Laboratory challenges of Plasmodium species identification in Aceh Province, Indonesia, a malaria elimination setting with newly discovered P. knowlesi.

The discovery of the life-threatening zoonotic infection Plasmodium knowlesi has added to the challenges of prompt and accurate malaria diagnosis and surveillance. In this study from Aceh Province, Indonesia, a malaria elimination setting where P. knowlesi endemicity was not previously known, we report the laboratory investigation and difficulties encountered when using molecular detection methods for quality assurance of microscopically identified clinical cases. From 2014 to 2015, 20 (49%) P. falciparum, 16 (39%) P. vivax, 3 (7%) P. malariae, and 2 (5%) indeterminate species were identified by microscopy from four sentinel health facilities. At a provincial-level reference laboratory, loop-mediated isothermal amplification (LAMP), a field-friendly molecular method, was performed and confirmed Plasmodium in all samples though further species-identification was limited by the unavailability of non-falciparum species-specific testing with the platform used. At a national reference laboratory, several molecular methods including nested PCR (nPCR) targeting the 18 small sub-unit (18S) ribosomal RNA, nPCR targeting the cytochrome-b (cytb) gene, a P. knowlesi-specific nPCR, and finally sequencing, were necessary to ultimately classify the samples as: 19 (46%) P. knowlesi, 8 (20%) P. falciparum, 14 (34%) P. vivax. Microscopy was unable to identify or mis-classified up to 56% of confirmed cases, including all cases of P. knowlesi. With the nPCR methods targeting the four human-only species, P. knowlesi was missed (18S rRNA method) or showed cross-reactivity for P. vivax (cytb method). To facilitate diagnosis and management of potentially fatal P. knowlesi infection and surveillance for elimination of human-only malaria in Indonesia and other affected settings, new detection methods are needed for testing at the point-of-care and in local reference laboratories.

Intersectoral collaboration for the prevention and control of vector borne diseases to support the implementation of a global strategy: A systematic review.

INTRODUCTION: Vector Borne Diseases (VBDs) have a major impact on public health and socio-economic development. Inter-sectoral collaboration was recommended as one of the key elements of Integrated Vector Management (IVM), however limited evidence measures the effect and contribution of intersectoral approaches including but not only IVM. This systematic review aims to assess the existing evidence on all forms of inter-sectoral collaboration in VBD control and prevention, identify any gaps and develop a framework from a global perspective. METHODS: Articles were identified through a search of PUBMED, Science of Direct, Web of Knowledge, Google Scholar and WHO archives using key words and excluded duplications (n = 2,034). The exclusion of non-VBDs control and prevention interventions resulted in 194 eligible titles/abstract/keywords for full text assessment. Further exclusion of non-peer reviewed articles, non-declaration of ethical clearance, reviews and expert opinion articles resulted in 50 articles finally being included for analysis with the extraction of data on outcome, factor/s influencing the effectiveness, indicators of collaboration and sustainability. RESULTS: Of the 50 articles included in the analysis, 19 articles were categorized as of moderate-strong quality. All articles compared pre- and post-intervention outcomes against disease or vector variables. Three papers included outcome variables on intersectoral collaboration and participation indicator. However, no paper undertook component analysis by different sectors or different activities. Only one paper compared cost data for community-intersectoral intervention for IRS and traditional "vertical" IRS. Six factors were identified as influencing the effectiveness of inter-sectoral collaboration. Five of six factors are the main ones, namely the approach (37/47), resources (34/47), relationships (33/47), management (29/47) and shared vision (20/47) factors. A conceptual framework has been developed based on this review. CONCLUSION: This review shows the importance of inter-sectoral collaboration to reduce VBDs or vector densities. However, very few studies measured how much inter-sectoral collaboration contributes to the impact. Further high-quality studies using inter-sectoral collaboration indicators are recommended to be undertaken.

Costs and cost-effectiveness of malaria reactive case detection using loop-mediated isothermal amplification compared to microscopy in the low transmission setting of Aceh Province, Indonesia.

BACKGROUND: Reactive case detection (RACD) is an active case finding strategy where households and neighbours of a passively identified case (index case) are screened to identify and treat additional malaria infections with the goal of gathering surveillance information and potentially reducing further transmission. Although it is widely considered a key strategy in low burden settings, little is known about the costs and the cost-effectiveness of different diagnostic methods used for RACD. The aims of this study were to measure the cost of conducting RACD and compare the cost-effectiveness of microscopy to the more sensitive diagnostic method loop-mediated isothermal amplification (LAMP). METHODS: The study was conducted in RACD surveillance sites in five sub-districts in Aceh Besar, Indonesia. The cost inputs and yield of implementing RACD with microscopy and/or LAMP were collected prospectively over a 20 months study period between May 2014 and December 2015. Costs and cost-effectiveness (USD) of the different strategies were examined. The main cost measures were cost per RACD event, per person screened, per population at risk (PAR); defined as total population in each sub-district, and per infection found. The main cost-effectiveness measure was incremental cost-effectiveness ratio (ICER), expressed as cost per malaria infection detected by LAMP versus microscopy. The effects of varying test positivity rate or diagnostic yield on cost per infection identified and ICER were also assessed. RESULTS: Among 1495 household members and neighbours screened in 36 RACD events, two infections were detected by microscopy and confirmed by LAMP, and four infections were missed by microscopy but detected by LAMP. The average total cost of conducting RACD using microscopy and LAMP was $1178 per event with LAMP-specific consumables and personnel being the main cost drivers. The average cost of screening one individual during RACD was $11, with an additional cost of diagnostics at $0.62 and $16 per person for microscopy and LAMP, respectively. As a public health intervention, RACD using both diagnostics cost an average of $0.42 per PAR per year. Comparing RACD using microscopy only versus RACD using LAMP only, the cost per infection found was $8930 and $6915, respectively. To add LAMP as an additional intervention accompanying RACD would cost $9 per individual screened annually in this setting. The ICER was estimated to be $5907 per additional malaria infection detected by LAMP versus microscopy. Cost per infection identified and ICER declined with increasing test positivity rate and increasing diagnostic yield. CONCLUSIONS: This study provides the first estimates on the cost and cost-effectiveness of RACD from a low transmission setting. Costs per individual screened were high, though costs per PAR were low. Compared to microscopy, the use of LAMP in RACD was more costly but more cost-effective for the detection of infections, with diminishing returns observed when findings were extrapolated to scenarios with higher prevalence of infection using more sensitive diagnostics. As malaria programmes consider active case detection and the integration of more sensitive diagnostics, these findings may inform strategic and budgetary planning.

Two clusters of Plasmodium knowlesi cases in a malaria elimination area, Sabang Municipality, Aceh, Indonesia.

In malaria elimination areas, malaria cases are sporadic and consist predominantly of imported cases. Plasmodium knowlesi cases have been reported throughout Southeast Asia where long-tailed and pig-tailed macaques and Anopheles leucosphyrus group mosquitoes are sympatric. The limitation of microscopic examination to diagnose P. knowlesi is well known. In consequence, no P. knowlesi case has previously been reported from routine health facility-based case finding activities in Indonesia. This report describes two clusters of unexpected locally acquired P. knowlesi cases found in an area where Plasmodium falciparum and Plasmodium vivax infection had been eliminated in Sabang Municipality, Aceh, Indonesia. The difficulties in diagnosis and response illustrate challenges that Southeast Asian countries will increasingly face as the formerly common malaria parasites P. falciparum and P. vivax are gradually eliminated from the region.

Piloting a programme tool to evaluate malaria case investigation and reactive case detection activities: results from 3 settings in the Asia Pacific.

BACKGROUND: Case investigation and reactive case detection (RACD) activities are widely-used in low transmission settings to determine the suspected origin of infection and identify and treat malaria infections nearby to the index patient household. Case investigation and RACD activities are time and resource intensive, include methodologies that vary across eliminating settings, and have no standardized metrics or tools available to monitor and evaluate them. METHODS: In response to this gap, a simple programme tool was developed for monitoring and evaluating (M&E) RACD activities and piloted by national malaria programmes. During the development phase, four modules of the RACD M&E tool were created to assess and evaluate key case investigation and RACD activities and costs. A pilot phase was then carried out by programme implementers between 2013 and 2015, during which malaria surveillance teams in three different settings (China, Indonesia, Thailand) piloted the tool over a period of 3 months each. This study describes summary results of the pilots and feasibility and impact of the tool on programmes. RESULTS: All three study areas implemented the RACD M&E tool modules, and pilot users reported the tool and evaluation process were helpful to identify gaps in RACD programme activities. In the 45 health facilities evaluated, 71.8% (97/135; min 35.3-max 100.0%) of the proper notification and reporting forms and 20.0% (27/135; min 0.0-max 100.0%) of standard operating procedures (SOPs) were available to support malaria elimination activities. The tool highlighted gaps in reporting key data indicators on the completeness for malaria case reporting (98.8%; min 93.3-max 100.0%), case investigations (65.6%; min 61.8-max 78.4%) and RACD activities (70.0%; min 64.7-max 100.0%). Evaluation of the SOPs showed that knowledge and practices of malaria personnel varied within and between study areas. Average monthly costs for conducting case investigation and RACD activities showed variation between study areas (min USD $844.80-max USD $2038.00) for the malaria personnel, commodities, services and other costs required to carry out the activities. CONCLUSION: The RACD M&E tool was implemented in the three pilot areas, identifying key gaps that led to impacts on programme decision making. Study findings support the need for routine M&E of malaria case reporting, case investigation and RACD activities. Scale-up of the RACD M&E tool in malaria-eliminating settings will contribute to improved programme performance to the high level that is required to reach elimination.

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

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

A comprehensive assessment of the malaria microscopy system of Aceh, Indonesia, in preparation for malaria elimination.

BACKGROUND: The Health Office of Aceh aims to eliminate malaria from Aceh Province, Indonesia by 2015. Malaria was formerly common in Aceh (population 4.5 million), but has declined dramatically in recent years consequent to post-tsunami control efforts. Successful elimination will depend upon rapid and accurate diagnosis and case follow-up at community level. A prerequisite to this is widespread coverage of high quality malaria diagnosis. This study describes the results of a comprehensive assessment of the malaria diagnostic capacity in Aceh as the province moves towards malaria elimination. METHODS: The study was conducted in 23 districts in Aceh from October 2010 to July 2011. Six types of questionnaires were used to collect data on competency of microscopists and laboratory capacity. Standardized slides were used to evaluate the proficiency of all microscopists. In addition, site visits to 17 primary health centres (PHC) assessed diagnostic practice and logistics capacity. RESULTS: Five hundred and seventy four malaria microscopists have been officially registered and assigned to duty in the 23 districts in Aceh Province. They work in 345 laboratories, predominantly in PHCs (69 %) and hospitals (25 %). Three laboratories were evaluated as adequate for all 30 elements, while 29 laboratories were adequate for less than five of 30 elements. Standardized proficiency tests showed that 413 microscopists were at basic (in training) level, with 10 advanced and 9 reference level. No microscopist achieved expert level. Neither the province nor any of Aceh's districts has a standardized inventory and logistics database for malaria diagnostics, nor did any of the surveyed laboratories operate a quality assurance programme for either microscopy or rapid diagnostic tests. CONCLUSIONS: The study highlights the importance of careful assessment of diagnostic capacity when embarking upon a large-scale malaria elimination programme. Aceh's laboratories have minimal infrastructure with nearly all microscopists still in training. On the positive side, a large workforce of microscopists has been assigned to laboratories with the needed equipment. Aceh will need to embark on a large-scale comprehensive quality assurance scheme if it is to achieve malaria elimination.

Progress towards malaria elimination in Sabang Municipality, Aceh, Indonesia.

BACKGROUND: Indonesia has set 2030 as its deadline for elimination of malaria transmission in the archipelago, with regional deadlines established according to present levels of malaria endemicity and strength of health infrastructure. The Municipality of Sabang which historically had one of the highest levels of malaria in Aceh province aims to achieve elimination by the end of 2013. METHOD: From 2008 to 2010, baseline surveys of malaria interventions, mapping of all confirmed malaria cases, categorization of residual foci of malaria transmission and vector surveys were conducted in Sabang, Aceh, a pilot district for malaria elimination in Indonesia. To inform future elimination efforts, mass screening from the focal areas to measure prevalence of malaria with both microscopy and PCR was conducted. G6PD deficiency prevalence was also measured. RESULT: Despite its small size, a diverse mixture of potential malaria vectors were documented in Sabang, including Anopheles sundaicus, Anopheles minimus, Anopheles aconitus and Anopheles dirus. Over a two-year span, the number of sub-villages with ongoing malaria transmission reduced from 61 to 43. Coverage of malaria diagnosis and treatment, IRS, and LLINs was over 80%. Screening of 16,229 residents detected 19 positive people, for a point prevalence of 0.12%. Of the 19 positive cases, three symptomatic infections and five asymptomatic infections were detected with microscopy and 11 asymptomatic infections were detected with PCR. Of the 19 cases, seven were infected with Plasmodium falciparum, 11 were infected with Plasmodium vivax, and one subject was infected with both species. Analysis of the 937 blood samples for G6PD deficiency revealed two subjects (0.2%) with deficient G6PD. DISCUSSION: The interventions carried out by the government of Sabang have dramatically reduced the burden of malaria over the past seven years. The first phase, carried out between 2005 and 2007, included improved malaria diagnosis, introduction of ACT for treatment, and scale-up of coverage of IRS and LLINs. The second phase, from 2008 to 2010, initiated to eliminate the persistent residual transmission of malaria, consisted of development of a malaria database to ensure rapid case reporting and investigation, stratification of malaria foci to guide interventions, and active case detection to hunt symptomatic and asymptomatic malaria carriers.