A emergência da dengue como desafio virológico: de doença-fantasma à endemia "de estimação", 1986-1987 / The emergence of dengue as a virological challenge: from phantom disease to "pet" endemic, 1986-1987

Resumo O artigo analisa como a dengue se apresentou como desafio virológico na década de 1980. O objetivo é entender o papel dos estudos virológicos na compreensão da doença e a construção de uma expertise em arboviroses. Embora surtos da doença já tivessem sido relatados ao longo do século XX, a dengue era pouco conhecida nas Américas até a epidemia de dengue hemorrágica em Cuba, em 1981. Quando em 1986 a doença atingiu a cidade de Nova Iguaçu (RJ), a equipe de virologistas liderada por Hermann Schatzmayr tomaria a doença como objeto, mobilizando esforços a partir da criação do Laboratório de Flavivírus do Instituto Oswaldo Cruz.

Abstract This article analyzes how dengue presented a virological challenge during the 1980s in order to explore the role of virological studies in understanding this disease and constructing expertise in arboviral diseases. Although outbreaks were reported throughout the twentieth century, dengue was barely known in the Americas until the epidemic of dengue fever in Cuba in 1981. When the disease reached the Brazilian city of Nova Iguaçu (RJ) in 1986, it became the focus of attention for a team of virologists led by Hermann Schatzmayr, who mobilized efforts after the creation of the Flavivirus Laboratory at the Oswaldo Cruz Institute.

Cross-Protection of Dengue Virus Infection against Congenital Zika Syndrome, Northeastern Brazil.

The Zika virus outbreak in Latin America resulted in congenital malformations, called congenital Zika syndrome (CZS). For unknown reasons, CZS incidence was highest in northeastern Brazil; one potential explanation is that dengue virus (DENV)-mediated immune enhancement may promote CZS development. In contrast, our analyses of historical DENV genomic data refuted the hypothesis that unique genome signatures for northeastern Brazil explain the uneven dispersion of CZS cases. To confirm our findings, we performed serotype-specific DENV neutralization tests in a case-control framework in northeastern Brazil among 29 Zika virus-seropositive mothers of neonates with CZS and 108 Zika virus-seropositive control mothers. Neutralization titers did not differ significantly between groups. In contrast, DENV seroprevalence and median number of neutralized serotypes were significantly lower among the mothers of neonates with CZS. Supported by model analyses, our results suggest that multitypic DENV infection may protect from, rather than enhance, development of CZS.

Joint Estimation of Relative Risk for Dengue and Zika Infections, Colombia, 2015-2016.

We jointly estimated relative risk for dengue and Zika virus disease (Zika) in Colombia, establishing the spatial association between them at the department and city levels for October 2015-December 2016. Cases of dengue and Zika were allocated to the 87 municipalities of 1 department and the 293 census sections of 1 city in Colombia. We fitted 8 hierarchical Bayesian Poisson joint models of relative risk for dengue and Zika, including area- and disease-specific random effects accounting for several spatial patterns of disease risk (clustered or uncorrelated heterogeneity) within and between both diseases. Most of the dengue and Zika high-risk municipalities varied in their risk distribution; those for Zika were in the northern part of the department and dengue in the southern to northeastern parts. At city level, spatially clustered patterns of dengue high-risk census sections indicated Zika high-risk areas. This information can be used to inform public health decision making.

History, epidemiology and diagnostics of dengue in the American and Brazilian contexts: a review.

Dengue virus (DENV), an arbovirus transmitted by mosquitoes, has become a major threat to American human life, reaching approximately 23 million cases from 1980 to 2017. Brazil is among the countries most affected by this terrible viral disease, with 13.6 million cases. DENV has four different serotypes, DENV1-4, which show a broad clinical spectrum. Dengue creates a staggering epidemiological and economic burden for endemic countries. Without a specific therapy and with a commercial vaccine that presents some problems relative to its full effectiveness, initiatives to improve vector control strategies, early disease diagnostics and the development of vaccines and antiviral drugs are priorities. In this study, we present the probable origins of dengue in America and the trajectories of its spread. Overall, dengue diagnostics are costly, making the monitoring of dengue epidemiology more difficult and affecting physicians' therapeutic decisions regarding dengue patients, especially in developing countries. This review also highlights some recent and important findings regarding dengue in Brazil and the Americas. We also summarize the existing DENV polymerase chain reaction (PCR) diagnostic tests to provide an improved reference since these tests are useful and accurate at discriminating DENV from other flaviviruses that co-circulate in the Americas. Additionally, these DENV PCR assays ensure virus serotyping, enabling epidemiologic monitoring.

Dengue in Rio Grande do Sul, Brazil: 2014 to 2016.

The first autochthonous dengue case in Rio Grande do Sul (RS), Southern Brazil, occurred in 2007. In 2008 and 2009, only imported cases were reported in RS, but from 2010 to 2013, reports of autochthonous infections increased significantly. This study analyzes and discusses laboratory, demographic, and clinical data regarding dengue cases in RS, from 2014 to 2016. This study analyzed 13,420 serum samples from notified patients with suspicion of dengue fever in RS from 2014 to 2016. Seasonality of positive cases, viral serotypes, and clinical and epidemiological aspects were analyzed. There was no difference in gender (P = .4); dengue fever occurred mainly in adults, with similar distribution among age groups. The number of dengue virus (DENV) cases increased from 89 cases in 2014 to 2518 in 2016. Dengue virus 1 was the most prevalent circulating serotype during this period (97.5% of cases). Dengue virus infections show peaks in March and April (late summer and early autumn), after periods of high temperatures and rainfall. In 2014, dengue cases were concentrated in the northwestern and eastern regions of RS, and in 2015 and 2016, the northern region also confirmed a high number of cases. With increase in DENV circulation in RS, a rise in the number of autochthonous infections was also observed, mainly in highly urbanized areas. This study revealed that circulation of DENV in RS increased significantly in 2015 and 2016, with a rise in the number of autochthonous infections and cocirculation with Chikungunya and Zika viruses, recently introduced into RS.

Características del virus del dengue y su pronóstico bioclimático en el Departamento de Cortés / Characteristic of the dengue virus and its bioclimatic prognosis in Cortés Department

Se efectuó un estudio observacional, descriptivo y transversal en el Departamento de Cortés, en Honduras, durante el período de 2003 a 2013, con vistas a determinar las características del dengue en esta región, describir su historicidad y desarrollar un modelo matemático de pronóstico basado en variables bioclimáticas. En la serie el sexo no constituyó un factor predisponente, mientras que los grupos etarios de 5-9 y de 20-49 años, el ser habitante en Choloma, Villanueva y Puerto Cortés, resultaron elementos importantes en la aparición del dengue. Asimismo las formas graves de la enfermedad en niños y jóvenes indicaron una baja memoria inmunológica y/o varias exposiciones a serotipos del virus. Se obtuvo un patrón definido, cíclico-epidémico (de 4 a 5 años) y estacional, pues correspondía al período lluvioso de la región. Finalmente, se concluyó que las condiciones climáticas de Cortés están condicionando la transmisión del dengue, de manera que puede ser posible la predicción de los acontecimientos epidémicos

An observational, descriptive and cross-sectional study was carried out in Cortés Department, Honduras, during the period of 2003 at 2013, aimed at determining the characteristics of dengue in this region, describing its history and developing a prognosis mathematical model based on bioclimatic variables. In the series, sex didn't constitute a predisposing factor, while the age groups 5-9 and 20-49 years, being inhabitant in Choloma, Villanueva and Puerto Cortés were important elements in the emergence of dengue. Also the severe forms of the disease in children and young persons indicated a low immunologic memory and/or several exposures to serotypes of the virus. A defined, seasonal recurrent-epidemic pattern was obtained (of 4 to 5 years), because it corresponded to the rainy period of the region. Finally, it was concluded that the climate conditions of Cortés are conditioning the transmission of dengue, so that the prognosis of the epidemic events can be possible

Advances in using Internet searches to track dengue.

Dengue is a mosquito-borne disease that threatens over half of the world's population. Despite being endemic to more than 100 countries, government-led efforts and tools for timely identification and tracking of new infections are still lacking in many affected areas. Multiple methodologies that leverage the use of Internet-based data sources have been proposed as a way to complement dengue surveillance efforts. Among these, dengue-related Google search trends have been shown to correlate with dengue activity. We extend a methodological framework, initially proposed and validated for flu surveillance, to produce near real-time estimates of dengue cases in five countries/states: Mexico, Brazil, Thailand, Singapore and Taiwan. Our result shows that our modeling framework can be used to improve the tracking of dengue activity in multiple locations around the world.

Leaking Containers: Success and Failure in Controlling the Mosquito Aedes aegypti in Brazil.

In 1958, the Pan American Health Organization declared that Brazil had successfully eradicated the mosquito Aedes aegypti, responsible for the transmission of yellow fever, dengue fever, chikungunya, and Zika virus. Yet in 2016 the Brazilian minister of health described the situation of dengue fever as "catastrophic." Discussing the recent epidemic of Zika virus, which amplified the crisis produced by the persistence of dengue fever, Brazil's president declared in January 2016 that "we are in the process of losing the war against the mosquito Aedes aegypti." I discuss the reasons for the failure to contain Aedes in Brazil and the consequences of this failure. A longue durée perspective favors a view of the Zika epidemic that does not present it as a health crisis to be contained with a technical solution alone but as a pathology that has the persistence of deeply entrenched structural problems and vulnerabilities.

Evolutionary history and spatiotemporal dynamics of DENV-1 genotype V in the Americas.

The genotype V has been the most prevalent dengue virus type 1 (DENV-1) clade circulating in the Americas over the last 40years. In this study, we investigate the spatiotemporal pattern of emergence and dissemination of DENV-1 lineages in the continent. We applied phylogenetic and phylogeographic approaches to a comprehensive data set of 836 DENV-1 E gene sequences of the genotype V isolated from 46 different countries around the world over a period of 50years (1962 to 2014). Our study reveals that genetic diversity of DENV-1 genotype V in the Americas resulted from two independent introductions of this genotype from India. The first genotype V strain was most probably introduced into the Lesser Antilles at around the early 1970s and this Caribbean region becomes the source population of several DENV-1 lineages that spread in the Americas during the 1970s and 1980s. Most of those lineages appear to become extinct during the 1990s, except one that persisted in Venezuela and later spread to other American countries, dominating the DENV-1 epidemics in the region from the early 2000s onwards. The second genotype V strain of Indian origin was also most probably introduced into the Lesser Antilles at around the early 1980s. This lineage remained almost undetected for nearly 15years, until it was introduced in Northern Brazil around the middle 1990s and later spread to other country regions. These results demonstrate that different geographic regions have played a role in maintaining and spreading the DENV-1 genotype V in the Americas over time. DENV-1 genotype V lineages have originated, spread and died out in the Americas with very different dynamics and the phenomenon of lineage replacement across successive DENV-1 epidemic outbreaks was a common characteristic in most American countries.

Co-infections with Chikungunya and Dengue Viruses, Guatemala, 2015.

We screened serum samples referred to the national reference laboratory in Guatemala that were positive for chikungunya or dengue viruses in June 2015. Co-infection with both viruses was detected by reverse transcription PCR in 46 (32%) of 144 samples. Specimens should be tested for both arboviruses to detect co-infections.

Reemergence of Dengue in Southern Texas, 2013.

During a dengue epidemic in northern Mexico, enhanced surveillance identified 53 laboratory-positive cases in southern Texas; 26 (49%) patients acquired the infection locally, and 29 (55%) were hospitalized. Of 83 patient specimens that were initially IgM negative according to ELISA performed at a commercial laboratory, 14 (17%) were dengue virus positive by real-time reverse transcription PCR performed at the Centers for Disease Control and Prevention. Dengue virus types 1 and 3 were identified, and molecular phylogenetic analysis demonstrated close identity with viruses that had recently circulated in Mexico and Central America. Of 51 household members of 22 dengue case-patients who participated in household investigations, 6 (12%) had been recently infected with a dengue virus and reported no recent travel, suggesting intrahousehold transmission. One household member reported having a recent illness consistent with dengue. This outbreak reinforces emergence of dengue in southern Texas, particularly when incidence is high in northern Mexico.

[Evolution of the theory and practices for the control of vector borne diseases]. / Evolución de la teoría y las prácticas en el control de las enfermedades transmitidas por vector.

The conceptual models of the public health have bonds with the advance in the knowledge of the VBDs. The establishment of the colonial empires, the sprouting of great scale sanitary interventions, the creation of tie international organisms dedicated to the promotion of the health, the participation of phylantropic institutions financing and organizing different health campaigns are only a few contributions to the field. This body of knowledge contributed to the birth and the progress of several medical disciplines, academic institutions and international organisms dedicated to the education of human resources, research and health services; establishing the production and reproduction bases of this intellectual field. The way that VBDs have been faced has also molded great part of the ideas and the practices in Public Health and its essence has been adopted to elaborate the prevention and control programs of other many problems of health.

Evolución de la teoría y las prácticas en el control de las enfermedades transmitidas por vector / Evolution of the theory and practices for the control of vector borne diseases

La configuración de los modelos conceptuales de la salud pública encuentran vínculos con el avance en el conocimiento de las ETV. El establecimiento de los imperios coloniales, el surgimiento de las intervenciones sanitarias a gran escala, la creación de organismos internacionales, la participación de sociedades filantrópicas en el financiamiento y organización de campañas de salud son sólo unas cuantas aportaciones al campo. Este cuerpo de conocimientos contribuyó al nacimiento y el progreso de varias disciplinas médicas, instituciones académicas y organismos internacionales dedicados a la formación de recursos humanos, la investigación y la prestación de servicios de salud, reconocidos como las bases de producción y reproducción de todo campo intelectual. La forma como se han enfrentado las ETV también ha moldeado el quehacer y las prácticas en salud pública, y su esencia ha sido adoptada para elaborar los programas de control y prevención de otros muchos problemas de salud.

The conceptual models of the public health have bonds with the advance in the knowledge of the VBDs. The establishment of the colonial empires, the sprouting of great scale sanitary interventions, the creation of tie international organisms dedicated to the promotion of the health, the participation of phylantropic institutions financing and organizing different health campaigns are only a few contributions to the field. This body of knowledge contributed to the birth and the progress of several medical disciplines, academic institutions and international organisms dedicated to the education of human resources, research and health services; establishing the production and reproduction bases of this intellectual field. The way that VBDs have been faced has also molded great part of the ideas and the practices in Public Health and its essence has been adopted to elaborate the prevention and control programs of other many problems of health.

Dengue contando uma história (Série Meio Ambiente Saudável) / Dengue telling a story (Series Healthy Environment)

Através de uma linguagem acessível, utilizando imagens desde 1846, conhecemos a história do mosquito da dengue. Temos também a orientação de como a doença é transmitida e o que deve-se fazer para a sua prevenção...

Characterization of the dengue outbreak in Nuevo Leon state, Mexico, 2010.

We studied serotypes circulating dengue virus (DENV) cases, entomological Breteau index, rain-fall index and epidemiology of groups affected during the 2010 outbreak in Nuevo Leon, Mexico. From 2,271 positive cases, 94% were dengue classic and 6% dengue hemorrhagic fever; DENV1 was mainly isolated (99%) (Central-American lineage of American-African-genotype). We found correlation between two environmental phenomena (Increment of rainfall and vector-indexes) (p ≤ 0.05) with epidemiological, clinical and risk of DENV-1 ongoing transmission.

Avaliação do perfil de mediadores séricos e proteínas intraplaquetárias em relação à plaquetopenia em pacientes infectados pelo vírus dengue / Evaluation of serum mediators profile and intraplatelet proteins in respect to thrombocytopenia in patients infected with dengue virus

Plaquetas são fragmentos celulares derivados dos megacariócitos, que desempenham papel na hemostasia, coagulação, angiogênese, inflamação e resposta imune. Na infecção humana pelo Vírus Dengue (DENV), plaquetas constituem uma das populações celulares mais afetadas devido à plaquetopenia e disfunção plaquetária. O objetivo deste trabalho foi investigar a influência de citocinas, quimiocina e fatores de crescimento séricos e de proteínas intraplaquetárias relacionadas à angiogênese, coagulação, regulação da matriz extracelular e inflamação na plaquetopenia de pacientes infectados pelo DENV. Para tal, realizamos: (i) estudo populacional de pacientes e obtenção de soro e plaquetas em 2013, (ii) ensaios multiplex de micrarranjo líquido para quantificação dos níveis séricos de citocinas, quimiocina e fatores de crescimento e (iii) ensaio de determinação do perfil de expressão 55 proteínas intraplaquetárias. Quarenta e três pacientes DENV foram confirmados, com predominância do DENV-4. Independente da forma clínica, pacientes DENV apresentaram níveis séricos elevados de IL-10, TNF-alfa, CXCL8/IL-8, mas não de IL-1beta e IFN-gama quando comparados aos controles sadios. Análises estatísticas demonstraram que níveis de IL-10 e IFN-gama apresentaram correlação, respectivamente inversa e direta com a contagem de plaquetas. Ainda, IL-10 diretamente com leucócitos e linfócitos e TNF-alfa com linfócitos. Vinte e cinco proteínas intraplaquetárias foram quantificadas, mas apenas cinco delas, PDGF-AA, TGF-beta1, HGF, IGFBP-1 e Angiopoetina-1, apresentaram correlação direta com a contagem de plaquetas nos pacientes DENV. A quantificação sérica de PDGF e VEGF demostrou que ambos estavam diminuídos no grupo DENV mais trombocitopênico...

Platelets are cell fragments derived from megakaryocytes, which play a role in hemostasis, coagulation, angiogenesis, inflammation and immune response. In human infection with dengue virus (DENV), platelets are one of the most affected cell populations due to thrombocytopeniaand platelet dysfunction. The objective of this study was to investigate the influence of serum cytokines, chemokines, intraplatelet growth factors and proteins related to angiogenesis, coagulation, regulation of extracellular matrix and inflammation in thrombocytopenia of patientsinfected with DENV. For this purpose, we conducted: (i) population study of patients and obtaining their serum and platelets in 2013, (ii) liquid microarray multiplex assays for quantitationof serum levels of cytokines, chemokine, and growth factors, and (iii) assay for determiningexpression profile of 55 intraplapletelet proteins. Forty-three DENV patients were confirmed, with a predominance of DENV-4. Regardless of type of DENV, levels of IL-10, TNF-alfa, CXCL8 /IL-8, but not IL-1beta and IFN-gama were higher on serum of patients compared to healthy individuals. Statistical analyses showed that levels of IL-10 and IFN-gama presented correlation, respectively, inverse and direct with platelet count. Furthermore, IL-10 was directly correlated with leukocytes, lymphocytes, TNF-alfa and with lymphocytes. Twenty-five intraplatelet proteins were quantified, but only five of them, PDGF-AA, TGF-beta1, HGF, angiopoietin-1 and IGFBP-1 weredirectly correlated with platelet count in DENV patients. Both levels of PDGF and VEGF were decreased in group of DENV thrombocytopenic...

Laboratory surveillance of dengue in Rio Grande do Sul, Brazil, from 2007 to 2013.

BACKGROUND: According to official records, dengue was introduced in Brazil in the 80's; since then several epidemics have occurred. Meanwhile, in Rio Grande do Sul (RS, Southern Brazil) the first autochthonous case occurred only in 2007. METHODOLOGY AND PRINCIPAL FINDINGS: In this study we report laboratory surveillance of dengue cases and seasonality of positive cases, describe serotypes and characterize the epidemiological pattern of dengue in RS from 2007 to 2013. A total of 9,779 serum samples from patients with suspected dengue fever were collected and submitted to molecular and/or serological analyses for dengue virus identification and serotyping, based on viral isolation, NS1 antigen detection and qRT-PCR, or Dengue IgM capture ELISA and MAC-ELISA. The first autochthonous dengue case in RS was confirmed in 2007 (DENV-3). While in 2008 and 2009 only imported cases were registered, autochthonous infection waves have been occurring since 2010. The highest number of dengue infections occurred in 2010, with DENV-1 and DENV-2 outbreaks in Northwestern RS. In 2011, another DENV-1 and DENV-2 outbreak occurred in the Northwestern region; moreover, DENV-4 was detected in travelers. In 2012, DENV-1 and DENV-4 co-circulated. DENV-2 circulation was only detected again in 2013, in high frequency (56.7%), co-circulating with DENV-4 (35%). Most infections occur in adults during summer. Differences in prevalence between genders were observed in 2007 (60% females), 2008 (60.8% males) and 2009 (77.5% males). CONCLUSIONS: According to results of dengue surveillance, there was an increase in the number of dengue cases in RS and of cities infested with Aedes aegypti, possibly as a consequence of introduction of new serotypes and the difficulty of health programs to control the vector.

Interação vírus-vetor: caracterização da região 3’ não-codificante (NC) de vírus dengue tipo 3 (DENV-3), isolados de mosquitos e humanos, após a infecção experimental sucessiva e simultânea em mosquitos / Virus-vector interaction: characterization of the 3 'non-coding (NC) type 3 dengue virus (DENV-3), isolated from human and mosquitoes after successive and simultaneous experimentally infected mosquitoes

A dengue é considerada a mais importante das doenças virais transmitida por artrópodes que acomete o homem. O vírus dengue (DENV) é mantido na natureza através de replicação cíclica em hospedeiros vertebrados e mosquitos Aedes, sendo o Aedes aegypti o principal vetor. O seqüenciamento completo de DENV-3 isolado de Ae. aegypti naturalmente infectado do Rio de Janeiro em 2001 e de um caso humano em 2002, demonstrou uma similaridade de 99 porcento com DENV-3 isolado de um caso fatal humano ocorrido no mesmo período. A análise da região 3´NC do genoma viral demonstrou uma mutação nesta região, sugerindo uma deleção de 8 nucleotídeos (nts) na inserção de 11nts, característica de DENV-3 isolados no Brasil. Neste estudo, avaliamos se as diferentes variantes de DENV-3 na interação vírus-vetor através da determinação da competência vetorial em Ae. aegypti. As cepas de DENV-3 BR74886 #5 (cepa representativa do vírus com inserção de 11nts na região 3’NC) e BR73356 #5 (cepa representativa do vírus com a deleção de 8 nts), apresentando títulos de 8 x 107 PFU/mL e 7,3 x 107 PFU/mL, respectivamente, mantiveram suas características na região 3’NC do genoma viral após cinco passagens em cultura celular e foram selecionadas para a infecção experimental. A estratégia de infecção consistiu na utilização de 2.925 fêmeas de Ae. aegypti, sendo que 2.340 da geração F1 da população de Tubiacanga (RJ) e 585 da cepa controle PaeaA população experimental se mostrou competente para transmitir as duas cepas virais de DENV-3, no entanto a disseminação viral no corpo do mosquito apresentou-se de forma heterogênea, sugerindo haver vantagens para a cepa com inserção de 11 nts, uma vez que disseminou-se mais rapidamente. Quando as fêmeas de Ae. aegypti foram alimentadas com ambas as cepas, a disseminação no vetor comportou-se de maneira semelhante à observada quando alimentadas com a cepa representativa da inserção de 11 nts...

Dengue is considered the most important arthropod-borne viral disease that affects humans. Dengue virus (DENV) is maintained in nature by a cyclic replication in vertebrate hosts and Aedes mosquitoes, with the Aedes aegypti as the main vector. The complete sequencing of a DENV-3 strain isolated from Ae. aegypti naturally infected in Rio de Janeiro in 2001 and from a human case occurred in 2002 demonstrated a similarity of 99 percent with a DENV-3 isolated from a human fatal case occurred in the same period. However, the analysis of the 3Untranslated Region (UTR) of the viral genome showed a mutation in thisregion, suggesting a deletion of 8 nucleotides (nts) within the 11 nucleotides insertion, characteristic of DENV-3 isolated in Brazil. In this study, we evaluated whether the distinct DENV-3 variants presenting those characteristics showeddifferences on the virus-vector interaction by determining the vectorcompetence of two populations of Ae. aegypti. The DENV-3 strain BR74886#5(with the 11nts insert in the region 3'UTR) and the strain BR73356#5 (with an 8 nts deletion), presented titers of 8 x 107 PFU/mL and 7.3 x 107PFU/mL,respectively, maintained its characteristics in the 3'UTR region of the viral genome after five passages in cell culture and were selected for experimental infection. The infection strategy consisted in the use of 2,925 female Ae. aegypti: 2,340 of a F1 generation from the Tubiacanga (RJ) population and 585 Paea control mosquitoes. The experimental population proved to be competentto transmit the two DENV-3 strains. However, the viral dissemination in thebody of the mosquito presented heterogeneously, suggesting that there are advantages for the strain with 11 nts insertion in the 3'UTR, once disseminated more rapidly...