#Dengue and #chikungunya among outpatients with acute undifferentiated #fever in #Kinshasa, #DRC: A cross-sectional study (PLoS Negl Trop Dis., abstract)

[Source: PLoS Neglected Tropical Diseases, full page: (LINK). Abstract, edited.]


Dengue and chikungunya among outpatients with acute undifferentiated fever in Kinshasa, Democratic Republic of Congo: A cross-sectional study

Sam Proesmans , Freddy Katshongo, John Milambu, Blaise Fungula, Hypolite Muhindo Mavoko, Steve Ahuka-Mundeke, Raquel Inocêncio da Luz, Marjan Van Esbroeck, Kevin K. Ariën, Lieselotte Cnops, Birgit De Smet, Pascal Lutumba, Jean-Pierre Van geertruyden, Veerle Vanlerberghe

Published: September 5, 2019 / DOI: https://doi.org/10.1371/journal.pntd.0007047 / This is an uncorrected proof.




Pathogens causing acute fever, with the exception of malaria, remain largely unidentified in sub-Saharan Africa, given the local unavailability of diagnostic tests and the broad differential diagnosis.


We conducted a cross-sectional study including outpatient acute undifferentiated fever in both children and adults, between November 2015 and June 2016 in Kinshasa, Democratic Republic of Congo. Serological and molecular diagnostic tests for selected arboviral infections were performed on blood, including PCR, NS1-RDT, ELISA and IFA for acute, and ELISA and IFA for past infections.


Investigation among 342 patients, aged 2 to 68 years (mean age of 21 years), with acute undifferentiated fever (having no clear focus of infection) revealed 19 (8.1%) acute dengue–caused by DENV-1 and/or DENV-2 –and 2 (0.9%) acute chikungunya infections. Furthermore, 30.2% and 26.4% of participants had been infected in the past with dengue and chikungunya, respectively. We found no evidence of acute Zika nor yellow fever virus infections. 45.3% of patients tested positive on malaria Rapid Diagnostic Test, 87.7% received antimalarial treatment and 64.3% received antibacterial treatment.


Chikungunya outbreaks have been reported in the study area in the past, so the high seroprevalence is not surprising. However, scarce evidence exists on dengue transmission in Kinshasa and based on our data, circulation is more important than previously reported. Furthermore, our study shows that the prescription of antibiotics, both antibacterial and antimalarial drugs, is rampant. Studies like this one, elucidating the causes of acute fever, may lead to a more considerate and rigorous use of antibiotics. This will not only stem the ever-increasing problem of antimicrobial resistance, but will–ultimately and hopefully–improve the clinical care of outpatients in low-resource settings.

Trial registration ClinicalTrials.gov NCT02656862.


Author summary

Malaria remains one of the most important causes of fever in sub-Saharan Africa. However, its share is declining, since the diagnosis and treatment of malaria have improved significantly over the years. Hence leading to an increase in the number of patients presenting with non-malarial fever. Often, obvious clinical signs and symptoms like cough or diarrhea are absent, probing the question: “What causes the fever?” Previous studies have shown that the burden of arboviral infections–like dengue and chikungunya–in sub-Saharan Africa is underestimated, which is why we screened for four common arboviral infections in patients presenting with ‘undifferentiated fever’ at an outpatient clinic in suburban Kinshasa, Democratic Republic of Congo. Among the patients tested, we found that one in ten presented with an acute arboviral infection and that almost one in three patients had been infected in the past. These findings suggest that clinicians should think about arboviral infections more often, thereby refraining from the prescription of antibiotics, a practice increasingly problematic given the global rise of antimicrobial resistance.


Citation: Proesmans S, Katshongo F, Milambu J, Fungula B, Muhindo Mavoko H, Ahuka-Mundeke S, et al. (2019) Dengue and chikungunya among outpatients with acute undifferentiated fever in Kinshasa, Democratic Republic of Congo: A cross-sectional study. PLoS Negl Trop Dis 13(9): e0007047. https://doi.org/10.1371/journal.pntd.0007047

Editor: Stuart D. Blacksell, Mahidol Univ, Fac Trop Med, THAILAND

Received: November 28, 2018; Accepted: August 6, 2019; Published: September 5, 2019

Copyright: © 2019 Proesmans et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: This study was co-funded by the framework agreement between the Institute of Tropical Medicine and the Belgian development cooperation (https://www.itg.be/E/cooperation) to VV and Vlaamse Interuniversitaire Raad – Universitaire Ontwikkelingssamenwerking (https://www.vliruos.be/en) (VLIR-UOS, Grant reference ZRDC2014MP083) to JPVG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Arbovirus; Dengue fever; Chikungunya fever; Malaria; Serology; Seroprevalence; DRC.



A protective #Zika virus E-dimer-based subunit #vaccine engineered to abrogate #ADE of #dengue #infection (Nat Immunol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Nat Immunol. 2019 Sep 2. doi: 10.1038/s41590-019-0477-z. [Epub ahead of print]

A protective Zika virus E-dimer-based subunit vaccine engineered to abrogate antibody-dependent enhancement of dengue infection.

Slon-Campos JL1, Dejnirattisai W1, Jagger BW2,3, López-Camacho C4, Wongwiwat W1, Durnell LA2, Winkler ES2, Chen RE2, Reyes-Sandoval A4, Rey FA5,6, Diamond MS2,7,8,9, Mongkolsapaya J10,11, Screaton GR12.

Author information: 1 Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. 2 Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA. 3 Department of Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI, USA. 4 Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK. 5 Unité de Virologie Structurale, Département de Virologie, Institut Pasteur, Paris, France. 6 Centre National de la Recherche Scientifique, Unité Mixte de Recherche 3569, Paris, France. 7 Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA. 8 Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO, USA. 9 Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO, USA. 10 Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. jmongkol@well.ox.ac.uk. 11 Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand. jmongkol@well.ox.ac.uk. 12 Division of Medical Sciences, University of Oxford, Oxford, UK. gavin.screaton@medsci.ox.ac.uk.



Infections with dengue virus (DENV) and Zika virus (ZIKV) can induce cross-reactive antibody responses. Two immunodominant epitopes-one to precursor membrane protein and one to the fusion loop epitope on envelope (E) protein-are recognized by cross-reactive antibodies1-3that are not only poorly neutralizing, but can also promote increased viral replication and disease severity via Fcγ receptor-mediated infection of myeloid cells-a process termed antibody-dependent enhancement (ADE)1,4,5. ADE is a significant concern for both ZIKV and DENV vaccines as the induction of poorly neutralizing cross-reactive antibodies may prime an individual for ADE on natural infection. In this report, we describe the design and production of covalently stabilized ZIKV E dimers, which lack precursor membrane protein and do not expose the immunodominant fusion loop epitope. Immunization of mice with ZIKV E dimers induces dimer-specific antibodies, which protect against ZIKV challenge during pregnancy. Importantly, the ZIKV E-dimer-induced response does not cross-react with DENV or induce ADE of DENV infection.

PMID: 31477918 DOI: 10.1038/s41590-019-0477-z

Keywords: Zika Virus; Vaccines; A.D.E.; Dengue fever; Animal models.


Chronic #dengue virus #encephalitis in a patient with progressive #dementia with extrapyramidal features (Ann Neurol., abstract)

[Source: Annals of Neurology, full page: (LINK). Abstract, edited.]

Chronic dengue virus encephalitis in a patient with progressive dementia with extrapyramidal features

Tory P. Johnson Ph.D.,  H. Benjamin Larman Ph.D.,  Myoung‐Hwa Lee Ph.D.,  Stephen S. Whitehead Ph.D., Jeffrey Kowalak Ph.D., Camilo Toro M.D., C. Christopher Lau Ph.D., Juyun Kim

First published: 28 August 2019 / DOI:  https://doi.org/10.1002/ana.25588

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/ana.25588.




To determine the underlying etiology in a patient with progressive dementia with extrapyramidal signs and chronic inflammation referred to the National Institutes of Health Undiagnosed Diseases Program.


Extensive investigations included metabolic profile, autoantibody panel, infectious etiologies, genetic screening, whole exome sequencing and the phage‐display assay, VirScan, for viral immune responses. An etiological diagnosis was established post‐mortem.


Using VirScan, enrichment of dengue viral antibodies were detected in cerebrospinal fluid as compared to serum. No virus was detected in serum or cerebrospinal fluid, but post‐mortem analysis confirmed dengue virus in the brain by immunohistochemistry, in situhybridization, quantitative polymerase chain reaction and sequencing. Dengue virus was also detectable by polymerase chain reaction and sequencing from brain biopsy tissue collected 33 months ante‐mortem, confirming a chronic infection despite a robust immune response directed against the virus. Immunoprofiling and whole exome sequencing of the patient did not reveal any immunodeficiency and sequencing of the virus demonstrated wild‐type dengue virus in the central nervous system.


Dengue virus is the most common arbovirus worldwide and represents a significant public health concern. Infections with dengue virus are usually self‐limiting and chronic dengue infections have not been previously reported. Our findings suggest that dengue virus infections may persist in the central nervous system and should be considered in patients with progressive dementia with extrapyramidal features in endemic regions or with relevant travel history. Further, this work highlights the utility of comprehensive antibody profiling assays to aid in the diagnosis of encephalitis of unknown etiologies.

This article is protected by copyright. All rights reserved.

Keywords: Dengue Fever; Encephalitis; Dementia; Neurology.


#Dengue #vascular #leak syndrome: insights into potentially new #treatment modalities (J Clin Invest., summary)

[Source: Journal of Clinical Investigation, full page: (LINK). Summary, edited.]

Commentary / DOI: 10.1172/JCI131170

Dengue vascular leak syndrome: insights into potentially new treatment modalities

Anna P. Durbin

First published August 26, 2019


Dengue viruses (DENV) are the most common cause of mosquito-borne viral illness in the world, affecting approximately 400 million people annually. Symptomatic illness ranges from a mild, self-limiting febrile illness to one manifested by plasma leakage that can lead to vascular collapse and death. In this issue of the JCI, Rathore et al. report that DENV can cause mast cell degranulation independently of mast cell infection, resulting in the release of the vasoactive mediators chymase and tryptase.


Keywords: Dengue fever; Dengue hemorrhagic fever.


#Dengue virus–elicited tryptase induces #endothelial #permeability and #shock (J Clin Invest., abstract)

[Source: Journal of Clinical Investigation, full page: (LINK). Abstract, edited.]

Research Article / Infectious disease / Vascular biology / Free access / DOI: 10.1172/JCI128426

Dengue virus–elicited tryptase induces endothelial permeability and shock

Abhay P.S. Rathore, Chinmay Kumar Mantri, Siti A.B. Aman, Ayesa Syenina, Justin Ooi, Cyril J. Jagaraj, Chi Ching Goh, Hasitha Tissera, Annelies Wilder-Smith, Lai Guan Ng, Duane J. Gubler, and Ashley L. St. John

First published July 2, 2019



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 showed that an 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 2 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.

Keywords: Dengue fever; Dengue hemorrhagic fever; Viral pathogenesis.


#Epidemiology of #Dengue, #Chikungunya, and #Zika Virus Disease in the #US States and Territories, 2017 (Am J Trop Med Hyg., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Am J Trop Med Hyg. 2019 Aug 19. doi: 10.4269/ajtmh.19-0309. [Epub ahead of print]

Epidemiology of Dengue, Chikungunya, and Zika Virus Disease in the U.S. States and Territories, 2017.

Adams LE1, Martin SW2, Lindsey NP2, Lehman JA2, Rivera A1, Kolsin J2, Landry K2, Staples JE2, Sharp TM1, Paz-Bailey G1, Fischer M2.

Author information: 1 Dengue Branch, Centers for Disease Control and Prevention, San Juan, Puerto Rico. 2 Arboviral Diseases Branch, Centers for Disease Control and Prevention, Fort Collins, Colorado.



Dengue, chikungunya, and Zika viruses, primarily transmitted by Aedes species mosquitoes, have caused large outbreaks in the Americas, leading to travel-associated cases and local mosquito-borne transmission in the United States. We describe the epidemiology of dengue, chikungunya, and noncongenital Zika virus disease cases reported from U.S. states and territories in 2017, including 971 dengue cases, 195 chikungunya cases, and 1,118 Zika virus disease cases. Cases of all three diseases reported from the territories were reported as resulting from local mosquito-borne transmission. Cases reported from the states were primarily among travelers, with only seven locally acquired mosquito-transmitted Zika virus disease cases reported from Texas (n = 5) and Florida (n = 2). In the territories, most dengue cases (n = 508, 98%) were reported from American Samoa, whereas the majority of chikungunya (n = 39, 100%) and Zika virus disease (n = 620, 93%) cases were reported from Puerto Rico. Temporally, the highest number of Zika virus disease cases occurred at the beginning of the year, followed by a sharp decline, mirroring decreasing case numbers across the Americas following large outbreaks in 2015 and 2016. Dengue and chikungunya cases followed a more seasonal pattern, with higher case numbers from July through September. Travelers to the United States and residents of areas with active virus transmission should be informed of both the ongoing risk from dengue, chikungunya, and Zika virus disease and personal protective measures to lower their risk of mosquito bites and to help prevent the spread of these diseases.

PMID: 31436154 DOI: 10.4269/ajtmh.19-0309

Keywords: Zika Virus; Dengue fever; Chikungunya fever; USA.


#Epidemiological profile of #Zika, #Dengue and #Chikungunya virus #infections identified by medical and molecular evaluations in #Rondonia, #Brazil (Rev Inst Med Trop Sao Paulo, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Rev Inst Med Trop Sao Paulo. 2019 Aug 19;61:e40. doi: 10.1590/S1678-9946201961040.

Epidemiological profile of Zika, Dengue and Chikungunya virus infections identified by medical and molecular evaluations in Rondonia, Brazil.

Vieira DS1,2,3, Zambenedetti MR4, Requião L4, Borghetti IA4,5, Luna LKS4, Santos AOD1,3, Taborda RLM3, Pereira DB3, Krieger MA4,6, Salcedo JMV1,3, Rampazzo RCP4.

Author information: 1 Fundação Oswaldo Cruz Rondônia, Porto Velho, Rondônia, Brazil. 2 Universidade Federal de Rondônia, Programa de Pós-Graduação em Biologia Experimental, Porto Velho, Rondônia, Brazil. 3 Centro de Pesquisa em Medicina Tropical, Porto Velho, Rondônia, Brazil. 4 Instituto de Biologia Molecular do Paraná, Curitiba, Paraná, Brazil. 5 Universidade Federal do Paraná, Departamento de Engenharia de Bioprocessos e Biotecnologia, Curitiba, Paraná, Brazil. 6 Instituto Carlos Chagas, Curitiba, Paraná, Brazil.



Several arboviruses have emerged and/or re-emerged in North, Central and South-American countries. Viruses from some regions of Africa and Asia, such as the Zika and Chikungunya virus have been introduced in new continents causing major public health problems. The aim of this study was to investigate the presence of RNA from Zika, Dengue and Chikungunya viruses in symptomatic patients from Rondonia, where the epidemiological profile is still little known, by one-step real-time RT-PCR. The main clinical signs and symtoms were fever (51.2%), headache (78%), chills (6.1%), pruritus (12.2%), exanthema (20.1%), arthralgia (35.3%), myalgia (26.8%) and retro-orbital pain (19.5%). Serum from 164 symptomatic patients were collected and tested for RNA of Zika, Dengue types 1 to 4 and Chikungunya viruses, in addition to antibodies against Dengue NS1 antigen. Direct microscopy for Malaria was also performed. Only ZIKV RNA was detected in 4.3% of the patients, and in the remaining 95.7% of the patients RNA for Zika, Dengue and Chikungunya viruses were not detected. This finding is intriguing as the region has been endemic for Dengue for a long time and more recently for Chikungunya virus as well. The results indicated that medical and molecular parameters obtained were suitable to describe the first report of symptomatic Zika infections in this region. Furthermore, the low rate of detection, compared to clinical signs and symptoms as the solely diagnosis criteria, suggests that molecular assays for detection of viruses or other pathogens that cause similar symptoms should be used and the corresponding diseases could be included in the compulsory notification list.

PMID: 31432989 DOI: 10.1590/S1678-9946201961040

Keywords: Zika Virus; Dengue fever; Chikungunya fever; Seroprevalence; Brazil.