#### PLOS Neglected Tropical Diseases

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ISSN / EISSN : 19352735 / 19352735
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Anuj Tiwari, David J. Blok, Mohammad Arif, Jan Hendrik Richardus
Published: 4 August 2020
PLOS Neglected Tropical Diseases, Volume 14; doi:10.1371/journal.pntd.0008521

Abstract:
India has the highest burden of leprosy in the world. Following a recent WHO guideline, the Indian National Leprosy Programme is introducing post-exposure prophylaxis with single-dose rifampicin (SDR-PEP) in all high-endemic districts of the country. The aim of this study is to estimate the long-term cost-effectiveness of SDR-PEP in different leprosy disability burden situations. We used a stochastic individual-based model (SIMCOLEP) to simulate the leprosy new case detection rate trend and the impact of implementing contact screening and SDR-PEP from 2016 to 2040 (25 years) in the Union Territory of Dadra Nagar Haveli (DNH) in India. Effects of the intervention were expressed as disability adjusted life years (DALY) averted under three assumption of disability prevention: 1) all grade 1 disability (G1D) cases prevented; 2) G1D cases prevented in PB cases only; 3) no disability prevented. Costs were US$2.9 per contact. Costs and effects were discounted at 3%. The incremental cost per DALY averted by SDR-PEP was US$ 210, US$447, and US$ 5,673 in the 25th year under assumption 1, 2, and 3, respectively. If prevention of G1D was assumed, the probability of cost-effectiveness was 1.0 at the threshold of US$2,000, which is equivalent to the GDP per capita of India. The probability of cost-effectiveness was 0.6, if no disability prevention was assumed. The cost per new leprosy case averted was US$ 2,873. Contact listing, screening and the provision of SDR-PEP is a cost-effective strategy in leprosy control in both the short (5 years) and long term (25 years). The cost-effectiveness depends on the extent to which disability can be prevented. As the intervention becomes increasingly cost-effective in the long term, we recommend a long-term commitment for its implementation. Leprosy is an infectious disease caused by the Mycobacterium leprae and is one of the major causes of preventable disability in low- and middle-income countries. Disabled people face lifelong socioeconomic challenges and are often excluded from society. It brings people affected by leprosy in a vicious cycle of poverty and disability. This cycle needs to be curbed through scientific evidence on health economic aspects of leprosy. Unfortunately, there is not much literature available on cost or cost-effectiveness of leprosy prevention. New prevention methods such as post-exposure chemoprophylaxis are now available, providing opportunity to collect up-to-date health economic evidence to support health policy and planning. Here, we present a cost-effectiveness study of contact screening in combination of post-exposure prophylaxis with single-dose rifampicin in the Union Territory of Dadra Nagar Haveli in India. We compare the intervention with the continuation of the routine leprosy control programme. As leprosy is moving towards elimination, evidence from this study will contribute to an investment case for leprosy elimination.
Morgane Verduyn, Nathalie Allou, Virgile Gazaille, Michel Andre, Tannvir Desroche, Marie-Christine Jaffar, Nicolas Traversier, Cecile Levin, Marie Lagrange-Xelot, Marie-Pierre Moiton, et al.
Published: 3 August 2020
PLOS Neglected Tropical Diseases, Volume 14; doi:10.1371/journal.pntd.0008476

Benjamin T. Schleenvoigt, Bernhard Theis, Michaela Wüst, Christina Forstner, Mathias W. Pletz, Stefan Hagel
Published: 3 August 2020
PLOS Neglected Tropical Diseases, Volume 14; doi:10.1371/journal.pntd.0008569

Murilo Sena Amaral, Ernesto Goulart, Luiz Carlos Caires-Júnior, David Abraham Morales-Vicente, Alessandra Soares-Schanoski, Roselane Paiva Gomes, Giovanna Gonçalves De Oliveira Olberg, Renato Mancini Astray, Jorge E. Kalil, Mayana Zatz, et al.
Published: 3 August 2020
PLOS Neglected Tropical Diseases, Volume 14; doi:10.1371/journal.pntd.0008424

Abstract:
Zika virus (ZIKV) causes congenital Zika syndrome (CZS), which is characterized by fetal demise, microcephaly and other abnormalities. ZIKV in the pregnant woman circulation must cross the placental barrier that includes fetal endothelial cells and trophoblasts, in order to reach the fetus. CZS occurs in ~1–40% of cases of pregnant women infected by ZIKV, suggesting that mothers’ infection by ZIKV during pregnancy is not deterministic for CZS phenotype in the fetus. Therefore, other susceptibility factors might be involved, including the host genetic background. We have previously shown that in three pairs of dizygotic twins discordant for CZS, neural progenitor cells (NPCs) from the CZS-affected twins presented differential in vitro ZIKV susceptibility compared with NPCs from the non-affected. Here, we analyzed human-induced-pluripotent-stem-cell-derived (hiPSC-derived) trophoblasts from these twins and compared by RNA-Seq the trophoblasts from CZS-affected and non-affected twins. Following in vitro exposure to a Brazilian ZIKV strain (ZIKVBR), trophoblasts from CZS-affected twins were significantly more susceptible to ZIKVBR infection when compared with trophoblasts from the non-affected. Transcriptome profiling revealed no differences in gene expression levels of ZIKV candidate attachment factors, IFN receptors and IFN in the trophoblasts, either before or after ZIKVBR infection. Most importantly, ZIKVBR infection caused, only in the trophoblasts from CZS-affected twins, the downregulation of genes related to extracellular matrix organization and to leukocyte activation, which are important for trophoblast adhesion and immune response activation. In addition, only trophoblasts from non-affected twins secreted significantly increased amounts of chemokines RANTES/CCL5 and IP10 after infection with ZIKVBR. Overall, our results showed that trophoblasts from non-affected twins have the ability to more efficiently activate genes that are known to play important roles in cell adhesion and in triggering the immune response to ZIKV infection in the placenta, and this may contribute to predict protection from ZIKV dissemination into fetuses’ tissues. The Zika virus (ZIKV) infection in adults is usually characterized by mild flu-like symptoms, with most cases remaining asymptomatic. However, in the last years, widespread ZIKV infection was shown for the first time to be associated with congenital Zika syndrome (CZS) and death of neonates. It is estimated that CZS occurs in ~1–40% of cases of pregnant women infected by ZIKV, which suggests that different susceptibility factors might be involved, including the host genetic background. Here, by analyzing trophoblast cells that recapitulate the placenta from three pairs of dizygotic twins discordant for CZS, we were able to show that trophoblasts from CZS-affected twins were significantly more susceptible to ZIKV infection when compared with trophoblasts from the non-affected twins. We also provide a detailed picture of genes differentially expressed by trophoblasts from the discordant twins after infection with ZIKV. These genes can be further investigated as possible therapeutic targets to avoid viral dissemination into developing fetus’ tissues. Our results suggest that CZS might be caused, among other factors, by a decreased ability of the placenta to respond to ZIKV infection in CZS-affected neonates, concomitant with a previously known deregulation of neural development genes in ZIKV-infected neuroprogenitor cells of these CZS-affected babies.
Emily F. Santos, Ângelo A. O. Silva, Leonardo M. Leony, Natália E. M. Freitas, Ramona T. Daltro, Carlos G. Regis-Silva, Rodrigo P. Del-Rei, Wayner V. Souza, Alejandro L. Ostermayer, Veruska M. Costa, et al.
Published: 3 August 2020
PLoS Neglected Tropical Diseases, Volume 14; doi:10.1371/journal.pntd.0008445

Abstract:
In Brazil, acute Chagas disease (ACD) surveillance involves mandatory notification, which allows for population-based epidemiological studies. We conducted a nationwide population-based ecological analysis of the spatiotemporal patterns of ACD notifications in Brazil using secondary surveillance data obtained from the Notifiable Diseases Information System (SINAN) maintained by Brazilian Ministry of Health. In this nationwide population-based ecological all cases of ACD reported in Brazil between 2001 and 2018 were included. Epidemiological characteristics and time trends were analyzed through joinpoint regression models and spatial distribution using microregions as the unit of analysis. A total of 5,184 cases of ACD were recorded during the period under study. The annual incidence rate in Brazil was 0.16 per 100,000 inhabitants/year. Three statistically significant changes in time trends were identified: a rapid increase prior to 2005 (Period 1), a stable drop from 2005 to 2009 (Period 2), followed by another increasing trend after 2009 (Period 3). Higher frequencies were noted in males and females in the North (all three periods) and in females in Northeast (Periods 1 and 2) macroregions, as well as in individuals aged between 20–64 years in the Northeast, and children, adolescents and the elderly in the North macroregion. Vectorial transmission was the main route reported during Period 1, while oral transmission was found to increase significantly in the North during the other periods. Spatiotemporal distribution was heterogeneous in Brazil over time. Despite regional differences, over time cases of ACD decreased significantly nationwide. An increasing trend was noted in the North (especially after 2007), and significant decreases occurred after 2008 among all microregions other than those in the North, especially those in the Northeast and Central-West macroregions. In light of the newly identified epidemiological profile of CD transmission in Brazil, we emphasize the need for strategically integrated entomological and health surveillance actions. Chagas disease (CD) infection is a debilitating and neglected disease that occurs in 21 Latin America countries. CD has two distinct phases: acute and chronic. The generally asymptomatic acute phase begins shortly after infection and can last up to four months. When symptoms do appear, they are typically mild and unspecific. Following this phase, infected individuals evolve to a long-lasting chronic phase, which can be either symptomatic or asymptomatic. In Brazil, only acute cases are mandatorily notifiable in the Brazilian Notifiable Diseases Information System (Brazilian Ministry of Health). Most chronic cases are unknown and untreated. Considering that epidemiological data related to ACD is publicly available, we have analyzed the spatiotemporal distribution of notified cases of ACD and evaluated relevant epidemiological indicators throughout Brazil from 2001 to 2018. The data present here may contribute to surveillance actions designed at preventing new CD cases. We observed 5,184 cases of ACD during the period under study. The annual incidence rate in Brazil was 0.16 per 100,000 inhabitants/year. Three distinct epidemiological periods were identified: a rapid increase prior to 2005 (Period 1), a stable drop from 2005 to 2009 (Period 2), followed by another increasing trend after 2009 (Period 3). Vectorial transmission was the main route reported during Period 1, while oral transmission was found to increase significantly in the North during the other periods. Despite regional differences, over time cases of ACD decreased significantly nationwide. An increasing trend was noted in the North (especially after 2007). In light of the newly identified epidemiological profile of CD transmission in Brazil, we emphasize the need for strategically integrated entomological and health surveillance actions.
Samuel Kariuki, Cecilia Mbae, Sandra Van Puyvelde, Robert Onsare, Susan Kavai, Celestine Wairimu, Ronald Ngetich, John Clemens, Gordon Dougan
Published: 3 August 2020
PLoS Neglected Tropical Diseases, Volume 14; doi:10.1371/journal.pntd.0008440

Abstract:
Invasive Non-typhoidal Salmonella (iNTS) disease is a major public health challenge, especially in Sub-Saharan Africa (SSA). In Kenya, mortality rates are high (20–25%) unless prompt treatment is instituted. The most common serotypes are Salmonella enterica serotype Typhimurium (S. Typhimurium) and Salmonella enterica serotype Enteritidis (S. Enteritidis). In a 5 year case-control study in children residing in the Mukuru informal settlement in Nairobi, Kenya, a total of 4201 blood cultures from suspected iNTS cases and 6326 fecal samples from age-matched controls were studied. From the laboratory cultures we obtained a total of 133 S. Typhimurium isolates of which 83(62.4%) came from cases (53 blood and 30 fecal) and 50(37.6%) from controls (fecal). A total of 120 S. Enteritidis consisted of 70(58.3%) from cases (43 blood and 27 fecal) and 50(41.7%) from controls (fecal). The S. Typhimurium population fell into two distinct ST19 lineages constituting 36.1%, as well as ST313 lineage I (27.8%) and ST313 lineage II (36.1%) isolates. The S. Enteritidis isolates fell into the global epidemic lineage (46.6%), the Central/Eastern African lineage (30.5%), a novel Kenyan-specific lineage (12.2%) and a phylogenetically outlier lineage (10.7%). Detailed phylogenetic analysis revealed a high level of relatedness between NTS from blood and stool originating from cases and controls, indicating a common source pool. Multidrug resistance was common throughout, with 8.5% of such isolates resistant to extended spectrum beta lactams. The high rate of asymptomatic carriage in the population is a concern for transmission to vulnerable individuals and this group could be targeted for vaccination if an iNTS vaccine becomes available. Blood-stream infections in young children in Sub-Saharan Africa cause high levels of morbidity and mortality. Non-typhoidal Salmonella (NTS) serovars Typhimurium and Enteritidis are especially important in causing blood-stream infections in Kenya. In this case-control study we examined a total of 4201 children with potential blood-stream infections and compared their NTS genotypes with those found in fecal samples of 6326 asymptomatic age-matched controls. From a phylogenetic analysis, we observed a high rate of carriage in cases and controls of multidrug resistant Salmonella genotypes with similarity to those causing invasive disease. We hypothesize that the high carriage rates in asymptomatic population may be contributing to maintenance and transmission of NTS disease among vulnerable population of children.
Awtum M. Brashear, Qi Fan, Yubing Hu, Yuling Li, Yan Zhao, Zenglei Wang, Yaming Cao, Jun Miao, Alyssa Barry, Liwang Cui
Published: 3 August 2020
PLoS Neglected Tropical Diseases, Volume 14; doi:10.1371/journal.pntd.0008506

Abstract:
Plasmodium vivax has become the predominant malaria parasite and a major challenge for malaria elimination in the Greater Mekong Subregion (GMS). Yet, our knowledge about the evolution of P. vivax populations in the GMS is fragmental. We performed whole genome sequencing on 23 P. vivax samples from the China-Myanmar border (CMB) and used 21 high-coverage samples to compare to over 200 samples from the rest of the GMS. Using genome-wide single nucleotide polymorphisms (SNPs), we analyzed population differentiation, genetic structure, migration and potential selection using an array of methods. The CMB parasites displayed a higher proportion of monoclonal infections, and 52% shared over 90% of their genomes in identity-by-descent segments with at least one other sample from the CMB, suggesting preferential expansion of certain parasite strains in this region, likely resulting from the P. vivax outbreaks occurring during this study period. Principal component, admixture, fixation index and phylogenetic analyses all identified that parasites from the CMB were genetically distinct from parasites from eastern parts of the GMS (Cambodia, Laos, Vietnam, and Thailand), whereas the eastern GMS parasite populations were largely undifferentiated. Such a genetic differentiation pattern of the P. vivax populations from the GMS parasite was largely explainable through geographic distance. Using the genome-wide SNPs, we narrowed down to a set of 36 SNPs for differentiating parasites from different areas of the GMS. Genome-wide scans to determine selection in the genome with two statistical methods identified genes potentially under drug selection, including genes associated with antifolate resistance and genes linked to chloroquine resistance in Plasmodium falciparum. Plasmodium vivax is an understudied malaria parasite compared to P. falciparum despite that it is the most common Plasmodium species outside of Africa. In the Greater Mekong Subregion (GMS), the increased proportion of P. vivax proves its resilience to conventional malaria control measures. Within the GMS malaria incidence is highly heterogeneous, typified by more intensive malaria transmission along international borders. Understanding the transmission between countries and tracking parasite introduction are therefore essential to eliminating malaria within this region. The China-Myanmar border (CMB) presents such an example wherein China has eliminated autochthonous malaria cases, while Myanmar has high malaria incidence. Malaria on the CMB is nearly entirely due to P. vivax, yet few studies investigated the genetics and evolution of the P. vivax populations in the area. Here we used whole-genome sequencing for a holistic analysis of P. vivax from the CMB and compared them to those from other sites of the GMS. Parasites on the CMB had a significantly higher proportion (75%) of monoclonal infection than parasites from other regions. Many of the CMB parasites showed significant genetic sharing that is consistent with the result of clonal expansion, consistent with the malaria outbreak occurring during the study period. While P. vivax parasites from the entire GMS were substantially mixed with no evidence of significant gene flow barriers, those from the CMB were more genetically distinct from other populations. Genome-wide scans for selection identified genes potentially under selection, and especially notable are genes associated with sulfadoxine/pyrimethamine resistance. Genes also under selection include those potentially encoding membrane channels and transporters, which were associated with drug resistance in Plasmodium falciparum. Moreover, this population genomic study also identified a set of 36 single nucleotide polymorphisms, which could serve as a barcode for differentiating parasites from various regions of the GMS, a task that is important for the final phase of regional malaria elimination.
Thao T. B. Nguyen, Veronique Dermauw, Hafid Dahma, Dung Thi Bui, Trang T. H. Le, Ngan T. T. Phi, Laetitia Lempereur, Bertrand Losson, Olivier Vandenberg, Dung Trung Do, et al.
Published: 3 August 2020
PLOS Neglected Tropical Diseases, Volume 14; doi:10.1371/journal.pntd.0008483

Abstract:
Clonorchiasis, caused by the fish-borne trematode Clonorchis sinensis, is a neglected tropical disease and a public health issue in endemic countries. In Vietnam, an in-depth analysis of risk factors for the condition is missing up to now. This study aimed to determine the prevalence of C. sinensis infection and associated risk factors in rural communities in northern Vietnam. A cross-sectional survey was conducted in 4 communes in Yen Bai and Thanh Hoa provinces where clonorchiasis is known to be present and raw fish consumption is a common. Using a simple random sampling approach, stool was collected from 841 participants over 6 years old for coprological examination, and a questionnaire measured knowledge, attitudes, and practices with regard to clonorchiasis in 757 participants over 15 years old. Univariable and multivariable logistic regression models were run to identify risk factors for infection with C. sinensis. The overall prevalence of C. sinensis infection was 40.4%, with commune prevalences ranging between 26.5% and 53.3%. In the final model, males were significantly more likely to be infected with C. sinensis (OR 2.00; 95% CI 1.31–3.05). Recent (i.e. last year) consumption of raw fish (OR 8.00, 95% CI 4.78–13.36), low education level (OR 5.57; 95% CI 2.37–13.07), lack of treatment (OR 1.82, 95% CI 1.15–2.89), being between 19 to 39 years old (OR 6.46; 95% CI 1.25–33.37), and the presence of an unhygienic toilet (OR 2.74, 95% CI 1.53–4.92) were significantly associated with C. sinensis infection. This study demonstrated a high prevalence of C. sinensis infection in rural communities in northern Vietnam. Thus, control measures including, mass drug administration for those communes should be applied to reduce the prevalence. Moreover, specific health education activities should be developed for risk groups in C. sinensis endemic areas. Clonorchiasis, caused by the fish-borne trematode Clonorchis sinensis, is a chronic liver infection and is classified as a neglected tropical disease, particularly in some Asian countries such as Vietnam. Light infections with C. sinensis are asymptomatic, yet heavy chronic infections are associated with clinical complications such as, bile duct obstruction, hepatic fibrosis and the most serious complication being bile duct cancer. We carried out a community-based study on C. sinensis infection in rural communities in northern Vietnam. Our results indicated that the Thac Ba lake area in Yen Bai province is a hot spot of C. sinensis infection, and that Thanh Hoa province remains an area with widespread small liver fluke infection. Eating raw fish was confirmed to be an important risk factor for C. sinensis infection in Vietnam. Presence of infection was furthermore associated with gender, age, education and hygienic practices. Mass drug administration and improved awareness campaigns for the population in these regions are needed. Setting-specific interventions targeting different risk groups should be considered to reduce the disease transmission.
Aouatif Saadi, Fatimaezzahra Amarir, Hind Filali, Séverine Thys, Abdelkbir Rhalem, Nathalie Kirschvink, Marianne Raes, Tanguy Marcotty, Mohamed Oukessou, Luc Duchateau, et al.
Published: 31 July 2020
PLOS Neglected Tropical Diseases, Volume 14; doi:10.1371/journal.pntd.0008410

Abstract:
Cystic echinococcosis (CE) is a major zoonosis in Morocco despite the launch of a national control programme in 2005. As its economic consequences have not been studied yet in Morocco, this study estimated CE impact in terms of monetary losses, disability-adjusted life years (DALY), and DALY for zoonotic diseases (zDALY) in the entire country and in specific regions for the 2011 to 2014 period. The direct monetary losses were related to organ seizure from infected animal in slaughterhouses, and to healthcare expenses as well as lost wages for infected humans. Animal production losses concerned milk yield, fertility, carcass weight, and wool production. Losses due to human infection were also composed of disability and productivity losses at work. Monte Carlo simulations were used to estimate monetary losses and zDALY values. Nationwide, the estimated DALY was 0.5 years per 100,000 persons per year, and the zDALY was 55 years per 100,000 persons per year. Total yearly losses were estimated at 73 million USD (54–92 million USD). However, losses differed significantly among regions. Most of the economic losses consisted of unperceived consequences, i.e. decreased animal production and reduced productivity of asymptomatic individuals. Future studies should determine the socioeconomic and epidemiological factors underlying the differences in economic losses among regions to develop better adapted control programmes. Cystic echinococcosis (CE) is a major neglected zoonosis in Morocco, despite the launch of a national control programme in 2005. The first study on CE in Morocco dates back to 1924. However, no evaluation of economic losses was made until now. The present study estimated the economic losses caused by CE in Morocco, at the national and regional scale, by combining financial and non-financial methods. Estimation of the direct and indirect losses caused by CE infection in humans and livestock (sheep, cattle, goats and camels) highlighted the important disease burden nationwide, amounting to 0.07% of Morocco Gross Domestic Product. The combination of methods brought information on the different CE-linked economic losses, including the unperceived consequences. These results indicate that the national CE control strategy did not result in a decrease of the disease burden, which calls for its evaluation and improvement.
Laura C. Bonney, Robert J. Watson, Gillian S. Slack, Andrew Bosworth, Nadina I. Vasileva Wand, Roger Hewson
Published: 31 July 2020
PLOS Neglected Tropical Diseases, Volume 14; doi:10.1371/journal.pntd.0008496

Abstract:
The unprecedented 2013/16 outbreak of Zaire ebolavirus (Ebola virus) in West Africa has highighted the need for rapid, high-throughput and POC diagnostic assays to enable timely detection and appropriate triaging of Ebola Virus Disease (EVD) patients. Ebola virus is highly infectious and prompt diagnosis and triage is crucial in preventing further spread within community and healthcare settings. Moreover, due to the ecology of Ebola virus it is important that newly developed diagnostic assays are suitable for use in both the healthcare environment and low resource rural locations. A LAMP assay was successfully developed with three detection formats; a real-time intercalating dye-based assay, a real-time probe-based assay to enable multiplexing and an end-point colourimetric assay to simplify interpretation for the field. All assay formats were sensitive and specific, detecting a range of Ebola virus strains isolated in 1976–2014; with Probit analysis predicting limits of detection of 243, 290 and 75 copies/reaction respectively and no cross-detection of related strains or other viral haemorrhagic fevers (VHF’s). The assays are rapid, (as fast as 5–7.25 mins for real-time formats) and robust, detecting Ebola virus RNA in presence of minimally diluted bodily fluids. Moreover, when tested on patient samples from the 2013/16 outbreak, there were no false positives and 93–96% of all new case positives were detected, with only a failure to detect very low copy number samples. These are a set of robust and adaptable diagnostic solutions, which are fast, easy-to-perform-and-interpret and are suitable for use on a range of platforms including portable low-power devices. They can be readily transferred to field-laboratory settings, with no specific equipment needs and are therefore ideally placed for use in locations with limited resources. This study describes the development of a set of interchangeable diagnostic assays for the detection of Ebola virus in patient samples. Each are rapid-turnaround, highly-specific (showing no detection of non-Ebola strains), sensitive and portable. These assays are ideally placed for field-use during outbreaks in low-resource countries and equally suited to use as conventional high-throughput laboratory tests. They encompass a colourimetric option with easy-to-interpret pink-to-yellow colour-change visualisation and real-time detection formats allowing the approximation of virus copy number, which helps monitoring of virus levels during infection. The inclusion of a probe-based detection method also leaves the door open for multi-pathogen detection, which could be useful for future VHF outbreaks, where the cause is unknown.