Michelle S. Hsiang

The changing epidemiology of malaria elimination: new strategies for new challenges

Malaria-eliminating countries achieved remarkable success in reducing their malaria burdens between 2000 and 2010. As a result, the epidemiology of malaria in these settings has become more complex. Malaria is increasingly imported, caused by Plasmodium vivax in settings outside sub-Saharan Africa, and clustered in small geographical areas or clustered demographically into subpopulations, which are often predominantly adult men, with shared social, behavioural, and geographical risk characteristics. The shift in the populations most at risk of malaria raises important questions for malaria-eliminating countries, since traditional control interventions are likely to be less effective. Approaches to elimination need to be aligned with these changes through the development and adoption of novel strategies and methods. Knowledge of the changing epidemiological trends of malaria in the eliminating countries will ensure improved targeting of interventions to continue to shrink the malaria map.

Costs and financial feasibility of malaria elimination

Summary The marginal costs and benefits of converting malaria programmes from a control to an elimination goal are central to strategic decisions, but empirical evidence is scarce. We present a conceptual framework to assess the economics of elimination and analyse a central component of that framework—potential short-term to medium-term financial savings. After a review that showed a dearth of existing evidence, the net present value of elimination in five sites was calculated and compared with effective control. The probability that elimination would be cost-saving over 50 years ranged from 0% to 42%, with only one site achieving cost-savings in the base case. These findings show that financial savings should not be a primary rationale for elimination, but that elimination might still be a worthy investment if total benefits are sufficient to outweigh marginal costs. Robust research into these elimination benefits is urgently needed.

Surveillance for Malaria Elimination in Swaziland: A National Cross-Sectional Study Using Pooled PCR and Serology

Background To guide malaria elimination efforts in Swaziland and other countries, accurate assessments of transmission are critical. Pooled-PCR has potential to efficiently improve sensitivity to detect infections; serology may clarify temporal and spatial trends in exposure. Methodology/Principal Findings Using a stratified two-stage cluster, cross-sectional design, subjects were recruited from the malaria endemic region of Swaziland. Blood was collected for rapid diagnostic testing (RDT), pooled PCR, and ELISA detecting antibodies to Plasmodium falciparum surface antigens. Of 4330 participants tested, three were RDT-positive yet false positives by PCR. Pooled PCR led to the identification of one P. falciparum and one P. malariae infection among RDT-negative participants. The P. falciparum-infected participant reported recent travel to Mozambique. Compared to performing individual testing on thousands of samples, PCR pooling reduced labor and consumable costs by 95.5%. Seropositivity was associated with age ≥20 years (11·7% vs 1·9%, P<0.001), recent travel to Mozambique (OR 4.4 [95% CI 1.0–19.0]) and residence in southeast Swaziland (RR 3.78, P<0.001). Conclusions The prevalence of malaria infection and recent exposure in Swaziland are extremely low, suggesting elimination is feasible. Future efforts should address imported malaria and target remaining foci of transmission. Pooled PCR and ELISA are valuable surveillance tools for guiding elimination efforts.

PCR-Based Pooling of Dried Blood Spots for Detection of Malaria Parasites: Optimization and Application to a Cohort of Ugandan Children

ABSTRACT Sensitive, high-throughput methods to detect malaria parasites in low-transmission settings are needed. PCR-based pooling strategies may offer a solution. We first used laboratory-prepared samples to compare 2 DNA extraction and 4 PCR detection methods across a range of pool sizes and parasite densities. Pooled Chelex extraction of DNA, followed by nested PCR of cytochrome b, was the optimal strategy, allowing reliable detection of a single low-parasitemic sample (100 parasites/μl) in pool sizes up to 50. This PCR-based pooling strategy was then compared with microscopy using 891 dried blood spots from a cohort of 77 Ugandan children followed for 2 years in an urban setting of low endemicity. Among 419 febrile episodes, 35 cases of malaria were detected using the PCR-based pooling strategy and 40 cases using microscopy. All five cases of malaria not detected by PCR were from samples stored for >2 years with parasitemia of <6,000/μl, highlighting the issue of possible DNA degradation with long-term storage of samples. Among 472 samples collected from asymptomatic children as part of routine surveillance, 15 (3.2%) were positive by PCR-based pooling compared to 4 (0.8%) by microscopy (P = 0.01). Thus, this PCR-based pooling strategy for detection of malaria parasites using dried blood spots offers a sensitive and efficient approach for malaria surveillance in low-transmission settings, enabling improved detection of asymptomatic submicroscopic infections and dramatic savings in labor and costs.

Reactive case detection for malaria elimination: real-life experience from an ongoing program in Swaziland.

As countries move towards malaria elimination, methods to identify infections among populations who do not seek treatment are required. Reactive case detection, whereby individuals living in close proximity to passively detected cases are screened and treated, is one approach being used by a number of countries including Swaziland. An outstanding issue is establishing the epidemiologically and operationally optimal screening radius around each passively detected index case. Using data collected between December 2009 and June 2012 from reactive case detection (RACD) activities in Swaziland, we evaluated the effect of screening radius and other risk factors on the probability of detecting cases by reactive case detection. Using satellite imagery, we also evaluated the household coverage achieved during reactive case detection. Over the study period, 250 cases triggered RACD, which identified a further 74 cases, showing the value of RACD over passive surveillance alone. Results suggest that the odds of detecting a case within the household of the index case were significantly higher than in neighbouring households (odds ratio (OR) 13, 95% CI 3.1–54.4). Furthermore, cases were more likely to be detected when RACD was conducted within a week of the index presenting at a health facility (OR 8.7, 95% CI 1.1–66.4) and if the index household had not been sprayed with insecticide (OR sprayed vs not sprayed 0.11, 95% CI 0.03–0.46). The large number of households missed during RACD indicates that a 1 km screening radius may be impractical in such resource limited settings such as Swaziland. Future RACD in Swaziland could be made more effective by achieving high coverage amongst individuals located near to index cases and in areas where spraying has not been conducted. As well as allowing the programme to implement RACD more rapidly, this would help to more precisely define the optimal screening radius.

Mass drug administration for the control and elimination of Plasmodium vivax malaria: An ecological study from Jiangsu province, China

BackgroundRecent progress in malaria control has caused renewed interest in mass drug administration (MDA) as a potential elimination strategy but the evidence base is limited. China has extensive experience with MDA, but it is not well documented.MethodsAn ecological study was conducted to describe the use of MDA for the control and elimination of Plasmodium vivax in Jiangsu Province and explore the association between MDA and malaria incidence. Two periods were focused on: 1973 to 1983 when malaria burden was high and MDA administered to highly endemic counties province-wide, and 2000 to 2009, when malaria burden was low and a focal approach was used in two counties. All available data about the strategies implemented, MDA coverage, co-interventions, incidence, and adverse events were collected and described. Joinpoint analysis was used to describe trends in incidence and the relationship between MDA coverage and incidence was explored in negative binomial regression models.ResultsFrom 1973 to 1983, MDA with pyrimethamine and primaquine was used on a large scale, with up to 30 million people in target counties covered in a peak year (50% of the total population). Joinpoint analyses identified declines in annual incidence, -56.7% (95% CI -75.5 to -23.7%) from 1973–1976 and -12.4% (95% CI -24.7 to 2.0%) from 1976–1983. Population average negative binomial models identified a relationship between higher total population MDA coverage and lower monthly incidence from 1973–1976, IRR 0.98 (95% CI 0.97 to 1.00), while co-interventions, rainfall and GDP were not associated. From 2000–2009, incidence in two counties declined (annual change -43.7 to -14.0%) during a time when focal MDA using chloroquine and primaquine was targeted to villages and/or individuals residing near passively detected index cases (median 0.04% of total population). Although safety data were not collected systematically, there were rare reports of serious but non-fatal events.ConclusionsIn Jiangsu Province, China, large-scale MDA was implemented and associated with declines in high P. vivax malaria transmission; a more recent focal approach may have contributed to interruption of transmission. MDA should be considered a potential key strategy for malaria control and elimination.

Rationale for short course primaquine in Africa to interrupt malaria transmission

Following the recent successes of malaria control in sub-Saharan Africa, the gametocytocidal drug primaquine needs evaluation as a tool to further reduce the transmission of Plasmodium falciparum malaria. The drug has scarcely been used in Africa because of concerns about its safety in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The evidence base for the use of primaquine as a transmission blocker is limited by a lack of comparable clinical and parasitological endpoints between trials. In March 2012, a group of experts met in London to discuss the existing evidence on the ability of primaquine to block malaria transmission, to define the roadblocks to the use of primaquine in Africa and to develop a roadmap to enable its rapid, safe and effective deployment. The output of this meeting is a strategic plan to optimize trial design to reach desired goals efficiently. The roadmap includes suggestions for a series of phase 1, 2, 3 and 4 studies to address specific hurdles to primaquine’s deployment. These include ex-vivo studies on efficacy, primaquine pharmacokinetics and pharmacodynamics and dose escalation studies for safety in high-risk groups. Phase 3 community trials are proposed, along with Phase 4 studies to evaluate safety, particularly in pregnancy, through pharmacovigilance in areas where primaquine is already deployed. In parallel, efforts need to be made to address issues in drug supply and regulation, to map G6PD deficiency and to support the evaluation of alternative gametocytocidal compounds.

Active case detection for malaria elimination: a survey among Asia Pacific countries.

BackgroundMoving from malaria control to elimination requires national malaria control programmes to implement strategies to detect both symptomatic and asymptomatic cases in the community. In order to do this, malaria elimination programmes follow up malaria cases reported by health facilities to carry out case investigations that will determine the origin of the infection, whether it has been imported or is due to local malaria transmission. If necessary, the malaria programme will also carry out active surveillance to find additional malaria cases in the locality to prevent further transmission. To understand current practices and share information on malaria elimination strategies, a survey specifically addressing country policies on case investigation and reactive case detection was carried out among fourteen countries of the Asia Pacific Malaria Elimination Network (APMEN).MethodsA questionnaire was distributed to the malaria control programme managers amongst 14 countries in the Asia Pacific who have national or sub-national malaria elimination goals.ResultsResults indicate that there are a wide variety of case investigation and active case detection activities employed by the 13 countries that responded to the survey. All respondents report conducting case investigation as part of surveillance activities. More than half of these countries conduct investigations for each case. Over half aim to accomplish the investigation within one to two days of a case report. Programmes collect a broad array of demographic data during investigation procedures and definitions for imported cases are varied across respondents. Some countries report intra-national (from a different province or district) importation while others report only international importation (from a different country). Reactive case detection in respondent countries is defined as screening households within a pre-determined radius in order to identify other locally acquired infections, whether symptomatic or asymptomatic. Respondents report that reactive case detection can be triggered in different ways, in some cases with only a single case report and in others if a defined threshold of multiple cases occurs. The spatial range of screening conducted varies from a certain number of households to an entire administrative unit (e g, village). Some countries target symptomatic people whereas others target all people in order to detect asymptomatic infections. The majority of respondent programmes collect a range of information from those screened for malaria, similar to the range of information collected during case investigation.ConclusionCase investigation and reactive case detection are implemented in the malaria elimination programmes in the Asia Pacific, however practices vary widely from country to country. There is little evidence available to support countries in deciding which methods to maintain, change or adopt for improved effectiveness and efficiency. The development and use of common evaluation metrics for these activities will allow malaria programmes to assess performance and results of resource-intensive surveillance measures and may benefit other countries that are considering implementing these activities.

Point of Care Testing for Malaria Using LAMP, Loop Mediated Isothermal Amplification

For over a century the laboratory diagnosis of malaria has relied on visualization of the parasite in blood smears. But microscopy is time and labor consuming and often inaccurate due to the considerable training and experience required. About 2 decades ago, immunochromatographic rapid diagnostic tests (RDTs) were introduced, providing a simpler and more rapid point of care diagnostic. However, RDTs, like blood smears, are limited in the detection of low-density infections. Nucleic acid amplification based assays offer markedly improved sensitivity, but standard polymerase chain reaction (PCR) diagnostics require hours of processing time, sophisticated technical skill, and expensive equipment to perform. Loop mediated isothermal amplification (LAMP) may offer the best of both worlds for malaria diagnostics, with the sensitivity of PCR but speed closer to that of RDTs. Highly sensitive diagnostics may not be appropriate in all situations. Patients with symptomatic malaria generally have high-density infections that are detectable by blood smears or RDTs, and in resource-limited settings, use of a more sophisticated assay may not be practical. However, when the goal is to interrupt transmission or eliminate malaria, there is a need to detect all infections, including asymptomatic infections, which are usually of low density [1]. In these lowendemic settings, subpatent infections, or those below the detection level of microscopy or RDT, are estimated to result in 20%–50% of all transmission episodes [2]. A malaria program that is serious about elimination cannot ignore these infections [3]. LAMP was developed in 2000 as a simple method to amplify DNA with high sensitivity, specificity, efficiency, and speed under isothermal conditions [4]. LAMP uses a DNA polymerase with strand displacement properties, usually from Bacillus stearothermophilus, obviating the need for a thermocycler. The assay has high specificity because amplification only occurs when 6 separate regions of target DNA are recognized. Specifically, amplification requires 2 inner and 2 outer primers, plus 2 additional loop-primers, which anneal at the loop structure in LAMP amplicons. This assay design enhances the sensitivity of the reaction and accelerates the reaction time to less than an hour, compared to typical PCR runs of several hours. Magnesium pyrophosphate precipitates after successful amplification, causing turbidity, and enabling visual detection. Alternatively, amplification can be detected as the loss of quenching of calcein, with emission of a fluorescent signal. The polymerases used for LAMP, which are less sensitive to inhibitors present in biological samples than some PCR polymerases, allow the use of simple and rapid DNA extraction methods such as “boil and spin” [5, 6]. Initially, LAMP was applied to pathogens causing food-borne disease, and kits to detect Salmonella, Legionella, Listeria, verotoxin-producing Escherichia coli, and Campylobacter have been commercialized. Promising assays have been developed for a variety of viruses including those causing severe acute respiratory syndrome (SARS), influenza, measles, human papilloma virus disease, and mumps. Methods have also been developed for diseases of resource-limited settings, including tuberculosis, human immunodeficiency virus (HIV) infection, and African trypanosomiasis. For malaria, the first reported primer sets for LAMP targeted the 18S ribosomal RNA gene [7]. Subsequent targeting of mitochondrial DNA provided Received and accepted 23 April 2014; electronically published 1 May 2014. Correspondence: Michelle S. Hsiang, MD, Malaria Elimination Initiative, Global Health Group, Division of Pediatric Infectious Diseases, Department of Pediatrics, University of California, San Francisco, 50 Beale St, 12th fl, Box 1224, San Francisco, CA 94105 (hsiangm@peds.ucsf.edu). The Journal of Infectious Diseases 2014;210:1167–9

Mapping residual transmission for malaria elimination

Eliminating malaria from a defined region involves draining the endemic parasite reservoir and minimizing local malaria transmission around imported malaria infections. In the last phases of malaria elimination, as universal interventions reap diminishing marginal returns, national resources must become increasingly devoted to identifying where residual transmission is occurring. The needs for accurate measures of progress and practical advice about how to allocate scarce resources require new analytical methods to quantify fine-grained heterogeneity in malaria risk. Using routine national surveillance data from Swaziland (a sub-Saharan country on the verge of elimination), we estimated individual reproductive numbers. Fine-grained maps of reproductive numbers and local malaria importation rates were combined to show ‘malariogenic potential’, a first for malaria elimination. As countries approach elimination, these individual-based measures of transmission risk provide meaningful metrics for planning programmatic responses and prioritizing areas where interventions will contribute most to malaria elimination. DOI: http://dx.doi.org/10.7554/eLife.09520.001