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Optimising cluster survey design for planning schistosomiasis preventive chemotherapy

PLoS Neglected Tropical Diseases News - 26 May 2017 - 9:00pm

by Sarah C. L. Knowles, Hugh J. W. Sturrock, Hugo Turner, Jane M. Whitton, Charlotte M. Gower, Samuel Jemu, Anna E. Phillips, Aboulaye Meite, Brent Thomas, Karsor Kollie, Catherine Thomas, Maria P. Rebollo, Ben Styles, Michelle Clements, Alan Fenwick, Wendy E. Harrison, Fiona M. Fleming

Background

The cornerstone of current schistosomiasis control programmes is delivery of praziquantel to at-risk populations. Such preventive chemotherapy requires accurate information on the geographic distribution of infection, yet the performance of alternative survey designs for estimating prevalence and converting this into treatment decisions has not been thoroughly evaluated.

Methodology/Principal findings

We used baseline schistosomiasis mapping surveys from three countries (Malawi, Côte d’Ivoire and Liberia) to generate spatially realistic gold standard datasets, against which we tested alternative two-stage cluster survey designs. We assessed how sampling different numbers of schools per district (2–20) and children per school (10–50) influences the accuracy of prevalence estimates and treatment class assignment, and we compared survey cost-efficiency using data from Malawi. Due to the focal nature of schistosomiasis, up to 53% simulated surveys involving 2–5 schools per district failed to detect schistosomiasis in low endemicity areas (1–10% prevalence). Increasing the number of schools surveyed per district improved treatment class assignment far more than increasing the number of children sampled per school. For Malawi, surveys of 15 schools per district and 20–30 children per school reliably detected endemic schistosomiasis and maximised cost-efficiency. In sensitivity analyses where treatment costs and the country considered were varied, optimal survey size was remarkably consistent, with cost-efficiency maximised at 15–20 schools per district.

Conclusions/Significance

Among two-stage cluster surveys for schistosomiasis, our simulations indicated that surveying 15–20 schools per district and 20–30 children per school optimised cost-efficiency and minimised the risk of under-treatment, with surveys involving more schools of greater cost-efficiency as treatment costs rose.

Albendazole increases the inflammatory response and the amount of Em2-positive small particles of <i>Echinococcus multilocularis</i> (spems) in human hepatic alveolar echinococcosis lesions

PLoS Neglected Tropical Diseases News - 25 May 2017 - 9:00pm

by Franz J. Ricken, Juliane Nell, Beate Grüner, Julian Schmidberger, Tanja Kaltenbach, Wolfgang Kratzer, Andreas Hillenbrand, Doris Henne-Bruns, Peter Deplazes, Peter Möller, Peter Kern, Thomas F. E. Barth

Background

Alveolar echinococcosis (AE) is caused by the metacestode stage of Echinococcus multilocularis. The inflammatory response to this infection is influenced by the interaction of the parasite with the host. We aimed to analyze human liver lesions infected with Echinococcus multilocularis and the changes of the cellular infiltrates during albendazole (ABZ) treatment.

Methodology/Principal findings

We analyzed liver tissue samples from 8 untreated patients, 5 patients treated with two daily doses of 400 mg ABZ for up to two months and 7 patients treated for more than two months with the same ABZ therapy. A broad panel of monoclonal antibodies was used to characterize the lesion by immunohistochemistry. A change in the cellular infiltrate was observed between the different chemotherapy times. During the initial phases of treatment an increase in CD15+ granulocytes and CD68+ histocytes as well as in small particles of Echinococcus multilocularis (spems) was observed in the tissue surrounding the metacestode. Furthermore, we observed an increase in CD4+ T cells, CD20+ B cells and CD38+ plasma cells during a longer duration of treatment.

Conclusions/Significance

ABZ treatment of AE leads to morphological changes characterized by an initial, predominantly acute, inflammatory response which is gradually replaced by a response of the adaptive immune system.

Hookworm infection is associated with decreased CD4<sup>+</sup> T cell counts in HIV-infected adult Ugandans

PLoS Neglected Tropical Diseases News - 25 May 2017 - 9:00pm

by Bozena M. Morawski, Miya Yunus, Emmanuel Kerukadho, Grace Turyasingura, Logose Barbra, Andrew Mijumbi Ojok, Andrew DiNardo, Stefanie Sowinski, David R. Boulware, Rojelio Mejia

Most studies evaluating epidemiologic relationships between helminths and HIV have been conducted in the pre-ART era, and evidence of the impact of helminth infections on HIV disease progression remains conflicting. Less is known about helminth infection and clinical outcomes in HIV-infected adults receiving antiretroviral therapy (ART). We sampled HIV-infected adults for eight gastrointestinal parasites and correlated parasitic infection with demographic predictors, and clinical and immunologic outcomes. Contrasting with previous studies, we measured parasitic infection with a quantitative, highly sensitive and specific polymerase chain reaction (PCR) method. This cohort study enrolled HIV-infected Ugandans from August-September 2013 in Mbale, Uganda and collected stool and blood samples at enrollment. Real-time PCR quantified stool: Ascaris lumbricoides, Ancylostoma duodenale, Necator americanus, Strongyloides stercoralis, Trichuris trichiura, Cryptosporidium spp., Entamoeba histolytica, and Giardia intestinalis infection. Generalized linear models assessed relationships between parasitic infection and clinical or demographic data. 35% of participants (71/202) tested positive for ≥1 helminth, mainly N. americanus (55/199, 28%), and 4.5% (9/202) were infected with ≥2 stool parasites. Participants with hookworm infection had lower average CD4+ cell counts (-94 cells/mcL, 95%CI: -141, -48 cells/mcL; p<0.001) after adjustment for sex, CD4+ nadir at clinic entry, and time on ART. The high prevalence of parasitic infection and correlation with decreased CD4+ concentrations highlight the need to re-examine the effects of invasive helminth co-infection in rural, HIV-infected populations in the era of widely available ART. Elucidating the relationship between hookworm infection and immune recovery could provide opportunities for health optimization, e.g. integrated deworming, in these vulnerable populations.

Unravelling the rate of action of hits in the <i>Leishmania donovani</i> box using standard drugs amphotericin B and miltefosine

PLoS Neglected Tropical Diseases News - 25 May 2017 - 9:00pm

by Diana Tegazzini, Juan Cantizani, Imanol Peña, Julio Martín, Jose M. Coterón

In recent years, the neglected diseases drug discovery community has elected phenotypic screening as the key approach for the identification of novel hit compounds. However, when this approach is applied, important questions related to the mode of action for these compounds remain unanswered. One of such questions is related to the rate of action, a useful piece of information when facing the challenge of prioritising the most promising hit compounds. In the present work, compounds of the “Leishmania donovani box” were evaluated using a rate of action assay adapted from a replicative intracellular high content assay recently developed. The potency of each compound was determined every 24 hours up to 96 hours, and standard drugs amphotericin B and miltefosine were used as references to group these compounds according to their rate of action. Independently of this biological assessment, compounds were also clustered according to their minimal chemical scaffold. Comparison of the results showed a complete correlation between the chemical scaffold and the biological group for the vast majority of compounds, demonstrating how the assay was able to bring information on the rate of action for each chemical series, a property directly linked to the mode of action. Overall, the assay here described permitted us to evaluate the rate of action of the “Leishmania donovani box” using two of the currently available drugs as references and, also, to propose a number of fast-acting chemical scaffolds present in the box as starting points for future drug discovery projects to the wider scientific community. The results here presented validate the use of this assay for the determination of the rate of action early in the discovery process, to assist in the prioritisation of hit compounds.

Health beliefs of school-age rural children in podoconiosis-affected families: A qualitative study in Southern Ethiopia

PLoS Neglected Tropical Diseases News - 25 May 2017 - 9:00pm

by Abebayehu Tora, Getnet Tadele, Abraham Aseffa, Colleen M. McBride, Gail Davey

Background

Several studies have suggested investigation of health beliefs in children to be an important pre-condition for primary prevention of disease. However, little effort has been made to understand these in the context of podoconiosis. This study therefore aimed to explore the health beliefs of school-age rural children in podoconiosis-affected families.

Methodology/Principal findings

A cross sectional qualitative study was conducted in March 2016 in Wolaita Zone, Southern Ethiopia. Data were collected through in-depth individual interviews (IDIs) and focus group discussions (FGDs), with a total of one hundred seventeen 9 to15-year-old children recruited from podoconiosis affected families. The study revealed various misconceptions regarding risk factors for podoconiosis. Most children believed barefoot exposure to dew, worms, snake bite, frog urine, other forms of poison, and contact with affected people to be major causes of the disease. Their knowledge about the role of heredity and that of long term barefoot exposure to irritant mineral particles was also weak. Though most participants correctly appraised their susceptibility to podoconiosis in relation to regular use of footwear and foot hygiene, others based their risk perceptions on factors they think beyond their control. They described several barriers to preventive behaviour, including uncomfortable footwear, shortage and poor adaptability of footwear for farm activities and sports, and shortage of soap for washing. Children also perceived low self-efficacy to practice preventive behaviour in spite of the barriers.

Conclusion/Significance

Health education interventions may enhance school-age children’s health literacy and be translated to preventive action. Overcoming practical challenges such as shortage of footwear and other hygiene facilities requires other forms of interventions such as livelihood strengthening activities. Linking podoconiosis-affected families with local governmental or non-governmental organizations providing socio-economic support for households may assist school-age children in those families to sustainably engage in preventive behaviours.

<i>Clonorchis sinensis</i> antigens alter hepatic macrophage polarization <i>in vitro</i> and <i>in vivo</i>

PLoS Neglected Tropical Diseases News - 24 May 2017 - 9:00pm

by Eun-Min Kim, You Shine Kwak, Myung-Hee YI, Ju Yeong Kim, Woon-Mok Sohn, Tai-Soon Yong

Clonorchis sinensis infection elicits hepatic inflammation, which can lead to cholangitis, periductal hepatic fibrosis, liver cirrhosis, and even cholangiocarcinoma. Hepatic macrophages are an intrinsic element of both innate and acquired immunity. This study was conducted to demonstrate the dynamics of hepatic macrophage polarization during C. sinensis infection in mice and to identify factors regulating this polarization. Treatment of hepatic macrophages isolated from normal mice with C. sinensis excretory/secretory products (ESPs) resulted in the preferential generation of classically activated hepatic macrophages (M1 macrophages) and the production of pro-inflammatory cytokines. Additionally, cells stimulated with C. sinensis ESPs exhibited changes in cellular morphology. During the early stages of C. sinensis infection, hepatic macrophages preferentially differentiated into M1 macrophages; however, during the C. sinensis mature worm stage, when eggs are released, there were significant increases in the abundance of both M1 macrophages and alternatively activated hepatic macrophages (M2 macrophages). Moreover, there was a further increase in the M2 macrophage count during the fibrotic and cirrhotic stage of infection. Notably, this fibrotic and cirrhotic stage promoted a strong increase in the proportion of Arg-1-producing macrophages (M2 phenotype), which were associated with fibrosis and tissue repair in the liver. Our results suggest that the dynamic polarization of hepatic macrophages as C. sinensis infection progresses is related to the histological lesions present in liver tissue. Hepatic macrophages thus play an important role in local immunity during C. sinensis infection.

Using G6PD tests to enable the safe treatment of <i>Plasmodium vivax</i> infections with primaquine on the Thailand-Myanmar border: A cost-effectiveness analysis

PLoS Neglected Tropical Diseases News - 24 May 2017 - 9:00pm

by Angela Devine, Minnie Parmiter, Cindy S. Chu, Germana Bancone, François Nosten, Ric N. Price, Yoel Lubell, Shunmay Yeung

Background

Primaquine is the only licensed antimalarial for the radical cure of Plasmodium vivax infections. Many countries, however, do not administer primaquine due to fear of hemolysis in those with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In other settings, primaquine is given without G6PD testing, putting patients at risk of hemolysis. New rapid diagnostic tests (RDTs) offer the opportunity to screen for G6PD deficiency prior to treatment with primaquine. Here we assessed the cost-effectiveness of using G6PD RDTs on the Thailand-Myanmar border and provide the model as an online tool for use in other settings.

Methods/Principal findings

Decision tree models for the management of P. vivax malaria evaluated the costs and disability-adjusted life-years (DALYs) associated with recurrences and primaquine-induced hemolysis from a health care provider perspective. Screening with G6PD RDTs before primaquine use was compared to (1) giving chloroquine alone and (2) giving primaquine without screening. Data were taken from a recent study on the impact of primaquine on P. vivax recurrences and a literature review. Compared to the use of chloroquine alone, the screening strategy had similar costs while averting 0.026 and 0.024 DALYs per primary infection in males and females respectively. Compared to primaquine administered without screening, the screening strategy provided modest cost savings while averting 0.011 and 0.004 DALYs in males and females respectively. The probabilistic sensitivity analyses resulted in a greater than 75% certainty that the screening strategy was cost-effective at a willingness to pay threshold of US$500, which is well below the common benchmark of per capita gross domestic product for Myanmar.

Conclusions/Significance

In this setting G6PD RDTs could avert DALYs by reducing recurrences and reducing hemolytic risk in G6PD deficient patients at low costs or cost savings. The model results are limited by the paucity of data available in the literature for some parameter values, including the mortality rates for both primaquine-induced hemolysis and P. vivax. The online model provides an opportunity to use different parameter estimates to examine the validity of these findings in other settings.

“We do not bury dead livestock like human beings”: Community behaviors and risk of Rift Valley Fever virus infection in Baringo County, Kenya

PLoS Neglected Tropical Diseases News - 24 May 2017 - 9:00pm

by Edna N. Mutua, Salome A. Bukachi, Bernard K. Bett, Benson A. Estambale, Isaac K. Nyamongo

Background

Rift Valley Fever (RVF), is a viral zoonotic disease transmitted by Aedes and Culex mosquitoes. In Kenya, its occurrence is associated with increased rains. In Baringo County, RVF was first reported in 2006 resulting in 85 human cases and 5 human deaths, besides livestock losses and livelihood disruptions. This study sought to investigate the county’s current RVF risk status.

Methodology and principal findings

A cross-sectional study on the knowledge, attitudes and practices of RVF was conducted through a mixed methods approach utilizing a questionnaire survey (n = 560) and 26 focus group discussions (n = 231). Results indicate that study participants had little knowledge of RVF causes, its signs and symptoms and transmission mechanisms to humans and livestock. However, most of them indicated that a person could be infected with zoonotic diseases through consumption of meat (79.2%) and milk (73.7%) or contact with blood (40%) from sick animals. There was a statistically significant relationship between being male and milking sick animals, consumption of milk from sick animals, consuming raw or cooked blood, slaughtering sick livestock or dead animals for consumption (all at p≤0.001), and handling sick livestock with bare hands (p = 0.025) with more men than women engaging in the risky practices. Only a few respondents relied on trained personnel or local experts to inspect meat for safety of consumption every time they slaughtered an animal at home. Sick livestock were treated using conventional and herbal medicines often without consulting veterinary officers.

Conclusions

Communities in Baringo County engage in behaviour that may increase their risk to RVF infections during an outbreak. The authors recommend community education to improve their response during outbreaks.

The impact of health promotion on trachoma knowledge, attitudes and practice (KAP) of staff in three work settings in remote Indigenous communities in the Northern Territory

PLoS Neglected Tropical Diseases News - 24 May 2017 - 9:00pm

by Fiona D. Lange, Kelly Jones, Rebecca Ritte, Haley E. Brown, Hugh R. Taylor

Background

Globally, trachoma is the leading cause of infectious blindness and Australia is the only developed country with endemic trachoma. It is found in remote Indigenous communities burdened with poverty, overcrowding and poor hygiene. Lack of culturally appropriate health promotion, a small trachoma workforce and lack of awareness and support for trachoma elimination in general, were early barriers.

Methods

A cross-sectional pre-post study using a convenience sample, was conducted in clinics, schools and community work-settings from 63 of the 82 remote Aboriginal communities identified as being at risk of trachoma in the Northern Territory (NT). The study assessed the effect of a multi-component health promotion strategy aimed at increasing knowledge, attitude and practice amongst health, education and community support settings staff. Data were collected between 2010 and 2012. The health promotion initiatives were introduced in communities in staggered delivery over a one-year period; 272 participants were surveyed at baseline and 261 at follow-up.

Results

Trachoma related knowledge, attitudes and practice increased across all settings and for all primary outcome measures. Across all settings, there was a significant increase in the proportion of participants reporting the most important thing to do if a child has a ‘dirty’ face is to ‘wash it every time its dirty’ (61.6% cf 69.7%; X2p = 0.047), a significant reduction in the proportion of respondents answering ‘no’ to the question “Is it normal for kids to have dirty faces in your community’ (40.5% cf 29.6%; X2p = 0.009) and a significant increase in reported capacity to teach others about trachoma prevention (70.8% cf 83.3%; X2p <0.001).

Conclusion

Health promotion was associated with increased trachoma knowledge, attitude and practice amongst health, education and community support staff working with children and in remote NT communities. In the early stages of the trachoma health promotion program, this increased trachoma awareness and improved local workforce capacity and support for trachoma elimination in three health promotion settings in remote communities in the NT.

MiR-277/4989 regulate transcriptional landscape during juvenile to adult transition in the parasitic helminth <i>Schistosoma mansoni</i>

PLoS Neglected Tropical Diseases News - 23 May 2017 - 9:00pm

by Anna V. Protasio, Stijn van Dongen, Julie Collins, Leonor Quintais, Diogo M. Ribeiro, Florian Sessler, Martin Hunt, Gabriel Rinaldi, James J. Collins, Anton J. Enright, Matthew Berriman

Schistosomes are parasitic helminths that cause schistosomiasis, a disease affecting circa 200 million people, primarily in underprivileged regions of the world. Schistosoma mansoni is the most experimentally tractable schistosome species due to its ease of propagation in the laboratory and the high quality of its genome assembly and annotation. Although there is growing interest in microRNAs (miRNAs) in trematodes, little is known about the role these molecules play in the context of developmental processes. We use the completely unaware “miRNA-blind” bioinformatics tool Sylamer to analyse the 3’-UTRs of transcripts differentially expressed between the juvenile and adult stages. We show that the miR-277/4989 family target sequence is the only one significantly enriched in the transition from juvenile to adult worms. Further, we describe a novel miRNA, sma-miR-4989 showing that its proximal genomic location to sma-miR-277 suggests that they form a miRNA cluster, and we propose hairpin folds for both miRNAs compatible with the miRNA pathway. In addition, we found that expression of sma-miR-277/4989 miRNAs are up-regulated in adults while their predicted targets are characterised by significant down-regulation in paired adult worms but remain largely undisturbed in immature “virgin” females. Finally, we show that sma-miR-4989 is expressed in tegumental cells located proximal to the oesophagus gland and also distributed throughout the male worms’ body. Our results indicate that sma-miR-277/4989 might play a dominant role in post-transcriptional regulation during development of juvenile worms and suggest an important role in the sexual development of female schistosomes.

Highly conserved type 1 pili promote enterotoxigenic <i>E</i>. <i>coli</i> pathogen-host interactions

PLoS Neglected Tropical Diseases News - 22 May 2017 - 9:00pm

by Alaullah Sheikh, Rasheduzzaman Rashu, Yasmin Ara Begum, F. Matthew Kuhlman, Matthew A. Ciorba, Scott J. Hultgren, Firdausi Qadri, James M. Fleckenstein

Enterotoxigenic Escherichia coli (ETEC), defined by their elaboration of heat-labile (LT) and/or heat-stable (ST) enterotoxins, are a common cause of diarrheal illness in developing countries. Efficient delivery of these toxins requires ETEC to engage target host enterocytes. This engagement is accomplished using a variety of pathovar-specific and conserved E. coli adhesin molecules as well as plasmid encoded colonization factors. Some of these adhesins undergo significant transcriptional modulation as ETEC encounter intestinal epithelia, perhaps suggesting that they cooperatively facilitate interaction with the host. Among genes significantly upregulated on cell contact are those encoding type 1 pili. We therefore investigated the role played by these pili in facilitating ETEC adhesion, and toxin delivery to model intestinal epithelia. We demonstrate that type 1 pili, encoded in the E. coli core genome, play an essential role in ETEC virulence, acting in concert with plasmid-encoded pathovar specific colonization factor (CF) fimbriae to promote optimal bacterial adhesion to cultured intestinal epithelium (CIE) and to epithelial monolayers differentiated from human small intestinal stem cells. Type 1 pili are tipped with the FimH adhesin which recognizes mannose with stereochemical specificity. Thus, enhanced production of highly mannosylated proteins on intestinal epithelia promoted FimH-mediated ETEC adhesion, while conversely, interruption of FimH lectin-epithelial interactions with soluble mannose, anti-FimH antibodies or mutagenesis of fimH effectively blocked ETEC adhesion. Moreover, fimH mutants were significantly impaired in delivery of both heat-stable and heat-labile toxins to the target epithelial cells in vitro, and these mutants were substantially less virulent in rabbit ileal loop assays, a classical model of ETEC pathogenesis. Collectively, our data suggest that these highly conserved pili play an essential role in virulence of these diverse pathogens.

Monitoring the elimination of human African trypanosomiasis: Update to 2014

PLoS Neglected Tropical Diseases News - 22 May 2017 - 9:00pm

by José R. Franco, Giuliano Cecchi, Gerardo Priotto, Massimo Paone, Abdoulaye Diarra, Lise Grout, Raffaele C. Mattioli, Daniel Argaw

Background

The World Health Organization (WHO) has targeted the elimination of Human African trypanosomiasis (HAT) ‘as a public health problem’ by 2020. The selected indicators of elimination should be monitored every two years, and we provide here a comprehensive update to 2014. The monitoring system is underpinned by the Atlas of HAT.

Results

With 3,797 reported cases in 2014, the corresponding milestone (5,000 cases) was surpassed, and the 2020 global target of ‘fewer than 2,000 reported cases per year’ seems within reach. The areas where HAT is still a public health problem (i.e. > 1 HAT reported case per 10,000 people per year) have halved in less than a decade, and in 2014 they corresponded to 350 thousand km2. The number and potential coverage of fixed health facilities offering diagnosis and treatment for HAT has expanded, and approximately 1,000 are now operating in 23 endemic countries. The observed trends are supported by sustained surveillance and improved reporting.

Discussion

HAT elimination appears to be on track. For gambiense HAT, still accounting for the vast majority of reported cases, progress continues unabated in a context of sustained intensity of screening activities. For rhodesiense HAT, a slow-down was observed in the last few years. Looking beyond the 2020 target, innovative tools and approaches will be increasingly needed. Coordination, through the WHO network for HAT elimination, will remain crucial to overcome the foreseeable and unforeseeable challenges that an elimination process will inevitably pose.

Dengue in Bali: Clinical characteristics and genetic diversity of circulating dengue viruses

PLoS Neglected Tropical Diseases News - 22 May 2017 - 9:00pm

by Dewi Megawati, Sri Masyeni, Benediktus Yohan, Asri Lestarini, Rahma F. Hayati, Febrina Meutiawati, Ketut Suryana, Tangking Widarsa, Dewa G. Budiyasa, Ngurah Budiyasa, Khin S. A. Myint, R. Tedjo Sasmono

A high number of dengue cases are reported annually in Bali. Despite the endemicity, limited data on dengue is available for Bali localities. Molecular surveillance study was conducted to explore the clinical and virological characteristics of dengue patients in urban Denpasar and rural Gianyar areas in Bali during the peak season in 2015. A total of 203 adult dengue-suspected patients were recruited in a prospective cross-sectional study. Demographic and clinical information were obtained, and dengue screening was performed using NS1 and IgM/IgG ELISAs. Viral RNA was subsequently extracted from patients’ sera for serotyping using conventional RT-PCR and Simplexa Dengue real-time RT-PCR, followed by genotyping with sequencing method. We confirmed 161 patients as having dengue by NS1 and RT-PCR. Among 154 samples successfully serotyped, the DENV-3 was predominant, followed by DENV-1, DENV-2, and DENV-4. Serotype predominance was different between Denpasar and Gianyar. Genotyping results classify DENV-1 isolates into Genotype I and DENV-2 as Cosmopolitan Genotype. The classification grouped isolates into Genotype I and II for DENV-3 and DENV-4, respectively. Clinical parameters showed no relationship between infecting serotypes and severity. We observed the genetic diversity of circulating DENV isolates and their relatedness with historical data and importation to other countries. Our data highlights the role of this tourist destination as a potential source of dengue transmission in the region.

Measuring changes in transmission of neglected tropical diseases, malaria, and enteric pathogens from quantitative antibody levels

PLoS Neglected Tropical Diseases News - 19 May 2017 - 9:00pm

by Benjamin F. Arnold, Mark J. van der Laan, Alan E. Hubbard, Cathy Steel, Joseph Kubofcik, Katy L. Hamlin, Delynn M. Moss, Thomas B. Nutman, Jeffrey W. Priest, Patrick J. Lammie

Background

Serological antibody levels are a sensitive marker of pathogen exposure, and advances in multiplex assays have created enormous potential for large-scale, integrated infectious disease surveillance. Most methods to analyze antibody measurements reduce quantitative antibody levels to seropositive and seronegative groups, but this can be difficult for many pathogens and may provide lower resolution information than quantitative levels. Analysis methods have predominantly maintained a single disease focus, yet integrated surveillance platforms would benefit from methodologies that work across diverse pathogens included in multiplex assays.

Methods/Principal findings

We developed an approach to measure changes in transmission from quantitative antibody levels that can be applied to diverse pathogens of global importance. We compared age-dependent immunoglobulin G curves in repeated cross-sectional surveys between populations with differences in transmission for multiple pathogens, including: lymphatic filariasis (Wuchereria bancrofti) measured before and after mass drug administration on Mauke, Cook Islands, malaria (Plasmodium falciparum) before and after a combined insecticide and mass drug administration intervention in the Garki project, Nigeria, and enteric protozoans (Cryptosporidium parvum, Giardia intestinalis, Entamoeba histolytica), bacteria (enterotoxigenic Escherichia coli, Salmonella spp.), and viruses (norovirus groups I and II) in children living in Haiti and the USA. Age-dependent antibody curves fit with ensemble machine learning followed a characteristic shape across pathogens that aligned with predictions from basic mechanisms of humoral immunity. Differences in pathogen transmission led to shifts in fitted antibody curves that were remarkably consistent across pathogens, assays, and populations. Mean antibody levels correlated strongly with traditional measures of transmission intensity, such as the entomological inoculation rate for P. falciparum (Spearman’s rho = 0.75). In both high- and low transmission settings, mean antibody curves revealed changes in population mean antibody levels that were masked by seroprevalence measures because changes took place above or below the seropositivity cutoff.

Conclusions/Significance

Age-dependent antibody curves and summary means provided a robust and sensitive measure of changes in transmission, with greatest sensitivity among young children. The method generalizes to pathogens that can be measured in high-throughput, multiplex serological assays, and scales to surveillance activities that require high spatiotemporal resolution. Our results suggest quantitative antibody levels will be particularly useful to measure differences in exposure for pathogens that elicit a transient antibody response or for monitoring populations with very high- or very low transmission, when seroprevalence is less informative. The approach represents a new opportunity to conduct integrated serological surveillance for neglected tropical diseases, malaria, and other infectious diseases with well-defined antigen targets.

Detecting infection hotspots: Modeling the surveillance challenge for elimination of lymphatic filariasis

PLoS Neglected Tropical Diseases News - 19 May 2017 - 9:00pm

by Julie R. Harris, Ryan E. Wiegand

Background

During the past 20 years, enormous efforts have been expended globally to eliminate lymphatic filariasis (LF) through mass drug administration (MDA). However, small endemic foci (microfoci) of LF may threaten the presumed inevitable decline of infections after MDA cessation. We conducted microsimulation modeling to assess the ability of different types of surveillance to identify microfoci in these settings.

Methods

Five or ten microfoci of radius 1, 2, or 3 km with infection marker prevalence (intensity) of 3, 6, or 10 times background prevalence were placed in spatial simulations, run in R Version 3.2. Diagnostic tests included microfilaremia, immunochromatographic test (ICT), and Wb123 ELISA. Population size was fixed at 360,000 in a 60 x 60 km area; demographics were based on literature for Sub-Saharan African populations. Background ICT prevalence in 6–7 year olds was anchored at 1.0%, and the prevalence in the remaining population was adjusted by age. Adults≥18 years, women aged 15–40 years (WCBA), children aged 6–7 years, or children≤5 years were sampled. Cluster (CS), simple random sampling (SRS), and TAS-like sampling were simulated, with follow-up testing of the nearest 20, 100, or 500 persons around each infection-marker-positive person. A threshold number of positive persons in follow-up testing indicated a suspected microfocus. Suspected microfoci identified during surveillance and actual microfoci in the simulation were compared to obtain a predictive value positive (PVP). Each parameter set was referred to as a protocol. Protocols were scored by efficiency, defined as the most microfoci identified, the fewest persons requiring primary and follow-up testing, and the highest PVP. Negative binomial regression was used to estimate aggregate effects of different variables on efficiency metrics.

Results

All variables were significantly associated with efficiency metrics. Additional follow-up tests beyond 20 did not greatly increase the number of microfoci detected, but significantly negatively impacted efficiency. Of 3,402 protocols evaluated, 384 (11.3%) identified all five microfoci (PVP 3.4–100.0%) and required testing 0.73–35.6% of the population. All used SRS and 378 (98.4%) only identified all five microfoci if they were 2–3 km diameter or high-intensity (6x or 10x); 374 (97.4%) required ICT or Wb123 testing to identify all five microfoci, and 281 (73.0%) required sampling adults or WCBA. The most efficient CS protocols identified two (40%) microfoci. After limiting to protocols with 1-km radius microfoci of 3x intensity (n = 378), eight identified all five microfoci; all used SRS and ICT and required testing 31.2–33.3% of the population. The most efficient CS and TAS-like protocols as well as those using microfilaremia testing identified only one (20%) microfocus when they were limited to 1-km radius and 3x intensity.

Conclusion

In this model, SRS, ICT, and sampling of adults maximized microfocus detection efficiency. Follow-up sampling of more persons did not necessarily increase protocol efficiency. Current approaches towards surveillance, including TAS, may not detect small, low-intensity LF microfoci that could remain after cessation of MDA. The model provides many surveillance protocols that can be selected for optimal outcomes.

Single-sex infection with female <i>Schistosoma mansoni</i> cercariae mitigates hepatic fibrosis after secondary infection

PLoS Neglected Tropical Diseases News - 19 May 2017 - 9:00pm

by Nicole Koslowski, Martina Sombetzki, Micha Loebermann, Robby Engelmann, Niels Grabow, Christoph H. Österreicher, Michael Trauner, Brigitte Mueller-Hilke, Emil C. Reisinger

Background

Infection with Schistosoma spp. affects more than 258 million people worldwide. Current treatment strategies are mainly based on the anthelmintic Praziquantel, which is effective against adult worms but neither prevents re-infection nor cures severe liver damage. The best long-term strategy to control schistosomiasis may be to develop an immunization. Therefore, we designed a two-step Schistosoma mansoni infection model to study the immune-stimulating effect of a primary infection with either male or female cercariae, measured on the basis of TH1/TH2-response, granuloma size and hepatic fibrosis after a secondary bisexual S. mansoni challenge.

Methodology/Principle findings

As a first step, mice were infected with exclusively female, exclusively male, or a mixture of male and female S. mansoni cercariae. 11 weeks later they were secondarily infected with male and female S. mansoni cercariae. At week 19, infection burden, granuloma size, collagen deposition, serum cytokine profiles and the expression of inflammatory genes were analyzed. Mice initially infected with female S. mansoni cercariae displayed smaller hepatic granulomas, livers and spleens, less hepatic fibrosis and higher expression of Ctla4. In contrast, a prior infection with male or male and female S. mansoni did not mitigate disease progression after a bisexual challenge.

Conclusions/Significance

Our findings provide evidence that an immunization against S. mansoni is achievable by exploiting gender-specific differences between schistosomes.

The phylogeography of <i>Myotis</i> bat-associated rabies viruses across Canada

PLoS Neglected Tropical Diseases News - 19 May 2017 - 9:00pm

by Susan Nadin-Davis, Noor Alnabelseya, M. Kimberly Knowles

As rabies in carnivores is increasingly controlled throughout much of the Americas, bats are emerging as a significant source of rabies virus infection of humans and domestic animals. Knowledge of the bat species that maintain rabies is a crucial first step in reducing this public health problem. In North America, several bat species are known to be rabies virus reservoirs but the role of bats of the Myotis genus has been unclear due to the scarcity of laboratory confirmed cases and the challenges encountered in species identification of poorly preserved diagnostic submissions by morphological traits alone. This study has employed a collection of rabid bat specimens collected across Canada over a 25 year period to clearly define the role of particular Myotis species as rabies virus reservoirs. The virus was characterised by partial genome sequencing and host genetic barcoding, used to confirm species assignment of specimens, proved crucial to the identification of certain bat species as disease reservoirs. Several variants were associated with Myotis species limited in their Canadian range to the westernmost province of British Columbia while others were harboured by Myotis species that circulate across much of eastern and central Canada. All of these Myotis-associated viral variants, except for one, clustered as a monophyletic MYCAN clade, which has emerged from a lineage more broadly distributed across North America; in contrast one distinct variant, associated with the long-legged bat in Canada, represents a relatively recent host jump from a big brown bat reservoir. Together with evidence from South America, these findings demonstrate that rabies virus has emerged in the Myotis genus independently on multiple occasions and highlights the potential for emergence of new viral-host associations within this genus.

<i>w</i>Mel limits zika and chikungunya virus infection in a Singapore <i>Wolbachia</i>-introgressed <i>Ae</i>. <i>aegypti</i> strain, <i>w</i>Mel-Sg

PLoS Neglected Tropical Diseases News - 19 May 2017 - 9:00pm

by Cheong Huat Tan, PeiSze Jeslyn Wong, Meizhi Irene LI, HuiTing Yang, Lee Ching Ng, Scott Leslie O’Neill

Background

Zika (ZIKV) and Chikungunya (CHIKV) viruses are emerging Aedes-borne viruses that are spreading outside their known geographic range and causing wide-scale epidemics. It has been reported that these viruses can be transmitted efficiently by Ae. aegypti. Recent studies have shown that Ae. aegypti when transinfected with certain Wolbachia strains shows a reduced replication and dissemination of dengue (DENV), Chikungunya (CHIKV), and Yellow Fever (YFV) viruses. The aim of this study was to determine whether the wMel strain of Wolbachia introgressed onto a Singapore Ae. aegypti genetic background was able to limit ZIKV and CHIKV infection in the mosquito.

Methodology/Principal findings

Five to seven-day old mosquitoes either infected or uninfected with wMel Wolbachia were orally infected with a Ugandan strain of ZIKV and several outbreak strains of CHIKV. The midgut and salivary glands of each mosquito were sampled at days 6, 9 and 13 days post infectious blood meal to determine midgut infection and salivary glands dissemination rates, respectively. In general, all wild type Ae. aegypti were found to have high ZIKV and CHIKV infections in their midguts and salivary glands, across all sampling days, compared to Wolbachia infected counterparts. Median viral titre for all viruses in Wolbachia infected mosquitoes were significantly lower across all time points when compared to wild type mosquitoes. Most significantly, all but two and one of the wMel infected mosquitoes had no detectable ZIKV and CHIKV, respectively, in their salivary glands at 14 days post-infectious blood meal.

Conclusions

Our results showed that wMel limits both ZIKV and CHIKV infection when introgressed into a Singapore Ae. aegypti genetic background. These results also strongly suggest that female Aedes aegypti carrying Wolbachia will have a reduced capacity to transmit ZIKV and CHIKV.

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