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Diagnostic accuracy cohort study and clinical value of the Histoplasma urine antigen (ALPHA Histoplasma EIA) for disseminated histoplasmosis among HIV infected patients: A multicenter study

PLoS Neglected Tropical Diseases News - 5 November 2018 - 10:00pm

by Pedro Torres-González, María Dolores Niembro-Ortega, Areli Martínez-Gamboa, Víctor Hugo Ahumada-Topete, Jaime Andrade-Villanueva, Javier Araujo-Meléndez, Alberto Chaparro-Sánchez, Brenda Crabtree-Ramírez, Sofia Cruz-Martínez, Armando Gamboa-Domínguez, Oscar I. Flores-Barrientos, Jesús Enrique Gaytán-Martínez, Luz Alicia González-Hernández, Christian Hernández-León, Víctor Hugo Lozano-Fernandez, Marisol Manríquez-Reyes, Martin Magaña-Aquino, Pedro Martínez-Ayala, Juan Pablo Ramírez-Hinojosa, Andrea Rangel-Cordero, Norma Erendira Rivera-Martínez, Edgardo Reyes-Gutiérrez, Gustavo Reyes-Terán, Patricia Rodríguez-Zulueta, Jesús Ruíz-Quiñones, Janeth Santiago-Cruz, Nancy Guadalupe Velázquez-Zavala, José Sifuentes-Osornio, Alfredo Ponce de León

Background

The Histoplasma urine antigen (HUAg) is the preferred method to diagnose progressive disseminated histoplasmosis (PDH) in HIV patients. In 2007, IMMY ALPHA Histoplasma EIA was approved for clinical for on-site use, and therefore useful for regions outside the United States. However, ALPHA-HUAg is considered inferior to the MVista-HUAg which is only available on referral. We aim to evaluate the diagnostic accuracy of ALPHA-HUAg.

Methodology/Principal findings

We conducted a multicenter, prospective, diagnostic test study in two secondary and eight tertiary-care facilities in Mexico. We included HIV patient with PDH suspicion and evaluated ALPHA-HUAg diagnostic accuracy using as reference standard the Histoplasma capsulatum growth on blood, bone marrow, and tissue cultures or compatible histopathologic exam (PDH–proven). We evaluated the results of 288 patients, 29.5% (85/288; 95% confidence interval [CI], 24.3–35.1) had PDH. The sensitivity of ALPHA-HUAg was 67.1% (95% CI, 56–76.8%) and the specificity was 97.5% (95% CI, 94.3%-99.1%). The positive likelihood ratio was 27.2 (95% CI; 11.6–74.4). In 10.5% of the PDH–proven patients, a co-existing opportunistic infection was diagnosed, mostly disseminated Mycobacterium avium complex infection.

Conclusions/Significance

We observed a high specificity but low sensitivity of IMMY-HUAg. The test may be useful to start early antifungals, but a culture-based approach is necessary since co-infections are frequent and a negative IMMY-HUAg result does not rule out PDH.

The economic value of identifying and treating Chagas disease patients earlier and the impact on <i>Trypanosoma cruzi</i> transmission

PLoS Neglected Tropical Diseases News - 5 November 2018 - 10:00pm

by Sarah M. Bartsch, Cameron M. Avelis, Lindsey Asti, Daniel L. Hertenstein, Martial Ndeffo-Mbah, Alison Galvani, Bruce Y. Lee

Background

The World Health Organization’s 2020 Goals for Chagas disease include access to antiparasitic treatment and care of all infected/ill patients. Policy makers need to know the economic value of identifying and treating patients earlier. However, the economic value of earlier treatment to cure and prevent the Chagas’ spread remains unknown.

Methods

We expanded our existing Chagas disease transmission model to include identification and treatment of Chagas disease patients. We linked this to a clinical and economic model that translated chronic Chagas disease cases into health and economic outcomes. We evaluated the impact and economic outcomes (costs, cost-effectiveness, cost-benefit) of identifying and treating different percentages of patients in the acute and indeterminate disease states in a 2,000-person village in Yucatan, Mexico.

Results

In the absence of early treatment, 50 acute and 22 new chronic cases occurred over 50 years. Identifying and treating patients in the acute stage averted 0.5–5.4 acute cases, 0.6–5.5 chronic cases, and 0.6–10.8 disability-adjusted life years (DALYs), saving $694-$7,419 and $6,976-$79,950 from the third-party payer and societal perspectives, respectively. Treating in the indeterminate stage averted 2.2–4.9 acute cases, 6.1–12.8 chronic cases, and 11.7–31.1 DALYs, saving $7,666-$21,938 from the third-party payer perspective and $90,530-$243,068 from the societal perspective. Treating patients in both stages averted ≤9 acute cases and ≤15 chronic cases. Identifying and treating patients early was always economically dominant compared to no treatment. Identifying and treating patients earlier resulted in a cumulative cost-benefit of $7,273-$224,981 at the current cost of identification and treatment.

Conclusions

Even when identifying and treating as little as 5% of cases annually, treating Chagas cases in the acute and indeterminate stages reduces transmission and provides economic and health benefits. This supports the need for improved diagnostics and access to safe and effective treatment.

Geographic variation in dengue seroprevalence and force of infection in the urban paediatric population of Indonesia

PLoS Neglected Tropical Diseases News - 2 November 2018 - 9:00pm

by Clarence C. Tam, Megan O’Driscoll, Anne-Frieda Taurel, Joshua Nealon, Sri Rezeki Hadinegoro

Understanding the heterogeneous nature of dengue transmission is important for prioritizing and guiding the implementation of prevention strategies. However, passive surveillance data in endemic countries are rarely adequately informative. We analyzed data from a cluster-sample, cross-sectional seroprevalence study in 1–18 year-olds to investigate geographic differences in dengue seroprevalence and force of infection in Indonesia. We used catalytic models to estimate the force of infection in each of the 30 randomly selected sub-districts. Based on these estimates, we determined the proportion of sub-districts expected to reach seroprevalence levels of 50%, 70% and 90% by year of age. We used population averaged generalized estimating equation models to investigate individual- and cluster-level determinants of dengue seropositivity. Dengue force of infection varied substantially across Indonesia, ranging from 4.3% to 30.0% between sub-districts. By age nine, 60% of sub-districts are expected to have a seroprevalence ≥70%, rising to 83% by age 11. Higher odds of seropositivity were associated with higher population density (OR = 1.54 per 10-fold rise in population density, 95% CI: 1.03–2.32) and with City (relative to Regency) administrative status (OR = 1.92, 95% CI: 1.32–2.79). Our findings highlight the substantial variation in dengue endemicity within Indonesia and the importance of understanding spatial heterogeneity in dengue transmission intensity for optimal dengue prevention strategies including future implementation of dengue vaccination programmes.

Comprehensive evaluation of stool-based diagnostic methods and benzimidazole resistance markers to assess drug efficacy and detect the emergence of anthelmintic resistance: A Starworms study protocol

PLoS Neglected Tropical Diseases News - 2 November 2018 - 9:00pm

by Johnny Vlaminck, Piet Cools, Marco Albonico, Shaali Ame, Mio Ayana, Jeffrey Bethony, Giuseppe Cringoli, Daniel Dana, Jennifer Keiser, Maria P. Maurelli, Antonio Montresor, Zeleke Mekonnen, Greg Mirams, Rodrigo Corrêa-Oliveira, Roger Prichard, Nour Rashwan, Laura Rinaldi, Somphou Sayasone, Eurion Thomas, Jaco J. Verweij, Jozef Vercruysse, Bruno Levecke

Background

To work towards reaching the WHO goal of eliminating soil-transmitted helminth (STH) infections as a public health problem, the total number of children receiving anthelmintic drugs has strongly increased over the past few years. However, as drug pressure levels rise, the development of anthelmintic drug resistance (AR) is more and more likely to appear. Currently, any global surveillance system to monitor drug efficacy and the emergence of possible AR is lacking. Consequently, it remains unclear to what extent the efficacy of drugs may have dropped and whether AR is already present. The overall aim of this study is to recommend the best diagnostic methods to monitor drug efficacy and molecular markers to assess the emergence of AR in STH control programs.

Methods

A series of drug efficacy trials will be performed in four STH endemic countries with varying drug pressure (Ethiopia and Brazil: low drug pressure, Lao PDR: moderate drug pressure and Tanzania: high drug pressure). These trials are designed to assess the efficacy of a single oral dose of 400 mg albendazole (ALB) against STH infections in school-aged children (SAC) by microscopic (duplicate Kato-Katz thick smear, Mini-FLOTAC and FECPAKG2) and molecular stool-based diagnostic methods (quantitative PCR (qPCR)). Data will be collected on the cost of the materials used, as well as the time required to prepare and examine stool samples for the different diagnostic methods. Following qPCR, DNA samples will also be submitted for pyrosequencing to assess the presence and prevalence of single nucleotide polymorphisms (SNPs) in the β-tubulin gene. These SNPs are known to be linked to AR in animal STHs.

Discussion

The results obtained by these trials will provide robust evidence regarding the cost-efficiency and diagnostic performance of the different stool-based diagnostic methods for the assessment of drug efficacy in control programs. The assessment of associations between the frequency of SNPs in the β-tubulin gene and the history of drug pressure and drug efficacy will allow the validation of these SNPs as a marker for AR in human STHs.

Trial registration

The trial was retrospectively registered the 7th of March 2018 on Clinicaltrials.gov (ID: NCT03465488).

Comparison of different drug regimens for the treatment of loiasis—A TropNet retrospective study

PLoS Neglected Tropical Diseases News - 1 November 2018 - 9:00pm

by Federico Gobbi, Emmanuel Bottieau, Olivier Bouchaud, Dora Buonfrate, Fernando Salvador, Gerardo Rojo-Marcos, Paola Rodari, Jan Clerinx, Begoña Treviño, Juan Paulo Herrera-Ávila, Andreas Neumayr, Guido Calleri, Andrea Angheben, Camilla Rothe, Lorenzo Zammarchi, Massimo Guerriero, Zeno Bisoffi

Background

Loa loa infection is endemic in limited areas of West-Central Africa. Loiasis has been associated with excess mortality, but clinical studies on its treatment are scant, particularly outside endemic areas, due to the rarity of cases diagnosed.

Methodology/Principal findings

With this retrospective TropNet (European Network for Tropical Medicine and Travel Health) study, we aimed at outlining the treatment schedules followed by different reference centers for tropical medicine across Europe. We gathered information about 238 cases of loiasis, 165 of which had follow up data. The regimens followed by the different centers were heterogeneous. The drugs most frequently administered were: diethylcarbamazine alone (74/165, 45.1%), ivermectin alone (41/165, 25%), albendazole + ivermectin (21/164, 11.6%), ivermectin + diethylcarbamazine (16/165, 9.7%).

Conclusions/Significance

The management of loiasis substantially differs across specialized travel clinics in Europe. These discrepancies could be due to different local protocols as well as to (un)availability of the drugs. An harmonization of clinical protocols for the treatment of loiasis would be suggested across reference centers for tropical medicine in Europe.

Beneficial effects of benznidazole in Chagas disease: NIH SaMi-Trop cohort study

PLoS Neglected Tropical Diseases News - 1 November 2018 - 9:00pm

by Clareci Silva Cardoso, Antonio Luiz P. Ribeiro, Claudia Di Lorenzo Oliveira, Lea Campos Oliveira, Ariela Mota Ferreira, Ana Luiza Bierrenbach, José Luiz Padilha Silva, Enrico Antonio Colosimo, João Eduardo Ferreira, Tzong-Hae Lee, Michael P. Busch, Arthur Lawrence Reingold, Ester Cerdeira Sabino

Background

The effectiveness of anti-parasite treatment with benznidazole in the chronic Chagas disease (ChD) remains uncertain. We evaluated, using data from the NIH-sponsored SaMi-Trop prospective cohort study, if previous treatment with benznidazole is associated with lower mortality, less advanced cardiac disease and lower parasitemia in patients with chronic ChD.

Methods

The study enrolled 1,959 ChD patients and abnormal electrocardiogram (ECG) from in 21 remote towns in Brazil. A total of 1,813 patients were evaluated at baseline and after two years of follow-up. Those who received at least one course of benznidazole were classified as treated group (TrG = 493) and those who were never treated as control group (CG = 1,320). The primary outcome was death after two-year follow-up; the secondary outcomes were presence at the baseline of major ChD-associated ECG abnormalities, NT-ProBNP levels suggestive of heart failure, and PCR positivity.

Results

Mortality after two years was 6.3%; it was lower in the TrG (2.8%) than the CG (7.6%); adjusted OR: 0.37 (95%CI: 0.21;0.63). The ECG abnormalities typical for ChD and high age-adjusted NT-ProBNP levels suggestive of heart failure were lower in the TrG than the CG, OR: 0.35 [CI: 0.23;0.53]. The TrG had significantly lower rates of PCR positivity, OR: 0.35 [CI: 0.27;0.45].

Conclusion

Patients previously treated with benznidazole had significantly reduced parasitemia, a lower prevalence of markers of severe cardiomyopathy, and lower mortality after two years of follow-up. If used in the early phases, benznidazole treatment may improve clinical and parasitological outcomes in patients with chronic ChD.

Trial registration

ClinicalTrials.gov, Trial registration: NCT02646943.

Developing mobile health applications for neglected tropical disease research

PLoS Neglected Tropical Diseases News - 1 November 2018 - 9:00pm

by Andrés Navarro, Luisa Rubiano, Juan David Arango, Carlos A. Rojas, Neal Alexander, Nancy Gore Saravia, Eliah Aronoff-Spencer

Mobile applications (apps) can bring health research and its potential downstream benefits closer to underserved populations. Drawing on experience developing an app for detecting and referring cases of cutaneous leishmaniasis in Colombia, called Guaral/app, we review key steps in creating such mobile health (mHealth) tools. These require consideration of the sociotechnical context using methods such as systems analysis and human-centered design (HCD), predicated on engagement and iteration with all stakeholders. We emphasize usability and technical concerns and describe the interdependency of technical and human considerations for mHealth systems in rural communities.

Identification of a host collagen inducing factor from the excretory secretory proteins of <i>Trichinella spiralis</i>

PLoS Neglected Tropical Diseases News - 1 November 2018 - 9:00pm

by Mi Kyung Park, Hae-Jin Kim, Min Kyoung Cho, Shin Ae Kang, So Young Park, Se Bok Jang, Hak Sun Yu

Background

In a previous study, we found that Trichinella spiralis muscle larva excretory and secretory proteins (ES-P) most likely activate collagen synthesis via TGF-β/Smad signaling, and this event could influence collagen capsule formation.

Methodology/Principal findings

In order to identify the specific collagen inducing factor, ES-P was fractionated by a Superdex 200 10/300 GL column. We obtained three large fractions, F1, F2, and F3, but only F3 had collagen gene inducing ability. After immunoscreening, 10 collagen inducing factor candidates were identified. Among them, TS 15–1 and TS 15–2 were identical to the putative trypsin of T. spiralis. The deduced TS 15–1 (M.W. = 72 kDa) had two conserved catalytic motifs, an N-terminal Tryp_SPc domain (TS 15-1n) and a C-terminal Tryp_SPc domain (TS 15-1c). To determine their collagen inducing ability, recombinant proteins (rTS 15-1n and rTS 15-1c) were produced using the pET-28a expression system. TS 15–1 is highly expressed during the muscle larval stage and has strong antigenicity. We determined that rTS 15-1c could elevate collagen I via activation of the TGF-β1 signaling pathway in vitro and in vivo.

Conclusion/Significance

In conclusion, we identified a host collagen inducing factor from T. spiralis ES-P using immunoscreening and demonstrated its molecular characteristics and functions.

Activity profiling of peptidases in <i>Angiostrongylus costaricensis</i> first-stage larvae and adult worms

PLoS Neglected Tropical Diseases News - 31 October 2018 - 9:00pm

by Karina M. Rebello, James H. McKerrow, Ester M. Mota, Anthony J. O´Donoghue, Ana Gisele C. Neves-Ferreira

Background

Angiostrongylus costaricensis is a relatively uncharacterized nematode that causes abdominal angiostrongyliasis in Latin America, a human parasitic disease. Currently, no effective pharmacological treatment for angiostrongyliasis exists. Peptidases are known to be druggable targets for a variety of diseases and are essential for several biological processes in parasites. Therefore, this study aimed to systematically characterize the peptidase activity of A. costaricensis in different developmental stages of this parasitic nematode.

Methodology/Principal findings

A library of diverse tetradecapeptides was incubated with cellular lysates from adult worms and from first-stage larvae (L1) and cleaved peptide products were identified by mass spectrometry. Lysates were also treated with class specific peptidase inhibitors to determine which enzyme class was responsible for the proteolytic activity. Peptidase activity from the four major mechanistic classes (aspartic, metallo, serine and cysteine) were detected in adult worm lysate, whereas aspartic, metallo and serine peptidases were found in the larval lysates. In addition, the substrate specificity profile was found to vary at different pH values.

Conclusions/Significance

The proteolytic activities in adult worm and L1 lysates were characterized using a highly diversified library of peptide substrates and the activity was validated using a selection of fluorescent substrates. Taken together, peptidase signatures for different developmental stages of this parasite has improved our understanding of the disease pathogenesis and may be useful as potential drug targets or vaccine candidates.

Epidemiological characterization of incident cases of <i>Rickettsia</i> infection in rural areas of Urabá region, Colombia

PLoS Neglected Tropical Diseases News - 31 October 2018 - 9:00pm

by Juan Carlos Quintero Vélez, Daniel Camilo Aguirre-Acevedo, Juan David Rodas, Margarita Arboleda, Adriana Troyo, Francisco Vega Aguilar, Lisardo Osorio Quintero, Carlos Rojas Arbeláez

Introduction

Most of the studies related to rickettsial infection in Colombia are cross-sectional because of the challenge in conducting prospective studies on infectious disease that may have a difficult diagnosis. Although cross-sectional studies are essential to detect people exposed to rickettsiae, they are not suited to demonstrate the recent circulation of this pathogen in areas at risk of transmission.

Objective

To characterize the epidemiology of incident cases of Spotted fever group (SFG) rickettsial infection in humans and equines from rural areas of Urabá region in Colombia where outbreaks of rickettsiae previously occurred.

Materials and methods

A prospective study was conducted in the Alto de Mulatos and Las Changas in the Urabá region. Serum samples and socio-ecological information were collected from 597 people enrolled in 2015, and a second sample was collected from 273 people a year later. Indirect immune-fluorescence assays for detection of IgG antibody against rickettsiae were done using slides with Rickettsia rickettsii antigens. A titer ≥128 was considered positive. Incident cases were defined as (i) serological conversion of IgG titers from seronegative to seropositive or (ii) at least a four-fold increase in IgG end point titers in the second sample.

Results

The cumulative incidence of rickettsial infection was 6.23% (95%CI 3.67–9.78) in humans and 32.31% (21/65) of incident cases in equines. Incident cases were mostly females (82.35%), the median age of cases was 41.02 years (IQR 18.62–54.1), and 29.41% reported tick bites during the study period. Results from multivariate analysis showed that removal of ticks after working outdoors is a protective factor for rickettsial infection (RR 0.26, 95%CI 0.08–0.84) and that a higher incidence of infection occurred in people who reported fever in the last year (RR 4.26, 95%CI 1.15–9.31).

Conclusions

These results showed recent circulation of SFG rickettsiae in areas where previous lethal outbreaks have been reported, supporting the implementation of preventive measures to halt rickettsial transmission in the studied communities.

An open label randomized clinical trial comparing the safety and effectiveness of one, two or three weekly pentamidine isethionate doses (seven milligrams per kilogram) in the treatment of cutaneous leishmaniasis in the Amazon Region

PLoS Neglected Tropical Diseases News - 31 October 2018 - 9:00pm

by Ellen Priscilla Nunes Gadelha, Rajendranath Ramasawmy, Bruna da Costa Oliveira, Nágila Moraes Rocha, Jorge Augusto de Oliveira Guerra, George Allan Villa Rouco da Silva, Tirza Gabrielle Ramos de Mesquita, Carolina Chrusciak Talhari Cortez, Anette Chrusciak Talhari

Background

American Cutaneous Leishmaniasis (ACL), a vector borne disease, is caused by various species of Leishmania and in the Amazonas, Leishmania guyanensis is predominant. The recommended drugs for treatment of cutaneous leishmaniasis (CL) in Brazil are pentavalent antimonials, pentamidine isethionate (PI) and amphotericin B. Pentamidine was initially used as metanolsulfonate or mesylate (Lomidine) at a dose of 4 mg/kg/daily, containing 2.3mg of base. This drug was withdrawn from the market in the eighties, and currently is available as PI. The PI dose required to achieve an equivalent dose of pentamidine base is 7 mg/kg, rather than the 4 mg/kg that is currently recommended in Brazil.

Objectives

The aim of this study was to evaluate the efficacy and safety of PI in a single dose, two or three doses of 7 mg/kg body weight, intramuscularly, with an interval of seven days between each dose.

Materials and methods

This study was conducted as a controlled, randomized, open–label clinical trial for a total number of 159 patients with CL. Individuals aged 16–64 years with one to six lesions of confirmed CL based on amastigotes visualization in direct examination of Giemsa stained of dermal scraping from the border of the lesion with no previous treatment for CL and no abnormal values for liver enzymes were eligible to participate in the study. Patients with history of diabetes, cardiac, renal, and hepatic disease as well as pregnant women were excluded. Cure was defined as complete healing in the diameters of the ulcers and lesions skin six months after the end of the treatment.

Results

From November 2013 to December 2015, 159 patients were screened and allocated in three groups for treatment with PI: i) 53 patients were treated with a single dose intramuscularly injection of 7 mg/kg body weight; ii) 53 received two doses of 7 mg/kg within an interval of seven days; and iii) 53 were treated with three doses of 7mg/kg with an interval of seven days between each dose. In 120 patients, L. guyanensis was identified. A cure rate of 45%, 81.1% and 96.2% were observed in the first, second and third group, respectively. The cure in the three PI dose group was higher compared to the single-dose (p<0.0001) and two-dose groups (p = 0.03). No serious adverse events occurred.

Conclusion

The present study shows that PI is a safe drug and its efficacy varied with the number of doses. The administration of PI in patients with ACL, predominantly caused by L. guyanensis, was mostly efficient in three or two doses of 7 mg/kg.

Trial registration

ClinicalTrials.gov NCT02919605

Participatory survey of Rift Valley fever in nomadic pastoral communities of North-central Nigeria: The associated risk pathways and factors

PLoS Neglected Tropical Diseases News - 30 October 2018 - 9:00pm

by Nma Bida Alhaji, Olutayo Olajide Babalobi, Yiltawe Wungak, Hussaini Gulak Ularamu

Background

Rift Valley fever (RVF) is an emerging neglected mosquito-borne viral zoonotic disease of domestic animals and humans, with potential for global expansion. The objectives of this study were: to assess perceived relative burden and seasonality of RVF in nomadic cattle herds and validate the burden with sero-prevalence impact; and assess perceived risk factors associated with the disease and risk pathways for RVF virus in nomadic pastoral herds of North-central Nigeria using pastoralists’ existing veterinary knowledge.

Methods

Participatory Epidemiology (PE) survey was conducted in Fulani nomadic pastoral communities domiciled in Niger State between January and December 2015. A cross-sectional sero-prevalence investigation was also carried out in nomadic pastoral cattle herds to validate outcomes of PE. A total of nine nomadic pastoral communities were purposively selected for qualitative impact assessment using Participatory Rural Appraisal tools, while 97 cattle randomly sampled from 15 purposively selected nomadic herds and had their sera analyzed using c-ELISA. Kendall’s Coefficient of Concordance W statistics and OpenEpi 2.3.1 were used for statistical analyses.

Results

Mean proportional piles (relative burden) of RVF (Gabi-gabiF) was 8.3%, and nomads agreement on the burden was strong (W = 0.6855) and statistically significant (P<0.001). This was validated by 11.3% (11/97; 95% CI: 6.1–18.9) sero-positivity (quantitative impact). Mean matrix scores of prominent clinical signs associated with RVF were fever (3.1), anorexia (2.1), abortion (4.1), nasal discharge (3.3), neurological disorder (8.4), diarrhoea (3.2), and sudden death (4.4), with strong agreement (W = 0.6687) and statistically significant (p<0.001). Mean proportional piles of pastoralists’ perceived risk factors identified to influenced RVF occurrence were: availability of mosquitoes (18 piles, 17.6%), high cattle density (16 piles, 15.9%) and high rainfall (12 piles, 12.2%). Agreement on the risk factors was strong (W = 0.8372) and statistically significant (p<0.01). Mean matrix scores for the Entry pathway of RVF virus into the nomadic pastoral herds were: presence of RVFV infected mosquitoes (tiny biting flies) (7.9), presence of infected cattle in herds (8.4), and contacts of herd with infected wild animals at grazing (10.1). Mean matrix scores for the Spread pathway of RVF virus in herds were bites of infected mosquitoes (5.1), contacts with infected aborted fetuses/fluids (7.8), and contaminated pasture with aborted fetuses/fluids (9.7). Agreement on risk pathways was strong (W = 0.6922) and statistically significant (p<0.03). Key informants scored RVF to occurred more in Damina or late rainy season (5.3), followed by Kaka or early dry season (3.3), with strong agreement (W = 0.8719) and statistically significant (P<0.01). This study highlighted the significant existing knowledge level about RVF contained in nomadic pastoralists.

Conclusions

The use of PE approach is needful in active surveillance of livestock diseases in pastoral communities domiciled in highly remote areas. RVF surveillance system, control and prevention programmes that take the identified risk factors and pathways into consideration will be beneficial to the livestock industry in Nigeria, and indeed Africa. An ‘OneHealth’ approach is needed to improve efficiency of RVF research, surveillance, prevention and control systems, so as to assure food security and public health in developing countries.

<i>SODB1</i> is essential for <i>Leishmania major</i> infection of Macrophages and Pathogenesis in Mice

PLoS Neglected Tropical Diseases News - 29 October 2018 - 9:00pm

by Bennett J. Davenport, Casey G. Martin, Stephen M. Beverley, David J. Orlicky, Andres Vazquez-Torres, Thomas E. Morrison

Leishmania species are sand fly-transmitted protozoan parasites that cause leishmaniasis, neglected tropical diseases that affect millions of people. Leishmania amastigotes must overcome a variety of host defenses, including reactive oxygen species (ROS) produced by the NADPH oxidase. Leishmania species encode three superoxide dismutases (SODs): the mitochondrial SODA and two glycosomal SODs (SODB1 and SODB2). SODs are metalloenzymes that function in antioxidant defense by converting superoxide to oxygen and hydrogen peroxide. Here, we investigated a role for SODB1 in Leishmania infection of macrophages and virulence in mice. We found that a single allele deletion of SODB1 (SODB1/⊗sodb1) had minimal effects on the replication of axenically-grown L. major promastigotes or differentiation to infective metacyclic promastigotes. Disruption of a single SODB1 allele also did not affect L. donovani differentiation to amastigotes induced axenically, or the replication of axenically-grown L. donovani promastigotes and amastigotes. In contrast, the persistence of SODB1/⊗sodb1 L. major in WT macrophages was impaired, and the development of cutaneous lesions in SODB1/⊗sodb1 L. major-infected C57BL/6 and BALB/c mice was strongly reduced. The reduced disease severity in mice was associated with reduced burdens of SODB1/⊗sodb1 L. major parasites in the foot at late, but not early times post-inoculation, as well as an impaired capacity to disseminate from the site of inoculation. Collectively, these data suggest that SODB1 is critical for L. major persistence in macrophages and virulence in mice.

Clinical and microscopic predictors of <i>Entamoeba histolytica</i> intestinal infection in travelers and migrants diagnosed with <i>Entamoeba histolytica/dispar</i> infection

PLoS Neglected Tropical Diseases News - 29 October 2018 - 9:00pm

by Steven Van Den Broucke, Jacob Verschueren, Marjan Van Esbroeck, Emmanuel Bottieau, Jef Van den Ende

Background

Amebiasis is a protozoal infection caused by Entamoeba histolytica, while the morphologically indistinguishable E. dispar is considered as non-pathogenic. Polymerase chain reaction (PCR) assays are necessary to differentiate both species. The most common clinical presentations of E. histolytica disease are amebic colitis and amebic liver abscess, but asymptomatic infection is also possible. We assessed the frequency and pattern of clinical symptoms and microscopic features in travelers/migrants associated with E. histolytica intestinal infection and compared them to those found in individuals with E. dispar infection.

Methods

We conducted a retrospective study at the travel clinic of the Institute of Tropical Medicine, Antwerp, Belgium on travelers/migrants found from 2006 to 2016 positive for Entamoeba histolytica/dispar through antigen detection and/or through microscopy confirmed by PCR. All files of individuals with a positive PCR for E. histolytica (= cases) and a random selection of an equal number of Entamoeba dispar carriers (= controls) were reviewed. We calculated the sensitivity, specificity and likelihood ratios (LRs) of clinical symptoms (blood in stool, mucus in stool, watery diarrhea, abdominal cramps, fever or any of these 5 symptoms) and of microscopic features (presence of trophozoites in direct and in sodium acetate-acetic acid-formalin (SAF)-fixed stool smears) to discriminate between E. histolytica and E. dispar infection.

Results

Of all stool samples positive for Entamoeba histolytica/dispar for which PCR was performed (n = 810), 30 (3.7%) were true E. histolytica infections, of which 39% were asymptomatic. Sensitivity, specificity and positive LRs were 30%, 100% and 300 (p 0.007) for presence of blood in stool; 22%, 100% and 222 (p 0.03) for mucus in stool; 44%, 90% and 4.7 (p 0.009) for cramps and 14%, 97% and 4.8 (p = 0.02) for trophozoites in direct smears. For watery diarrhea, fever and for trophozoites in SAF fixated smears results were non-significant.

Conclusions

E. histolytica infection was demonstrated in a small proportion of travelers/migrants with evidence of Entamoeba histolytica/dispar infection. In this group, history of blood and mucus in stool and cramps had good to strong confirming power (LR+) for actual E. histolytica infection. Trophozoites were also predictive for true E. histolytica infection but in direct smears only.

Development of reverse genetics systems and investigation of host response antagonism and reassortment potential for Cache Valley and Kairi viruses, two emerging orthobunyaviruses of the Americas

PLoS Neglected Tropical Diseases News - 29 October 2018 - 9:00pm

by James I. Dunlop, Agnieszka M. Szemiel, Aitor Navarro, Gavin S. Wilkie, Lily Tong, Sejal Modha, Daniel Mair, Vattipally B. Sreenu, Ana Da Silva Filipe, Ping Li, Yan-Jang S. Huang, Benjamin Brennan, Joseph Hughes, Dana L. Vanlandingham, Stephen Higgs, Richard M. Elliott, Alain Kohl

Orthobunyaviruses such as Cache Valley virus (CVV) and Kairi virus (KRIV) are important animal pathogens. Periodic outbreaks of CVV have resulted in the significant loss of lambs on North American farms, whilst KRIV has mainly been detected in South and Central America with little overlap in geographical range. Vaccines or treatments for these viruses are unavailable. One approach to develop novel vaccine candidates is based on the use of reverse genetics to produce attenuated viruses that elicit immune responses but cannot revert to full virulence. The full genomes of both viruses were sequenced to obtain up to date genome sequence information. Following sequencing, minigenome systems and reverse genetics systems for both CVV and KRIV were developed. Both CVV and KRIV showed a wide in vitro cell host range, with BHK-21 cells a suitable host cell line for virus propagation and titration. To develop attenuated viruses, the open reading frames of the NSs proteins were disrupted. The recombinant viruses with no NSs protein expression induced the production of type I interferon (IFN), indicating that for both viruses NSs functions as an IFN antagonist and that such attenuated viruses could form the basis for attenuated viral vaccines. To assess the potential for reassortment between CVV and KRIV, which could be relevant during vaccination campaigns in areas of overlap, we attempted to produce M segment reassortants by reverse genetics. We were unable to obtain such viruses, suggesting that it is an unlikely event.

Seroprevalence for the tick-borne relapsing fever spirochete <i>Borrelia turicatae</i> among small and medium sized mammals of Texas

PLoS Neglected Tropical Diseases News - 29 October 2018 - 9:00pm

by Brittany A. Armstrong, Alexander Kneubehl, Aparna Krishnavajhala, Hannah K. Wilder, William Boyle, Edward Wozniak, Carson Phillips, Kristen Hollywood, Kristy O. Murray, Taylor G. Donaldson, Pete D. Teel, Ken Waldrup, Job E. Lopez

Background

In low elevation arid regions throughout the Southern United States, Borrelia turicatae is the principal agent of tick-borne relapsing fever. However, endemic foci and the vertebrate hosts involved in the ecology of B. turicatae remain undefined. Experimental infection studies suggest that small and medium sized mammals likely maintain B. turicatae in nature, while the tick vector is a long-lived reservoir.

Methodology/principal findings

Serum samples from wild caught rodents, raccoons, and wild and domestic canids from 23 counties in Texas were screened for prior exposure to B. turicatae. Serological assays were performed using B. turicatae protein lysates and recombinant Borrelia immunogenic protein A (rBipA), a diagnostic protein that is unique to RF spirochetes and may be a species-specific antigen.

Conclusions/significance

Serological responses to B. turicatae were detected from 24 coyotes, one gray fox, two raccoons, and one rodent from six counties in Texas. These studies indicate that wild canids and raccoons were exposed to B. turicatae and are likely involved in the pathogen’s ecology. Additionally, more work should focus on evaluating rodent exposure to B. turicatae and the role of these small mammals in the pathogen’s maintenance in nature.

A simian-adenovirus-vectored rabies vaccine suitable for thermostabilisation and clinical development for low-cost single-dose pre-exposure prophylaxis

PLoS Neglected Tropical Diseases News - 29 October 2018 - 9:00pm

by Chuan Wang, Pawan Dulal, Xiangyang Zhou, Zhiquan Xiang, Hooman Goharriz, Ashley Banyard, Nicky Green, Livia Brunner, Roland Ventura, Nicolas Collin, Simon J. Draper, Adrian V. S. Hill, Rebecca Ashfield, Anthony R. Fooks, Hildegund C. Ertl, Alexander D. Douglas

Background

Estimates of current global rabies mortality range from 26,000 to 59,000 deaths per annum. Although pre-exposure prophylaxis using inactivated rabies virus vaccines (IRVs) is effective, it requires two to three doses and is regarded as being too expensive and impractical for inclusion in routine childhood immunization programmes.

Methodology/ Principal findings

Here we report the development of a simian-adenovirus-vectored rabies vaccine intended to enable cost-effective population-wide pre-exposure prophylaxis against rabies. ChAdOx2 RabG uses the chimpanzee adenovirus serotype 68 (AdC68) backbone previously shown to achieve pre-exposure protection against rabies in non-human primates. ChAdOx2 differs from AdC68 in that it contains the human adenovirus serotype 5 (AdHu5) E4 orf6/7 region in place of the AdC68 equivalents, enhancing ease of manufacturing in cell lines which provide AdHu5 E1 proteins in trans.We show that immunogenicity of ChAdOx2 RabG in mice is comparable to that of AdC68 RabG and other adenovirus serotypes expressing rabies virus glycoprotein. High titers of rabies virus neutralizing antibody (VNA) are elicited after a single dose. The relationship between levels of VNA activity and rabies virus glycoprotein monomer-binding antibody differs after immunization with adenovirus-vectored vaccines and IRV vaccines, suggesting routes to further enhancement of the efficacy of the adenovirus-vectored candidates. We also demonstrate that ChAdOx2 RabG can be thermostabilised using a low-cost method suitable for clinical bio-manufacture and ambient-temperature distribution in tropical climates. Finally, we show that a dose-sparing effect can be achieved by formulating ChAdOx2 RabG with a simple chemical adjuvant. This approach could lower the cost of ChAdOx2 RabG and other adenovirus-vectored vaccines.

Conclusions/ Significance

ChAdOx2 RabG may prove to be a useful tool to reduce the human rabies death toll. We have secured funding for Good Manufacturing Practice- compliant bio-manufacture and Phase I clinical trial of this candidate.

Designed mono- and di-covalent inhibitors trap modeled functional motions for <i>Trypanosoma cruzi</i> proline racemase in crystallography

PLoS Neglected Tropical Diseases News - 29 October 2018 - 9:00pm

by Patricia de Aguiar Amaral, Delphine Autheman, Guilherme Dias de Melo, Nicolas Gouault, Jean-François Cupif, Sophie Goyard, Patricia Dutra, Nicolas Coatnoan, Alain Cosson, Damien Monet, Frederick Saul, Ahmed Haouz, Philippe Uriac, Arnaud Blondel, Paola Minoprio

Chagas disease, caused by Trypanosoma cruzi, affects millions of people in South America and no satisfactory therapy exists, especially for its life threatening chronic phase. We targeted the Proline Racemase of T. cruzi, which is present in all stages of the parasite life cycle, to discover new inhibitors against this disease. The first published crystal structures of the enzyme revealed that the catalytic site is too small to allow any relevant drug design. In previous work, to break through the chemical space afforded to virtual screening and drug design, we generated intermediate models between the open (ligand free) and closed (ligand bound) forms of the enzyme. In the present work, we co-crystallized the enzyme with the selected inhibitors and found that they were covalently bound to the catalytic cysteine residues in the active site, thus explaining why these compounds act as irreversible inhibitors. These results led us to the design of a novel, more potent specific inhibitor, NG-P27. Co-crystallization of this new inhibitor with the enzyme allowed us to confirm the predicted protein functional motions and further characterize the chemical mechanism. Hence, the catalytic Cys300 sulfur atom of the enzyme attacks the C2 carbon of the inhibitor in a coupled, regiospecific—stereospecific Michael reaction with trans-addition of a proton on the C3 carbon. Strikingly, the six different conformations of the catalytic site in the crystal structures reported in this work had key similarities to our intermediate models previously genrated by inference of the protein functional motions. These crystal structures span a conformational interval covering roughly the first quarter of the opening mechanism, demonstrating the relevance of modeling approaches to break through chemical space in drug design.

Spatial-temporal clustering analysis of yaws on Lihir Island, Papua New Guinea to enhance planning and implementation of eradication programs

PLoS Neglected Tropical Diseases News - 29 October 2018 - 9:00pm

by Eric Q. Mooring, Oriol Mitjà, Megan B. Murray

Background

In the global program for the eradication of yaws, assessments of the prevalence of the disease are used to decide where to initiate mass treatment. However, the smallest administrative unit that should be used as the basis for making decisions is not clear. We investigated spatial and temporal clustering of yaws to help inform the choice of implementation unit.

Methodology/Principal findings

We analyzed 11 years of passive surveillance data on incident yaws cases (n = 1448) from Lihir Island, Papua New Guinea. After adjusting for age, sex, and trends in health-seeking, we detected three non-overlapping spatial-temporal clusters (p < 1 × 10−17, p = 1.4 × 10−14, p = 1.4 × 10−8). These lasted from 28 to 47 months in duration and each encompassed between 4 and 6 villages. We also assessed spatial clustering of prevalent yaws cases (n = 532) that had been detected in 7 biannual active case finding surveys beginning in 2013. We identified 1 statistically significant cluster in each survey. We considered the possibility that schools that serve multiple villages might be loci of transmission, but we found no evidence that incident cases of yaws among 8- to 14-year-olds clustered within primary school attendance areas (p = 0.6846).

Conclusions/Significance

These clusters likely reflect transmission of yaws across village boundaries; villages may be epidemiologically linked to a degree such that mass drug administration may be more effectively implemented at a spatial scale larger than the individual village.

Spatial prediction of risk areas for vector transmission of <i>Trypanosoma cruzi</i> in the State of Paraná, southern Brazil

PLoS Neglected Tropical Diseases News - 26 October 2018 - 9:00pm

by Andréia Mantovani Ferro e Silva, Thadeu Sobral-Souza, Maurício Humberto Vancine, Renata Lara Muylaert, Ana Paula de Abreu, Sandra Marisa Pelloso, Maria Dalva de Barros Carvalho, Luciano de Andrade, Milton Cezar Ribeiro, Max Jean de Ornelas Toledo

After obtaining certification of the absence of transmission of the Trypanosoma cruzi by Triatoma infestans in 2006, other native species of protozoan vectors have been found in human dwellings within municipalities of the State of Paraná, Southern Brazil. However, the spatial distribution of T. cruzi vectors and how climatic and landscape combined variables explain the distribution are still poorly understood. The goal of this study was to predict the potential distribution of T. cruzi vectors as a proxy for Chagas disease transmission risk using Ecological Niche Models (ENMs) based on climatic and landscape variables. We hypothesize that ENM based on both climate and landscape variables are more powerful than climate-only or landscape-only models, and that this will be true independent of vector species. A total of 2,662 records of triatomines of five species were obtained by community-based entomological surveillance from 2007 to 2013. The species with the highest number of specimens was Panstrongylus megistus (73%; n = 1,943), followed by Panstrongylus geniculatus (15.4%; 411), Rhodnius neglectus (6.0%; 159), Triatoma sordida (4.5%; 119) and Rhodnius prolixus (1.1%; 30). Of the total, 71.9% were captured at the intradomicile. T. cruzi infection was observed in 19.7% of the 2,472 examined insects. ENMs were generated based on selected climate and landscape variables with 1 km2 spatial resolution. Zonal statistics were used for classifying the municipalities as to the risk of occurrence of synanthropic triatomines. The integrated analysis of the climate and landscape suitability on triatomines geographical distribution was powerful on generating good predictive models. Moreover, this showed that some municipalities in the northwest, north and northeast of the Paraná state have a higher risk of T. cruzi vector transmission. This occurs because those regions present high climatic and landscape suitability values for occurrence of their vectors. The frequent invasion of houses by infected triatomines clearly indicates a greater risk of transmission of T. cruzi to the inhabitants. More public health attention should be given in the northern areas of the State of Paraná, which presents high climate and landscape suitabilities for the disease vectors. In conclusion, our results–through spatial analysis and predictive maps–showed to be effective in identifying areas of potential distribution and, consequently, in the definition of strategic areas and actions to prevent new cases of Chagas' disease, reinforcing the need for continuous and robust surveillance in these areas.

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