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Field evaluation of a locally produced rapid diagnostic test for early detection of cholera in Bangladesh

31 January 2019 - 10:00pm

by Md. Taufiqul Islam, Ashraful Islam Khan, Md. Abu Sayeed, Jakia Amin, Kamrul Islam, Nur Alam, Nishat Sultana, Noor Jahan, Md. Mahbubur Rashid, Zahid Hasan Khan, Mazharul Islam Zion, Mokibul Hassan Afrad, Shah Alam Siddique, Farhana Khanam, Yasmin Ara Begum, Muhammad Shariful Islam, Firdausi Qadri

Background

Cholera remains a substantial health burden in Asia and Africa particularly in resource poor settings. The standard procedures to identify the etiological organism V. cholerae are isolation from microbiological culture from stool as well as Polymerase Chain Reaction (PCR). Both the processes are highly lab oriented, labor extensive, time consuming, and expensive. In an effort to control for outbreaks and epidemics; an effective, convenient, quick and relatively less expensive detection method is imperative, without compromising the sensitivity and specificity that exists at present. The objective of this component of the study was to evaluate the effectiveness of a locally produced rapid diagnostic test (RDT) for cholera diagnosis.

Methods

In Bangladesh, nationwide cholera surveillance is ongoing in 22 hospitals covering all 8 divisions of the country since June, 2016. In the surveillance, stool samples have been collected from patients presenting to hospitals with acute watery diarrhea. Crystal VCTM (Span diagnostics, India) and Cholkit (locally produced RDT) have been used to detect V. cholerae from stool samples. Samples have also been sent to the main laboratory at icddr,b where the culture based isolation is routinely performed. All the tests were carried out for both direct and enriched stool samples. RDT sensitivity and specificity were calculated using stool culture as the gold standard.

Results

A total of 7720 samples were tested. Among these, 5865 samples were solely tested with Crystal VC and 1355 samples with Cholkit whereas 381 samples were tested with both the RDTs. In comparison with culture, direct testing with Crystal VC showed a sensitivity of 72% (95% CI: 50.6% to 87.9%) and specificity of 86.8% (95% CI: 82.8% to 90.1%). After enrichment the sensitivity and specificity was 68% (95% CI: 46.5% to 85.1%) and 97.5% (95% CI: 95.3% to 98.8%) respectively. The direct Cholkit test showed sensitivity of 76% (95% CI: 54.9% to 90.6%) and specificity of 90.2% (95% CI: 86.6% to 93.1%).

Conclusion

This evaluation has demonstrated that the sensitivity and specificity of Cholkit is similar to the commercially available test, Crystal VC when used in field settings for detecting V. cholerae from stool specimens. The findings from this study suggest that the Cholkit could be a possible alternative for cholera endemic regions where V. cholerae O1 is the major causative organism causing cholera.

Evaluation of direct costs associated with alveolar and cystic echinococcosis in Austria

31 January 2019 - 10:00pm

by Felix Lötsch, Christine M. Budke, Herbert Auer, Klaus Kaczirek, Fredrik Waneck, Heimo Lagler, Michael Ramharter

Background

Cystic echinococcosis (CE) is a globally occurring zoonosis, whereas alveolar echinococcosis (AE) is endemic only in certain parts of the Northern Hemisphere. The socioeconomic impact of human echinococcosis has been shown to be considerable in highly endemic regions. However, detailed data on direct healthcare-related costs associated with CE and AE are scarce for high income countries. The aim of this study was to evaluate direct costs of human disease caused by CE and AE in Austria.

Methods

Clinical data from a registry maintained at a national reference center for echinococcosis at the Medical University of Vienna were obtained for the years 2012–2014. These data were used in conjunction with epidemiological data from Austria’s national disease reporting system and diagnostic reference laboratory for echinococcosis to assess nationwide costs attributable to CE and AE.

Results

In Austria, total modelled direct costs were 486,598€ (95%CI 341,825€ – 631,372€) per year for CE, and 683,824€ (95%CI 469,161€ - 898,486€) for AE. Median costs per patient with AE from diagnosis until the end of a 10-year follow-up period were 30,832€ (25th– 75th percentile: 23,197€ - 31,220€) and 62,777€ (25th– 75th percentile: 60,806€ - 67,867€) for inoperable and operable patients, respectively. Median costs per patients with CE from diagnosis until end of follow-up after 10 years were 16,253€ (25th– 75th percentile: 8,555€ - 24,832€) and 1,786€ (25th– 75th percentile: 736€ - 2,146€) for patients with active and inactive cyst stages, respectively. The first year after inclusion was the most cost-intense year in the observed period, with hospitalizations and albendazole therapy the main contributors to direct costs.

Conclusions

This study provides detailed information on direct healthcare-related costs associated with CE and AE in Austria, which may reflect trends for other high-income countries. Surgery and albendazole therapy, due to surprisingly high drug prices, were identified as important cost-drivers. These data will be important for cost-effectiveness analyses of possible prevention programs.

Probabilistic logic analysis of the highly heterogeneous spatiotemporal HFRS incidence distribution in Heilongjiang province (China) during 2005-2013

31 January 2019 - 10:00pm

by Junyu He, George Christakos, Jiaping Wu, Piotr Jankowski, Andreas Langousis, Yong Wang, Wenwu Yin, Wenyi Zhang

Background

Hemorrhagic fever with renal syndrome (HFRS) is a zoonosis caused by hantavirus (belongs to Hantaviridae family). A large amount of HFRS cases occur in China, especially in the Heilongjiang Province, raising great concerns regarding public health. The distribution of these cases across space-time often exhibits highly heterogeneous characteristics. Hence, it is widely recognized that the improved mapping of heterogeneous HFRS distributions and the quantitative assessment of the space-time disease transition patterns can advance considerably the detection, prevention and control of epidemic outbreaks.

Methods

A synthesis of space-time mapping and probabilistic logic is proposed to study the distribution of monthly HFRS population-standardized incidences in Heilongjiang province during the period 2005–2013. We introduce a class-dependent Bayesian maximum entropy (cd-BME) mapping method dividing the original dataset into discrete incidence classes that overcome data heterogeneity and skewness effects and can produce space-time HFRS incidence estimates together with their estimation accuracy. A ten-fold cross validation analysis is conducted to evaluate the performance of the proposed cd-BME implementation compared to the standard class-independent BME implementation. Incidence maps generated by cd-BME are used to study the spatiotemporal HFRS spread patterns. Further, the spatiotemporal dependence of HFRS incidences are measured in terms of probability logic indicators that link class-dependent HFRS incidences at different space-time points. These indicators convey useful complementary information regarding intraclass and interclass relationships, such as the change in HFRS transition probabilities between different incidence classes with increasing geographical distance and time separation.

Results

Each HFRS class exhibited a distinct space-time variation structure in terms of its varying covariance parameters (shape, sill and correlation ranges). Given the heterogeneous features of the HFRS dataset, the cd-BME implementation demonstrated an improved ability to capture these features compared to the standard implementation (e.g., mean absolute error: 0.19 vs. 0.43 cases/105 capita) demonstrating a point outbreak character at high incidence levels and a non-point spread character at low levels. Intraclass HFRS variations were found to be considerably different than interclass HFRS variations. Certain incidence classes occurred frequently near one class but were rarely found adjacent to other classes. Different classes may share common boundaries or they may be surrounded completely by another class. The HFRS class 0–68.5% was the most dominant in the Heilongjiang province (covering more than 2/3 of the total area). The probabilities that certain incidence classes occur next to other classes were used to estimate the transitions between HFRS classes. Moreover, such probabilities described the dependency pattern of the space-time arrangement of HFRS patches occupied by the incidence classes. The HFRS transition probabilities also suggested the presence of both positive and negative relations among the main classes. The HFRS indicator plots offer complementary visualizations of the varying probabilities of transition between incidence classes, and so they describe the dependency pattern of the space-time arrangement of the HFRS patches occupied by the different classes.

Conclusions

The cd-BME method combined with probabilistic logic indicators offer an accurate and informative quantitative representation of the heterogeneous HFRS incidences in the space-time domain, and the results thus obtained can be interpreted readily. The same methodological combination could also be used in the spatiotemporal modeling and prediction of other epidemics under similar circumstances.

The long run impact of early childhood deworming on numeracy and literacy: Evidence from Uganda

31 January 2019 - 10:00pm

by Kevin Croke, Rifat Atun

Background

Up to 1.45 billion people currently suffer from soil transmitted helminth infection, with the largest burden occurring in Africa and Asia. Safe and cost effective deworming treatment exists, but there is a debate about mass distribution of this treatment in high prevalence settings. While the World Health Organization recommends mass administration of anthelmintic drugs for preschool and school-aged children in high (>20%) prevalence settings, and several long run follow up studies of an influential trial have suggested large benefits that persist over time, recent systematic reviews have called this recommendation into question.

Methods and findings

This paper analyzes the long-term impact of a cluster-randomized trial in eastern Uganda that provided mass deworming treatment to preschool aged children from 2000 to 2003 on the numeracy and literacy skills of children and young adults living in those villages in 2010-2015. This study uses numeracy and literacy data collected seven to twelve years after the end of the deworming trial in a randomly selected subset of communities from the original trial, by an education-focused survey that had no relationship to the deworming study. Building on an earlier working paper which used data from 2010 and 2011 survey rounds, this paper uses an additional four years of numeracy and literacy data (2012, 2013, 2014, and 2015). Aggregating data from all survey rounds, the difference between numeracy scores in treatment versus control communities is 0.07 standard deviations (SD) (95% CI -0.10, 0.24, p = 0.40), the difference in literacy scores is 0.05 SD (95% CI -0.16, 0.27, p = 0.62), and the difference in total scores is 0.07 SD (95% CI -0.11, 0.25, p = 0.44). There are significant differences in program impact by gender, with numeracy and literacy differentially positively affected for girls, and by age, with treatment effects larger for the primary school aged subsample. There are also significant treatment interactions for those living in households with more treatment-eligible children. There is no evidence of differential treatment effects on age at program eligibility or number of years of program eligibility.

Conclusions

Mass deworming of preschool aged children in high prevalence communities in Uganda resulted in no statistically significant gains in numeracy or literacy 7-12 years after program completion. Point estimates were positive but imprecise; the study lacked sufficient power to rule out substantial positive effects or more modest negative effects. However, there is suggestive evidence that deworming was relatively more beneficial for girls, primary school aged children, and children living in households with other treated children.

Research approval

As this analysis was conducted on secondary data which is publicly available, no research approval was sought or received. All individual records were anonymized by the data provider prior to public release.

Bivalent oral cholera vaccination induces a memory B cell response to the <i>V</i>. <i>cholerae</i> O1-polysacchide in Haitian adults

31 January 2019 - 10:00pm

by Brie Falkard, Richelle C. Charles, Wilfredo R. Matias, Leslie M. Mayo-Smith, J. Gregory Jerome, Evan S. Offord, Peng Xu, Pavol Kováč, Edward T. Ryan, Firdausi Qadri, Molly F. Franke, Louise C. Ivers, Jason B. Harris

The bivalent killed whole-cell oral cholera vaccine (BivWC) is being increasingly used to prevent cholera. The presence of O-antigen-specific memory B cells (MBC) has been associated with protective immunity against cholera, yet MBC responses have not been evaluated after BivWC vaccination. To address this knowledge gap, we measured V. cholerae O1-antigen MBC responses following BivWC vaccination. Adults in St. Marc, Haiti, received 2 doses of the BivWC vaccine, Shanchol, two weeks apart. Participants were invited to return at days 7, 21, 44, 90, 180 and 360 after the initial vaccination. Serum antibody and MBC responses were assessed at each time-point before and following vaccination. We observed that vaccination with BivWC resulted in significant O-antigen specific MBC responses to both Ogawa and Inaba serotypes that were detected by day 21 and remained significantly elevated over baseline for up to 12 months following vaccination. The BivWC oral cholera vaccine induces durable MBC responses to the V. cholerae O1-antigen. This suggests that long-term protection observed following vaccination with BivWC could be mediated or maintained by MBC responses.

Integrated delivery of school health interventions through the school platform: Investing for the future

31 January 2019 - 10:00pm

by Laura J. Appleby, Gemechu Tadesse, Yonas Wuletawu, Nigussie G. Dejene, Jack E. T. Grimes, Michael D. French, Askale Teklu, Berhanu Moreda, Nebiyu Negussu, Biruck Kebede, Elodie Yard, Iain Gardiner, Lesley J. Drake

School health and nutrition (SHN) programmes are recognized as a significant contributor to both health and education sector goals. The school system offers an ideal platform from which to deliver basic health interventions that target the most common health conditions affecting school-age children (SAC) in low-income countries, leading to improved participation and learning outcomes. However, governments require evidence to cost, design, and implement these programmes. In Ethiopia, prevalent health conditions affecting SAC's education participation and learning outcomes include infection with soil-transmitted helminths (STHs), hunger, and malnutrition. In recognition of the multiple issues affecting the health and education of SAC, the government has taken a proactive approach, coordinating an integrated SHN programme designed to be implemented in partnership and monitored and financed through a single, integrated mechanism. The programme, known as the Enhanced School Health Initiative (ESHI), integrates three complimentary health interventions: deworming; school feeding; and provision of a water, sanitation, and hygiene (WASH) package in schools, which in delivery aim to maximize the benefits of each of the individual components. Operational research surrounding the ESHI programme includes both qualitative and quantitative analyses. Here, we present an overview of the ESHI programme and its genesis. We also introduce three additional supporting papers that provide in-depth analyses of key findings, including the baseline situational analysis, the costs, and community perceptions of the programme. The findings from ESHI provide initial evidence to develop an understanding of the related costs and synergies of integrating multiple health interventions onto a single platform. The work has translated into strengthened institutional capacity and improved cross-sectoral coordination. The government is now committed to supporting 25 million school children in Ethiopia through SHN. The ESHI model serves as a reference point for other countries looking to scale up targeted SHN interventions.

Food insecurity and self-reported cholera in Haitian households: An analysis of the 2012 Demographic and Health Survey

30 January 2019 - 10:00pm

by Aaron Richterman, Molly F. Franke, Georgery Constant, Gregory Jerome, Ralph Ternier, Louise C. Ivers

Background

Both cholera and food insecurity tend to occur in impoverished communities where poor access to food, inadequate sanitation, and an unsafe water supply often coexist. The relationship between the two, however, has not been well-characterized.

Methods

We performed a secondary analysis of household-level data from the 2012 Demographic and Health Survey in Haiti, a nationally and sub-nationally representative cross-sectional household survey conducted every five years. We used multivariable logistic regression to evaluate the relationship between household food security (as measured by the Household Hunger Scale) and (1) reported history of cholera since 2010 by any person in the household and (2) reported death by any person in the household from cholera (among households reporting at least one case). We performed a complete case analysis because there were <1% missing data for all variables.

Results

There were 13,181 households in the survey, 2,104 of which reported at least one household member with history of cholera. After adjustment for potential confounders, both moderate hunger in the household [Adjusted Odds Ratio (AOR) 1.51, 95% Confidence Interval (CI) 1.30–1.76; p <.0001] and severe hunger in the household (AOR 1.73, 95% CI 1.45–2.08; p <.0001) were significantly associated with reported history of cholera in the household. Severe hunger in the household (AOR 1.85, 95% CI 1.05–3.26; p = 0.03), but not moderate hunger in the household, was independently associated with reported death from cholera in households with at least one case of cholera.

Conclusions

In this study we identified an independent relationship between household food insecurity and both reported history of cholera and death from cholera in a general population. The directionality of this relationship is uncertain and should be further explored in future prospective research.

Yellow fever virus is susceptible to sofosbuvir both <i>in vitro</i> and <i>in vivo</i>

30 January 2019 - 10:00pm

by Caroline S. de Freitas, Luiza M. Higa, Carolina Q. Sacramento, André C. Ferreira, Patrícia A. Reis, Rodrigo Delvecchio, Fabio L. Monteiro, Giselle Barbosa-Lima, Harrison James Westgarth, Yasmine Rangel Vieira, Mayara Mattos, Natasha Rocha, Lucas Villas Bôas Hoelz, Rennan Papaleo Paes Leme, Mônica M. Bastos, Gisele Olinto L. Rodrigues, Carla Elizabeth M. Lopes, Celso Martins Queiroz-Junior, Cristiano X. Lima, Vivian V. Costa, Mauro M. Teixeira, Fernando A. Bozza, Patrícia T. Bozza, Nubia Boechat, Amilcar Tanuri, Thiago Moreno L. Souza

Yellow fever virus (YFV) is a member of the Flaviviridae family. In Brazil, yellow fever (YF) cases have increased dramatically in sylvatic areas neighboring urban zones in the last few years. Because of the high lethality rates associated with infection and absence of any antiviral treatments, it is essential to identify therapeutic options to respond to YFV outbreaks. Repurposing of clinically approved drugs represents the fastest alternative to discover antivirals for public health emergencies. Other Flaviviruses, such as Zika (ZIKV) and dengue (DENV) viruses, are susceptible to sofosbuvir, a clinically approved drug against hepatitis C virus (HCV). Our data showed that sofosbuvir docks onto YFV RNA polymerase using conserved amino acid residues for nucleotide binding. This drug inhibited the replication of both vaccine and wild-type strains of YFV on human hepatoma cells, with EC50 values around 5 μM. Sofosbuvir protected YFV-infected neonatal Swiss mice and adult type I interferon receptor knockout mice (A129-/-) from mortality and weight loss. Because of its safety profile in humans and significant antiviral effects in vitro and in mice, Sofosbuvir may represent a novel therapeutic option for the treatment of YF. Key-words: Yellow fever virus; Yellow fever, antiviral; sofosbuvir

Integrated seroprevalence-based assessment of <i>Wuchereria bancrofti</i> and <i>Onchocerca volvulus</i> in two lymphatic filariasis evaluation units of Mali with the SD Bioline Onchocerciasis/LF IgG4 Rapid Test

30 January 2019 - 10:00pm

by Housseini Dolo, Yaya Ibrahim Coulibaly, Benoit Dembele, Boubacar Guindo, Siaka Yamoussa Coulibaly, Ilo Dicko, Salif Seriba Doumbia, Massitan Dembele, Mamadou Oumar Traore, Seydou Goita, Mamadou Dolo, Lamine Soumaoro, Michel Emmanuel Coulibaly, Abdallah Amadou Diallo, Dansine Diarra, Yaobi Zhang, Robert Colebunders, Thomas B. Nutman

Background

Mali has become increasingly interested in the evaluation of transmission of both Wuchereria bancrofti and Onchocerca volvulus as prevalences of both infections move toward their respective elimination targets. The SD Bioline Onchocerciasis/LF IgG4 Rapid Test was used in 2 evaluation units (EU) to assess its performance as an integrated surveillance tool for elimination of lymphatic filariasis (LF) and onchocericiasis.

Methodology/Principal findings

A cross sectional survey with SD Bioline Onchocerciasis/LF IgG4 Rapid Test was piggy-backed onto a transmission assessment survey (TAS) (using the immunochromatographic card test (ICT) Binax Filariasis Now test for filarial adult circulating antigen (CFA) detection) for LF in Mali among 6–7 year old children in 2016 as part of the TAS in two EUs namely Kadiolo-Kolondieba in the region of Sikasso and Bafoulabe -Kita-Oussoubidiagna-Yelimane in the region of Kayes.In the EU of Kadiolo- Kolondieba, of the 1,625 children tested, the overall prevalence of W. bancrofti CFA was 0.62% (10/1,625) [CI = 0.31–1.09]; while that of IgG4 to Wb123 was 0.19% (3/1,600) [CI = 0.04–0.50]. The number of positives tested with the two tests were statistically comparable (p = 0.09). In the EU of Bafoulabe-Kita-Oussoubidiagna-Yelimane, an overall prevalence of W. bancrofti CFA was 0% (0/1,700) and that of Wb123 IgG4 antibody was 0.06% (1/1,700), with no statistically significant difference between the two rates (p = 0.99).In the EU of Kadiolo- Kolondieba, the prevalence of Ov16-specific IgG4 was 0.19% (3/1,600) [CI = 0.04–0.50]. All 3 positives were in the previously O. volvulus-hyperendemic district of Kolondieba. In the EU of Bafoulabe-Kita-Oussoubidiagna-Yelimane, an overall prevalence of Ov16-specific IgG4 was 0.18% (3/1,700) [CI = 0.04–0.47]. These 3 Ov16 IgG4 positives were from previously O.volvulus-mesoendemic district of Kita.

Conclusions/Significance

The SD Bioline Onchocerciasis/LF IgG4 Rapid test appears to be a good tool for integrated exposure measures of LF and onchocerciasis in co-endemic areas.

Utility of rabies neutralizing antibody detection in cerebrospinal fluid and serum for ante-mortem diagnosis of human rabies

29 January 2019 - 10:00pm

by Tina Damodar, Reeta S. Mani, P. V. Prathyusha

Background

Early ante-mortem laboratory confirmation of human rabies is essential to aid patient management and institute public health measures. Few studies have highlighted the diagnostic value of antibody detection in CSF/serum in rabies, and its utility is usually undermined owing to the late seroconversion and short survival in infected patients. This study was undertaken to examine the ante-mortem diagnostic utility and prognostic value of antibody detection by rapid fluorescent focus inhibition test (RFFIT) in cerebrospinal fluid (CSF)/serum samples received from clinically suspected human rabies cases from January 2015 to December 2017.

Methodology/Principal findings

Samples collected ante-mortem and post-mortem from 130 and 6 patients with clinically suspected rabies respectively, were received in the laboratory during the study period. Ante-mortem laboratory confirmation was achieved in 55/130 (42.3%) cases. Real time PCR for detection of viral nucleic acid performed on saliva, nuchal skin, brain tissue and CSF samples could confirm the diagnosis in 15 (27.2%) of the 55 laboratory confirmed cases. Ante-mortem diagnosis could be achieved by RFFIT (in CSF and/or serum) in 45 (34.6%) of the 130 clinically suspected cases, accounting for 81.8% of the total 55 laboratory confirmed cases. The sensitivity of CSF RFFIT increased with the day of sample collection (post-onset of symptoms) and was found to be 100% after 12 days of illness. Patients who had received prior vaccination had an increased probability of a positive RFFIT and negative PCR result. Patients who were positive by RFFIT alone at initial diagnosis had longer survival (albeit with neurological sequelae) than patients who were positive by PCR alone or both RFFIT and PCR.

Conclusions/Significance

Detection of antibodies in the CSF/serum is a valuable ante-mortem diagnostic tool in human rabies, especially in patients who survive beyond a week. It was also found to have a limited role as a prognostic marker to predict outcomes in patients.

Neglected tropical diseases in children: An assessment of gaps in research prioritization

29 January 2019 - 10:00pm

by Chris A. Rees, Peter J. Hotez, Michael C. Monuteaux, Michelle Niescierenko, Florence T. Bourgeois

Background

Despite the known burden of neglected tropical diseases (NTDs) on child health, there is limited information on current efforts to increase pediatric therapeutic options. Our objective was to quantify and characterize research activity and treatment availability for NTDs in children in order to inform the prioritization of future research efforts.

Methodology/Principal findings

We conducted a review of the World Health Organization’s (WHO) International Clinical Trials Registry Platform to assess research activity for NTDs. The burden of disease of each NTD was measured in terms of disability adjusted life years (DALYs), which was extracted from the Global Health Data Exchange. First- and second-line medications for each NTD were identified from WHO guidelines. We reviewed FDA drug labels for each medication to determine whether they were adequately labeled for use in children. Descriptive statistics, binomial tests, and Spearman’s rank order correlations were calculated to assess research activity compared to burden of disease. Children comprised 34% of the 20 million DALYs resulting from NTDs, but pediatric trials contributed just 17% (63/369) of trials studying these conditions (p<0.001 for binomial test). Conditions that were particularly under-represented in pediatric populations compared to adults included rabies, leishmaniasis, scabies, and dengue. Pediatric drug trial activity was poorly correlated with pediatric burden of disease across NTDs (Spearman’s rho = 0.41, p = 0.12). There were 47 medications recommended by the WHO for the treatment of NTDs, of which only 47% (n = 22) were adequately labeled for use in children. Of the 25 medications lacking adequate pediatric labeling, three were under study in pediatric trials.

Conclusions/Significance

There is a substantial gap between the burden of disease for NTDs in children and research devoted to this population. Most medications lack adequate pediatric prescribing information, highlighting the urgency to increase pediatric research activity for NTDs with high burden of disease and limited treatment options.

Epidemiology of West Nile Virus in the Eastern Mediterranean region: A systematic review

29 January 2019 - 10:00pm

by Sana Eybpoosh, Mehdi Fazlalipour, Vahid Baniasadi, Mohammad Hassan Pouriayevali, Farzin Sadeghi, Abbas Ahmadi Vasmehjani, Mohammad Hadi Karbalaie Niya, Roger Hewson, Mostafa Salehi-Vaziri

Background

West Nile Virus (WNV), a member of the genus Flavivirus, is one of the most widely distributed arboviruses in the world. Despite some evidence for circulation of WNV in countries summarized by the World Health Organization as the Eastern Mediterrian Region Office (EMRO), comprehensive knowledge about its epidemiology remains largely unknown. This study aims to provide a concise review of the published literature on WNV infections in the Eastern Mediterranean regional office of WHO (EMRO).

Methodology/principal findings

A systematic review of WNV prevalence studies on humans, animals and vectors in the EMRO region was performed by searching: Web of Science, Science Direct, Scopus, PubMed, Embase and Google Scholar. Finally, 77 citations were included, comprising 35 seroprevalence studies on general population (24460 individuals), 15 prevalence studies among patients (3439 individuals), 22 seroprevalence studies among animals (10309 animals), and 9 studies on vectors (184242 vector species). Of the 22 countries in this region, five had no data on WNV infection among different populations. These countries include Kuwait, Bahrain, Oman, Syria and Somalia. On the other hand, among countries with available data, WNV-specific antibodies were detected in the general population of all investigated countries including Djibouti (0.3–60%), Egypt (1–61%), Iran (0–30%), Iraq (11.6–15.1%), Jordan (8%), Lebanon (0.5–1%), Libya (2.3%), Morocco (0–18.8%), Pakistan (0.6–65.0%), Sudan (2.2–47%), and Tunisia (4.3–31.1%). WNV RNA were also detected in patient populations of Iran (1.2%), Pakistan (33.3%), and Tunisia (5.3% –15.9%). WNV-specific antibodies were also detected in a wide range of animal species. The highest seropositivity rate was observed among equids (100% in Morocco) and dogs (96% in Morocco). The highest seroprevalence among birds was seen in Tunisia (23%). In addition, WNV infection was detected in mosquitoes (Culex, and Aedes) and ticks (Argas reflexus hermanni). The primary vector of WNV (Culex pipiens s.l.) was detected in Djibouti, Egypt, Iran and Tunisia, and in mosquitoes of all these countries, WNV was demonstrated.

Conclusions

This first systematic regional assessment of WNV prevalence provides evidence to support the circulation of WNV in the EMRO region as nearly all studies showed evidence of WNV infection in human as well as animal/vector populations. These findings highlight the need for continued prevention and control strategies and the collection of epidemiologic data for WNV epidemic status, especially in countries that lack reliable surveillance systems.

Knowledge, attitudes, and practices regarding rabies in Grenada

29 January 2019 - 10:00pm

by Lindonne Glasgow, Andre Worme, Emmanuel Keku, Martin Forde

Objective

While Grenada attained a zero-human-rabies case status since 1970, the authors conducted the first study to assess knowledge, attitudes, and practices that may contribute to this status as well as to receive feedback about the rabies control program in Grenada.

Methodology

A cross-sectional survey was conducted in July, 2017 with 996 households on the mainland. A questionnaire was administered to collect information on knowledge of rabies and prevention, vaccination practices, perception of institutional responsibilities for rabies control, and evaluation of the anti-rabies program.

Results

Of the 996 households, 617 (62%) had owners of animals that can be infected with rabies and were included in the analysis. Respondents were very aware of rabies as a disease that can infect animals and humans. The rate of participation in the vaccination program was 51.6% for pets and 38.0% for livestock. About 40% of respondents were knowledgeable about the extent of protection from the rabies vaccine. Respondents did not demonstrate exceptionally high levels of knowledge about animals that were likely to be infected with rabies, neither the anti-rabies programs that were conducted in Grenada. The three most frequent recommendations made to improve the rabies-control programs were: increase education programs, control the mongoose population, and expand the vaccination period each year.

Conclusions

Conducting a comprehensive national rabies education program, expanding the vaccination program, and increasing the rate of animal vaccination are important steps that need to be taken to maintain the current zero-human-case status.

Mechanisms underpinning the permanent muscle damage induced by snake venom metalloprotease

29 January 2019 - 10:00pm

by Harry F. Williams, Ben A. Mellows, Robert Mitchell, Peggy Sfyri, Harry J. Layfield, Maryam Salamah, Rajendran Vaiyapuri, Henry Collins-Hooper, Andrew B. Bicknell, Antonios Matsakas, Ketan Patel, Sakthivel Vaiyapuri

Snakebite is a major neglected tropical health issue that affects over 5 million people worldwide resulting in around 1.8 million envenomations and 100,000 deaths each year. Snakebite envenomation also causes innumerable morbidities, specifically loss of limbs as a result of excessive tissue/muscle damage. Snake venom metalloproteases (SVMPs) are a predominant component of viper venoms, and are involved in the degradation of basement membrane proteins (particularly collagen) surrounding the tissues around the bite site. Although their collagenolytic properties have been established, the molecular mechanisms through which SVMPs induce permanent muscle damage are poorly understood. Here, we demonstrate the purification and characterisation of an SVMP from a viper (Crotalus atrox) venom. Mass spectrometry analysis confirmed that this protein is most likely to be a group III metalloprotease (showing high similarity to VAP2A) and has been referred to as CAMP (Crotalus atrox metalloprotease). CAMP displays both collagenolytic and fibrinogenolytic activities and inhibits CRP-XL-induced platelet aggregation. To determine its effects on muscle damage, CAMP was administered into the tibialis anterior muscle of mice and its actions were compared with cardiotoxin I (a three-finger toxin) from an elapid snake (Naja pallida) venom. Extensive immunohistochemistry analyses revealed that CAMP significantly damages skeletal muscles by attacking the collagen scaffold and other important basement membrane proteins, and prevents their regeneration through disrupting the functions of satellite cells. In contrast, cardiotoxin I destroys skeletal muscle by damaging the plasma membrane, but does not impact regeneration due to its inability to affect the extracellular matrix. Overall, this study provides novel insights into the mechanisms through which SVMPs induce permanent muscle damage.

Assessment of trachoma in suspected endemic areas within 16 provinces in mainland China

28 January 2019 - 10:00pm

by Jialiang Zhao, Silvio Paolo Mariotti, Serge Resnikoff, Yuqin Wang, Shicheng Yu, Mingguang He, Yingchuan Fan, Haidong Zou, Wenfang Zhang, Yading Jia, Lihua Wang, Huaijin Guan, Xiao Xu, Leilei Zhan, Lei An, Quanfu Ye, Ningli Wang

Background

China used to be among the countries with a high prevalence of trachoma. At the launch of The Global Elimination of Trachoma (GET) 2020 campaign by the World Health Organization (WHO) in 1996, China was placed on the list of countries endemic for trachoma based on historical data. However, empirical observation and routinely collected eye care data were suggesting that trachoma was no longer a public health problem. To determine whether the GET 2020 goals had been met in P. R. China, we conducted a targeted assessment with national scope.

Methodology/principal finding

Province assessment teams, trained in WHO Trachoma Rapid Assessment (TRA) methodology and in WHO simplified trachoma grading system, carried out assessments in 16 provinces (among them, 2 provinces conducted pilot assessment). Based on the published literature, including national and international reports, suspected trachoma-endemic areas within each province were identified. Within these areas, trachomatous inflammation- follicular (TF) assessments were carried out in at least 50 grade-one children in primary schools serving villages with the lowest socio-economic development. Trachomatous trichiasis (TT) and corneal opacity (CO) assessments were conducted among persons aged 15 and over in villages within the catchment area of the selected schools. Of 8,259 children examined in 128 primary schools in 97 suspected trachoma endemic areas, only 16 cases of conjunctivitis were graded as TF. 38 cases with TT were found among the 339,013 examined residents in villages surrounding the schools. Among these 97 suspected trachoma endemic areas in only three was the prevalence of TT more than 0.2%.

Conclusions/significance

This large study suggested that trachoma was not a public health problem in 16 provinces that had been previously suspected to be endemic. These findings will facilitate planning for elimination of trachoma from PR China.

Community-level chlamydial serology for assessing trachoma elimination in trachoma-endemic Niger

28 January 2019 - 10:00pm

by Jessica S. Kim, Catherine E. Oldenburg, Gretchen Cooley, Abdou Amza, Boubacar Kadri, Baido Nassirou, Sun Yu Cotter, Nicole E. Stoller, Sheila K. West, Robin L. Bailey, Jeremy D. Keenan, Bruce D. Gaynor, Travis C. Porco, Thomas M. Lietman, Diana L. Martin

Background

Program decision-making for trachoma elimination currently relies on conjunctival clinical signs. Antibody tests may provide additional information on the epidemiology of trachoma, particularly in regions where it is disappearing or elimination targets have been met.

Methods

A cluster-randomized trial of mass azithromycin distribution strategies for trachoma elimination was conducted over three years in a mesoendemic region of Niger. Dried blood spots were collected from a random sample of children aged 1–5 years in each of 24 study communities at 36 months after initiation of the intervention. A multiplex bead assay was used to test for antibodies to two Chlamydia trachomatis antigens, Pgp3 and CT694. We compared seropositivity to either antigen to clinical signs of active trachoma (trachomatous inflammation—follicular [TF] and trachomatous inflammation—intense [TI]) at the individual and cluster level, and to ocular chlamydia prevalence at the community level.

Results

Of 988 children with antibody data, TF prevalence was 7.8% (95% CI 6.1 to 9.5) and TI prevalence was 1.6% (95% CI 0.9 to 2.6). The overall prevalence of antibody positivity to Pgp3 was 27.2% (95% CI 24.5 to 30), and to CT694 was 23.7% (95% CI 21 to 26.2). Ocular chlamydia infection prevalence was 5.2% (95% CI 2.8 to 7.6). Seropositivity to Pgp3 and/or CT694 was significantly associated with TF at the individual and community level and with ocular chlamydia infection and TI at the community level. Older children were more likely to be seropositive than younger children.

Conclusion

Seropositivity to Pgp3 and CT694 correlates with clinical signs and ocular chlamydia infection in a mesoendemic region of Niger.

Trial registration

ClinicalTrials.gov NCT00792922.

Triple oral beta-lactam containing therapy for Buruli ulcer treatment shortening

28 January 2019 - 10:00pm

by María Pilar Arenaz-Callao, Rubén González del Río, Ainhoa Lucía Quintana, Charles J. Thompson, Alfonso Mendoza-Losana, Santiago Ramón-García

The potential use of clinically approved beta-lactams for Buruli ulcer (BU) treatment was investigated with representative classes analyzed in vitro for activity against Mycobacterium ulcerans. Beta-lactams tested were effective alone and displayed a strong synergistic profile in combination with antibiotics currently used to treat BU, i.e. rifampicin and clarithromycin; this activity was further potentiated in the presence of the beta-lactamase inhibitor clavulanate. In addition, quadruple combinations of rifampicin, clarithromycin, clavulanate and beta-lactams resulted in multiplicative reductions in their minimal inhibitory concentration (MIC) values. The MIC of amoxicillin against a panel of clinical isolates decreased more than 200-fold within this quadruple combination. Amoxicillin/clavulanate formulations are readily available with clinical pedigree, low toxicity, and orally and pediatric available; thus, supporting its potential inclusion as a new anti-BU drug in current combination therapies.

Differential immunoglobulin and complement levels in leprosy prior to development of reversal reaction and erythema nodosum leprosum

28 January 2019 - 10:00pm

by Francianne M. Amorim, Maurício L. Nobre, Larissa S. Nascimento, Alesson M. Miranda, Glória R. G. Monteiro, Francisco P. Freire-Neto, Maria do Carmo Palmeira Queiroz, José W. Queiroz, Malcolm S. Duthie, Marcos R. Costa, Steven G. Reed, Warren D. Johnson Jr., Kathryn M. Dupnik, Selma M. B. Jeronimo

Background

Leprosy is a treatable infectious disease caused by Mycobacterium leprae. However, there is additional morbidity from leprosy-associated pathologic immune reactions, reversal reaction (RR) and erythema nodosum leprosum (ENL), which occur in 1 in 3 people with leprosy, even with effective treatment of M. leprae. There is currently no predictive marker in use to indicate which people with leprosy will develop these debilitating immune reactions. Our peripheral blood mononuclear cell (PBMC) transcriptome analysis revealed that activation of the classical complement pathway is common to both RR and ENL. Additionally, differential expression of immunoglobulin receptors and B cell receptors during RR and ENL support a role for the antibody-mediated immune response during both RR and ENL. In this study, we investigated B-cell immunophenotypes, total and M. leprae-specific antibodies, and complement levels in leprosy patients with and without RR or ENL. The objective was to determine the role of these immune mediators in pathogenesis and assess their potential as biomarkers of risk for immune reactions in people with leprosy.

Methodology/findings

We followed newly diagnosed multibacillary leprosy cases (n = 96) for two years for development of RR or ENL. They were compared with active RR (n = 35), active ENL (n = 29), and healthy household contacts (n = 14). People with leprosy who subsequently developed ENL had increased IgM, IgG1, and C3d-associated immune complexes with decreased complement 4 (C4) at leprosy diagnosis. People who developed RR also had decreased C4 at leprosy diagnosis. Additionally, elevated anti-M. leprae antibody levels were associated with subsequent RR or ENL.

Conclusions

Differential co-receptor expression and immunoglobulin levels before and during immune reactions intimate a central role for humoral immunity in RR and ENL. Decreased C4 and elevated anti-M. leprae antibodies in people with new diagnosis of leprosy may be risk factors for subsequent development of leprosy immune reactions.

Population genetic structure and geographical variation in <i>Neotricula aperta</i> (Gastropoda: Pomatiopsidae), the snail intermediate host of <i>Schistosoma mekongi</i> (Digenea: Schistosomatidae)

28 January 2019 - 10:00pm

by Stephen W. Attwood, Liang Liu, Guan-Nan Huo

Background

Neotricula aperta is the snail-intermediate host of the parasitic blood-fluke Schistosoma mekongi which causes Mekong schistosomiasis in Cambodia and the Lao PDR. Despite numerous phylogenetic studies only one DNA-sequence based population-genetic study of N. aperta had been published, and the origin, structure and persistence of N. aperta were poorly understood. Consequently, a phylogenetic and population genetic study was performed, with addition of new data to pre-existing DNA-sequences for N. aperta from remote and inaccessible habitats, including one new taxon from Laos and 505 bp of additional DNA-sequence for all sampled taxa,.

Principal findings

Spatial Principal Component Analysis revealed the presence of significant spatial-genetic clustering. Genetic-distance-based clustering indicated four populations with near perfect match to a priori defined ecogeographical regions. Spring-dwelling taxa were found to form an ecological isolate relative to other N. aperta. The poor dispersal capabilities suggested by spatial-genetic analyses were confirmed by Bayesian inference of migration rates. Population divergence time estimation implied a mid-Miocene colonisation of the present range, with immediate and rapid radiation in each ecogeographical region. Estimated effective population sizes were large (120–310 thousand).

Conclusions

The strong spatial-genetic structure confirmed the poor dispersal capabilities of N. aperta—suggesting human-mediated reintroduction of disease to controlled areas as the primary reason for control failure. The isolation of the spring-dwelling taxa and ecogeographical structure suggests adaptation of sub-populations to different habitats; the epidemiological significance of this needs investigation. The large effective population sizes indicate that the high population densities observed in surveyed habitats are also present in inaccessible areas; affording great potential for recrudescence driven by animal-reservoir transmission in remote streams. Mid-Miocene colonisation implies heterochronous evolution of these snails and associated schistosomes and suggests against coevolution of snail and parasite. Heterochronicity favours ecological factors as shapers of host-parasite specificity and greater potential for escape from schistosomiasis control through host-switching.

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