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Journal ArticleDOI

More Dengue, More Questions

01 May 2005-Emerging Infectious Diseases (Centers for Disease Control and Prevention)-Vol. 11, Iss: 5, pp 740-741
TL;DR: It is concluded that age-specific hospitalization and death rates were a measure of intrinsic susceptibility to vascular permeability during secondary DENV-2 virus infections, and the youngest children were found to be at greatest risk.
Abstract: Dengue is epidemic or endemic in virtually every country in the tropics; it is even cited in the Guinness World Records, 2002, as the world's most important viral hemorrhagic fever and the most geographically widespread of the arthropodborne viruses. As illustrated in this issue of Emerging Infectious Diseases, dengue epidemics are expanding rapidly, as is the literature on the subject. That dengue was transmitted in the United States for nearly 1 year in 2001 (1) should serve as a wake up call to Americans, most of whom are ignorant of the threat of this disease. Both the major dengue vectors, Aedes aegypti and Ae. albopictus, are widely distributed in the continental United States. This emerging disease continues to baffle and challenge epidemiologists and clinicians. Despite endemicity of 3 or more different dengue viruses, why does severe dengue occur in some populations and not in others? Why are children principally affected in some areas and adults in others? How can severe dengue reliably be recognized early enough to permit appropriate therapy to be applied? Recent studies point in the direction of answers to these questions. During an infection with any of the 4 dengue viruses, the principal threat to human health resides in the ability of the infecting virus to produce an acute febrile syndrome characterized by clinically significant vascular permeability, dengue hemorrhagic fever (DHF). However, because at onset vascular permeability exhibits only subtle changes, how can a diagnosis be made early enough to begin life-saving intravenous treatment? In persons with light skin color, the standard syphygmomanometer cuff tourniquet test has been widely used to screen children in outpatient settings; a positive test result is an early warning of incipient DHF. Because of genetic diversity among humans, the tourniquet test as a screening tool requires widespread evaluation and validation. In a prospective study of 1,136 Vietnamese children with serologically confirmed overt dengue infections, the tourniquet test had a sensitivity of 41.6%, a specificity of 94.4%, a positive predictive value of 98.3%, and a negative predictive value of 17.3% (2). A positive result should prompt close observation, but a negative result does not exclude an ongoing dengue infection. A more robust screening test could result from the studies of Wills et al., who measured the size and charge characteristics of proteins leaking through the endothelial sieve in DHF patients (3). Such changes are caused, presumably, by a cytokine cascade, as yet incompletely identified. Their observations suggest that capillaries leak in most overt dengue infections, but fluid loss is not at levels that alter cardiovascular status. Quantitative differences in duration and amount of protein leak demarcate DHF from dengue fever. Importantly, the authors found increased amounts of serum proteins, increased differential protein excretion, and increased amounts of heparan sulfate in the urine of DHF patients. Detecting protein or heparan sulfate in acute-phase urine could provide early evidence of increased vascular permeability. Humans are not uniformly susceptible to the DHF syndrome. HLA gene distribution correlates with increased susceptibility as well as with increased resistance (4). In addition, a powerful resistance gene is found in blacks (5). Importantly, susceptibility to vascular permeability during a dengue infection is age-related. This conclusion comes from a study of the age distribution of patients hospitalized during the 1981 DHF epidemic in Cuba. In that epidemic, persons 2–50 years of age were exposed to infections with dengue 1 virus (DENV-1) from 1977 to 1979 and DENV-2 virus in 1981 at similar rates (6). Thus, age-specific hospitalization and death rates were a measure of intrinsic susceptibility to vascular permeability during secondary DENV-2 virus infections. The youngest children were found to be at greatest risk; rates fell rapidly and were lowest in older teenagers and young adults, rising again somewhat in older patients. The susceptibility of young children to DHF precisely paralleled age-related changes in microvascular permeability measured in normal children and adults. That cytokines, not virus, damage endothelial cells during the course of a dengue infection could be inferred from a recently published immunopathology study of human tissues from DHF patients (7). Despite in vitro evidence that dengue viruses infect human endothelial cells, dengue virus was found to have replicated in vivo in monocytes, macrophages, and B lymphocytes. While endothelial cells stained for dengue antigens, this staining was concluded to be the result of in vivo deposition of virus-antibody complexes but not cellular infection. Differences in intrinsic virulence are widely believed to explain the ability of some dengue virus strains to cause DHF while others do not. Indeed, phenotypic attributes of avirulent American DENV-2 genotype viruses appear to correlate with differences in disease severity (8). A different explanation was provided by a prospective fever study in Iquitos, Peru. In 1990, DENV-1 virus entered Iquitos and became endemic. In 1995, widespread, mostly silent infections with American genotype DENV-2 were detected. Many persons infected with DENV-2 had antibodies elicited by an earlier DENV-1 infection. In contrast to Cuba, DHF did not develop in any of these secondarily infected persons. Antibodies to DENV-1 in the sera of Iquitos residents strongly neutralized American genotype DENV-2 viruses, but not virulent Asian genotype DENV-2 viruses isolated from DHF epidemics in the Americas (9). DENV-2 antigenic differences, reflected in heterotypic neutralization by antibodies to DENV-1, appeared to result in downregulated infection severity and corresponding clinical expression. In the American tropics, with the exception of Cuba in 1981, most dengue cases were observed initially in adults. An illustration of this phenomenon is exhibited by the recent outbreak in Hawaii, where primary infections with DENV-1 virus produced dengue fever syndrome in adults. Dengue fever syndrome in susceptible adults may be contrasted to the innate susceptibility of children for vascular permeability syndrome during a secondary dengue virus infection. In Southeast Asia, the epicenter of DHF epidemics in children, dengue infection rates are falling, resulting in changing epidemiologic patterns of DHF. In Thailand, for example, the modal age at which children are hospitalized for DHF has steadily increased over the past several decades (A. Nisalak, pers. comm.). In addition, because an increasing number of persons experience their first dengue infection at an older age, dengue fever cases are now appearing in adults.

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Citations
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Journal ArticleDOI
TL;DR: In vivo binding assays showed that the Tet-EDIII-Co1 protein was delivered specifically to M cells in Peyer's patches while the tetravalent protein lacking the Co1 ligand did not, which demonstrated the efficient targeting of this antigenic protein through the mucosal-specific ligand.

15 citations

Dissertation
15 Dec 2015
TL;DR: Assessing the status of single and dual infections all over the country, investigate the presence of chikungunya, assess the efficiency of the surveillance procedures routinely established and assess the diversity of mosquito populations and their potential respective role underlines the need of novel approaches for surveillance.
Abstract: Dengue and chikungunya are both transmitted by Aedes aegypti and Aedes albopictus and can cause potentially severe and or debilitating chronic disease. They are the fastest spreading diseases, in part because of the climate change. Vietnam is a hyperendemicity country for dengue and is at risk to be like neighboring Cambodia affected both by dengue and chikungunya and be an overlapping area of distribution for both viruses. The aim of this PhD work was therefore to assess the status of single and dual infections all over the country, investigate the presence of chikungunya, assess the efficiency of the surveillance procedures routinely established and assess the diversity of mosquito populations and their potential respective role. A first part of the PhD dissertation is devoted to a bibliographic review. The second part comprises three chapters associated to three different publications. The first chapter is devoted to a surveillance study in the general hospital if the Southern Province of Dong Thap. A cohort of 131 patients with acute fever symptoms was investigated for the presence of dengue and chikungunya. 101 patients out of 131 were confirmed with dengue. All four dengue serotypes were detected with a predominance of DENV2 and DENV4. No chikungunya infection was detected although reported in neighboring Cambodia. A differential efficiency of serological dengue detection was observed. Efficiency was 29% upon admission and 53% after seven days on the same patients. There is thus a clear risk of dengue being underestimated while chikungunya is not systematically detected. Changes in detection and surveillance procedures are therefore proposed to increase the efficiency of dengue detection and continue the monitoring the emergence of CHIKV. The second Chapter is dedicated to the respective role of A. aegypti and A. albopictus in the 2011 outbreak in the Northern capital city of Hanoi. Only DENV-1 and DENV-2 serotypes were detected from the 140 patients hospitalized. A positive correlation was found between the population density of A. aegypti and the number of human cases and duration of outbreaks. This was not observed for A. albopictus. Three pools of A. aegypti were positive with dengue virus, two with DENV-1 and one with DENV-2. This work indicate clearly the role of A. aegypti in the 2011 Hanoi epidemics. The last chapter of the PhD is devoted to a crosscutting country wide survey in five provinces border with Lao PDR and Cambodia. In this work, a total of 558 serum samples were collected from patients admitted in the 2012-2014 period in five provincial preventive medicine centers with acute fever and symptoms compatible to DENV-CHIKV infection. All four dengue serotypes were found altogether but not in the same province. Only two serotypes were found at the maximum in a single province. No CHIKV was detected. A total of 1104 adult mosquitoes were collected inside and outside houses at the same place. Mosquito population density and vector indexes were assessed following capture of larvae. Differing densities of mosquito populations were found with the highest one being in the Long An province border with Cambodia. Dengue viruses were detected mostly in A. albopictus. CHIKV was also detected in A. albopictus mosquitoes. The phylogenetic analysis of the collected mosquitoes showed a large diversity of genotypes, all of them having been described in other parts of the world. This part of the PhD work underline the dual role of A. aegypti and A. albopictus, the increasing role of the latter and the high level of man-related very long distance mobility of mosquitoes. This work underlines the need of novel approaches for surveillance both at the clinical and at the entomological level to efficiently tackle the risk of dengue and chikungunya outbreaks.

15 citations


Cites result from "More Dengue, More Questions"

  • ...The age distribution reported in this study differs from other works which reported dengue mainly in children (507) (508) (509) (510) (511) (512) (513) (514)....

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Journal ArticleDOI
TL;DR: Dengue is at risk of being underestimated and chikungunya is not systematically detected, changes in detection and surveillance procedures are discussed to increase efficiency of dengue detection and continue the monitoring the emergence of CHIKV in Dong Thap province and in Vietnam.

14 citations

Journal ArticleDOI
TL;DR: D Dengue is an avoidable disease that should disappear from mortality statistics as a cause of death and the event is avoidable if the proposed activities from the Estrategia de Gestión Integrada (EGI)-Dengue are implemented and evaluated.
Abstract: Introduccion. El dengue en Colombia es un importante problema de salud publica debido a las enormes perdidas economicas y sociales que ha provocado, especialmente durante los picos epidemicos. Objetivo. Describir el comportamiento de la mortalidad por dengue en Colombia entre 1985 y 2012. Materiales y metodos. Se hizo un estudio descriptivo. La informacion se obtuvo de las bases de datos de mortalidad y de las proyecciones de poblacion de 1985 a 2012 del Departamento Administrativo Nacional de Estadistica (DANE). Se estimaron tasas de mortalidad, razon de tasas y letalidad. Resultados. Se registraron 1.990 muertes por dengue durante el periodo senalado. Las tasas de mortalidad por dengue aumentaron entre 1985 y 1998. Las tasas mas altas se presentaron en hombres menores de 5 anos y de 65 o mas anos de edad. Entre 1995 y 2012 los municipios de categorias 1 a 4 tambien presentaron las tasas mas altas. La letalidad durante el periodo vario entre 0,01 y 0,39 %. Conclusion. El dengue es una enfermedad evitable que deberia desaparecer de las estadisticas de mortalidad como causa de defuncion. La muerte es evitable en la medida en que se implementen y evaluen las actividades propuestas en la Estrategia de Gestion Integrada (EGI)-Dengue. Se recomienda impulsar el desarrollo de una cultura informatica que contribuya a la toma de decisiones y a priorizar la utilizacion de los recursos asignados.

14 citations

Journal ArticleDOI
TL;DR: Para conseguir un control efectivo of the infeccion es preciso realizar estudios epidemiologicos, que como el nuestro, contribuyan a disenar estrategias preventivas adecuadas.
Abstract: Antecedentes El dengue es una enfermedad infecciosa emergente, considerada actualmente como un problema de salud publica mundial. Material y metodos Se incluyeron en el estudio todos los casos positivos de dengue confirmados de pacientes menores de 18 anos, durante los anos 2000-2005. En las muestras recibidas en los primeros 3 dias de la enfermedad se aislo el virus mediante cultivo y en las recibidas entre los dias 5-30 por serologia. Se analizaron las caracteristicas clinicas y epidemiologicas de los pacientes. Resultados Se incluyeron 457 pacientes (57,6 % ninas). La mediana de edad fue de 13 anos (rango interquartilico = 6). Se detecto un predominio de la infeccion en las zonas urbanas y en los meses de mayo-noviembre. Se registraron 2 epidemias en los anos 2001 (33,9 %) y primeros 8 meses de 2005 (23,1 %). Las manifestaciones clinicas mas frecuentes fueron: fiebre (95,2 %); cefalea (74,2 %); escalofrios (65,9 %); exantema (63,5 %); mialgias (51,9 %), y dolor retroorbitario (51,6 %). No se observaron diferencias significativas segun el sexo pero si al dividir a los pacientes en grupos de edad; menores de 5 anos, 6-10 anos y mayores de 10 anos. En el 53,0 % de los pacientes se registro el antecedente de contacto con otro sujeto infectado en los 15 dias previos. Se diagnosticaron 7 casos de dengue hemorragico de los cuales cuatro murieron. Conclusiones En Panama el dengue continua siendo un importante problema de salud publica. Para conseguir un control efectivo de la infeccion es preciso realizar estudios epidemiologicos, que como el nuestro, contribuyan a disenar estrategias preventivas adecuadas.

13 citations


Cites background from "More Dengue, More Questions"

  • ...2006;64(6):517-22 Al comparar la frecuencia de las diferentes manifestaciones según el sexo no se obtuvieron diferencias estadísticamente significativas....

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  • ...2006;64(6):517-22 a subsequent dengue-4 and dengue-1 epidemic in Puerto Rico in 1998....

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  • ...2006;64(6):517-22 519 Larrú Martínez B, et al....

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  • ...2006;64(6):517-22 INTRODUCCIÓN El dengue es la enfermedad viral transmitida por artrópodos que más morbimortalidad ocasiona mundialmente1....

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  • ...2006;64(6):517-22 521 Larrú Martínez B, et al....

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References
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Journal ArticleDOI
Kala Jessie1, Mun Yik Fong1, Shamala Devi1, Sai Kit Lam1, K. Thong Wong1 
TL;DR: Tissue specimens from patients with serologically or virologically confirmed dengue infections are studied by immunohistochemistry (IHC) and in situ hybridization (ISH), to localize viral antigen and RNA, respectively.
Abstract: Dengue viral antigens have been demonstrated in several types of naturally infected human tissues, but little is known of whether these same tissues have detectable viral RNA. We studied tissue specimens from patients with serologically or virologically confirmed dengue infections by immunohistochemistry (IHC) and in situ hybridization (ISH), to localize viral antigen and RNA, respectively. IHC was performed on specimens obtained from 5 autopsies and 24 biopsies and on 20 blood-clot samples. For ISH, antisense riboprobes to the dengue E gene were applied to tissue specimens in which IHC was positive. Viral antigens were demonstrated in Kupffer and sinusoidal endothelial cells of the liver; macrophages, multinucleated cells, and reactive lymphoid cells in the spleen; macrophages and vascular endothelium in the lung; kidney tubules; and monocytes and lymphocytes in blood-clot samples. Positive-strand viral RNA was detected in the same IHC-positive cells found in the spleen and blood-clot samples. The strong, positive ISH signal in these cells indicated a high copy number of viral RNA, suggesting replication.

548 citations

Journal ArticleDOI
TL;DR: A retrospective seroepidemiological survey was conducted in Cerro, a densely populated district in Havana City, Cuba, finding children infected by DEN-1 virus followed byDEN-2 virus had a high risk of acquiring dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS).
Abstract: In Cuba, 2 epidemics of dengue virus occurred: 1 caused by DEN-1 in 1977 and 1 caused by DEN-2 in 1981. The latter was associated with cases of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). To study viral risk factors for DHF/DSS, a retrospective seroepidemiological survey was conducted in Cerro, a densely populated district in Havana City. The prevalence of plaque reduction neutralizing antibodies to DEN-1 and DEN-2 viruses was measured in 1,295 individuals (children and adults). Of these, 43.7% were immune to DEN-1 virus and 23.6% to DEN-2 virus. Of those individuals who were immune, 26.1% were immune to DEN-1 virus only, 6% to DEN-2 virus only, and 17.6% to both viruses. The DEN-2 virus infection rate in DEN-1 immune individuals was 3.8 times higher than in non-immune individuals. The 5 DHF/DSS cases in the sample had evidence of DEN-1 virus plus DEN-2 virus infections. Three were children and 2 were young adults. No cases were found in individuals infected with DEN-1 virus or DEN-2 virus only. Children infected by DEN-1 virus followed by DEN-2 virus had a high risk of acquiring DHF/DSS. Blacks and whites were equally infected with DEN-1 and DEN-2 viruses.

351 citations

Journal ArticleDOI
TL;DR: This outbreak underscores the importance of maintaining surveillance and control of potential disease vectors even in the absence of an imminent disease threat.
Abstract: Autochthonous dengue infections were last reported in Hawaii in 1944. In September 2001, the Hawaii Department of Health was notified of an unusual febrile illness in a resident with no travel history; dengue fever was confirmed. During the investigation, 1,644 persons with locally acquired denguelike illness were evaluated, and 122 (7%) laboratory-positive dengue infections were identified; dengue virus serotype 1 was isolated from 15 patients. No cases of dengue hemorrhagic fever or shock syndrome were reported. In 3 instances autochthonous infections were linked to a person who reported denguelike illness after travel to French Polynesia. Phylogenetic analyses showed the Hawaiian isolates were closely associated with contemporaneous isolates from Tahiti. Aedes albopictus was present in all communities surveyed on Oahu, Maui, Molokai, and Kauai; no Ae. aegypti were found. This outbreak underscores the importance of maintaining surveillance and control of potential disease vectors even in the absence of an imminent disease threat.

320 citations

Journal ArticleDOI
TL;DR: Age is an important variable in the outcome of secondary DEN-2 infections, and DHF/DSS case fatality and hospitalization rates are highest in young infants and the elderly, and the risk that a child will die during a secondary DEN 2 infection is nearly 15-fold higher than the risk in adults.

302 citations

Journal ArticleDOI
TL;DR: It is confirmed that classical HLA class I alleles are associated with the clinical outcome of exposure to dengue virus, in previously exposed and immunologically primed individuals.
Abstract: Little is known of the role of classical HLA-A and -B class I alleles in determining resistance, susceptibility, or the severity of acute viral infections. Appropriate paradigms for immunogenetic studies of acute viral infections are dengue fever (DF) and dengue hemorrhagic fever (DHF). Both primary and secondary infections with dengue virus (DEN) serotypes 1, 2, 3 or 4, can result in either clinically less severe DF or the more severe DHF. In secondary exposures, a memory response is induced in immunologically primed individuals, which can both clear the infecting dengue virus and contribute to its pathology. In a case-control study of 263 ethnic Thai patients infected with either DEN-1, -2, -3 or -4, we detected HLA class I associations with secondary infections, but not in immunologically naive patients with primary infections. HLA-A*0203 was associated with the less severe DF, regardless of the secondary infecting virus serotype. By contrast, HLA-A*0207 was associated with susceptibility to the more severe DHF in patients with secondary DEN-1 and DEN-2 infections only. Conversely, HLA-B*51 was associated with the development of DHF in patients with secondary infections, and HLA-B*52 was associated with DF in patients with secondary DEN-1 and DEN-2 infections. Moreover, HLA-B44, B62, B76 and B77 also appeared to be protective against developing clinical disease after secondary dengue virus infection. These results confirm that classical HLA class I alleles are associated with the clinical outcome of exposure to dengue virus, in previously exposed and immunologically primed individuals.

238 citations