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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TL;DR: Analyzing data from Thailand's 72 provinces, Derek Cummings and colleagues find that decreases in birth and death rates can explain the shift in age distribution of dengue hemorrhagic fever.
Abstract: Background: An increase in the average age of dengue hemorrhagic fever (DHF) cases has been reported in Thailand. The cause of this increase is not known. Possible explanations include a reduction in transmission due to declining mosquito populations, declining contact between human and mosquito, and changes in reporting. We propose that a demographic shift toward lower birth and death rates has reduced dengue transmission and lengthened the interval between large epidemics. Methods and Findings: Using data from each of the 72 provinces of Thailand, we looked for associations between force of infection (a measure of hazard, defined as the rate per capita at which susceptible individuals become infected) and demographic and climactic variables. We estimated the force of infection from the age distribution of cases from 1985 to 2005. We find that the force of infection has declined by 2% each year since a peak in the late 1970s and early 1980s. Contrary to recent findings suggesting that the incidence of DHF has increased in Thailand, we find a small but statistically significant decline in DHF incidence since 1985 in a majority of provinces. The strongest predictor of the change in force of infection and the mean force of infection is the median age of the population. Using mathematical simulations of dengue transmission we show that a reduced birth rate and a shift in the population’s age structure can explain the shift in the age distribution of cases, reduction of the force of infection, and increase in the periodicity of multiannual oscillations of DHF incidence in the absence of other changes. Conclusions: Lower birth and death rates decrease the flow of susceptible individuals into the population and increase the longevity of immune individuals. The increase in the proportion of the population that is immune increases the likelihood that an infectious mosquito will feed on an immune individual, reducing the force of infection. Though the force of infection has decreased by half, we find that the critical vaccination fraction has not changed significantly, declining from an average of 85% to 80%. Clinical guidelines should consider the impact of continued increases in the age of dengue cases in Thailand. Countries in the region lagging behind Thailand in the demographic transition may experience the same increase as their population ages. The impact of demographic changes on the force of infection has been hypothesized for other diseases, but, to our knowledge, this is the first observation of this phenomenon. Please see later in the article for the Editors’ Summary.
226 citations
Cites background from "More Dengue, More Questions"
...Recently, an increasing number of DHF cases among older individuals has been observed in Thailand [1,2]....
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...One hypothesis is that the force of infection (the per capita rate at which susceptible individuals become infected) is declining because of reductions in vector abundance or contact between human and vector, possibly as a result of control efforts or economic development [2,6]....
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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 "More Dengue, More Questions"
...DHF first came to attention in the 1950s and has since spread rapidly throughout the tropical world (Halstead, 2005)....
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TL;DR: Incidence of DHF over the past 45 years in Indonesia increased rapidly with peak incidence shifting from young children to older age groups, and the shifting age pattern should have consequences for targeted surveillance and prevention.
Abstract: Background: Increases in human population size, dengue vector-density and human mobility cause rapid spread of dengue virus in Indonesia. We investigated the changes in dengue haemorrhagic fever (DHF) incidence in Indonesia over a 45-year period and determined age-specific trends in annual DHF incidence. Methods: Using an on-going nationwide dengue surveillance program starting in 1968, we evaluated all DHF cases and related deaths longitudinally up to 2013. Population demographics were used to calculate annual incidence and case fatality ratios (CFRs). Age-specific data on DHF available from 1993 onwards were used to assess trends in DHF age-distribution. Time-dependency of DHF incidence and CFRs was assessed using the Cochrane-Armitage trend test. Results: The annual DHF incidence increased from 0.05/100,000 in 1968 to ~ 35-40/100,000 in 2013, with superimposed epidemics demonstrating a similar increasing trend with the highest epidemic occurring in 2010 (85.70/100,000; p < 0.01). The CFR declined from 41% in 1968 to 0.73% in 2013 (p < 0.01). Mean age of DHF cases increased during the observation period. Highest incidence of DHF was observed among children aged 5 to 14 years up to 1998, but declined thereafter (p < 0.01). In those aged 15 years or over, DHF incidence increased (p < 0.01) and surpassed that of 5 to 14 year olds from 1999 onwards. Conclusions: Incidence of DHF over the past 45 years in Indonesia increased rapidly with peak incidence shifting from young children to older age groups. The shifting age pattern should have consequences for targeted surveillance and prevention.
153 citations
Cites background from "More Dengue, More Questions"
...Furthermore, travellers from non-endemic countries to endemic dengue areas are at risk of contracting dengue disease, and pose a health threat to non-endemic regions where competent mosquito vectors are currently found [9-12]....
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TL;DR: Attention is focused on outbreaks of dengue and chikungunya occurring in previously disease-free areas and factors associated with the long-distance spread of the vector-borne infections, such as mutations increasing viral fitness, climate change, urbanization, and globalization of humans and vectors.
Abstract: Mosquito-borne virus infections, such as dengue and chikungunya, are continuously expanding their geographical range. The dengue virus, which is known to be a common cause of febrile illness in tropical areas of the Old World, is now widespread in the Americas. In most affected areas, all the four dengue virus serotypes have circulated. Recently, small clusters of dengue have been identified also in Southern Europe during the hot season. The chikungunya virus, initially restricted to Central Africa, where is a common cause of sporadic cases or small outbreaks, and Asia, where it is used to cause large epidemics, has recently invaded new territories. After ravaging Indian Ocean Islands and the Indian subcontinent, CHIKV caused an outbreak in north-eastern Italy. Recently, chikungunya has reached the Caribbean, causing for the first time a large epidemic on the American continent. Although Aedes aegypti is the main vector of both viruses, Aedes albopictus, the Asian 'Tiger' mosquito, is now playing an increasingly important role, contributing to their spread in temperate climate areas. Hereby, we focus the attention on outbreaks of dengue and chikungunya occurring in previously disease-free areas and discuss factors associated with the long-distance spread of the vector-borne infections, such as mutations increasing viral fitness, climate change, urbanization, and globalization of humans and vectors.
132 citations
TL;DR: The challenges for prevention and control in the Americas are discussed, with solutions only targeting the vector reduce the impact of interventions and there is no sustainable control.
Abstract: Dengue is the most important vector-borne disease in the Americas and threatens the lifes of millions of people in developing countries. Imprecise morbidity and mortality statistics underestimate the magnitude of dengue as a regional health problem. As a result, it is considered a low priority by the health sector with no timely steps for effective control. Dengue is perceived as a problem of "others" (individually, collectively and institutionally), therefore responsibility for its control is passed on to others (neighbors, the community, municipality, health institutions, or other governmental agencies). With no precise risk indicators available there is little opportunity for timely diagnoses, treatment, health interventions or vector control (poor surveillance). Solutions only targeting the vector reduce the impact of interventions and there is no sustainable control. Without political commitment there are insufficient resources to face the problem. This paper discusses the challenges for prevention and control in the Americas.
102 citations
References
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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
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
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
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
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