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Background: Preventative chemotherapy and mass drug administration have been identified as effective strategies for the prevention, treatment, control and elimination of several NTDs in the Asia-Pacific region. Qualitative research can provide in-depth insight into the social dynamics and processes underlying effective implementation of and adherence to mass drug administration programs. This scoping review examines published qualitative literature to examine factors influencing community perceptions and acceptability of mass drug administration approaches to control NTDs in the Asia-Pacific region. Methodology: Twenty-four peer reviewed published papers reporting qualitative data from community members and stakeholders engaged in the implementation of mass drug administration programs were identified as eligible for inclusion. Findings: This systematic scoping review presents available data from studies focussing on lymphatic filariasis, soil-transmitted helminths and scabies in eight national settings (India, Indonesia, Philippines, Bangladesh, Laos, American Samoa, Papua New Guinea, Fiji). The review highlights the profoundly social nature of individual, interpersonal and institutional influences on community perceptions of willingness to participate in mass drug administration programs for control of neglected tropical diseases (NTD). Future NTD research and control efforts would benefit from a stronger qualitative social science lens to mass drug administration implementation, a commitment to understanding and addressing the social and structural determinants of NTDs and NTD control in complex settings, and efforts to engage local communities as equal partners and experts in the co-design of mass drug administration and other efforts to prevent, treat, control and eliminate NTDs. Conclusion: For many countries in the Asia-Pacific region, the "low hanging fruit has been picked" in terms of where mass drug administration has worked and transmission has been stopped. The settings that remain–such as remote areas of Fiji and Papua New Guinea, or large, highly populated, multi-cultural urban settings in India and Indonesia–present huge challenges going forward. Author summary: Qualitative research can provide in-depth insight into the social dynamics and processes underlying effective implementation of and adherence to mass drug administration programs. This scoping review examines published qualitative literature to examine factors influencing community perceptions and acceptability of mass drug administration approaches to control neglected tropical diseases (NTDs) in the Asia-Pacific region. Our analyses highlight the profoundly social nature of individual, interpersonal and institutional influences on community perceptions of willingness to participate in mass drug administration programs for control of NTDs. For many countries in the Asia-Pacific region, the "low hanging fruit has been picked" in terms of where mass drug administration has worked and transmission has been stopped. The settings that remain–e.g. remote areas of Fiji and Papua New Guinea, or large, highly populated, multi-cultural urban settings in India and Indonesia–present huge challenges going forward. Future NTD research and control efforts would benefit from a stronger qualitative social science lens to mass drug administration implementation, a commitment to understanding the socio-structural determinants of NTDs and NTD control in complex settings, and engaging local communities as equal partners and experts in the co-design of mass drug administration and other efforts to prevent, treat, control and eliminate NTDs. [ABSTRACT FROM AUTHOR]

Background: Approximately 70% of the global burden of dengue disease occurs on the Asian continent, where many large urban centres provide optimal environments for sustained endemic transmission and periodic epidemic cycles. Jakarta, the capital of Indonesia, is a densely populated megacity with hyperendemic dengue transmission. Characterization of the spatiotemporal distribution of dengue transmission intensity is of key importance for optimal implementation of novel control and prevention programmes, including vaccination. In this paper we use mathematical models to provide the first detailed description of spatial and temporal variability in dengue transmission intensity in Jakarta. Methodology/Principal findings: We applied catalytic models in a Bayesian framework to age-stratified dengue case notification data to estimate dengue force of infection and reporting probabilities in 42 subdistricts of Jakarta. The model was fitted to yearly and average annual data covering a 10-year period between 2008 and 2017. We estimated a long-term average annual transmission intensity of 0.130 (95%CrI: 0.129–0.131) per year in Jakarta province, ranging from 0.090 (95%CrI: 0.077–0.103) to 0.164 (95%CrI: 0.153–0.174) across subdistricts. Annual average transmission intensity in Jakarta province during the 10-year period ranged from 0.012 (95%CrI: 0.011–0.013) in 2017 to 0.124 (95%CrI: 0.121–0.128) in 2016. Conclusions/Significance: While the absolute number of dengue case notifications cannot be relied upon as a measure of endemicity, the age-distribution of reported dengue cases provides valuable insights into the underlying nature of transmission. Our estimates from yearly and average annual case notification data represent the first detailed estimates of dengue transmission intensity in Jakarta's subdistricts. These will be important to consider when assessing the population-level impact and cost-effectiveness of potential control and prevention programmes in Jakarta province, such as the controlled release of Wolbachia-carrying mosquitoes and vaccination. Author summary: Characterization of the spatiotemporal distribution of dengue transmission intensity, a key measure of population infection risk, can inform the optimal use and deployment of control and prevention programmes. Jakarta, the capital of Indonesia, is a large urban centre with hyperendemic dengue transmission. We fitted catalytic models to age-stratified dengue surveillance data reported in Jakarta's subdistricts from 2008 to 2017. We estimated a long-term average annual transmission intensity of 0.130 (95%CrI: 0.129–0.131) per year in Jakarta province, which varied across subdistricts from 0.090 (95%CrI: 0.077–0.103) per year in Sawah Besar to 0.164 (95%CrI: 0.153–0.174) per year in Pasar Rebo. We observed significant spatiotemporal variation and clustering of transmission intensity in Jakarta. Our estimates obtained from the analysis of yearly and cumulative case-notification data reported between 2008 and 2017 represent the first detailed estimates of average dengue transmission intensity, which will be key to assess the potential impact of future control and prevention programmes in Jakarta province. [ABSTRACT FROM AUTHOR]

The International Classification of Function, Disability, and Health (ICF—WHO, 2001) recognizes several dimensions of disability, such as body structure and function (and impairment thereof), activity (and activity restrictions) and participation (and participation restriction) and their interactions with contextual factor (personal and environmental). In this study, we map and analyse the relationship between the components of ICF in leprosy patients from two rural areas in Indonesia: Lewoleba (East Nusa Tenggara) and Likupang (North Minahasa). This study was part of a community outreach program by the KATAMATAKU team from Universitas Indonesia. The body structure was graded using the WHO hand and feet disability grade and the number of enlarged nerves, while the body function was measured by the Jebsen Taylor Hand Function Test (JTT) and Timed-up and Go (TUG). Activity limitation and participation restriction were measured using the Screening Activity Limitation Safety Awareness (SALSA) Scale and Participation Scale (P-scale), respectively. There were 177 leprosy patients from the two regions and 150 patients with complete data were included in the analysis. We found 82% (95% CI: 75.08%-87.32%) of subjects with multibacillary leprosy, 10.67% (95% CI: 6.67%-16.62%) of subjects with grade 2 WHO hand disability, and 9.33% (95% CI: 5.64%-15.06%) of subjects with grade 2 WHO foot disability. Assessment using the SALSA Scale showed 29.33% of subjects with limitation activity and 11.33% with participation restriction. Age was shown to have positive correlations with SALSA, JTT, and TUG. Inter-dimensional analysis showed that the SALSA scale had significant positive correlations with the number of nerve enlargements, P-scale, JTT, and TUG. SALSA scores of grade 2 WHO hand and foot disability were also significantly higher than grades 1 and 0. The participation scale also had a positive correlation with JTT but not TUG. Hand disability seemed to affect societal participation while foot did not. We used the ICF to describe and analyse dimensions of leprosy-related disability in Indonesia. Author summary: Disability is the long-term outcome of untreated leprosy or Hansen's disease, which is caused by peripheral nerve invasion of the Mycobacterium leprae. It is a serious and life-limiting complication for leprosy patients. Currently, seven regions in Indonesia have not yet achieved the state of disease elimination. In addition, Indonesia has not succeeded in achieving the sub-target of the rate of new cases with grade 2 disability in 2023. The concept of disability and health including the body structure, body function, personal and environmental domains, activity limitation, and participation restriction, is provided by the ICF. Through the framework, we could assess the aspects of disability and its relationship to one another in leprosy patients. Furthermore, the early detection, screening, and management programs for leprosy have not included aspects of disability and rehabilitative measures for restoration. Thus, the purpose of this study is to find the impact of leprosy-related disability on the patients' body function, activity, and participation. We reported 150 leprosy patients from two rural areas of Indonesia and found significant relationships between specific indicators, which would be useful for rehabilitative management programs in the future. [ABSTRACT FROM AUTHOR]

Background: Stigma plays in an important role in the lives of persons affected by neglected tropical diseases, and assessment of stigma is important to document this. The aim of this study is to test the cross-cultural validity of the Community Stigma Scale (EMIC-CSS) and the Social Distance Scale (SDS) in the field of leprosy in Cirebon District, Indonesia. Methodology/principle findings: Cultural equivalence was tested by assessing the conceptual, item, semantic, operational and measurement equivalence of these instruments. A qualitative exploratory study was conducted to increase our understanding of the concept of stigma in Cirebon District. A process of translation, discussions, trainings and a pilot study followed. A sample of 259 community members was selected through convenience sampling and 67 repeated measures were obtained to assess the psychometric measurement properties. The aspects and items in the SDS and EMIC-CSS seem equally relevant and important in the target culture. The response scales were adapted to ensure that meaning is transferred accurately and no changes to the scale format (e.g. lay out, statements or questions) of both scales were made. A positive correlation was found between the EMIC-CSS and the SDS total scores (r = 0.41). Cronbach's alphas of 0.83 and 0.87 were found for the EMIC-CSS and SDS. The exploratory factor analysis indicated for both scales an adequate fit as unidimensional scale. A standard error of measurement of 2.38 was found in the EMIC-CSS and of 1.78 in the SDS. The test-retest reliability coefficient was respectively, 0.84 and 0.75. No floor or ceiling effects were found. Conclusions/significance: According to current international standards, our findings indicate that the EMIC-CSS and the SDS have adequate cultural validity to assess social stigma in leprosy in the Bahasa Indonesia-speaking population of Cirebon District. We believe the scales can be further improved, for instance, by adding, changing and rephrasing certain items. Finally, we provide suggestions for use with other neglected tropical diseases. Author Summary: Persons affected by neglected tropical diseases, such as, Buruli ulcer, lymphatic filariasis, onchocerciasis, leishmaniasis and leprosy, can experience stigma. One important source of stigma are members in the community. Neighbours, religious leaders, and community leaders can exclude, reject, blame or devalue a person affected by one of these diseases. It is important to be able to assess this type of stigma for the prevention and management of these diseases. Assessing stigma is not an easy task. There are several instruments available, but these were developed with different aims or tested in different settings. We can use these instruments, but we need to be sure that they assess what we want them to assess and whether the instrument produces consistent results. In this paper the authors report a study that investigated the validity of two scales that assess stigma in the community towards people affected by leprosy in Indonesia. The names of the scales are Explanatory Model Interview Catalogue Community Stigma Scale (EMIC-CSS) and Social Distance Scale (SDS). The results show the two scales to be adequately valid and reliable in the target culture. There are, however, also several improvements possible and the authors provide suggestions how to incorporate these. In addition, the authors provide recommendations for the use of these scales among people affected by other neglected tropical diseases. [ABSTRACT FROM AUTHOR]

Background: Can deliberate interaction between the public and persons affected by leprosy reduce stigmatization? The study described in this paper hypothesises that it can and assesses the effectiveness of a ‘contact intervention’. Methods/Principal Findings: This cluster-randomized controlled intervention study is part of the Stigma Assessment and Reduction of Impact (SARI) project conducted in Cirebon District, Indonesia. Testimonies, participatory videos and comics given or made by people affected by leprosy were used as methods to facilitate a dialogue during so-called ‘contact events’. A mix of seven quantitative and qualitative methods, including two scales to assess aspects of stigma named the SDS and EMIC-CSS, were used to establish a baseline regarding stigma and knowledge of leprosy, monitor the implementation and assess the impact of the contact events. The study sample were community members selected using different sampling methods. The baseline shows a lack of knowledge about leprosy, a high level of stigma and contrasting examples of support. In total, 91 contact events were organised in 62 villages, directly reaching 4,443 community members (mean 49 per event). The interview data showed that knowledge about leprosy increased and that negative attitudes reduced. The adjusted mean total score of the EMIC-CSS reduced by 4.95 points among respondents who had attended a contact event (n = 58; p <0.001, effect size = 0.75) compared to the score at baseline (n = 213); for the SDS this was 3.56 (p <0.001, effect size = 0.81). About 75% of those attending a contact event said they shared the information with others (median 10 persons). Conclusions/Significance: The contact intervention was effective in increasing knowledge and improving public attitudes regarding leprosy. It is relatively easy to replicate elsewhere and does not require expensive technology. More research is needed to improve scalability. The effectiveness of a contact intervention to reduce stigma against other neglected tropical diseases and conditions should be evaluated. [ABSTRACT FROM AUTHOR]

Background: Rabies has been a serious public health threat in Flores Island, Indonesia since it was introduced in 1997. To control the disease, annual dog vaccination campaigns have been implemented to vaccinate all dogs free of charge. Nevertheless, the uptake rate of the vaccination campaigns has been low. The objective of this paper is to identify risk factors associated with the uptake of rabies control measures by individual dog owners in Flores Island. Methodology/principal findings: A total of 450 dog owners from 44 randomly selected villages in the Sikka and Manggarai regencies were interviewed regarding their socio-demographic factors, knowledge of rabies, and their uptake of rabies control measures. The majority of dog owners surveyed (>90%) knew that rabies is a fatal disease and that it can be prevented. Moreover, 68% of the dog owners had a high level of knowledge about available rabies control measures. Fifty-two percent of the dog owners had had at least one of their dogs vaccinated during the 2012 vaccination campaign. Vaccination uptake was significantly higher for dog owners who resided in Sikka, kept female dogs for breeding, had an income of more than one million Rupiah, and had easy access to their village. The most important reasons not to join the vaccination campaign were lack of information about the vaccination campaign schedule (40%) and difficulty to catch the dog during the vaccination campaign (37%). Conclusions/significance: Dog owners in Flores Island had a high level of knowledge of rabies and its control, but this was not associated with uptake of the 2012 vaccination campaign. Geographical accessibility was one of the important factors influencing the vaccination uptake among dog owners. Targeted distribution of information on vaccination schedules and methods to catch and restrain dogs in those villages with poor accessibility may increase vaccination uptake in the future. Author Summary: Rabies has been a serious public health threat in Flores Island since its introduction in 1997, with significant economic consequences for the government due to the cost of providing vaccines for humans and dogs. Vaccination of dogs against rabies offers a safe and effective means to prevent rabies in humans in the long term. The local government of Flores Island has implemented dog vaccination campaigns throughout the island, free of charge for all dog owners. However, the uptake rate of vaccinating dogs is too low to control the disease. Identifying factors associated with the dog owners' decisions to vaccinate their dogs provides information to policy makers to increase vaccination uptake in the future. This study evaluated the impact of rabies knowledge and socio-demographic factors of dog owners on the uptake of the 2012 dog vaccination campaign. Overall, the uptake rate of the 2012 vaccination campaign was low. Levels of knowledge about rabies and its control were high, but not associated with uptake of vaccination. Geographical accessibility was significantly associated with vaccination uptake. Targeted distribution of information in those villages with poor accessibility may increase vaccination uptake in the future. Information should cover vaccination schedules and methods to restrain dogs. [ABSTRACT FROM AUTHOR]

Background: All four serotypes of dengue virus are endemic in Indonesia, where the population at risk for infection exceeds 200 million people. Despite continuous control efforts that were initiated more than four decades ago, Indonesia still suffers from multi-annual cycles of dengue outbreak and dengue remains as a major public health problem. Dengue vaccines have been viewed as a promising solution for controlling dengue in Indonesia, but thus far its potential acceptability has not been assessed. Methodology/Principal Findings: We conducted a household survey in the city of Bandung, Indonesia by administering a questionnaire to examine (i) acceptance of a hypothetical pediatric dengue vaccine; (ii) participant's willingness-to-pay (WTP) for the vaccine, had it not been provided for free; and (iii) whether people think vector control would be unnecessary if the vaccine was available. A proportional odds model and an interval regression model were employed to identify determinants of acceptance and WTP, respectively. We demonstrated that out of 500 heads of household being interviewed, 94.2% would agree to vaccinate their children with the vaccine. Of all participants, 94.6% were willing to pay for the vaccine with a median WTP of US$1.94. In addition, 7.2% stated that vector control would not be necessary had there been a dengue vaccination program. Conclusions/Significance: Our results suggest that future dengue vaccines can have a very high uptake even when delivered through the private market. This, however, can be influenced by vaccine characteristics and price. In addition, reduction in community vector control efforts may be observed following vaccine introduction but its potential impact in the transmission of dengue and other vector-borne diseases requires further study. Author Summary: While methods for vector control such as mosquito breeding source reduction and focal insecticide spraying that have been practiced to reduce dengue transmission in Indonesia have had limited success, dengue vaccines are expected to be an effective control method. However, even if an efficacious vaccine is developed, public acceptance and viable financing mechanisms are crucial for a successful introduction and sustainability of a new vaccination program. In this paper, we report public acceptance and willingness-to-pay for a hypothetical dengue vaccine for children that would be made available in the future. We found a very high proportion of surveyed participants, more than ninety-four percent, were willing to accept and pay for the vaccine. These findings provide a strong support for a dengue vaccination program. On the other hand, we also found a small possibility of reduction in vector control efforts if a dengue vaccination program is put in place. This could have a potential to increase the transmission of other vector-borne diseases and should be taken into account when introducing a dengue vaccination program. [ABSTRACT FROM AUTHOR]

Background: One challenge to achieving Lymphatic filariasis (LF) elimination is the persistent coverage-compliance gap during annual mass drug administration (MDA) and the risk of ongoing transmission among never treated individuals. Our analysis examined factors associated with individuals who were never treated during MDA. Methods: Data were derived from two cross-sectional surveys conducted in Waihaong and Air Salobar Health Center in 2018 and 2019. We analyzed information from 1915 respondents aged 18+ years. The study outcome was individuals who self-reported never treatment during any round of MDA. All potential predictors were grouped into socio-demographic, health system, therapy and individual factors. Logistic regression analyses were used to examine factors associated with never treatment in any year of MDA. Results: Nearly half (41%) of respondents self-reported they were never treated during any round of MDA. Factors associated with increased odds of never treatment were respondents working in formal sectors (aOR = 1.75, p = 0.040), living in the catchment area of Waihaong Health Center (aOR = 2.33, p = 0.029), and those perceiving the possibility of adverse events after swallowing LF drugs (aOR = 2.86, p<0.001). Respondents reporting difficulty swallowing all the drugs (aOR = 3.12, p<0.001) and having difficulties remembering the time to swallow the drugs (aOR = 1.53, p = 0.049) also had an increased odds of never treatment. The highest odds of never treatment were associated with respondents reporting almost none of their family members took LF drugs (aOR = 3.93, p<0.001). Respondents confident that they knew how to swallow LF drugs had a reduced odds (aOR = 0.26, p<0.001) of never treatment. Conclusions: Efforts to reassure community members about adverse events, specific instructions on how to take LF drugs, and improving awareness that MDA participation is part of one's contribution to promoting community health are essential drivers for uptake with LF drugs during MDA. Author summary: Lymphatic filariasis (LF) remains an important public health issues in endemic areas in Indonesia. One potential challenge to achieving LF elimination is the risk posed by never treatment during mass drug administration (MDA). Although Ambon City in Maluku Province, Indonesia, initiated its annual MDA in 2009, the microfilaria rate in 2016 still exceeded the threshold for elimination as a public health problem. In 2018 and 2019, we conducted a community-based study in the catchment areas of Air Salobar and Waihaong Health Centers, Ambon to improve treatment coverage and reduce the coverage-compliance gap in MDA for LF. Using data from the two cross-sectional surveys, our analysis examined factors associated with never treatment. We found the role of employment, healthcare catchment area, perceived possibility of side effects after swallowing LF drugs, difficulties in swallowing and remembering when to swallow all LF drugs and knowledge of how to swallow LF drugs were associated with the likelihood of never treatment. Recommendations to improve MDA uptake include the need to reassure community members about side effects, provide specific instructions on how to take LF drugs, and promote the message that MDA participation is part of one's contribution to community health. [ABSTRACT FROM AUTHOR]

Information on the insecticide resistance profiles of Aedes aegypti in Indonesia is fragmentary because of the lack of wide-area insecticide resistance surveillance. We collected Ae. aegypti from 32 districts and regencies in 27 Indonesian provinces and used WHO bioassays to evaluate their resistance to deltamethrin, permethrin, bendiocarb, and pirimiphos-methyl. To determine the possible resistance mechanisms of Ae. aegypti, synergism tests were conducted using piperonyl butoxide (PBO) and S,S,S-tributylphosphorotrithioates (DEF). The Ae. aegypti from all locations exhibited various levels of resistance to pyrethroids. Their resistance ratio (RR50) to permethrin and deltamethrin ranged from 4.08× to 127× and from 4.37× to 72.20×, respectively. In contrast with the findings of other studies, most strains from the highly urbanized cities on the island of Java (i.e., Banten, Jakarta, Bandung, Semarang, Yogyakarta, and Surabaya) exhibited low to moderate resistance to pyrethroids. By contrast, the strains collected from the less populated Kalimantan region exhibited very high resistance to pyrethroids. The possible reasons are discussed herein. Low levels of resistance to bendiocarb (RR50, 1.24–6.46×) and pirimiphos-methyl (RR50, 1.01–2.70×) were observed in all tested strains, regardless of locality. PBO and DEF synergists significantly increased the susceptibility of Ae. aegypti to permethrin and deltamethrin and reduced their resistance ratio to less than 16×. The synergism tests suggested the major involvement of cytochrome P450 monooxygenases and esterases in conferring pyrethroid resistance. On the basis of our results, we proposed a 6-month rotation of insecticides (deltamethrin + synergists ➝ bendiocarb ➝ permethrin + synergists ➝ pirimiphos-methyl) and the use of an insecticide mixture containing pyrethroid and pyrimiphos-methyl to control Ae. aegypti populations and overcome the challenge of widespread Ae. aegypti resistance to pyrethroid in Indonesia. Author summary: Insecticide resistance is a major impediment to the successful management of vector-transmitted diseases because it increases the vector's chances of surviving under insecticide treatment. In Indonesia, the implementation of insecticide resistance management at the national level is particularly challenging due to the vast area and regional disparities in terms of population, health, and socioeconomic status. Previous studies on determining insecticide resistance of Aedes mosquito only focused on several cities in some provinces of Indonesia, making resistance monitoring results difficult to interpret and arguably reflect the generality in Indonesia. To complicate the matter, data released by the Ministry of Agriculture of Indonesia in 2022 showed that approximately 82% of insecticides registered to control Ae. aegypti in Indonesia are pyrethroid-based products. Principally, we found that the synergists PBO and DEF significantly reduce the resistance of field Ae. aegypti from Indonesia toward permethrin and deltamethrin. Bendiocarb and pirimiphos-methyl remain highly toxic to the field strains of Ae. aegypti. We suggest the feasible choice of insecticide group for Ae. aegypti vector management based on the currently registered insecticide inventory. The finding also underscores the urgent need to approve other non-pyrethroid-based insecticides as alternative tools for reducing the risk of resistance development during an outbreak. [ABSTRACT FROM AUTHOR]

The arbovirus vector Aedes albopictus (Asian tiger mosquito) is common throughout the Indo-Pacific region, where most global dengue transmission occurs. We analysed population genomic data and tested for cryptic species in 160 Ae. albopictus sampled from 16 locations across this region. We found no evidence of cryptic Ae. albopictus but found multiple intraspecific COI haplotypes partitioned into groups representing three Asian lineages: East Asia, Southeast Asia and Indonesia. Papua New Guinea (PNG), Vanuatu and Christmas Island shared recent coancestry, and Indonesia and Timor-Leste were likely invaded from East Asia. We used a machine learning trained on morphologically sexed samples to classify sexes using multiple genetic features and then characterized the wAlbA and wAlbB Wolbachia infections in 664 other samples. The wAlbA and wAlbB infections as detected by qPCR showed markedly different patterns in the sexes. For females, most populations had a very high double infection incidence, with 67% being the lowest value (from Timor-Leste). For males, the incidence of double infections ranged from 100% (PNG) to 0% (Vanuatu). Only 6 females were infected solely by the wAlbA infection, while rare uninfected mosquitoes were found in both sexes. The wAlbA and wAlbB densities varied significantly among populations. For mosquitoes from Torres Strait and Vietnam, the wAlbB density was similar in single-infected and superinfected (wAlbA and wAlbB) mosquitoes. There was a positive association between wAlbA and wAlbB infection densities in superinfected Ae. albopictus. Our findings provide no evidence of cryptic species of Ae. albopictus in the region and suggest site-specific factors influencing the incidence of Wolbachia infections and their densities. We also demonstrate the usefulness of ddRAD tag depths as sex-specific mosquito markers. The results provide baseline data for the exploitation of Wolbachia-induced cytoplasmic incompatibility (CI) in dengue control. Author summary: The mosquito Aedes albopictus transmits dengue and other arboviruses. This study investigates the genetics of these mosquitoes and their endosymbiont Wolbachia in the Indo-Pacific region, where 70% of global dengue transmission occurs. The analysis of mitochondrial DNA sequences showed no evidence of cryptic Ae. albopictus but suggested three Asian lineages: East Asia, Southeast Asia and Indonesia. Papua New Guinea, Vanuatu and Christmas Island shared recent coancestry, and Indonesia and Timor-Leste were likely invaded from East Asia. We used bioinformatics to classify sexes and then characterized the wAlbA and wAlbB Wolbachia infections via both bioinformatics and quantitative PCR. We found markedly different patterns of wAlbA and wAlbB infections in the sexes. The wAlbA and wAlbB densities varied significantly among populations, suggesting site-specific factors influencing the incidence of Wolbachia infections and their densities. We also demonstrate the usefulness of next generation sequencing data in developing molecular markers that can be repeatedly reanalysed to investigate new issues as these arise. These results provide baseline data for the exploitation of Wolbachia-induced cytoplasmic incompatibility in dengue control. [ABSTRACT FROM AUTHOR]

Mosquitoes are important vectors that transmit pathogens to human and other vertebrates. Each mosquito species has specific ecological requirements and bionomic traits that impact human exposure to mosquito bites, and hence disease transmission and vector control. A study of human biting mosquitoes and their bionomic characteristics was conducted in West Sumba and Southwest Sumba Districts, Nusa Tenggara Timur Province, Indonesia from May 2015 to April 2018. Biweekly human landing catches (HLC) of night biting mosquitoes both indoors and outdoors caught a total of 73,507 mosquito specimens (59.7% non-Anopheles, 40.3% Anopheles). A minimum of 22 Culicinae species belonging to four genera (Aedes, Armigeres, Culex, Mansonia), and 13 Anophelinae species were identified. Culex quinquefasciatus was the dominant Culicinae species, Anopheles aconitus was the principal Anopheles species inland, while An. sundaicus was dominant closer to the coast. The overall human biting rate (HBR) was 10.548 bites per person per night (bpn) indoors and 10.551 bpn outdoors. Mosquitoes biting rates were slightly higher indoors for all genera with the exception of Anopheles, where biting rates were slightly higher outdoors. Diurnal and crepuscular Aedes and Armigeres demonstrated declining biting rates throughout the night while Culex and Anopheles biting rates peaked before midnight and then declined. Both anopheline and non-anopheline populations did not have a significant association with temperature (p = 0.3 and 0.88 respectively), or rainfall (p = 0.13 and 0.57 respectively). The point distribution of HBR and seasonal variables did not have a linear correlation. Data demonstrated similar mosquito–human interactions occurring outdoors and indoors and during early parts of the night implying both indoor and outdoor disease transmission potential in the area–pointing to the need for interventions in both spaces. Integrated vector analysis frameworks may enable better surveillance, monitoring and evaluation strategies for multiple diseases. Author summary: This study outlines the array of mosquitoes that bite humans at night on the island of Sumba, Indonesia, with data on behavioural traits that impact when and where disease transmission may occur. Biweekly human landing catches (HLCs) were performed in four selected houses in 12 clusters (villages) from sunset to sunrise over a three years period (May 2015 to April 2018). The collection and analysis of 73,507 mosquito specimens revealed the presence of various species of Anopheles, Aedes, Culex, Armigeres and Mansonia, that potentially transmit several diseases including malaria, filaria, dengue and other mosquito borne viral diseases. Even though these data represent only night-time collections, this represents a comprehensive geographic description and inventory of species, bionomics and temporal distribution of mosquitoes on the island of Sumba. Data demonstrate that the high diversity of species with associated diversity in behaviours results in mosquito-human contact occurring throughout the night and both indoors and outdoors–relevant to both disease transmission and intervention applicability. Vector specific behaviours are specifically relevant to intervention strategies for specific diseases. The use of molecular methods to determine and validate morphological identification of specimens resulted in the characterization of multiple novel sequences–indicating the presence of undescribed species, members of cryptic species complexes or species without molecular data. Species identification using molecular methods are essential towards determine vector species compositions–especially in areas where data is absent. Though the correlation between temperature, rainfall and HBR was not statistically significant, the presence of mosquito populations throughout the year allow for perennial transmission of mosquito-borne diseases. Overall, these findings represent baseline and novel data for Sumba and may be utilized to develop disease and vector-specific or integrated strategies that mitigate the transmission of mosquito borne diseases in Indonesia. [ABSTRACT FROM AUTHOR]

The World Health Organization has raised concerns about the increasing number of Hansen disease (HD) relapses worldwide, especially in Brazil, India, and Indonesia that report the highest number of recurrent cases. Relapses are an indicator of MDT effectiveness and can reflect Mycobacterium leprae persistence or re-infection. Relapse is also a potential marker for the development or progression of disability. In this research, we studied a large cohort of persons affected by HD treated with full fixed-dose multibacillary (MB) multidrug therapy (MDT) followed for up to 20 years and observed that relapses are a rare event. We estimated the incidence density of relapse in a cohort of patients classified to receive MB regime (bacillary index (BI) > 0), diagnosed between September 1997 and June 2017, and treated with twelve-dose MB-MDT at a HD reference center in Rio de Janeiro, Brazil. We obtained the data from the data management system of the clinic routine service. We linked the selected cases to the dataset of relapses of the national HD data to confirm possible relapse cases diagnosed elsewhere. We diagnosed ten cases of relapse in a cohort of 713 patients followed-up for a mean of 12.1 years. This resulted in an incidence rate of 1.16 relapse cases per 1000 person-year (95% CI = 0.5915–2.076). The accumulated risk was 0.025 in 20 years. The very low risk observed in this cohort of twelve-dose-treated MB patients reinforces the success of the current MDT scheme. Author summary: People affected by Hansen disease that have many skin patches or lumps receive twelve-dose multibacillary multidrug therapy. After the fixed-dose regime, they are released from treatment and are considered cured. However, some of these people may have a recurrence of skin lesions or peripheral nerve problems after several years. Clinicians, scientists, and the World Health Organization are concerned about this problem, known as relapse, which seems to be increasing in countries where Hansen disease is common, especially in Brazil, India, and Indonesia. It is important to demonstrate regular proof that the therapy remains effective to treat people affected by Hansen disease. In this study, we showed that the recurrence of signs and symptoms of Hansen disease after the twelve-dose multibacillary treatment is rare. These findings are good evidence of the success of the current multibacillary scheme. [ABSTRACT FROM AUTHOR]

Improved treatments for lymphatic filariasis (LF) could accelerate the global elimination program for this disease. A triple drug combination of the anti-filarial drugs ivermectin, diethylcarbamazine (DEC) and albendazole (IDA) has been shown to be safe and effective for achieving sustained clearance of microfilariae (Mf) of the filarial parasite Wuchereria bancrofti from human blood. However, the triple drug combination has not been previously been evaluated for treatment of brugian filariasis, which accounts for about 10% of the global LF burden. This hospital-based clinical trial compared the safety and efficacy of IDA with that of the standard treatment (DEC plus albendazole, DA) in persons with Brugia timori infections on Sumba island, Indonesia. Fifty-five asymptomatic persons with B. timori Mf were treated with either a single oral dose of IDA (28 subjects) or with DEC plus albendazole (DA, 27 subjects). Participants were actively monitored for adverse events (AE) for two days after treatment by nurses and physicians who were masked regarding treatment assignments. Passive monitoring was performed by clinical teams that visited participant's home villages for an additional five days. Microfilaremia was assessed by membrane filtration of 1 ml night blood at baseline, at 24h and one year after treatment. IDA was more effective than DA for completely clearing Mf at 24 hours (25/28, 89% vs. 11/27, 41%, P < 0.001). By 12 months after treatment, only one of 28 IDA recipients had Mf in their blood (4%) vs. 10 of 27 (37%) in persons treated with DA (P = 0.002). Approximately 90% of participants had antibodies to recombinant filarial antigen BmR1 at baseline. Antibody prevalence decreased to approximately 30% in both treatment groups at 12 months. About 45% of persons in both treatment groups experienced AE such as fever, muscle aches, lower back, joint and abdominal pain. These were mostly mild and most common during the first two days after treatment. No participant experienced a severe or serious AE. This study showed that IDA was well-tolerated and significantly more effective for clearing B. timori Mf from the blood than DA. Larger studies should be performed to further assess the safety and efficacy of IDA as a mass drug administration regimen to eliminate brugian filariasis. Trial Registration:NCT02899936. Author summary: Improved treatments for lymphatic filariasis (LF) could accelerate the global elimination program for this disease. A triple drug combination of the anti-filarial drugs ivermectin, diethylcarbamazine (DEC) and albendazole (IDA) has been shown to be safe and effective for achieving sustained clearance of microfilariae (Mf) of the filarial parasite Wuchereria bancrofti from human blood. However, the triple drug combination has not been previously been evaluated for treatment of brugian filariasis, which accounts for about 10% of the global LF burden. This hospital-based clinical trial compared the safety and efficacy of IDA with that of the standard treatment (DEC plus albendazole, DA) in persons with Brugia timori infections on Sumba island, Indonesia. Fifty-five asymptomatic persons with B. timori Mf were treated with either a single oral dose of IDA (28 subjects) or with DA (27 subjects). Adverse events (AE) were assessed in the hospital for two days after treatment and for another five days in participants' home villages. IDA was much more effective than DA for clearing Mf from the blood at 24 hr. Only 1 person (4% of those treated) had Mf in their blood one year after IDA, while 10 persons (37%) treated with DA were Mf positive at that time. About 45% of persons in both treatment groups experienced mostly mild AE as fever, muscle aches, lower back, joint and abdominal pain (mostly during the first two days after treatment). This study showed that IDA was well-tolerated and significantly more effective than DA for clearing B. timori Mf from the blood. Larger studies should be performed to further assess the safety and efficacy of IDA as a mass drug administration regimen to eliminate brugian filariasis. [ABSTRACT FROM AUTHOR]

Background: Many countries will not reach elimination targets for lymphatic filariasis in 2020 using the two-drug treatment regimen (diethylcarbamazine citrate [DEC] and albendazole [DA]). A cluster-randomized, community-based safety study performed in Fiji, Haiti, India, Indonesia and Papua New Guinea tested the safety and efficacy of a new regimen of ivermectin, DEC and albendazole (IDA). Methodology/Principal findings: To assess acceptability of IDA and DA, a mixed methods study was embedded within this community-based safety study. The study objective was to assess the acceptability of IDA versus DA. Community surveys were performed in each country with randomly selected participants (>14 years) from the safety study participant list in both DA and IDA arms. In depth interviews (IDI) and focus group discussions (FGD) assessed acceptability-related themes. In 1919 individuals, distribution of sex, microfilariae (Mf) presence and circulating filarial antigenemia (CFA), adverse events (AE) and age were similar across arms. A composite acceptability score summed the values from nine indicators (range 9–36). The median (22.5) score indicated threshold of acceptability. There was no difference in scores for IDA and DA regimens. Mean acceptability scores across both treatment arms were: Fiji 33.7 (95% CI: 33.1–34.3); Papua New Guinea 32.9 (95% CI: 31.9–33.8); Indonesia 30.6 (95% CI: 29.8–31.3); Haiti 28.6 (95% CI: 27.8–29.4); India 26.8 (95% CI: 25.6–28) (P<0.001). AE, Mf or CFA were not associated with acceptability. Qualitative research (27 FGD; 42 IDI) highlighted professionalism and appreciation for AE support. No major concerns were detected about number of tablets. Increased uptake of LF treatment by individuals who had never complied with MDA was observed. Conclusions/Significance: IDA and DA regimens for LF elimination were highly and equally acceptable in individuals participating in the community-based safety study in Fiji, Haiti, India, Indonesia, and Papua New Guinea. Country variation in acceptability was significant. Acceptability of the professionalism of the treatment delivery was highlighted. Author summary: The acceptability of a new combination treatment regimen for lymphatic filariasis (ivermectin, plus DEC and albendazole, or IDA) was assessed as part of a larger community-based safety study in Fiji, Haiti, India, Indonesia and Papua New Guinea. To understand how trial participants and communities felt about the new treatment, a survey was carried out with people who had participated in the safety study receiving either the standard treatment [DEC plus albendazole (DA)] or the new treatment regimen (IDA). Focus group discussions and in-depth interviews were performed in the same communities. Results showed that there was no difference in acceptability between the DA and IDA. Adverse events and presence of filarial infection did not affect acceptability. The most important indicator associated with acceptability was country. All countries accepted the treatment regimens. Fiji had the highest acceptability scores, followed by Papua New Guinea, Indonesia, Haiti and India. Results from the qualitative research showed that study participants appreciated the professionalism of the drug delivery team and the support offered for the management of any adverse events. [ABSTRACT FROM AUTHOR]

Australia, home to the iconic dingo, is currently free from canine rabies. However northern Australia, including Indigenous communities with large free-roaming domestic dog populations, is at increased risk of rabies incursion from nearby Indonesia. We developed a novel agent-based stochastic spatial rabies spread model to evaluate the potential spread of rabies within the dingo population of the Northern Peninsula Area (NPA) region of northern Australia. The model incorporated spatio-temporal features specific to this host-environment system, including landscape heterogeneity, demographic fluctuations, dispersal movements and dingo ecological parameters—such as home range size and density—derived from NPA field studies. Rabies spread between dingo packs in nearly 60% of simulations. In such situations rabies would affect a median of 22 dingoes (approximately 14% of the population; 2.5–97.5 percentiles: 2–101 dingoes) within the study area which covered 1,131 km2, and spread 0.52 km/week for 191 days. Larger outbreaks occurred in scenarios in which an incursion was introduced during the dry season (vs. wet season), and close to communities (vs. areas with high risk of interaction between dingoes and hunting community dogs). Sensitivity analyses revealed that home range size and duration of infectious clinical period contributed most to the variance of outputs. Although conditions in the NPA would most likely not support a sustained propagation of the disease in the dingo population, due to the predicted number of infected dingoes following a rabies incursion and the proximity of Indigenous communities to dingo habitat, we conclude that the risk for human transmission could be substantial. Author summary: Although Australia is free from canine rabies, an incursion from nearby rabies-infected Indonesian islands is a realistic threat. The ubiquitous presence of dingoes in the wild, in association with large populations of free-roaming domestic dogs from northern Australian Indigenous communities, increases the risk of a rabies outbreak. Using a newly developed simulation model, we investigated the potential spread of rabies in a northern Australian dingo population. Nearly 60% of model simulations resulted in more than one pack infected. When spread did occur, outbreaks affected a median of 22 dingoes (an estimated 14% of the population in this area). The duration of infection, proportion of the population infected and spatial spread of the outbreak was greatest when rabies was introduced during the dry season and close to communities. Our results demonstrate that an incursion of rabies into the northern Australian dingo population would likely lead to a rabies outbreak, which would in turn pose a substantial threat to Indigenous communities in northern Australia. [ABSTRACT FROM AUTHOR]

Background: Understanding how knowledge, attitudes and practices regarding leprosy differ in endemic countries can help us develop targeted educational and behavioural change interventions. This study aimed to examine the differences and commonalities in and determinants of knowledge, attitudes, practices and fears regarding leprosy in endemic districts in India and Indonesia. Principle findings: A cross-sectional mixed-methods design was used. Persons affected by leprosy, their close contacts, community members and health workers were included. Through interview-administered questionnaires we assessed knowledge, attitudes, practices and fears with the KAP measure, EMIC-CSS and SDS. In addition, semi-structured interviews and focus group discussions were conducted. The quantitative data were analysed using stepwise multivariate regression. Determinants of knowledge and stigma that were examined included age, gender, participant type, education, occupation, knowing someone affected by leprosy and district. The qualitative data were analysed using open, inductive coding and content analysis. We administered questionnaires to 2344 participants (46% from India, 54% from Indonesia) as an interview. In addition, 110 participants were interviewed in-depth and 60 participants were included in focus group discussions. Knowledge levels were low in both countries: 88% of the participants in India and 90% of the participants in Indonesia had inadequate knowledge of leprosy. In both countries, cause, mode of transmission, early symptoms and contagiousness of leprosy was least known, and treatment and treatability of leprosy was best known. In both countries, health workers had the highest leprosy knowledge levels and community members the highest stigma levels (a mean score of up to 17.4 on the EMIC-CSS and 9.1 on the SDS). Data from the interviews indicated that people were afraid of being infected by leprosy. Local beliefs and misconceptions differed, for instance that leprosy is in the family for seven generations (Indonesia) or that leprosy is a result of karma (India). The determinants of leprosy knowledge and stigma explained 10–29% of the variability in level of knowledge and 3–10% of the variability in level of stigma. Conclusion: Our findings show the importance of investigating the perceptions regarding leprosy prior to educational interventions in communities: even though knowledge levels were similar, local beliefs and misconceptions differed per setting. The potential determinants we included in our study explained very little of the variability in level of knowledge and stigma and should be explored further. Detailed knowledge of local knowledge gaps, beliefs and fears can help tailor health education to local circumstances. Author summary: This study aimed to examine the differences and commonalities in and determinants of knowledge, attitudes, practices and fears regarding leprosy in endemic districts in India and Indonesia. Persons affected by leprosy, their close contacts, community members and health workers were included. We administered questionnaires (the KAP measure, EMIC-CSS and SDS) to 2344 participants. In addition, 110 participants were interviewed in-depth and 60 participants were included in focus group discussions. Knowledge levels were low. In both countries, cause, mode of transmission, early symptoms and contagiousness of leprosy was least known, and treatment and treatability of leprosy was best known. In both countries, health workers had the highest leprosy knowledge levels and community members the highest stigma levels. Data from the interviews indicated that people were afraid of being infected by leprosy. Local beliefs and misconceptions differed. The potential determinants we included in our study explained very little of the variability in level of knowledge and stigma and should be explored further. Our findings show the importance of investigating the perceptions regarding leprosy prior to educational interventions in communities: even though knowledge levels were similar, local beliefs and misconceptions differed per setting. [ABSTRACT FROM AUTHOR]

Soil-transmitted helminth (STH) infections are endemic in Indonesia. However, prevalence data for many parts of the country are incomplete. The aim of this study was to determine human STH prevalence and knowledge and practices relating to STH risk behaviour, to provide a current view of the status of STH infection in rural communities in Central Java. A cross-sectional survey of 16 villages was conducted in Semarang, Central Java in 2015. Demographic and household data together with information about knowledge and practices relating to STH and hygiene were elicited through face-to-face interviews. Stool samples were collected and examined using the flotation method. Children (aged 2–12 years) also had their haemoglobin (Hb) levels, height and weight data collected, and BMI estimated. Data were analysed using univariate logistic regression analysis. A total of 6,466 individuals with a mean age of 33.5 years (range: 2–93) from 2,195 households were interviewed. The overall prevalence of STH was 33.8% with Ascaris lumbricoides (roundworm) the predominant nematode identified (prevalence = 26.0%). Hookworm and Trichuris trichiura (whipworm) were found in 7.9% and 1.8% of participants, respectively. Females were at increased odds of infection with A. lumbricoides (adjusted OR 1.14, 95% CI [1.02–1.29], p = 0.02). Adults in age groups 51–60 and over 60 years had the highest odds of being infected with hookworm (adjusted OR 3.01, 95% CI [1.84–4.91], p<0.001 and adjusted OR 3.79, 95% CI [2.30–6.26], p<0.001, respectively) compared to 6–12 year olds. Farmers also had higher odds of being infected with hookworm (adjusted OR 2.36, 95% CI [1.17–4.76], p = 0.02) compared to other occupation categories. Poverty (OR 2.14, 95% CI [1.77–2.58], p<0.001), overcrowding (OR 1.35, 95% CI [1.27–1.44], p<0.001), goat ownership (OR 1.61, 95% CI [1.10–2.41], p = 0.02) and the presence of dry floor space in the home (OR 0.73, 95% CI [0.58–0.91], p = 0.01) were all household factors significantly associated with an increased odds of infection. Infection with STH was not significantly associated with the gastrointestinal illness (p>0.05), BMI or Hb levels; however, one third of all 2–12 year olds surveyed were found to be anaemic (i.e. Hb concentrations below 110g/l or 115g/l for children under 5 and 5 years or older, respectively), with a greater proportion of school-age children at risk. Knowledge and behaviour related to hygiene and gastrointestinal diseases varied widely and were generally not associated with STH infection. The study revealed that STH infection remains endemic in Central Java despite ongoing deworming programs. Current control efforts would benefit from being re-evaluated to determine a more effective way forward. Author summary: Among the major NTDs, STH are one of the most common disabling chronic infections. Currently available drug treatments, whilst considered safe and generally well tolerated, do not confer protection against new infections. In Indonesia, prevalences of STH of up to 90% have been reported but these estimates are based on data from the 1980s and 90s. More up-to-date STH prevalence estimates are urgently needed to help guide future control efforts. A cross-sectional survey was conducted in rural villages in Semarang, Central Java to determine human STH prevalence and associated risk factors. One-third of all cohort participants were positive for STH with prevalences of 26%, 7.9% and 1.8% identified for Ascaris lumbricoides, hookworm and Trichuris trichiura at 7.9% and 1.8%, respectively. Risk of A. lumbricoides infection was higher for females, whilst farmers and adults over 50 had an increased risk of hookworm infection. Poverty, overcrowding in the home and goat ownership were also associated with an increased risk at the household level. Soil-transmitted helminthiases remains a significant health problem in Central Java, Indonesia, exacerbated by limited knowledge about STH, poor sanitation and hygiene and poverty prevalent in the region. Control efforts would benefit from an integrated approach emphasising WASH, health education and chemotherapy. Further studies investigating environmental contamination with STH in and around homes in endemic areas could provide further insight into links between household factors and STH identified in our study. [ABSTRACT FROM AUTHOR]

Anopheles sundaicus s.l. is an important malaria vector primarily found in coastal landscapes of western and central Indonesia. The species complex has a wide geographical distribution in South and Southeast Asia and exhibits ecological and behavioural variability over its range. Studies on understanding the distribution of different members in the complex and their bionomics related to malaria transmission might be important guiding more effective vector intervention strategies. Female An. sundaicus s.l. were collected from seven provinces, 12 locations in Indonesia representing Sumatra: North Sumatra, Bangka-Belitung, South Lampung, and Bengkulu; in Java: West Java; and the Lesser Sunda Islands: West Nusa Tenggara and East Nusa Tenggara provinces. Sequencing of ribosomal DNA ITS2 gene fragments and two mitochondrial DNA gene markers, COI and cytb, enabled molecular identification of morphologically indistinguishable members of the complex. Findings allowed inference on the distribution of the An. sundaicus s.l. present in Indonesia and further illustrate the phylogenetic relationships of An. epiroticus within the complex. A total of 370 An. sundaicus s.l specimens were analysed for the ITS2 fragment. The ITS2 sequence alignment revealed two consistent species-specific point mutations, a T>C transition at base 479 and a G>T transversion at base 538 that differentiated five haplotypes: TG, CG, TT, CT, and TY. The TG haplotype matched published An. epiroticus–indicative sequences from Thailand, Vietnam and peninsular Malaysia. The previously described insertion event (base 603) was observed in all identified specimens. Analysis of the COI and cytb genes revealed no consistent nucleotide variations that could definitively distinguish An. epiroticus from other members in the Sundaicus Complex. The findings indicate and support the existence of An. epiroticus in North Sumatra and Bangka-Belitung archipelago. Further studies are recommended to determine the full distributional extent of the Sundaicus complex in Indonesia and investigate the role of these species in malaria transmission. Author summary: In Indonesia, more than 80 species of Anopheles have been documented, of which approximately 24 species are regarded as malaria vectors. Many of these mosquitoes are members of species complexes, being morphologically indistinguishable from other member sibling species. The Anopheles sundaicus complex (s.l.) has a wide geographical distribution in South and Southeast Asia, and exhibits ecological and behavioural variability over its range. Anopheles sundaicus s.l. is an important malaria vector present primarily in coastal areas of western and central Indonesia. Cytologic, isozyme, and molecular methods have been used to distinguish members of the complex in Indonesia, with several species being reported in different localities. This study aims to explore the distribution of the An. sundaicus complex in Indonesia using molecular methods. Female Anopheles sundaicus s.l. were collected from 12 localities within seven provinces in western to south-central Indonesia. The findings indicate the presence of An. epiroticus in North Sumatra and Bangka-Belitung archipelago off the eastern coast of central Sumatra. Further studies are required to determine the full distributional extent of the An. sundaicus complex in Indonesia and investigate the role of each species in malaria transmission. [ABSTRACT FROM AUTHOR]

Background: The epidemiology of acute febrile illness, a common cause of hospitalization in Indonesia, has not been systematically studied. Methodology/Principal gindings: This prospective observational study enrolled febrile patients (temperature ≥38°C) aged ≥1 year from July 2013 until June 2016 at eight government referral teaching hospitals in seven provincial capitals in Indonesia. Patients were managed according to the hospital standard-of-care (SOC), and blood samples were drawn for molecular and serological assays. Clinical data, laboratory results, and specimens for additional tests were collected at enrollment, days 14–28, and at three months. Regular follow-up visits were then scheduled for every three months either until symptoms resolved or until one year. In total, this study included 1,486 adult and pediatric patients presenting with multi-organ (768, 51.7%), gastrointestinal (497, 33.0%), respiratory (114, 7.7%), constitutional (62, 4.2%), skin and soft-tissue (24, 1.6%), central nervous system (17, 1.1%), or genitourinary (4, 0.3%) manifestations. Microbiological diagnoses were found in 1,003/1,486 (67.5%) participants, of which 351/1,003 (35.0%) were not diagnosed during hospitalization using SOC diagnostic tests. Missed diagnoses included all cases caused by Rickettsia spp., chikungunya, influenza, and Seoul virus. The most common etiologic agents identified were dengue virus (467, 46.6%), Salmonella spp. (103, 10.3%), and Rickettsia spp. (103, 10.3%). The overall mortality was 89 (5.9%). Conclusions/Significance: Febrile illness in Indonesia has various microbiologic etiologies and substantial overall mortality. Diagnostic limitations and lack of epidemiologic data resulted in potentially treatable, and at times fatal, diseases being missed. Author summary: In tropical countries like Indonesia, fever due to infectious disease is the most common reason for hospitalization. However, diagnoses are mostly unconfirmed, as diagnostic tests are not available or are not performed due to budget constraints. Consequently, many patients are only treated based on clinical syndromes. To gain a better understanding of the epidemiology of acute fever in Indonesia, we conducted a study at eight hospitals in the seven largest cities from 2013–2016. We enrolled 1,486 subjects aged ≥1 year with acute fever ≥38°C. Blood cultures were mandatory for all subjects, while cultures of other biological specimens, microscopic examinations, and rapid tests for specific pathogens were based on clinical judgment and availability. Retrospectively, we performed molecular and serological testing for a panel of bacterial and viral pathogens for systemic, respiratory, and diarrheal diseases. We found six pathogens to be the most prevalent: dengue virus (47%), Salmonella Typhi/Paratyphi (10%), Rickettsia typhi (10%), influenza virus (7%), Leptospira spp. (5%), and chikungunya virus (4%). Rickettsia typhi, influenza, and chikungunya had not been considered in the differential diagnosis of any subject at the hospitals. Thus, multiple pathogens were associated with acute febrile illnesses, and a subset of treatable cases were missed. This may have resulted in increased overall mortality. [ABSTRACT FROM AUTHOR]

Background: Dengue is associated with significant economic expenditure and it is estimated that the Asia Pacific region accounts for >50% of the global cost. Indonesia has one of the world’s highest dengue burdens; Aedes aegypti and Aedes albopictus are the primary and secondary vectors. In the absence of local data on disease cost, this study estimated the annual economic burden during 2015 of both hospitalized and ambulatory dengue cases in Indonesia. Methods: Total 2015 dengue costs were calculated using both prospective and retrospective methods using data from public and private hospitals and health centres in three provinces: Yogyakarta, Bali and Jakarta. Direct costs were extracted from billing systems and claims; a patient survey captured indirect and out-of-pocket costs at discharge and 2 weeks later. Adjustments across sites based on similar clinical practices and healthcare landscapes were performed to fill gaps in cost estimates. The national burden of dengue was extrapolated from provincial data using data from the three sites and applying an empirically-derived epidemiological expansion factor. Results: Total direct and indirect costs per dengue case assessed at Yogyakarta, Bali and Jakarta were US$791, US$1,241 and US$1,250, respectively. Total 2015 economic burden of dengue in Indonesia was estimated at US$381.15 million which comprised US$355.2 million for hospitalized and US$26.2 million for ambulatory care cases. Conclusion: Dengue imposes a substantial economic burden for Indonesian public payers and society. Complemented with an appropriate weighting method and by accounting for local specificities and practices, these data may support national level public health decision making for prevention/control of dengue in public health priority lists. [ABSTRACT FROM AUTHOR]

Rabies continues to pose a significant threat to human and animal health in regions of Indonesia. Indonesia has an extensive network of veterinary diagnostic laboratories and the 8 National laboratories are equipped to undertake diagnostic testing for rabies using the commercially-procured direct fluorescent antibody test (FAT), which is considered the reference (gold standard) test. However, many of the Indonesian Provincial diagnostic laboratories do not have a fluorescence microscope required to undertake the FAT. Instead, certain Provincial laboratories continue to screen samples using a chemical stain-based test (Seller’s stain test, SST). This test has low diagnostic sensitivity, with negative SST-tested samples being forwarded to the nearest National laboratory resulting in significant delays for completion of testing and considerable additional costs. This study sought to develop a cost-effective and diagnostically-accurate immunoperoxidase antigen detection (RIAD) test for rabies that can be readily and quickly performed by the resource-constrained Provincial laboratories. This would reduce the burden on the National laboratories and allow more rapid diagnoses and implementation of post-exposure prophylaxis. The RIAD test was evaluated using brain smears fixed with acetone or formalin and its performance was validated by comparison with established rabies diagnostic tests used in Indonesia, including the SST and FAT. A proficiency testing panel was distributed between Provincial laboratories to assess the reproducibility of the test. The performance of the RIAD test was improved by using acetone fixation of brain smears rather than formalin fixation such that it was of equivalent accuracy to that of the World Organisation for Animal Health (OIE)-recommended FAT, with both tests returning median diagnostic sensitivity and specificity values of 0.989 and 0.993, respectively. The RIAD test and FAT had higher diagnostic sensitivity than the SST (median = 0.562). Proficiency testing using a panel of 6 coded samples distributed to 16 laboratories showed that the RIAD test had good reproducibility with an overall agreement of 97%. This study describes the successful development, characterisation and use of a novel RIAD test and its fitness for purpose as a screening test for use in provincial Indonesian veterinary laboratories. [ABSTRACT FROM AUTHOR]

Background: As the Global Programme to Eliminate Lymphatic Filariasis (LF) approaches its 2020 goal, an increasing number of districts will enter the endgame phase where drug coverage rates from mass drug administration (MDA) are used to assess whether MDA can be stopped. As reported, the gap between reported and actual drug coverage in some contexts has overestimated the true rates, thus causing premature administration of transmission assessment surveys (TAS) that detect ongoing LF transmission. In these cases, districts must continue with additional rounds of MDA. Two districts in Indonesia (Agam District, Depok City) fit this criteria—one had not met the pre-TAS criteria and the other, had not passed the TAS criteria. In both cases, the district health teams needed insight into their drug delivery programs in order to improve drug coverage in the subsequent MDA rounds. Methodology/Principal Findings: To inform the subsequent MDA round, a micronarrative survey tool was developed to capture community members’ experience with MDA and the social realm where drug delivery and compliance occur. A baseline survey was implemented after the 2013 MDA in endemic communities in both districts using the EPI sampling criteria (n = 806). Compliance in the last MDA was associated with perceived importance of the LF drugs for health (p<0.001); perceived safety of the LF drugs (p<0.001) and knowing someone in the household has complied (p<0.001). Results indicated that specialized messages were needed to reach women and younger men. Both districts used these recommendations to implement changes to their MDA without additional financial support. An endline survey was performed after the 2014 MDA using the same sampling criteria (n = 811). Reported compliance in the last MDA improved in both districts from 57% to 77% (p<0.05). Those who reported having ever taken the LF drug rose from 79% to 90% (p<0.001) in both sites. Conclusions/Significance: Micronarrative surveys were shown to be a valid and effective tool to detect operational issues within MDA programs. District health staff felt ownership of the results, implementing feasible changes to their programs that resulted in significant improvements to coverage and compliance in the subsequent MDA. This kind of implementation research using a micronarrative survey tool could benefit underperforming MDA programs as well as other disease control programs where a deeper understanding is needed to improve healthcare delivery. [ABSTRACT FROM AUTHOR]

Background: Dengue has emerged as one of the most important infectious diseases in the last five decades. Evidence indicates the expansion of dengue virus endemic areas and consequently the exponential increase of dengue virus infections across the subtropics. The clinical manifestations of dengue virus infection include sudden fever, rash, headache, myalgia and in more serious cases, spontaneous bleeding. These manifestations occur in children as well as in adults. Defining the epidemiology of dengue in a given area is critical to understanding the disease and devising effective public health strategies. Methodology/Principal Findings: Here, we report the results from a prospective cohort study of 4380 adults in West Java, Indonesia, from 2000–2004 and 2006–2009. A total of 2167 febrile episodes were documented and dengue virus infections were confirmed by RT-PCR or serology in 268 cases (12.4%). The proportion ranged from 7.6 to 41.8% each year. The overall incidence rate of symptomatic dengue virus infections was 17.3 cases/1,000 person years and between September 2006 and April 2008 asymptomatic infections were 2.6 times more frequent than symptomatic infections. According to the 1997 WHO classification guidelines, there were 210 dengue fever cases, 53 dengue hemorrhagic fever cases (including one dengue shock syndrome case) and five unclassified cases. Evidence for sequential dengue virus infections was seen in six subjects. All four dengue virus serotypes circulated most years. Inapparent dengue virus infections were predominantly associated with DENV-4 infections. Conclusions/Significance: Dengue virus was responsible for a significant percentage of febrile illnesses in an adult population in West Java, Indonesia, and this percentage varied from year to year. The observed incidence rate during the study period was 43 times higher than the reported national or provincial rates during the same time period. A wide range of clinical severity was observed with most infections resulting in asymptomatic disease. The circulation of all four serotypes of dengue virus was observed in most years of the study. [ABSTRACT FROM AUTHOR]

Domestic dog rabies is an endemic disease in large parts of the developing world and also epidemic in previously free regions. For example, it continues to spread in eastern Indonesia and currently threatens adjacent rabies-free regions with high densities of free-roaming dogs, including remote northern Australia. Mathematical and simulation disease models are useful tools to provide insights on the most effective control strategies and to inform policy decisions. Existing rabies models typically focus on long-term control programs in endemic countries. However, simulation models describing the dog rabies incursion scenario in regions where rabies is still exotic are lacking. We here describe such a stochastic, spatially explicit rabies simulation model that is based on individual dog information collected in two remote regions in northern Australia. Illustrative simulations produced plausible results with epidemic characteristics expected for rabies outbreaks in disease free regions (mean R0 1.7, epidemic peak 97 days post-incursion, vaccination as the most effective response strategy). Systematic sensitivity analysis identified that model outcomes were most sensitive to seven of the 30 model parameters tested. This model is suitable for exploring rabies spread and control before an incursion in populations of largely free-roaming dogs that live close together with their owners. It can be used for ad-hoc contingency or response planning prior to and shortly after incursion of dog rabies in previously free regions. One challenge that remains is model parameterisation, particularly how dogs' roaming and contacts and biting behaviours change following a rabies incursion in a previously rabies free population. Author Summary: Rabies in domestic dog populations still causes >50,000 human deaths worldwide each year. While its eradication by vaccination of the reservoir population (dogs and wildlife) was successful in many parts of the world, it is still present in the developing world and continues to spread to new regions. Theoretical rabies models supporting control plans do exist for rabies endemic regions; however these models usually provide information for long-term programs. Here, we describe a novel rabies simulation model for application in rabies-free regions experiencing an incursion. The model simulates a rabies outbreak in the free-ranging dog population in remote indigenous communities in northern Australia. Vaccination, dog density reduction and dog confinement are implemented as control strategies. Model outputs suggest that the outbreak lasts for an average of 7 months and typically spreads through all communities of the region. Dog vaccination was found to be the most effective response strategy. The model produces plausible results and can be used to provide information for ad-hoc response planning before and shortly after rabies incursion. [ABSTRACT FROM AUTHOR]

Background: Outside of Africa, P. falciparum and P. vivax usually coexist. In such co-endemic regions, successful malaria control programs have a greater impact on reducing falciparum malaria, resulting in P. vivax becoming the predominant species of infection. Adding to the challenges of elimination, the dormant liver stage complicates efforts to monitor the impact of ongoing interventions against P. vivax. We investigated molecular approaches to inform the respective transmission dynamics of P. falciparum and P. vivax and how these could help to prioritize public health interventions. Methodology/ Principal Findings: Genotype data generated at 8 and 9 microsatellite loci were analysed in 168 P. falciparum and 166 P. vivax isolates, respectively, from four co-endemic sites in Indonesia (Bangka, Kalimantan, Sumba and West Timor). Measures of diversity, linkage disequilibrium (LD) and population structure were used to gauge the transmission dynamics of each species in each setting. Marked differences were observed in the diversity and population structure of P. vivax versus P. falciparum. In Bangka, Kalimantan and Timor, P. falciparum diversity was low, and LD patterns were consistent with unstable, epidemic transmission, amenable to targeted intervention. In contrast, P. vivax diversity was higher and transmission appeared more stable. Population differentiation was lower in P. vivax versus P. falciparum, suggesting that the hypnozoite reservoir might play an important role in sustaining local transmission and facilitating the spread of P. vivax infections in different endemic settings. P. vivax polyclonality varied with local endemicity, demonstrating potential utility in informing on transmission intensity in this species. Conclusions/ Significance: Molecular approaches can provide important information on malaria transmission that is not readily available from traditional epidemiological measures. Elucidation of the transmission dynamics circulating in a given setting will have a major role in prioritising malaria control strategies, particularly against the relatively neglected non-falciparum species. Author Summary: The malaria parasite Plasmodium vivax is a growing public health burden across the globe. Largely overshadowed by the more fatal P. falciparum parasite, increasing reports of anti-malarial drug resistance and life-threatening disease complications demand concerted efforts to eliminate P. vivax. Outside of Africa, P. vivax usually co-exists with P. falciparum. In these regions, malaria interventions have demonstrated greater success against falciparum. The authors genotyped P. vivax and P. falciparum parasites from 4 co-endemic sites in Indonesia, and used the data to gauge how frequently and how focally parasites were transmitted, and how much they spread between sites. Their results indicated that whilst the P. falciparum populations displayed evidence of low and unstable transmission, the P. vivax populations were more diverse and exhibited more stable transmission patterns, requiring different intervention approaches. Relative to P. falciparum, the P. vivax parasites demonstrated evidence of greater spread between populations, possibly facilitated by the dormant liver stage which enables P. vivax to be carried asymptomatically in patients for long periods of time. These findings highlight the need to reconcile the intervention requirements for non-falciparum malaria species in co-endemic regions, and the general utility of parasite genotyping to facilitate surveillance. [ABSTRACT FROM AUTHOR]

Safe treatment of Plasmodium vivax requires diagnosis of both the infection and status of erythrocytic glucose-6-phosphate dehydrogenase (G6PD) activity because hypnozoitocidal therapy against relapse requires primaquine, which causes a mild to severe acute hemolytic anemia in G6PD deficient patients. Many national malaria control programs recommend primaquine therapy without G6PD screening but with monitoring due to a broad lack of G6PD deficiency screening capacity. The degree of risk in doing so hinges upon the level of residual G6PD activity among the variants present in any given area. We conducted studies on Sumba Island in eastern Indonesia in order to assess the potential threat posed by primaquine therapy without G6PD screening. We sampled 2,033 residents of three separate districts in western Sumba for quantitative G6PD activity and 104 (5.1%) were phenotypically deficient (<4.6U/gHb; median normal 10U/gHb). The villages were in two distinct ecosystems, coastal and inland. A positive correlation occurred between the prevalence of malaria and G6PD deficiency: 5.9% coastal versus inland 0.2% for malaria (P<0.001), and 6.7% and 3.1% for G6PD deficiency (P<0.001) at coastal and inland sites, respectively. The dominant genotypes of G6PD deficiency were Vanua Lava, Viangchan, and Chatham, accounting for 98.5% of the 70 samples genotyped. Subjects expressing the dominant genotypes all had less than 10% of normal enzyme activities and were thus considered severe variants. Blind administration of anti-relapse primaquine therapy at Sumba would likely impose risk of serious harm. Author Summary: G6PD deficiency affects over 400 million people worldwide. This enormously diverse disorder causes acute hemolytic anemia upon exposure to oxidizing chemicals, e.g., naphthalene, some sulfa drugs, and certain antimalarials, including primaquine. The primary public health concern with G6PD deficiency involves that latter drug, the only one available for the radical cure of vivax and ovale malarias. Absent primaquine therapy, patients will suffer multiple recurrent attacks called relapses in the two years following the primary attack. Primaquine in G6PD-deficient patients triggers a mild to severe acute hemolytic anemia, depending upon dose administered and the specific variant involved. Relatively high therapeutic doses in severely deficient variants will threaten life. Malaria therapeutic policy and practice regarding primaquine may hinge upon the prevalence and severity of G6PD deficiency weighed against the therapeutic benefit of averting risk of relapse and attendant morbidity, mortality and onward transmission. In the current study we aimed to inform that weighing by characterizing the frequency and type of G6PD deficiency occurring in populations enduring endemic vivax malaria transmission on a single island in eastern Indonesia. The findings infer risk of serious harm caused by primaquine administered to residents of unknown G6PD status. [ABSTRACT FROM AUTHOR]

Dengue virus (DENV) transmission is ubiquitous throughout the tropics. More than 70% of the current global dengue disease burden is borne by people who live in the Asia-Pacific region. We sequenced the E gene of DENV isolated from travellers entering Western Australia between 2010–2012, most of whom visited Indonesia, and identified a diverse array of DENV1-4, including multiple co-circulating viral lineages. Most viruses were closely related to lineages known to have circulated in Indonesia for some time, indicating that this geographic region serves as a major hub for dengue genetic diversity. Most notably, we identified a new lineage of DENV-2 (Cosmopolitan genotype) that emerged in Bali in 2011–2012. The spread of this lineage should clearly be monitored. Surveillance of symptomatic returned travellers provides important and timely information on circulating DENV serotypes and genotypes, and can reveal the herald wave of dengue and other emerging infectious diseases. Author Summary: Dengue is currently the most rapidly spreading mosquito-borne viral disease of humans, and is endemic in most tropical and sub-tropical countries. An estimated 390 million infections occur annually, and over 70% of the current global dengue disease burden is borne by people who live in Southeast Asia and the Western Pacific region. DENV serotype and genotype data is lacking in many parts of this region, limiting our attempts to understand the observed patterns of hyperendemicity and disease severity. Many countries in the Southeast Asia and Western Pacific region are popular tourist destinations, and dengue has been identified as a cause of travel-related illness in people returning from endemic countries. We sequenced the E gene of DENV isolated from travellers returning to Western Australia from 7 countries throughout Asia between 2010 and 2012. The majority of DENV originated in Indonesia, predominantly Bali, a popular travel destination for Australians. We identified hyperendemic transmission of all four DENV serotypes in Bali in 2010; circulating DENV included dominant local strains which had circulated for several years in Indonesia and Singapore, as well as strains more recently introduced into Bali from other countries in the region. Finally, we show the emergence of a new lineage of DENV2 (Cosmopolitan genotype) in 2011–2012, which should be monitored. Travellers may act as sentinels and provide important information on DENV genotypes and linages circulating in countries where locally generated detailed genetic data may not be available. [ABSTRACT FROM AUTHOR]

Canine rabies can be effectively controlled by vaccination with readily available, high-quality vaccines. These vaccines should provide protection from challenge in healthy dogs, for the claimed period, for duration of immunity, which is often two or three years. It has been suggested that, in free-roaming dog populations where rabies is endemic, vaccine-induced protection may be compromised by immuno-suppression through malnutrition, infection and other stressors. This may reduce the proportion of dogs that seroconvert to the vaccine during vaccination campaigns and the duration of immunity of those dogs that seroconvert. Vaccination coverage may also be limited through insufficient vaccine delivery during vaccination campaigns and the loss of vaccinated individuals from populations through demographic processes. This is the first longitudinal study to evaluate temporal variations in rabies vaccine-induced serological responses, and factors associated with these variations, at the individual level in previously unvaccinated free-roaming dog populations. Individual-level serological and health-based data were collected from three cohorts of dogs in regions where rabies is endemic, one in South Africa and two in Indonesia. We found that the vast majority of dogs seroconverted to the vaccine; however, there was considerable variation in titres, partly attributable to illness and lactation at the time of vaccination. Furthermore, >70% of the dogs were vaccinated through community engagement and door-to-door vaccine delivery, even in Indonesia where the majority of the dogs needed to be caught by net on successive occasions for repeat blood sampling and vaccination. This demonstrates the feasibility of achieving population-level immunity in free-roaming dog populations in rabies-endemic regions. However, attrition of immune individuals through demographic processes and waning immunity necessitates repeat vaccination of populations within at least two years to ensure communities are protected from rabies. These findings support annual mass vaccination campaigns as the most effective means to control canine rabies. Author Summary: Canine-mediated rabies is a horrific disease that claims tens of thousands of human lives every year, particularly in Asia and Africa. The disease can be effectively controlled through mass vaccination of dogs with high-quality vaccines; however, questions remain over the effectiveness of vaccination where the health status of free-roaming dogs may be compromised and the life expectancy and access to these dogs may be limited. This study evaluated rabies-vaccine induced immune responses and vaccine delivery in previously unvaccinated, free-roaming dog populations in two rabies endemic regions in Asia and Africa, to better understand the effectiveness of vaccination campaigns. We found that the majority of dogs seroconverted to the vaccine regardless of health status. Excellent vaccination coverage was achieved through community engagement and door-to-door vaccine delivery, even where the majority of the dogs needed to be caught by net for vaccination. However, attrition of immune individuals through demographic processes and waning immunity reinforces the importance of frequent and regular vaccination campaigns to ensure effective vaccination coverage is maintained. [ABSTRACT FROM AUTHOR]

Indonesia, a populous nation with a growing economy, is facing a high concentration of neglected tropical diseases (NTDs) that could hinder its development. The Ministry of Health and the World Health Organization are collaborating to eliminate these diseases by establishing a suitable health and scientific infrastructure. The country also grapples with extreme poverty, with a significant portion of the population living on less than $2 per day. NTDs such as helminth and bacterial infections pose a threat to the health and well-being of the population, especially the poorest individuals. The Indonesian Ministry of Health (IMOH) is taking action to control and eliminate NTDs, focusing on diseases like schistosomiasis, lymphatic filariasis, neglected bacterial infections, and neglected viral infections like dengue. Their plan includes mass drug administration, health education, and environmental management. The IMOH is receiving financial support from organizations like USAID and collaborating with research institutes to develop new diagnostics, drugs, and vaccines. These efforts are crucial for poverty reduction and the elimination of NTDs in Southeast Asia. [Extracted from the article]

Background: More than 200,000 new cases of leprosy were reported by 105 countries in 2011. The disease is a public health problem in Brazil, particularly within high-burden pockets in the Amazon region where leprosy is hyperendemic among children. Methodology: We applied geographic information systems and spatial analysis to determine the spatio-temporal pattern of leprosy cases in a hyperendemic municipality of the Brazilian Amazon region (Castanhal). Moreover, we performed active surveillance to collect clinical, epidemiological and serological data of the household contacts of people affected by leprosy and school children in the general population. The occurrence of subclinical infection and overt disease among the evaluated individuals was correlated with the spatio-temporal pattern of leprosy. Principal Findings: The pattern of leprosy cases showed significant spatio-temporal heterogeneity (p<0.01). Considering 499 mapped cases, we found spatial clusters of high and low detection rates and spatial autocorrelation of individual cases at fine spatio-temporal scales. The relative risk of contracting leprosy in one specific cluster with a high detection rate is almost four times the risk in the areas of low detection rate (RR = 3.86; 95% CI = 2.26–6.59; p<0.0001). Eight new cases were detected among 302 evaluated household contacts: two living in areas of clusters of high detection rate and six in hyperendemic census tracts. Of 188 examined students, 134 (71.3%) lived in hyperendemic areas, 120 (63.8%) were dwelling less than 100 meters of at least one reported leprosy case, 125 (66.5%) showed immunological evidence (positive anti-PGL-I IgM titer) of subclinical infection, and 9 (4.8%) were diagnosed with leprosy (8 within 200 meters of a case living in the same area). Conclusions/Significance: Spatial analysis provided a better understanding of the high rate of early childhood leprosy transmission in this region. These findings can be applied to guide leprosy control programs to target intervention to high risk areas. Author Summary: Leprosy can lead to physical disabilities and deformities if not diagnosed and treated early. Even today, the disease affects more than 200,000 people per year, particularly the poorest people from developing countries, such as India, Brazil and Indonesia. Cases among children <15 years old have been used as an important indicator of recent transmission in the community. Recently, geographic information systems and spatial analysis have become important tools for epidemiology, helping to understand the transmission dynamics of several diseases. In this work, we determined the spatial and temporal distribution of leprosy in a hyperendemic municipality of the Brazilian Amazon region. In association with clinical, epidemiological and serological data of household contacts and school children in the general population, we further correlated the occurrence of subclinical infection and overt disease with the distribution of reported cases. We identified heterogeneity in the distribution of leprosy, with significant clusters of high and low detection rates. Our analysis revealed that children with leprosy or those harboring subclinical infection were in close proximity to spatial and temporal clusters of leprosy cases. These findings can be applied to guide leprosy control programs to target intervention more systematically to areas where the risk of leprosy is high. [ABSTRACT FROM AUTHOR]

Background: The lymphatic filarial parasite Brugia timori occurs only in eastern Indonesia where it causes high morbidity. The absence of an animal reservoir, the inefficient transmission by Anopheles mosquitoes and the high sensitivity to DEC/albendazole treatment make this species a prime candidate for elimination by mass drug administration (MDA). Methodology/Principal Findings: We evaluated the effect of MDA using DEC and albendazole on B. timori and soil transmitted helminths (STH) in a cross-sectional study of a sentinel village on Alor Island annually over a period of 10 years. Pre-MDA the microfilaria (MF) prevalence was 26% and 80% of the residents had filaria-specific IgG4 antibodies. In 2010, 34 months after the 6th round of MDA, MF and antibody rates were only 0.17% and 6.4%, respectively. The MDA campaign had also a beneficial effect on STH. Baseline prevalence rates for Ascaris, hookworm and Trichuris were 34%, 28%, and 11%, respectively; these rates were reduced to 27%, 4%, and 2% one year after the 5th round of MDA. Unfortunately, STH rates rebounded 34 months after cessation of MDA and approached pre-MDA rates. However, the intensity of STH infection in 2009 was still reduced, and no heavy infections were detected. Conclusions/Significance: MDA with DEC/albendazole has had a major impact on B. timori MF and IgG4 antibody rates, providing a proof of principle that elimination is feasible. We also documented the value of annual DEC/albendazole as a mass de-worming intervention and the importance of continuing some form of STH control after cessation of MDA for filariasis. Author Summary: The impact of six annual rounds of mass drug administration (MDA) using DEC combined with albendazole on brugian filariasis and soil-transmitted helminths (STH) was evaluated. Microfilaria rates of B. timori dropped quickly after MDA and were below 1% for 34 months after stopping intervention when the study ended. The prevalence of filarial-specific IgG4 antibodies in the community as measured by the Brugia Rapid test was about 80% before MDA and dropped slowly to about 6% at the end of the study period. MDA had also a beneficial effect on STH, especially on hookworm, but prevalence rates rebounded 34 months after cessation of MDA and quickly approached pre-control levels, while infection intensity was still reduced. Our study indicated that B. timori infection can be eliminated by DEC/albendazole MDA and that the anti-filarial IgG4 rate in the community significantly declines over time. While lymphatic filariasis (LF) MDA can be considered as a powerful general deworming campaign, STH infection rates rebound quickly and a supplementary control strategy is needed after LF MDA is ceased. [ABSTRACT FROM AUTHOR]

Chikungunya virus (CHIKV) is known to cause sporadic or explosive outbreaks. However, little is known about the endemic transmission of CHIKV. To ascertain the endemic occurrence of CHIKV transmission, we tested blood samples from patients with a non-dengue febrile illness who participated in a prospective cohort study of factory workers in Bandung, Indonesia. From August 2000 to June 2004, and September 2006 to April 2008, 1901 febrile episodes occurred and 231 (12.2%) dengue cases were identified. The remaining febrile cases were evaluated for possible CHIKV infection by measuring anti-CHIKV IgM and IgG antibodies in acute and convalescent samples. Acute samples of serologically positive cases were subsequently tested for the presence of CHIKV RNA by RT-PCR and/or virus isolation. A total of 135 (7.1%) CHIKV infections were identified, providing an incidence rate of 10.1/1,000 person years. CHIKV infections were identified all year round and tended to increase during the rainy season (January to March). Severe illness was not found and severe arthralgia was not a prominently reported symptom. Serial post-illness samples from nine cases were tested to obtain a kinetic picture of IgM and IgG anti-CHIKV antibodies. Anti-CHIKV IgM antibodies were persistently detected in high titers for approximately one year. Three patients demonstrated evidence of possible sequential CHIKV infections. The high incidence rate and continuous chikungunya cases in this adult cohort suggests that CHIKV is endemically transmitted in Bandung. Further characterization of the circulating strains and surveillance in larger areas are needed to better understand CHIKV epidemiology in Indonesia. Author Summary: Chikungunya is one of the neglected diseases. It has only attracted attention during outbreaks, in particular, the large epidemics in the Indian Ocean in 2005–2006. To our knowledge, there has never been any surveillance to determine the transmission of this virus among humans in non-outbreak settings. Such surveillance is particularly important because it will provide a better estimate of the disease burden and valuable information on how this virus is maintained outside outbreaks. Our study, conducted between 2000 and 2008 in Bandung, West Java, Indonesia, yielded several important findings: 1. Chikungunya is an important cause of fever among adults in Bandung, Indonesia. 2. The clinical symptoms are mostly mild and short lasting. 3. In addition to previously described epidemiological features involving episodic outbreaks, it is also continuously transmitted throughout the year. 4. A few patients may have experienced more than one chikungunya virus infection. 5. Only the Asian genotype was found and not the East Central South African genotype that was responsible for the 2005 outbreak in the Indian Ocean. 6. The persistence of IgM for a long period after illness may complicate the interpretation of laboratory results. [ABSTRACT FROM AUTHOR]

Dengue disease is currently a major health problem in Indonesia and affects all provinces in the country, including Semarang Municipality, Central Java province. While dengue is endemic in this region, only limited data on the disease epidemiology is available. To understand the dynamics of dengue in Semarang, we conducted clinical, virological, and demographical surveillance of dengue in Semarang and its surrounding regions in 2012. Dengue cases were detected in both urban and rural areas located in various geographical features, including the coastal and highland areas. During an eight months' study, a total of 120 febrile patients were recruited, of which 66 were serologically confirmed for dengue infection using IgG/IgM ELISA and/or NS1 tests. The cases occurred both in dry and wet seasons. Majority of patients were under 10 years old. Most patients were diagnosed as dengue hemorrhagic fever, followed by dengue shock syndrome and dengue fever. Serotyping was performed in 31 patients, and we observed the co-circulation of all four dengue virus (DENV) serotypes. When the serotypes were correlated with the severity of the disease, no direct correlation was observed. Phylogenetic analysis of DENV based on Envelope gene sequence revealed the circulation of DENV-2 Cosmopolitan genotype and DENV-3 Genotype I. A striking finding was observed for DENV-1, in which we found the co-circulation of Genotype I with an old Genotype II. The Genotype II was represented by a virus strain that has a very slow mutation rate and is very closely related to the DENV strain from Thailand, isolated in 1964 and never reported in other countries in the last three decades. Moreover, this virus was discovered in a cool highland area with an elevation of 1,001 meters above the sea level. The discovery of this old DENV strain may suggest the silent circulation of old virus strains in Indonesia. Author Summary: We studied dengue disease in Semarang municipality, Central Java, one of the endemic regions in Indonesia. The disease occurred in wide geographical regions which include urban, rural, coastal, and highland areas. All four dengue virus serotypes were found. The infecting serotypes were not associated with disease severities. We also determined the genotype of the circulating viruses. One of the interesting findings was the presence of an old genotype of DENV-1 which has never been reported in the last three decades, which may suggest the silent circulation of this particular genotype in Semarang. These findings offer the first information of the clinical, virological and demographical aspects of the dengue disease in Semarang, Indonesia. [ABSTRACT FROM AUTHOR]

Background: Identification of dengue patients at risk for progressing to severe disease is difficult. Significant plasma leakage is a hallmark of severe dengue infection which can suddenly lead to hypovolemic shock around the time of defervescence. We hypothesized that the detection of subclinical plasma leakage may identify those at risk for severe dengue. The aim of the study was to determine the predictive diagnostic value of serial ultrasonography for severe dengue. Methodology/Principal Findings: Daily bedside ultrasounds were performed with a handheld ultrasound device in a prospective cohort of adult Indonesians with dengue. Timing, localization and relation to dengue severity of the ultrasonography findings were determined, as well as the relation with serial hematocrit and albumin values. The severity of dengue was retrospectively determined by WHO 2009 criteria. A total of 66 patients with proven dengue infection were included in the study of whom 11 developed severe dengue. Presence of subclinical plasma leakage at enrollment had a positive predictive value of 35% and a negative predictive value of 90% for severe dengue. At enrollment, 55% of severe dengue cases already had subclinical plasma leakage, which increased to 91% during the subsequent days. Gallbladder wall edema was more pronounced in severe than in non-severe dengue patients and often preceded ascites/pleural effusion. Serial hematocrit and albumin measurements failed to identify plasma leakage and patients at risk for severe dengue. Conclusions/Significance: Serial ultrasonography, in contrast to existing markers such as hematocrit, may better identify patients at risk for development of severe dengue. Patients with evidence of subclinical plasma leakage and/or an edematous gallbladder wall by ultrasonography merit intensive monitoring for development of complications. [ABSTRACT FROM AUTHOR]

Background: HIV-associated subacute meningitis is mostly caused by tuberculosis or cryptococcosis, but often no etiology can be established. In the absence of CT or MRI of the brain, toxoplasmosis is generally not considered as part of the differential diagnosis. Methodology/Principal Findings: We performed cerebrospinal fluid real time PCR and serological testing for Toxoplasma gondii in archived samples from a well-characterized cohort of 64 HIV-infected patients presenting with subacute meningitis in a referral hospital in Indonesia. Neuroradiology was only available for 6 patients. At time of presentation, patients mostly had newly diagnosed and advanced HIV infection (median CD4 count 22 cells/mL), with only 17.2% taking ART, and 9.4% PJP-prophylaxis. CSF PCR for T. Gondii was positive in 21 patients (32.8%). Circulating toxoplasma IgG was present in 77.2% of patients tested, including all in whom the PCR of CSF was positive for T. Gondii. Clinically, in the absence of neuroradiology, toxoplasmosis was difficult to distinguish from tuberculosis or cryptococcal meningitis, although CSF abnormalities were less pronounced. Mortality among patients with a positive CSF T. Gondii PCR was 81%, 2.16-fold higher (95% CI 1.04–4.47) compared to those with a negative PCR. Conclusions/Significance: Toxoplasmosis should be considered in HIV-infected patients with clinically suspected subacute meningitis in settings where neuroradiology is not available. Author Summary: If HIV-infected patients present with seizures, focal neurological symptoms or confusion, a CT-scan or MRI of the brain is normally made. If mass lesions are found (and the CD4 cell count is sufficiently low), cerebral toxoplasmosis is suspected, and often treated empirically. However, some of the symptoms of cerebral toxoplasmosis may mimic those of subacute meningitis. Therefore, in settings where no cerebral imaging can be performed, HIV-associated cerebral toxoplasmosis may be under-diagnosed. We retrospectively looked for toxoplasmosis in a cohort of HIV-infected patients presenting with subacute meningitis in an Indonesian hospital, where neuroradiology was not available for most patients. Patients mostly came with newly diagnosed and advanced HIV infection and few were on HIV-treatment or PJP-prophylaxis. Molecular testing of cerebrospinal fluid (CSF) was positive for Toxoplasma gondii in 32% of patients, serology was positive in 78%. Clinically, in the absence of neuroradiology, toxoplasmosis was difficult to distinguish from tuberculosis or cryptococcal meningitis. A positive CSF T. gondii PCR was associated with a two-fold increased mortality. We conclude that toxoplasmosis should be considered in HIV-infected patients with clinically suspected subacute meningitis in settings where neuroradiology is not available. [ABSTRACT FROM AUTHOR]

Background: Death adders (Acanthophis spp) are found in Australia, Papua New Guinea and parts of eastern Indonesia. This study aimed to investigate the clinical syndrome of death adder envenoming and response to antivenom treatment. Methodology/Principal Findings: Definite death adder bites were recruited from the Australian Snakebite Project (ASP) as defined by expert identification or detection of death adder venom in blood. Clinical effects and laboratory results were collected prospectively, including the time course of neurotoxicity and response to treatment. Enzyme immunoassay was used to measure venom concentrations. Twenty nine patients had definite death adder bites; median age 45 yr (5–74 yr); 25 were male. Envenoming occurred in 14 patients. Two further patients had allergic reactions without envenoming, both snake handlers with previous death adder bites. Of 14 envenomed patients, 12 developed neurotoxicity characterised by ptosis (12), diplopia (9), bulbar weakness (7), intercostal muscle weakness (2) and limb weakness (2). Intubation and mechanical ventilation were required for two patients for 17 and 83 hours. The median time to onset of neurotoxicity was 4 hours (0.5–15.5 hr). One patient bitten by a northern death adder developed myotoxicity and one patient only developed systemic symptoms without neurotoxicity. No patient developed venom induced consumption coagulopathy. Antivenom was administered to 13 patients, all receiving one vial initially. The median time for resolution of neurotoxicity post-antivenom was 21 hours (5–168). The median peak venom concentration in 13 envenomed patients with blood samples was 22 ng/mL (4.4–245 ng/mL). In eight patients where post-antivenom bloods were available, no venom was detected after one vial of antivenom. Conclusions/Significance: Death adder envenoming is characterised by neurotoxicity, which is mild in most cases. One vial of death adder antivenom was sufficient to bind all circulating venom. The persistent neurological effects despite antivenom, suggests that neurotoxicity is not reversed by antivenom. Author Summary: Death adders are a genus of venomous snakes found in Australia, Papua New Guinea and Indonesia. Death adder envenoming is a rare but important health problem in Australasia. Definite death adder bites were recruited as part of the Australian Snakebite Project (ASP). Clinical effects, laboratory results and response to antivenom treatment were recorded for each case. Death adder envenoming was confirmed by enzyme immunoassay in blood collected from patients. The most important clinical effect was neurotoxicity, which was mild in most cases. One vial of antivenom was shown to be effective at binding circulating death adder venom. However, antivenom had little effect on the neurotoxicity that developed in envenomed patients and neurotoxicity took on average one day to resolve. This study supports the idea of presynaptic neurotoxicity in death adder envenoming which was previously thought to be due to post-synaptic neurotoxicity. The study calls into question the benefit of antivenom, with poor response shown in patients with both mild and severe envenoming. [ABSTRACT FROM AUTHOR]

Infection with filarial parasites is associated with T cell hyporesponsiveness, which is thought to be partly mediated by their ability to induce regulatory T cells (Tregs) during human infections. This study investigates the functional capacity of Tregs from different groups of filarial patients to suppress filaria-specific immune responses during human filariasis. Microfilaremic (MF), chronic pathology (CP) and uninfected endemic normal (EN) individuals were selected in an area endemic for Brugia timori in Flores island, Indonesia. PBMC were isolated, CD4CD25hi cells were magnetically depleted and in vitro cytokine production and proliferation in response to B. malayi adult worm antigen (BmA) were determined in total and Treg-depleted PBMC. In MF subjects BmA-specific T and B lymphocyte proliferation as well as IFN-gamma, IL-13 and IL-17 responses were lower compared to EN and CP groups. Depletion of Tregs restored T cell as well as B cell proliferation in MF-positives, while proliferative responses in the other groups were not enhanced. BmA-induced IL-13 production was increased after Treg removal in MF-positives only. Thus, filaria-associated Tregs were demonstrated to be functional in suppressing proliferation and possibly Th2 cytokine responses to BmA. These suppressive effects were only observed in the MF group and not in EN or CP. These findings may be important when considering strategies for filarial treatment and the targeted prevention of filaria-induced lymphedema. Author Summary: Lymphatic filariasis is a neglected disease still prominent in low-resource settings and is very disabling when it progresses to chronic pathology caused by lymphedema. Until now, studies on the contribution of Tregs to lymphocyte hyporesponsiveness in human filariasis have focused on frequency and phenotypic characteristics of these cells. We have looked at the functional consequence of the presence of Tregs in filaria-specific immune responses during different stages of human lymphatic filariasis. Proliferation of not only T cells, but also B cells, was decreased in patients with microfilaremia compared to uninfected individuals and chronic pathology (lymphedema) patients. The suppressed lymphocyte proliferative responses were increased after in vitro removal of Tregs in the microfilaria-positive group only, indicating the presence of filaria-specific functional Tregs in microfilaremic patients which are not as active in subjects with chronic pathology or without infection. Th2 cytokine responses were specifically enhanced in microfilaremics as well after Treg depletion, suggesting Treg-associated suppression of filaria-specific Th2 responses. Taken together, filaria-specific Treg contribute to immune modulation during microfilaremia and might need to be considered in therapeutic strategies to prevent chronic pathology induced by filarial infection. [ABSTRACT FROM AUTHOR]

Background: Coma complicates Plasmodium falciparum infection but is uncommonly associated with P. vivax. Most series of vivax coma have been retrospective and have not utilized molecular methods to exclude mixed infections with P. falciparum. Methods: We prospectively enrolled patients hospitalized in Timika, Indonesia, with a Glasgow Coma Score (GCS) ≤10 and P. vivax monoinfection on initial microscopy over a four year period. Hematological, biochemical, serological, radiological and cerebrospinal fluid (CSF) examinations were performed to identify other causes of coma. Repeat microscopy, antigen detection and polymerase chain reaction (PCR) were performed to exclude infections with other Plasmodium species. Results: Of 24 patients fulfilling enrolment criteria, 5 had clear evidence for other non-malarial etiologies. PCR demonstrated 10 mixed infections and 3 P. falciparum monoinfections. 6 (25%) patients had vivax monoinfection and no apparent alternative cause, with a median GCS of 9 (range 8–10) and a median coma duration of 42 (range 36–48) hours. CSF leukocyte counts were <10/ul (n = 3); 2 of the 3 patients without CSF examination recovered with antimalarial therapy alone. One patient had a tremor on discharge consistent with a post-malarial neurological syndrome. No patient had other organ dysfunction. The only death was associated with pure P. falciparum infection by PCR. Vivax monoinfection-associated risk of coma was estimated at 1 in 29,486 clinical vivax infections with no deaths. In comparison, the risk of falciparum-associated coma was estimated at 1 in 1,276 clinical infections with an 18.5% mortality rate. Conclusions: P. vivax-associated coma is rare, occurring 23 times less frequently than that seen with falciparum malaria, and is associated with a high proportion of non-malarial causes and mixed infections using PCR. The pathogenesis of coma associated with vivax malaria, particularly the role of comorbidities, is uncertain and requires further investigation. Author Summary: An estimated 132 to 391 million cases of Plasmodium vivax occur annually, accounting for up to 50% of malaria cases in South and East Asia. Vivax malaria is called "benign tertian malaria" and is not considered to be associated with life threatening or severe complications. Recently, observational studies and case series or reports have reported features of severe disease normally only seen in falciparum malaria, including coma. However, the majority of these reports did not exclude mixed infections using molecular methods or estimate the risk to the population in an endemic area. In Indonesia Papua, which has a high rate of vivax malaria and drug resistance, we prospectively enrolled all patients with coma and vivax monoinfection by microscopy over a 4 year period. We excluded falciparum malaria by molecular and antigenic methods, and sought evidence for other central nervous system (CNS) infections by cerebrospinal fluid microscopic examination. The majority of patients had evidence of mixed infections with P. falciparum or non-malarial causes of coma, however six patients had clinically significant coma, with no evidence of falciparum malaria or other CNS infections. The study was limited by the absence of bacterial cultures. Our study highlights that P. vivax can be associated with coma, but that this phenomenon is 23 times less frequent than that seen with falciparum malaria and was not associated with a fatal outcome. [ABSTRACT FROM AUTHOR]

Background: A variety of obstacles including bureaucracy and lack of resources have interfered with timely detection and reporting of dengue cases in many endemic countries. Surveillance efforts have turned to modern data sources, such as Internet search queries, which have been shown to be effective for monitoring influenza-like illnesses. However, few have evaluated the utility of web search query data for other diseases, especially those of high morbidity and mortality or where a vaccine may not exist. In this study, we aimed to assess whether web search queries are a viable data source for the early detection and monitoring of dengue epidemics. Methodology/Principal Findings: Bolivia, Brazil, India, Indonesia and Singapore were chosen for analysis based on available data and adequate search volume. For each country, a univariate linear model was then built by fitting a time series of the fraction of Google search query volume for specific dengue-related queries from that country against a time series of official dengue case counts for a time-frame within 2003–2010. The specific combination of queries used was chosen to maximize model fit. Spurious spikes in the data were also removed prior to model fitting. The final models, fit using a training subset of the data, were cross-validated against both the overall dataset and a holdout subset of the data. All models were found to fit the data quite well, with validation correlations ranging from 0.82 to 0.99. Conclusions/Significance: Web search query data were found to be capable of tracking dengue activity in Bolivia, Brazil, India, Indonesia and Singapore. Whereas traditional dengue data from official sources are often not available until after some substantial delay, web search query data are available in near real-time. These data represent valuable complement to assist with traditional dengue surveillance. Author Summary: A variety of obstacles, including bureaucracy and lack of resources, delay detection and reporting of dengue and exist in many countries where the disease is a major public health threat. Surveillance efforts have turned to modern data sources such as Internet usage data. People often seek health-related information online and it has been found that the frequency of, for example, influenza-related web searches as a whole rises as the number of people sick with influenza rises. Tools have been developed to help track influenza epidemics by finding patterns in certain web search activity. However, few have evaluated whether this approach would also be effective for other diseases, especially those that affect many people, that have severe consequences, or for which there is no vaccine. In this study, we found that aggregated, anonymized Google search query data were also capable of tracking dengue activity in Bolivia, Brazil, India, Indonesia and Singapore. Whereas traditional dengue data from official sources are often not available until after a long delay, web search query data is available for analysis within a day. Therefore, because it could potentially provide earlier warnings, these data represent a valuable complement to traditional dengue surveillance. [ABSTRACT FROM AUTHOR]