Dengue Vaccines Regulatory Pathways: A Report on Two Meetings with Regulators of Developing Countries

Richard Mahoney and colleagues summarize two recent meetings convened by the Pediatric Dengue Vaccine Initiative and the Developing Countries' Vaccine Regulators Network on regulatory issues that need to be addressed before licensing dengue vaccines

Epidemiology of Dengue Virus in Iquitos, Peru 1999 to 2005: Interepidemic and Epidemic Patterns of Transmission

To develop prevention (including vaccines) and control programs for dengue fever, a significant mosquito-borne disease in the tropics, there is an urgent need for comprehensive long term field epidemiological studies. We report results from a study that monitored ∼2,400 school children and some adult family members for dengue infection at 6 month intervals from 1999 to 2005, in the Amazonian city of Iquitos, Peru. At enrollment, ∼80% of the participants had a previous infection with DENV serotypes 1 and 2 or both. During the first 15 months, about 3 new infections for every 100 participants were observed among the study participants. In 2001, DENV-3, a serotype not previously observed in the region, invaded Iquitos in a process characterized by 3 distinct periods: amplification over at least a 5–6 month period, replacement of previously circulating serotypes, and epidemic transmission when incidence peaked. Incidence patterns of new infections were geographically distinct from baseline prevalence rates prior to arrival of DENV-3, but closely mirrored them during the invasion. DENV transmission varied geographically corresponding to elevated mosquito densities. The invasion of a novel serotype is often characterized by 5–6 months of silent transmission before traditional surveillance programs detect the virus. This article sets the stage for subsequent publications on dengue epidemiology

Clinical and Virological Study of Dengue Cases and the Members of Their Households: The Multinational DENFRAME Project

Dengue is the most important mosquito-borne viral disease in humans. This disease is now endemic in more than 100 countries and threatens more than 2.5 billion people living in tropical countries. It currently affects about 50 to 100 million people each year. It causes a wide range of symptoms, from an inapparent to mild dengue fever, to severe forms, including dengue hemorrhagic fever. Currently no specific vaccine or antiviral drugs are available. We carried out a prospective clinical study in South-East Asia and Latin America, of virologically confirmed dengue-infected patients attending the hospital, and members of their households. Among 215 febrile dengue subjects, 177 agreed to household investigation. Based on our data, we estimated the proportion of dengue-infected household members to be about 45%. At the time of the home visit, almost three quarters of (29/39) presented an inapparent dengue infection. The proportion of inapparent dengue infection was higher in South-East Asia than in Latin America. These findings confirm the complexity of dengue disease in humans and the need to strengthen multidisciplinary research efforts to improve our understanding of virus transmission and host responses to dengue virus in various human populations

Clinical and Virological Factors Influencing the Performance of a NS1 Antigen-Capture Assay and Potential Use as a Marker of Dengue Disease Severity

Dengue is the most prevalent arthropod-borne disease in tropical regions. The clinical manifestation may vary from asymptomatic to potentially fatal dengue shock syndrome. Early laboratory confirmation of dengue diagnosis is essential since many symptoms are not specific. Dengue non-structural protein 1 (NS1) may be used in simple antigen-capture ELISA for early detection of dengue virus infection. Our result demonstrated that the Platelia NS1 antigen detection kit had a quite low overall sensitivity. However, sensitivity rises significantly when used in combination with MAC-ELISA. When taking into account the various forms of dengue infection, the NS1 antigen detection was found relatively high in patients sampled during the first 3 days of fever onset, in patients with primary infection, DENV-1 infection, with high level of viremia and in mild form of dengue fever. In asymptomatically infected individuals, RT-PCR assay has proved to be more sensitive than NS1 antigen detection. Moreover, the NS1 antigen level correlated significantly with high viremia and low level of NS1 antigen was associated with more severe disease

Spatio-Temporal Tracking and Phylodynamics of an Urban Dengue 3 Outbreak in São Paulo, Brazil

The dengue virus has a single-stranded positive-sense RNA genome of ∼10.700 nucleotides with a single open reading frame that encodes three structural (C, prM, and E) and seven nonstructural (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) proteins. It possesses four antigenically distinct serotypes (DENV 1–4). Many phylogenetic studies address particularities of the different serotypes using convenience samples that are not conducive to a spatio-temporal analysis in a single urban setting. We describe the pattern of spread of distinct lineages of DENV-3 circulating in São José do Rio Preto, Brazil, during 2006. Blood samples from patients presenting dengue-like symptoms were collected for DENV testing. We performed M-N-PCR using primers based on NS5 for virus detection and identification. The fragments were purified from PCR mixtures and sequenced. The positive dengue cases were geo-coded. To type the sequenced samples, 52 reference sequences were aligned. The dataset generated was used for iterative phylogenetic reconstruction with the maximum likelihood criterion. The best demographic model, the rate of growth, rate of evolutionary change, and Time to Most Recent Common Ancestor (TMRCA) were estimated. The basic reproductive rate during the epidemics was estimated. We obtained sequences from 82 patients among 174 blood samples. We were able to geo-code 46 sequences. The alignment generated a 399-nucleotide-long dataset with 134 taxa. The phylogenetic analysis indicated that all samples were of DENV-3 and related to strains circulating on the isle of Martinique in 2000–2001. Sixty DENV-3 from São José do Rio Preto formed a monophyletic group (lineage 1), closely related to the remaining 22 isolates (lineage 2). We assumed that these lineages appeared before 2006 in different occasions. By transforming the inferred exponential growth rates into the basic reproductive rate, we obtained values for lineage 1 of R0 = 1.53 and values for lineage 2 of R0 = 1.13. Under the exponential model, TMRCA of lineage 1 dated 1 year and lineage 2 dated 3.4 years before the last sampling. The possibility of inferring the spatio-temporal dynamics from genetic data has been generally little explored, and it may shed light on DENV circulation. The use of both geographic and temporally structured phylogenetic data provided a detailed view on the spread of at least two dengue viral strains in a populated urban area

Pleurodese nos derrames pleurais malignos: um inquérito entre médicos em países da América do Sul e Central Pleurodesis for malignant pleural effusions: a survey of physicians in South and Central America

OBJETIVO: A pleurodese é uma alternativa eficaz no controle dos derrames pleurais malignos, mas existem controvérsias a respeito de sua indicação e técnica. O objetivo deste estudo foi avaliar como é realizada a pleurodese em países da América do Sul e Central. MÉTODOS: Profissionais que realizam pleurodese responderam um questionário sobre critérios de indicação para pleurodese, técnicas utilizadas e desfechos. RESULTADOS: Nossa amostra envolveu 147 profissionais no Brasil, 49 em outros países da América do Sul e 36 em países da América Central. Mais de 50% dos participantes realizavam pleurodese somente se confirmada a malignidade no derrame pleural. Entretanto, escalas de dispneia e de status de performance eram raramente utilizadas para indicar o procedimento. Aproximadamente 75% dos participantes no Brasil e na América Central preferiam realizar a pleurodese somente no caso de recidiva do derrame, e a expansão pulmonar deveria variar de 90% a 100%. O talco slurry foi o agente mais utilizado, instilado via drenos de calibre intermediário. A toracoscopia foi realizada em menos de 25% dos casos. Febre e dor torácica foram os efeitos adversos mais comuns, e empiema ocorreu em < 14% dos casos. A média de sobrevida após o procedimento variou entre 6 e 12 meses. CONCLUSÕES: Há variações consideráveis quanto aos critérios de indicação para pleurodese, técnicas utilizadas e desfechos entre os países. Talco slurry é o agente mais frequentemente utilizado, e a toracoscopia é a primeira escolha no Brasil. Os baixos índices de complicações e o tempo de sobrevida elevado indicam que a pleurodese é efetiva e causa poucos efeitos adversos.<br>OBJECTIVE: Pleurodesis is an effective alternative for the control of malignant pleural effusions. However, there is as yet no consensus regarding the indications for the procedure and the techniques employed therein. The objective of this study was to evaluate how pleurodesis is performed in South and Central America. METHODS: Professionals who perform pleurodesis completed a questionnaire regarding the indications for the procedure, the techniques used therein, and the outcomes obtained. RESULTS: Our sample comprised 147 respondents in Brazil, 49 in other South American countries, and 36 in Central America. More than 50% of the respondents reported performing pleurodesis only if pleural malignancy had been confirmed. However, scores on dyspnea and performance status scales were rarely used as indications for the procedure. Nearly 75% of the respondents in Brazil and in Central America preferred to perform pleurodesis only for recurrent effusions and stated that lung expansion should be 90-100%. Talc slurry, instilled via medium-sized chest tubes, was the agent most often employed. Thoracoscopy was performed in less than 25% of cases. Fever and chest pain were the most common side effects, and empyema occurred in < 14% of cases. The mean survival time after the procedure was most often reported to be 6-12 months. CONCLUSIONS: There was considerable variation among the countries evaluated in terms of the indications for pleurodesis, techniques used, and outcomes. Talc slurry is the agent most commonly used, and thoracoscopy is the technique of choice in Brazil. Pleurodesis is an effective procedure that has few side effects, as evidenced by the low complication rates and high survival times