Towards a comprehensive research and development plan to support the control, elimination and eradication of neglected tropical diseases.

To maximise the likelihood of success, global health programmes need repeated, honest appraisal of their own weaknesses, with research undertaken to address any identified gaps. There is still much to be learned to optimise work against neglected tropical diseases. To facilitate that learning, a comprehensive research and development plan is required. Here, we discuss how such a plan might be developed.

Finding hotspots: development of an adaptive spatial sampling approach.

The identification of disease hotspots is an increasingly important public health problem. While geospatial modeling offers an opportunity to predict the locations of hotspots using suitable environmental and climatological data, little attention has been paid to optimizing the design of surveys used to inform such models. Here we introduce an adaptive sampling scheme optimized to identify hotspot locations where prevalence exceeds a relevant threshold. Our approach incorporates ideas from Bayesian optimization theory to adaptively select sample batches. We present an experimental simulation study based on survey data of schistosomiasis and lymphatic filariasis across four countries. Results across all scenarios explored show that adaptive sampling produces superior results and suggest that similar performance to random sampling can be achieved with a fraction of the sample size.

Oncomelania hupensis quadrasi: Snail intermediate host of Schistosoma japonicum in the Philippines.

Oncomelania hupensis quadrasi is the snail intermediate host of Schistosoma japonicum in the Philippines. It was discovered by Dr. Marcos Tubangui in 1932 more than two decades after the discovery of the disease in the country in 1906. This review, the first for O. h. quadrasi, presents past and present works on the taxonomy, biology, ecology, control, possible paleogeographic origin of the snail intermediate host and future in research, control and surveillance of the snail. Extensive references are made of other subspecies of O. hupensis such as the subspecies in China for which majority of the advances has been accomplished. Contrasting views on whether the snail is to be considered an independent species of Oncomelania or as one of several subspecies of Oncomelania hupensis are presented. Snail control methods such as chemical methods using synthetic and botanical molluscicides, environmental manipulation and biological control are reviewed. Use of technologies such as Remote Sensing, Geographical Information System and landscape genetics is stressed for snail surveillance. Control and prevention efforts in the Philippines have consistently focused on mass drug administration which has proved inadequate in elimination of the disease. An integrated approach that includes snail control, environmental sanitation and health education has been proposed. Population movement such as migration for employment and economic opportunities and ecotourism and global climate change resulting in heavy rains and flooding challenge the gains of control and elimination efforts. Concern for possible migration of snails to non-endemic areas is expressed given the various changes both natural and mostly man-made favoring habitat expansion.

Current status of neglected tropical diseases (NTDs) in the Philippines.

In the Philippines, ten NTDs are prevalent, but only six namely LF, schistosomiasis, STH, food-borne trematodiases, rabies and leprosy are considered to be of public health importance. The 81 provinces in the country are endemic for at least one of these NTDs. Others may be endemic for two or even more of these diseases. Since 2000, after the Philippines accepted and implemented the WHO guidelines for NTDs prevention, control and elimination, significant progress has been achieved in reducing the magnitude of NTDs endemic in the country. Since 2009, out of 46 filariasis-endemic provinces, the number of provinces that has eliminated LF has progressively increased so that by 2015, 76% are already LF-free. By 2019, only four provinces remain endemic for LF. For schistosomiasis, as of 2012, report from the Department of Health (DOH) put the number of high endemic provinces at 10, moderately endemic at 6 and low to elimination levels at 12. For STH, results of the National Parasite Survey in the Philippines among school-aged children conducted in 2015 by the Research Institute for Tropical Medicine, the research arm of the Philippine DOH, however, showed that the overall cumulative prevalence was 28.4% with a prevalence range between 7.1% and 67.4%. The figures are way above the <20% prevalence standard set by the World Health Organization. Control and prevention efforts for FBTs just gained traction with the call of WHO for elimination of NTDs in 2015. There is an urgent need to update information by an intensive national baseline survey that can validate previous data as well as generate new information on the magnitude of the FBT problem in the Philippines. For leprosy, elimination activities have been intensified in high prevalence areas and from 2009 to 2013, case detection and prevalence were sustained at <1.0 per 10,000 population. Rabies elimination activities have been effective that by 2011, only five regions out of 16 remained with the highest number of rabies cases. In a period of seven years from 2010 to 2017, the number of rabies-free provinces and municipalities increased from 3 to 49. Problems continue to hound the NTD programmes in the Philippines as priorities shift to more urgent health problems in a country that is weighed down not only by the triple burden of disease but serious health consequences of emergencies and disasters and the fast-growing population itself. Paradigm shifts are suggested to replace the traditional and conventional perspectives of control. These include change from disease approach to intervention approach to allow for integration of strategies targeting several NTDs and multisectoral, multidisciplinary approach requiring strong, viable and sustainable partnerships involving various agencies of the government, public and private sector, pharmaceuticals, academe, researchers, local government units and the endemic communities themselves.

The evaluation of Animal Bite Treatment Centers in the Philippines from a patient perspective.

BACKGROUND: The Philippines has built an extensive decentralised network of Animal Bite Treatment Centers (ABTCs) to help bite victims receive timely rabies post-exposure prophylaxis (PEP) at little cost. This study surveyed patients in the community and at ABTCs of three provinces to assess animal bite/scratch incidence, health-seeking behaviour and PEP-related out-of pocket expenses (OOPE). METHODOLOGY AND PRINCIPAL FINDINGS: During community surveys in 90 barangays (neighbourhoods), 53% of households reported at least one animal bite /scratch injury over the past 3 years, similar across urban and rural barangays. Overall bite/scratch incidences in 2016-17 were 67.3, 41.9 and 48.8 per 1,000 population per year for Nueva Vizcaya, Palawan and Tarlac respectively. Incidences were around 50% higher amongst those under 15 years of age, compared to -those older than 15. Household awareness of the nearest ABTCs was generally over 80%, but only 44.9% sought proper medical treatment and traditional remedies were still frequently used. The proportion of patients seeking PEP was not related to the distance or travel time to the nearest ABTC. For those that did not seek medical treatment, most cited a lack of awareness or insufficient funds and almost a third visited a traditional healer. No deaths from bite/scratch injuries were reported. A cohort of 1,105 patients were interviewed at six ABTCs in early 2017. OOPE varied across the ABTCs, from 5.53 USD to 37.83 USD per patient, primarily dependent on the need to pay for immunization if government supplies had run out. Overall, 78% of patients completed the recommended course, and the main reason for non-completion was a lack of time, followed by insufficient funds. Dog observation data revealed that 85% of patients were not truly exposed to rabies, and education in bite prevention might reduce provoked bites and demand for PEP. An accompanying paper details the ABTC network from the health provider's perspective.

The evaluation of operating Animal Bite Treatment Centers in the Philippines from a health provider perspective.

BACKGROUND: The Philippine government has an extensive network of 513 Animal Bite Treatment Centers (ABTCs) to supply rabies post exposure prophylaxis (PEP), reaching over 1 million bite victims in 2016. The network was evaluated using a review of existing national and provincial data, key informant interviews and surveys in sample ABTCs to determine the cost-effectiveness of this network in preventing human rabies deaths. METHODOLOGY AND PRINCIPAL FINDINGS: One urban and one rural ABTC in each of three selected provinces were studied in more detail. PEP delivery generally followed national guidance based on best practices, but there was evidence of operational challenges in supplying all ABTCs with adequate biologics and recently trained staff. Funding was contributed by different levels of government and in some clinics, patients paid for a significant fraction of the total cost. From a health provider perspective including both fixed and variable costs, the average PEP course delivered cost USD 32.91 /patient across urban ABTCs (with higher patient throughput) and USD 57.21 /patient across rural ABTCs. These costs suggests that PEP provision in the Philippines cost USD 37.6 million in 2016, with a cost per life saved of USD 8,290. An analysis of the 2,239 suspected rabies deaths from 2008 to 2016 showed no significant decline, and from 2014-16 an average of 8,534 years of life were lost annually. The incidence of rabies deaths from 2014-16 was not clearly related to the provision of ABTCs (per 100,000 population) or human population density, but deaths were more common in higher income provinces. CONCLUSIONS/SIGNIFICANCE: In the context of comprehensive rabies control (including dog vaccination and public awareness) ways to reduce this high expenditure on PEP should be explored, to most cost-effectively reach the elimination of human rabies deaths. This paper is accompanied by another containing data on the operation of ABTCs network from a patient perspective.

INVESTIGATION OF MOSQUITOES WITH EMPHASIS ON AEDES (FINLAYA) POICILIUS, PUTATIVE VECTOR OF BANCROFTIAN FILARIASIS ON PANAY ISLAND, THE PHILIPPINES.

Entomological investigations were conducted in four remaining lymphatic filariasis endemic provinces of Panay Island, The Philippines to determine mosquito species present in these areas and to identify host preference and biting activity of Aedes (Finlaya) poicilius Theobald, primary vector of nocturnal periodic Wuchereria bancrofti in The Philippines. Sampling techniques targeted nocturnally active mosquito species using a carabao-baited trap (CBT) and human-landing collection (HLC), the latter taking place from 06:00 to 12:00 pm. A total of 25,536 mosquitoes comprising 42 species and 7 genera were collected from CBT, whilst HLC acquired 6,486 mosquitoes comprising 28 species and 5 genera. Three known or potential vectors of human filarial were collected, namely, Aedes poicilius, Culex quinquefasciatus and Mansonia uniformis. The peak landing (biting) activity for Ae. poicilius was between 09:00 and 11:00 pm. Comparisons between CBT and HLC yields showed this species to be more zoophilic. Based on observed mosquito behavior and interviews with residents, vector-host contact was promoted by the local practice of staying overnight in makeshift shelters in high risk areas without adequate protection against mosquito bites. Results of this survey will augment information for integrating vector control and mass drug administration into an island-wide lymphatic filariasis elimination program.

World Rabies Day campaign in the Philippines.

BACKGROUND: Rabies is a fatal disease, claiming the lives of around 59,000 people annually worldwide. It is considered a neglected and underreported disease leading to inadequate support from governments. Apart from dog vaccination and proper animal bite management, an integral part of a successful rabies control program is community education. The Philippine government conducts an extensive nationwide annual World Rabies Day (WRD) celebration as part of its community education. METHODS: Strong inter-sectoral collaboration at the national level is a key factor for the success of WRD, capitalizing on the partners' strengths to mobilize various sectors. Strategies include the National WRD Celebration and releasing national government memorandums. An invitation letter campaign was initiated, encouraging stakeholders to register their activities. Banners were given as an incentive for those who registered. Mass and social media were also utilized to promote WRD. RESULTS: Registered WRD events held in the Philippines rose from 10 events in 2012, to 37 events in 2013, to 66 events in 2014 and 76 events in 2015. The individual activities involved veterinary services and information, communication, and education (IEC) activities. Nine unique WRD IEC activities are highlighted in this paper. Promotion of WRD through social media was also utilized in recent years. More news items were published online than those printed in newspapers and aired on television. CONCLUSION: The campaign's success underlines the value of a national government-led program. The national rabies program sets the agenda for priority activities including the WRD campaign. Its capacity to allocate funds for the program also denotes stability which is beneficial for local program implementers. Different segments of society were tapped through various strategies. The campaign's flexibility allowed for a large range of activities and presented opportunities for expanding partnerships and integration with others interventions for its sustainability. With appropriate tools and government support, the extensive WRD campaign in the Philippines can be replicated in other countries. The strategies discussed prove that since different localities celebrate WRD in their own way, other countries can also organize activities adapted to their culture and contribute to the global campaign against rabies.

Mapping the Risk of Soil-Transmitted Helminthic Infections in the Philippines.

BACKGROUND: In order to increase the efficient allocation of soil-transmitted helminth (STH) disease control resources in the Philippines, we aimed to describe for the first time the spatial variation in the prevalence of A. lumbricoides, T. trichiura and hookworm across the country, quantify the association between the physical environment and spatial variation of STH infection and develop predictive risk maps for each infection. METHODOLOGY/PRINCIPAL FINDINGS: Data on STH infection from 35,573 individuals across the country were geolocated at the barangay level and included in the analysis. The analysis was stratified geographically in two major regions: 1) Luzon and the Visayas and 2) Mindanao. Bayesian geostatistical models of STH prevalence were developed, including age and sex of individuals and environmental variables (rainfall, land surface temperature and distance to inland water bodies) as predictors, and diagnostic uncertainty was incorporated. The role of environmental variables was different between regions of the Philippines. This analysis revealed that while A. lumbricoides and T. trichiura infections were widespread and highly endemic, hookworm infections were more circumscribed to smaller foci in the Visayas and Mindanao. CONCLUSIONS/SIGNIFICANCE: This analysis revealed significant spatial variation in STH infection prevalence within provinces of the Philippines. This suggests that a spatially targeted approach to STH interventions, including mass drug administration, is warranted. When financially possible, additional STH surveys should be prioritized to high-risk areas identified by our study in Luzon.

Towards effective prevention and control of helminth neglected tropical diseases in the Western Pacific Region through multi-disease and multi-sectoral interventions.

Neglected tropical diseases (NTDs) cause serious health, social and economic burdens in the countries of the World Health Organization Western Pacific Region. Among the NTDs, helminth infections are particularly prominent with regard to the number of infected individuals and health impact. Co-endemicity is common among impoverished and marginalized populations. To achieve effective and sustainable control of helminth NTDs, a deeper understanding of the social-ecological systems governing their endemicity and strategies beyond preventive chemotherapy are required to tackle the multiple causes of infection and re-infection. We discuss the feasibility of implementing multi-disease, multi-sectoral intervention packages for helminth NTDs in the Western Pacific Region. After reviewing the main determinants for helminth NTD endemicity and current control strategies, key control activities that involve or concern other programmes within and beyond the health sector are discussed. A considerable number of activities that have an impact on more than one helminth NTD are identified in a variety of sectors, suggesting an untapped potential for synergies. We also highlight the challenges of multi-sectoral collaboration, particularly of involving non-health sectors. We conclude that multi-sectoral collaboration for helminth NTD control is feasible if the target diseases and sectors are carefully selected. To do so, an incentive analysis covering key stakeholders in the sectors is crucial, and the disease-control strategies need to be well understood. The benefits of multi-disease, multi-sectoral approaches could go beyond immediate health impacts by contributing to sustainable development, raising educational attainment, increasing productivity and reducing health inequities.

New endemic foci of schistosomiasis infections in the Philippines.

Schistosomiasis affects 28 provinces in the Philippines found along the southeastern part where there is continuous rainfall throughout the year. In 2002 and 2005 respectively, two new endemic foci were reported in the northernmost (Gonzaga, Cagayan) and central (Calatrava, Negros Occidental) parts of the country. This study conducted in March 2008-March 2009 confirmed the presence of the disease by determining its prevalence using four diagnostic tests - Kato-Katz, circumoval precipitin test (COPT), ELISA and ultrasonography. Oncomelania hupensis quadrasi was identified through snail surveys conducted in possible snail habitats in the seven new endemic villages. Animal surveys through stool examination confirmed the presence of schistosomiasis infection in animals in Gonzaga but not in Calatrava. Compared to Calatrava, Gonzaga demonstrated markedly higher prevalence of schistosomiasis using all four diagnostic methods. Proximity of snail habitats to human habitation including higher snail density and snail infection rate could be responsible for the high prevalence. Snail sites were more widespread in Gonzaga whereas those in Calatrava were confined only in areas not frequented by the general population except by farmers. GIS maps showing spatial distribution of snails in Gonzaga and Calatrava indicated differences in elevation among the snail sites. It is hypothesized that the snail intermediate host has been in these sites for sometime but discovered only lately. Migration of people from endemic provinces into Gonzaga and Calatrava brought in cases and in the presence of snail intermediate hosts, emergence of disease was just a matter of time.

Geographical distribution of human Schistosoma japonicum infection in The Philippines: tools to support disease control and further elimination.

Schistosoma japonicum infection is believed to be endemic in 28 of the 80 provinces of The Philippines and the most recent data on schistosomiasis prevalence have shown considerable variability between provinces. In order to increase the efficient allocation of parasitic disease control resources in the country, we aimed to describe the small-scale spatial variation in S. japonicum prevalence across The Philippines, quantify the role of the physical environment in driving the spatial variation of S. japonicum, and develop a predictive risk map of S. japonicum infection. Data on S. japonicum infection from 35,754 individuals across the country were geo-located at the barangay level and included in the analysis. The analysis was then stratified geographically for the regions of Luzon, the Visayas and Mindanao. Zero-inflated binomial Bayesian geostatistical models of S. japonicum prevalence were developed and diagnostic uncertainty was incorporated. Results of the analysis show that in the three regions, males and individuals aged ⩾20years had significantly higher prevalence of S. japonicum compared with females and children <5years. The role of the environmental variables differed between regions of The Philippines. Schistosoma japonicum infection was widespread in the Visayas whereas it was much more focal in Luzon and Mindanao. This analysis revealed significant spatial variation in the prevalence of S. japonicum infection in The Philippines. This suggests that a spatially targeted approach to schistosomiasis interventions, including mass drug administration, is warranted. When financially possible, additional schistosomiasis surveys should be prioritised for areas identified to be at high risk but which were under-represented in our dataset.

Transmission assessment surveys (TAS) to define endpoints for lymphatic filariasis mass drug administration: a multicenter evaluation.

BACKGROUND: Lymphatic filariasis (LF) is targeted for global elimination through treatment of entire at-risk populations with repeated annual mass drug administration (MDA). Essential for program success is defining and confirming the appropriate endpoint for MDA when transmission is presumed to have reached a level low enough that it cannot be sustained even in the absence of drug intervention. Guidelines advanced by WHO call for a transmission assessment survey (TAS) to determine if MDA can be stopped within an LF evaluation unit (EU) after at least five effective rounds of annual treatment. To test the value and practicality of these guidelines, a multicenter operational research trial was undertaken in 11 countries covering various geographic and epidemiological settings. METHODOLOGY: The TAS was conducted twice in each EU with TAS-1 and TAS-2 approximately 24 months apart. Lot quality assurance sampling (LQAS) formed the basis of the TAS survey design but specific EU characteristics defined the survey site (school or community), eligible population (6-7 year olds or 1(st)-2(nd) graders), survey type (systematic or cluster-sampling), target sample size, and critical cutoff (a statistically powered threshold below which transmission is expected to be no longer sustainable). The primary diagnostic tools were the immunochromatographic (ICT) test for W. bancrofti EUs and the BmR1 test (Brugia Rapid or PanLF) for Brugia spp. EUs. PRINCIPAL FINDINGS/CONCLUSIONS: In 10 of 11 EUs, the number of TAS-1 positive cases was below the critical cutoff, indicating that MDA could be stopped. The same results were found in the follow-up TAS-2, therefore, confirming the previous decision outcome. Sample sizes were highly sex and age-representative and closely matched the target value after factoring in estimates of non-participation. The TAS was determined to be a practical and effective evaluation tool for stopping MDA although its validity for longer-term post-MDA surveillance requires further investigation.

A national baseline prevalence survey of schistosomiasis in the Philippines using stratified two-step systematic cluster sampling design.

For the first time in the country, a national baseline prevalence survey using a well-defined sampling design such as a stratified two-step systematic cluster sampling was conducted in 2005 to 2008. The purpose of the survey was to stratify the provinces according to prevalence of schistosomiasis such as high, moderate, and low prevalence which in turn would be used as basis for the intervention program to be implemented. The national survey was divided into four phases. Results of the first two phases conducted in Mindanao and the Visayas were published in 2008. Data from the last two phases showed three provinces with prevalence rates higher than endemic provinces surveyed in the first two phases thus changing the overall ranking of endemic provinces at the national level. Age and sex distribution of schistosomiasis remained the same in Luzon and Maguindanao. Soil-transmitted and food-borne helminthes were also recorded in these surveys. This paper deals with the results of the last 2 phases done in Luzon and Maguindanao and integrates all four phases in the discussion.

Elimination of lymphatic filariasis in Southeast Asia.

Approximately 15 million people with lymphatic filariasis (LF) live in Southeast Asia. Wuchereria bancrofti (transmitted by the Mansonia and Anopheles vectors), Brugia malayi and Brugia timori (both transmitted by Culex quinquefasciatus) are the filarial species in this region. The endemic countries are: Cambodia, Lao People's Democratic Republic, the Philippines, Indonesia, Thailand and Timor-Leste, which have all agreed to eliminate transmission of the disease by 2020. The public health interventions with respect to LF are based on the 1997 World Health Assembly resolution (WHA 50.29) which recommends elimination of the disease through mass drug administration (MDA) using diethylcarbamazine (DEC) and albendazole. The drugs are generally donated and as governments contribute 60-90% of the operational costs, MDA is deemed to be comparatively inexpensive for local administrations in relation to other public health programmes. So far, elimination has been accomplished only in the People's Republic of China (P.R. China) and this achievement is therefore described here in some detail. Resurgences have occurred but they have been successfully dealt with. Historically, the endemic areas in P.R. China covered 16,514 townships (or urban sub-districts), situated in 864 counties (or cities) in 14 provinces (or autonomous regions or municipalities). The total population at risk of infection in all endemic areas of P.R. China was originally 342 million.

Prevalence survey of schistosomiasis in Mindanao and the Visayas, The Philippines.

The first two phases of a national prevalence survey of schistosomiasis in The Philippines were completed in Mindanao in 2005 and the Visayas in the first quarter of 2007. The design was a stratified two-step systematic cluster sampling, with two Kato-Katz thick smears examined from each participant. In Mindanao, a total of 22 provinces spread in six regions were covered by the survey with five barangays (equivalent to a village) per province for a total of 110 barangays. The response rate was 70.9% with a total of 21,390 individuals examined. The province of Maguindanao, a known endemic area for schistosomiasis japonica, failed to take part in the survey. In the Visayas, 10 out of 11 provinces, spread out in three regions, participated in the survey. There were 6321 respondents for an overall participation rate of 32.2%. Mindanao showed a wider coverage of the disease than the Visayas (60% versus 45%). By region, Caraga or Region 13 ranked first in Mindanao and Region 8 in the Visayas. By province, Agusan del Sur is first on the list, followed by Northern Samar and then Eastern Samar. Overall, the prevalence rate among males is higher than that of females suggesting the occupational hazard of farming and fishing among the males. The higher exposure among farmers and fishermen is also borne out by the age distribution of the disease. Prevalence remains consistently high among the adults compared with the younger age groups. The survey also covered other helminth infections that can be detected in a stool survey, notably soil-transmitted helminthes and food-borne trematodes.

Contrasting Wuchereria bancrofti microfilaria rates in two Mangyan-populated Philippine villages.

Lymphatic filariasis caused by infection with Wuchereria bancrofti and Brugia malayi is endemic in 45 of 77 provinces in The Philippines. To prepare the island of Mindoro for mass treatment using diethylcarbamazine and albendazole, complete census data were collected in rural villages. A sample of individuals selected from each of two adjacent villages was examined for microfilaremia. Microfilariae were detected from thin smears in 34 (13%) of 272 patients examined from the village of Bayanan and 10 (3.4%) of 292 in the village of Mangangan (P < 0.01, by chi-square test). In these villages, the majority of those infected were members of the ethnic group known as Mangyans: 33 (97%) of 24 in Bayanan and 7 (70%) of 10 in Mangangan (risk ratio = 89, 95% confidence interval = 33-240, P < 0.001.) In children examined who were less than 10 years of age (n = 165), girls were more commonly infected than boys, even though the proportion of males in the general population was greater. Understanding sociocultural characteristics and related behaviors in future observations among the Mangyan may help to explain local differences in the distribution of filariasis. This information should also be helpful in designing more culturally appropriate strategies for the control of lymphatic filariasis among ethnic minorities in The Philippines.