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The paediatric participation scale measuring participation restrictions among former Buruli Ulcer patients under the age of 15 in Ghana and Benin: Development and first validation results

14 March 2019 - 9:00pm

by Dorien T. Beeres, Jacolien Horstman, Pierre van der Tak, Richard O. Phillips, Kabiru M. Abass, Tjip van der Werf, Roch C. Johnson, Ghislain E. Sopoh, Janine de Zeeuw, Pieter U. Dijkstra, Yves T. Barogui, Ymkje Stienstra

Background

Buruli Ulcer (BU) is a neglected tropical disease caused by Mycobacterium ulcerans. Former BU patients may experience participation restrictions due to physical limitations, stigmatization and other social factors. A scale that measures participation restrictions among children, who represent almost half of the affected population, has not been developed yet. Here, we present the development of a scale that measures participation restrictions in former BU paediatric patients, the psychometric properties of this scale and the scales’ results.

Methods

Items were selected and a scale was developed based on interviews with health care workers and former BU patients in and around the BU treatment centre in Lalo, Benin. Construct validity was tested using six a priori formulated hypotheses. Former BU patients under 15 years of age who received treatment in one of the BU treatment centres in Ghana and Benin between 2007–2012 were interviewed.

Results

A feasible 16-item scale that measures the concept of participation among children under 15 years of age was developed. In total, 109 (Ghana) and 90 (Benin) former BU patients were interviewed between 2012–2017. Five construct validity hypotheses were confirmed of which 2 hypotheses related to associations with existing questionnaires were statistically significant (p<0.05).In Ghana 77% of the former patients had a Paediatric Participation (PP) scale score of 0 compared to 22% in Benin. More severe lesions related to BU were seen in Benin. Most of the reported participation problems were related to sports, mainly in playing games with others, going to the playfield and doing sports at school.

Conclusion

The preliminary results of the PP-scale validation are promising but further validation is needed. The developed PP-scale may be valid for use in patients with more severe BU lesions. This is the first research to confirm that former BU patients under 15-year face participation restrictions in important aspects of their lives.

<i>In vitro</i> model of postoncosphere development, and <i>in vivo</i> infection abilities of <i>Taenia solium</i> and <i>T</i>. <i>saginata</i>

14 March 2019 - 9:00pm

by Sandra Palma, Nancy Chile, Rogger P. Carmen-Orozco, Grace Trompeter, Kayla Fishbeck, Virginia Cooper, Laura Rapoport, Edson G. Bernal-Teran, Beth J. Condori, Robert H. Gilman, Manuela R. Verastegui, for the Cysticercosis Working Group in Peru

Taenia solium is known to cause human cysticercosis while T. saginata does not. Comparative in vitro and in vivo studies on the oncosphere and the postoncospheral (PO) forms of T. solium and T. saginata may help to elucidate why cysticercosis can occur from one and not the other. The aim of this study was to use in vitro culture assays and in vivo models to study the differences in the development of the T. solium and T. saginata oncosphere. Furthermore, this study aimed to evaluate the expression of cytokines and metalloproteinases (MMPs) in human peripheral blood mononuclear cells (PBMCs), which were stimulated by these oncospheres and PO antigens. T. solium and T. saginata activated oncospheres (AO) were cultured in INT-407 and HCT-8 intestinal cells for 180 days. The T. solium began to die while the T. saginata grew for 180 days and developed to cysticerci in INT-407 cells. Rats were inoculated intracranially with AO and PO forms of either T. saginata or T. solium. Rats infected with T. solium AO and PO forms developed neurocysticercosis (NCC), while those infected with the T. saginata did not. Human PMBCs were stimulated with antigens of AO and PO forms of both species, and the production of cytokines and metalloproteinases (MMPs) was measured. The T. solium AO antigen stimulated a higher production of IL-4, IL-5, IL-13, IFN-γ, and IL-2 cytokines compared to T. saginata AO. In the PO form, the T. saginata PO antigen increased the production of IL-4, IL-5, IL-13, IFN-γ, IL-1β, IL-6, IL-10, TNF-α and IL-12 cytokines compared to T. solium, suggesting that this global immune response stimulated by different forms could permit survival or destruction of the parasite depending of their life-cycle stage. Regarding MMPs, T. solium AO antigen stimulated a higher production of MMP-9 compared to T. saginata AO antigen, which may be responsible for altering the permeability of intestinal cells and facilitating breakdown of the blood-brain barrier during the process of invasion of host tissue.

Molecular and antigenic characterization of <i>Trypanosoma cruzi</i> TolT proteins

14 March 2019 - 9:00pm

by Maite Lobo, Virginia Balouz, Luciano Melli, Giannina Carlevaro, María E. Cortina, María de los Milagros Cámara, Gaspar E. Cánepa, Santiago J. Carmona, Jaime Altcheh, Oscar Campetella, Andrés E. Ciocchini, Fernán Agüero, Juan Mucci, Carlos A. Buscaglia

Background

TolT was originally described as a Trypanosoma cruzi molecule that accumulated on the trypomastigote flagellum bearing similarity to bacterial TolA colicins receptors. Preliminary biochemical studies indicated that TolT resolved in SDS-PAGE as ~3–5 different bands with sizes between 34 and 45 kDa, and that this heterogeneity could be ascribed to differences in polypeptide glycosylation. However, the recurrent identification of TolT-deduced peptides, and variations thereof, in trypomastigote proteomic surveys suggested an intrinsic TolT complexity, and prompted us to undertake a thorough reassessment of this antigen.

Methods/Principle findings

Genome mining exercises showed that TolT constitutes a larger-than-expected family of genes, with at least 12 polymorphic members in the T. cruzi CL Brener reference strain and homologs in different trypanosomes. According to structural features, TolT deduced proteins could be split into three robust groups, termed TolT-A, TolT-B, and TolT-C, all of them showing marginal sequence similarity to bacterial TolA proteins and canonical signatures of surface localization/membrane association, most of which were herein experimentally validated. Further biochemical and microscopy-based characterizations indicated that this grouping may have a functional correlate, as TolT-A, TolT-B and TolT-C molecules showed differences in their expression profile, sub-cellular distribution, post-translational modification(s) and antigenic structure. We finally used a recently developed fluorescence magnetic beads immunoassay to validate a recombinant protein spanning the central and mature region of a TolT-B deduced molecule for Chagas disease serodiagnosis.

Conclusion/Significance

This study unveiled an unexpected genetic and biochemical complexity within the TolT family, which could be exploited for the development of novel T. cruzi biomarkers with diagnostic/therapeutic applications.

Insects in anthelminthics research: Lady beetle-derived harmonine affects survival, reproduction and stem cell proliferation of <i>Schistosoma mansoni</i>

14 March 2019 - 9:00pm

by Josina Kellershohn, Laura Thomas, Arnold Grünweller, Roland K. Hartmann, Martin Hardt, Andreas Vilcinskas, Christoph G. Grevelding, Simone Haeberlein

Natural products have moved into the spotlight as possible sources for new drugs in the treatment of helminth infections including schistosomiasis. Surprisingly, insect-derived compounds have largely been neglected so far in the search for novel anthelminthics, despite the generally recognized high potential of insect biotechnology for drug discovery. This motivated us to assess the antischistosomal capacity of harmonine, an antimicrobial alkaloid from the harlequin ladybird Harmonia axyridis that raised high interest in insect biotechnology in recent years. We observed remarkably pleiotropic effects of harmonine on physiological, cellular, and molecular processes in adult male and female Schistosoma mansoni at concentrations as low as 5 μM in vitro. This included tegumental damage, gut dilatation, dysplasia of gonads, a complete stop of egg production at 10 μM, and increased production of abnormally shaped eggs at 5 μM. Motility was reduced with an EC50 of 8.8 μM and lethal effects occurred at 10–20 μM within 3 days of culture. Enzyme inhibition assays revealed acetylcholinesterase (AChE) as one potential target of harmonine. To assess possible effects on stem cells, which represent attractive anthelminthic targets, we developed a novel in silico 3D reconstruction of gonads based on confocal laser scanning microscopy of worms after EdU incorporation to allow for quantification of proliferating stem cells per organ. Harmonine significantly reduced the number of proliferating stem cells in testes, ovaries, and also the number of proliferating parenchymal neoblasts. This was further supported by a downregulated expression of the stem cell markers nanos-1 and nanos-2 in harmonine-treated worms revealed by quantitative real-time PCR. Our data demonstrate a multifaceted antischistosomal activity of the lady beetle-derived compound harmonine, and suggest AChE and stem cell genes as possible targets. Harmonine is the first animal-derived alkaloid detected to have antischistosomal capacity. This study highlights the potential of exploiting insects as a source for the discovery of anthelminthics.

Nutritional stress targets LeishIF4E-3 to storage granules that contain RNA and ribosome components in <i>Leishmania</i>

14 March 2019 - 9:00pm

by Rohit Shrivastava, Matan Drory-Retwitzer, Michal Shapira

Leishmania parasites lack pathways for de novo purine biosynthesis. The depletion of purines induces differentiation into virulent metacyclic forms. In vitro, the parasites can survive prolonged periods of purine withdrawal changing their morphology to long and slender cells with an extended flagellum, and decreasing their translation rates. Reduced translation leads to the appearance of discrete granules that contain LeishIF4E-3, one of the six eIF4E paralogs encoded by the Leishmania genome. We hypothesize that each is responsible for a different function during the life cycle. LeishIF4E-3 is a weak cap-binding protein paralog, but its involvement in translation under normal conditions cannot be excluded. However, in response to nutritional stress, LeishIF4E-3 concentrates in specific cytoplasmic granules. LeishIF4E-3 granulation can be induced by the independent elimination of purines, amino acids and glucose. As these granules contain mature mRNAs, we propose that these bodies store inactive transcripts until recovery from stress occurs. In attempt to examine the content of the nutritional stress-induced granules, they were concentrated over sucrose gradients and further pulled-down by targeting in vivo tagged LeishIF4E-3. Proteomic analysis highlighted granule enrichment with multiple ribosomal proteins, suggesting that ribosome particles are abundant in these foci, as expected in case of translation inhibition. RNA-binding proteins, RNA helicases and metabolic enzymes were also enriched in the granules, whereas no degradation enzymes or P-body markers were detected. The starvation-induced LeishIF4E-3-containing granules, therefore, appear to store stalled ribosomes and ribosomal subunits, along with their associated mRNAs. Following nutritional stress, LeishIF4E-3 becomes phosphorylated at position S75, located in its less-conserved N-terminal extension. The ability of the S75A mutant to form granules was reduced, indicating that cellular signaling regulates LeishIF4E-3 function.

A novel diagnostic algorithm equipped on an automated hematology analyzer to differentiate between common causes of febrile illness in Southeast Asia

14 March 2019 - 9:00pm

by Susantina Prodjosoewojo, Silvita F. Riswari, Hofiya Djauhari, Herman Kosasih, L. Joost van Pelt, Bachti Alisjahbana, Andre J. van der Ven, Quirijn de Mast

Background

Distinguishing arboviral infections from bacterial causes of febrile illness is of great importance for clinical management. The Infection Manager System (IMS) is a novel diagnostic algorithm equipped on a Sysmex hematology analyzer that evaluates the host response using novel techniques that quantify cellular activation and cell membrane composition. The aim of this study was to train and validate the IMS to differentiate between arboviral and common bacterial infections in Southeast Asia and compare its performance against C-reactive protein (CRP) and procalcitonin (PCT).

Methodology/Principal findings

600 adult Indonesian patients with acute febrile illness were enrolled in a prospective cohort study and analyzed using a structured diagnostic protocol. The IMS was first trained on the first 200 patients and subsequently validated using the complete cohort. A definite infectious etiology could be determined in 190 of 463 evaluable patients (41%), including 89 arboviral infections (81 dengue and 8 chikungunya), 94 bacterial infections (26 murine typhus, 16 salmonellosis, 6 leptospirosis and 46 cosmopolitan bacterial infections), 3 concomitant arboviral-bacterial infections, and 4 malaria infections. The IMS detected inflammation in all but two participants. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the IMS for arboviral infections were 69.7%, 97.9%, 96.9%, and 77.3%, respectively, and for bacterial infections 77.7%, 93.3%, 92.4%, and 79.8%. Inflammation remained unclassified in 19.1% and 22.5% of patients with a proven bacterial or arboviral infection. When cases of unclassified inflammation were grouped in the bacterial etiology group, the NPV for bacterial infection was 95.5%. IMS performed comparable to CRP and outperformed PCT in this cohort.

Conclusions/Significance

The IMS is an automated, easy to use, novel diagnostic tool that allows rapid differentiation between common causes of febrile illness in Southeast Asia.

Use of oral cholera vaccine as a vaccine probe to determine the burden of culture-negative cholera

14 March 2019 - 9:00pm

by Justin Im, Md. Taufiqul Islam, Faisal Ahmmed, Deok Ryun Kim, Yun Chon, K Zaman, Ashraful Islam Khan, Mohammad Ali, Florian Marks, Firdausi Qadri, John D. Clemens

Analyses of stool from patients with acute watery diarrhea (AWD) using sensitive molecular diagnostics have challenged whether fecal microbiological cultures have acceptably high sensitivity for cholera diagnosis. If true, these findings imply that current estimates of the global burden of cholera, which rely largely on culture-confirmation, may be underestimates. We conducted a vaccine probe study to evaluate this possibility, assessing whether an effective killed oral cholera vaccine (OCV) tested in a field trial in a cholera-endemic population conferred protection against cholera culture-negative AWD, with the assumption that if cultures are indeed insensitive, OCV protection in such cases should be detectable. We re-analysed the data of a Phase III individually-randomized placebo-controlled efficacy trial of killed OCVs conducted in Matlab, Bangladesh in 1985. We calculated the protective efficacy (PE) of a killed whole cell-only (WC-only) OCV against first-episodes of cholera culture-negative AWD during two years of post-dosing follow-up. In secondary analyses, we evaluated PE against cholera culture-negative AWD by age at vaccination, season of onset, and disease severity. In this trial 50,770 people received at least 2 complete doses of either WC-only OCV or placebo, and 791 first episodes of AWD were reported during the follow-up period, of which 365 were culture-positive for Vibrio cholerae O1. Of the 426 culture-negative AWD episodes, 215 occurred in the WC group and 211 occurred in the placebo group (adjusted PE = -1.7%; 95%CI -23.0 to 13.9%, p = 0.859). No measurable PE of OCV was observed against all or severe cholera culture-negative AWD when measured overall or by age and season subgroups. In this OCV probe study we detected no vaccine protection against AWD episodes for which fecal cultures were negative for Vibrio cholera O1. Results from this setting suggest that fecal cultures from patients with AWD were highly sensitive for cholera episodes that were etiologically attributable to this pathogen. Similar analyses of other OCV randomized controlled trials are recommended to corroborate these findings.

Melioidosis: The hazards of incomplete peer-review

14 March 2019 - 9:00pm

by Direk Limmathurotsakul, Frances Daily, Sotharith Bory, Gaetan Khim, W. Joost Wiersinga, Alfredo G. Torres, David A. B. Dance, Bart J. Currie

Serological proteomic screening and evaluation of a recombinant egg antigen for the diagnosis of low-intensity <i>Schistosoma mansoni</i> infections in endemic area in Brazil

14 March 2019 - 9:00pm

by Vanessa Silva-Moraes, Lisa Marie Shollenberger, William Castro-Borges, Ana Lucia Teles Rabello, Donald A. Harn, Lia Carolina Soares Medeiros, Wander de Jesus Jeremias, Liliane Maria Vidal Siqueira, Caroline Stephane Salviano Pereira, Maria Luysa Camargos Pedrosa, Nathalie Bonatti Franco Almeida, Aureo Almeida, Jose Roberto Lambertucci, Nídia Francisca de Figueiredo Carneiro, Paulo Marcos Zech Coelho, Rafaella Fortini Queiroz Grenfell

Background

Despite decades of use of control programs, schistosomiasis remains a global public health problem. To further reduce prevalence and intensity of infection, or to achieve the goal of elimination in low-endemic areas, there needs to be better diagnostic tools to detect low-intensity infections in low-endemic areas in Brazil. The rationale for development of new diagnostic tools is that the current standard test Kato-Katz (KK) is not sensitive enough to detect low-intensity infections in low-endemic areas. In order to develop new diagnostic tools, we employed a proteomics approach to identify biomarkers associated with schistosome-specific immune responses in hopes of developing sensitive and specific new methods for immunodiagnosis.

Methods and findings

Immunoproteomic analyses were performed on egg extracts of Schistosoma mansoni using pooled sera from infected or non-infected individuals from a low-endemic area of Brazil. Cross reactivity with other soil-transmitted helminths (STH) was determined using pooled sera from individuals uniquely infected with different helminths. Using this approach, we identified 23 targets recognized by schistosome acute and chronic sera samples. To identify immunoreactive targets that were likely glycan epitopes, we compared these targets to the immunoreactivity of spots treated with sodium metaperiodate oxidation of egg extract. This treatment yielded 12/23 spots maintaining immunoreactivity, suggesting that they were protein epitopes. From these 12 spots, 11 spots cross-reacted with sera from individuals infected with other STH and 10 spots cross-reacted with the negative control group. Spot number 5 was exclusively immunoreactive with sera from S. mansoni-infected groups in native and deglycosylated conditions and corresponds to Major Egg Antigen (MEA). We expressed MEA as a recombinant protein and showed a similar recognition pattern to that of the native protein via western blot. IgG-ELISA gave a sensitivity of 87.10% and specificity of 89.09% represented by area under the ROC curve of 0.95. IgG-ELISA performed better than the conventional KK (2 slides), identifying 56/64 cases harboring 1–10 eggs per gram of feces that were undiagnosed by KK parasitological technique.

Conclusions

The serological proteome approach was able to identify a new diagnostic candidate. The recombinant egg antigen provided good performance in IgG-ELISA to detect individuals with extreme low-intensity infections (1 egg per gram of feces). Therefore, the IgG-ELISA using this newly identified recombinant MEA can be a useful tool combined with other techniques in low-endemic areas to determine the true prevalence of schistosome infection that is underestimated by the KK method. Further, to overcome the complexity of ELISA in the field, a second generation of antibody-based rapid diagnostic tests (RDT) can be developed.

Retraction: Vector competence of biting midges and mosquitoes for Shuni virus

13 March 2019 - 9:00pm

by The PLOS Neglected Tropical Diseases Editors and Staff

Spatial distribution, prevalence and potential risk factors of Tungiasis in Vihiga County, Kenya

12 March 2019 - 9:00pm

by Ruth Monyenye Nyangacha, David Odongo, Florence Oyieke, Christine Bii, Erastus Muniu, Stanley Chasia, Missiani Ochwoto

Background

Tungiasis is a parasitic disease caused by the sand flea Tunga penetrans also known as jigger flea. Communities living in precarious conditions in tropical and sub tropical countries bear the brunt of the infection. The main objective of this study was to determine the burden of Tungiasis in Vihiga County in Kenya.

Methods

This was a cross-sectional study conducted in 21 villages in 3 Sub-locations in Vihiga County, western Kenya. A total of 437 participants, 5 years old and above were clinically examined for the presence of tungiasis after consenting to take part in the study. Diagnosis was made following standard methods. A semi- structured questionnaire was administered to assess socio-demographic factors, housing, presence and ownership of animals, knowledge and practice related to tungiasis. Data were analyzed using bivariate and multivariate regression analysis. GIS was used to map the geographic distribution of tungiasis in the area.

Results

The overall prevalence was found to be (21.5%; 95% CI: 17.7–25.3%). The cases were analysed and visualized in a map form. Multivariate analysis suggested that the occurrence of tungiasis was associated with variables that indicated low economic status (like a monthly income of Ksh ≤ 1000 (adjusted odds ratio 27.85; 95% CI: 4.13–187.59), earthen floor (0.36; 0.13–1.024) and lack of toilet facilities (4.27; 0.82–22.34), age of participant ≤14 (27.414; 10.02–74.99), no regular use of closed footwear (1.98; 0.987–3.97) and common resting place inside the house (1.93; 0.96–3.89).

Conclusions

Tungiasis is an important health problem in Vihiga County occasioned by the low economic status of the people affected. Factors that point to poverty contribute to the occurrence of tungiasis. These findings suggest a need to design control strategies for tungiasis that are cost effective and easily accessible.

<i>Strongyloides stercoralis</i> infection: A systematic review of endemic cases in Spain

12 March 2019 - 9:00pm

by Maria Barroso, Fernando Salvador, Adrián Sánchez-Montalvá, Pau Bosch-Nicolau, Israel Molina

Background

Strongyloides stercoralis infection, a neglected tropical disease, is widely distributed. Autochthonous cases have been described in Spain, probably infected long time ago. In recent years the number of diagnosed cases has increased due to the growing number of immigrants, travelers and refugees, but endemically acquired cases in Spain remains undetermined.

Methodology

We systematically searched the literature for references on endemic strongyloidiasis cases in Spain. The articles were required to describe Strongyloides stercoralis infection in at least one Spanish-born person without a history of travel to endemic areas and be published before 31st May 2018. Epidemiological data from patients was collected and described individually as well as risk factors to acquisition of the infection, diagnostic technique that lead to the diagnosis, presence of eosinophilia and clinical symptoms at diagnosis.

Findings

Thirty-six studies were included, describing a total of 1083 patients with an average age of 68.3 years diagnosed with endemic strongyloidiasis in Spain. The vast majority of the cases were described in the province of Valencia (n = 1049). Two hundred and eight of the 251 (82.9%) patients in whom gender was reported were male, and most of them had current or past dedication to agriculture. Seventy percent had some kind of comorbidity. A decreasing trend in the diagnosed cases per year is observed from the end of last decade. However, there are still nefigw diagnoses of autochthonous cases of strongyloidiasis in Spain every year.

Conclusions

With the data provided by this review it is likely that in Spain strongyloidiasis might have been underestimated. It is highly probable that the infection remains undiagnosed in many cases due to low clinical suspicion among Spanish population without recent travel history in which the contagion probably took place decades ago.

Assessment of false negative rates of lactate dehydrogenase-based malaria rapid diagnostic tests for <i>Plasmodium ovale</i> detection

11 March 2019 - 9:00pm

by Jianxia Tang, Feng Tang, Hongru Zhu, Feng Lu, Sui Xu, Yuanyuan Cao, Yaping Gu, Xiaoqin He, Huayun Zhou, Guoding Zhu, Jun Cao

Currently, malaria rapid diagnostic tests (RDTs) are widely used for malaria diagnosis, but test performance and the factors that lead to failure of Plasmodium ovale detection are not well understood. In this study, three pLDH-based RDTs were evaluated using cases in China that originated in Africa. The sensitivity of Wondfo Pf/Pan, CareStart pLDH PAN and SD BIOLINE Pf/Pan in P. ovale detection was 70, 55 and 18%, respectively. CareStart was worse at detecting P. o. curtisi (36.5%) than at detecting P. o. wallikeri (75.0%), and SD could not detect P. o. curtisi. The overall detection ratio of all three RDTs decreased with parasite density and pLDH concentration. Wondfo, CareStart and SD detected only 75.0, 78.1 and 46.9% of the P. ovale cases, respectively, even when the parasitemia were higher than 5000 parasites/μL. Subspecies of P. ovale should be considered while to improve RDT quality for P. ovale diagnosis to achieve the goal of malaria elimination.

A polyvalent coral snake antivenom with broad neutralization capacity

11 March 2019 - 9:00pm

by María Carlina Castillo-Beltrán, Juan Pablo Hurtado-Gómez, Vladimir Corredor-Espinel, Francisco Javier Ruiz-Gómez

Coral snakes of the genus Micrurus have a high diversity and a wide distribution in the Americas. Despite envenomings by these animals are uncommon, accidents are often severe and may result in death. Producing an antivenom to treat these envenomings has been challenging since coral snakes are difficult to catch, produce small amounts of venom, and the antivenoms produced have shown limited cross neutralization. Here we present data of cross neutralization among monovalent antivenoms raised against M. dumerilii, M. isozonus, M. mipartitus and M. surinamensis and the development of a new polyvalent coral snake antivenom, resulting from the mix of monovalent antivenoms. Our results, show that this coral snake antivenom has high neutralizing potency and wide taxonomic coverage, constituting a possible alternative for a long sought Pan-American coral snake antivenom.

Active surveillance identified a neglected burden of macular cases of Post Kala-azar Dermal Leishmaniasis in West Bengal

11 March 2019 - 9:00pm

by Ritika Sengupta, Surya Jyati Chowdhury, Srija Moulik, Manab Kumar Ghosh, Bibhuti Saha, Nilay Kanti Das, Mitali Chatterjee

Background

Post Kala-azar Dermal Leishmaniasis (PKDL) develops in patients apparently cured of Visceral Leishmaniasis (VL), and is the strongest contender for being the disease reservoir. Therefore, existence of a few cases is sufficient to trigger an epidemic of VL in a given community, emphasizing the need for its active detection and in turn ensuring success of the current elimination program. This study explored the impact of active surveillance on the demographic profile of PKDL patients in West Bengal.

Methodology/Principal findings

Patients with PKDL were recruited through passive (2003-date, n = 100) and active surveillance (2015-date, n = 202), the former from outpatient departments of dermatology in medical colleges in West Bengal and the latter through an active door-to-door survey in four VL hyper-endemic districts of West Bengal. Passive surveillance indicated a male preponderance and a predominance of polymorphic lesions, whereas active surveillance indicated absence of any gender bias and more importantly, macular PKDL constituted almost 50% of the population burden. In terms of polymorphic vs. macular PKDL, the former appeared at a later age, their disease duration was longer and had a higher parasite burden. In the polymorphic variant, the lesional distribution was asymmetrical, comprised of papules/nodules/macules that were present mainly in sun-exposed areas whereas in macular cases, the hypopigmented patches were diffusely present all over the body.

Conclusions/Significance

Active surveillance unraveled a disease component whose demographic profile showed important differences with PKDL cases who sought treatment in government hospitals. Detection of a higher proportion of macular cases indicates that this variant is not an uncommon presentation as conventionally stated in text books, and should be studied in greater detail to ensure success of the ongoing Leishmaniasis elimination programme.

Perinatal analyses of Zika- and dengue virus-specific neutralizing antibodies: A microcephaly case-control study in an area of high dengue endemicity in Brazil

11 March 2019 - 9:00pm

by Priscila M. S. Castanha, Wayner V. Souza, Cynthia Braga, Thalia V. B. De Araújo, Ricardo A. A. Ximenes, Maria de Fátima P. M. Albuquerque, Ulisses R. Montarroyos, Demócrito B. Miranda-Filho, Marli T. Cordeiro, Rafael Dhalia, Ernesto T. A. Marques Jr., Laura C. Rodrigues, Celina M. T. Martelli, Microcephaly Epidemic Research Group

Laboratory confirmation of Zika virus (ZIKV) infection during pregnancy is challenging due to cross-reactivity with dengue virus (DENV) and limited knowledge about the kinetics of anti-Zika antibody responses during pregnancy. We described ZIKV and DENV serological markers and the maternal-fetal transfer of antibodies among mothers and neonates after the ZIKV microcephaly outbreak in Northeast Brazil (2016). We included 89 microcephaly cases and 173 neonate controls at time of birth and their mothers. Microcephaly cases were defined as newborns with a particular head circumference (2 SD below the mean). Two controls without microcephaly were matched by the expected date of delivery and area of residence. We tested maternal serum for recent (ZIKV genome, IgM and IgG3 anti-NS1) and previous (ZIKV and DENV neutralizing antibodies [NAbs]) markers of infection. Multiple markers of recent or previous ZIKV and DENV infection in mothers were analyzed using principal component analysis (PCA). At delivery, 5.6% of microcephaly case mothers and 1.7% of control mothers were positive for ZIKV IgM. Positivity for ZIKV IgG3 anti-NS1 was 8.0% for case mothers and 3.5% for control mothers. ZIKV NAbs was slightly higher among mothers of cases (69.6%) than that of mothers of controls (57.2%; p = 0.054). DENV exposure was detected in 85.8% of all mothers. PCA discriminated two distinct components related to recent or previous ZIKV infection and DENV exposure. ZIKV NAbs were higher in newborns than in their corresponding mothers (p<0.001). We detected a high frequency of ZIKV exposure among mothers after the first wave of the ZIKV outbreak in Northeast Brazil. However, we found low sensitivity of the serological markers to recent infection (IgM and IgG3 anti-NS1) in perinatal samples of mothers of microcephaly cases. Since the neutralization test cannot precisely determine the time of infection, testing for ZIKV immune status should be performed as early as possible and throughout pregnancy to monitor acute Zika infection in endemic areas.

A combined experimental-computational approach for spatial protection efficacy assessment of controlled release devices against mosquitoes (<i>Anopheles</i>)

11 March 2019 - 9:00pm

by Ulrich R. Bernier, Daniel L. Kline, Agustin Vazquez-Abad, Melynda Perry, Lee W. Cohnstaedt, Pablo Gurman, Sebastián D’hers, Noel M. Elman

This work describes the use of entomological studies combined with in silico models (computer simulations derived from numerical models) to assess the efficacy of a novel device for controlled release of spatial repellents. Controlled Release Devices (CRDs) were tested with different concentrations of metofluthrin and tested against An. quadrimaculatus mosquitoes using arm-in cage, semi-field, and outdoor studies. Arm-in-cage trials showed an approximate mean values for mosquito knockdown of 40% and mosquito bite reduction of 80% for the optimal metofluthrin formulation for a 15-minute trial. Semi-field outdoor studies showed a mean mortality of a 50% for 24 hour trial and 75% for a 48 hour trial for optimal concentrations. Outdoors studies showed an approximate mean mortality rate of 50% for a 24 hour trial for optimal concentrations. Numerical simulations based on Computational Fluid Dynamics (CFD) were performed in order to obtain spatial concentration profiles for 24 hour and 48 hour periods. Experimental results were correlated with simulation results in order to obtain a functional model that linked mosquito mortality with the estimated spatial concentration for a given period of time. Such correlation provides a powerful insight in predicting the effectiveness of the CRDs as a vector-control tool. While CRDs represent an alternative to current spatial repellent delivery methods, such as coils, candles, electric repellents, and passive emanators based on impregnated strips, the presented method can be applied to any spatial vector control treatment by correlating entomological endpoints, i.e. mortality, with in-silico simulations to predict overall efficacy. The presented work therefore presents a new methodology for improving design, development and deployment of vector-control tools to reduce transmission of vector-borne diseases, including malaria and dengue.

Analysis of a meningococcal meningitis outbreak in Niger – potential effectiveness of reactive prophylaxis

11 March 2019 - 9:00pm

by Matt D. T. Hitchings, Matthew E. Coldiron, Rebecca F. Grais, Marc Lipsitch

Background

Seasonal epidemics of bacterial meningitis in the African Meningitis Belt carry a high burden of disease and mortality. Reactive mass vaccination is used as a control measure during epidemics, but the time taken to gain immunity from the vaccine reduces the flexibility and effectiveness of these campaigns. Targeted reactive antibiotic prophylaxis could be used to supplement reactive mass vaccination and further reduce the incidence of meningitis, and the potential effectiveness and efficiency of these strategies should be explored.

Methods and findings

Data from an outbreak of meningococcal meningitis in Niger, caused primarily by Neisseria meningitidis serogroup C, is used to estimate clustering of meningitis cases at the household and village level. In addition, reactive antibiotic prophylaxis and reactive vaccination strategies are simulated to estimate their potential effectiveness and efficiency, with a focus on the threshold and spatial unit used to declare an epidemic and initiate the intervention.There is village-level clustering of suspected meningitis cases after an epidemic has been declared in a health area. Risk of suspected meningitis among household contacts of a suspected meningitis case is no higher than among members of the same village. Village-wide antibiotic prophylaxis can target subsequent cases in villages: across of range of parameters pertaining to how the intervention is performed, up to 220/672 suspected cases during the season are potentially preventable. On the other hand, household prophylaxis targets very few cases. In general, the village-wide strategy is not very sensitive to the method used to declare an epidemic. Finally, village-wide antibiotic prophylaxis is potentially more efficient than mass vaccination of all individuals at the beginning of the season, and than the equivalent reactive vaccination strategy.

Conclusions

Village-wide antibiotic prophylaxis should be considered and tested further as a response against outbreaks of meningococcal meningitis in the Meningitis Belt, as a supplement to reactive mass vaccination.

A little goes a long way: Weak vaccine transmission facilitates oral vaccination campaigns against zoonotic pathogens

8 March 2019 - 10:00pm

by Andrew J. Basinski, Scott L. Nuismer, Christopher H. Remien

Zoonotic pathogens such as Ebola and rabies pose a major health risk to humans. One proven approach to minimizing the impact of a pathogen relies on reducing its prevalence within animal reservoir populations using mass vaccination. However, two major challenges remain for vaccination programs that target free-ranging animal populations. First, limited or challenging access to wild hosts, and second, expenses associated with purchasing and distributing the vaccine. Together, these challenges constrain a campaign’s ability to maintain adequate levels of immunity in the host population for an extended period of time. Transmissible vaccines could lessen these constraints, improving our ability to both establish and maintain herd immunity in free-ranging animal populations. Because the extent to which vaccine transmission could augment current wildlife vaccination campaigns is unknown, we develop and parameterize a mathematical model that describes long-term mass vaccination campaigns in the US that target rabies in wildlife. The model is used to investigate the ability of a weakly transmissible vaccine to (1) increase vaccine coverage in campaigns that fail to immunize at levels required for herd immunity, and (2) decrease the expense of campaigns that achieve herd immunity. When parameterized to efforts that target rabies in raccoons using vaccine baits, our model indicates that, with current vaccination efforts, a vaccine that transmits to even one additional host per vaccinated individual could sufficiently augment US efforts to preempt the spread of the rabies virus. Higher levels of transmission are needed, however, when spatial heterogeneities associated with flight-line vaccination are incorporated into the model. In addition to augmenting deficient campaigns, our results show that weak vaccine transmission can reduce the costs of vaccination campaigns that are successful in attaining herd immunity.

Mapping of lymphatic filariasis in loiasis areas: A new strategy shows no evidence for <i>Wuchereria bancrofti</i> endemicity in Cameroon

8 March 2019 - 10:00pm

by Samuel Wanji, Mathias Eyong Esum, Abdel Jelil Njouendou, Amuam Andrew Mbeng, Patrick W. Chounna Ndongmo, Raphael Awah Abong, Jerome Fru, Fanny F. Fombad, Gordon Takop Nchanji, Glory Ngongeh, Narcisse V. Ngandjui, Peter Ivo Enyong, Helen Storey, Kurt C. Curtis, Kerstin Fischer, Joseph R. Fauver, Daphne Lew, Charles W. Goss, Peter U. Fischer

Background

Mapping of lymphatic filariasis (LF) caused by Wuchereria bancrofti largely relies on the detection of circulating antigen using ICT cards. Several studies have recently shown that this test can be cross-reactive with sera of subjects heavily infected with Loa loa and thus mapping results in loiasis endemic areas may be inaccurate.

Methodology/Principal findings

In order to develop an LF mapping strategy for areas with high loiasis prevalence, we collected day blood samples from 5,001 subjects residing in 50 villages that make up 6 health districts throughout Cameroon. Antigen testing using Filarial Test Strip (FTS, a novel platform that uses the same reagents as ICT) revealed an overall positivity rate of 1.1% and L. loa microfilaria (Mf) rates of up to 46%. Among the subjects with 0 to 8,000 Mf/ml in day blood, only 0.4% were FTS positive, while 29% of subjects with >8,000 Mf/ml were FTS positive. A Mf density of >8,200 Mf/ml was determined as the cut point at which positive FTS results should be excluded from the analysis. No FTS positive samples were also positive for W. bancrofti antibodies as measured by two different point of care tests that use the Wb123 antigen not found in L. loa. Night blood examination of the FTS positive subjects showed a high prevalence of L. loa Mf with densities up to 12,710 Mf/ml. No W. bancrofti Mf were identified, as confirmed by qPCR. Our results show that high loads of L. loa Mf in day blood are a reliable indicator of FTS positivity, and Wb123 rapid test proved to be relatively specific.

Conclusions/Significance

Our study provides a simple day blood-based algorithm for LF mapping in loiasis areas. The results indicate that many districts that were formerly classified as endemic for LF in Cameroon are non-endemic and do not require mass drug administration for elimination of LF.

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