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Animal models of congenital zika syndrome provide mechanistic insight into viral pathogenesis during pregnancy

PLoS Neglected Tropical Diseases News - 22 October 2020 - 9:00pm

by Harish Narasimhan, Anna Chudnovets, Irina Burd, Andrew Pekosz, Sabra L. Klein

In utero Zika virus (ZIKV; family Flaviviridae) infection causes a distinct pattern of birth defects and disabilities in the developing fetus and neonate that has been termed congenital zika syndrome (CZS). Over 8,000 children were affected by the 2016 to 2017 ZIKV outbreak in the Americas, many of whom developed CZS as a result of in utero exposure. To date, there is no consensus about how ZIKV causes CZS; animal models, however, are providing mechanistic insights. Using nonhuman primates, immunocompromised mice, immunocompetent mice, and other animal models (e.g., pigs, sheep, guinea pigs, and hamsters), studies are showing that maternal immunological responses, placental infection and inflammation, as well as viral genetic factors play significant roles in predicting the downstream consequences of in utero ZIKV infection on the development of CZS in offspring. There are thousands of children suffering from adverse consequences of CZS. Therefore, the animal models developed to study ZIKV-induced adverse outcomes in offspring could provide mechanistic insights into how other viruses, including influenza and hepatitis C viruses, impact placental viability and fetal growth to cause long-term adverse outcomes in an effort to identify therapeutic treatments.

The neglected challenge: Vaccination against rickettsiae

PLoS Neglected Tropical Diseases News - 22 October 2020 - 9:00pm

by Anke Osterloh

Over the last decades, rickettsioses are emerging worldwide. These diseases are caused by intracellular bacteria. Although rickettsioses can be treated with antibiotics, a vaccine against rickettsiae is highly desired for several reasons. Rickettsioses are highly prevalent, especially in poor countries, and there are indications of the development of antibiotic resistance. In addition, some rickettsiae can persist and cause recurrent disease. The development of a vaccine requires the understanding of the immune mechanisms that are involved in protection as well as in immunopathology. Knowledge about these immune responses is accumulating, and efforts have been undertaken to identify antigenic components of rickettsiae that may be useful as a vaccine. This review provides an overview on current knowledge of adaptive immunity against rickettsiae, which is essential for defense, rickettsial antigens that have been identified so far, and on vaccination strategies that have been used in animal models of rickettsial infections.

Neuroinflammation associated with scrub typhus and spotted fever group rickettsioses

PLoS Neglected Tropical Diseases News - 22 October 2020 - 9:00pm

by James Fisher, Galen Card, Lynn Soong

Scrub typhus and spotted fever rickettsioses (SFR) are understudied, vector-borne diseases of global significance. Over 1 billion individuals are at risk for scrub typhus alone in an endemic region, spanning across eastern and southern Asia to Northern Australia. While highly treatable, diagnostic challenges make timely antibiotic intervention difficult for these diseases. Delayed therapy may lead to severe outcomes affecting multiple organs, including the central nervous system (CNS), where infection and associated neuroinflammation may be lethal or lead to lasting sequelae. Meningitis and encephalitis are prevalent in both scrub typhus and SFR. Additionally, case reports detailing focal neurological deficits have come to light, with attention to both acute and chronic sequelae of infection. Despite the increasing number of clinical reports outlining neurologic consequences of these diseases, relatively little research has examined underlying mechanisms of neuroinflammation. Animal models of scrub typhus have identified cerebral T-cell infiltration and vascular damage associated with endothelial infection and neuropathogenesis. Differential gene expression analysis of brain tissues during murine scrub typhus have revealed selective increases in CXCR3 ligands, proinflammatory and type-1 cytokines and chemokines, and cytotoxicity molecules, as well as alterations in the complement pathway. In SFR, microglial expansion and macrophage infiltration contribute to neurological disease progression. This narrative Review highlights clinical neurologic features of scrub typhus and SFR and evaluates our current understanding of basic research into neuroinflammation for both diseases in animal models. Further investigation into key mediators of neuropathogenesis may yield prognostic markers and treatment regimens for severe patients.

Quantifying and mapping the burden of human and animal rabies in Iraq

PLoS Neglected Tropical Diseases News - 22 October 2020 - 9:00pm

by Mashair Z. Ismail, Najlaa K. AL- Hamdi, Ali N. AL- Amery, Denise A. Marston, Lorraine McElhinney, Emma Taylor, Victor del Rio Vilas, Thani M. Dadan, Anthony R. Fooks, Daniel L. Horton

Rabies was first reported in ancient Iraqi civilizations, yet it remains a poorly quantified and important public health threat in the region. Efforts to control rabies in Iraq including dog population control, and vaccination of livestock and dogs, have increased since 2010. Officially reported data on human rabies, dog bites, and animal rabies cases between 2012 and 2017 are analysed here to assess the effect of existing control efforts, to inform future strategies, and to highlight gaps in surveillance and reporting. The results of molecular characterization of 32 viruses from animal cases from throughout Iraq are presented, to improve the understanding of rabies dynamics in the animal reservoir. Although annual numbers of reported human cases were lower in the period between 2012 and 2017 than prior to 2010, human cases continue. There was a distinct gender and age bias among human cases with nine cases in males for every one female and twice as many cases in children than adults. Spatial clustering analysis and phylogenetic evidence suggests rabies is endemic throughout the country, with no regional variation in risk, but better surveillance and reporting is required to underpin control strategies.

What are the implications of Zika Virus for infant feeding? A synthesis of qualitative evidence concerning Congenital Zika Syndrome (CZS) and comparable conditions

PLoS Neglected Tropical Diseases News - 21 October 2020 - 9:00pm

by Christopher Carroll, Andrew Booth, Fiona Campbell, Clare Relton

If a mother contracts the Zika Virus before or during pregnancy, then there is a risk of the child developing Congenital Zika Syndrome (CZS). An infant can then experience problems feeding due to the specific physical and developmental consequences of Congenital Zika Syndrome (CZS), such as microcephaly, dysphagia and an increased likelihood of choking. This qualitative evidence synthesis accesses direct and indirect evidence to inform WHO infant feeding guidelines. We conducted a qualitative evidence synthesis of the values and preferences of relevant stakeholders (e.g. pregnant women, mothers, family members and health practitioners) concerning infant (0–2 years) feeding in the presence of: 1) CZS (the‘direct evidence’); 2) severe disability and nonprogressive, chronic encephalopathies (‘indirect evidence’), which present with similar problems. Authors’ findings were extracted, synthesised using thematic synthesis techniques, and confidence in the findings were assessed using GRADE-CERQual. Six CZS-specific studies (all from Brazil) were included in the direct evidence, with a further eight indirect studies reporting feeding difficulties in infants with severe disability and nonprogressive, chronic encephalopathies. Included studies highlighted: breast-feeding represented the preference for all mothers in the studies in both reviews, and the inability to do so affected bonding between parents and child, and generated fear and anxiety relating to feeding choices, especially around the risks of choking and swallowing; the perception that health professionals were often unable to offer appropriate advice; the potential value of training; and a strong desire to achieve individual maternal autonomy in infant feeding decisions. Confidence in most findings ranged from low to moderate. The evidence base has limitations, but consistently reported that parents of children with feeding difficulties due to Congenital Zika Syndrome, or similar, need information, advice and counselling, and substantial emotional support. Parents perceive that these needs are often neither recognised nor satisfied; optimal feeding and support strategies for this population have not yet been identified.

Synthetic sex-aggregation pheromone of <i>Lutzomyia longipalpis</i>, the South American sand fly vector of <i>Leishmania infantum</i>, attracts males and females over long-distance

PLoS Neglected Tropical Diseases News - 20 October 2020 - 9:00pm

by Mikel A. González, Melissa Bell, Cristian F. Souza, Rafael Maciel-de-Freitas, Reginaldo P. Brazil, Orin Courtenay, James G. C. Hamilton

Background

In South America the sand fly Lutzomyia longipalpis is the predominant vector of Leishmania infantum, the parasite that causes canine and human visceral leishmaniasis. Co-location of synthetic male sex-aggregation pheromone with an insecticide provided protection against canine seroconversion, parasite infection, reduced tissue parasite loads, and female sand fly densities at households. Optimising the sex-aggregation pheromone + insecticide intervention requires information on the distance over which female and male Lu. longipalpis would be attracted to the synthetic pheromone in the field.

Methodology/Principal findings

Wild Lu. longipalpis were collected at two peridomestic study sites in Governador Valadares (Minas Gerais, Brazil). Sand flies were marked with coloured fluorescent powder using an improved protocol and then released into an existing domestic chicken shed at two independent sites, followed by recapture at synthetic-pheromone host-odour baited traps placed up to 30 metres distant from the release point.In total 1704 wild-caught Lu. longipalpis were released into the two chicken sheds. Overall 4.3% of the marked flies were recaptured in the pheromone baited experimental chicken sheds compared to no marked flies recaptured in the control sheds. At the first site, 14 specimens (10.4% of the marked and released specimens) were recaptured at 10m, 36 (14.8%) at 20m, and 15 (3.4%) at 30m. At the second site, lower recapture rates were recorded; 8 marked specimens (1.3%) were recaptured at 5 and 10m and no marked specimens were recaptured at 15m. Approximately 7x more marked males than females were recaptured although males were only 2x as common as females in the released population. 52% of the marked Lu. longipalpis were collected during the first night of sampling, 32% on the second night, and 16% on the third night.

Conclusions/Significance

The study established that both male and female sand flies can be attracted to the synthetic sex-aggregation pheromone in the presence of host odour over distances up to at least 30m in the field depending on local environmental and meterological conditions.

Homologous and heterologous re-challenge with <i>Salmonella</i> Typhi and <i>Salmonella</i> Paratyphi A in a randomised controlled human infection model

PLoS Neglected Tropical Diseases News - 20 October 2020 - 9:00pm

by Malick M. Gibani, Celina Jin, Sonu Shrestha, Maria Moore, Lily Norman, Merryn Voysey, Elizabeth Jones, Luke Blackwell, Helena Thomaides-Brears, Jennifer Hill, Christoph J. Blohmke, Hazel C. Dobinson, Philip Baker, Claire Jones, Danielle Campbell, Yama F. Mujadidi, Emma Plested, Lorena Preciado-Llanes, Giorgio Napolitani, Alison Simmons, Melita A. Gordon, Brian Angus, Thomas C. Darton, Vincenzo Cerundulo, Andrew J. Pollard

Enteric fever is a systemic infection caused by Salmonella Typhi or Paratyphi A. In many endemic areas, these serovars co-circulate and can cause multiple infection-episodes in childhood. Prior exposure is thought to confer partial, but incomplete, protection against subsequent attacks of enteric fever. Empirical data to support this hypothesis are limited, and there are few studies describing the occurrence of heterologous-protection between these closely related serovars. We performed a challenge-re-challenge study using a controlled human infection model (CHIM) to investigate the extent of infection-derived immunity to Salmonella Typhi or Paratyphi A infection. We recruited healthy volunteers into two groups: naïve volunteers with no prior exposure to Salmonella Typhi/Paratyphi A and volunteers previously-exposed to Salmonella Typhi or Paratyphi A in earlier CHIM studies. Within each group, participants were randomised 1:1 to oral challenge with either Salmonella Typhi (104 CFU) or Paratyphi A (103 CFU). The primary objective was to compare the attack rate between naïve and previously challenged individuals, defined as the proportion of participants per group meeting the diagnostic criteria of temperature of ≥38°C persisting for ≥12 hours and/or S. Typhi/Paratyphi bacteraemia up to day 14 post challenge. The attack-rate in participants who underwent homologous re-challenge with Salmonella Typhi was reduced compared with challenged naïve controls, although this reduction was not statistically significant (12/27[44%] vs. 12/19[63%]; Relative risk 0.70; 95% CI 0.41–1.21; p = 0.24). Homologous re-challenge with Salmonella Paratyphi A also resulted in a lower attack-rate than was seen in challenged naïve controls (3/12[25%] vs. 10/18[56%]; RR0.45; 95% CI 0.16–1.30; p = 0.14). Evidence of protection was supported by a post hoc analysis in which previous exposure was associated with an approximately 36% and 57% reduced risk of typhoid or paratyphoid disease respectively on re-challenge. Individuals who did not develop enteric fever on primary exposure were significantly more likely to be protected on re-challenge, compared with individuals who developed disease on primary exposure. Heterologous re-challenge with Salmonella Typhi or Salmonella Paratyphi A was not associated with a reduced attack rate following challenge. Within the context of the model, prior exposure was not associated with reduced disease severity, altered microbiological profile or boosting of humoral immune responses. We conclude that prior Salmonella Typhi and Paratyphi A exposure may confer partial but incomplete protection against subsequent infection, but with a comparable clinical and microbiological phenotype. There is no demonstrable cross-protection between these serovars, consistent with the co-circulation of Salmonella Typhi and Paratyphi A. Collectively, these data are consistent with surveillance and modelling studies that indicate multiple infections can occur in high transmission settings, supporting the need for vaccines to reduce the burden of disease in childhood and achieve disease control. Trial registration NCT02192008; clinicaltrials.gov.

Outdoor Residual Insecticide Spraying (ODRS), a New Approach for the Control of the Exophilic Vectors of Human Visceral Leishmaniasis: <i>Phlebotomus orientalis</i> in East Africa

PLoS Neglected Tropical Diseases News - 20 October 2020 - 9:00pm

by Dia-Eldin A. Elnaiem, Osman Dakein, Ahmed Mohammed-Ali Alawad, Bashir Alsharif, Altayeb Khogali, Tayseer Jibreel, Omran F. Osman, Hassan Has’san, Atia Mohamed Atia, Mousab Elhag, Margriet Den Boer, Koert Ritmeijer, Caryn Bern, Jorge Alvar, Noteila Khalid, Orin Courtenay

Visceral Leishmaniasis (VL) due to Leishmania donovani is a neglected protozoan parasitic disease in humans, which is usually fatal if untreated. Phlebotomus orientalis, the predominant VL vector in East Africa, is a highly exophilic/exophagic species that poses a major challenge to current Integrated Vector Management (IVM). Here we report results of pilot studies conducted in rural villages in Gedarif state, Sudan, to evaluate outdoor residual spraying of 20mg active ingredient (a.i.) /m2 deltamethrin insecticide applied to the characteristic household compound boundary reed fence and to the outside of household buildings (Outdoor Residual Insecticide Spraying, ODRS), and as an alternative, spraying restricted to the boundary fence only (Restricted Outdoor Residual Insecticide Spraying, RODRS). Four to six clusters of 20 households were assigned to insecticide treatments or control in three experiments. Changes in sand fly numbers were monitored over 2,033 trap-nights over 43–76 days follow-up in four sentinel houses per cluster relative to unsprayed control clusters. Sand fly numbers were monitored by sticky traps placed on the ground on the inside (“outdoor”) and the outside (“peridomestic”) of the boundary fence, and by CDC light traps suspended outdoors in the household compound. The effects of ODRS on sand fly numbers inside sleeping huts were monitored by insecticide knockdown. After a single application, ODRS reduced P. orientalis abundance by 83%-99% in outdoor and peridomestic trap locations. ODRS also reduced numbers of P. orientalis found resting inside sleeping huts. RODRS reduced outdoor and peridomestic P. orientalis by 60%-88%. By direct comparison, RODRS was 58%-100% as effective as ODRS depending on the trapping method. These impacts were immediate on intervention and persisted during follow-up, representing a large fraction of the P. orientalis activity season. Relative costs of ODRS and RODRS delivery were $5.76 and $3.48 per household, respectively. The study demonstrates the feasibility and high entomological efficacy of ODRS and RODRS, and the expected low costs relative to current IVM practises. These methods represent novel sand fly vector control tools against predominantly exophilic/exophagic sand fly vectors, aimed to lower VL burdens in Sudan, with potential application in other endemic regions in East Africa.

An updated antennal lobe atlas for the yellow fever mosquito <i>Aedes aegypti</i>

PLoS Neglected Tropical Diseases News - 20 October 2020 - 9:00pm

by Shruti Shankar, Conor J. McMeniman

The yellow fever mosquito Aedes aegypti is a prolific vector of arboviral and filarial diseases that largely relies on its sense of smell to find humans. To facilitate in-depth analysis of the neural circuitry underlying Ae. aegypti olfactory-driven behaviors, we generated an updated in vitro atlas for the antennal lobe olfactory brain region of this disease vector using two independent neuronal staining methods. We performed morphological reconstructions with replicate fixed, dissected and stained brain samples from adult male and female Ae. aegypti of the LVPib12 genome reference strain and determined that the antennal lobe in both sexes is comprised of approximately 80 discrete glomeruli. Guided by landmark features in the antennal lobe, we found 63 of these glomeruli are stereotypically located in spatially invariant positions within these in vitro preparations. A posteriorly positioned, mediodorsal glomerulus denoted MD1 was identified as the largest spatially invariant glomerulus in the antennal lobe. Spatial organization of glomeruli in a recently field-derived strain of Ae. aegypti from Puerto Rico was conserved, despite differences in antennal lobe shape relative to the inbred LVPib12 strain. This model in vitro atlas will serve as a useful community resource to improve antennal lobe annotation and anatomically map projection patterns of neurons expressing target genes in this olfactory center. It will also facilitate the development of chemotopic maps of odor representation in the mosquito antennal lobe to decode the molecular and cellular basis of Ae. aegypti attraction to human scent and other chemosensory cues.

The function of peroxisome proliferator-activated receptors PPAR-γ and PPAR-δ in <i>Mycobacterium leprae</i>-induced foam cell formation in host macrophages

PLoS Neglected Tropical Diseases News - 19 October 2020 - 9:00pm

by Yuqian Luo, Kazunari Tanigawa, Akira Kawashima, Yuko Ishido, Norihisa Ishii, Koichi Suzuki

Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae). In lepromatous leprosy (LL), skin macrophages, harboring extensive bacterial multiplication, gain a distinctive foamy appearance due to increased intracellular lipid load. To determine the mechanism by which M. leprae modifies the lipid homeostasis in host cells, an in vitro M. leprae infection system, using human macrophage precursor THP-1 cells and M. leprae prepared from the footpads of nude mice, was employed. RNA extracted from skin smear samples of patients was used to investigate host gene expressions before and after multidrug therapy (MDT). We found that a cluster of peroxisome proliferator-activated receptor (PPAR) target genes associated with adipocyte differentiation were strongly induced in M. leprae-infected THP-1 cells, with increased intracellular lipid accumulation. PPAR-δ and PPAR-γ expressions were induced by M. leprae infection in a bacterial load-dependent manner, and their proteins underwent nuclear translocalization after infection, indicating activation of PPAR signaling in host cells. Either PPAR-δ or PPAR-γ antagonist abolished the effect of M. leprae to modify host gene expressions and inhibited intracellular lipid accumulation in host cells. M. leprae-specific gene expressions were detected in the skin smear samples both before and after MDT, whereas PPAR target gene expressions were dramatically diminished after MDT. These results suggest that M. leprae infection activates host PPAR signaling to induce an array of adipocyte differentiation-associated genes, leading to accumulation of intracellular lipids to accommodate M. leprae parasitization. Certain PPAR target genes in skin lesions may serve as biomarkers for monitoring treatment efficacy.

The pattern of anthrax at the wildlife-livestock-human interface in Zimbabwe

PLoS Neglected Tropical Diseases News - 19 October 2020 - 9:00pm

by Norman L. Mukarati, Gift Matope, Michel de Garine-Wichatitsky, Daud N. Ndhlovu, Alexandre Caron, Davies M. Pfukenyi

Anthrax is an important but neglected zoonosis in southern Africa and elsewhere which occurs naturally in herbivorous wildlife and livestock. Fatal outbreaks in animals are spaced by potentially extended periods of non-activity during which the bacterium is maintained in soil. The ecology of the pathogen in the multi-host system and the environment is still not fully understood. This study investigated the patterns of anthrax in Zimbabwe in order to better understand the occurrence of disease in susceptible wildlife and livestock and hence its control. The study used available data in governmental reports between 1995 and 2018 and structured interviewer-administered questionnaires of local communities in three porous wildlife-livestock-human interface sites where livestock/wildlife interactions were documented from previous researches. Two non-interface sites were also included for comparison based on known previous anthrax outbreaks. Respondents from non-interface sites had significantly higher odds (χ2 = 23.2, OR = 3.5, 2.1

Nuclear and kinetoplast DNA analyses reveal genetically complex <i>Leishmania</i> strains with hybrid and mito-nuclear discordance in Peru

PLoS Neglected Tropical Diseases News - 19 October 2020 - 9:00pm

by Ahmed Tabbabi, Abraham G. Cáceres, T. Pershing Bustamante Chauca, Chisato Seki, Yanisa Choochartpong, Daiki Mizushima, Daisuke S. Yamamoto, Yoshihisa Hashiguchi, Hirotomo Kato

Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis of the mannose phosphate isomerase (mpi) gene was applied to 134 skin samples collected from patients with cutaneous leishmaniasis (CL) in Peru for identification of the infecting parasite at the species level, and the results were compared with those of cytochrome b (cyt b) gene sequencing obtained in previous studies. Although most results (121/134) including 4 hybrids of Leishmania (Viannia) braziliensis and L. (V.) peruviana corresponded to those obtained in the previous study, PCR-RFLP analyses revealed the distribution of putative hybrid strains between L. (V.) peruviana and L. (V.) lainsoni in two samples, which has never been reported. Moreover, parasite strains showing discordance between kinetoplast and nuclear genes (kDNA and nDNA), so-called mito-nuclear discordance, were identified in 11 samples. Of these, six strains had the kDNAs of L. (V.) braziliensis or L. (V.) peruviana and nDNAs of L. (V.) guyanensis, and three strains had the kDNAs of L. (V.) shawi and nDNAs of L. (V.) braziliensis. The rest were identified as mito-nuclear discordance strains having kDNAs of L. (V.) braziliensis or L. (V.) peruviana and nDNAs of L. (V.) lainsoni, and kDNAs of L. (V.) lainsoni and nDNAs of L. (V.) braziliensis. The results demonstrate that Leishmania strains in Peru are genetically more complex than previously considered.

Effects of ‘The Vicious Worm’ educational software on <i>Taenia solium</i> knowledge among key pork supply chain workers in Zambia

PLoS Neglected Tropical Diseases News - 19 October 2020 - 9:00pm

by Victor Vaernewyck, Kabemba Evans Mwape, Chishimba Mubanga, Brecht Devleesschauwer, Sarah Gabriël, Chiara Trevisan

The neglected zoonotic cestode Taenia solium is endemic in many low- and middle-income countries, including Zambia. The parasite infects humans and pigs, inflicting high socioeconomic and disease burdens in endemic areas. Health education is regarded as an important component in T. solium control and previous studies indicate that ‘The Vicious Worm’ may be an effective T. solium health education tool for Tanzanian medical and agricultural professionals and Zambian primary school students. This study aimed to assess the effects of health education using ‘The Vicious Worm’ among Zambian pork supply chain workers, because the pork supply chain greatly influences food safety and security in Zambia. Half-day educational workshops using ‘The Vicious Worm’ and subsequent follow-up sessions were organized in the Lusaka and Katete districts of Zambia in March and April 2019. Questionnaires were administered before, after, and three weeks after the use of ‘The Vicious Worm’ to assess the program’s impact on knowledge uptake and short-term retention. Focus group discussions were conducted to assess the program’s user experience and the participants’ beliefs, attitudes, and insights. In total, 47 pork supply chain workers participated: 25 from Lusaka and 22 from Katete. Overall, knowledge about T. solium was significantly higher (p<0.001) both immediately after, and three weeks after the use of ‘The Vicious Worm’ compared to baseline knowledge. Focus group discussions indicated incipient attitudinal and behavioral change, as well as a positive reception of the software; with participants describing the software as simple, educative, and useful to share knowledge. The study results indicate that workshops using ‘The Vicious Worm’ may be effective for short-term T. solium health education among key pork supply chain workers. Follow-up studies are required to assess long-term effects, transfer of knowledge and behavioral change. However, educational interventions with ‘The Vicious Worm’ could be considered for integrated T. solium control programs in sub-Saharan Africa, especially if the educational content is further simplified and clarified.

Orthohantaviruses infections in humans and rodents in Baoji, China

PLoS Neglected Tropical Diseases News - 19 October 2020 - 9:00pm

by Hui Tian, Wei-Fang Tie, Hongbing Li, Xiaoqian Hu, Guang-Cheng Xie, Luan-Ying Du, Wen-Ping Guo

In recent years, hemorrhagic fever with renal syndrome (HFRS) incidence has been becoming a severe public health problem again due to its significant increase in Shaanxi Province, China. Baoji, located in the Guanzhong Plain in the central parts of Shaanxi Province, has been severely affected by HFRS since its first emergence in 1955. To better understand the epidemiology of orthohantaviruses infection in humans and the causative agents carried by the rodents, the long-term incidence patterns were analyzed and a molecular epidemiological investigation of orthohantaviruses infection in humans and rodents was performed. During 1984–2019, 13,042 HFRS cases were registered in Baoji, including 275 death cases. Except the first high prevalence of HFRS in 1988–1993, another two epidemic peaks were observed in 1998–2003 and 2012, respectively, although vaccination project was started since 1996. During the same period, HFRS cases in Baoji mainly were recorded in winter suggesting they may be caused by Hantaan orthohantavirus (HTNV), while a small peak of HFRS was also found in summer with unknown reason. Nucleotide identity and phylogenetic analyses demonstrated that a novel clade of HTNV sequences recovered from HFRS cases were closely related to those from rodents, including species close contact with humans, suggesting a direct viral transmission from rodents to humans and the important role in the HTNV transmission the nontraditional rodent hosts may play. Moreover, two distant related Dabieshan orthohantavirus (DBSV) lineages were also identified in Niviventer niviventer in this area demonstrating its considerable genetic diversity. Our data indicated that continual spillover of HTNV from rodents to humans, contributing to the high prevalence of HFRS in humans in Baoji.

Evaluation of a facility-based inspection tool to assess lymphedema management services in Vietnam

PLoS Neglected Tropical Diseases News - 19 October 2020 - 9:00pm

by Do Trung Dung, Vu Thi Lam Binh, Caitlin M. Worrell, Molly Brady, Victoria Walsh, Aya Yajima, Zeina Sifri, LeAnne M. Fox

Assuring availability of services for patients with lymphedema is required for countries to be validated as having achieved elimination of lymphatic filariasis (LF). A direct inspection protocol (DIP) tool, designed to measure the readiness to provide quality lymphedema management services, has recently been developed. The DIP tool includes 14 indicators across six quality themes: trained staff, case management and education materials, water infrastructure, medications and commodities, patient tracking system, and staff knowledge. We evaluated the use of the tool in Vietnam, where data were needed to inform validation efforts. To apply the tool in Vietnam, we compiled a list of 219 commune health stations (CHS) with known lymphedema patients and conducted a cross-sectional survey in 32 CHS; including 24 in Red River Delta region, 2 in the North Central region, and 6 in the South Central Coast region. The mean facility score, calculated by assigning 1 point per indicator, was 8.8 of 14 points (63%, range 4[29%]-13[93%]). Percentage of surveyed facilities with staff trained in last two years was 0%; availability of lymphedema management guidelines (56%); availability of information, education, and communication materials (16%); reliable improved water infrastructure (94%); availability of antiseptics (81%), antifungals (44%), analgesics or anti-inflammatories (97%), antibiotics (94%); supplies for lymphedema and acute attack management (100%); lymphedema patients recorded in last 12 months (9%); staff knowledge about lymphedema signs/symptoms (63%), lymphedema management strategies (72%), signs/symptoms of acute attacks (81%), and acute attack management strategies (75%). The tool allowed standardized assessment of readiness to provide quality services. Lack of trained health staff, limited patient tracking, and depletion of education materials were identified as challenges and addressed by the national program. Survey data were included in the validation dossier, providing evidence necessary for WHO to validate Vietnam as having eliminated lymphatic filariasis in 2018.

Anthelminthic treatment receipt and its predictors in Lake Victoria fishing communities, Uganda: Intervention coverage results from the LaVIISWA cluster randomised trial

PLoS Neglected Tropical Diseases News - 19 October 2020 - 9:00pm

by Hellen Akurut, Richard E. Sanya, Lawrence Lubyayi, Margaret Nampijja, Moses Kizza, James Kaweesa, Robert Kizindo, Moses Sewankambo, Denis Nsubuga, Edridah Tukahebwa, Narcis B. Kabatereine, Alison M. Elliott, Emily L. Webb, for the LaVIISWA trial team

Background

Mass drug administration (MDA) is a cornerstone of control of parasitic helminths. In schistosomiasis-endemic areas with >50% of school-aged children infected, community-wide MDA with praziquantel is recommended by the World Health Organisation (WHO), with target coverage of >75%. Using data from a cluster-randomised trial of MDA treatment strategies, we aimed to describe the proportion of eligible residents who received MDA and predictors of treatment receipt, and to assess associations with helminth prevalence.

Methods

In the Koome islands of Lake Victoria, Uganda, where baseline schistosomiasis prevalence (by single stool sample, Kato-Katz) was 52% overall (all ages) and 67% among school-aged children, we conducted a cluster-randomised trial of community-wide, intensive MDA (quarterly single-dose praziquantel 40mg/kg; triple-dose albendazole 400mg) versus standard, Uganda government intervention (annual single-dose praziquantel 40mg/kg; 6-monthly single-dose albendazole). Twenty-six fishing villages were randomised, 13 per trial arm, for four years. At each treatment round, praziquantel treatment and the first dose of albendazole treatment were directly observed by the study team, registers of village residents were updated and the proportion receiving treatment among those eligible recorded.

Results

During the four-year MDA, at each treatment round an average of 13,382 people were registered in the 26 villages (7,153 and 6,229 in standard and intensive intervention villages, respectively). Overall, the proportion of those eligible receiving praziquantel was lower than for albendazole (60% versus 65%), particularly in the standard arm (61% versus 71%) compared to the intensive arm (60% versus 62%). Albendazole receipt was lower when given concurrently with praziquantel. Absence was the commonest reason for non-receipt of treatment (81% albendazole, 77% praziquantel), followed by refusal (14% albendazole, 18% praziquantel). Proportions receiving treatment were lowest among school-aged children, but did not differ by sex. Longitudinal analysis of a subgroup of residents who did not move during the study period found that persistent non-receipt of treatment in this subgroup was rare. Refusal to receive treatment was highest among adults and more common among females.

Conclusion

In schistosomiasis high-risk communities, a combination of approaches to increasing treatment coverage, such as extended periods of treatment delivery, and the provision of incentives, may be required to achieve WHO targets.

Temporal trends of cutaneo-mucous histoplasmosis in persons living with HIV in French Guiana: Early diagnosis defuses South American strain dermotropism

PLoS Neglected Tropical Diseases News - 19 October 2020 - 9:00pm

by Sophie Morote, Mathieu Nacher, Romain Blaizot, Balthazar Ntab, Denis Blanchet, Kinan Drak Alsibai, Magalie Demar, Félix Djossou, Pierre Couppié, Antoine Adenis

Histoplasmosis is the most frequent opportunistic infection and the first cause of mortality in HIV-infected patients in French Guiana and presumably in much of Latin America. Mucocutaneous lesions of histoplasmosis are considered as rare and late manifestations of the disease. It has been debated whether the greater proportion of cutaneo-mucous presentations in South America relative to the USA was the reflection of Histoplasma strains with increased dermotropism or simply delayed diagnosis and advanced immunosuppression. The objective of this study was to describe the clinical presentation, frequency, prognosis and temporal trends of cutaneomucous histoplasmosis in French Guiana. A retrospective study of patients with AIDS-related disseminated histoplasmosis followed in the three hospitals of French Guiana was performed between 1981 and 2014. Incident cases of histoplasmosis, proved by pathology and/or mycological examinations, were studied. Mucocutaneous histoplasmosis was confirmed by a positive cutaneous or mucosal biopsy. Mucocutaneous lesions were polymorphic. Ninety percent of patients were profoundly immunocompromised patients (CD4<50/mm3) and over 80% were not on antiretroviral treatment. The frequency of mucocutaneous forms and case fatality of disseminated histoplasmosis within one month of antifungal treatment significantly decreased over time (p<0,001). In this South American territory, diagnostic and therapeutic improvements have led to the quasi disappearance of cutaneous manifestations. There may be South American dermotropism in the laboratory but at the bedside early diagnosis seems to be the main parameter explaining the proportion of cutaneomucous presentations in South America relative to the USA.

Quorum sensing N-Acyl homoserine lactones are a new class of anti-schistosomal

PLoS Neglected Tropical Diseases News - 19 October 2020 - 9:00pm

by Helen Whiteland, Alessandra Crusco, Lisa W. Bloemberg, Jamie Tibble-Howlings, Josephine Forde-Thomas, Avril Coghlan, Patrick J. Murphy, Karl F. Hoffmann

Background

Schistosomiasis is a prevalent neglected tropical disease that affects approximately 300 million people worldwide. Its treatment is through a single class chemotherapy, praziquantel. Concerns surrounding the emergence of praziquantel insensitivity have led to a need for developing novel anthelmintics.

Methodology/Principle findings

Through evaluating and screening fourteen compounds (initially developed for anti-cancer and anti-viral projects) against Schistosoma mansoni, one of three species responsible for most cases of human schistosomiasis, a racemic N-acyl homoserine (1) demonstrated good efficacy against all intra mammalian lifecycle stages including schistosomula (EC50 = 4.7 μM), juvenile worms (EC50 = 4.3 μM) and adult worms (EC50 = 8.3 μM). To begin exploring structural activity relationships, a further 8 analogues of this compound were generated, including individual (R)- and (S)- enantiomers. Upon anti-schistosomal screening of these analogues, the (R)- enantiomer retained activity, whereas the (S)- lost activity. Furthermore, modification of the lactone ring to a thiolactone ring (3) improved potency against schistosomula (EC50 = 2.1 μM), juvenile worms (EC50 = 0.5 μM) and adult worms (EC50 = 4.8 μM). As the effective racemic parent compound is structurally similar to quorum sensing signaling peptides used by bacteria, further evaluation of its effect (along with its stereoisomers and the thiolactone analogues) against Gram+ (Staphylococcus aureus) and Gram- (Escherichia coli) species was conducted. While some activity was observed against both Gram+ and Gram- bacteria species for the racemic compound 1 (MIC 125 mg/L), the (R) stereoisomer had better activity (125 mg/L) than the (S) (>125mg/L). However, the greatest antimicrobial activity (MIC 31.25 mg/L against S. aureus) was observed for the thiolactone containing analogue (3).

Conclusion/Significance

To the best of our knowledge, this is the first demonstration that N-Acyl homoserines exhibit anthelmintic activities. Furthermore, their additional action on Gram+ bacteria opens a new avenue for exploring these molecules more broadly as part of future anti-infective initiatives.

Clinical course and potential predictive factors for pneumonia of adult patients with Coronavirus Disease 2019 (COVID-19): A retrospective observational analysis of 193 confirmed cases in Thailand

PLoS Neglected Tropical Diseases News - 16 October 2020 - 9:00pm

by Wannarat A. Pongpirul, Surasak Wiboonchutikul, Lantharita Charoenpong, Nayot Panitantum, Apichart Vachiraphan, Sumonmal Uttayamakul, Krit Pongpirul, Weerawat Manosuthi, Wisit Prasithsirikul

Clinical spectrum of Coronavirus Disease 2019 (COVID-19) remains unclear, especially with regard to the presence of pneumonia. We aimed to describe the clinical course and final outcomes of adult patients with laboratory-confirmed COVID-19 in the full spectrum of disease severity. We also aimed to identify potential predictive factors for COVID-19 pneumonia. We conducted a retrospective study among adult patients with laboratory-confirmed COVID-19 who were hospitalized at Bamrasnaradura Infectious Diseases Institute, Thailand, between January 8 and April 16, 2020. One-hundred-and-ninety-three patients were included. The median (IQR) age was 37.0 (29.0–53.0) years, and 58.5% were male. The median (IQR) incubation period was 5.5 (3.0–8.0) days. More than half (56%) of the patients were mild disease severity, 22% were moderate, 14% were severe, and 3% were critical. Asymptomatic infection was found in 5%. The final clinical outcomes in 189 (97.9%) were recovered and 4 (2.1%) were deceased. The incidence of pneumonia was 39%. The median (IQR) time from onset of illness to pneumonia detection was 7.0 (5.0–9.0) days. Bilateral pneumonia was more prevalent than unilateral pneumonia. In multivariable logistic regression, increasing age (OR 2.55 per 10-year increase from 30 years old; 95% CI, 1.67–3.90; p<0.001), obesity (OR 8.74; 95%CI, 2.06–37.18; p = 0.003), and higher temperature at presentation (OR 4.59 per 1°C increase from 37.2°C; 95% CI, 2.30–9.17; p<0.001) were potential predictive factors for COVID-19 pneumonia. Across the spectrum of disease severities, most patients with COVID-19 in our cohort had good final clinical outcomes. COVID-19 pneumonia was found in one-third of them. Older age, obesity, and higher fever at presentation were independent predictors of COVID-19 pneumonia.

Health state utility values in people living with HTLV-1 and in patients with HAM/TSP: The impact of a neglected disease on the quality of life

PLoS Neglected Tropical Diseases News - 16 October 2020 - 9:00pm

by Carolina Rosadas, Tatiane Assone, Marina Yamashita, Adine Adonis, Marzia Puccioni-Sohler, Marisa Santos, Arthur Paiva, Jorge Casseb, Augusto C. P. Oliveira, Graham P. Taylor

Background: HTLV-1 is a neglected sexually transmitted infection despite being the cause of disabling neurological disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is no treatment for this infection and public health policies are essential to reduce its transmission. However, there are no data to support adequate cost-effective analysis in this field. The aim of this study was to obtain health state utility values for individuals with HAM/TSP and HTLV-1 asymptomatic carriers (AC). The impact of both states on quality of life (QoL) is described and compared to other diseases. Methods: A cross-sectional observational study of 141 individuals infected with HTLV-1 (79 with HAM/TSP and 62 AC) from three Brazilian states (Rio de Janeiro, São Paulo and Alagoas) and from the United Kingdom. Participants completed a validated general health questionnaire (EQ-5D, Euroqol) from which country specific health state utility values are generated. Clinical and epidemiological data were collated. Principal findings: Health state utility value for HAM/TSP was 0.2991. QoL for 130 reported clinical conditions ranges from 0.35 to 0.847. 12% reported their quality of life as worse as death. Low QoL was associated with severity rather than duration of disease with a moderate inverse correlation between QoL and Osame’s Motor Disability Score (-0.4933) Patients who are wheelchair dependent had lowest QoL whilst those still walking unaided had the highest. AC also reported impaired QoL (0.7121) compared to general population. Conclusion: HTLV-1 and its associated neurological disease has a marked impact on QoL. This study provides robust data to support the development of cost-utility analysis of interventions for HTLV-1.

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