Publications by authors named "Duane J Gubler"

110 Publications

Th1-Polarized, Dengue Virus-Activated Human Mast Cells Induce Endothelial Transcriptional Activation and Permeability.

Viruses 2020 12 2;12(12). Epub 2020 Dec 2.

Program in Emerging Infectious Diseases, Duke-National University of Singapore, Singapore 169857, Singapore.

Dengue virus (DENV), an arbovirus, strongly activates mast cells (MCs), which are key immune cells for pathogen immune surveillance. In animal models, MCs promote clearance of local peripheral DENV infections but, conversely, also promote pathological vascular leakage when widely activated during systemic DENV infection. Since DENV is a human pathogen, we sought to ascertain whether a similar phenomenon could occur in humans by characterizing the products released by human MCs (huMCs) upon direct (antibody-independent) DENV exposure, using the phenotypically mature huMC line, ROSA. DENV did not productively infect huMCs but prompted huMC release of proteases and eicosanoids and induced a Th1-polarized transcriptional profile. In co-culture and trans-well systems, huMC products activated human microvascular endothelial cells, involving transcription of vasoactive mediators and increased monolayer permeability. This permeability was blocked by MC-stabilizing drugs, or limited by drugs targeting certain MC products. Thus, MC stabilizers are a viable strategy to limit MC-promoted vascular leakage during DENV infection in humans.
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http://dx.doi.org/10.3390/v12121379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761533PMC
December 2020

Arboviruses: A global public health threat.

Vaccine 2020 05 24;38(24):3989-3994. Epub 2020 Apr 24.

Duke NUS Medical School, Singapore. Electronic address:

A conference on «ARBOVIRUSES, A GLOBAL PUBLIC HEALTH THREAT» was organized on June 20-22, 2018 at the Merieux Foundation Conference Center in Veyrier du Lac, France, to review and raise awareness to the global public health threat of epidemic arboviruses, and to advance the discussion on the control and prevention of arboviral diseases. The presentations by scientists and public health officials from Asia, the Americas, Europe and Africa strengthened the notion that arboviral diseases of both humans and domestic animals are progressively becoming dominant public health problems in the world. The repeated occurrence of recent deadly epidemics strongly reinforces the call for action against these viral diseases, and the need for developing effective vaccines, drugs, vector control tools and strong prevention programs.
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http://dx.doi.org/10.1016/j.vaccine.2020.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180381PMC
May 2020

Geospatial analysis of dengue emergence in rural areas in the Southern Province of Sri Lanka.

Trans R Soc Trop Med Hyg 2020 06;114(6):408-414

Duke Global Health Institute, Durham, NC 27710, USA.

Background: Dengue is a major cause of acute febrile illness in Sri Lanka. Dengue has historically been considered an urban disease. In 2012-2013, we documented that acute dengue was surprisingly associated with self-reported rural residence in the Southern Province of Sri Lanka.

Methods: Patients admitted with an acute febrile illness were enrolled from June 2012-May 2013 in a cross-sectional surveillance study at the largest tertiary care hospital in the Southern Province. Acute dengue was diagnosed by serology and virology testing. Site visits were performed to collect residential geographical coordinates. Spatial variation in odds of acute dengue was modeled using a spatial generalized additive model predicted onto a grid of coordinate pairs covering the Southern Province.

Results: Of 800 patients, 333 (41.6%) had laboratory-confirmed acute dengue. Dengue was spatially heterogeneous (local probability of acute dengue 0.26 to 0.42). There were higher than average odds of acute dengue in the rural northeast of the Southern Province and lower than average odds in the urbanized southwest of the Southern Province, including the city Galle.

Conclusions: Our study further affirms the emergence of dengue in rural southern Sri Lanka and highlights both the need for real-time geospatial analyses to optimize public health activities as well as the importance of strengthening dengue surveillance in non-urban areas.
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http://dx.doi.org/10.1093/trstmh/trz123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528758PMC
June 2020

Recombination of B- and T-cell epitope-rich loci from Aedes- and Culex-borne flaviviruses shapes Zika virus epidemiology.

Antiviral Res 2020 02 16;174:104676. Epub 2019 Dec 16.

Departmento de Medicina, Universidad del Norte, Barranquilla, Colombia.

Sporadic human Zika virus (ZIKV) infections have been recorded in Africa and Asia since the 1950s. Major epidemics occurred only after ZIKV emerged in the Pacific islands and spread to the Americas. Specific biological determinants of the explosive epidemic nature of ZIKV have not been identified. Phylogenetic studies revealed incongruence in ZIKV placement in relation to Aedes-borne dengue viruses (DENV) and Culex-borne flaviviruses. We hypothesized that this incongruence reflects interspecies recombination resulting in ZIKV evasion of cross-protective T-cell immunity. We investigated ZIKV phylogenetic incongruence in relation to: DENV T-cell epitope maps experimentally identified ex vivo, published B-cell epitope loci, and CD8 T-cell epitopes predicted in silico for mosquito-borne flaviviruses. Our findings demonstrate that the ZIKV proteome is a hybrid of Aedes-borne DENV proteins interspersed amongst Culex-borne flavivirus proteins derived through independent interspecies recombination events. These analyses infer that DENV-associated proteins in the ZIKV hybrid proteome generated immunodominant human B-cell responses, whereas ZIKV recombinant derived Culex-borne flavivirus-associated proteins generated immunodominant CD8 and/or CD4 T-cell responses. In silico CD8 T-cell epitope ZIKV cross-reactive prediction analyses verified this observation. We propose that by acquiring cytotoxic T-cell epitope-rich regions from Culex-borne flaviviruses, ZIKV evaded DENV-generated T-cell immune cross-protection. Thus, Culex-borne flaviviruses, including West Nile virus and Japanese encephalitis virus, might induce cross-protective T-cell responses against ZIKV. This would explain why explosive ZIKV epidemics occurred in DENV-endemic regions of Micronesia, Polynesia and the Americas where Culex-borne flavivirus outbreaks are infrequent and why ZIKV did not cause major epidemics in Asia where Culex-borne flaviviruses are widespread.
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http://dx.doi.org/10.1016/j.antiviral.2019.104676DOI Listing
February 2020

Dengue pre-vaccination serology screening for the use of Dengvaxia®.

J Travel Med 2019 Dec;26(8)

Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore.

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http://dx.doi.org/10.1093/jtm/taz092DOI Listing
December 2019

Is Dengvaxia a useful vaccine for dengue endemic areas?

BMJ 2019 Oct 3;367:l5710. Epub 2019 Oct 3.

Bethesda, MD, USA

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http://dx.doi.org/10.1136/bmj.l5710DOI Listing
October 2019

Dengue virus-elicited tryptase induces endothelial permeability and shock.

J Clin Invest 2019 07 2;129(10):4180-4193. Epub 2019 Jul 2.

Program in Emerging Infectious Diseases, Duke-National University of Singapore, Singapore.

Dengue virus (DENV) infection causes a characteristic pathology in humans involving dysregulation of the vascular system. In some patients with dengue hemorrhagic fever (DHF), vascular pathology can become severe, resulting in extensive microvascular permeability and plasma leakage into tissues and organs. Mast cells (MCs), which line blood vessels and regulate vascular function, are able to detect DENV in vivo and promote vascular leakage. Here, we identified that a MC-derived protease, tryptase, is consequential for promoting vascular permeability during DENV infection, through inducing breakdown of endothelial cell tight junctions. Injected tryptase alone was sufficient to induce plasma loss from the circulation and hypovolemic shock in animals. A potent tryptase inhibitor, nafamostat mesylate, blocked DENV-induced vascular leakage in vivo. Importantly, in two independent human dengue cohorts, tryptase levels correlated with the grade of DHF severity. This study defines an immune mechanism by which DENV can induce vascular pathology and shock.
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http://dx.doi.org/10.1172/JCI128426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763290PMC
July 2019

Application of a targeted-enrichment methodology for full-genome sequencing of Dengue 1-4, Chikungunya and Zika viruses directly from patient samples.

PLoS Negl Trop Dis 2019 04 25;13(4):e0007184. Epub 2019 Apr 25.

Duke-NUS Medical School, Singapore.

The frequency of epidemics caused by Dengue viruses 1-4, Zika virus and Chikungunya viruses have been on an upward trend in recent years driven primarily by uncontrolled urbanization, mobility of human populations and geographical spread of their shared vectors, Aedes aegypti and Aedes albopictus. Infections by these viruses present with similar clinical manifestations making them challenging to diagnose; this is especially difficult in regions of the world hyperendemic for these viruses. In this study, we present a targeted-enrichment methodology to simultaneously sequence the complete viral genomes for each of these viruses directly from clinical samples. Additionally, we have also developed a customized computational tool (BaitMaker) to design these enrichment baits. This methodology is robust in its ability to capture diverse sequences and is amenable to large-scale epidemiological studies. We have applied this methodology to two large cohorts: a febrile study based in Colombo, Sri Lanka taken during the 2009-2015 dengue epidemic (n = 170) and another taken during the 2016 outbreak of Zika virus in Singapore (n = 162). Results from these studies indicate that we were able to cover an average of 97.04% ± 0.67% of the full viral genome from samples in these cohorts. We also show detection of one DENV3/ZIKV co-infected patient where we recovered full genomes for both viruses.
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http://dx.doi.org/10.1371/journal.pntd.0007184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504110PMC
April 2019

Yellow fever: is Asia prepared for an epidemic?

Lancet Infect Dis 2019 03;19(3):241-242

Global Dengue and Aedes-transmitted Diseases Consortium, Seoul, Korea.

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http://dx.doi.org/10.1016/S1473-3099(19)30050-7DOI Listing
March 2019

What is the prospect of a safe and effective dengue vaccine for travellers?

J Travel Med 2019 Sep;26(6)

Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore. Global Dengue and Aedes-Transmitted Diseases Consortium (GDAC).

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http://dx.doi.org/10.1093/jtm/tay153DOI Listing
September 2019

Development of standard clinical endpoints for use in dengue interventional trials: introduction and methodology.

BMC Med Res Methodol 2018 11 15;18(1):134. Epub 2018 Nov 15.

Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.

Background: As increasing numbers of dengue vaccines and therapeutics are in clinical development, standardized consensus clinical endpoint definitions are urgently needed to assess the efficacy of different interventions with respect to disease severity. We aimed to convene dengue experts representing various sectors and dengue endemic areas to review the literature and propose clinical endpoint definitions for moderate and severe disease based on the framework provided by the WHO 2009 classification.

Methods: The endpoints were first proposed and discussed in a structured expert consultation. After that, the Delphi method was carried out to assess the usefulness, validity and feasibility of the standardized clinical disease endpoints for interventional dengue research.

Results: Most respondents (> 80%) agreed there is a need for both standardized clinical endpoints and operationalization of severe endpoints. Most respondents (67%) felt there is utility for moderate severity endpoints, but cited challenges in their development. Hospitalization as a moderate endpoint of disease severity or measure of public health impact was deemed to be useful by only 47% of respondents, but 89% felt it could bring about supplemental information if carefully contextualized according to data collection setting. Over half of the respondents favored alignment of the standard endpoints with the WHO guidelines (58%), but cautioned that the endpoints could have ramifications for public health practice. In terms of data granularity of the endpoints, there was a slight preference for a categorical vs numeric system (e.g. 1-10) (47% vs 34%), and 74% of respondents suggested validating the endpoints using large prospective data sets.

Conclusion: The structured consensus-building process was successful taking into account the history of the debate around potential endpoints for severe dengue. There is clear support for the development of standardized endpoints for interventional clinical research and the need for subsequent validation with prospective data sets. Challenges include the complexity of developing moderate disease research endpoints for dengue.
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http://dx.doi.org/10.1186/s12874-018-0601-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238344PMC
November 2018

Pandemic yellow fever: a potential threat to global health via travelers.

Authors:
Duane J Gubler

J Travel Med 2018 01;25(1)

Emerging Infectious Diseases, Duke-NUS Medical School, 8 College Road, Singapore.

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http://dx.doi.org/10.1093/jtm/tay097DOI Listing
January 2018

Development of standard clinical endpoints for use in dengue interventional trials.

PLoS Negl Trop Dis 2018 10 4;12(10):e0006497. Epub 2018 Oct 4.

Emerging Infectious Diseases Programme, Duke-NUS Medical School, Singapore.

Dengue is a major public health problem worldwide. Although several drug candidates have been evaluated in randomized controlled trials, none has been effective and at present, early recognition of severe dengue and timely supportive care are used to reduce mortality. While the first dengue vaccine was recently licensed, and several other candidates are in late stage clinical trials, future decisions regarding widespread deployment of vaccines and/or therapeutics will require evidence of product safety, efficacy and effectiveness. Standard, quantifiable clinical endpoints are needed to ensure reproducibility and comparability of research findings. To address this need, we established a working group of dengue researchers and public health specialists to develop standardized endpoints and work towards consensus opinion on those endpoints. After discussion at two working group meetings and presentations at international conferences, a Delphi methodology-based query was used to finalize and operationalize the clinical endpoints. Participants were asked to select the best endpoints from proposed definitions or offer revised/new definitions, and to indicate whether contributing items should be designated as optional or required. After the third round of inquiry, 70% or greater agreement was reached on moderate and severe plasma leakage, moderate and severe bleeding, acute hepatitis and acute liver failure, and moderate and severe neurologic disease. There was less agreement regarding moderate and severe thrombocytopenia and moderate and severe myocarditis. Notably, 68% of participants agreed that a 50,000 to 20,000 mm3 platelet range be used to define moderate thrombocytopenia; however, they remained divided on whether a rapid decreasing trend or one platelet count should be case defining. While at least 70% agreement was reached on most endpoints, the process identified areas for further evaluation and standardization within the context of ongoing clinical studies. These endpoints can be used to harmonize data collection and improve comparability between dengue clinical trials.
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http://dx.doi.org/10.1371/journal.pntd.0006497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171842PMC
October 2018

Unexpected outbreaks of arbovirus infections: lessons learned from the Pacific and tropical America.

Lancet Infect Dis 2018 11 19;18(11):e355-e361. Epub 2018 Jun 19.

Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore.

Pandemic arboviruses have emerged as a major global health problem in the past four decades. Predicting where and when the next arbovirus epidemic will occur is a challenge, but history suggests that arboviral black swan events (epidemics that are difficult to predict and that have an extreme effect) will continue to occur as urban growth and globalisation expand. We briefly review unexpected arbovirus epidemics that have occurred in the past 50 years, with emphasis on the American and Pacific regions, to illustrate their unpredictability, and to highlight the need for improved global preparedness, including laboratory-based surveillance, prevention, and control programmes.
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http://dx.doi.org/10.1016/S1473-3099(18)30269-XDOI Listing
November 2018

Potential yellow fever epidemics in unexposed populations.

Authors:
Duane J Gubler

Bull World Health Organ 2018 May;96(5):299

Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.

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http://dx.doi.org/10.2471/BLT.18.213298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985433PMC
May 2018

Potential Point-of-Care Testing for Dengue Virus in the Field.

J Clin Microbiol 2018 05 25;56(5). Epub 2018 Apr 25.

Program on Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore.

The four serotypes of dengue virus (DENV) cause one of the most important and rapidly emerging mosquito-borne viral diseases in humans. Of the currently available diagnostic tests for dengue, the reverse transcription-PCR (RT-PCR) assay is the most sensitive and specific, and so it is commonly used as the gold standard. However, the requirement of a sophisticated and expensive thermal cycler makes it very difficult to use as a point-of-care diagnostic test in resource-limited regions where dengue is endemic. Tsai et al. (J Clin Microbiol 56:e01865-17, 2018, https://doi.org/10.1128/JCM.01865-17) report the analytical and clinical performances of a reverse transcription-insulated isothermal PCR (RT-iiPCR) assay with a portable nucleic acid analyzer for rapid detection of the four DENV serotypes; its reproducibility and complete agreement on clinical samples with the multiplex RT-PCR assay developed by the Centers for Disease Control and Prevention suggest that the dengue RT-iiPCR is a potential point-of-care test. Compared with other DENV RNA detection methods, the unique isothermal PCR design of RT-iiPCR, together with further improvements, would represent a promising new type of field-deployable diagnostic test for dengue.
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http://dx.doi.org/10.1128/JCM.00203-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5925702PMC
May 2018

Evaluation of the WHO 2009 classification for diagnosis of acute dengue in a large cohort of adults and children in Sri Lanka during a dengue-1 epidemic.

PLoS Negl Trop Dis 2018 02 9;12(2):e0006258. Epub 2018 Feb 9.

Hubert-Yeargan Center for Global Health, Durham, NC, United States of America.

Background: Dengue is a leading cause of fever and mimics other acute febrile illnesses (AFI). In 2009, the World Health Organization (WHO) revised criteria for clinical diagnosis of dengue.

Methodology/principal Findings: The new WHO 2009 classification of dengue divides suspected cases into three categories: dengue without warning signs, dengue with warning signs and severe dengue. We evaluated the WHO 2009 classification vs physicians' subjective clinical diagnosis (gestalt clinical impression) in a large cohort of patients presenting to a tertiary care center in southern Sri Lanka hospitalized with acute febrile illness. We confirmed acute dengue in 388 patients (305 adults ≥ 18 years and 83 children), including 103 primary and 245 secondary cases, of 976 patients prospectively enrolled with AFI. At presentation, both adults and children with acute dengue were more likely than those with other AFI to have leukopenia and thrombocytopenia. Additionally, adults were more likely than those with other AFI to have joint pain, higher temperatures, and absence of crackles on examination whereas children with dengue were more likely than others to have sore throat, fatigue, oliguria, and elevated hematocrit and transaminases. Similarly, presence of joint pain, thrombocytopenia, and absence of cough were independently associated with secondary vs primary dengue in adults whereas no variables were different in children. The 2009 WHO dengue classification was more sensitive than physicians' clinical diagnosis for identification of acute dengue (71.5% vs 67.1%), but was less specific. However, despite the absence of on-site diagnostic confirmation of dengue, clinical diagnosis was more sensitive on discharge (75.2%). The 2009 WHO criteria classified almost 75% as having warning signs, even though only 9 (2.3%) patients had evidence of plasma leakage and 16 (4.1%) had evidence of bleeding.

Conclusions/significance: In a large cohort with AFI, we identified features predictive of dengue vs other AFI and secondary vs primary dengue in adults versus children. The 2009 WHO dengue classification criteria had high sensitivity but low specificity compared to physicians' gestaldt diagnosis. Large cohort studies will be needed to validate the diagnostic yield of clinical impression and specific features for dengue relative to the 2009 WHO classification criteria.
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http://dx.doi.org/10.1371/journal.pntd.0006258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823472PMC
February 2018

Innovative and New Approaches to Laboratory Diagnosis of Zika and Dengue: A Meeting Report.

J Infect Dis 2018 03;217(7):1060-1068

Lee Kong Chian School of Medicine, Singapore.

Epidemics of dengue, Zika, and other arboviral diseases are increasing in frequency and severity. Current efforts to rapidly identify and manage these epidemics are limited by the short diagnostic window in acute infection, the extensive serologic cross-reactivity among flaviviruses, and the lack of point-of-care diagnostic tools to detect these viral species in primary care settings. The Partnership for Dengue Control organized a workshop to review the current landscape of Flavivirus diagnostic tools, identified current gaps, and developed strategies to accelerate the adoption of promising novel technologies into national programs. The rate-limiting step to bringing new diagnostic tools to the market is access to reference materials and well-characterized clinical samples to facilitate performance evaluation. We suggest the creation of an international laboratory-response consortium for flaviviruses with a decentralized biobank of well-characterized samples to facilitate assay validation. Access to proficiency panels are needed to ensure quality control, in additional to in-country capacity building.
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http://dx.doi.org/10.1093/infdis/jix678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279137PMC
March 2018

History and Emergence of Zika Virus.

J Infect Dis 2017 12;216(suppl_10):S860-S867

Unit of Emerging Infectious Disease, Institut Louis Malardé Papeete, Tahiti, Polynésie.

Zika virus was discovered in East Africa in 1947 by the Rockefeller Foundation during investigations on the ecology of yellow fever. Although it was subsequently shown to have widespread distribution in Africa and Asia, it was not known to cause epidemics until 2007. This paper describes the history of the virus discovery, emergence and evolution as an epidemic virus, and the its evolving clinical spectrum.
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http://dx.doi.org/10.1093/infdis/jix451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853376PMC
December 2017

Chymase Level Is a Predictive Biomarker of Dengue Hemorrhagic Fever in Pediatric and Adult Patients.

J Infect Dis 2017 11;216(9):1112-1121

Programme in Emerging Infectious Diseases, Duke-National University of Singapore.

Background: Most patients with dengue experience mild disease, dengue fever (DF), while few develop the life-threatening diseases dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). No laboratory tests predict DHF or DSS. We evaluated whether the serum chymase level can predict DHF or DSS in adult and pediatric patients and the influence of preexisting conditions (PECs) on chymase levels.

Methods: Serum chymase levels were measured in patients presenting with undifferentiated fever to hospitals in Colombo District, Sri Lanka. The value of serum the chymase concentration and clinical signs and symptoms as predictors of DHF and/or DSS was evaluated by multivariate analysis. We assessed the influence of age, PECs, and day after fever onset on the robustness of the chymase level as a biomarker for DHF and/or DSS.

Results: An elevated chymase level in acute phase blood samples was highly indicative of later diagnosis of DHF or DSS for pediatric and adult patients with dengue. No recorded PECs prevented an increase in the chymase level during DHF. However, certain PECs (obesity and cardiac or lung-associated diseases) resulted in a concomitant increase in chymase levels among adult patients with DHF.

Conclusions: These results show that patients with acute dengue who present with high levels of serum chymase consistently are at greater risk of DHF. The chymase level is a robust prognostic biomarker of severe dengue for adult and pediatric patients.
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http://dx.doi.org/10.1093/infdis/jix447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853622PMC
November 2017

Analysis of Dengue Serotype 4 in Sri Lanka during the 2012-2013 Dengue Epidemic.

Am J Trop Med Hyg 2017 Jul;97(1):130-136

Duke-NUS Medical School, Singapore.

The four serotypes of dengue virus (DENV-1, -2, -3, and -4) have had a rapidly expanding geographic range and are now endemic in over 100 tropical and subtropical countries. Sri Lanka has experienced periodic dengue outbreaks since the 1960s, but since 1989 epidemics have become progressively larger and associated with more severe disease. The dominant virus in the 2012 epidemic was DENV-1, but DENV-4 infections were also commonly observed. DENV-4 transmission was first documented in Sri Lanka when it was isolated from a traveler in 1978, but has been comparatively uncommon since dengue surveillance began in the early 1980s. To better understand the molecular epidemiology of DENV-4 infections in Sri Lanka, we conducted whole-genome sequencing on dengue patient samples from two different geographic locations. Phylogenetic analysis indicates that all sequenced DENV-4 strains belong to genotype 1 and are most closely related to DENV-4 viruses previously found in Sri Lanka and those recently found to be circulating in India and Pakistan.
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http://dx.doi.org/10.4269/ajtmh.16-0540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508889PMC
July 2017

Vertebrate Reservoirs of Arboviruses: Myth, Synonym of Amplifier, or Reality?

Viruses 2017 07 13;9(7). Epub 2017 Jul 13.

Program in Emerging Infectious Diseases, Duke-NUS Medical School, 8 College Rd., Singapore 169857 Singapore.

The rapid succession of the pandemic of arbovirus diseases, such as dengue, West Nile fever, chikungunya, and Zika fever, has intensified research on these and other arbovirus diseases worldwide. Investigating the unique mode of vector-borne transmission requires a clear understanding of the roles of vertebrates. One major obstacle to this understanding is the ambiguity of the arbovirus definition originally established by the World Health Organization. The paucity of pertinent information on arbovirus transmission at the time contributed to the notion that vertebrates played the role of reservoir in the arbovirus transmission cycle. Because this notion is a salient feature of the arbovirus definition, it is important to reexamine its validity. This review addresses controversial issues concerning vertebrate reservoirs and their role in arbovirus persistence in nature, examines the genesis of the problem from a historical perspective, discusses various unresolved issues from multiple points of view, assesses the present status of the notion in light of current knowledge, and provides options for a solution to resolve the issue.
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http://dx.doi.org/10.3390/v9070185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537677PMC
July 2017

Peridomestic Aedes malayensis and Aedes albopictus are capable vectors of arboviruses in cities.

PLoS Negl Trop Dis 2017 Jun 26;11(6):e0005667. Epub 2017 Jun 26.

Program in Emerging Infectious Disease, Duke-NUS Medical School, Singapore.

Background: Dengue and chikungunya are global re-emerging mosquito-borne diseases. In Singapore, sustained vector control coupled with household improvements reduced domestic mosquito populations for the past 45 years, particularly the primary vector Aedes aegypti. However, while disease incidence was low for the first 30 years following vector control implementation, outbreaks have re-emerged in the past 15 years. Epidemiological observations point to the importance of peridomestic infection in areas not targeted by control programs. We investigated the role of vectors in peri-domestic areas.

Methods: We carried out entomological surveys to identify the Aedes species present in vegetated sites in highly populated areas and determine whether mosquitoes were present in open-air areas frequented by people. We compared vector competence of Aedes albopictus and Aedes malayensis with Ae. aegypti after oral infection with sympatric dengue serotype 2 and chikungunya viruses. Mosquito saliva was tested for the presence of infectious virus particles as a surrogate for transmission following oral infection.

Results: We identified Aedes albopictus and Aedes malayensis throughout Singapore and quantified their presence in forested and opened grassy areas. Both Ae. albopictus and Ae. malayensis can occupy sylvatic niches and were highly susceptible to both arboviruses. A majority of saliva of infected Ae. malayensis contained infectious particles for both viruses.

Conclusions: Our study reveals the prevalence of competent vectors in peri-domestic areas, including Ae. malayensis for which we established the vector status. Epidemics can be driven by infection foci, which are epidemiologically enhanced in the context of low herd immunity, selective pressure on arbovirus transmission and the presence of infectious asymptomatic persons, all these conditions being present in Singapore. Learning from Singapore's vector control success that reduced domestic vector populations, but has not sustainably reduced arboviral incidence, we suggest including peri-domestic vectors in the scope of vector management.
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http://dx.doi.org/10.1371/journal.pntd.0005667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501678PMC
June 2017

An update on Zika virus infection.

Lancet 2017 Nov 21;390(10107):2099-2109. Epub 2017 Jun 21.

Unit of Emerging Infectious Diseases, Institut Louis Malardé, Tahiti, French Polynesia.

The epidemic history of Zika virus began in 2007, with its emergence in Yap Island in the western Pacific, followed in 2013-14 by a larger epidemic in French Polynesia, south Pacific, where the first severe complications and non-vector-borne transmission of the virus were reported. Zika virus emerged in Brazil in 2015 and was declared a national public health emergency after local researchers and physicians reported an increase in microcephaly cases. In 2016, WHO declared the recent cluster of microcephaly cases and other neurological disorders reported in Brazil a global public health emergency. Similar clusters of microcephaly cases were also observed retrospectively in French Polynesia in 2014. In 2015-16, Zika virus continued its spread to cause outbreaks in the Americas and the Pacific, and the first outbreaks were reported in continental USA, Africa, and southeast Asia. Non-vector-borne transmission was confirmed and Zika virus was established as a cause of severe neurological complications in fetuses, neonates, and adults. This Review focuses on important updates and gaps in the knowledge of Zika virus as of early 2017.
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http://dx.doi.org/10.1016/S0140-6736(17)31450-2DOI Listing
November 2017

Valine/isoleucine variants drive selective pressure in the VP1 sequence of EV-A71 enteroviruses.

BMC Infect Dis 2017 05 8;17(1):333. Epub 2017 May 8.

Cirad, UMR 17, Intertryp, TA-A17/G, Campus International de Baillarguet, 34398, Montpellier Cedex 5, France.

Background: In 2011-2012, Northern Vietnam experienced its first large scale hand foot and mouth disease (HFMD) epidemic. In 2011, a major HFMD epidemic was also reported in South Vietnam with fatal cases. This 2011-2012 outbreak was the first one to occur in North Vietnam providing grounds to study the etiology, origin and dynamic of the disease. We report here the analysis of the VP1 gene of strains isolated throughout North Vietnam during the 2011-2012 outbreak and before.

Methods: The VP1 gene of 106 EV-A71 isolates from North Vietnam and 2 from Central Vietnam were sequenced. Sequence alignments were analyzed at the nucleic acid and protein level. Gene polymorphism was also analyzed. A Factorial Correspondence Analysis was performed to correlate amino acid mutations with clinical parameters.

Results: The sequences were distributed into four phylogenetic clusters. Three clusters corresponded to the subgenogroup C4 and the last one corresponded to the subgenogroup C5. Each cluster displayed different polymorphism characteristics. Proteins were highly conserved but three sites bearing only Isoleucine (I) or Valine (V) were characterized. The isoleucine/valine variability matched the clusters. Spatiotemporal analysis of the I/V variants showed that all variants which emerged in 2011 and then in 2012 were not the same but were all present in the region prior to the 2011-2012 outbreak. Some correlation was found between certain I/V variants and ethnicity and severity.

Conclusions: The 2011-2012 outbreak was not caused by an exogenous strain coming from South Vietnam or elsewhere but by strains already present and circulating at low level in North Vietnam. However, what triggered the outbreak remains unclear. A selective pressure is applied on I/V variants which matches the genetic clusters. I/V variants were shown on other viruses to correlate with pathogenicity. This should be investigated in EV-A71. I/V variants are an easy and efficient way to survey and identify circulating EV-A71 strains.
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http://dx.doi.org/10.1186/s12879-017-2427-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5422960PMC
May 2017

Prevention and control of dengue-the light at the end of the tunnel.

Lancet Infect Dis 2017 03 7;17(3):e79-e87. Epub 2017 Feb 7.

Emerging Infectious Diseases Programme, Duke-NUS Medical School, National University of Singapore, Singapore.

Advances in the development of new dengue control tools, including vaccines and vector control, herald a new era of desperately needed dengue prevention and control. The burden of dengue has expanded for decades, and now affects more than 120 countries. Complex, large-scale global forces have and will continue to contribute to the expansion of dengue, including population growth, unplanned urbanisation, and suboptimal mosquito control in urban centres. Although no so-called magic bullets are available, there is new optimism following the first licensure of a dengue vaccine and other promising vaccine candidates, and the development of novel vector control interventions to help control dengue and other expanding mosquito-borne diseases such as Zika virus. Implementation of effective and sustainable immunisation programmes to complement existing methods will add complexity to the health systems of affected countries, which have varying levels of robustness and maturity. Long-term high prioritisation and adequate resources are needed. The way forward is full commitment to addressing a complex disease with a set of solutions integrating vaccination and vector control methods. A whole systems approach is thus needed to integrate these various approaches and strategies for controlling dengue within the goal of universal health coverage. The ultimate objective of these interventions will be to reduce the disease burden in a sustainable and equitable manner.
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http://dx.doi.org/10.1016/S1473-3099(16)30471-6DOI Listing
March 2017

Mitigating Diseases Transmitted by Aedes Mosquitoes: A Cluster-Randomised Trial of Permethrin-Impregnated School Uniforms.

PLoS Negl Trop Dis 2017 01 19;11(1):e0005197. Epub 2017 Jan 19.

Umeå Centre for Global Health Research, Epidemiology and Global Health, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.

Background: Viral diseases transmitted via Aedes mosquitoes are on the rise, such as Zika, dengue, and chikungunya. Novel tools to mitigate Aedes mosquitoes-transmitted diseases are urgently needed. We tested whether commercially insecticide-impregnated school uniforms can reduce dengue incidence in school children.

Methods: We designed a cluster-randomised controlled trial in Thailand. The primary endpoint was laboratory-confirmed dengue infections. Secondary endpoints were school absenteeism; and impregnated uniforms' 1-hour knock-down and 24 hour mosquito mortality as measured by standardised WHOPES bioassay cone tests at baseline and after repeated washing. Furthermore, entomological assessments inside classrooms and in outside areas of schools were conducted.

Results: We enrolled 1,811 pupils aged 6-17 from 5 intervention and 5 control schools. Paired serum samples were obtained from 1,655 pupils. In the control schools, 24/641 (3.7%) and in the intervention schools 33/1,014 (3.3%) students had evidence of new dengue infections during one school term (5 months). There was no significant difference in proportions of students having incident dengue infections between the intervention and control schools, with adjustment for clustering by school. WHOPES cone tests showed a 100% knock down and mortality of Aedes aegypti mosquitoes exposed to impregnated clothing at baseline and up to 4 washes, but this efficacy rapidly declined to below 20% after 20 washes, corresponding to a weekly reduction in knock-down and mosquito mortality by 4.7% and 4.4% respectively. Results of the entomological assessments showed that the mean number of Aedes aegypti mosquitoes caught inside the classrooms of the intervention schools was significantly reduced in the month following the introduction of the impregnated uniforms, compared to those collected in classrooms of the control schools (p = 0.04).

Conclusions: Entomological assessments showed that the intervention had some impact on the number of Aedes mosquitoes inside treatment schools immediately after impregnation and before insecticidal activity declined. However, there was no serological evidence of protection against dengue infections over the five months school term, best explained by the rapid washing-out of permethrin after 4 washes. If rapid washing-out of permethrin could be overcome by novel technological approaches, insecticide-treated clothes might become a potentially cost-effective and scalable intervention to protect against diseases transmitted by Aedes mosquitoes such as dengue, Zika, and chikungunya.

Trial Registration: ClinicalTrials.gov NCT01563640.
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http://dx.doi.org/10.1371/journal.pntd.0005197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5245776PMC
January 2017

Epidemic arboviral diseases: priorities for research and public health.

Lancet Infect Dis 2017 03 21;17(3):e101-e106. Epub 2016 Dec 21.

Department of Entomology and Nematology, University of California, Davis, CA.

For decades, arboviral diseases were considered to be only minor contributors to global mortality and disability. As a result, low priority was given to arbovirus research investment and related public health infrastructure. The past five decades, however, have seen an unprecedented emergence of epidemic arboviral diseases (notably dengue, chikungunya, yellow fever, and Zika virus disease) resulting from the triad of the modern world: urbanisation, globalisation, and international mobility. The public health emergency of Zika virus, and the threat of global spread of yellow fever, combined with the resurgence of dengue and chikungunya, constitute a wake-up call for governments, academia, funders, and WHO to strengthen programmes and enhance research in aedes-transmitted diseases. The common features of these diseases should stimulate similar research themes for diagnostics, vaccines, biological targets and immune responses, environmental determinants, and vector control measures. Combining interventions known to be effective against multiple arboviral diseases will offer the most cost-effective and sustainable strategy for disease reduction. New global alliances are needed to enable the combination of efforts and resources for more effective and timely solutions.
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http://dx.doi.org/10.1016/S1473-3099(16)30518-7DOI Listing
March 2017