Battling Malaria in Rural Zambia with Modern Technology: A Qualitative Study on the Value of Cell Phones, Geographical Information Systems, Asymptomatic Carriers and Rapid Diagnostic Tests to Identify, Treat and Control Malaria

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Abstract

During the last decade much progress has been made in reducing malaria transmission in Macha, Southern Province, Zambia. Introduction of artemisinin combination therapies as well as mass screenings of asymptomatic carriers is believed to have contributed the most. When an endemic malaria situation is moving towards a non-endemic situation the resident population loses acquired immunity and therefore active case detection and efficient surveillance is crucial to prevent epidemic outbreaks. Our purpose was to evaluate the impact of cell phone surveillance and geographical information systems on malaria control in Macha. Furthermore, it evaluates what screening and treatment of asymptomatic carriers and implementation of rapid diagnostic tests in rural health care has led to. Ten in-depth semi-structured interviews, field observations and data collection were performed at the Macha Research Trust and at surrounding rural health centers. This qualitative method was inspired by rapid assessment procedure. The cell phone surveillance has been easily integrated in health care, and its integration with Geographical Information Systems has provided the ability to follow malaria transmission on a weekly basis. In addition, active case detection of asymptomatic carriers has been fruitful, which is reflected in it soon being applied nationwide. Furthermore, rapid diagnostic tests have provided rural health centers with reliable malaria diagnostics, thereby decreasing excessive malaria treatments and selection for drug resistance. This report reflects the importance of asymptomatic carriers in targeting malaria elimination, as well as development of effective surveillance systems when transmission decreases. Such an approach would be cost-efficient in the long run through positive effects in reduced child mortality and relief in health care.

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A Research Agenda for Malaria Eradication: Diagnoses and Diagnostics

(2011)

Summary Points New and improved screening tools and strategies are required for detection and management of very low-density parasitemia in the field Improved quality control is required for rapid diagnostic tests (RDTs) and microscopy in the field, to ensure confidence in diagnosis for case management More sensitive tests are required for Plasmodium vivax for case management Field-ready glucose-6-phosphate dehydrogenase (G6PD) deficiency tests and strategies for use to allow safe use of drugs against P. vivax liver stages are needed New strategies to manage parasite-negative individuals are needed to justify the continued inclusion of malaria diagnostics in febrile disease management in very low transmission areas. Introduction As malaria transmission declines across much of its range and the possibility of elimination (reduction of transmission to zero in a defined geographical area) is increasingly considered [1],[2], accurate diagnosis and case identification through the demonstration of malaria parasites in sick patients presenting to health workers (“passive case detection”) is ever more important. During case management in all settings, all symptomatic patients with demonstrated parasitemia should be considered to be malaria cases, and all parasitemic patients should be given definitive antimalarial treatment. Accurate diagnosis is essential both to target antimalarial drugs and to enable effective management of the frequently fatal nonmalarial febrile illnesses [3] that share signs and symptoms with malaria [4]–[13]. However, the very low levels of transmission now being attained in many countries present new challenges that will demand new diagnostic tools and strategies, in particular, a change from passive case detection to “active” case detection. That is, as the elimination agenda is increasingly followed [14], improvements in current field diagnostics (microscopy and rapid diagnostic tests [RDTs]) for case management and new diagnostics that can detect very low levels of Plasmodium in the blood of asymptomatic individuals (and, in the case of P. vivax, in the blood of symptomatic individuals) who may contribute to continuing malaria transmission [15]–[21] will become essential. Furthermore, novel strategies will be needed to incorporate these new and improved diagnostics into routine health service activities. More specifically, to avoid onward transmission, elimination programs for malaria will increasingly need to focus on detecting the highest possible fraction of infections in the general population through active rather than passive case detection. This change of focus will be essential because Plasmodium infections can persist at low densities for different lengths of time with no significant symptoms [16],[22],[23], and, in the case of P. vivax and Plasmodium ovale, as a latent stage in the liver that is not directly detectable. The contributions of these unseen reservoirs to the maintenance of transmission will depend on the success of detection and management of new cases and the coverage of vector and other control measures in the area [24],[25]. Thus, the usefulness of active case detection will vary with the epidemiology and health resources in an area and is itself a subject requiring further research [26]. Countries with successful “sustained control,” (the reduction of malaria transmission to a locally acceptable and sustained level through intensive use of vector control and effective case management) [14], will also need to adjust their diagnostic strategies as transmission declines to low levels and as they consider elimination. Importantly, until eradication of malaria (the reduction of transmission to zero worldwide) is achieved (and diagnostics therefore no longer required), efforts to eliminate malaria will continue to require diagnostics strategies as reintroduction will remain possible. This article, which summarizes the deliberations of the malERA Consultative Group on Diagnoses and Diagnostics, proposes a research agenda for the tools required for this process; related articles address broader issues of health service requirements and case management that will arise from their use [26],[27]. Figure 1 shows the position of different diagnostic approaches/tests in relation to morbidity, parasite prevalence, and densities and the different stages towards malaria elimination. Given the changing priorities for diagnoses and diagnostics as transmission reduces, in our discussion of the research needs for diagnostics, we distinguish between the two broad but overlapping areas of case management and surveillance/screening. This distinction is reflected in the target product profiles presented in Table 1. In both areas, sustainability will require integration with the general health system, and as much commonality as possible between diagnostics for different diseases. Thus we discuss priority setting in the context of the approaches already in use, or in the pipeline, for other diseases managed at the same levels of the health system. Because P. falciparum and P. vivax are the most prevalent plasmodia, the following discussion concentrates on these species, which most commonly present as mono-species infections. However, as P. falciparum infections decline, P. ovale may become relatively more prominent in areas where it is endemic, with implications for detection and management similar to those for P. vivax. Similarly, only time will tell whether transmission of Plasmodium malariae, which is transmitted across a broad geographical range, but at low prevalence, can be reduced using the measures applied to P. falciparum, or whether it will require specific strategies and tools. Notably, however, elimination of the zoonotic Plasmodium knowlesi is likely to require unique strategies (Figure 1). 10.1371/journal.pmed.1000396.g001 Figure 1 The position of different diagnostic approaches/tests in relation to morbidity, parasite prevalence, densities, and different stages towards malaria elimination. Image credit: Fusión Creativa. 10.1371/journal.pmed.1000396.t001 Table 1 Target product profiles for malaria diagnostics. Characteristic Case Management in Elimination Settings Screening/Surveillance (District Level or Below) Technical specifications Analytic sensitivity (parasite/µl)a E, 100–200, D 95%, D≥99% E>95%, D≥99% Analytic specificity Negative all pathogens, common blood disorders Negative all pathogens, common blood disorders Diagnostic specificity E>90%, D>95% E>99% surveillance low-transmission areas, E>95% screening Temperature stability E>35°C, D>45°Cc (2 y) E, 30°C; D, 45°C for short periods Integrity of packaging E, Moisture proof E, Moisture proof Species detection/differentiation: Pf predominant areasd E, Pf; D, Pf/pan E, Pf; D, Pf/pan Pf and non-Pf areas E, Pf/pan E, Pf/pan; D, differentiation all species Genotyping No No/Oe Ability to detect gametocytes No O Ability to detect hypnozoites No D Health systems and technical specifications Packaging of tests or reagentsf D, individual; D, all required consumables enclosed; D, bulk packaging displays temperature violations D, all required consumables enclosed; D, bulk packaging displays temperature violations Field stability/shelf life of consumablesg E, 2 y from manufacture (≥18 mo in country) E, 12 mo (6 mo since country); D, 2 y from manufacture (≥18 mo in country) Training requirements D, half-day of community-level health worker D, 0.9 Kappa>0.9 Instrumentation and laboratory infrastructure requirements E, no external power source; D, all provided with test D, all provided with test D, desirable; E, essential; O, optional. a Analytic sensitivity: detection threshold against the marker of the infective agent (target) in controlled conditions. Diagnostic sensitivity: proportion (percent) of target cases detected by the test in the setting of intended use. The sensitivity required for P. vivax is generally at least that required for P. falciparum, and the parameters here should be applied to both. To achieve the required diagnostic sensitivity in low-prevalence settings, a greater analytic sensitivity (lower threshold of detection) may be required in some cases. b Not required for febrile case management, but in an elimination setting, it would be desirable to detect incidental parasitemia at this level. c Essential where stored in the field in ambient temperatures that frequently reach this level. Ambient temperature of prolonged storage in place of use should be considered the essential temperature stability requirement for a particular product. d Areas in which infections are almost exclusively monospecies or mixed species P. falciparum infections. It is likely that many such infections have subpatent coinfections with other species. Where this represents a minority of infections, treatment on the basis of P. falciparum alone is likely to be acceptable from a programmatic and public health point of view. Non-P. falciparum infections are likely to become relatively more prominent as P. falciparum infections decline in prevalence, making the detection of non-P. falciparum species more desirable. e May be of importance in areas undergoing certification for elimination. f All inner (individual test) packaging should display, at a minimum: manufacturer name, product name, expiry date, lot number, target use (malaria). g Outcome of temperature stability and integrity of packaging (ability to exclude moisture). h Rapidity of results: For case management, results must be available before a patient is likely to leave the clinic. For surveillance, result availability in time for finding and managing cases is highly desirable. Diagnostic Strategies for Programs in the Intensified Control Phase Identification of parasitemia in febrile patients is essential in all of the programmatic phases of the continuum from malaria control to elimination, although the challenges for health systems in maintaining this activity in areas where malaria has become rare will be more prominent, as will the importance of detecting asymptomatic infections of low parasite density. The ongoing role of other routine interventions, such as intermittent preventive treatment in pregnancy, needs reevaluating as elimination is approached. Moreover, because the distribution of malaria transmission is often highly heterogeneous within a country, strategies may need to vary at a subnational level. Analyses of past experiences and operations research are required to guide decisions on when these changes in emphasis should take place as control progresses [27],[28]. Although programs in areas of higher transmission will be less likely to engage in active case finding of individuals with low parasite densities, surveillance is nevertheless necessary to detect trends and the impact of interventions, and requires appropriate, high-throughput diagnostic tools. In addition to the diagnosis of malaria, it will be critical to have diagnostic capabilities for other causes of presenting illness, particularly fever. A sick adult or parent of a febrile child may not be satisfied with a diagnosis of “not malaria,” and both patients and providers require guidance on the integrated management of childhood illnesses, to ensure that appropriate alternative and specific treatment is available and provided. Experience in eliminating malaria and maintaining elimination (or very low transmission) in sub-Saharan Africa is lacking, but experience from other areas suggests that resource requirements may be prohibitive and long-term maintenance of very low transmission and prevention of rebound unachievable using conventional management [29],[30]. Innovative approaches are therefore required. Diagnostic tools capable of detecting very low parasite densities (1 parasite/µl blood) in asymptomatic individuals will increasingly be required for active case detection and population surveillance to obtain a true picture of the prevalence of parasitemia and probability of transmission (as distinct from symptomatic malaria) [16]–[21]. Active case detection and treatment will be required whenever ongoing transmission is suspected and in high-risk populations (including those crossing borders), if the likelihood of ongoing transmission is to be eliminated. In these circumstances, test specificity is of increased importance because the absence of false positive results is critical in understanding the presence or absence of transmission [26]. Diagnostic Strategies for Programs in Areas Where Elimination Has Taken Place Once malaria is eliminated in a given area, considerable resources will be required to detect reintroduction through surveillance and to maintain capacity for rapid management and investigation of any cases found, as long as the risk factors that support transmission are still in place. Screening of migrant populations, screening of populations around detected cases, and case management tools for screening suspected patients, such as recent travelers or geographical associates of malaria cases may be needed. The tools to achieve these activities must be readily available in an environment where technicians are likely to be unskilled in the use of malaria diagnostic tests, particularly microscopy [27]. Thus, the requirements for surveillance and screening in areas where malaria has been eliminated, but risk of transmission is present, are similar to those of programs in an elimination phase. However, case management tools that are minimally dependent on previous technician experience in diagnosing malaria will be of particular importance. Diagnostic Tools for Case Management in an Elimination Setting In settings where there is risk of autochthonous or imported malaria, diagnostics must be capable of rapidly and accurately detecting and quantifying parasitemia in febrile patients, and identifying species. In addition, highly sensitive diagnostic tools are needed for passive case detection and case management at health care facilities (public or private) that report to the national health information or disease surveillance systems. The issues around diagnostics in both case management and surveillance and control settings have a large impact on, and are impacted by, monitoring and evaluation requirements and health systems implementation issues such as the development of improved supply lines and logistics management, reporting of results and commodity consumption, and adherence of health workers and patients to management consistent with diagnostic results. These are all important areas where pooling of knowledge and sometimes operational research is required to maximize the impact of the diagnostic tools discussed below [26],[27]. Light Microscopy When performed to a high standard, light microscopy is capable of accurately identifying and quantifying Plasmodium parasites with sufficient rapidity for case management in most settings. It remains the operational gold standard in both control and elimination settings. However, the quality of light microscopy in the field is often inadequate [31]–[36] and limited by factors such as the instability and difficult preparation of currently used Romanowsky-based stains [37]–[39], poorly maintained, low quality equipment, and inadequate training, supervision, and quality assurance. Additionally, as malaria transmission decreases, it is likely that light microscopy technician skills may be redeployed elsewhere. Consequently, research into sustainable ways to maintain high-quality light microscopy in field settings, including innovative training, supervisory, and quality-assurance systems, is badly needed. More consistent and stable staining techniques are also required. This area of research has been ignored for the past 60 to 100 years, but has the potential to improve field accuracy significantly and may also improve the potential of the new reading techniques discussed below. Large volumes of slides pose particular challenges with respect to reading, especially in settings with low parasite prevalence where microscopist performance is hard to maintain [26]. Digital Microscopy Computer-assisted analysis of Giemsa-stained slides (possibly combined with automated staining), or digitized image transfer (potentially via mobile telephone) to a reference centre for review by an expert microscopist may enable greater consistency in parasite detection [40]–[44]. Additional research is required to determine whether these techniques will detect lower parasite densities than can be obtained by traditional light microscopy. Related techniques under development use software analysis of the scatter of various wavelengths of light to identify Plasmodium parasites and other pathogens. Although these digital techniques have the potential to improve field detection of malaria parasites, field-ready versions are not yet available, and it is not known whether these tools will meet the requirements for use in resource-poor settings. Fluorescent-Assisted Microscopy Fluorescent-assisted microscopy (FAM)-based methods—for example, the quantitative buffy coat (QBC) method [45], incorporation of a fluorescent probe (fluorescence in situ hybridization [FISH]) or of parasite DNA [46], or antigen staining—has been used to a limited extent in various programs. FAM methods may eventually speed up slide reading and reduce operator error. High-throughput FAM may become possible if high specificity can be maintained by the absence of low artifactual staining. However, at present FAM cannot differentiate between species, a capability considered a major advantage of light microscopy over today's antigen-detection tests, although species-specific markers for FISH assays and fluorescent-tagged monoclonal antibodies are being developed. In addition, the applicability of FAM to parasite quantitation is not clear and FAM requires specialized equipment that will limit where it can be used. Antigen-Detecting RDTs RDTs based on the detection of specific parasite antigens that use a platform design of lateral immunochromatographic flow (dipsticks or plastic cassettes) have started to change the way malaria is diagnosed in endemic settings. RDTs are increasingly being used at the community level and in control programs for case management and in prevalence surveys. Good RDTs reliably detect parasitemia down to 100–200 parasites/µl, which is comparable to the sensitivity of routine well-performed light microscopy [47]. In general, RDTs are simple to use. With training and quality assurance, they can be used by peripheral facility and village health workers to determine whether malaria parasites are present in a patient. However, increasing use in field settings suggests that many commercial RDTs have variable detection thresholds and field stability [48]. Systems for monitoring performance and routine quality control of manufactured product lots are therefore required. Three parasite antigen types are targeted by currently available RDTs. Histidine-rich protein 2 (HRP2)-detecting tests have high sensitivity and specificity for P. falciparum but detectable antigen frequently persists after parasite clearance. The presence of HRP2 deletions in areas of South America also limits the use of these tests [49]. Commercial tests for Plasmodium lactate dehydrogenase (pLDH) have yielded variable results and, in general, have less potential to detect low parasite densities and greater susceptibility to deterioration under storage at high temperature than HRP2-based tests [48],[50]. However, species-specific (P. falciparum and P. vivax) and pan Plasmodium species-specific pLDH-based tests are available. Finally, tests targeting pan-specific parasite aldolase have shown inadequate detection thresholds in recent comparative trials, possibly because of the low concentrations of this target antigen in parasites [48]. The development of RDTs targeting other antigens may improve species identification (critical for elimination of P. vivax) and address some of the deficiencies of the current RDTs. In particular, current tests for P. vivax, which lack consistency in sensitivity and stability, might benefit from the use of monoclonal antibodies that target new antigens or improved manufacturing standards. Quality-Control Methods for Malaria RDTs Standardized quality-control methods for RDTs are important for confirming test quality and ensuring that health workers and patients trust results. As with microscopy [39], quality assurance of RDTs requires a comprehensive, organized program [47],[51]. Such programs are absent in many countries. The development of standardized panels containing known concentrations of target antigens will greatly broaden the reach, applicability, and sustainability of RDT quality-control programs. Parasite-based panels that use cryo-preserved parasite preparations [52] are currently available at a centralized (regional) level, but panels that are easier to standardize and widely available are needed. Likewise, standardized regulatory approval and procurement in keeping with best practices will reduce the requirement for investment by individual procurement agencies in quality control and product evaluation programs. The development of low-cost tools for confirming quality at the national and field level (positive controls [53]) is also necessary to improve reach and sustainability. Finally, novel approaches that use PCR to confirm RDT results might eventually be useful. Diagnostic Tools for Active Case Detection and Community Surveys For use in active surveillance and case finding, a diagnostic tool must be suitable for use in resource-poor field settings. Diagnostic tests must therefore be supportable at the district level or below, be affordable and low-maintenance, require less operator training than current methods, and have a low requirement for consumables. They should also detect very low parasite densities and distinguish between all locally prevalent Plasmodium species, be minimally invasive, and provide sufficiently rapid results to facilitate effective case management when an infection is identified. For use in prevalence surveys, where immediate management of asymptomatic parasitemia is not the aim, testing at a more centralized level may be sufficient. But, even in this context, rapid feedback and case management are desirable. Molecular (DNA) Detection Current methods of detecting circulating parasites by demonstrating parasite DNA through amplification of ribosomal RNA (rRNA) genes by PCR assays represent the overall gold standard of malaria diagnostics. When sample concentration methods are used, 0.5 parasite/µl unconcentrated blood or lower can be detected. Quantitative PCR can be used to determine the concentration of circulating DNA and therefore estimate the density of circulating parasites. Survey and testing techniques, including pooling of samples, can reduce costs [54] but also reduce sensitivity to some extent by diluting samples. At present, the application of PCR-based methods is restricted to well-equipped laboratories with specially trained technicians, partly because the need to avoid contamination (which leads to false-positive results) requires a very high standard of laboratory practice. PCR capacity is consequently limited in resource-poor malaria-endemic countries, where considerable investment would be required to establish and maintain it. PCR capacity-building programs are underway in several African countries through the Malaria Clinical Trials Alliance (MCTA). However, its restriction to well-equipped laboratories limits the applicability of PCR for surveillance and asymptomatic parasitemia case finding because timely feedback to allow the treatment of identified cases is impossible in most endemic areas. The development and field demonstration of high-throughput field-applicable PCR technologies is therefore needed to allow wider use of PCR in endemic settings. Another molecular detection method based on DNA amplification is loop-attenuated isothermal amplification (LAMP). This method, which amplifies DNA (usually mitochondrial) with a single thermal cycle, has the potential to reduce the training and infrastructure requirements of molecular diagnosis [55]–[57], and would allow the timely feedback of results needed for case management. LAMP could also be used for surveillance, for detection of low-density parasitemia, and for monitoring parasite presence in antimalarial drug-efficacy monitoring and drug trials. However, LAMP has not yet been adequately field tested for wide-scale use or developed in a format suitable for the processes of high sample numbers. Hemozoin Detection Hemozoin, a by-product of Plasmodium metabolism, can be detected through refraction/absorbance of laser light of certain frequencies, and has been used to detect malaria and to determine species. Current field-ready technologies are based on flow cytometers. Their application is limited to screening, however, because of low sensitivity at low parasite densities [58]–[62]. Current research activities include the development of transcutaneous hemozoin detection. If sufficiently sensitive and specific, this approach might offer a noninvasive test for malaria for mass-population screening of, for example, individuals moving into a malaria elimination area. Hemozoin detection may find a place in routine case management if appropriate tools can be developed. Antigen-Detection Tests Current antigen-detecting RDTs (see earlier for details) are likely to miss a significant proportion of asymptomatic cases in low-transmission settings [16],[22],[23],[39]. Thus, although the current generation of RDTs can indicate the presence of malaria in a community, they cannot determine the true prevalence of parasite carriage. Research aimed towards increasing the sensitivity of existing RDTs may not change this situation because of the limitations of the currently available technology. Some antigen-detecting ELISAs are more sensitive than RDTs. Furthermore, because they can also be used to quantify antigen, they have been used to monitor drug efficacy. Antigen-detecting ELISAs may also facilitate high-throughput testing. However, their use is currently limited by laboratory and training requirements. Antibody Detection Antibody detection (see also [27]) is currently available in ELISA and RDT formats, and is a sensitive way to demonstrate past exposure to malaria parasites (past infection). Because antibodies may not be detectable in blood-stage infections of very recent onset, these tests are inappropriate for case management. However, they may be useful in detecting established P. falciparum infections in which the blood-stage parasite density has fallen below the limits of light microscopy or antigen-detecting RDTs [63]. Detection of antisporozoite antibodies (so-called anti-CSP antibodies) alone or in combination with antibodies to blood-stage parasites has also been suggested as a surrogate for detecting individuals with a high likelihood of carrying P. vivax hypnozoites (evidence of infection) [64]–[68]. However, anti-CSP antibody responses are usually low and transient, especially in areas of low and moderate transmission, which renders this test unreliable. Because antibody-detecting tests can identify parasite-infected individuals who are undetectable by antigen detection or light microscopy because of low parasite density, they could be used to screen populations such as migrants or blood donors to identify asymptomatic individuals at risk of transmitting malaria. They could also be used for identifying foci of recent transmission in areas that are otherwise malaria free and to determine the presence or absence of recent malaria transmission in specific populations, such as young children. They therefore have potential applications in confirming areas free of transmission during a defined period, provided they are further refined and developed in terms of sensitivity and specificity. Specific Issues for Reduction and Elimination of P. vivax Transmission Detection of Hypnozoites P. vivax detection and management will become increasingly important as control measures reduce P. falciparum transmission. In many programs, P. vivax already causes the majority of clinical malaria episodes. Because P. vivax can remain latent in the liver but produces relapse, its effective management normally requires the use of 8-aminoquinolones to clear hypnozoites from the liver. No current diagnostic technique is capable of detecting P. vivax hypnozoites, and none are in development, although tests that can detect the presence of hypnozoites are a key research and development need wherever and whenever elimination has a chance of becoming a realistic goal. While symptomatic cases of P. vivax can be assumed to harbor liver stages and managed accordingly, a method for detecting hypnozoites would enable populations in P. vivax-endemic areas to be screened during the nontransmission season for asymptomatic individuals likely to have relapses who could then be treated before they become symptomatic and transmit in the following transmission season. Screening could therefore reduce the use of 8-aminoquinolones in mass-treatment programs in P. vivax-endemic areas, which would reduce the probability of drug-related severe side effects in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals (see next section). At present, compliance issues with the long course of primaquine (generally 14 days) have limited the broad application of this approach, and therefore the need for a diagnostic test for hypnozoites [24]. Potential biomarkers to detect hypnozoites include direct markers of metabolic activity, released antigens, markers of host immune response, and indirect serological markers of other stages (e.g., sporozoites). A lack of known markers of hypnozoite metabolic activity and markers of immunity limits the potential to assess the likely gains from investment in this area, and more knowledge of the biology of hypnozoites, perhaps through the development of liver-stage cultures, is required to determine whether such tests can be developed [69]. Detection of G6PD Deficiency The only drug currently licensed for the radical cure of P. vivax infection is primaquine, and the only investigational drug showing promise is tafenoquine, Both these 8-aminoquinolones cause hemolysis in G6PD-deficient individuals, the clinical importance of which varies with the particular G6PD-deficiency phenotype, and the starting hemoglobin concentration, and may depend on how the drugs are administered [70]. Because eliminating P. vivax reservoirs will probably involve the use of a hypnozoiticidal drug [24], unless a non–8-aminoquinolone drug is developed, G6PD testing is likely to be required for wide-scale elimination of P. vivax. The requirements for such a test differ somewhat from those of parasite-detecting RDTs, because testing should only be required once in a lifetime and is not urgently required; the use of hypnozoiticidal drugs can be delayed if necessary. So, for example, a G6PD test does not have the stability requirements of an antigen-detecting RDT. Current tests for G6PD deficiency nevertheless have limitations regarding storage requirements and the complexity of the procedure, so research is needed to develop new tests. Importantly, addressing G6PD deficiency will also involve research into test implementation—how should samples be tested, where should tests be done, and how should results be recorded to facilitate retrieval? Moreover, to decide whether further development of field-applicable G6PD tests is needed also requires more data on the distribution of G6PD phenotypes and on the efficacy and safety of alternatives to the standard hypnozoiticidal primaquine regimen. Other Research Priorities for Future Malaria Diagnostics Noninvasive Sampling Current RDTs detect antigen in peripheral blood samples obtained by finger prick. This method is generally acceptable for case management in the formal health care sector, but it presents some logistical challenges at the community level and in some private sector settings, particularly with regard to the potential risks of blood-borne infection. In addition, invasive tests may not be fully accepted in some settings, particularly when taking samples from asymptomatic individuals, which could diminish access to malaria diagnosis, treatment, and surveillance. Noninvasive sampling (for example, saliva or urine collection) has the potential to overcome these impediments but, at present, the limitations of sensitivity of nonblood sampling are even greater than the limitations of blood sampling combined with antigen-detecting RDTs for screening and surveillance [71]–[73]. Published trials of antigen sampling from saliva and urine, for example, have demonstrated inadequate sensitivity, probably because of the low concentration of available antigen in these samples [71],[74]. Urine sampling may also present practical and cultural constraints. Techniques that concentrate antigen may have potential if they can be made practical for use in low-resource settings, but no such techniques are currently available. Additionally, if quantification is required, these methods would need to incorporate a standard to allow for variations in concentration of saliva or urine. Multiplexing Multiple diagnoses from one assay or “multiplexing” is made possible by, for example, the inclusion of multiple PCR-based nucleic acid probes in a single test or the inclusion of antibodies specific for nonmalarial diseases or of pathological markers of disease severity. The inclusion of antibodies targeting nonmalarial diseases in RDTs in their common format (visually read immunochromatographic tests) increases the technical challenge of achieving the stability needed for sufficient shelf life and makes interpretation of results more complex. The usefulness of such tests is also limited by the ability of the health system to provide appropriate management for each etiological agent that may be identified, and the highly variable prevalence of potential target differential diagnoses within malaria-endemic areas. However, as malaria rates drop through successful control programs, the overall fever rate may not change significantly. Accordingly, it will be increasingly important to integrate management of malaria with that of other febrile diseases, at the point of diagnosis, if the program is to remain credible and sustainable (see also [27]). Nonmalarial fever will need to be diagnosed with sufficient accuracy to allow practitioners to manage the main causes of fever successfully and to at least distinguish major bacterial infections manageable with common antibiotics from nonbacterial infections. Research and development needs for multiplexing include the development of field-ready multiplex tests for malaria and nonmalarial diseases, which are not currently widely available, and research into the inclusion of markers for inflammation or severe disease in malaria tests, which would offer the potential to guide the referral of patients who require urgent management (see also [27]). Finally, the issue of complexity of interpretation in multidisease diagnostics needs to be addressed by the development of automated readers, particularly in combination with technology that allows multiple distinguishable markers to be captured in a single test line. Pooling Samples for Surveillance, Gametocyte Detection, and Genotyping Three other potential research priorities were discussed by the Consultative Group, but the consensus was that research into pooling samples, gametocyte detection, and genotyping was less urgent. Thus, although the idea of pooling individual samples to detect parasitemia in very low transmission settings is intrinsically appealing and could result in cost savings using currently available tests, the Consultative Group felt that the limited quantity of antigen or DNA in pooled samples would severely limit the sensitivity of this approach. Similarly, the group decided that the development of a detection test for gametocytes should not be viewed as a high priority requirement. Finally, although WHO guidelines recommend genotyping of parasites during elimination phases [39], there is debate about whether research into methods for genotyping would be programmatically useful, particularly for P. falciparum. The resource needs to achieve genotyping are massive, and the long feedback time for results is likely to reduce the exercise to one of academic interest only. Genotyping could be useful for P. vivax infections to determine whether a blood-stage infection is new or a relapse. However, it has not yet been possible to develop methods that will reliably distinguish between relapse, recrudescence, and reinfection because of the multiplicity of hypnozoite genotypes present in P. vivax-infected individuals. Genotyping might, however, be useful in suspected outbreak or in new foci of transmission to determine the source of parasites, particularly when elimination in an area is being confirmed [26]. Sustaining the Effort The central importance of active case detection in each programmatic stage towards elimination has been comprehensively dealt with by several of the other malERA Consultative Groups [24]–[27]. However, whether active case detection can be achieved at sufficiently high and sustainable levels will depend to a great extent on the field utility and costs of the diagnostic and other tools eventually adopted for this role and on how these tests are used. Importantly, when malaria is rare and no longer perceived by local health services and the community to be of significant public health concern, ways must be found to maintain the resources needed to test febrile cases for parasitemia to prevent resurgence of infection. Because malaria parasite detection will be competing for resources with other disease priorities with higher mortality, it will be necessary to target diagnostics to those cases more likely to be malaria rather than necessarily screening whole populations (although some form of screening, and the ability to respond rapidly to reintroduction, will continue to be necessary [26]–[28]. It will also be important to integrate malaria detection more fully with other health service activities and, as nonmalarial causes of fever become predominant, it will be critical to provide appropriate diagnosis and management of alternative causes so that compliance is maintained through confidence in the ability of the health system to provide solutions to clinical problems. Conclusions Malaria elimination in the most challenging settings will require improvements in point-of-care tests for case management, and the development of new tests capable of identifying very low parasite densities in asymptomatic individuals in field settings for mass screening and treatment. As a result of our discussions, we propose a research and development agenda for diagnoses and diagnostics that should stimulate and facilitate the development, validation, and use of such tests (see Box 1). Box 1. Summary of the Research and Development Agenda for Diagnosis and Diagnostics Overarching questions What proportion of effort should be directed to screening and surveillance versus early case detection at various time points in elimination? Question to be addressed by modeling and validated in different areas. Do we need microscopy for elimination, or can other tests replace it? Programmatic issues Further data on thresholds of (i) parasite density likely to cause symptoms in low-transmission settings with variable or waning immunity, and (ii) transmission potential of cases with parasitemia below the threshold of microscopy and RDTs Diagnostic tests for nonmalarial febrile illness in malaria-endemic and malaria-elimination settings Distribution of severe G6PD variants Technical issues: case-management tools High priority Stable tests for case management in low-training, low-technology settings with sensitivity sufficient for community-level case management, including: Antigen-detecting RDTs Greater consistency in P. falciparum detection, particularly in the case of nonpersistent antigens More sensitive and stable tests to detect non-P. falciparum parasites Clarification of the programmatic/implementation requirements that will ensure good impact in the field Standardized low-cost positive controls for antigen-detecting RDTs suitable for field use Sustainable tools for quality control of RDTs at a country level. Further investigation of nonblood sampling to determine the potential for detecting recoverable antigen in these samples. More consistent, reliable staining methods for microscopy G6PD deficiency mapping and identification (if 8-amino-quinolones are to be used) Medium priority Multiplexing: Other diseases, markers of severity Field G6PD detection (may be more important if tafenoquine approved), or raised priorities for P. vivax relapse prevention Tools to standardize and improve microscopy interpretation Low priority Hypnozoite detection (becomes a high priority if feasibility can be demonstrated through further research on hypnozoite biology, identifying good biomarkers). Technical issues: surveillance tools High priority Field-applicable tools for detection of low-density parasitemia in a high-throughput manner, suitable for surveys and active detection of parasite carriage in time to allow management of positive cases Tools for minimally invasive, very rapid detection of low-density parasite infections suitable for screening of migrants/travelers Innovation with potential for major operational impact Noninvasive, low-density parasite detection Low-hanging fruit with immediate application for elimination High-throughput field molecular detection, capable of use at district level or below Positive control methods for RDTs Because malaria generally occurs in low-resource settings, the profits likely to be made from malaria diagnostic development and manufacture, particularly in the face of low mortality, are limited. The current market place for malaria rapid tests is dominated by small to medium-sized manufacturers, who are unlikely to be able to make the major investments needed to address these priorities alone. Thus, the role of donor agencies and product development partnerships and research institutions in enabling research and development and in providing the expertise and field access necessary to shape products to meet program needs will be an essential element of diagnostics development. Critically strong and focused, mainly public-private, partnerships will need to built and nurtured.

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A Research Agenda for Malaria Eradication: Monitoring, Evaluation, and Surveillance

(2011)

Summary Points As countries approach malaria elimination, monitoring, evaluation, and surveillance activities will need to shift from measuring morbidity and mortality to detecting infections and measuring transmission Diagnostic tools (in particular, practical, field-ready tools for the detection of asymptomatic infection and DNA-based and serological biomarkers for malaria infection and transmission), and methods for tracking population movements will need to be developed and improved Development and use of better malaria distribution maps to guide elimination efforts requires more research Research is needed to assess and compare the performance of malaria transmission metrics at near zero transmission; new metrics will need to be developed for use in this setting Research should also be undertaken to test and improve the feasibility, efficiency, and cost-effectiveness of new information systems Introduction Monitoring (the systematic tracking of program actions over time) and evaluation (the examination of progress and its determinants) activities measure how well public health programs operate over time and whether they are achieving their program milestones (markers of progress within and transition between phases) and ultimate goals. In the context of malaria program scale-up, monitoring and evaluation focuses on the evaluation of burden reduction, specifically morbidity and mortality [1]. However, as programs successfully reduce transmission to near-elimination levels, the measurement of malaria-associated morbidity and mortality burden becomes increasingly difficult and insensitive, particularly since a substantial proportion of infections will be asymptomatic in countries that experienced high infection rates in the recent past. Thus, burden measures that only detect clinical illness will not provide good estimates of ongoing transmission as countries approach elimination, and malaria program monitoring and evaluation and surveillance methods will need to focus on detecting infections (with or without symptoms) and measuring transmission dynamics as the primary indicators of interest. The malERA Consultative Group on Monitoring, Evaluation, and Surveillance focused on defining the monitoring and evaluation and surveillance research and development needs as malaria elimination efforts unfold over the next 5–20 years. Information gaps and research needs were identified by the group by considering several broad thematic areas: lessons learned from countries that have recently achieved malaria elimination [2] or elimination of other diseases; the required evolution of the malaria monitoring and evaluation framework and indicators; surveillance as an intervention to reduce transmission; measurement of transmission interruption and maintenance of zero transmission; the tools (currently available and in the pipeline) needed, including diagnostics (screening, confirmation, and transmission measurement), mapping, and communication; and implementation issues. Information and research needs that were identified include: systematic reviews of existing information and experience, and assembly of that work into guidance; protocol or standards development for conduct of certain activities; and research and development activities to produce new information where guidance or experience does not exist, and new tools where these will enhance capabilities. The World Health Organization (WHO) and the Roll Back Malaria (RBM) Global Malaria Action Plan (GMAP) characterize different “phases” of malaria control as programs progressively reduce transmission, though it is understood that these phases are part of a continuum rather than abrupt shifts [3],[4]. At high levels of transmission, initial efforts are focused on scaling up for impact (SUFI). Sustained control efforts subsequently lead to further transmission reduction. As very low levels of transmission are reached, programs move from a focus on control to a focus on pre-elimination and elimination, and finally prevention of reintroduction. Where appropriate, we shall indicate where proposed research and development activities would fit into this malaria elimination framework. Lessons Learned from Other Diseases or Current Malaria Elimination Programs Several diseases other than malaria have been proposed for eradication or elimination. General lessons learned from these other disease elimination efforts have been summarized and underscore the critical role that monitoring and evaluation and surveillance play in these efforts [5]–[9]. The essential role of monitoring and evaluation and surveillance in informing elimination program efforts is particularly clear in past smallpox efforts and ongoing polio activities. Many countries have either eliminated or are in the process of pursuing malaria elimination. There is, therefore, a clear need to systematically review and summarize the monitoring and evaluation and surveillance lessons learned from both successful and unsuccessful disease elimination programs. In the context of malaria elimination, efforts are underway to summarize and disseminate recently accrued experience [2],[10]. This review work should be done even before the elimination phase. General needs for monitoring and evaluation and surveillance that have already emerged from experience with elimination efforts for malaria and for other diseases include the need for: improved management of systems; improved identification of infected individuals; enhanced methods for engaging and developing community support; improved information sharing for advocacy (at the community level and involving high level leaders); and improved ways of conducting surveillance activities in the private sector. Past experience also indicates that current and future tools and strategies for monitoring and evaluation and surveillance will need to be tailored to the individual epidemiological, entomological, and socio-cultural situation. Monitoring and Evaluation Framework and Indicators The current Monitoring and Evaluation Framework for malaria comprises a series of activities, namely, Assessments and Planning, Inputs, Processes, Outputs, Outcomes (intermediate effects), and Impact (long-term effects; Figure 1A) [1]. Each part of this schema can be monitored with a specific set of indicators that tracks progress in program implementation. Historically, the malaria community has focused on illness and mortality reduction as indicators of impact, but will these and the other current indicators shown in Figure 1A serve us well for elimination efforts? 10.1371/journal.pmed.1000400.g001 Figure 1 (A) Malaria monitoring and evaluation framework and illustrative data types. Source: adapted from [3]. (B) Evolving malaria monitoring and evaluation framework with emphasis on transmission. Image credit: Fusión Creativa. There is general consensus that these coverage indicators will continue to be useful because high intervention coverage will need to be maintained en route to elimination, especially in Africa where transmission is intense. However, as elimination is approached, other indicators will need to be adapted and new ones will need to be introduced. For example, indicators that track the proportion of cases with parasitological confirmation or that focus on coverage of individuals in specific geographic areas where foci of transmission are located will be needed. Similarly, if transmission blocking vaccines are deployed, coverage with the vaccine will need to be tracked. The utility of indicators and databases for parasite strain information that could differentiate indigenous from imported cases may need to be evaluated. In addition, methods and indicators for tracking population movements within and between countries and quantifying their contribution to the risk of malaria transmission may be useful. Furthermore, greatly reduced malaria morbidity and mortality levels (achieved through intervention scale-up and sustained control) will need to be monitored, although ultimately, as elimination approaches, the measure of impact will need to be infection and transmission (sometimes from introduced cases), and programs will need to include active case detection and case-based investigation and response within a revised Monitoring and Evaluation Framework (Figure 1B) (also see [11],[12]). Surveillance as an Intervention As noted in the Introduction, monitoring and evaluation are critically required for measurement of malaria control program success. Over time, the term “surveillance” has become somewhat synonymous to some with monitoring and evaluation, but the WHO Global Malaria Eradication Program (GMEP), which lasted from 1955 to 1969, defined surveillance quite specifically as an integral action or intervention within that eradication program (Box 1) [13]. Box 1. Definitions of Surveillance Per conventional use: Surveillance is the ongoing, systematic collection, analysis, and interpretation of data, often incidence of cases of disease or infection. Surveillance data are used to plan, implement, and evaluate the progress in public health programs. Per the WHO Global Malaria Eradication Program: In malaria eradication terminology, surveillance was that part of the program aimed at the discovery, investigation, and elimination of continuing transmission, the prevention and cure of infections, and the final substantiation of claimed eradication. The individual functions of surveillance are case detection, parasitological examination, antimalarial drug treatment, epidemiological investigation, entomological investigation, elimination of foci by either residual spraying or mass drug administration, case follow-up, and community follow-up. In this definition, surveillance is seen as an intervention [16]. Malaria programs contemplating an elimination strategy must be prepared to change their strategies of monitoring and evaluation and surveillance as transmission is reduced [14],[15]. Thus, many countries begin scale-up of malaria control interventions with relatively high levels of malaria transmission and develop monitoring and evaluation programs that rely on the collection of routine information (often from health facilities and health management information systems) and on periodic population-based surveys. Together, these approaches collect information on intervention coverage and use as well as changes in malaria burden, but, as transmission intensity drops to near elimination levels, surveillance as defined by GMEP needs to increase (Table 1). 10.1371/journal.pmed.1000400.t001 Table 1 Program activities and methods for transmission reduction in populations. Potential Activity Description and Purpose Prevalence surveys Usually population-based surveys to stratify risk, evaluate impact of interventions, and track progress towards elimination Active case detection Regular efforts to ascertain fever and infection in the community Focused screening for infections (“active infection detection”) Targeted search for main sources of rare cases (of Pf, Pv, drug-resistant Pf) and eliminating them Case investigation Detecting infections/cases around index cases for response Mass screening and treatment Screening large segments of the population to find and treat cases Mass drug administrationa Administration of treatment to large segments of the populations regardless of infection status to reduce infections in a population with a relatively high infection rate Surveillance for drug-resistant parasites Enrollment of cases and follow-up of presence, density, or absence of parasites for in vivo resistance surveillance to assess treatment efficacy Detection of gametocytaemiab Find infections that contribute to ongoing transmission so that they can be treated to reduce transmission Confirmation of elimination/detection of reintroductionc Measurement of ongoing infection and transmission through sampling and use of biomarkers such as DNA or serology Border screening/transit screeningd Rapid diagnostic testing of people crossing borders to allow immediate treatment of positives a Note that mass drug administration is controversial for a variety of reasons but is presented here for completeness sake as it has been used to some benefit in the past (see also [25]). b See also [11] and [25]. c See also [11] and [44]. d See also [12]. Pf, P. falciparum; Pv, P. vivax. In the context of malaria elimination programs, the goal is to achieve complete reporting of each case of infection to health authorities, regardless of whether symptoms of fever or illness are present. Critically, malaria control programs usually identify individuals with fever/symptoms and laboratory-confirmed malaria parasite infection as “malaria cases,” but do not systematically assess the extent of asymptomatic malaria infection. As transmission decreases and individuals have less exposure to malaria, they lose acquired immunity and a higher proportion of infections present with symptoms. However, in populations in rapid transition from high exposure to low exposure, the proportion of persons with enough acquired immunity to harbour asymptomatic infections may remain substantial [16]. For example, in a low transmission setting in the western Pacific, >80% of infections identified in a recent cross-sectional population-based survey were afebrile [17]. Because asymptomatic infections are a reservoir of transmission to others, it is critical to seek all infections rather than just symptomatic cases as a method to reduce transmission. For surveillance, standardized definitions for case/infection reporting are needed, along with a strong mandate for notification to health authorities of all malaria cases/infections in both public and private settings [18]. An important area for further research, therefore, is to investigate how tools such as legal requirements, financial inducements, and other novel approaches can be used to improve the coordination of detection and reporting of infections from the private sector to public health authorities. Importantly, all malaria cases/infections must be epidemiologically investigated, and linked to geographic and laboratory data (species and genotyping) so that the source and potential spread of infection can be quickly addressed. Furthermore, reporting systems must be able to analyze reported data rapidly to assess trends over time and place, particularly as transmission drops and cases of infection become increasingly focal in distribution [19]. Although some control programs in endemic areas have malaria early warning systems, these systems need better performance characteristics (for example, better linkages with local information systems) before they can be truly useful in malaria elimination. Assuming that effective infection detection and prompt and timely reporting exist, it is crucial that surveillance systems respond effectively to detected foci of infections and ultimately to individual infections in order to reduce transmission to a reproduction rate (R 0) of <1. Although many programmatic responses to detected infections exist, there is neither a systematic description of such responses nor a well-defined evidence base to suggest the optimal strategic approach. For surveillance to be effective as an intervention, research on useful and efficient modes of both detection and response must be undertaken [20]. At the most basic level, it is currently unclear when programs transitioning to very low transmission conditions should add active case and infection detection to their response strategies, and whether additional vector control interventions are needed [21]. The evolution of these actions and the optimal sequence and mix needs further evaluation as is also discussed in the malERA paper on modeling [22]. Finally, countries embarking on malaria elimination must establish a system for continuous data validation to identify problems and to prepare for the process of certification of elimination [23],[24]. The concept of “good surveillance practices” should be implemented early to facilitate evaluation of the quality of the surveillance programs in the process of certification. Any system needs to be responsive and iterative to improve surveillance. Tools to Improve the Efficacy and Efficiency of Malaria Elimination The overall strategic approach and mix of actions to address transmission is critical, but the identification and development of key tools and actions to optimize these strategic actions is equally important. Improved diagnostics for screening and surveillance, optimal use of drugs to reduce transmission [25], better mapping and use of mapping to track foci of infections, and improved communications for timely sharing of information and response are all important. Diagnostics Tests that are sensitive enough to detect asymptomatic infections (as opposed to symptomatic infections or cases) are needed for elimination [26]. Ultimately, for simplicity and efficiency, it will be preferable to have the same test for both surveillance and case management. Elimination has already been achieved in some areas of low endemicity using currently available diagnostic tools (principally microscopy), but future efforts will include areas of previously high transmission that have achieved significant reductions through intervention scale-up. Existing diagnostic tools will need to be improved to achieve elimination in these more challenging transmission areas. Microscopy has some limitations in human resource capacity needs, sensitivity and ease of widespread use at the community level. Similarly, currently available rapid diagnostic tests (RDTs) have limited sensitivity compared with PCR, and need to be improved in terms of specificity, ease of use, cost, shelf stability under tropical conditions, Plasmodium vivax detection, ability to return to negative after treatment, and multispecies detection capacity where this is an issue [27]. As discussed in the malERA paper on Diagnoses and Diagnostics [11], rapid techniques not requiring blood sampling could provide major breakthroughs. There is also a need to address issues around effective supervision and support. In particular, as transmission decreases, residual foci of infection may cluster in difficult-to-access populations that are underserved and less likely to access the health system. Strategies need to be developed and tested for improving access to and tracking of these populations for screening and surveillance of infection. Finally, for eradication, diagnostic tools to measure transmission and its interruption will be critical. There is considerable interest in refining current serological tests (ELISA) to assist in the diagnosis of recent infection (incidence). Serology and other potential biomarkers are discussed in more detail below. Mapping and Stratification Maps of the global distribution of P. vivax and Plasmodium falciparum that were generated by the Malaria Atlas Project have recently been published, but there is little research on how best to use these maps in the context of elimination [28],[29], and current mapping initiatives are limited by data availability, especially for scenarios that require high resolution. Maps can help define which low transmission areas are possible elimination targets, and can define the limits of adverse conditions for transmission, such as aridity and temperature. Maps can also help to determine where additional survey work is necessary for better spatial resolution of endemicity. On a global scale, mapping malaria distribution will allow stratification to inform decision making and allow for interventions to be targeted or prioritized [29],[30]. When allied with modeling, such maps can indicate which combinations of interventions may be most appropriate and how much these will cost [22],[31]. However, for optimal utility, maps will need to be sensitive to different ecological scenarios and should provide enough detail of the principal factors governing transmission. From a technical point of view, more detailed maps are feasible, and linking mapping databases with other technologies such as Google will increase ease of access to mapping information. For maps at regional or national levels, the spatial resolution of the information required is greater than that required for global scale risk mapping. Integration of mapping activities with the outputs of surveillance systems and other data sources (for example, intervention coverage and vector distribution) can provide the level of detail required to support effective elimination efforts. However, the incorporation of existing techniques for rapid mapping and the development of methods for optimal information dissemination to all levels of the malaria control programme remain major research challenges, as does the need to update protocols that do not currently incorporate our ability to image, map, and display information remotely, technologies that have been revolutionized since the Global Malaria Eradication Program. As we progress closer to the goal of elimination, finer scale mapping will be required to identify residual foci [32]. Geographical reconnaissance remains part of control and elimination attempts in many countries and relies on local knowledge to make largely hand-drawn maps of potential foci and known vector breeding sites. This approach needs to be modernized to include a simple, user-friendly, and consistent methodology for micro-mapping. High resolution satellite imagery can detect households and water bodies at unprecedented spatial resolutions and thus replace some of the logistic burden in reconnaissance required to support elimination activities [33]. The use of maps to help find rare events such as individual cases of malaria is also a very poorly developed area that needs further research. Efficient signatures of transmission hotspots or disease foci (environmental, entomological, and human) are also not well known, so a final challenge will be to integrate novel monitoring and evaluation metrics with the existing mapping suite. Communication Technologies Technological advances in communications and reporting systems (data collection, aggregation, and dissemination) offer potential improvements for surveillance in the context of elimination and eradication. Other prerequisites for good communication and reporting include basic health systems, and the capacity to analyze and use data to improve program performance. Most importantly, it is only the relevant and useful surveillance information that is required for prompt and timely communication. Examples of potential enhancements to improve timely reporting include widespread implementation of cell phone technology [34], which has been used with considerable success in some areas such as Zanzibar and Madagascar to provide cluster detection and response [35]. Systems such as real-time internet Web-based reporting are also being explored. As noted above, the development of methods to integrate surveillance reporting technology with mapping tools is a priority. Critically, systems developed for collection, reporting, analysis, and dissemination of information must be structured so that they enhance decision-making and programmatic direction at the local (district) level. In addition, these systems must enhance the capacity of the program to provide useful and timely information to policy makers so that program status and progress towards elimination is clear and well explained [36]. Resistance and High-Risk Populations Tracking antimalarial drug resistance is an important activity in the context of malaria control, but it becomes less important in situations where there are relatively few cases who must all receive curative treatment. Thus, as elimination is approached, all outpatient therapy might be better administered as “directly observed therapy” as with tuberculosis. Because of inconsistent and inadequate access to health systems, difficult-to-access populations may be at increased risk of harbouring individuals with drug-resistant parasites. Strategies to improve access to these populations were discussed earlier (see also [25]). As elimination is approached, declining transmission and thus fewer cases pose considerable challenges to monitoring for drug resistance because recruitment of sufficient numbers of patients is difficult and thus studies are prolonged and expensive. Simple drug efficacy protocols worked into routine surveillance activities at sentinel sites may be of some use; follow-up of all treated cases may be another approach to ensure that individuals have cleared parasites [37]. Molecular markers for resistance could be useful for population-level screening, although new assays relevant to current treatment drugs, particularly the artemisinins, need to be developed. Simple field PCR-based tools would be of use, both for resistance testing and to differentiate recrudescence from new infections [11]. Although no vaccine is currently available, it is likely that vaccines may be in use in the next decade. A challenge will be to monitor vaccines for efficacy against antigenically diverse parasites in the population, for their preventive effects against severe disease, and for their effects in settings with changing transmission, as well as for their effects on transmission itself (see also [38]). Newer molecular biology approaches may be useful in which human genes are used to predict immunological responses. Case control methodology can also be used to evaluate vaccine performance [39]. Tools for Transmission Measurement: Metrics Accurate measurement of malaria transmission is essential for monitoring and evaluation of malaria control programs that are approaching interruption of transmission and elimination. Past and present metrics for measuring malaria transmission in humans in endemic regions were recently systematically reviewed [14] and include: the proportion of individuals in a population with a palpable spleen (spleen rate); the proportion of individuals in a population with a laboratory-confirmed parasite infection per unit time (parasite rate [PR]); and the annual parasite incidence ([API], the product of the annual blood examination rate and slide positivity rate) [13],[14]. The entomological inoculation rate ([EIR], the number of infective bites per person per unit time) remains the gold standard measure of transmission. A valid metric, or a combination of metrics, for measuring the interruption of transmission nationally or subnationally is critical as elimination is approached; but the existing metrics all have serious limitations when transmission is approaching zero, including the EIR, which is difficult, expensive, and virtually impossible to measure when there is very low transmission. For example, API (or alternatively annual case incidence) is an important metric of transmission that can be obtained from routine surveillance reporting even when the PR falls below 5%. However, to ascertain API accurately, all cases in the population must be identified through comprehensive and complete surveillance of the target population, ideally using both passive and active detection. API ascertained through passive detection alone only records those symptomatic individuals who are captured through the routine surveillance system and would, therefore, provide a biased (too low) estimate of transmission for the entire target population. Additionally, its failure to detect individuals with asymptomatic infections in the population would critically hinder the clearance of parasites from human reservoirs when working towards elimination. Similarly, to obtain an unbiased estimate of PR for a target population where the combination of passive and active detection is incomplete, probability sampling of the population is required (see next section also), but this is problematic when transmission is reduced to nonrandom residual foci of cases. Furthermore, using PR ascertained from probability biomarker surveys for validation of freedom from disease is challenging, with sample size and resultant uncertainty dependent on the probability of committing a type 1 and 2 error, the size of the population being sampled, and the sensitivity and specificity of the diagnostic test [40]. Thus, unless extremely large sample sizes are used, PR will provide imprecise measures at near zero transmission. Research is needed, therefore, to develop new metrics for transmission and to improve or modify data systems for these kinds of measurements. Tools for Transmission Measurement: Sampling and Surveys To assess progress in intervention scale-up, nationally representative household surveys, such as the Malaria Indicator Survey (MIS), Demographic and Health Survey (DHS), and the UNICEF Multiple Indicator Cluster Survey (MICS), are recommended data collection instruments, Such surveys can provide population-based, relatively accurate, estimates of malaria intervention coverage, and parasite infection prevalence in the population, and should be useful in assessing sustained coverage of malaria interventions on a periodic basis, typically every 3–5 years. However, once scale-up has been achieved and infection prevalence is approaching zero, or has been disrupted, such national surveys, with sample sizes typically of at least 2,000 households, would not be feasible for routine monitoring of low and/or focal malaria transmission. Alternative sampling methods for ascertaining population-based measures of malaria transmission are therefore needed. Ideally, such novel sampling strategies would approximate a “probability survey” (a survey having a known, nonzero probability of selection of all individuals for which it is desired to obtain estimates), while remaining logistically feasible to implement on a routine basis. Once transmission has been interrupted, population-based collection of biological samples for detection of present infections, or serology for detection of past exposure and infection, could prove important for routine monitoring of populations, although improved assays will be required. Such approaches might include routine sampling of populations through antenatal clinics, immunization programs, and schools. Assessment of the validity of these new approaches for obtaining relatively unbiased population estimates will be needed. To maintain interrupted transmission or elimination, malaria control programs need to be able to obtain representative and precise estimates of parasite exposure and present infections among mobile populations, especially those that frequently cross national borders. Although respondent-driven sampling (a sampling approach in which existing study subjects recruit future subjects from among their acquaintances) has been used for ascertaining point estimates among hidden populations, this approach would likely be inappropriate for monitoring malaria transmission among mobile populations. One approach that should be tested for routine monitoring of mobile populations is time location sampling (TLS), a variation of traditional two-stage cluster sampling in which the primary sampling units are time-location settings where mobile and/or hidden populations are known to congregate. Assessment of the accuracy of TLS estimates of parasite infection prevalence among mobile populations is needed, as well as cost-effectiveness in relation to other sampling methods. Biomarkers for Transmission Measurement Serologic methods are currently an area of renewed interest as a potentially valuable tool for robust transmission measurement. Serology has been used to measure malaria exposure in humans for many years and was prominent in early elimination attempts [41],[42]. But, as these elimination attempts were scaled back, so was the use of serological characterization. With little use over several decades, these serologic assays lacked standardized, reproducible, and objective methods [43]. Recent technological improvements (for example, techniques that facilitate the production of antigens) mean that serology has now become a much more robust tool for transmission measurement [44]. However, there is a need to standardize protocols and antigens; currently there are many different methodologies with associated variation in results. Fundamental issues relating to the generation and maintenance of antibody responses in children and adults also need to be addressed. Other research and development needs include the development of serological assays that are sensitive and specific for different Plasmodium species. Assays also need to be developed that show cumulative exposure to the parasite, as well as recent changes in transmission intensity by measuring both the prevalence and the magnitude of the antibody response. Serological methods might also be developed that distinguish between relapse and new infection with P. vivax by measuring exposure to mosquito saliva through the detection of antisaliva antibodies. PCR or similar molecular amplification–based methods may also prove useful for the measurement of transmission reduction/interruption, especially if pooled sampling and high-throughput automated techniques are used to handle large numbers of samples [45]. There is limited experience to date with these methods as tools to measure transmission; further research may help to elucidate their potential. For all biomarkers, the most desirable assays would not require blood sampling so research into biomarkers in saliva or other bodily fluids is needed. Finally, for all biomarkers, there is a need to develop criteria that define an area as “malaria free.” Concluding Remarks The new strategies proposed in this paper by the malERA Consultative Group on Monitoring, Evaluation, and Surveillance for eradication have major implications for implementation, and research is needed to test best systems of delivery for acceptability, feasibility, efficiency, and cost-effectiveness. Box 2 draws our discussions together in the form of a research and development agenda for monitoring, evaluation, and surveillance. Box 2. Summary of the Research and Development Agenda for Monitoring, Evaluation, and Surveillance Update the malaria monitoring and evaluation Framework to include transmission reduction, and develop key data elements for a surveillance system from a systematic review of previous elimination attempts Systematically review lessons learned from experiences with surveillance as an intervention to determine how it can be tailored to various programmatic settings Identify appropriate program time points for introduction of malaria infection detection in active or passive modes Develop improved diagnostic tools for use in monitoring and evaluation and surveillance, focusing on practical field-ready tools for detection of asymptomatic infection Develop information systems to monitor malaria infections, facilitate timely local program decisions and responses to reduce transmission Develop methods, indicators, and shareable databases for parasite strain information to better track transmission Develop methods for accessing and tracking population movements and quantifying their contribution and risk of malaria transmission Explore how maps can be constructed to: show the probability of a threshold of transmission being exceeded; incorporate a wider range of metrics such as serological and entomological data; assess cost-effectiveness of national stratification initiatives based on remotely sensed satellite data Perform a systematic review to assess and compare metrics of malaria transmission at near zero transmission levels; research the validity of novel metrics to measure transmission at near zero levels, and to measure transmission potential within areas where transmission has been eliminated Assess the precision, bias, feasibility, and cost-effectiveness of novel sampling methods for routine monitoring of present and past infections in target populations, including mobile populations Conduct research to develop biomarkers such as DNA-based methods or serology as monitoring and evaluation and surveillance tools

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Sentinel surveillance system for early outbreak detection in Madagascar

Laurence Randrianasolo, Yolande Raoelina, Maherisoa Ratsitorahina … (2010)

Background Following the outbreak of chikungunya in the Indian Ocean, the Ministry of Health directed the necessary development of an early outbreak detection system. A disease surveillance team including the Institut Pasteur in Madagascar (IPM) was organized to establish a sentinel syndromic-based surveillance system. The system, which was set up in March 2007, transmits patient data on a daily basis from the various voluntary general practitioners throughout the six provinces of the country to the IPM. We describe the challenges and steps involved in developing a sentinel surveillance system and the well-timed information it provides for improving public health decision-making. Methods Surveillance was based on data collected from sentinel general practitioners (SGP). The SGPs report the sex, age, visit date and time, and symptoms of each new patient weekly, using forms addressed to the management team. However, the system is original in that SGPs also report data at least once a day, from Monday to Friday (number of fever cases, rapid test confirmed malaria, influenza, arboviral syndromes or diarrhoeal disease), by cellular telephone (encrypted message SMS). Information can also be validated by the management team, by mobile phone. This data transmission costs 120 ariary per day, less than US$1 per month. Results In 2008, the sentinel surveillance system included 13 health centers, and identified 5 outbreaks. Of the 218,849 visits to SGPs, 12.2% were related to fever syndromes. Of these 26,669 fever cases, 12.3% were related to Dengue-like fever, 11.1% to Influenza-like illness and 9.7% to malaria cases confirmed by a specific rapid diagnostic test. Conclusion The sentinel surveillance system represents the first nationwide real-time-like surveillance system ever established in Madagascar. Our findings should encourage other African countries to develop their own syndromic surveillance systems. Prompt detection of an outbreak of infectious disease may lead to control measures that limit its impact and help prevent future outbreaks.

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Journal

Journal ID (nlm-ta): J Public Health Africa

Journal ID (iso-abbrev): J Public Health Africa

Journal ID (publisher-id): JPHIA

Title: Journal of Public Health in Africa

Publisher: PAGEPress Publications, Pavia, Italy

ISSN (Print): 2038-9922

ISSN (Electronic): 2038-9930

Publication date (Electronic): 04 February 2014

Publication date Collection: 04 February 2014

Volume: 5

Issue: 1

Electronic Location Identifier: 171

Affiliations

Faculty of Medicine, Lund University , Sweden

Author notes

Simrishamnsgatan 18, 21423 Malmö, Sweden. +46709269977. lak09dny@ 123456student.lu.se

Contributions: the authors contributed equally.

Conflict of interests: the authors report no conflict of interests.

Article

DOI: 10.4081/jphia.2014.171

PMC ID: 5345455

SO-VID: 7ed01318-2c9d-4168-be9e-014641294ef6

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 01 October 2011

Date revision received : 27 September 2013

Date accepted : 07 November 2013

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Figures: 3, Tables: 0, Equations: 0, References: 24, Pages: 5

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Authors: Willem A Odendaal, Jocelyn Anstey Watkins, Natalie Leon …

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A Research Agenda for Malaria Eradication: Diagnoses and Diagnostics

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