Dengue is a systemic viral infection transmitted between humans by Aedes mosquitoes. For some patients, dengue is a life-threatening illness. There are currently no licensed vaccines or specific therapeutics, and substantial vector control efforts have not stopped its rapid emergence and global spread. The contemporary worldwide distribution of the risk of dengue virus infection and its public health burden are poorly known. Here we undertake an exhaustive assembly of known records of dengue occurrence worldwide, and use a formal modelling framework to map the global distribution of dengue risk. We then pair the resulting risk map with detailed longitudinal information from dengue cohort studies and population surfaces to infer the public health burden of dengue in 2010. We predict dengue to be ubiquitous throughout the tropics, with local spatial variations in risk influenced strongly by rainfall, temperature and the degree of urbanization. Using cartographic approaches, we estimate there to be 390 million (95% credible interval 284-528) dengue infections per year, of which 96 million (67-136) manifest apparently (any level of disease severity). This infection total is more than three times the dengue burden estimate of the World Health Organization. Stratification of our estimates by country allows comparison with national dengue reporting, after taking into account the probability of an apparent infection being formally reported. The most notable differences are discussed. These new risk maps and infection estimates provide novel insights into the global, regional and national public health burden imposed by dengue. We anticipate that they will provide a starting point for a wider discussion about the global impact of this disease and will help to guide improvements in disease control strategies using vaccine, drug and vector control methods, and in their economic evaluation.

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The global distribution and burden of dengue

Zika virus (ZIKV) has recently caused a pandemic disease, and many cases of ZIKV infection in pregnant women resulted in abortion, stillbirth, deaths and congenital defects including microcephaly, which now has been proposed as ZIKV congenital syndrome. This study aimed to investigate the in situ immune response profile and mechanisms of neuronal cell damage in fatal Zika microcephaly cases. Brain tissue samples were collected from 15 cases, including 10 microcephalic ZIKV-positive neonates with fatal outcome and five neonatal control flavivirus-negative neonates that died due to other causes, but with preserved central nervous system (CNS) architecture. In microcephaly cases, the histopathological features of the tissue samples were characterized in three CNS areas (meninges, perivascular space, and parenchyma). The changes found were mainly calcification, necrosis, neuronophagy, gliosis, microglial nodules, and inflammatory infiltration of mononuclear cells. The in situ immune response against ZIKV in the CNS of newborns is complex. Despite the predominant expression of Th2 cytokines, other cytokines such as Th1, Th17, Treg, Th9, and Th22 are involved to a lesser extent, but are still likely to participate in the immunopathogenic mechanisms of neural disease in fatal cases of microcephaly caused by ZIKV.

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In situ immune response and mechanisms of cell damage in central nervous system of fatal cases microcephaly by Zika virus

Summary A widespread epidemic of Zika virus (ZIKV) infection was reported in 2015 in South and Central America and the Caribbean. A major concern associated with this infection is the apparent increased incidence of microcephaly in fetuses born to mothers infected with ZIKV. In this report, we describe the case of an expectant mother who had a febrile illness with rash at the end of the first trimester of pregnancy while she was living in Brazil. Ultrasonography performed at 29 weeks of gestation revealed microcephaly with calcifications in the fetal brain and placenta. After the mother requested termination of the pregnancy, a fetal autopsy was performed. Micrencephaly (an abnormally small brain) was observed, with almost complete agyria, hydrocephalus, and multifocal dystrophic calcifications in the cortex and subcortical white matter, with associated cortical displacement and mild focal inflammation. ZIKV was found in the fetal brain tissue on reversetranscriptase–polymerase-chain-reaction (RT-PCR) assay, with consistent findings on electron microscopy. The complete genome of ZIKV was recovered from the fetal brain.

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Zika Virus Associated with Microcephaly

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(16)00562-6.pdf

Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study

L'incidence annuelle du syndrome de Guillain-Barre est de 1,5/100000 habitants La mortalite actuelle est estimee a environ 5 % d'apres des essais therapeutiques recents, bien conduits Dix pour cent des malades gardent des sequelles motrices tres invalidantes un an apres le debut des premiers signes neurologiques La prise en charge de ces malades necessite des equipes entrainees, multidisciplinaires, pouvant pratiquer l'ensemble des therapeutiques specifiques La corticotherapie per os'ou par voie intraveineuse est inefficace Les echanges plasmatiques sont le premier traitement dont l'efficacite a ete demontree par rapport a un groupe controle Les indications sont maintenant mieux connues Les formes benignes (marche possible) beneficient de 2 echanges plasmatiques; 2 echanges supplementaires sont realises en cas d'aggravation Dans les formes intermediaires (marche impossible) et les formes severes (recours a la ventilation mecanique), 4 echanges plasmatiques sont conseilles Il n'est pas utile d'augmenter leur nombre dans les formes severes ou en cas d'absence d'amelioration De fortes doses d'immunoglobulines donnees par voie intraveineuse (lq IV) [0,4 g/kg/j pendant 5 jours] sont aussi efficaces que les echanges plasmatiques dans les formes intermediaires et severes Dans ces formes, le choix entre Ig IV et echanges plasmatiques depend des contre-indications respectives de ces traitements et de leur faisabilite Les travaux en cours ont comme objectif de mieux preciser les indications respectives des echanges plasmatiques et des lq IV dans des formes de gravite differente, leur morbidite comparee, la dose optimale des lq IV

[Guillain-Barré syndrome].

In December 2013, during a Zika virus (ZIKV) outbreak in French Polynesia, a patient in Tahiti sought treatment for hematospermia, and ZIKV was isolated from his semen. ZIKV transmission by sexual intercourse has been previously suspected. This observation supports the possibility that ZIKV could be transmitted sexually.

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Potential Sexual Transmission of Zika Virus

To the Editor: Isolated in 1947 from a rhesus monkey in Zika forest, Uganda, Zika virus (ZIKV) is a mosquito-borne flavivirus (1) For half a century, ZIKV was described only as causing sporadic human infections in Africa and Asia, which was mostly confirmed by serologic methods (2) In 2007, the first ZIKV outbreak reported outside Africa and Asia was retrospectively documented from biological samples of patients on Yap Island, Federated States of Micronesia, North Pacific, who had received an incorrect diagnosis of dengue virus (DENV) (3,4) We report here the early investigations that led to identification of ZIKV as the causative agent of an outbreak that started in October 2013 in French Polynesia

French Polynesia is a French overseas territory located in the South Pacific The ≈270,000 inhabitants live on 67 islands distributed into 5 archipelagoes (Society, Marquesas, Tuamotu, Gambier, and Austral Islands) Surveillance for acute febrile illnesses is coordinated by the Department of Health with the contribution of a sentinel network of public and private practitioners, the main public hospital (Centre Hospitalier du Taaone), and the public health and research institute (Institut Louis Malarde [ILM]) As part of this syndromic surveillance system, ILM has implemented protocols for detecting arboviruses that are known to cause outbreaks in French Polynesia, such as DENV, or that pose a risk for causing epidemics because of the presence of potential mosquito vectors In addition, ILM provides DENV serotype identification for other Pacific island countries, including Yap State, as part of the regional surveillance of dengue (5) For that reason, a ZIKV reverse transcription PCR (RT-PCR) protocol by Lanciotti et al (3) was implemented at ILM

In October 2013 (week 41), a 53-year-old women (patient 1) and 2 other members of the household—her 52-year-old husband (patient 2) and her 42-year-old son-in-law (patient 3)—experienced a mild dengue-like illness consisting of low fever (<38°C), asthenia, wrist and fingers arthralgia, headache, and rash Patients 2 and 3 also had conjunctivitis Patient 1 had swollen ankles and aphthous ulcers For all 3 patients, results were negative for DENV by RT-PCR and nonstructural protein 1 (NS1) antigen tests (5), for West-Nile virus by RT-PCR, and for chikungunya virus by RT-PCR; results of RT-PCR for ZIKV were equivocal for patients 1 and 2 During week 43, a 57-year-old patient (patient 4) reported similar symptoms; results of RT-PCR for DENV were negative, but results of RT-PCR for ZIKV were positive ZIKV infection was then confirmed by sequencing of the genomic position 858–1138 encompassing the prM/E protein coding regions of ZIKV (GenBank accession no {"type":"entrez-nucleotide","attrs":{"text":"KJ579441","term_id":"636632075"}}KJ579441) The protocol was approved by the Ethics Committee of French Polynesia (reference no 66/CEPF) Phylogenetic analysis of the sequence (Figure) showed ZIKV strain Cambodia 2010-FSS13025 (GenBank accession no {"type":"entrez-nucleotide","attrs":{"text":"JN860885","term_id":"380036385"}}JN860885) as the closest strain (6)



Figure

Phylogenetic analysis of partial M/E genes of 2 ZIKV strains, French Polynesia, 2013 The evolutionary history was inferred by using the maximum-likelihood method based on the Kimura 2-parameter model The percentage of trees in which the associated taxa 



Concomitant with these investigations, the Department of Health recorded an increased number of patients with a mild dengue-like syndrome and rash who were visiting primary care physicians Given this information, we performed RT-PCR for ZIKV on 10 samples collected during weeks 43 and 44 from patients living in different archipelagoes that had tested negative for DENV NS1 antigen Four samples gave negative results; 4, positive; and 2, equivocal Sequencing of 1 ZIKV-positive sample from a patient in Nuku Hiva, Marquesas Islands (GenBank accession no {"type":"entrez-nucleotide","attrs":{"text":"KJ579442","term_id":"636632077"}}KJ579442) showed that it had 100% homology with the fragment sequenced from patient 4 who lived in Tahiti, Society Islands The phylogenetic tree shows that the ZIKV that recently emerged in French Polynesia is similar to Cambodia 2010 and Yap State 2007 strains, which corroborates previous findings of an expansion of ZIKV Asian lineage (7,8) ZIKV was then isolated by inoculating Vero cells with RT-PCR samples positive for ZIKV After 6 days of propagation, ZIKV-infected cells were detected by indirect immunofluorescence assay using specific hyperimmune mouse ascitic fluids provided by the Institut Pasteur (Dakar, Senegal) (9)

By week 51, the practitioners’ network recorded 5,895 patients with suspected ZIKV infections, leading to an estimate of 19,000 suspected cases when extrapolated to other care centers (adjusted to the mean consultation visits) Serum from 584 patients was tested by RT-PCR for ZIKV; 294 samples were positive

This ZIKV outbreak is the largest documented and the first known to be caused by an arbovirus other than DENV in French Polynesia To assess when ZIKV circulation in French Polynesia might have started, we will be conducting a retrospective study on DENV NS1 antigen–negative samples collected before the first ZIKV cases were detected Investigations of the clinical features of ZIKV infections are ongoing Particularly, because French Polynesia is experiencing concomitant ZIKV, DENV-1, and DENV-3 outbreaks, attention will be paid to whether sequential infections may affect disease outcome Otherwise, because French Polynesia hosts several mosquito species, notably Aedes aegypti, already known to transmit ZIKV (10), but also other potential vectors, such as Ae polynesiensis, human and entomologic surveillances have been reinforced to clarify the emergence factors of this outbreak

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Zika virus, French polynesia, South pacific, 2013.

Since October 2013, French Polynesia has experienced the largest documented outbreak of Zika virus (ZIKAV) infection. To prevent transmission of ZIKAV by blood transfusion, specific nucleic acid testing of blood donors was implemented. From November 2013 to February 2014: 42 (3%) of 1,505 blood donors, although asymptomatic at the time of blood donation, were found positive for ZIKAV by PCR. Our results serve to alert blood safety authorities about the risk of post-transfusion Zika fever.

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Claudine Roche

Papers

Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study

Potential Sexual Transmission of Zika Virus

Zika virus, French polynesia, South pacific, 2013.

Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014.

Detection of Zika virus in saliva