Persistent emergence of dengue.
01 May 2005-Emerging Infectious Diseases (Centers for Disease Control and Prevention)-Vol. 11, Iss: 5, pp 738-739
TL;DR: The disease dengue fever is a short-duration, nonfatal illness characterized by sudden onset of headache, retroorbital pain, high fever, joint pain, and rash and having uncomplicated DF can presage having DHF, which is the major international public health concern.
Abstract: The disease dengue fever (DF; also known as breakbone fever, dandy fever, and by other names) can be caused by any of 4 viruses within the virus family Flaviviridae, genus Flavivirus, i.e., dengue virus types 1–4 (DENV-1–4). Dengue fever is a short-duration, nonfatal illness characterized by sudden onset of headache, retroorbital pain, high fever, joint pain, and rash. Whereas uncomplicated DF usually is the case, the picture can be much darker than that. Through a mechanism known as immune enhancement, sequential infections with certain dengue viruses set the stage for a far more serious complication, dengue hemorrhagic fever (DHF) and dengue shock syndrome, so that having uncomplicated DF can presage having DHF (1).
DHF is characterized by high fever, vascular permeability, bleeding, enlargement of the liver, and circulatory failure (dengue shock syndrome). In mild or moderate cases, signs and symptoms subside after the fever subsides, but in severe cases the patient's condition suddenly deteriorates, body temperature decreases, and the circulatory system begins to fail. The patient then may quickly go into shock and die within a day, or quickly recover, if volume therapy is instituted (2).
Dengue viruses are transmitted from person to person or from monkey to monkey through infected female mosquitoes of the genus Aedes. The mosquito acquires the virus by taking a blood meal from an infected human, the principal amplifying host for these viruses, or from an infected monkey. Humans circulate these viruses in their blood (viremia) for 7 to 10 days after infection, allowing ample time for mosquitoes, often many mosquitoes, to feed and become infected. After an intrinsic incubation period of 1 week to 10 days, the mosquito is capable of transmitting the virus to a new host while blood feeding.
During epidemics of dengue, attack rates may be 80%–90% in susceptible persons. Although, it is not usually recognized, more than half the people who are infected with a dengue virus may be asymptomatic, which would indicate a substantial underreporting of infections. These comprise a substantial number of people who may have been primed for more serious illness at a later date and are unaware of their situation.
The global prevalence of dengue has increased substantially recently. Dengue is endemic in ≈100 countries in Southeast Asia, Africa, the Western Pacific, the Americas, Africa, and the eastern Mediterranean area (available from http://www.who.int/mediacentre/factsheets/fs117/en/), with imported cases essentially everywhere tourists, business people, and military personnel travel, whether dengue is recognized there or not. More than 2 billion of the approximately 6.5 billion inhabitants of this planet are at risk of acquiring dengue, and the World Health Organization has estimated that "there may be 50 million cases of dengue infection worldwide every year" (available from http://www.who.int/mediacentre/factsheets/fs117/en/). However, this is a misstatement. Either there are 50 million dengue infections (some with illness, some not) or there are 50 million people sick with dengue each year. Infections are not the same as illnesses.
The mild form of dengue is a serious annoyance and often is painful for those with it. However, DHF is the major international public health concern. Before 1970, a total of 9 countries had reported DHF epidemics; by 1995, >4 times that number reported such outbreaks. Most of these countries are in Southeast Asia and the Western Pacific, but with the worldwide spread of all dengue types, this disease threatens residents in tropical and subtropical regions, predominantly in urban and semiurban areas. In 2001, ≈600,000 cases of dengue were reported in the Americas, of which 15,000 were cases of DHF, more than twice the number of DHF cases in the Americas in 1995 (available from http://www.who.int/mediacentre/factsheets/fs117/en/). In 2001 alone, Brazil reported nearly 400,000 cases, including 670 cases of DHF. Not only is the geographic distribution of dengue spreading, but the seriousness of its complications is being recognized (available from http://www.cdc.gov/search.do?action=search&queryText=dengue). An estimated 500,000 persons with DHF require hospitalization each year, a substantial proportion of whom are children. Tragically, DHF is a leading cause of hospitalization and death of children in several Asian countries. Case-fatality rates can exceed 20%, are usually 2.5%, but can be reduced to <1% with rapid recognition and proper treatment.
In countries that are prepared for dengue and its complications, diagnostic services are available. We are able to sequence these viruses and determine their origins and evolutionary determinants. We can, to some degree, control the vector mosquitoes (Aedes aegypti and Ae. albopictus). Our knowledge of the pathophysiology of DHF is quite sophisticated (2,3). A vast literature is available about these viruses and the diseases they cause. Why, then, does dengue continue to spread? If we cannot eradicate dengue (and its vector Ae. aegypti) from populations on islands, from where can we eradicate it? Politics or misdirected funding, as always, has something to do with this, but the situation is much more complicated than that. Unless transovarial transmission (passage of virus from female to offspring through the egg) is much more important than it appears to be, other mechanisms are at play. Univalent vaccines for these viruses have been prepared but, for the most part, health authorities are (justifiably) unwilling to use such vaccines because they have the potential to stimulate the production of antibodies, which would prime vaccinees for DHF by immune enhancement. Fortunately, novel approaches (development of incompetent mosquitoes), development of modern tetravalent vaccines, and development of chimeric vaccine viruses (4), using classic as well as molecular approaches will soon be available and hold out promise of tools we need to eliminate or eradicate this scourge.
This issue of Emerging Infectious Diseases includes some very interesting reports on dengue and its clinical complications, dengue diagnosis, and dengue epidemiology. These add considerably to the scientific record.
Citations
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TL;DR: The successful transinfection of A. aegypti with the avirulent wMel strain of Wolbachia, which induces the reproductive phenotype cytoplasmic incompatibility with minimal apparent fitness costs and high maternal transmission, providing optimal phenotypic effects for invasion is described.
Abstract: Dengue fever is the most important mosquito-borne viral disease of humans with more than 50 million cases estimated annually in more than 100 countries. Disturbingly, the geographic range of dengue is currently expanding and the severity of outbreaks is increasing. Control options for dengue are very limited and currently focus on reducing population abundance of the major mosquito vector, Aedes aegypti. These strategies are failing to reduce dengue incidence in tropical communities and there is an urgent need for effective alternatives. It has been proposed that endosymbiotic bacterial Wolbachia infections of insects might be used in novel strategies for dengue control. For example, the wMelPop-CLA Wolbachia strain reduces the lifespan of adult A. aegypti mosquitoes in stably transinfected lines. This life-shortening phenotype was predicted to reduce the potential for dengue transmission. The recent discovery that several Wolbachia infections, including wMelPop-CLA, can also directly influence the susceptibility of insects to infection with a range of insect and human pathogens has markedly changed the potential for Wolbachia infections to control human diseases. Here we describe the successful transinfection of A. aegypti with the avirulent wMel strain of Wolbachia, which induces the reproductive phenotype cytoplasmic incompatibility with minimal apparent fitness costs and high maternal transmission, providing optimal phenotypic effects for invasion. Under semi-field conditions, the wMel strain increased from an initial starting frequency of 0.65 to near fixation within a few generations, invading A. aegypti populations at an accelerated rate relative to trials with the wMelPop-CLA strain. We also show that wMel and wMelPop-CLA strains block transmission of dengue serotype 2 (DENV-2) in A. aegypti, forming the basis of a practical approach to dengue suppression.
1,146 citations
TL;DR: Engineering of transgenic A. aegypti that show a high level of resistance against DENV-2 provides a powerful tool for developing population replacement strategies to control transmission of dengue viruses.
Abstract: Mosquitoes (Aedes aegypti) were genetically modified to exhibit impaired vector competence for dengue type 2 viruses (DENV-2). We exploited the natural antiviral RNA interference (RNAi) pathway in the mosquito midgut by constructing an effector gene that expresses an inverted-repeat (IR) RNA derived from the premembrane protein coding region of the DENV-2 RNA genome. The A. aegypti carboxypeptidase A promoter was used to express the IR RNA in midgut epithelial cells after ingestion of a bloodmeal. The promoter and effector gene were inserted into the genome of a white-eye Puerto Rico Rexville D (Higgs’ white eye) strain by using the nonautonomous mariner MosI transformation system. A transgenic family, Carb77, expressed IR RNA in the midgut after a bloodmeal. Carb77 mosquitoes ingesting an artificial bloodmeal containing DENV-2 exhibited marked reduction of viral envelope antigen in midguts and salivary glands after infection. DENV-2 titration of individual mosquitoes showed that most Carb77 mosquitoes poorly supported virus replication. Transmission in vitro of virus from the Carb77 line was significantly diminished when compared to control mosquitoes. The presence of DENV-2-derived siRNAs in RNA extracts from midguts of Carb77 and the loss of the resistance phenotype when the RNAi pathway was interrupted proved that DENV-2 resistance was caused by a RNAi response. Engineering of transgenic A. aegypti that show a high level of resistance against DENV-2 provides a powerful tool for developing population replacement strategies to control transmission of dengue viruses.
387 citations
TL;DR: Advances have underscored the fact that DHF/DSS pathogenesis is a complex, multifactorial process involving cocirculation of various dengue virus serotypes and the interplay of host and viral factors that influence disease severity.
Abstract: The past four decades has witnessed a consolidation of the original observations made in the 1970s that dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) have an immunological basis. Following reinfection with a dengue virus of different serotype, severe disease is linked to high levels of antibody-enhanced viral replication early in illness which is followed by a cascade of memory T-cell activation and a 'storm' of inflammatory cytokines and other chemical mediators. These compounds are released mainly from T cells, monocytes/macrophages and endothelial cells, and ultimately cause an increase in vascular permeability. The consolidation of the evidence has been largely due to several important prospective sero-epidemiological studies in areas endemic for DHF/DSS, which have shown that risk of severe disease is significantly higher in secondary dengue infections. These advances have underscored the fact that DHF/DSS pathogenesis is a complex, multifactorial process involving cocirculation of various dengue virus serotypes and the interplay of host and viral factors that influence disease severity. The continued search to define risk factors in susceptible populations must be combined with the new techniques of molecular virology and innovative approaches in vaccine design to achieve the ultimate objective of developing a safe and effective vaccine.
271 citations
TL;DR: Records of the occurrence of both yellow fever and Dengue during the 20th century have been collected together and are used to define their climatic limits using remotely sensed satellite data within a discriminant analytical model framework.
Abstract: Yellow fever has been subjected to partial control for decades, but there are signs that case numbers are now increasing globally, with the risk of local epidemic outbreaks. Dengue case numbers have also increased dramatically during the past 40 years and different serotypes have invaded new geographical areas. Despite the temporal changes in these closely related diseases, and their enormous public health impact, few attempts have been made to collect a comprehensive dataset of their spatial and temporal distributions. For this review, records of the occurrence of both diseases during the 20th century have been collected together and are used to define their climatic limits using remotely sensed satellite data within a discriminant analytical model framework. The resulting risk maps for these two diseases identify their different environmental requirements, and throw some light on their potential for co-occurrence in Africa and South East Asia.
193 citations
Cites background from "Persistent emergence of dengue."
...Widespread movements of troops and refugees during and after World War II introduced vectors and viruses into many new areas, and this trend has continued (Calisher, 2005) with the growth of global transport networks (Tatem et al., this volume, pp. 293–343)....
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...Widespread movements of troops and refugees during and after World War II introduced vectors and viruses into many new areas, and this trend has continued (Calisher, 2005) with the growth of global transport networks (Tatem et al....
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TL;DR: Some clinical presentations of dengue disease and laboratory findings in adults are different from those in children, and adults as well as pediatric cases of DHF need appropriate and prompt case management to reduce the mortality rate ofDHF.
162 citations
References
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TL;DR: This work has identified a severe syndrome, dengue hemorrhagic fever/dengue shock syndrome, in Southeast Asian children, which recently has also been identified in children infected with the virus in Puerto Rico.
Abstract: Dengue viruses occur as four antigenically related but distinct serotypes transmitted to humans by Aedes aegypti mosquitoes. These viruses generally cause a benign syndrome, dengue fever, in the American and African tropics, and a severe syndrome, dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), in Southeast Asian children. This severe syndrome, which recently has also been identified in children infected with the virus in Puerto Rico, is characterized by increased vascular permeability and abnormal hemostasis. It occurs in infants less than 1 year of age born to dengue-immune mothers and in children 1 year and older who are immune to one serotype of dengue virus and are experiencing infection with a second serotype. Dengue viruses replicate in cells of mononuclear phagocyte lineage, and subneutralizing concentrations of dengue antibody enhance dengue virus infection in these cells. This antibody-dependent enhancement of infection regulates dengue disease in human beings, although disease severity may also be controlled genetically, possibly by permitting and restricting the growth of virus in monocytes. Monoclonal antibodies show heterogeneous distribution of antigenic epitopes on dengue viruses. These epitopes serve to regulate disease: when antibodies to shared antigens partially neutralize heterotypic virus, infection and disease are dampened; enhancing antibodies alone result in heightened disease response. Further knowledge of the structure of dengue genomes should permit rapid advances in understanding the pathogenetic mechanisms of dengue.
1,607 citations
TL;DR: Profound T-cell activation and death may contribute to the systemic disturbances leading to DHF, and original antigenic sin in the T- cell responses may suppress or delay viral elimination, leading to higher viral loads and increased immunopathology.
Abstract: Dengue virus presents a growing threat to public health in the developing world. Four major serotypes of dengue virus have been characterized, and epidemiological evidence shows that dengue hemorrhagic fever (DHF), the more serious manifestation of the disease, occurs more frequently upon reinfection with a second serotype. We have studied dengue virus–specific T-cell responses in Thai children. During acute infection, few dengue-responsive CD8+ T cells were recovered; most of those present showed an activated phenotype and were undergoing programmed cell death. Many dengue-specific T cells were of low affinity for the infecting virus and showed higher affinity for other, probably previously encountered strains. Profound T-cell activation and death may contribute to the systemic disturbances leading to DHF, and original antigenic sin in the T-cell responses may suppress or delay viral elimination, leading to higher viral loads and increased immunopathology.
779 citations
TL;DR: In vitro antibody-dependent infection of PBL provides a possible model for study of pathogenetic mechanisms in infants with dengue shock syndrome who passively acquire maternal anti-dengue IgG.
Abstract: Cultured mononuclear peripheral blood leukocytes (PBL) from nonimmune human beings and monkeys are nonpermissive to dengue 2 virus (D2V) infection at multiplicities of infection of 0.001-0.1, but become permissive when non-neutralizing dengue antibody is added to medium. D2V infection occurred in PBL prepared from anti-coagulated but not from defibrinated plasma. Infection enhancement was produced by multiple lots of heterotypic anti-dengue raised in several mammalian species. Homotypic anti-dengue neutralized D2V at high concentrations but enhanced at low concentrations; enhancement end point in one serum was 1:320,000. The infection-enhancing factor was a noncytophilic antibody of the IgG class. D2V infection occurred in the absence of heat-labile complement components but did not occur when complexes were prepared with anti- dengue F(ab)(2). Treatment of PBL with several proteases increased permissiveness to D2V infection by immune complexes but not by virus alone. Two rhesus monkey serums collected 14 days after D2V infection contained an IgG antibody with high-titered enhancing activity but with no hemagglutination-inhibition or neutralizing activity. Virus-antibody complexes are irreversibly attached to PBL within 15 min and completely internalized in 60 min. There was considerable variation in cellular infection in different experiments, however, maximum virus yields usually exceeded 1,000 plaque-forming units per 1 x 10(6) PBL occurring between 2 and 4 days in culture. In vitro antibody-dependent infection of PBL provides a possible model for study of pathogenetic mechanisms in infants with dengue shock syndrome who passively acquire maternal anti-dengue IgG.
760 citations
TL;DR: This report is the first to demonstrate the safety of a recombinant DEN virus tetravalent vaccine in a formal neurovirulence test, as well as its protective efficacy in a monkey challenge model.
Abstract: To construct chimeric YF/DEN viruses (ChimeriVax-DEN), the premembrane (prM) and envelope (E) genes of yellow fever (YF) 17D virus were replaced with those of each wild-type (WT) dengue (DEN) virus representing serotypes 1 to 4. ChimeriVax-DEN1-4 vaccine viruses were prepared by electroporation of Vero cells with RNA transcripts prepared from viral cDNA (F. Guirakhoo, J. Arroyo, K. V. Pugachev, C. Miller, Z.-X. Zhang, R. Weltzin, K. Georgakopoulos, J. Catalan, S. Ocran, K. Soike, M. Ratteree, and T. P. Monath, J. Virol. 75:7290-7304, 2001; F. Guirakhoo, K. Pugachev, J. Arroyo, C. Miller, Z.-X. Zhang, R. Weltzin, K. Georgakopoulos, J. Catalan, S. Ocran, K. Draper, and T. P. Monath, Virology 298:146-159, 2002). Progeny viruses were subjected to three rounds of plaque purifications to produce the Pre-Master Seed viruses at passage 7 (P7). Three further passages were carried out using U.S. current Good Manufacturing Practices (cGMP) to produce the Vaccine Lot (P10) viruses. Preclinical studies demonstrated that the vaccine candidates are replication competent and genetically stable and do not become more neurovirulent upon 20 passages in Vero cells. The safety of a tetravalent vaccine was determined and compared to that of YF-VAX in a formal monkey neurovirulence test. Brain lesions produced by the tetravalent ChimeriVax-DEN vaccine were significantly less severe than those observed with YF-VAX. The immunogenicity and protective efficacy of four different tetravalent formulations were evaluated in cynomolgus monkeys following a single-dose subcutaneous vaccination followed by a virulent virus challenge 6 months later. All monkeys developed low levels of viremia postimmunization, and all the monkeys that had received equal concentrations of either a high-dose (5,5,5,5) or a low-dose (3,3,3,3) formulation seroconverted against all four DEN virus serotypes. Twenty-two (92%) of 24 monkeys were protected as determined by lack of viremia post-challenge. This report is the first to demonstrate the safety of a recombinant DEN virus tetravalent vaccine in a formal neurovirulence test, as well as its protective efficacy in a monkey challenge model.
253 citations