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Validity and reliability of telephone administration of the patient specific functional scale for the assessment of recovery from snakebite envenomation

PLoS Neglected Tropical Diseases News - 13 December 2019 - 10:00pm

by Rebecca G. Theophanous, Joao Ricardo Nickenig Vissoci, Fan Hui Wen, S. Michelle Griffin, Victoria E. Anderson, Michael E. Mullins, Nicklaus P. Brandehoff, Eugenia B. Quackenbush, Sean P. Bush, Eric A. Toschlog, Spencer C. Greene, Kapil Sharma, Kurt Kleinschmidt, Nathan P. Charlton, S. Rutherfoord Rose, Richard Schwartz, Brandon Lewis, Eric J. Lavonas, Charles J. Gerardo

Objectives

Although more than 1.8 million people survive snakebite envenomation each year, their recovery is understudied. Obtaining long-term follow-up is challenging in both high- and low-resource settings. The Patient-Specific Functional Scale (PSFS) is an easily administered, well-accepted patient-reported outcome that is validated for assessing limb recovery from snakebite envenomation. We studied whether the PSFS is valid and reliable when administered by telephone.

Methods

This is a secondary analysis of data from a randomized clinical trial. We analyzed the results of PSFS collected in-person on days 3, 7, 14, 21, and 28 and by telephone on days 10, 17, and 24. We assessed the following scale psychometric properties: (a) content validity (ceiling and floor effects), (b) internal structure and consistency (Cronbach’s alpha), and (c) temporal and external validity using Intraclass Correlation Coefficient (ICC). Temporal stability was assessed using Spearman’s correlation coefficient and agreement between adjacent in-person and telephonic assessments with Cohen’s kappa. Bland Altman analysis was used to assess differential bias in low and high score results.

Results

Data from 74 patients were available for analysis. Floor effects were seen in the early post-injury time points (median: 3 (IQR: 0, 5) at 3 days post-enrollment) and ceiling effects in the late time points (median: 9 (IQR: 8, 10). Internal consistency was good to excellent with both in-person (Cronbach α: 0.91 (95%CI 0.88, 0.95)) and telephone administration (0.81 (0.73, 0.89). Temporal stability was also good (ICC: 0.83 (0.72, 0.89) in-person, 0.80 (0.68, 0.88) telephone). A strong linear correlation was found between in-person and telephone administration (Spearman’s ρ: 0.83 (CI: 0.78, 0.84), consistency was assessed as excellent (Cohen’s κ 0.81 (CI: 0.78, 0.84), and Bland Altman analysis showed no systematic bias.

Conclusions

Telephone administration of the PSFS provides valid, reliable, and consistent data for the assessment of recovery from snakebite envenomation.

<i>Trypanosoma cruzi</i> transmission dynamics in a synanthropic and domesticated host community

PLoS Neglected Tropical Diseases News - 13 December 2019 - 10:00pm

by Alheli Flores-Ferrer, Etienne Waleckx, Guilhem Rascalou, Eric Dumonteil, Sébastien Gourbière

Trypanosoma cruzi is the causative agent of Chagas disease, a Neglected Tropical Disease affecting 8 million people in the Americas. Triatomine hematophagous vectors feed on a high diversity of vertebrate species that can be reservoirs or dead-end hosts, such as avian species refractory to T. cruzi. To understand its transmission dynamics in synanthropic and domesticated species living within villages is essential to quantify disease risk and assess the potential of zooprophylaxis. We developed a SI model of T. cruzi transmission in a multi-host community where vector reproduction and parasite transmission depend on a triatomine blood-feeding rate accounting for vector host preferences and interference while feeding. The model was parameterized to describe T. cruzi transmission in villages of the Yucatan peninsula, Mexico, using the information about Triatoma dimidiata vectors and host populations accumulated over the past 15 years. Extensive analyses of the model showed that dogs are key reservoirs and contributors to human infection, as compared to synanthropic rodents and cats, while chickens or other domesticated avian hosts dilute T. cruzi transmission despite increasing vector abundance. In this context, reducing the number of dogs or increasing avian hosts abundance decreases incidence in humans by up to 56% and 39%, respectively, while combining such changes reduces incidence by 71%. Although such effects are only reached over >10-years periods, they represent important considerations to be included in the design of cost-effective Integrated Vector Management. The concomitant reduction in T. cruzi vector prevalence estimated by simulating these zooprophylactic interventions could indeed complement the removal of colonies from the peridomiciles or the use of insect screens that lower vector indoor abundance by ~60% and ~80%. These new findings reinforce the idea that education and community empowerment to reduce basic risk factors is a cornerstone to reach and sustain the key objective of interrupting Chagas disease intra-domiciliary transmission.

Optimising targets for tsetse control: Taking a fly’s-eye-view to improve the colour of synthetic fabrics

PLoS Neglected Tropical Diseases News - 12 December 2019 - 10:00pm

by Roger D. Santer, Glyn A. Vale, David Tsikire, Steve J. Torr

The savannah tsetse flies, Glossina morsitans morsitans and G. pallidipes, are important vectors of Rhodesian human African trypanosomiasis and animal African trypanosomiasis in East and southern Africa. We tested in Zimbabwe whether robust, synthetic fabrics, and innovative fly’s-eye-view approaches to optimise fabric colour, can improve insecticide-treated targets employed for tsetse control. Flies were caught by electrocution at a standard target comprising a 1m x 1m black cotton cloth panel with 1m x 0.5m black polyester net panels on each side. Catches were subdivided by species and sex. Tsetse catches were unaffected by substitution of the black cotton with a blue polyester produced for riverine tsetse targets. Exchanging the net panels for phthalogen blue cotton to simulate the target routinely used in Zimbabwe significantly reduced catches of female G. m. morsitans (mean catch 0.7 times that at standard), with no effect on other tsetse catches. However, significantly greater proportions of the catch were intercepted at the central panel of the Zimbabwe (means 0.47–0.79) versus standard designs (0.11–0.29). We also engineered a new violet polyester cloth using models of tsetse attraction based upon fly photoreceptor responses. With and without odour lure, catches of females of both species at the violet target were significantly greater than those at standard (means 1.5–1.6 times those at standard), and typical blue polyester targets (means 0.9–1.3 times those at standard). Similar effects were observed for males under some combinations of species and odour treatment. The proportions of catch intercepted at the central panel of the violet target (means 0.08–0.18) were intermediate between those at standard and typical blue polyester. Further, the reflectance spectrum of violet polyester was more stable under field conditions than that of black cotton. Our results demonstrate the effectiveness of photoreceptor-based models as a novel means of improving targets to control tsetse and trypanosomiases.

Genomes of <i>Leishmania</i> parasites directly sequenced from patients with visceral leishmaniasis in the Indian subcontinent

PLoS Neglected Tropical Diseases News - 12 December 2019 - 10:00pm

by Malgorzata A. Domagalska, Hideo Imamura, Mandy Sanders, Frederik Van den Broeck, Narayan Raj Bhattarai, Manu Vanaerschot, Ilse Maes, Erika D’Haenens, Keshav Rai, Suman Rijal, Matthew Berriman, James A. Cotton, Jean-Claude Dujardin

Whole genome sequencing (WGS) is increasingly used for molecular diagnosis and epidemiology of infectious diseases. Current Leishmania genomic studies rely on DNA extracted from cultured parasites, which might introduce sampling and biological biases into the subsequent analyses. Up to now, direct analysis of Leishmania genome in clinical samples is hampered by high levels of human DNA and large variation in parasite load in clinical samples. Here, we present a method, based on target enrichment of Leishmania donovani DNA with Agilent SureSelect technology, that allows the analysis of Leishmania genomes directly in clinical samples. We validated our protocol with a set of artificially mixed samples, followed by the analysis of 63 clinical samples (bone marrow or spleen aspirates) from visceral leishmaniasis patients in Nepal. We were able to identify genotypes using a set of diagnostic SNPs in almost all of these samples (97%) and access comprehensive genome-wide information in most (83%). This allowed us to perform phylogenomic analysis, assess chromosome copy number and identify large copy number variants (CNVs). Pairwise comparisons between the parasite genomes in clinical samples and derived in vitro cultured promastigotes showed a lower aneuploidy in amastigotes as well as genomic differences, suggesting polyclonal infections in patients. Altogether our results underline the need for sequencing parasite genomes directly in the host samples

Distribution of insecticide resistance and mechanisms involved in the arbovirus vector <i>Aedes aegypti</i> in Laos and implication for vector control

PLoS Neglected Tropical Diseases News - 12 December 2019 - 10:00pm

by Sébastien Marcombe, Bénédicte Fustec, Julien Cattel, Somesanith Chonephetsarath, Phoutmany Thammavong, Nothasin Phommavanh, Jean-Philippe David, Vincent Corbel, Ian W. Sutherland, Jeffrey C. Hertz, Paul T. Brey

Background

The yellow fever mosquito Aedes aegypti is the major vector of dengue, yellow fever, Zika, and Chikungunya viruses. Worldwide vector control is largely based on insecticide treatments but, unfortunately, vector control programs are facing operational challenges due to mosquitoes becoming resistant to commonly used insecticides. In Southeast Asia, resistance of Ae. aegypti to chemical insecticides has been documented in several countries but no data regarding insecticide resistance has been reported in Laos. To fill this gap, we assessed the insecticide resistance of 11 Ae. aegypti populations to larvicides and adulticides used in public health operations in the country. We also investigated the underlying molecular mechanisms associated with resistance, including target site mutations and detoxification enzymes putatively involved in metabolic resistance.

Methods & results

Bioassays on adults and larvae collected in five provinces revealed various levels of resistance to organophosphates (malathion and temephos), organochlorine (DDT) and pyrethroids (permethrin and deltamethrin). Synergist bioassays showed a significant increased susceptibility of mosquitoes to insecticides after exposure to detoxification enzyme inhibitors. Biochemical assays confirmed these results by showing significant elevated activities of cytochrome P450 monooxygenases (P450), glutathione S-transferases (GST) and carboxylesterases (CCE) in adults. Two kdr mutations, V1016G and F1534C, were detected by qPCR at low and high frequency, respectively, in all populations tested. A significant negative association between the two kdr mutations was detected. No significant association between kdr mutations frequency (for both 1534C and 1016G) and survival rate to DDT or permethrin (P > 0.05) was detected. Gene Copy Number Variations (CNV) were detected for particular detoxification enzymes. At the population level, the presence of CNV affecting the carboxylesterase CCEAE3A and the two cytochrome P450 CYP6BB2 and CYP6P12 were significantly correlated to insecticide resistance.

Conclusions

These results suggest that both kdr mutations and metabolic resistance mechanisms are present in Laos but their impact on phenotypic resistance may differ in proportion at the population or individual level. Molecular analyses suggest that CNV affecting CCEAE3A previously associated with temephos resistance is also associated with malathion resistance while CNV affecting CYP6BB2 and CYP6P12 are associated with pyrethroid and possibly DDT resistance. The presence of high levels of insecticide resistance in the main arbovirus vector in Laos is worrying and may have important implications for dengue vector control in the country.

Gender-related factors affecting health seeking for neglected tropical diseases: findings from a qualitative study in Ethiopia

PLoS Neglected Tropical Diseases News - 12 December 2019 - 10:00pm

by Alexandra Wharton-Smith, Christian Rassi, Esey Batisso, Giuseppina Ortu, Rebecca King, Misganu Endriyas, Helen Counihan, Prudence Hamade, Dawit Getachew

Background

Despite known gender-specific differences in terms of prevalence, transmission and exposure to neglected tropical diseases (NTDs), there is limited discussion of the influence of gender in NTD programmes and interventions. There is a paucity of research on how gender interacts with NTD service provision and uptake. This study, part of broader implementation research in Ethiopia, applied a gender lens to health seeking for five NTDs: lymphatic filariasis, podoconiosis, schistosomiasis, soil-transmitted helminth infection and trachoma.

Methodology/principal findings

The study was conducted in a district of the Southern Nations, Nationalities, and Peoples' Region of Ethiopia where the five NTDs are prevalent. A qualitative methodology was adopted to explore participants’ perspectives and experiences. Data generation methods included 20 interviews and four focus group discussions. Community members, volunteer Health Development Army leaders, Health Extension Workers and a range of health workers at the health post, health centre and hospital level (n = 59) were purposively sampled. Interviews and focus group discussions were audio recorded, transcribed verbatim into English then analysed through open coding, drawing on constant comparative methods.Gender related factors affected care seeking for NTDs and were described as reasons for not seeking care, delayed care seeking and treating NTDs with natural remedies. Women faced additional challenges in seeking health care due to gender inequalities and power dynamics in their domestic partnerships. Participants recommended raising community awareness about NTDs, however this remains problematic due to gender and social norms around appropriate discourse with members of the opposite gender.

Conclusions/significance

The findings from this study provide crucial insights into how gender interacts with accessing health services, at different levels of the health system. If we are committed to leaving no one behind and achieving universal health coverage, it is essential to address gender disparities to access and utilisation of interventions delivered by national NTD programmes.

Cutaneous leishmaniasis in Syria: A review of available data during the war years: 2011–2018

PLoS Neglected Tropical Diseases News - 12 December 2019 - 10:00pm

by Ghada Muhjazi, Albis Francesco Gabrielli, José Antonio Ruiz-Postigo, Hoda Atta, Mona Osman, Hyam Bashour, Atef Al Tawil, Hania Husseiny, Rasmieh Allahham, Richard Allan

Background

Cutaneous leishmaniasis (CL) has historically been reported from Syria. Since 2011, the country has been affected by a war, which has impacted health and health services. Over the same period, an increase in the number of cases of CL has been reported from several areas across the country and by a number of authors. This study aims to provide the first quantitative evidence of the epidemiological evolution of CL in Syria during the war.

Materials and methods

Data on number of CL cases for the period 2011–2018 were extracted from three different surveillance systems: the Ministry of Health (MoH) routine surveillance system, the MoH/WHO sentinel-syndromic Early Warning Alert and Response System (EWARS), and surveillance data collected by the international nongovernmental organization (NGO) the MENTOR Initiative. Data were cleaned and merged to generate the best possible estimates on number of CL cases; incidence of CL was also calculated based on data on resident population. Data reported from the years preceding the conflict (2007–2010) were also added to the analysis for comparative purposes.

Results

The analysis of data from the three available sources over the period considered indicates that number of reported cases progressively grew from prewar levels to reach a peak in 2015, decreased in 2016, remained stable in 2017, and increased again in 2018. Such a trend was mirrored by changes in incidence of infection. Some governorates, which used to report low numbers of CL cases, started recording higher number of cases after the onset of the war.

Conclusion

The war coincided with a major rise in reported number of CL cases and incidence of infection, although an increasing trend was already appreciable before its onset.

Predicting and designing therapeutics against the Nipah virus

PLoS Neglected Tropical Diseases News - 12 December 2019 - 10:00pm

by Neeladri Sen, Tejashree Rajaram Kanitkar, Ankit Animesh Roy, Neelesh Soni, Kaustubh Amritkar, Shreyas Supekar, Sanjana Nair, Gulzar Singh, M. S. Madhusudhan

Despite Nipah virus outbreaks having high mortality rates (>70% in Southeast Asia), there are no licensed drugs against it. In this study, we have considered all 9 Nipah proteins as potential therapeutic targets and computationally identified 4 putative peptide inhibitors (against G, F and M proteins) and 146 small molecule inhibitors (against F, G, M, N, and P proteins). The computations include extensive homology/ab initio modeling, peptide design and small molecule docking. An important contribution of this study is the increased structural characterization of Nipah proteins by approximately 90% of what is deposited in the PDB. In addition, we have carried out molecular dynamics simulations on all the designed protein-peptide complexes and on 13 of the top shortlisted small molecule ligands to check for stability and to estimate binding strengths. Details, including atomic coordinates of all the proteins and their ligand bound complexes, can be accessed at http://cospi.iiserpune.ac.in/Nipah. Our strategy was to tackle the development of therapeutics on a proteome wide scale and the lead compounds identified could be attractive starting points for drug development. To counter the threat of drug resistance, we have analysed the sequences of the viral strains from different outbreaks, to check whether they would be sensitive to the binding of the proposed inhibitors.

Proficiency test for rabies serology: A design complying with international standards for a reliable assessment of participating laboratories

PLoS Neglected Tropical Diseases News - 11 December 2019 - 10:00pm

by Marine Wasniewski, Michel Laurentie, Franca Rizzo, Alexandre Servat, Michel Aubert, Florence Cliquet

Background

Domestic carnivores can introduce rabies into disease-free countries or areas if they are incubating the disease and transported during the pre-symptomatic period. For pets moved into the European Union, the European Commission decided to establish a system of community approval of laboratories willing to carry out the rabies serological controls to guarantee an effective control system. As the specific institute to coordinate the approval of the laboratories, designated by the European Commission in 2000, our laboratory organizes annual proficiency tests (PT) for laboratories already agreed or willing to be agreed to perform rabies serological controls (by detecting rabies virus neutralizing antibodies only) in the frame of international trade.

Methodology/Principal findings

The assessment criteria of this PT rely on the analysis of the specificity and the intra-laboratory consistency. The approach used to evaluate the degree of laboratory consistency is based on the use of compiled data obtained from previous PT campaigns, and is measured by the quality of a regression model. By using historical data for calculating assigned values and associated standard deviations, instead of values obtained from only one campaign, they became robust without any additional statistical treatment. In the present paper, more than 800 historical values were compiled for each of the regression parameters.

Conclusions/Significance

Since the beginning of these PT schemes in 1999, the overall percentage of failing laboratories remained stable over the years (4.1%) while the number of participants increased to 79 in 2018. This highlighted the robustness and the consistency of the statistical analyses used to assess the laboratory’s performance over the years. The improvements carried out and the consistency of our statistical analyses have resulted in the compliance of the rabies serology PT with the ISO/IEC 17043 and ISO 13528:2015 International Standards.

IL-4/IL-13 polarization of macrophages enhances Ebola virus glycoprotein-dependent infection

PLoS Neglected Tropical Diseases News - 11 December 2019 - 10:00pm

by Kai J. Rogers, Bethany Brunton, Laura Mallinger, Dana Bohan, Kristina M. Sevcik, Jing Chen, Natalie Ruggio, Wendy Maury

Background

Ebolavirus (EBOV) outbreaks, while sporadic, cause tremendous morbidity and mortality. No therapeutics or vaccines are currently licensed; however, a vaccine has shown promise in clinical trials. A critical step towards development of effective therapeutics is a better understanding of factors that govern host susceptibility to this pathogen. As macrophages are an important cell population targeted during virus replication, we explore the effect of cytokine polarization on macrophage infection.

Methods/Main findings

We utilized a BSL2 EBOV model virus, infectious, recombinant vesicular stomatitis virus encoding EBOV glycoprotein (GP) (rVSV/EBOV GP) in place of its native glycoprotein. Macrophages polarized towards a M2-like anti-inflammatory state by combined IL-4 and IL-13 treatment were more susceptible to rVSV/EBOV GP, but not to wild-type VSV (rVSV/G), suggesting that EBOV GP-dependent entry events were enhanced by these cytokines. Examination of RNA expression of known surface receptors that bind and internalize filoviruses demonstrated that IL-4/IL-13 stimulated expression of the C-type lectin receptor DC-SIGN in human macrophages and addition of the competitive inhibitor mannan abrogated IL-4/IL-13 enhanced infection. Two murine DC-SIGN-like family members, SIGNR3 and SIGNR5, were upregulated by IL-4/IL-13 in murine macrophages, but only SIGNR3 enhanced virus infection in a mannan-inhibited manner, suggesting that murine SIGNR3 plays a similar role to human DC-SIGN. In vivo IL-4/IL-13 administration significantly increased virus-mediated mortality in a mouse model and transfer of ex vivo IL-4/IL-13-treated murine peritoneal macrophages into the peritoneal cavity of mice enhanced pathogenesis.

Significance

These studies highlight the ability of macrophage polarization to influence EBOV GP-dependent virus replication in vivo and ex vivo, with M2a polarization upregulating cell surface receptor expression and thereby enhancing virus replication. Our findings provide an increased understanding of the host factors in macrophages governing susceptibility to filoviruses and identify novel murine receptors mediating EBOV entry.

Genetic diversity of laboratory strains and implications for research: The case of <i>Aedes aegypti</i>

PLoS Neglected Tropical Diseases News - 9 December 2019 - 10:00pm

by Andrea Gloria-Soria, John Soghigian, David Kellner, Jeffrey R. Powell

The yellow fever mosquito (Aedes aegypti), is the primary vector of dengue, Zika, and chikungunya fever, among other arboviral diseases. It is also a popular laboratory model in vector biology due to its ease of rearing and manipulation in the lab. Established laboratory strains have been used worldwide in thousands of studies for decades. Laboratory evolution of reference strains and contamination among strains are potential severe problems that could dramatically change experimental outcomes and thus is a concern in vector biology. We analyzed laboratory and field colonies of Ae. aegypti and an Ae. aegypti-derived cell line (Aag2) using 12 microsatellites and ~20,000 SNPs to determine the extent of divergence among laboratory strains and relationships to their wild relatives. We found that 1) laboratory populations are less genetically variable than their field counterparts; 2) colonies bearing the same name obtained from different laboratories may be highly divergent; 3) present genetic composition of the LVP strain used as the genome reference is incompatible with its presumed origin; 4) we document changes in two wild caught colonies over ~16 generations of colonization; and 5) the Aag2 Ae. aegypti cell line has experienced minimal genetic changes within and across laboratories. These results illustrate the degree of variability within and among strains of Ae. aegypti, with implications for cross-study comparisons, and highlight the need of a common mosquito repository and the implementation of strain validation tools.

Helminth-induced Th2 cell dysfunction is distinct from exhaustion and is maintained in the absence of antigen

PLoS Neglected Tropical Diseases News - 9 December 2019 - 10:00pm

by Johanna A. Knipper, Alasdair Ivens, Matthew D. Taylor

T cell-intrinsic regulation, such as anergy, adaptive tolerance and exhaustion, is central to immune regulation. In contrast to Type 1 and Type 17 settings, knowledge of the intrinsic fate and function of Th2 cells in chronic Type 2 immune responses is lacking. We previously showed that Th2 cells develop a PD-1/PD-L2-dependent intrinsically hypo-responsive phenotype during infection with the filarial nematode Litomosoides sigmodontis, denoted by impaired functionality and parasite killing. This study aimed to elucidate the transcriptional changes underlying Th2 cell-intrinsic hypo-responsiveness, and whether it represents a unique and stable state of Th2 cell differentiation. We demonstrated that intrinsically hypo-responsive Th2 cells isolated from L. sigmodontis infected mice stably retained their dysfunctional Th2 phenotype upon transfer to naïve recipients, and had a divergent transcriptional profile to classical Th2 cells isolated prior to hypo-responsiveness and from mice exposed to acute Type 2 stimuli. Hypo-responsive Th2 cells displayed a distinct transcriptional profile to exhausted CD4+ T cells, but upregulated Blimp-1 and the anergy/regulatory-associated transcription factors Egr2 and c-Maf, and shared characteristics with tolerised T cells. Hypo-responsive Th2 cells increased mRNA expression of the soluble regulatory factors Fgl2, Cd38, Spp1, Areg, Metrnl, Lgals3, and Csf1, and a subset developed a T-bet+IFN-γ+ Th2/Th1 hybrid phenotype, indicating that they were not functionally inert. Contrasting with their lost ability to produce Th2 cytokines, hypo-responsive Th2 cells gained IL-21 production and IL-21R blockade enhanced resistance to L. sigmodontis. IL-21R blockade also increased the proportion of CD19+PNA+ germinal centre B cells and serum levels of parasite specific IgG1. This indicates a novel regulatory role for IL-21 during filarial infection, both in controlling protection and B cell responses. Thus, Th2 cell-intrinsic hypo-responsiveness is a distinct and stable state of Th2 cell differentiation associated with a switch from a classically active IL-4+IL-5+ Th2 phenotype, to a non-classical dysfunctional and potentially regulatory IL-21+Egr2+c-Maf+Blimp-1+IL-4loIL-5loT-bet+IFN-γ+ Th2 phenotype. This divergence towards alternate Th2 phenotypes during chronicity has broad implications for the outcomes and treatment of chronic Type 2-related infections and diseases.

Howler monkeys are the reservoir of malarial parasites causing zoonotic infections in the Atlantic forest of Rio de Janeiro

PLoS Neglected Tropical Diseases News - 9 December 2019 - 10:00pm

by Filipe Vieira Santos de Abreu, Edmilson dos Santos, Aline Rosa Lavigne Mello, Larissa Rodrigues Gomes, Denise Anete Madureira de Alvarenga, Marcelo Quintela Gomes, Waldemir Paixão Vargas, Cesare Bianco-Júnior, Anielle de Pina-Costa, Danilo Simonini Teixeira, Alessandro Pecego Martins Romano, Pedro Paulo de Abreu Manso, Marcelo Pelajo-Machado, Patrícia Brasil, Cláudio Tadeu Daniel-Ribeiro, Cristiana Ferreira Alves de Britto, Maria de Fátima Ferreira-da-Cruz, Ricardo Lourenço-de-Oliveira

Background

Although malaria cases have substantially decreased in Southeast Brazil, a significant increase in the number of Plasmodium vivax-like autochthonous human cases has been reported in remote areas of the Atlantic Forest in the past few decades in Rio de Janeiro (RJ) state, including an outbreak during 2015–2016. The singular clinical and epidemiological aspects in several human cases, and collectively with molecular and genetic data, revealed that they were due to the non-human primate (NHP) parasite Plasmodium simium; however, the understanding of the autochthonous malarial epidemiology in Southeast Brazil can only be acquired by assessing the circulation of NHP Plasmodium in the foci and determining its hosts.

Methodology

A large sampling effort was carried out in the Atlantic forest of RJ and its bordering states (Minas Gerais, São Paulo, Espírito Santo) for collecting and examining free-living NHPs. Blood and/or viscera were analyzed for Plasmodium infections via molecular and microscopic techniques.

Principal findings

In total, 146 NHPs of six species, from 30 counties in four states, were tested, of which majority were collected from RJ. Howler monkeys (Alouatta clamitans) were the only species found infected. In RJ, 26% of these monkeys tested positive, of which 17% were found to be infected with P. simium. Importantly, specific single nucleotide polymorphisms–the only available genetic markers that differentiate P. simium from P. vivax–were detected in all P. simium infected A. clamitans despite their geographical origin of malarial foci. Interestingly, 71% of P. simium infected NHPs were from the coastal slope of a mountain chain (Serra do Mar), where majority of the human cases were found. Plasmodium brasilianum/malariae was initially detected in 14% and 25% free-living howler monkeys in RJ and in the Espírito Santo (ES) state, respectively. Moreover, the malarial pigment was detected in the spleen fragments of 50% of a subsample comprising dead howler monkeys in both RJ and ES. All NHPs were negative for Plasmodium falciparum.

Conclusions/Significance

Our data indicate that howler monkeys act as the main reservoir for the Atlantic forest human malarial parasites in RJ and other sites in Southeast Brazil and reinforce its zoonotic characteristics.

Clinical and epidemiologic characteristics associated with dengue during and outside the 2016 outbreak identified in health facility-based surveillance in Ouagadougou, Burkina Faso

PLoS Neglected Tropical Diseases News - 6 December 2019 - 10:00pm

by Jacqueline K. Lim, Yaro Seydou, Mabel Carabali, Ahmed Barro, Desire Lucien Dahourou, Kang Sung Lee, Teguewende Nikiema, Suk Namkung, Jung-Seok Lee, Mee Young Shin, Emmanuel Bonnet, Therese Kagone, Losseni Kaba, Tansy Edwards, Paul-André Somé, Jae Seung Yang, Neal Alexander, In-Kyu Yoon, Valéry Ridde

Background

In Africa, the magnitude of dengue virus (DENV) transmission is largely unknown. In Burkina Faso, several outbreaks have been reported and data are often based on findings from outbreak investigations.

Methods

To better understand dengue epidemiology and clinical characteristics in Burkina Faso, a fever surveillance study was conducted among patients aged 1–55 years, who presented with non-malarial febrile illness at five primary healthcare facilities in Ouagadougou, Burkina Faso from December 2014 to February 2017, encompassing a 3-month dengue outbreak in September-November 2016. Acute and convalescent blood samples were collected within an interval of 10–21 days between visits. Acute samples were tested with dengue rapid diagnostic tests (RDT) and a selected subset with RT-PCR, and all acute/convalescent samples with IgM/IgG ELISA.

Results

Among 2929 non-malarial febrile patients, 740 (25%) were dengue–positive based on RT-PCR and/or IgM/IgG ELISA; 428 out of 777 patients (55%) and 312 out of 2152 (14%) were dengue-positive during outbreak and non-outbreak periods, respectively. There were 11% (316/2929) and 4% (129/2929) patients showing positive for NS1 and IgM, on the RDT, respectively. DENV 2 predominated during the outbreak, whereas DENV 3 predominated before the outbreak. Only 25% of dengue-positive cases were clinically diagnosed with suspected dengue. The odds of requiring observation for ≤3 days (versus routine outpatient care) were 11 times higher among dengue-positive cases than non-dengue cases. In adjusted analyses, dengue-positivity was associated with rash and retro-orbital pain (OR = 2.6 and 7.4, respectively) during the outbreak and with rash and nausea/vomiting (OR = 1.5 and 1.4, respectively) during the non-outbreak period.

Conclusion

Dengue virus is an important pathogen in Burkina Faso, accounting for a substantial proportion of non-malarial fevers both during and outside outbreak, but is only infrequently suspected by clinicians. Additional longitudinal data would help to further define characteristics of dengue for improved case detection and surveillance.

<i>Taenia solium</i> cysticercosis and taeniasis in urban settings: Epidemiological evidence from a health-center based study among people with epilepsy in Dar es Salaam, Tanzania

PLoS Neglected Tropical Diseases News - 6 December 2019 - 10:00pm

by Veronika Schmidt, Marie-Claire O’Hara, Bernard Ngowi, Karl-Heinz Herbinger, John Noh, Patricia Procell Wilkins, Vivien Richter, Christian Kositz, William Matuja, Andrea Sylvia Winkler

In Africa, urbanization is happening faster than ever before which results in new implications for transmission of infectious diseases. For the zoonotic parasite Taenia solium, a major cause of acquired epilepsy in endemic countries, the prevalence in urban settings is unknown. The present study investigated epidemiological, neurological, and radiological characteristics of T. solium cysticercosis and taeniasis (TSCT) in people with epilepsy (PWE) living in Dar es Salaam, Tanzania, one of the fastest growing cities worldwide. A total of 302 PWE were recruited from six health centers in the Kinondoni district of Dar es Salaam. Serological testing for T. solium cysticercosis-antigen (Ag) and -antibodies (Abs) and for T. solium taeniasis-Abs was performed in all PWE. In addition, clinical and radiological examinations that included cranial computed tomography (CT) were performed. With questionnaires, demographic data from study populations were collected, and factors associated with TSCT were assessed. Follow-up examinations were conducted in PWE with TSCT. T. solium cysticercosis-Ag was detected in three (0.99%; 95% CI: 0–2.11%), -Abs in eight (2.65%; 95% CI: 0.84–4.46%), and taeniasis-Abs in five (1.66%; 95% CI: 0.22–3.09%) of 302 PWE. Six PWE (1.99%; 95% CI: 0.41–3.56%) were diagnosed with neurocysticercosis (NCC). This study demonstrates the presence of TSCT in Dar es Salaam, however, NCC was only associated with a few cases of epilepsy. The small fraction of PWE with cysticercosis- and taeniasis-Abs may suggest that active transmission of T. solium plays only a minor role in Dar es Salaam. A sufficiently powered risk analysis was hampered by the small number of PWE with TSCT; therefore, further studies are required to determine the exact routes of infection and risk behavior of affected individuals.

Challenges in diagnosing scrub typhus among hospitalized patients with undifferentiated fever at a national tertiary hospital in northern Vietnam

PLoS Neglected Tropical Diseases News - 5 December 2019 - 10:00pm

by Shungo Katoh, Ngo Chi Cuong, Sugihiro Hamaguchi, Pham Thanh Thuy, Do Duy Cuong, Le Kim Anh, Nguyen Thi Hien Anh, Dang Duc Anh, Eiichiro Sando, Motoi Suzuki, Hiromi Fujita, Michio Yasunami, Keisuke Yoshihara, Lay-Myint Yoshida, Daniel Henry Paris, Koya Ariyoshi

Background

Scrub typhus (ST) is a leading cause of non-malarial febrile illness in Southeast Asia, but evidence of its true disease burden is limited because of difficulties of making the clinical diagnosis and lack of adequate diagnostic tests. To describe the epidemiology and clinical characteristics of ST, we conducted an observational study using multiple diagnostic assays at a national tertiary hospital in Hanoi, Vietnam.

Methodology/Principal findings

We enrolled 1,127 patients hospitalized with documented fever between June 2012 and May 2013. Overall, 33 (2.9%) patients were diagnosed with ST by PCR and/or screening of ELISA for immunoglobulin M (IgM) with confirmatory tests: 14 (42.4%) were confirmed by indirect immunoperoxidase assay (IIP), and 19 (57.6%) were by IIP and PCR. Living by farming, conjunctival injection, eschar, aspartate aminotransferase elevation, and alanine aminotransferase elevation were significantly associated with ST cases (adjusted odds ratios (aORs): 2.8, 3.07, 48.8, 3.51, and 4.13, respectively), and having a comorbidity and neutrophilia were significantly less common in ST cases (aORs: 0.29 and 0.27, respectively). The majority of the ST cases were not clinically diagnosed with rickettsiosis (72.7%). Dominant IIP reactions against a single antigen were identified in 15 ST cases, whereas indistinguishably high reactions against multiple antigens were seen in 11 ST cases. The most frequently observed dominant IIP reaction was against Karp antigen (eight cases) followed by Gilliam (four cases). The highest diagnostic accuracy of IgM ELISA in acute samples was 78%. In a phylogenetic analysis of the 56-kDa type-specific antigen gene, the majority (14 cases) were located in the Karp-related branch followed by the Gilliam-related (two cases), Kato-related (two cases), and TA763-related clades (one case).

Conclusions/Significance

Both the clinical and laboratory diagnoses of ST remain challenging at a tertiary hospital. Implementation of both serological and nucleic acid amplification assays covering endemic O. tsutsugamushi strains is essential.

Whole genome sequencing of <i>Entamoeba nuttalli</i> reveals mammalian host-related molecular signatures and a novel octapeptide-repeat surface protein

PLoS Neglected Tropical Diseases News - 5 December 2019 - 10:00pm

by Masayuki Tanaka, Takashi Makiuchi, Tomoyoshi Komiyama, Takashi Shiina, Ken Osaki, Hiroshi Tachibana

The enteric protozoa Entamoeba histolytica is the causative agent of amebiasis, which is one of the most common parasitic diseases in developed and developing countries. Entamoeba nuttalli is the genetically closest species to E. histolytica in current phylogenetic analyses of Entamoeba species, and is prevalent in wild macaques. Therefore, E. nuttalli may be a key organism in which to investigate molecules required for infection of human or non-human primates. To explore the molecular signatures of host-parasite interactions, we conducted de novo assembly of the E. nuttalli genome, utilizing self-correction of PacBio long reads and polishing corrected reads using Illumina short reads, followed by comparative genomic analysis with two other mammalian and a reptilian Entamoeba species. The final draft assembly of E. nuttalli included 395 contigs with a total length of approximately 23 Mb, and 9,647 predicted genes, of which 6,940 were conserved with E. histolytica. In addition, we found an E. histolytica-specific repeat known as ERE2 in the E. nuttalli genome. GO-term enrichment analysis of mammalian host-related molecules indicated diversification of transmembrane proteins, including AIG1 family and BspA-like proteins that may be involved in the host-parasite interaction. Furthermore, we identified an E. nuttalli-specific protein that contained 42 repeats of an octapeptide ([G,E]KPTDTPS). This protein was shown to be localized on the cell surface using immunofluorescence. Since many repeat-containing proteins in parasites play important roles in interactions with host cells, this unique octapeptide repeat-containing protein may be involved in colonization of E. nuttalli in the intestine of macaques. Overall, our draft assembly provides a valuable resource for studying Entamoeba evolution and host-parasite selection.

The impact of vector migration on the effectiveness of strategies to control gambiense human African trypanosomiasis

PLoS Neglected Tropical Diseases News - 5 December 2019 - 10:00pm

by Martial L. Ndeffo-Mbah, Abhishek Pandey, Katherine E. Atkins, Serap Aksoy, Alison P. Galvani

Background

Several modeling studies have been undertaken to assess the feasibility of the WHO goal of eliminating gambiense human African trypanosomiasis (g-HAT) by 2030. However, these studies have generally overlooked the effect of vector migration on disease transmission and control. Here, we evaluated the impact of vector migration on the feasibility of interrupting transmission in different g-HAT foci.

Methods

We developed a g-HAT transmission model of a single tsetse population cluster that accounts for migration of tsetse fly into this population. We used a model calibration approach to constrain g-HAT incidence to ranges expected for high, moderate and low transmission settings, respectively. We used the model to evaluate the effectiveness of current intervention measures, including medical intervention through enhanced screening and treatment, and vector control, for interrupting g-HAT transmission in disease foci under each transmission setting.

Results

We showed that, in low transmission settings, under enhanced medical intervention alone, at least 70% treatment coverage is needed to interrupt g-HAT transmission within 10 years. In moderate transmission settings, a combination of medical intervention and a vector control measure with a daily tsetse mortality greater than 0.03 is required to achieve interruption of disease transmission within 10 years. In high transmission settings, interruption of disease transmission within 10 years requires a combination of at least 70% medical intervention coverage and at least 0.05 tsetse daily mortality rate from vector control. However, the probability of achieving elimination in high transmission settings decreases with an increased tsetse migration rate.

Conclusion

Our results suggest that the WHO 2030 goal of G-HAT elimination is, at least in theory, achievable. But the presence of tsetse migration may reduce the probability of interrupting g-HAT transmission in moderate and high transmission foci. Therefore, optimal vector control programs should incorporate monitoring and controlling of vector density in buffer areas around foci of g-HAT control efforts.

Beyond the ‘big four’: Venom profiling of the medically important yet neglected Indian snakes reveals disturbing antivenom deficiencies

PLoS Neglected Tropical Diseases News - 5 December 2019 - 10:00pm

by R. R. Senji Laxme, Suyog Khochare, Hugo Francisco de Souza, Bharat Ahuja, Vivek Suranse, Gerard Martin, Romulus Whitaker, Kartik Sunagar

Background

Snakebite in India causes the highest annual rates of death (46,000) and disability (140,000) than any other country. Antivenom is the mainstay treatment of snakebite, whose manufacturing protocols, in essence, have remained unchanged for over a century. In India, a polyvalent antivenom is produced for the treatment of envenomations from the so called ‘big four’ snakes: the spectacled cobra (Naja naja), common krait (Bungarus caeruleus), Russell’s viper (Daboia russelii), and saw-scaled viper (Echis carinatus). In addition to the ‘big four’, India is abode to many other species of venomous snakes that have the potential to inflict severe clinical or, even, lethal envenomations in their human bite victims. Unfortunately, specific antivenoms are not produced against these species and, instead, the ‘big four’ antivenom is routinely used for the treatment.

Methods

We characterized the venom compositions, biochemical and pharmacological activities and toxicity profiles (mouse model) of the major neglected yet medically important Indian snakes (E. c. sochureki, B. sindanus, B. fasciatus, and two populations of N. kaouthia) and their closest ‘big four’ congeners. By performing WHO recommended in vitro and in vivo preclinical assays, we evaluated the efficiencies of the commercially marketed Indian antivenoms in recognizing venoms and neutralizing envenomations by these neglected species.

Findings

As a consequence of dissimilar ecologies and diet, the medically important snakes investigated exhibited dramatic inter- and intraspecific differences in their venom profiles. Currently marketed antivenoms were found to exhibit poor dose efficacy and venom recognition potential against the ‘neglected many’. Premium Serums antivenom failed to neutralise bites from many of the neglected species and one of the ‘big four’ snakes (North Indian population of B. caeruleus).

Conclusions

This study unravels disturbing deficiencies in dose efficacy and neutralisation capabilities of the currently marketed Indian antivenoms, and emphasises the pressing need to develop region-specific snakebite therapy for the ‘neglected many’.

Intralesional infiltration versus parenteral use of meglumine antimoniate for treatment of cutaneous leishmaniasis: A cost-effectiveness analysis

PLoS Neglected Tropical Diseases News - 5 December 2019 - 10:00pm

by Nayara C. Brito, Tália S. Machado de Assis, Ana Rabello, Gláucia Cota

Cutaneous leishmaniasis (LC) is a complex and variable disease in terms of epidemiology, aetiology, pathology and clinical characteristics. The mainstay of treatment is still pentavalent antimony (Sbv) compounds administered systemically, despite their recognized toxicity. The advantages of antimony intralesional (IL) infiltration are the use of lower doses of Sbv and, therefore, less toxic effects. The objective of this study was to estimate the cost-effectiveness ratio of intralesional meglumine antimoniate therapy (IL-MA) compared with endovenous meglumine antimoniate therapy (EV-MA) for the treatment of CL in the context of the Brazilian National Health System (SUS). An analytical decision model (decision tree) was developed using TreeAge Pro 2018 software. Data from the open-label, uncontrolled phase II clinical trial evaluating IL-MA were used as a reference for posology, efficacy, and adverse event rates (AE). The same premises for the intravenous approach (EV-MA) were extracted from systematic literature reviews. Macro and micro calculations of spending were included in the analysis. The IL-MA and EV-MA strategies had a total cost per patient cured of US$330.81 and US$494.16, respectively. The intralesional approach was dominant, meaning it was more economic and effective than was endovenous therapy. The incremental cost-effectiveness ratio showed that IL-MA could result in savings of US$864.37 for each additional patient cured, confirming that the IL-MA strategy is cost effective in the context of the Brazilian public health scenario.

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