RESUMO
BACKGROUND: Infection with dengue viruses (DENV) leads to a spectrum of disease outcomes. The pathophysiology of severe versus non-severe manifestations of DENV infection may be driven by host responses, which could be reflected in the transcriptional profiles of peripheral blood immune cells. METHODOLOGY/PRINCIPAL FINDINGS: We conducted genome-wide microarray analysis of whole blood RNA from 34 DENV-infected children in Nicaragua collected on days 3-6 of illness, with different disease manifestations. Gene expression analysis identified genes that are differentially regulated between clinical subgroups. The most striking transcriptional differences were observed between dengue patients with and without shock, especially in the expression of mitochondrial ribosomal proteins associated with protein biosynthesis. In the dengue hemorrhagic fever patients, one subset of differentially expressed genes encode neutrophil-derived anti-microbial peptides associated with innate immunity. By performing a meta-analysis of our dataset in conjunction with previously published datasets, we confirmed that DENV infection in vivo is associated with large changes to protein and nucleic acid metabolism. Additionally, whereas in vitro infection leads to an increased interferon signature, this was not consistently observed from in vivo patient samples, suggesting that the interferon response in vivo is relatively transient and was no longer observed by days 3-6 of illness. CONCLUSIONS/SIGNIFICANCE: These data highlight important differences between different manifestations of severity during DENV infection as well as identify some commonalities. Compilation of larger datasets in the future across multiple studies, as we have initiated in this report, may well lead to better prediction of disease manifestation via a systems biology approach.
Assuntos
Dengue/genética , Regulação da Expressão Gênica , Adolescente , Criança , Pré-Escolar , Análise por Conglomerados , Dengue/sangue , Dengue/metabolismo , Vírus da Dengue , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Lactente , Interferons/biossíntese , Interferons/genética , Masculino , Nicarágua , Reação em Cadeia da Polimerase , Transdução de SinaisRESUMO
BACKGROUND: Dengue is the most prevalent mosquito-borne viral disease in humans and a major urban public health problem worldwide. METHODS: A prospective cohort study of approximately 3800 children initially aged 2-9 years was established in Managua, Nicaragua, in 2004 to study the natural history of dengue transmission in an urban pediatric population. Blood samples from healthy subjects were collected annually prior to the dengue season, and identification of dengue cases occurred via enhanced passive surveillance at the study health center. RESULTS: Over the first four years of the study, seroprevalence of anti-dengue virus (DENV) antibodies increased from 22%-40% in the 2-year-old cohort and 90%-95% in the 9-year-old cohort. The incidence of symptomatic dengue cases and the ratio of inapparent to symptomatic DENV infection varied substantially from year to year. The switch in dominant transmission from DENV-1 to DENV-2 was accompanied by an increase in disease severity but, paradoxically, a decrease in transmission. Phylogeographic analysis of full-length DENV-2 sequences revealed strong geographic clustering of dengue cases. CONCLUSIONS: This large-scale cohort study of dengue in the Americas demonstrates year-to-year variation of dengue within a pediatric population, revealing expected patterns in transmission while highlighting the impact of interventions, climate, and viral evolution.
Assuntos
Dengue/epidemiologia , Dengue/transmissão , Vigilância da População , Distribuição por Idade , Criança , Pré-Escolar , Análise por Conglomerados , Vírus da Dengue/classificação , Feminino , Humanos , Incidência , Masculino , Nicarágua/epidemiologia , Estudos Prospectivos , Estudos Soroepidemiológicos , SorotipagemRESUMO
Dengue is a major problem worldwide, and improving case management is a significant priority. In consultation with colleagues in Thailand, changes in management of hospitalized dengue cases were introduced in Nicaragua, including oral rather than intravenous (IV) fluids upon admission, continuous monitoring of clinical and laboratory signs, and use of IV fluids principally during the critical phase and colloids in management of shock. Two periods were compared, before (2003) and after (2005) their implementation, to assess impact. In 2003, 182 hospitalized laboratory-confirmed dengue cases 0-14 years of age who presented < or = 5 days post-symptom onset were included in the study; 46 were enrolled in 2005. Outcomes included significant reductions in days of IV fluid administration ( P = 0.0001), number of patients receiving IV fluids ( P < 0.0001), and duration of hospitalization ( P < 0.0001), and a non-significant reduction in the number of admissions to the intensive care unit from 8 in 2003 to 0 in 2005 ( P = 0.36). This study demonstrates concrete gains in dengue patient care and case management.
Assuntos
Administração de Caso , Dengue/terapia , Hidratação/métodos , Hospitais/normas , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Tempo de Internação , Masculino , Nicarágua , Estudos RetrospectivosRESUMO
Dengue is a mosquito-borne viral disease that is a major public health problem worldwide. In 2004, the Pediatric Dengue Cohort Study was established in Managua, Nicaragua, to study the natural history and transmission of dengue in children. Here, the authors describe the study design, methods, and results from 2004 to 2008. Initially, 3,721 children 2-9 years of age were recruited through door-to-door visits. Each year, new children aged 2 years are enrolled in the study to maintain the age structure. Children are provided with medical care through the study, and data from each medical visit are recorded on systematic study forms. All participants presenting with suspected dengue or undifferentiated fever are tested for dengue by virologic, serologic, and molecular biologic assays. Yearly blood samples are collected to detect inapparent dengue virus infections. Numerous information and communications technologies are used to manage study data, track samples, and maintain quality control, including personal data assistants, barcodes, global information systems, and fingerprint scans. Close collaboration with the Nicaraguan Ministry of Health and use of almost entirely local staff are essential components for success. This study is providing critical data on the epidemiology and transmission of dengue in the Americas needed for future vaccine trials.
Assuntos
Dengue/epidemiologia , Sistemas de Informação Geográfica/organização & administração , Pesquisa sobre Serviços de Saúde/métodos , Gestão da Informação/métodos , Sistemas de Informação/estatística & dados numéricos , Avaliação da Tecnologia Biomédica/métodos , Criança , Pré-Escolar , Dengue/transmissão , Feminino , Seguimentos , Humanos , Incidência , Masculino , Nicarágua/epidemiologia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de TempoRESUMO
BACKGROUND: Numerous immunological approaches exist to diagnose dengue or detect dengue virus (DENV) infections. OBJECTIVES: To determine the best immunological markers and specimen types for dengue diagnosis and for measuring incidence of DENV infection in community-based studies. STUDY DESIGN: In one study, acute- and convalescent-phase samples were collected from hospitalized suspected pediatric dengue cases in Managua, Nicaragua, from September 2003 to February 2004. A second study examined specimens collected in a community setting in Managua before and after the 2003-2004 dengue season to measure incidence of DENV infection. In both studies, detection of anti-DENV IgM, IgA, and IgG in serum, filter-paper blood spots, and saliva was compared to a gold standard performed on serum samples. RESULTS: For dengue diagnosis, the highest sensitivity and specificity was obtained by measuring IgM or IgA in serum or filter-paper blood spots; intermediate and poor results were obtained in saliva for IgM and IgA, respectively. Detection of IgG alone in serum, filter-paper blood spots, or saliva functioned best for measuring DENV infection. CONCLUSIONS: Detection of IgM and IgA in serum and filter-paper blood spots yielded optimal results for diagnosis of dengue cases, whereas IgG was the best marker for measuring incidence of DENV infection.
Assuntos
Anticorpos Antivirais/análise , Anticorpos Antivirais/sangue , Sangue/imunologia , Dengue/diagnóstico , Saliva/imunologia , Soro/imunologia , Adolescente , Criança , Pré-Escolar , Dengue/epidemiologia , Feminino , Humanos , Imunoglobulina A/análise , Imunoglobulina A/sangue , Imunoglobulina G/análise , Imunoglobulina G/sangue , Imunoglobulina M/análise , Imunoglobulina M/sangue , Lactente , Masculino , Nicarágua/epidemiologia , Sensibilidade e Especificidade , Estudos Soroepidemiológicos , Testes SorológicosRESUMO
To characterize the production patterns of the dengue virus vector Aedes aegypti (L.) (Diptera: Culcidae), pupal surveys were conducted in selected neighborhoods of two major cities in Nicaragua. In León, 833 houses were visited in July and September 2003, corresponding to the beginning and middle of the dengue season; in Managua, 1,365 homes were visited in July 2003. In total, 7,607 containers were characterized, of which 11% were positive for Ae. aegypti larvae and 4% for pupae. In addition to barrels, potted plants and superficial water on tarps and in puddles were identified as highly productive sites. Univariate and multivariate analysis revealed frequency of container use, use of a lid, and rainwater filling as key variables affecting pupal positivity. Importantly, this survey demonstrated the risk associated with the presence of lids, the limited temporal efficacy of temephos, and the lack of association of water availability with risky water storage practices. Finally, we introduce the concept of an efficiency value and an accompanying graphical display system that can facilitate development of targeted pupal control strategies. These data underscore the importance of entomological surveillance of pupal productivity to gather information from which to derive streamlined, efficient, and effective vector control measures to reduce the density of Aedes mosquito larvae and pupae and thus the risk for dengue.
Assuntos
Aedes/fisiologia , Insetos Vetores/fisiologia , Animais , Cruzamento , Água Doce/parasitologia , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Larva/fisiologia , Modelos Logísticos , Controle de Mosquitos/métodos , Nicarágua , Densidade Demográfica , Vigilância da População , Pupa/fisiologia , Fatores de Risco , Temefós/farmacologia , População UrbanaRESUMO
To investigate the incidence of dengue virus (DENV) infection in Nicaragua, a 2-year prospective study was conducted in schoolchildren 4-16 years old in the capital city of Managua. Blood samples were collected before the rainy season in 2001, 2002 and 2003, and were assayed for DENV-specific antibodies. Participants were monitored for dengue-like illness, and acute and convalescent blood samples were collected from suspected dengue cases. In 2001 and 2002, 602 and 397 students were recruited, respectively, and paired annual serum samples were available from 467 and 719 participants in 2001-2002 and 2002-2003, respectively. The overall seroprevalence of anti-DENV antibodies was 91%, increasing from 75% at age 4 to 100% at age 16. The incidence of DENV infection was 12% in Year 1 and 6% in Year 2 (P < 0.001). During Year 1, four laboratory-confirmed dengue cases were detected, with one DENV2 isolate; during Year 2, there were six confirmed dengue cases, with one DENV1 isolate. These and additional circulating serotypes were confirmed by plaque reduction neutralisation test. This study demonstrates surprisingly high transmission of DENV in urban Nicaragua.
Assuntos
Anticorpos Antivirais/sangue , Vírus da Dengue/imunologia , Dengue/epidemiologia , Adolescente , Distribuição por Idade , Criança , Pré-Escolar , Dengue/diagnóstico , Dengue/imunologia , Feminino , Humanos , Incidência , Masculino , Nicarágua/epidemiologia , Estudos Prospectivos , Sensibilidade e Especificidade , Estudos SoroepidemiológicosRESUMO
Dengue, the most prevalent arthropod-borne viral disease of humans, is caused by four serotypes of dengue virus (DENV 1-4). Although all four DENV serotypes cause a range of illness, defining precisely which clinical characteristics are associated with the distinct serotypes has been elusive. A cross-sectional study was conducted on 984 and 313 hospitalized children with confirmed DENV infections during two time periods, respectively, in the same hospitals in Nicaragua: a 3-year period (1999-2001) when DENV-2 accounted for 96% of the viruses identified, and the 2003 dengue season when DENV-1 predominated (87% of identified serotypes). When the two periods were compared, more shock (OR 1.91, 95% CI 1.35-2.71) and internal hemorrhage (OR 2.05, CI 1.16-3.78) were observed in the period when DENV-2 predominated, whereas increased vascular permeability was associated to a greater degree with the DENV-1 period (OR 2.36, CI 1.80-3.09). Compared with the DENV-2 period, the DENV-1 season was associated with more hospitalized primary dengue cases (OR 3.86, CI 2.72-5.48) and more primary DENV infections with severe manifestations (OR 2.93, CI 2.00-4.28). These findings provide new data to characterize the pathogenic potential of distinct DENV serotypes in human populations.
Assuntos
Vírus da Dengue/crescimento & desenvolvimento , Dengue/classificação , Adolescente , Anticorpos Antivirais/sangue , Criança , Pré-Escolar , Estudos Transversais , Dengue/sangue , Dengue/patologia , Dengue/virologia , Feminino , Hematócrito , Hemorragia/patologia , Hemorragia/virologia , Humanos , Lactente , Masculino , Contagem de Plaquetas , Sorotipagem , Choque/patologia , Choque/virologia , Trombocitopenia/patologia , Trombocitopenia/virologiaRESUMO
Larvae of Aedes albopictus, a mosquito known for transmitting dengue virus, were identified in the city of León, Nicaragua, in 2003. Mosquito larvae were collected from a total of 2,225 residences in the 2 largest cities in Nicaragua during the period from June to September of 2003, and larval Ae. albopictus were identified in 4 homes in León. This represents the 1st detection of Ae. albopictus in a major Nicaraguan urban center, and increased control efforts appear to have eliminated the mosquito subsequently from León. The presence of Ae. albopictus in urban Nicaragua highlights the need for surveillance of areas thought to be free of the mosquito so that early detection and control activities can prevent its spread.