efficiently developed to predict An. arabiensis population dynamics, and to assess the efficiency of various control strategies. In addition, the model framework is built to accommodate human population dynamics with the ability to predict malaria incidence in future.

Concurrent malaria and arbovirus infections in Kedougou, southeastern Senegal

Abstract: Malaria is one of the leading causes of acute febrile illness (AFI) in Africa. With the advent of malaria rapid diagnostic tests, misdiagnosis and co-morbidity with other diseases has been highlighted by an increasing number of studies. Although arboviral infections and malaria are both vector-borne diseases and often have an overlapping geographic distribution in sub-Saharan Africa, information about their incidence rates and concurrent infections is scarce. From July 2009 to March 2013 patients from seven healthcare facilities of the Kedougou region presenting with AFI were enrolled and tested for malaria and arboviral infections, i.e., yellow fever (YFV), West Nile (WNV), dengue (DENV), chikungunya (CHIKV), Crimean Congo haemorrhagic fever (CCHFV), Zika (ZIKV), and Rift Valley fever viruses (RVFV). Malaria parasite infections were investigated using thick blood smear (TBS) and rapid diagnostics tests (RDT) while arbovirus infections were tested by IgM antibody detection (ELISA) and RT-PCR assays. Data analysis of single or concurrent malaria and arbovirus was performed using R software. A total of 13,845 patients, including 7387 with malaria and 41 with acute arbovirus infections (12 YFV, nine ZIKV, 16 CHIKV, three DENV, and one RVFV) were enrolled. Among the arbovirus-infected patients, 48.7 % (20/41) were co-infected with malaria parasites at the following frequencies: CHIKV 18.7 % (3/16), YFV 58.3 % (7/12), ZIKV 88.9 % (8/9), DENV 33.3 % (1/3), and RVF 100 % (1/1). Fever ≥40 °C was the only sign or symptom significantly associated with dual malaria parasite/arbovirus infection. Concurrent malaria parasite and arbovirus infections were detected in the Kedougou region from 2009 to 2013 and need to be further documented, including among asymptomatic individuals, to assess its epidemiological and clinical impact.

The role of early detection and treatment in malaria elimination.

Abstract: Falciparum malaria persists in hard-to-reach areas or demographic groups that are missed by conventional healthcare systems but could be reached by trained community members in a malaria post (MP). The main focus of a MP is to provide uninterrupted and rapid access to rapid diagnostic tests (RDTs) and artemisinin-based combination therapy (ACT) too all inhabitants of a village. RDTs allow trained community members to perform malaria diagnosis accurately and prescribe appropriate treatment, reducing as much as possible any delay between the onset of fever and treatment. Early treatment with ACT and with a low-dose of primaquine prevents further transmission from human to mosquito. A functioning MP represents an essential component of any malaria elimination strategy. Implementing large-scale, high-coverage, community-based early diagnosis and treatment through MPs requires few technological innovations but relies on a very well structured organization able to train, supervise and supply MPs, to monitor activity and to perform strict malaria surveillance.

Community engagement and population coverage in mass anti-malarial administrations: a systematic literature review

Abstract: Mass anti-malarial administration has been proposed as a key component of the malaria elimination strategy in South East Asia. The success of this approach depends on the local malaria epidemiology, nature of the anti-malarial regimen and population coverage. Community engagement is used to promote population coverage but little research has systematically analysed its impact. This systematic review examines population coverage and community engagement in programmes of mass anti-malarial drug administration. This review builds on a previous review that identified 3049 articles describing mass anti-malarial administrations published between 1913 and 2011. Further search and application of a set of criteria conducted in the current review resulted in 51 articles that were retained for analysis. These 51 papers described the population coverage and/or community engagement in mass anti-malarial administrations. Population coverage was quantitatively assessed and a thematic analysis was conducted on the community engagement activities. The studies were conducted in 26 countries: in diverse healthcare and social contexts where various anti-malarial regimens under varied study designs were administered. Twenty-eight articles reported only population coverage; 12 described only community engagement activities; and 11 community engagement and population coverage. Average population coverage was 83% but methods of calculating coverage were frequently unclear or inconsistent. Community engagement activities included providing health education and incentives, using community structures (e.g. existing hierarchies or health infrastructure), mobilizing human resources, and collaborating with government at some level (e.g. ministries of health). Community engagement was often a process involving various activities throughout the duration of the intervention. The mean population coverage was over 80% but incomplete reporting of calculation methods limits conclusions and comparisons between studies. Various community engagement activities and approaches were described, but many articles contained limited or no details. Other factors relevant to population coverage, such as the social, cultural and study context were scarcely reported. Further research is needed to understand the factors that influence population coverage and adherence in mass anti-malarial administrations and the role community engagement activities and approaches play in satisfactory participation.

An integrated risk and vulnerability assessment framework for climate change and malaria transmission in East Africa.

Abstract: Malaria is one of the key research concerns in climate change-health relationships. Numerous risk assessments and modelling studies provide evidence that the transmission range of malaria will expand with rising temperatures, adversely impacting on vulnerable communities in the East African highlands. While there exist multiple lines of evidence for the influence of climate change on malaria transmission, there is insufficient understanding of the complex and interdependent factors that determine the risk and vulnerability of human populations at the community level. Moreover, existing studies have had limited focus on the nature of the impacts on vulnerable communities or how well they are prepared to cope. In order to address these gaps, a systems approach was used to present an integrated risk and vulnerability assessment framework for studies of community level risk and vulnerability to malaria due to climate change. Drawing upon published literature on existing frameworks, a systems approach was applied to characterize the factors influencing the interactions between climate change and malaria transmission. This involved structural analysis to determine influential, relay, dependent and autonomous variables in order to construct a detailed causal loop conceptual model that illustrates the relationships among key variables. An integrated assessment framework that considers indicators of both biophysical and social vulnerability was proposed based on the conceptual model. A major conclusion was that this integrated assessment framework can be implemented using Bayesian Belief Networks, and applied at a community level using both quantitative and qualitative methods with stakeholder engagement. The approach enables a robust assessment of community level risk and vulnerability to malaria, along with contextually relevant and targeted adaptation strategies for dealing with malaria transmission that incorporate both scientific and community perspectives.

Plasmodium vivax gametocyte infectivity in sub-microscopic infections

Abstract: The use of molecular techniques has put in the spotlight the existence of a large mass of malaria sub-microscopic infections among apparently healthy populations. These sub-microscopic infections are considered an important pool for maintained malaria transmission. In order to assess the appearance of Plasmodium vivax gametocytes in circulation, gametocyte density and the parasite infectivity to Anopheles mosquitoes, a study was designed to compare three groups of volunteers either experimentally infected with P. vivax sporozoites (early infections; n = 16) or naturally infected patients (acute malaria, n = 16 and asymptomatic, n = 14). In order to determine gametocyte stage, a quantitative reverse transcriptase PCR (RT-qPCR) assay targeting two sexual stage-specific molecular markers was used. Parasite infectivity was assessed by membrane feeding assays (MFA). In early infections P. vivax gametocytes could be detected starting at day 7 without giving rise to infected mosquitoes during 13 days of follow-up. Asymptomatic carriers, with presumably long-lasting infections, presented the highest proportion of mature gametocytes and were as infective as acute patients. This study shows the potential role of P. vivax asymptomatic carriers in malaria transmission should be considered when new policies are envisioned to redirect malaria control strategies towards targeting asymptomatic infections as a tool for malaria elimination.

A Phase II pilot trial to evaluate safety and efficacy of ferroquine against early Plasmodium falciparum in an induced blood-stage malaria infection study.

Abstract: Ferroquine (SSR97193) is a candidate anti-malarial currently undergoing clinical trials for malaria. To better understand its pharmacokinetic (PK) and pharmacodynamic (PD) parameters the compound was tested in the experimentally induced blood stage malaria infection model in volunteers. Male and non-pregnant female aged 18–50 years were screened for this phase II, controlled, single-centre clinical trial. Subjects were inoculated with ~1800 viable Plasmodium falciparum 3D7A-infected human erythrocytes, and treated with a single-dose of 800 mg ferroquine. Blood samples were taken at defined time-points to measure PK and PD parameters. The blood concentration of ferroquine and its active metabolite, SSR97213, were measured on dry blood spot samples by ultra-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS). Parasitaemia and emergence of gametocytes were monitored by quantitative PCR. Safety was determined by recording adverse events and monitoring clinical laboratory assessments during the course of the study. Eight subjects were enrolled into the study, inoculated with infected erythrocytes and treated with 800 mg ferroquine. Ferroquine was rapidly absorbed with maximal exposure after 4–8 and 4–12 h exposure for SSR97213. Non-compartmental PK analysis resulted in estimates for half-lives of 10.9 and 23.8 days for ferroquine and SSR97213, respectively. Parasite clearance as reported by parasite reduction ratio was 162.9 (95 % CI 141–188) corresponding to a parasite clearance half-life of 6.5 h (95 % CI: 6.4–6.7 h). PK/PD modelling resulted in a predicted minimal parasiticidal concentration of 20 ng/mL, and the single dosing tested in this study was predicted to maintain an exposure above this threshold for 454 h (37.8 days). Although ferroquine was overall well tolerated, transient elevated transaminase levels were observed in three subjects. Paracetamol was the only concomitant treatment among the two out of these three subjects that may have played a role in the elevated transaminases levels. No clinically significant ECG abnormalities were observed. The parameters and PK/PD model derived from this study pave the way to the further rational development of ferroquine as an anti-malarial partner drug. The safety of ferroquine has to be further explored in controlled human trials. Trial registration anzctr.org.au (registration number: ACTRN12613001040752), registered 18/09/2013

Trends of imported malaria in China 2010-2014: analysis of surveillance data.

Abstract: Background To describe the epidemiologic profile and trends of imported malaria, and to identify the populations at risk of malaria in China during 2010–2014.

Time series analysis of malaria in Afghanistan: using ARIMA models to predict future trends in incidence

Abstract: Malaria remains endemic in Afghanistan. National control and prevention strategies would be greatly enhanced through a better ability to forecast future trends in disease incidence. It is, therefore, of interest to develop a predictive tool for malaria patterns based on the current passive and affordable surveillance system in this resource-limited region. This study employs data from Ministry of Public Health monthly reports from January 2005 to September 2015. Malaria incidence in Afghanistan was forecasted using autoregressive integrated moving average (ARIMA) models in order to build a predictive tool for malaria surveillance. Environmental and climate data were incorporated to assess whether they improve predictive power of models. Two models were identified, each appropriate for different time horizons. For near-term forecasts, malaria incidence can be predicted based on the number of cases in the four previous months and 12 months prior (Model 1); for longer-term prediction, malaria incidence can be predicted using the rates 1 and 12 months prior (Model 2). Next, climate and environmental variables were incorporated to assess whether the predictive power of proposed models could be improved. Enhanced vegetation index was found to have increased the predictive accuracy of longer-term forecasts. Results indicate ARIMA models can be applied to forecast malaria patterns in Afghanistan, complementing current surveillance systems. The models provide a means to better understand malaria dynamics in a resource-limited context with minimal data input, yielding forecasts that can be used for public health planning at the national level.

Prevalence of Plasmodium spp.in illegal gold miners in French Guiana in 2015: a hidden but critical malaria reservoir

Abstract: Malaria is endemic in French Guiana, an overseas territory of France on the Guiana Shield. Since 2005, notified malaria cases are decreasing. However, new data show that malaria affects many Brazilian gold miners working illegally in French Guiana, the majority of whom are not counted in official data. In addition, one major concern is the usual practice of improper self-treatment in this mining population, raising fear of the development of anti-malarial resistance. This prospective study, conducted in 2015, aimed to estimate the prevalence of Plasmodium spp. in illegal gold miners working in French Guiana. The recruitment of gold miners was carried out in resting sites along the French Guiana-Suriname border, where they go for supplies, medical care or leisure. After recording agreement, three malaria diagnostic methods were performed: rapid diagnostic test, microscopy and PCR. Among 421 persons recruited in the study, malaria prevalence, detected by nested-PCR, was 22.3 % (CI [18.3–26.3], n = 94/421) of which 84 % were asymptomatic. This significant malaria reservoir in a mobile and illegal population with difficult access to a health care system raises the threat of artemisinin resistance and puts the population of the Guiana Shield at risk of new transmission foci while countries of the region aim at malaria elimination. Even though French legislation may hamper dealing with this population, France must face the reality of malaria in illegal gold miners in order to meet its commitment to malaria elimination.

Health workers' compliance to rapid diagnostic tests (RDTs) to guide malaria treatment: a systematic review and meta-analysis.

Abstract: The World Health Organization recommends malaria to be confirmed by either microscopy or a rapid diagnostic test (RDT) before treatment. The correct use of RDTs in resource-limited settings facilitates basing treatment onto a confirmed diagnosis; contributes to speeding up considering a correct alternative diagnosis, and prevents overprescription of anti-malarial drugs, reduces costs and avoids unnecessary exposure to adverse drug effects. This review aims to evaluate health workers’ compliance to RDT results and factors contributing to compliance. A PROSPERO-registered systematic review was conducted to evaluate health workers’ compliance to RDTs in sub-Saharan Africa, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies published up to November 2015 were searched without language restrictions in Medline/Ovid, Embase, Cochrane Central Register of Controlled Trials, Web of Science, LILACS, Biosis Previews and the African Index Medicus. The primary outcome was health workers treating patients according to the RDT results obtained. The literature search identified 474 reports; 14 studies were eligible and included in the quantitative analysis. From the meta-analysis, health workers’ overall compliance in terms of initiating treatment or not in accordance with the respective RDT results was 83 % (95 % CI 80–86 %). Compliance to positive and negative results was 97 % (95 % CI 94–99 %) and 78 % (95 % CI 66–89 %), respectively. Community health workers had higher compliance rates to negative test results than clinicians. Patient expectations, work experience, scepticism of results, health workers’ cadres and perceived effectiveness of the test, influenced compliance. With regard to published data, compliance to RDT appears to be generally fair in sub-Saharan Africa; compliance to negative results will need to improve to prevent mismanagement of patients and overprescribing of anti-malarial drugs. Improving diagnostic capacity for other febrile illnesses and developing local evidence-based guidelines may help improve compliance and management of negative RDT results. Trial registration: CRD42015016151 (PROSPERO)

Changes in lipid composition during sexual development of the malaria parasite Plasmodium falciparum

Abstract: The development of differentiated sexual stages (gametocytes) within human red blood cells is essential for the propagation of the malaria parasite, since only mature gametocytes will survive in the mosquito’s midgut. Hence gametocytogenesis is a pre-requisite for transmission of the disease. Physiological changes involved in sexual differentiation are still enigmatic. In particular the lipid metabolism—despite being central to cellular regulation and development—is not well explored. Here the lipid profiles of red blood cells infected with the five different sexual stages of Plasmodium falciparum were analysed by mass spectrometry and compared to those from uninfected and asexual trophozoite infected erythrocytes. Fundamental differences between erythrocytes infected with the different parasite stages were revealed. In mature gametocytes many lipids that decrease in the trophozoite and early gametocyte infected red blood cells are regained. In particular, regulators of membrane fluidity, cholesterol and sphingomyelin, increased significantly during gametocyte maturation. Neutral lipids (serving mainly as caloriometric reserves) increased from 3 % of total lipids in uninfected to 27 % in stage V gametocyte infected red blood cells. The major membrane lipid class (phospholipids) decreased during gametocyte development. The lipid profiles of infected erythrocytes are characteristic for the particular parasite life cycle and maturity stages of gametocytes. The obtained lipid profiles are crucial in revealing the lipid metabolism of malaria parasites and identifying targets to interfere with this deadly disease.

The development of malaria diagnostic techniques: a review of the approaches with focus on dielectrophoretic and magnetophoretic methods.

Abstract: The large number of deaths caused by malaria each year has increased interest in the development of effective malaria diagnoses. At the early-stage of infection, patients show non-specific symptoms or are asymptomatic, which makes it difficult for clinical diagnosis, especially in non-endemic areas. Alternative diagnostic methods that are timely and effective are required to identify infections, particularly in field settings. This article reviews conventional malaria diagnostic methods together with recently developed techniques for both malaria detection and infected erythrocyte separation. Although many alternative techniques have recently been proposed and studied, dielectrophoretic and magnetophoretic approaches are among the promising new techniques due to their high specificity for malaria parasite-infected red blood cells. The two approaches are discussed in detail, including their principles, types, applications and limitations. In addition, other recently developed techniques, such as cell deformability and morphology, are also overviewed in this article.

Tafenoquine treatment of Plasmodium vivax malaria: suggestive evidence that CYP2D6 reduced metabolism is not associated with relapse in the Phase 2b DETECTIVE trial

Abstract: Tafenoquine (TQ) and primaquine (PQ) are 8-aminoquinolines (8-AQ) with anti-hypnozoite activity against vivax malaria. PQ is the only FDA-approved medicine for preventing relapsing Plasmodium vivax infection and TQ is currently in phase 3 clinical trials for the same indication. Recent studies have provided evidence that cytochrome P450 (CYP) metabolism via CYP2D6 plays a role in PQ efficacy against P. vivax and have suggested that this effect may extend to other 8-AQs, including TQ. Here, a retrospective pharmacogenetic (PGx) investigation was performed to assess the impact of CYP2D6 metabolism on TQ and PQ efficacy in the treatment of P. vivax in the DETECTIVE study (TAF112582), a recently completed, randomized, phase 2b dose-ranging clinical trial. The impact of CYP2D6 on TQ pharmacokinetics (PK) was also investigated in TAF112582 TQ-treated subjects and in vitro CYP metabolism of TQ was explored. A limitation of the current study is that TAF112582 was not designed to be well powered for PGx, thus our findings are based on TQ or PQ efficacy in CYP2D6 intermediate metabolizers (IM), as there were insufficient poor metabolizers (PM) to draw any conclusion on the impact of the PM phenotype on efficacy. The impact of genetically-predicted CYP2D6 reduced metabolism on relapse-free efficacy six months post-dosing of TQ or PQ, both administered in conjunction with chloroquine (CQ), was assessed using exact statistical methods in 198 P. vivax-infected study participants comparing IM to extensive metabolizers (EM). The influence of CYP2D6 metabolizer phenotypes on TQ PK was assessed comparing median TQ area under the curve (AUC). In vitro metabolism of TQ was investigated using recombinant, over-expressed human CYP enzymes and human hepatocytes. Metabolite identification experiments were performed using liquid chromatography-mass spectrometry. Reduction of CYP2D6 activity was not associated with an increase in relapse-rate in TQ-treated subjects (p = 0.57). In contrast, and in accordance with recent literature, CYP2D6 IMs were more common (p = 0.05) in PQ-treated subjects who relapsed (50 %) than in subjects who remained relapse-free (17 %). Further, CYP2D6 metabolizer phenotypes had no significant effect on TQ AUC, and only minimal metabolism of TQ could be detected in hepatic in vitro systems. Together, these data provide preliminary evidence that in CYP2D6 IMs, TQ efficacy in P. vivax-infected individuals is not diminished to the same extent as PQ. As there were no PMs in either the TQ or PQ treatment arms of TAF112582, no conclusions could be drawn on potential differences in PMs. These findings suggest that differential effects of CYP2D6 metabolism on TQ and PQ efficacy could be a differentiation factor between these 8-AQs, but results remain to be confirmed prospectively in the ongoing phase 3 studies.

Common asymptomatic and submicroscopic malaria infections in Western Thailand revealed in longitudinal molecular and serological studies: a challenge to malaria elimination.

Abstract: Despite largely successful control efforts, malaria remains a significant public health problem in Thailand. Based on microscopy, the northwestern province of Tak, once Thailand’s highest burden area, is now considered a low-transmission region. However, microscopy is insensitive to detect low-level parasitaemia, causing gross underestimation of parasite prevalence in areas where most infections are subpatent. The objective of this study was to assess the current epidemiology of malaria prevalence using molecular and serological detection methods, and to profile the antibody responses against Plasmodium as it relates to age, seasonal changes and clinical manifestations during infection. Three comprehensive cross-sectional surveys were performed in a sentinel village and from febrile hospital patients, and whole blood samples were collected from infants to elderly adults. Genomic DNA isolated from cellular fraction was screened by quantitative-PCR for the presence of Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale and Plasmodium knowlesi. Plasma samples were probed on protein microarray to obtain antibody response profiles from the same individuals. Within the studied community, 90.2 % of Plasmodium infections were submicroscopic and asymptomatic, including a large number of mixed-species infections. Amongst febrile patients, mixed-species infections comprised 68 % of positive cases, all of which went misdiagnosed and undertreated. All samples tested showed serological reactivity to Plasmodium antigens. There were significant differences in the rates of antibody acquisition against P. falciparum and P. vivax, and age-related differences in species-specific immunodominance of response. Antibodies against Plasmodium increased along the ten-month study period. Febrile patients had stronger antibody responses than asymptomatic carriers. Despite a great decline in malaria prevalence, transmission is still ongoing at levels undetectable by traditional methods. As current surveillance methods focus on case management, malaria transmission in Thailand will not be interrupted if asymptomatic submicroscopic infections are not detected and treated.

Cerebral malaria is associated with long-term mental health disorders: a cross sectional survey of a long-term cohort

Abstract: Cerebral malaria (CM) and severe malarial anaemia (SMA) are associated with neuro-developmental impairment in African children, but long-term mental health disorders in these children are not well defined. A cohort of children previously exposed to CM (n = 173) or SMA (n = 99) had neurologic assessments performed and screening for behaviour difficulties using the Strengths and Difficulties Questionnaire (SDQ) a median of 21 months after the disease episode. These findings were compared to concurrently recruited community children (CC, n = 108). Participants with SDQ total difficulties score ≥17 had a mental health interview with the child and adolescent version of the Mini-International Neuropsychiatric Interview (MINI-KID) and a sample had brain magnetic resonance imaging (MRI). Fifty-five children had SDQ score ≥17. On the MINI-KID, these children were classified as having no difficulties (n = 18), behaviour difficulties only (n = 13) or a mental health disorder (n = 24). Behaviour difficulties were seen in similar frequencies in CM (3.5 %), SMA (4.0 %) and CC (2.8 %). In contrast, mental health disorders were most frequent in CM (10.4 %), followed by SMA (4.0 %) and CC (1.8 %). Externalizing disorders (conduct, oppositional defiance and attention deficit hyperactivity) were the most common mental health disorders. The median total coma duration was 72 (IQR 36.0–115.0) h in patients with mental health disorders compared to 48 (IQR 28.5–78.7) h in those without, p = 0.039. Independent risk factors for mental health disorder included neurologic deficit at discharge (OR 4.09 (95 % CI 1.60, 10.5) and seizure recurrences during hospitalization, (OR 2.80, 95 % CI 1.13, 6.97). Brain MRI findings consistent with small vessel ischaemic neural injury was seen in over half of these children. Cerebral malaria may predispose children to mental health disorders, possibly as a consequence of ischaemic neural injury. There is urgent need for programmes of follow-up, diagnosis and interventions for these children.