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1.  The Impact of the Demographic Transition on Dengue in Thailand: Insights from a Statistical Analysis and Mathematical Modeling 
PLoS Medicine  2009;6(9):e1000139.
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.
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
Editors' Summary
Background
Every year, dengue infects 50–100 million people living in tropical and subtropical areas. The four closely related viruses that cause dengue are transmitted to people through the bites of female Aedes aegypti mosquitoes, which acquire dengue virus by feeding on the blood of an infected person. Although some people who become infected with dengue virus have no symptoms, many develop dengue fever, a severe, flu-like illness that lasts for a few days. Other people—more than half a million a year—develop dengue hemorrhagic fever, which causes bleeding from the gums and nose and bruising, or dengue shock syndrome in which circulatory failure also occurs. Both these potentially fatal conditions are associated with sequential infections with dengue virus—nonfatal infection with dengue virus of one type provides lifelong immunity against that type but only temporary protection against infection with dengue viruses of other types. There is no vaccine to prevent dengue and no specific treatment for the disease. However, standard medical care—in particular, replacement of lost fluids—can prevent most deaths from dengue.
Why Was This Study Done?
Historically, dengue has mainly affected young children but, recently, its age distribution has shifted towards older age groups in several Southeast Asian countries, including Thailand. In addition, the interval between large increases in incidence (epidemics) of dengue hemorrhagic fever has lengthened. It is important to know why these changes are happening because they could affect how dengue infections are dealt with in these countries. One idea is that an ongoing shift towards lower birth and death rates (the demographic transition; this occurs as countries move from a pre-industrial to an industrial economy) is reducing dengue transmission rates by reducing the “force of infection” (the rate at which susceptible individuals become infected). As birth and death rates decline, immune individuals account for more of the population so mosquitoes are more likely to bite an immune individual, which reduces the force of infection. Similarly, because susceptible individuals enter the population by being born, changing the birth rate alters the interval between epidemics. In this study, the researchers test whether the demographic transition might be responsible for the changing pattern of dengue infection in Thailand.
What Did the Researchers Do and Find?
The researchers retrieved data on dengue infection, demographic data (the population's age structure and birth and death rates), socioeconomic data, and climatic data for Thailand from 1980 to 2005 from various sources. They then fitted the data on dengue cases to several mathematical models to estimate the force of infection for each year. This analysis suggested that the force of infection has declined by 2% every year since the early1980s. Next, the researchers used statistical methods to show that the strongest predictor of this decline is the increase in the median age of the population (a measure of the average age of the population). Finally, using mathematical simulations of dengue transmission, they showed that a reduced birth rate and a shift in the population's age structure are sufficient to explain the recent shift in the age distribution of dengue cases, the reduction of the force of infection, and the increased interval between epidemics of dengue hemorrhagic fever.
What Do These Findings Mean?
The findings of all modeling studies depend on how the mathematical models are built and the accuracy of the data fed into them. Nevertheless, these findings suggest that recent changes in birth and death rates in Thailand are sufficient to produce the observed changes in the age distribution of dengue and periodicity of dengue outbreaks. One implication of these findings is that other countries in Southeast Asia that follow Thailand in the demographic transition may experience similar shifts in the pattern of dengue infections as the age structure of their populations changes. This means that clinical guidelines for the management of dengue infections in Southeast Asia will need to be adjusted to allow for the increasing age of dengue cases. Finally, although the researchers' calculations show the force of infection has fallen substantially over the past two decades, they also show that when a dengue vaccine becomes available, it will still be necessary to vaccinate most of the population to halt dengue transmission.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000139
This study is further discussed in a PLoS Medicine Perspective by Cameron Simmons and Jeremy Farrar
The US Centers for Disease Control and Prevention provides detailed information about dengue fever and dengue hemorrhagic fever (in English and Spanish)
The World Health Organization provides information about dengue and dengue hemorrhagic fever around the world (in several languages) and detailed information about dengue in Southeast Asia
Links to additional information about dengue are provided by MedlinePlus (in English and Spanish)
Wikipedia has a page about the demographic transition (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1000139
PMCID: PMC2726436  PMID: 19721696
2.  Spatial and Temporal Clustering of Dengue Virus Transmission in Thai Villages 
PLoS Medicine  2008;5(11):e205.
Background
Transmission of dengue viruses (DENV), the leading cause of arboviral disease worldwide, is known to vary through time and space, likely owing to a combination of factors related to the human host, virus, mosquito vector, and environment. An improved understanding of variation in transmission patterns is fundamental to conducting surveillance and implementing disease prevention strategies. To test the hypothesis that DENV transmission is spatially and temporally focal, we compared geographic and temporal characteristics within Thai villages where DENV are and are not being actively transmitted.
Methods and Findings
Cluster investigations were conducted within 100 m of homes where febrile index children with (positive clusters) and without (negative clusters) acute dengue lived during two seasons of peak DENV transmission. Data on human infection and mosquito infection/density were examined to precisely (1) define the spatial and temporal dimensions of DENV transmission, (2) correlate these factors with variation in DENV transmission, and (3) determine the burden of inapparent and symptomatic infections. Among 556 village children enrolled as neighbors of 12 dengue-positive and 22 dengue-negative index cases, all 27 DENV infections (4.9% of enrollees) occurred in positive clusters (p < 0.01; attributable risk [AR] = 10.4 per 100; 95% confidence interval 1–19.8 per 100]. In positive clusters, 12.4% of enrollees became infected in a 15-d period and DENV infections were aggregated centrally near homes of index cases. As only 1 of 217 pairs of serologic specimens tested in positive clusters revealed a recent DENV infection that occurred prior to cluster initiation, we attribute the observed DENV transmission subsequent to cluster investigation to recent DENV transmission activity. Of the 1,022 female adult Ae. aegypti collected, all eight (0.8%) dengue-infected mosquitoes came from houses in positive clusters; none from control clusters or schools. Distinguishing features between positive and negative clusters were greater availability of piped water in negative clusters (p < 0.01) and greater number of Ae. aegypti pupae per person in positive clusters (p = 0.04). During primarily DENV-4 transmission seasons, the ratio of inapparent to symptomatic infections was nearly 1:1 among child enrollees. Study limitations included inability to sample all children and mosquitoes within each cluster and our reliance on serologic rather than virologic evidence of interval infections in enrollees given restrictions on the frequency of blood collections in children.
Conclusions
Our data reveal the remarkably focal nature of DENV transmission within a hyperendemic rural area of Thailand. These data suggest that active school-based dengue case detection prompting local spraying could contain recent virus introductions and reduce the longitudinal risk of virus spread within rural areas. Our results should prompt future cluster studies to explore how host immune and behavioral aspects may impact DENV transmission and prevention strategies. Cluster methodology could serve as a useful research tool for investigation of other temporally and spatially clustered infectious diseases.
Investigating dengue cases identified by testing febrile schoolchildren in rural Thai villages, Mammen P. Mammen and colleagues find a pattern of focal spread to houses neighboring those of case patients.
Editors' Summary
Background.
Every year, over 50 million people living in tropical and subtropical urban and semi-urban areas become infected with dengue (a mosquito-borne viral infection) and several hundred thousand develop a potentially lethal complication called dengue hemorrhagic fever. Dengue is caused by four closely related viruses that are transmitted to people through the bites of infected female Aedes aegypti mosquitoes. These day-biting insects, which breed in household water containers and in the water that collects in used tires and other discarded containers, acquire dengue virus through feeding on the blood of an infected person. Some people who become infected with dengue virus have no symptoms but others develop high fever, a rash, and severe headache that lasts two to seven days. In dengue hemorrhagic fever, small blood vessels become leaky, which causes nose and gum bleeds, bruising and, in the worst cases, failure of the circulatory system and death. There is no specific treatment for dengue fever or dengue hemorrhagic fever but standard medical care—in particular, replacement of lost blood fluids—helps most people survive the latter condition.
Why Was This Study Done?
There is no vaccine to prevent dengue. As a result the only way to minimize dengue outbreaks is to control mosquito numbers through environmental management—providing piped water, encouraging people not to store water in open containers, and removing other sources of standing water—and by applying insecticides to areas where mosquitoes breed. During outbreaks, because Ae. aegypti mosquitoes rest in houses, insecticides are also often sprayed in dwellings in the affected areas. However, to improve dengue prevention and surveillance, public-health officials need to know much more about the patterns of dengue virus transmission and about the factors that underlie these patterns. In this study, therefore, the researchers test the idea that dengue virus transmission occurs in localized neighborhood clusters over short periods of time.
What Did the Researchers Do and Find?
The researchers used “cluster investigations” to examine the pattern of dengue virus transmission among school children in several rural villages in Thailand, a country where dengue is very common (hyperendemic). Primary school children with fever were identified during two seasons of peak dengue virus transmission. Each child was characterized as a dengue-positive index case (by finding dengue virus in their blood) or as a dengue-negative index case. Data on human infection and mosquito infection and density were then collected within 100 meters of the homes of each index case—the “cluster area.” Not all the neighbors of the index cases participated in the study but among the 556 village children who did participate, there were 27 dengue infections, all of which occurred in clusters centered on the homes of the dengue-positive index cases. In the positive clusters, one in eight of the enrolled children became infected within 15 days of the index case becoming ill. Among 1,000 Ae. aegypti mosquitoes collected inside and around the houses in each cluster, only eight were infected with dengue and these were all collected from houses in positive clusters. Finally, there was a greater availability of piped water and fewer Ae. aegypti pupae in the negative clusters than in the positive clusters.
What Do These Findings Mean?
Although this study did not sample all the children or mosquitoes within each cluster area, these findings show that in an area where dengue is hyperendemic, dengue virus transmission among children occurs in localized areas and over short time periods. The findings also suggest that focal transmission is associated with recent dengue virus introductions and that one or a few mosquitoes are likely responsible for all the transmission in each cluster. Although it would be impractical to set up surveillance of all the school children in Thailand for dengue infections, these findings suggest that improved detection of cases within schools combined with local spraying inside the homes in the immediate vicinity of any affected children could help to halt dengue virus transmission. Future cluster studies could explore how human behavior and human immunity affect dengue virus transmission and could also be used to investigate other temporally and spatially clustered infectious diseases, including malaria.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050205.
Read the related PLoS Medicine Perspective by Steven Riley
The US Centers for Disease Control and Prevention provides detailed information about dengue fever, including a questions and answers section in English and Spanish
The World Health Organization provides information on dengue and dengue hemorrhagic fever around the world (in several languages)
Links to additional information about dengue are provided by MedlinePlus (in English and Spanish)
doi:10.1371/journal.pmed.0050205
PMCID: PMC2577695  PMID: 18986209
3.  Population Density, Water Supply, and the Risk of Dengue Fever in Vietnam: Cohort Study and Spatial Analysis 
PLoS Medicine  2011;8(8):e1001082.
Results from 75,000 geo-referenced households in Vietnam during two dengue epidemics reveal that human population densities typical of villages are most prone to dengue outbreaks; rural areas may contribute as much to dissemination of dengue fever as do cities.
Background
Aedes aegypti, the major vector of dengue viruses, often breeds in water storage containers used by households without tap water supply, and occurs in high numbers even in dense urban areas. We analysed the interaction between human population density and lack of tap water as a cause of dengue fever outbreaks with the aim of identifying geographic areas at highest risk.
Methods and Findings
We conducted an individual-level cohort study in a population of 75,000 geo-referenced households in Vietnam over the course of two epidemics, on the basis of dengue hospital admissions (n = 3,013). We applied space-time scan statistics and mathematical models to confirm the findings. We identified a surprisingly narrow range of critical human population densities between around 3,000 to 7,000 people/km2 prone to dengue outbreaks. In the study area, this population density was typical of villages and some peri-urban areas. Scan statistics showed that areas with a high population density or adequate water supply did not experience severe outbreaks. The risk of dengue was higher in rural than in urban areas, largely explained by lack of piped water supply, and in human population densities more often falling within the critical range. Mathematical modeling suggests that simple assumptions regarding area-level vector/host ratios may explain the occurrence of outbreaks.
Conclusions
Rural areas may contribute at least as much to the dissemination of dengue fever as cities. Improving water supply and vector control in areas with a human population density critical for dengue transmission could increase the efficiency of control efforts.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Dengue fever is a viral infection common in tropical and subtropical regions that is characterized by sudden high fever, severe headache, muscle and joint pains, and a rash. The virus is transmitted by the bite of female Aedes aegypti mosquitoes. Although dengue is not usually fatal, infection rates can be as high as 90% among those who have not been previously exposed to the virus, and in a small proportion of cases the disease can develop into dengue hemorrhagic fever, which is life threatening. It is estimated that 500,000 people are hospitalized every year with dengue hemorrhagic fever. Incidence of dengue fever is increasing, and two-fifths of the world's population, approximately 2.5 billion people, are now at risk from the disease in over 100 endemic countries.
Why Was This Study Done?
There is no specific treatment for dengue fever, other than managing symptoms and ensuring hydration, and no vaccine available. The best way to counter the spread of dengue fever is to target the mosquito vector, with one of the more effective methods being the disruption of mosquito habitats, in particular eliminating standing water such as in unused tires, open water storage containers, or even flower vases, where mosquitoes lay their eggs and larvae develop. Because the geographic range of the mosquitoes that transmit dengue has increased, there has been a rapid rise in global dengue epidemics over the last 30 years with Southeast Asia and the Western Pacific being most severely affected. In this study researchers aimed to define areas in Vietnam that were most at risk of dengue fever by looking at population density and water supply.
What Did the Researchers Do and Find?
The researchers studied a population in Kanh-Hoa Province in south-central Vietnam (∼350,000 people) that was affected by two dengue epidemics between January 2005 and June 2008. They included all patients admitted to two public hospitals that could be linked to census data from 2006 (3,013 patients). These data enabled the researchers to calculate both the population density and the proportion of households with access to tap water within 100 meters of each patient's household.
The researchers found that low population densities, typical of rural villages (around 110 people residing within a 100-meter radius), had the highest rate of dengue fever. They also found that in those neighborhoods where less than 20% of households had tap water there was a peak in dengue fever rates at a population density of 190 people residing within 100 meters. On an individual household level they found that absence of tap water was associated with an increased risk of dengue fever.
In the absence of data on larvae and mosquito abundance the researchers used a mathematical model to show that when mosquito numbers were limited the highest risk of dengue occurred at very low population densities. However, if mosquito numbers were limited only at high human population densities, dengue fever risk peaked at low-to-moderate human population densities. The model suggests that the provision of tap water changes the risk of dengue because mosquito numbers are limited.
What Do These Findings Mean?
People living in low-to-moderate population densities, such as rural villages, without access to tap water have the highest risk of contracting dengue fever. The use of water storage vessels provides breeding sites for mosquitoes and leads to a high mosquito-to-human ratio and an increased individual dengue risk. In more populated urban areas with tap water, mosquito breeding sites are limited so the relative risk of dengue for an individual is less because the mosquito-to-human ratio is smaller. Populated areas still contribute substantially to dengue epidemics, however, because the absolute number of people who can contract dengue is high.
The authors point out some limitations in their study, such as only looking at the most severe cases of dengue in patients who were admitted to hospital and assuming that all taps were functional.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001082.
WHO provides information on dengue fever including a dengue fact sheet
The CDC provides information on the Aedes aegypti mosquito and a global health map that reports areas at risk of dengue
doi:10.1371/journal.pmed.1001082
PMCID: PMC3168879  PMID: 21918642
4.  Evaluation of the Traditional and Revised WHO Classifications of Dengue Disease Severity 
Dengue is a major public health problem worldwide and continues to increase in incidence. Dengue virus (DENV) infection leads to a range of outcomes, including subclinical infection, undifferentiated febrile illness, Dengue Fever (DF), life-threatening syndromes with fluid loss and hypotensive shock, or other severe manifestations such as bleeding and organ failure. The long-standing World Health Organization (WHO) dengue classification and management scheme was recently revised, replacing DF, Dengue Hemorrhagic Fever (DHF), and Dengue Shock Syndrome (DSS) with Dengue without Warning Signs, Dengue with Warning Signs (abdominal pain, persistent vomiting, fluid accumulation, mucosal bleeding, lethargy, liver enlargement, increasing hematocrit with decreasing platelets) and Severe Dengue (SD; dengue with severe plasma leakage, severe bleeding, or organ failure). We evaluated the traditional and revised classification schemes against clinical intervention levels to determine how each captures disease severity using data from five years (2005–2010) of a hospital-based study of pediatric dengue in Managua, Nicaragua. Laboratory-confirmed dengue cases (n = 544) were categorized using both classification schemes and by level of care (I–III). Category I was out-patient care, Category II was in-patient care that did not meet criteria for Category III, which included ICU admission, ventilation, administration of inotropic drugs, or organ failure. Sensitivity and specificity to capture Category III care for DHF/DSS were 39.0% and 75.5%, respectively; sensitivity and specificity for SD were 92.1% and 78.5%, respectively. In this data set, DENV-2 was found to be significantly associated with DHF/DSS; however, this association was not observed with the revised classification. Among dengue-confirmed cases, the revised WHO classification for severe dengue appears to have higher sensitivity and specificity to identify cases in need of heightened care, although it is no longer as specific for a particular pathogenic entity as was the traditional schema.
Author Summary
Dengue is a mosquito-transmitted viral disease that is a major public health problem worldwide. Dengue virus (DENV) infection leads to Dengue Fever (DF) and a spectrum of life-threatening syndromes with fluid loss and hypotensive shock or other severe manifestations. Recently, the traditional World Health Organization (WHO) dengue classification scheme (classic DF, Dengue Hemorrhagic Fever (DHF), and Dengue Shock Syndrome (DSS)) was replaced with Dengue without Warning Signs, Dengue with Warning Signs and Severe Dengue (SD). Using data from 544 laboratory-confirmed dengue cases recruited over five years of a hospital-based study of pediatric dengue in Managua, Nicaragua, we evaluated the traditional and revised classification schemes against clinical intervention levels (I–III) to determine how each captures disease severity. The sensitivity and specificity to capture Category III care for DHF/DSS were 39.0% and 75.5%, respectively, and for SD were 92.1% and 78.5%, respectively. Interestingly, DENV-2 was significantly associated with DHF/DSS; however, this association was not observed with the revised classification. This study indicates that among dengue-confirmed cases, the revised WHO classification appears to have higher sensitivity and specificity for identifying cases in need of heightened care, although it is no longer as specific for a particular pathogenic entity as was the traditional schema.
doi:10.1371/journal.pntd.0001397
PMCID: PMC3210746  PMID: 22087348
5.  Multiyear Climate Variability and Dengue—El Niño Southern Oscillation, Weather, and Dengue Incidence in Puerto Rico, Mexico, and Thailand: A Longitudinal Data Analysis 
PLoS Medicine  2009;6(11):e1000168.
Michael Johansson and colleagues use wavelet analysis to show that there is limited evidence for a multiyear relationship between climate and dengue incidence in Puerto Rico, Mexico, and Thailand.
Background
The mosquito-borne dengue viruses are a major public health problem throughout the tropical and subtropical regions of the world. Changes in temperature and precipitation have well-defined roles in the transmission cycle and may thus play a role in changing incidence levels. The El Niño Southern Oscillation (ENSO) is a multiyear climate driver of local temperature and precipitation worldwide. Previous studies have reported varying degrees of association between ENSO and dengue incidence.
Methods and Findings
We analyzed the relationship between ENSO, local weather, and dengue incidence in Puerto Rico, Mexico, and Thailand using wavelet analysis to identify time- and frequency-specific association. In Puerto Rico, ENSO was transiently associated with temperature and dengue incidence on multiyear scales. However, only local precipitation and not temperature was associated with dengue on multiyear scales. In Thailand, ENSO was associated with both temperature and precipitation. Although precipitation was associated with dengue incidence, the association was nonstationary and likely spurious. In Mexico, no association between any of the variables was observed on the multiyear scale.
Conclusions
The evidence for a relationship between ENSO, climate, and dengue incidence presented here is weak. While multiyear climate variability may play a role in endemic interannual dengue dynamics, we did not find evidence of a strong, consistent relationship in any of the study areas. The role of ENSO may be obscured by local climate heterogeneity, insufficient data, randomly coincident outbreaks, and other, potentially stronger, intrinsic factors regulating transmission dynamics.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, as many as 50–100 million people become infected with one of four closely related dengue viruses through the bite of a female Aedes aegypti mosquito that has acquired the virus by feeding on infected human blood. Dengue is endemic (always present) in many tropical and subtropical countries but its incidence (the number of new cases in a population over a given time period) follows a seasonal pattern. This is because the abundance of Ae. aegypti is regulated by rainfall, which provides breeding sites and stimulates egg hatching, and by temperature, which influences the insects' survival and their rate of development and reproduction. Temperature also affects the mosquitoes' ability to transmit dengue virus—higher temperatures increase transmission rates. Although some people who become infected with dengue have no symptoms, many develop dengue fever, a severe, flu-like illness that lasts a few days. Other people—more than half a million a year—develop dengue hemorrhagic fever, a potentially fatal condition. There is no vaccine to prevent dengue and no specific treatment for the disease, but standard medical care can prevent most deaths from dengue.
Why Was This Study Done?
As well as seasonal variations in the incidence of dengue, large dengue outbreaks (epidemics) occur every few years. To help with health care planning, public health officials would like a way to predict when these epidemics are likely to occur, but to develop such a system requires a good understanding of the factors that lead to major epidemics. Although variations in host–virus interactions (for example, changes in host immunity to dengue) almost certainly play an important role in the timing of dengue epidemics, interannual changes in temperature and rainfall could also be involved. One major cause of global interannual weather variation is the El Niño Southern Oscillation (ENSO), a climate cycle centered on the Pacific Ocean that repeats every 3–4 years. Previous studies have reported varying degrees of association between ENSO and dengue. In this study, the researchers reanalyze the relationship between ENSO, local weather, and dengue incidence in three dengue-endemic countries using “wavelet analysis.” This mathematical technique can separate the effects of seasonal weather variations on dengue incidence from those of interannual weather fluctuations.
What Did the Researchers Do and Find?
The researchers retrieved data on the incidence of dengue fever and dengue hemorrhagic fever in Puerto Rico, Thailand and Mexico since the mid 1980s from national surveillance systems. They also collected historical weather data for each country and information on ENSO. They then used these data and wavelet analysis to investigate the relationship between ENSO, local weather, and dengue incidence in each country on the annual scale and on the multiyear scale. On the annual scale, temperature, rainfall, and dengue incidence were strongly associated in all three countries. On the multiyear scale, ENSO was associated with temperature and with dengue incidence in Puerto Rico, but only for part of the study period. Only local rainfall was associated with the incidence of dengue in that country. The lack of a direct path of association from ENSO to either weather variable to dengue incidence suggests that the ENSO–dengue association may be a spurious result. In Thailand, ENSO was associated with both temperature and rainfall, and rainfall was associated with dengue incidence. However, detailed analysis suggests that this latter association was also probably spurious. Finally, there was no association between any of the variables in Mexico on the multiyear scale.
What Do These Findings Mean?
Although these findings show a strong associations between both temperature and rainfall and dengue incidence on the annual scale in Puerto Rico, Thailand, and Mexico, they provide little evidence for any relationship between ENSO, climate, and dengue incidence. Multiyear climate variability may play a role in interannual variations in dengue incidence, the researchers suggest, but their study does not provide any evidence for a strong and consistent relationship between climate variability and dengue incidence. It is possible that the effects of ENSO on dengue incidence are being masked by local variations in weather or by stronger factors regulating disease transmission such as host–virus or host–vector interactions. Future studies into the relationship between dengue outbreaks and multiyear climate variability will need to include these and other factors. For now, however, information on ENSO cannot be used to design an early warning system for dengue outbreaks.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000168.
This study is further discussed in a PLoS Medicine Perspective by Pejman Rohani
The US Centers for Disease Control and Prevention provides detailed information about dengue fever and dengue hemorrhagic fever (in English and Spanish)
The World Health Organization provides information on dengue fever and dengue hemorrhagic fever around the world (in several languages)
Links to additional resources about dengue are provided by MedlinePlus (in English and Spanish)
Wikipedia has pages on the El Nio Southern Oscillation and on wavelet analysis (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1000168
PMCID: PMC2771282  PMID: 19918363
6.  Decision Tree Algorithms Predict the Diagnosis and Outcome of Dengue Fever in the Early Phase of Illness 
Background
Dengue is re-emerging throughout the tropical world, causing frequent recurrent epidemics. The initial clinical manifestation of dengue often is confused with other febrile states confounding both clinical management and disease surveillance. Evidence-based triage strategies that identify individuals likely to be in the early stages of dengue illness can direct patient stratification for clinical investigations, management, and virological surveillance. Here we report the identification of algorithms that differentiate dengue from other febrile illnesses in the primary care setting and predict severe disease in adults.
Methods and Findings
A total of 1,200 patients presenting in the first 72 hours of acute febrile illness were recruited and followed up for up to a 4-week period prospectively; 1,012 of these were recruited from Singapore and 188 from Vietnam. Of these, 364 were dengue RT-PCR positive; 173 had dengue fever, 171 had dengue hemorrhagic fever, and 20 had dengue shock syndrome as final diagnosis. Using a C4.5 decision tree classifier for analysis of all clinical, haematological, and virological data, we obtained a diagnostic algorithm that differentiates dengue from non-dengue febrile illness with an accuracy of 84.7%. The algorithm can be used differently in different disease prevalence to yield clinically useful positive and negative predictive values. Furthermore, an algorithm using platelet count, crossover threshold value of a real-time RT-PCR for dengue viral RNA, and presence of pre-existing anti-dengue IgG antibodies in sequential order identified cases with sensitivity and specificity of 78.2% and 80.2%, respectively, that eventually developed thrombocytopenia of 50,000 platelet/mm3 or less, a level previously shown to be associated with haemorrhage and shock in adults with dengue fever.
Conclusion
This study shows a proof-of-concept that decision algorithms using simple clinical and haematological parameters can predict diagnosis and prognosis of dengue disease, a finding that could prove useful in disease management and surveillance.
Author Summary
Dengue illness appears similar to other febrile illness, particularly in the early stages of disease. Consequently, diagnosis is often delayed or confused with other illnesses, reducing the effectiveness of using clinical diagnosis for patient care and disease surveillance. To address this shortcoming, we have studied 1,200 patients who presented within 72 hours from onset of fever; 30.3% of these had dengue infection, while the remaining 69.7% had other causes of fever. Using body temperature and the results of simple laboratory tests on blood samples of these patients, we have constructed a decision algorithm that is able to distinguish patients with dengue illness from those with other causes of fever with an accuracy of 84.7%. Another decision algorithm is able to predict which of the dengue patients would go on to develop severe disease, as indicated by an eventual drop in the platelet count to 50,000/mm3 blood or below. Our study shows a proof-of-concept that simple decision algorithms can predict dengue diagnosis and the likelihood of developing severe disease, a finding that could prove useful in the management of dengue patients and to public health efforts in preventing virus transmission.
doi:10.1371/journal.pntd.0000196
PMCID: PMC2263124  PMID: 18335069
7.  Predictive Value of Proteinuria in Adult Dengue Severity 
Background
Dengue is an important viral infection with different presentations. Predicting disease severity is important in triaging patients requiring hospital care. We aim to study the value of proteinuria in predicting the development of dengue hemorrhagic fever (DHF), utility of urine dipstick test as a rapid prognostic tool.
Methodology and principal findings
Adult patients with undifferentiated fever (n = 293) were prospectively enrolled at the Infectious Disease Research Clinic at Tan Tock Seng Hospital, Singapore from January to August 2012. Dengue infection was confirmed in 168 (57%) by dengue RT-PCR or NS1 antigen detection. Dengue cases had median fever duration of 6 days at enrolment. DHF was diagnosed in 34 cases according to the WHO 1997 guideline. Dengue fever (DF) patients were predominantly younger and were mostly seen in the outpatient setting with higher platelet level. Compared to DF, DHF cases had significantly higher peak urine protein creatinine ratio (UPCR) during clinical course (26 vs. 40 mg/mmol; p<0.001). We obtained a UPCR cut-off value of 29 mg/mmol based on maximum AUC in ROC curves of peak UPCR for DF versus DHF, corresponding to 76% sensitivity and 60% specificity. Multivariate analysis with other readily available clinical and laboratory variables increased the AUC to 0.91 with 92% sensitivity and 80% specificity. Neither urine dipstick at initial presentation nor peak urine dipstick value during the entire illness was able to discriminate between DF and DHF.
Conclusions
Proteinuria measured by a laboratory-based UPCR test may be sensitive and specific in prognosticating adult dengue patients.
Author Summary
Dengue infection is getting more common in recent years, affecting all age groups. Currently, there is no specific treatment for dengue. Close clinical monitoring and careful fluid therapy is the only way of management for those with severe dengue disease, i.e., dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). It is crucial to know among patients with dengue, who will potentially progress to DHF/DSS in the most reliable, economical and fastest way, so as to prioritise limited resources. We investigated the presence of protein in urine as an indicator of progression to DHF/DSS. Adult patients with dengue were enrolled to our clinic. Clinical data, blood and urine were collected. We found that patients who were going to develop DHF/DSS had increased protein one day prior to developing to DHF/DSS. DHF/DSS cases had higher protein levels in urine compared to patients with just dengue fever. Laboratory-based urine protein data, when used together with other readily available blood tests, helped to detect 92% of DHF cases correctly. Currently available clinic-based urine protein test strip was not useful in predicting severe disease. Future studies may improve the ability of the clinic-based tests, thus reducing the reliance on laboratory testing.
doi:10.1371/journal.pntd.0002712
PMCID: PMC3930505  PMID: 24587464
8.  Early Clinical Features of Dengue Virus Infection in Nicaraguan Children: A Longitudinal Analysis 
Background
Tens of millions of dengue cases and approximately 500,000 life-threatening complications occur annually. New tools are needed to distinguish dengue from other febrile illnesses. In addition, the natural history of pediatric dengue early in illness in a community-based setting has not been well-defined.
Methods
Data from the multi-year, ongoing Pediatric Dengue Cohort Study of approximately 3,800 children aged 2–14 years in Managua, Nicaragua, were used to examine the frequency of clinical signs and symptoms by day of illness and to generate models for the association of signs and symptoms during the early phase of illness and over the entire course of illness with testing dengue-positive. Odds ratios (ORs) and 95% confidence intervals were calculated using generalized estimating equations (GEE) for repeated measures, adjusting for age and gender.
Results
One-fourth of children who tested dengue-positive did not meet the WHO case definition for suspected dengue. The frequency of signs and symptoms varied by day of illness, dengue status, and disease severity. Multivariable GEE models showed increased odds of testing dengue-positive associated with fever, headache, retro-orbital pain, myalgia, arthralgia, rash, petechiae, positive tourniquet test, vomiting, leukopenia, platelets ≤150,000 cells/mL, poor capillary refill, cold extremities and hypotension. Estimated ORs tended to be higher for signs and symptoms over the course of illness compared to the early phase of illness.
Conclusions
Day-by-day analysis of clinical signs and symptoms together with longitudinal statistical analysis showed significant associations with testing dengue-positive and important differences during the early phase of illness compared to the entire course of illness. These findings stress the importance of considering day of illness when developing prediction algorithms for real-time clinical management.
Author Summary
Dengue virus causes an estimated 50 million dengue cases and approximately 500,000 life-threatening complications annually. New tools are needed to distinguish dengue from other febrile illnesses. In addition, the natural history of pediatric dengue early in illness in a community-based setting has not been well-defined. Here, we describe the clinical spectrum of pediatric dengue over the course of illness in a community setting by using five years of data from an ongoing prospective cohort study of children in Managua, Nicaragua. Day-by-day analysis of clinical signs and symptoms together with longitudinal statistical analysis showed significant associations with testing dengue-positive and important differences during the early phase of illness compared to the entire course of illness. These findings are important for clinical practice since outside of the hospital setting, clinicians may see dengue patients toward the beginning of their illness and utilize that information to decide whether their patient has dengue or another febrile illness. The results of these models should be extended for the development of prediction algorithms to aid clinicians in diagnosing suspected dengue.
doi:10.1371/journal.pntd.0001562
PMCID: PMC3295819  PMID: 22413033
9.  Best Practices in Dengue Surveillance: A Report from the Asia-Pacific and Americas Dengue Prevention Boards 
Background
Dengue fever is a virus infection that is spread by the Aedes aegypti mosquito and can cause severe disease especially in children. Dengue fever is a major problem in tropical and sub-tropical regions of the world.
Methodology/Principal Findings
We invited dengue experts from around the world to attend meetings to discuss dengue surveillance. We reviewed literature, heard detailed reports on surveillance programs, and shared expert opinions.
Results
Presentations by 22 countries were heard during the 2.5 day meetings. We describe the best methods of surveillance in general, the stakeholders in dengue surveillance, and the steps from mosquito bite to reporting of a dengue case to explore how best to carry out dengue surveillance. We also provide details and a comparison of the dengue surveillance programs by the presenting countries.
Conclusions/Significance
The experts provided recommendations for achieving the best possible data from dengue surveillance accepting the realities of the real world (e.g., limited funding and staff). Their recommendations included: (1) Every dengue endemic country should make reporting of dengue cases to the government mandatory; (2) electronic reporting systems should be developed and used; (3) at minimum dengue surveillance data should include incidence, hospitalization rates, deaths by age group; (4) additional studies should be completed to check the sensitivity of the system; (5) laboratories should share expertise and data; (6) tests that identify dengue virus should be used in patients with fever for four days or less and antibody tests should be used after day 4 to diagnose dengue; and (7) early detection and prediction of dengue outbreaks should be goals for national surveillance systems.
Author Summary
The Pediatric Dengue Vaccine Initiative organized Dengue Prevention Boards in the Asia-Pacific and the Americas regions consisting of dengue experts from endemic countries. Both Boards convened meetings to review issues in surveillance. Through presentations, facilitated discussions, and surveys, the Boards identified best practices in dengue surveillance including: (1) Dengue should be a notifiable disease in endemic countries; (2) World Health Organization regional case definitions should be consistently applied; (3) electronic reporting systems should be developed and used broadly to speed delivery of data to stakeholders; (4) minimum reporting should include incidence rates of dengue fever, dengue hemorrhagic fever, dengue shock syndrome, and dengue deaths, and hospitalization and mortality rates should be reported by age group; (5) periodic additional studies (e.g., capture/recapture) should be conducted to assess under-detection, under-reporting, and the quality of surveillance; (6) laboratory methods and protocols should be standardized; (7) national authorities should encourage laboratories to develop networks to share expertise and data; and (8) RT-PCR and virus isolation (and possibly detection of the NS1 protein) are the recommended methods for confirmation of an acute dengue infection, but are recommended only for the four days after onset of fever—after day 4, IgM-capture enzyme-linked immunosorbent assay is recommended.
doi:10.1371/journal.pntd.0000890
PMCID: PMC2982842  PMID: 21103381
10.  Association of Mast Cell-Derived VEGF and Proteases in Dengue Shock Syndrome 
Background
Recent in-vitro studies have suggested that mast cells are involved in Dengue virus infection. To clarify the role of mast cells in the development of clinical Dengue fever, we compared the plasma levels of several mast cell-derived mediators (vascular endothelial cell growth factor [VEGF], soluble VEGF receptors [sVEGFRs], tryptase, and chymase) and -related cytokines (IL-4, -9, and -17) between patients with differing severity of Dengue fever and healthy controls.
Methodology/Principal Findings
The study was performed at Children's Hospital No. 2, Ho Chi Minh City, and Vinh Long Province Hospital, Vietnam from 2002 to 2005. Study patients included 103 with Dengue fever (DF), Dengue hemorrhagic fever (DHF), and Dengue shock syndrome (DSS), as diagnosed by the World Health Organization criteria. There were 189 healthy subjects, and 19 febrile illness patients of the same Kinh ethnicity. The levels of mast cell-derived mediators and -related cytokines in plasma were measured by ELISA. VEGF and sVEGFR-1 levels were significantly increased in DHF and DSS compared with those of DF and controls, whereas sVEGFR-2 levels were significantly decreased in DHF and DSS. Significant increases in tryptase and chymase levels, which were accompanied by high IL-9 and -17 concentrations, were detected in DHF and DSS patients. By day 4 of admission, VEGF, sVEGFRs, and proteases levels had returned to similar levels as DF and controls. In-vitro VEGF production by mast cells was examined in KU812 and HMC-1 cells, and was found to be highest when the cells were inoculated with Dengue virus and human Dengue virus-immune serum in the presence of IL-9.
Conclusions
As mast cells are an important source of VEGF, tryptase, and chymase, our findings suggest that mast cell activation and mast cell-derived mediators participate in the development of DHF. The two proteases, particularly chymase, might serve as good predictive markers of Dengue disease severity.
Author Summary
To clarify the involvement of mast cells in the development of severe Dengue diseases, plasma levels of mast cell-derived mediators, namely vascular endothelial cell growth factor (VEGF), tryptase, and chymase, were estimated in Dengue patients and control subjects in Vietnam. The levels of the mediators were significantly increased in Dengue hemorrhagic fever (DHF) and Dengue shock syndrome (DSS) patients compared with those of Dengue fever (DF) and control (febrile illness and healthy subjects) patients, and the soluble form of VEGF receptors (sVEGFR)-1 and -2 levels were significantly changed in the patients with severe disease. After 2–4 days of admission, the mediator levels had returned to similar levels as those of DF and control subjects. Furthermore, the levels of the Th17 cell-derived mast-cell activators IL-9 and -17 were increased in DHF and DSS. In-vitro production of VEGF in human mast cells was significantly enhanced in the presence of IL-9 when these cells were inoculated with Dengue virus in the presence of human Dengue virus-immune serum. As mast cells are an important source of VEGF, and tryptase and chymase are considered to be specific markers for mast cell activation, mast cells and mast cell-derived mediators might participate in the development of DHF/DSS.
doi:10.1371/journal.pntd.0001505
PMCID: PMC3283553  PMID: 22363824
11.  Dengue Infection in Children in Ratchaburi, Thailand: A Cohort Study. II. Clinical Manifestations 
Background
Dengue infection is one of the most important mosquito-borne diseases. More data regarding the disease burden and the prevalence of each clinical spectrum among symptomatic infections and the clinical manifestations are needed. This study aims to describe the incidence and clinical manifestations of symptomatic dengue infection in Thai children during 2006 through 2008.
Study Design
This study is a school-based prospective open cohort study with a 9,448 person-year follow-up in children aged 3–14 years. Active surveillance for febrile illnesses was done in the studied subjects. Subjects who had febrile illness were asked to visit the study hospital for clinical and laboratory evaluation, treatment, and serological tests for dengue infection. The clinical data from medical records, diary cards, and data collection forms were collected and analyzed.
Results
Dengue infections were the causes of 12.1% of febrile illnesses attending the hospital, including undifferentiated fever (UF) (49.8%), dengue fever (DF) (39.3%) and dengue hemorrhagic fever (DHF) (10.9%). Headache, anorexia, nausea/vomiting and myalgia were common symptoms occurring in more than half of the patients. The more severe dengue spectrum (i.e., DHF) had higher temperature, higher prevalence of nausea/vomiting, abdominal pain, rash, diarrhea, petechiae, hepatomegaly and lower platelet count. DHF cases also had significantly higher prevalence of anorexia, nausea/vomiting and abdominal pain during day 3–6 and diarrhea during day 4–6 of illness. The absence of nausea/vomiting, abdominal pain, diarrhea, petechiae, hepatomegaly and positive tourniquet test may predict non-DHF.
Conclusion
Among symptomatic dengue infection, UF is most common followed by DF and DHF. Some clinical manifestations may be useful to predict the more severe disease (i.e., DHF). This study presents additional information in the clinical spectra of symptomatic dengue infection.
Author Summary
Dengue infection is one of the most important diseases transmitted to human by mosquito bite. The disease may be mild or severe. This study reveals the occurrence and clinical features of diseases caused by dengue infection in a 3-year follow-up in school-children aged 3–14 years in Ratchaburi Province, Thailand using an active surveillance for the episodes of fever. Children who had fever were laboratory tested for the evidence of dengue infection and recorded for clinical features. It was found that most of dengue infected patients had headache, anorexia, nausea/vomiting, and muscle ache. About half of the patients had clinical symptoms that closely mimic other diseases, especially respiratory tract infection, and were incorrectly diagnosed by pediatricians. Only 11% of the patients had more a severe disease called “dengue hemorrhagic fever.” This severe disease may be predicted by the presence of anorexia, nausea/vomiting, and abdominal pain after the second day of illness. This study provides better understanding in this disease.
doi:10.1371/journal.pntd.0001520
PMCID: PMC3289597  PMID: 22389735
12.  A Prospective Nested Case-Control Study of Dengue in Infants: Rethinking and Refining the Antibody-Dependent Enhancement Dengue Hemorrhagic Fever Model 
PLoS Medicine  2009;6(10):e1000171.
Analyses of a prospective case-control study of infant dengue by Daniel Libraty and colleagues casts doubt on the antibody-dependent enhancement model for dengue hemorrhagic fever.
Background
Dengue hemorrhagic fever (DHF) is the severe and life-threatening syndrome that can develop after infection with any one of the four dengue virus (DENV) serotypes. DHF occurs almost exclusively in individuals with secondary heterologous DENV infections and infants with primary DENV infections born to dengue immune mothers. The widely accepted explanation for the pathogenesis of DHF in these settings, particularly during infancy, is antibody-dependent enhancement (ADE) of DENV infection.
Methods and Findings
We conducted a prospective nested case-control study of DENV infections during infancy. Clinical data and blood samples were collected from 4,441 mothers and infants in up to two pre-illness study visits, and surveillance was performed for symptomatic and inapparent DENV infections. Pre-illness plasma samples were used to measure the associations between maternally derived anti-DENV3 antibody-neutralizing and -enhancing capacities at the time of DENV3 infection and development of infant DHF.
The study captured 60 infants with DENV infections across a wide spectrum of disease severity. DENV3 was the predominant serotype among the infants with symptomatic (35/40) and inapparent (15/20) DENV infections, and 59/60 infants had a primary DENV infection. The estimated in vitro anti-DENV3 neutralizing capacity at birth positively correlated with the age of symptomatic primary DENV3 illness in infants. At the time of symptomatic DENV3 infection, essentially all infants had low anti-DENV3 neutralizing activity (50% plaque reduction neutralizing titers [PRNT50] ≤50) and measurable DENV3 ADE activity. The infants who developed DHF did not have significantly higher frequencies or levels of DENV3 ADE activity compared to symptomatic infants without DHF. A higher weight-for-age in the first 3 mo of life and at illness presentation was associated with a greater risk for DHF from a primary DENV infection during infancy.
Conclusions
This prospective nested case-control study of primarily DENV3 infections during infancy has shown that infants exhibit a full range of disease severity after primary DENV infections. The results support an initial in vivo protective role for maternally derived antibody, and suggest that a DENV3 PRNT50 >50 is associated with protection from symptomatic DENV3 illness. We did not find a significant association between DENV3 ADE activity at illness onset and the development of DHF compared with less severe symptomatic illness. The results of this study should encourage rethinking or refinement of the current ADE pathogenesis model for infant DHF and stimulate new directions of research into mechanisms responsible for the development of DHF during infancy.
Trial registration
ClinicalTrials.gov NCT00377754
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, dengue infects 50–100 million people living in tropical and subtropical areas. The four closely related viruses that cause dengue (DENV1–4) are transmitted to people through the bites of female Aedes aegypti mosquitoes, which acquire the viruses by feeding on the blood of an infected person. Many people who become infected with DENV have no symptoms but some develop dengue fever, a severe, flu-like illness that lasts a few days. Other people—about half a million a year—develop a potentially fatal condition called dengue hemorrhagic fever (DHF). In DHF, which can be caused by any of the DENVs, small blood vessels become leaky and friable. This leakiness causes nose and gum bleeds, bruising and, in the worst cases, failure of the circulatory system and death. There is no vaccine to prevent dengue and no specific treatment for dengue fever or DHF. However, with standard medical care—in particular, replacement of lost fluids—most people can survive DHF.
Why Was This Study Done?
DHF is increasingly common, but why do only some people develop DHF after infection with DENV? The widely accepted explanation for the development of DHF is “antibody-dependent enhancement” (ADE) of DENV infection. DHF occurs almost exclusively in two settings; (i) children and adults who become infected with a second DENV serotype after an initial “primary” DENV infection with a different serotype, and (ii) infants with primary DENV infections whose mothers have some DENV immunity. The ADE model suggests that in individuals who develop DHF, although there are some antibodies (proteins made by the immune system to fight infections) against DENV in their blood (in secondary heterologous infections, antibodies left over from the primary infection; in infants with primary infections, antibodies acquired from their mothers before birth), these antibodies cannot “neutralize” the virus. Instead, they bind to it and enhance its uptake by certain immune system cells, thus increasing viral infectivity and triggering an immunological cascade that results in DHF. In this prospective, nested case-control study, the researchers directly test the ADE model for infant DHF. In a prospective study, a group of people is selected and followed to see if they develop a disease; in a nested case-control study, each case is compared with people in the group who do not develop the disease.
What Did the Researchers Do and Find?
The researchers collected clinical data and blood samples from 4,441 mothers and their babies at up to two pre-illness study visits. They then followed the infants for a year to see which of them developed symptomatic and symptom-free DENV infections. Finally, they used the pre-illness blood samples to estimate the maternally derived anti-DENV antibody-neutralizing and -enhancing capacities in the infants at the time of DENV infection. 60 infants were infected with DENV—mainly DENV3—during the study. All but one infection was a primary infection. The infected infants showed a wide range of disease severity. Infants who had a high DENV3 neutralizing capacity at birth tended to develop symptomatic DENV3 infections later than infants who had a low DENV3 neutralizing capacity at birth. All the infants who developed a symptomatic DENV3 infection had a low estimated DENV3 neutralizing activity at the time of infection, and nearly all had measurable levels of DENV3 ADE activity. Infants who developed DHF did not have significantly higher frequencies or levels of DENV3 ADE activity than DENV3-infected infants with less severe symptoms.
What Do These Findings Mean?
These findings indicate that maternally derived anti-DENV3 antibody initially provides protection against dengue infections. That is, babies born to DENV immune mothers are protected against dengue infections by maternally derived antibodies. Over time, the level of these antibodies declines until eventually the infant becomes susceptible to DENV infections. However, the lack of a significant association between the estimated level of DENV3 ADE activity at illness onset and the development of DHF rather than a less severe illness throws doubt onto (but does not completely rule out) the current ADE pathogenesis model for infant DHF, at least for DENV3 infections. The results of this study, the researchers conclude, should encourage rethinking or refinement of the ADE model for infant DHF and should promote further prospective studies into the development of DHF during infancy.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000171.
TropIKA.net provides review articles, news, opinions, research articles, and reports on dengue (in English)
The US Centers for Disease Control and Prevention provide detailed information about dengue fever and dengue hemorrhagic fever (in English and Spanish)
The World Health Organization provides information on dengue fever and dengue hemorrhagic fever around the world (in several languages)
Links to additional resources about dengue are provided by MedlinePlus (in English and Spanish)
Wikipedia has a page on antibody-dependent enhancement of viral infections (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1000171
PMCID: PMC2762316  PMID: 19859541
13.  Factors Associated with Dengue Shock Syndrome: A Systematic Review and Meta-Analysis 
Background
The pathogenesis of dengue shock syndrome (DSS, grade 3 and 4) is not yet completely understood. Several factors are reportedly associated with DSS, a more severe form of dengue infection that reportedly causes 50 times higher mortality compared to that of dengue patients without DSS. However, the results from these reports remain inconclusive. To better understand the epidemiology, clinical manifestation, and pathogenesis of DSS for development of new therapy, we systematically reviewed and performed a meta-analysis of relevant studies that reported factors in both DSS and dengue hemorrhagic fever (DHF, grade 1 and 2) patients.
Methods and Findings
PubMed, EMBASE, Scopus, Google Scholar, Dengue Bulletin, Cochrane Library, Virtual Health Library, and a manual search of reference lists of articles published before September 2010 were used to retrieve relevant studies. A meta-analysis using fixed- or random-effects models was used to calculate pooled odds ratios (OR) or event rate with corresponding 95% confidence intervals. Assessment of heterogeneity and publication bias, meta-regression analysis, subgroup analysis, sensitivity analysis, and analysis of factor-specific relationships were further performed. There were 198 studies constituting 203 data sets that met our eligibility criteria. Our meta-regression analysis showed a sustained reduction of DSS/dengue hemorrhagic fever (DHF) ratio over a period of 40 years in Southeast Asia, especially in Thailand. The meta-analysis revealed that age, female sex, neurological signs, nausea/vomiting, abdominal pain, gastrointestinal bleeding, hemoconcentration, ascites, pleural effusion, hypoalbuminemia, hypoproteinemia, hepatomegaly, levels of alanine transaminase and aspartate transaminase, thrombocytopenia, prothrombin time, activated partial thromboplastin time, fibrinogen level, primary/secondary infection, and dengue virus serotype-2 were significantly associated with DSS when pooling all original relevant studies.
Conclusions
The results improve our knowledge of the pathogenesis of DSS by identifying the association between the epidemiology, clinical signs, and biomarkers involved in DSS.
Author Summary
Dengue is one of the most common viral diseases transmitted by infected mosquitoes. It may range from asymptomatic or self-limiting dengue fever (DF) to severe dengue characterized by plasma leakage (dengue hemorrhagic fever, DHF) and dengue shock syndrome (DSS). Death from dengue infection occurs mostly in DSS, and the mortality of DSS is reportedly 50 times higher compared to that of dengue patients without DSS. Several factors associated with DSS have been reported in individual studies; however, the associations for some factors are not observed consistently across studies. Therefore, we conducted a systematic review of the literature to clarify this issue. The study showed persons with younger age, female sex, neurological signs, nausea/vomiting, abdominal pain, gastrointestinal bleeding, increased hemoconcentration, ascites, pleural effusion, hypoalbuminemia, hypoproteinemia, hepatomegaly, increased level of ALT or AST, thrombocytopenia, coagulation dysregulation, secondary infection, and infection of dengue virus serotype 2 are more likely to have DSS. This result improves our knowledge of the clinical manifestation and pathogenesis of DSS.
doi:10.1371/journal.pntd.0002412
PMCID: PMC3784477  PMID: 24086778
14.  Temporal Dynamics of the Transcriptional Response to Dengue Virus Infection in Nicaraguan Children 
Dengue is the most prevalent mosquito-borne human illness worldwide. The ability to predict disease severity during the earliest days of the illness is a long-sought, but unachieved goal.
We examined human genome-wide transcript abundance patterns in daily peripheral blood mononuclear cell (PBMC) samples from 41 children hospitalized with dengue virus (DENV) infection in Nicaragua, as well as 8 healthy control subjects. Nine patients had primary dengue fever (DF1), 11 had dengue fever with serologic evidence of prior DENV infection, i.e., secondary dengue fever (DF2), 12 had dengue hemorrhagic fever (DHF), and 9 had dengue shock syndrome (DSS). We identified 2,092 genes for which transcript abundance differed significantly between patients on days 3–6 of fever and healthy subjects (FDR<1%). Prior DENV infection explained the greatest amount of variation in gene expression among patients. The number of differentially expressed genes was greatest on fever day 3 in patients with DF1, while the number in patients with DF2 or DHF/DSS was greatest on day 5. Genes associated with the mitotic cell cycle and B cell differentiation were expressed at higher levels, and genes associated with signal transduction and cell adhesion were expressed at lower levels, in patients versus healthy controls. On fever day 3, a set of interferon-stimulated gene transcripts was less abundant in patients who subsequently developed DSS than in other patient groups (p<0.05, ranksum). Patients who later developed DSS also had higher levels of transcripts on day 3 associated with mitochondrial function (p<0.01, ranksum). These day 3 transcript abundance findings were not evident on subsequent fever days.
In conclusion, we identified differences in the timing and magnitude of human gene transcript abundance changes in DENV patients that were associated with serologic evidence of prior infection and with disease severity. Some of these differential features may predict the outcome of DENV infection.
Author Summary
Infection with dengue virus (DENV) causes dengue fever, the most prevalent mosquito-borne illness of humans worldwide. Tens of millions of cases occur annually; up to 500,000 patients develop additional life-threatening complications, including hemorrhage and shock. The clinical course of the disease evolves rapidly, making it difficult to identify patients at risk for severe disease and suggesting that biological events associated with the development of severe disease may be short-lived. We examined gene expression patterns in the blood of children hospitalized with DENV infection, and found that patients with differences in disease severity and history of previous DENV infection shared a common set of gene expression features, but the timing and magnitude of these features differed. In our study, prior DENV infection explained the greatest amount of variation in gene expression among patients. We discovered features of gene expression on day 3 that were associated with subsequent disease severity—features that were not apparent on subsequent days, emphasizing the importance of looking at temporal patterns of gene expression in acute infection.
doi:10.1371/journal.pntd.0001966
PMCID: PMC3527342  PMID: 23285306
15.  Dengue Deaths in Puerto Rico: Lessons Learned from the 2007 Epidemic 
Background
The incidence and severity of dengue in Latin America has increased substantially in recent decades and data from Puerto Rico suggests an increase in severe cases. Successful clinical management of severe dengue requires early recognition and supportive care.
Methods
Fatal cases were identified among suspected dengue cases reported to two disease surveillance systems and from death certificates. To be included, fatal cases had to have specimen submitted for dengue diagnostic testing including nucleic acid amplification for dengue virus (DENV) in serum or tissue, immunohistochemical testing of tissue, and immunoassay detection of anti-DENV IgM from serum. Medical records from laboratory-positive dengue fatal case-patients were reviewed to identify possible determinants for death.
Results
Among 10,576 reported dengue cases, 40 suspect fatal cases were identified, of which 11 were laboratory-positive, 14 were laboratory-negative, and 15 laboratory-indeterminate. The median age of laboratory-positive case-patients was 26 years (range 5 months to 78 years), including five children aged <15 years; 7 sought medical care at least once prior to hospital admission, 9 were admitted to hospital and 2 died upon arrival. The nine hospitalized case-patients stayed a mean of 15 hours (range: 3–48 hours) in the emergency department (ED) before inpatient admission. Five of the nine case-patients received intravenous methylprednisolone and four received non-isotonic saline while in shock. Eight case-patients died in the hospital; five had their terminal event on the inpatient ward and six died during a weekend. Dengue was listed on the death certificate in only 5 instances.
Conclusions
During a dengue epidemic in an endemic area, none of the 11 laboratory-positive case-patients who died were managed according to current WHO Guidelines. Management issues identified in this case-series included failure to recognize warning signs for severe dengue and shock, prolonged ED stays, and infrequent patient monitoring.
Author Summary
Dengue is a major public health problem in the tropics and subtropics; an estimated 50 million cases occur annually and 40 percent of the world's population lives in areas with dengue virus (DENV) transmission. Dengue has a wide range of clinical presentations from an undifferentiated acute febrile illness, classic dengue fever, to severe dengue (i.e., dengue hemorrhagic fever or dengue shock syndrome). About 5% of patients develop severe dengue, which is more common with second or subsequent infections. No vaccines are available to prevent dengue, and there are no specific antiviral treatments for patients with dengue. However, early recognition of shock and intensive supportive therapy can reduce risk of death from ∼10% to less than 1% among severe dengue cases. Reviewing dengue deaths is one means to identify issues in clinical management. These findings can be used to develop healthcare provider education to minimize dengue morbidity and mortality.
doi:10.1371/journal.pntd.0001614
PMCID: PMC3328431  PMID: 22530072
16.  Dengue fever presenting with acute cerebellitis: a case report 
BMC Research Notes  2014;7:125.
Background
The incidence of dengue fever is on the rise in tropical countries. In Sri Lanka, nearly 45,000 patients were reported in 2012. With the increasing numbers, rare manifestations of dengue are occasionally encountered. We report a patient who presented with bilateral cerebellar signs as the presenting feature of dengue.
Case presentation
A 45-year-old previously healthy female from the suburbs of Colombo, Sri Lanka presented with an acute febrile illness associated with unsteadiness of gait. Clinical examination revealed a scanning dysarthria and marked horizontal nystagmus with bilateral dysmetria, dysdiadokokinesia and incordination more prominent on the right. Her gait was wide-based and ataxic with a tendency to fall to the right more than to the left. Dengue nonstructural protein antigen 1 test and IgM antibody testing both became positive indicating acute dengue infection. She recovered from the febrile episode within 9 days since the onset of fever but cerebellar symptoms outlasted the fever by one week. The magnetic resonance imaging of brain was normal and cerebellar signs resolved spontaneously by day 17 of the illness.
Conclusions
Cerebellar syndrome in association with dengue fever has been reported in only four instances and our patient is the first reported case of dengue fever presenting with cerebellitis as the first manifestation of disease. This case report is intended to highlight the occurrence of acute cerebellitis as a presenting syndrome of the expanding list of unusual neurological manifestations of dengue infection.
doi:10.1186/1756-0500-7-125
PMCID: PMC3973998  PMID: 24598036
17.  Prediction of Dengue Disease Severity among Pediatric Thai Patients Using Early Clinical Laboratory Indicators 
Background
Dengue virus is endemic in tropical and sub-tropical resource-poor countries. Dengue illness can range from a nonspecific febrile illness to a severe disease, Dengue Shock Syndrome (DSS), in which patients develop circulatory failure. Earlier diagnosis of severe dengue illnesses would have a substantial impact on the allocation of health resources in endemic countries.
Methods and Findings
We compared clinical laboratory findings collected within 72 hours of fever onset from a prospective cohort children presenting to one of two hospitals (one urban and one rural) in Thailand. Classification and regression tree analysis was used to develop diagnostic algorithms using different categories of dengue disease severity to distinguish between patients at elevated risk of developing a severe dengue illness and those at low risk. A diagnostic algorithm using WBC count, percent monocytes, platelet count, and hematocrit achieved 97% sensitivity to identify patients who went on to develop DSS while correctly excluding 48% of non-severe cases. Addition of an indicator of severe plasma leakage to the WHO definition led to 99% sensitivity using WBC count, percent neutrophils, AST, platelet count, and age.
Conclusions
This study identified two easily applicable diagnostic algorithms using early clinical indicators obtained within the first 72 hours of illness onset. The algorithms have high sensitivity to distinguish patients at elevated risk of developing severe dengue illness from patients at low risk, which included patients with mild dengue and other non-dengue febrile illnesses. Although these algorithms need to be validated in other populations, this study highlights the potential usefulness of specific clinical indicators early in illness.
Author Summary
Patients with severe dengue illness typically develop complications in the later stages of illness, making early clinical management of all patients with suspected dengue infection difficult. An early prediction tool to identify which patients will have a severe dengue illness will improve the utilization of limited hospital resources in dengue endemic regions. We performed classification and regression tree (CART) analysis to establish predictive algorithms of severe dengue illness. Using a Thai hospital pediatric cohort of patients presenting within the first 72 hours of a suspected dengue illness, we developed diagnostic decision algorithms using simple clinical laboratory data obtained on the day of presentation. These algorithms correctly classified near 100% of patients who developed a severe dengue illness while excluding upwards of 50% of patients with mild dengue or other febrile illnesses. Our algorithms utilized white blood cell counts, percent white blood cell differentials, platelet counts, elevated aspartate aminotransferase, hematocrit, and age. If these algorithms can be validated in other regions and age groups, they will help in the clinical management of patients with suspected dengue illness who present within the first three days of fever onset.
doi:10.1371/journal.pntd.0000769
PMCID: PMC2914746  PMID: 20689812
18.  Acute appendicitis complicated by mass formation occurring simultaneously with serologically proven dengue fever: a case report 
Introduction
Acute abdomen and acute appendicitis are unusual clinical presentations that occur in dengue infection–caused illness. Lymphoid hyperplasia and mesenteric adenitis are possible explanations, although vasculitis in the pathology of dengue infection has not been reported. Authors of previous case reports have described mimicking of acute appendicitis discovered upon surgical treatment. Dengue virus has not been proven to cause acute appendicitis.
Case presentation
We report a case of an 8-year-old Sinhalese boy who developed acute appendicitis during the acute phase of serologically confirmed dengue fever. Although abdominal pain, vomiting and right-sided tenderness were present at the time of admission, a diagnosis of acute appendicitis was considered only 18 hours later, when abdominal guarding and a well-defined mass in the right iliac fossa were detected clinically and ultrasonographically. Conservative management with intravenous antibiotics was successful.
Conclusion
In areas where dengue is endemic, awareness of dengue viral infection as a non-surgical cause of acute abdomen, as well as its ability to mimic acute appendicitis, is important because unnecessary surgery-related morbidity can be decreased. However, delaying or missing the diagnosis of acute appendicitis can result in serious complications. This message is particularly relevant to clinicians, especially pediatricians and surgeons, who encounter large numbers of patients during dengue epidemics and run the risk of missing the diagnosis of acute appendicitis. Likewise, delaying or missing the diagnosis of dengue hemorrhagic fever can lead to dengue shock syndrome and even death. This case highlights the need for careful evaluation of each patient who presents with acute abdomen and dengue infection.
doi:10.1186/1752-1947-8-116
PMCID: PMC4234973  PMID: 24708584
Acute appendicitis; Dengue fever
19.  Immature Dengue Virus: A Veiled Pathogen? 
PLoS Pathogens  2010;6(1):e1000718.
Cells infected with dengue virus release a high proportion of immature prM-containing virions. In accordance, substantial levels of prM antibodies are found in sera of infected humans. Furthermore, it has been recently described that the rates of prM antibody responses are significantly higher in patients with secondary infection compared to those with primary infection. This suggests that immature dengue virus may play a role in disease pathogenesis. Interestingly, however, numerous functional studies have revealed that immature particles lack the ability to infect cells. In this report, we show that fully immature dengue particles become highly infectious upon interaction with prM antibodies. We demonstrate that prM antibodies facilitate efficient binding and cell entry of immature particles into Fc-receptor-expressing cells. In addition, enzymatic activity of furin is critical to render the internalized immature virus infectious. Together, these data suggest that during a secondary infection or primary infection of infants born to dengue-immune mothers, immature particles have the potential to be highly infectious and hence may contribute to the development of severe disease.
Author Summary
Dengue virus represents a major emerging arboviral pathogen circulating in the (sub)tropical regions of the world, putting 2.5 billion people at risk of infection. Each of the four circulating serotypes can cause disease ranging from febrile illness to devastating manifestations including dengue hemorrhagic fever and dengue shock syndrome. Severe illness is observed in individuals experiencing a re-infection with a heterologous dengue virus serotype and in infants born to dengue-immune mothers, presumably due to antibody-dependent enhancement of infection. Interestingly, it has been recently reported that patients experiencing a secondary infection have elevated levels of antibodies directed against the prM protein of immature dengue virus particles. Although it is known that cells infected with dengue virus release substantial amounts of prM-containing virions, numerous functional studies have demonstrated that immature particles lack the ability to infect cells. Herein, we show that essentially non-infectious fully immature dengue virions become virtually as infectious as wild type virus particles in the presence of prM antibodies. Anti-prM antibodies facilitate efficient binding and entry of immature dengue virus into cells carrying Fc-receptors. Furthermore, furin activity in target cells is critical for triggering infectivity of immature virus. These data indicate that immature dengue virus has the potential to be highly infectious and hence may contribute to disease pathogenesis.
doi:10.1371/journal.ppat.1000718
PMCID: PMC2798752  PMID: 20062797
20.  Role of Humoral versus Cellular Responses Induced by a Protective Dengue Vaccine Candidate 
PLoS Pathogens  2013;9(10):e1003723.
With 2.5 billion people at risk, dengue is a major emerging disease threat and an escalating public health problem worldwide. Dengue virus causes disease ranging from a self-limiting febrile illness (dengue fever) to the potentially fatal dengue hemorrhagic fever/dengue shock syndrome. Severe dengue disease is associated with sub-protective levels of antibody, which exacerbate disease upon re-infection. A dengue vaccine should generate protective immunity without increasing severity of disease. To date, the determinants of vaccine-mediated protection against dengue remain unclear, and additional correlates of protection are urgently needed. Here, mice were immunized with viral replicon particles expressing the dengue envelope protein ectodomain to assess the relative contribution of humoral versus cellular immunity to protection. Vaccination with viral replicon particles provided robust protection against dengue challenge. Vaccine-induced humoral responses had the potential to either protect from or exacerbate dengue disease upon challenge, whereas cellular immune responses were beneficial. This study explores the immunological basis of protection induced by a dengue vaccine and suggests that a safe and efficient vaccine against dengue should trigger both arms of the immune system.
Author Summary
Dengue virus is an escalating public health threat for over 2.5 billion people worldwide. The disease caused by dengue virus ranges from mild (dengue fever) to lethal (dengue hemorrhagic fever, dengue shock syndrome). To date, there is no cure or vaccine for dengue. One of the challenges to developing a safe and efficient dengue vaccine is that antibodies, usually induced by vaccines to protect the host from re-infection, can increase the severity of dengue disease if they are not present in sufficient amounts to neutralize the virus. An efficient vaccine is urgently needed to slow down the progression of dengue disease, but little is known about the way the immune system protects the body against dengue re-infection. Using a protective vaccine candidate for dengue, the present study evaluates in mice the relative contribution of T cells and antibodies to protection against dengue. We show that the antibody component of an immune response that is overall protective had the ability, when isolated from the other components of the immune system, to either decrease or increase viral burden, whereas T cells reduced viral burden in all situations tested. Our results suggest that vaccine development efforts should focus on approaches that induce both T cell and antibody responses against dengue virus.
doi:10.1371/journal.ppat.1003723
PMCID: PMC3814346  PMID: 24204271
21.  Gene Expression Patterns of Dengue Virus-Infected Children from Nicaragua Reveal a Distinct Signature of Increased Metabolism 
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.
Author Summary
Dengue is a widespread viral disease for which over 3 billion people are at risk. There are no drug treatments or vaccines available for this disease. It is also difficult for physicians to predict which patients are at highest risk for the severe manifestations known as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). We used genome-wide transcriptional profiling analysis to study peripheral blood responses to dengue among patients from Nicaragua. We found that patients with severe manifestations involving shock had very different transcriptional profiles from dengue patients with mild and moderate illness. We then compared our results with other microarray experiments on dengue patients available from public databases and confirmed that dengue is often associated with large changes to the metabolic processes within cells. This approach could identify prognostic markers for severe dengue as well as provide a better understanding of the pathophysiology associated with different grades of disease severity.
doi:10.1371/journal.pntd.0000710
PMCID: PMC2886038  PMID: 20559541
22.  Evaluation of the Diagnostic Accuracy of a New Dengue IgA Capture Assay (Platelia Dengue IgA Capture, Bio-Rad) for Dengue Infection Detection 
PLoS Neglected Tropical Diseases  2015;9(3):e0003596.
Considering the short lifetime of IgA antibodies in serum and the key advantages of antibody detection ELISAs in terms of sensitivity and specificity, Bio-Rad has just developed a new ELISA test based on the detection of specific anti-dengue IgA. This study has been carried out to assess the performance of this Platelia Dengue IgA Capture assay for dengue infection detection. A total of 184 well-characterized samples provided by the French Guiana NRC sera collection (Laboratory of Virology, Institut Pasteur in French Guiana) were selected among samples collected between 2002 and 2013 from patients exhibiting a dengue-like syndrome. A first group included 134 sera from confirmed dengue-infected patients, and a second included 50 sera from non-dengue infected patients, all collected between day 3 and day 15 after the onset of fever. Dengue infection diagnoses were all confirmed using reference assays by direct virological identification using RT-PCR or virus culture on acute sera samples or on paired acute-phase sera samples of selected convalescent sera. This study revealed: i) a good overall sensitivity and specificity of the IgA index test, i.e., 93% and 88% respectively, indicating its good correlation to acute dengue diagnosis; and ii) a good concordance with the Panbio IgM capture ELISA. Because of the shorter persistence of dengue virus-specific IgA than IgM, these results underlined the relevance of this new test, which could significantly improve dengue diagnosis accuracy, especially in countries where dengue virus is (hyper-) endemic. It would allow for additional refinement of dengue diagnostic strategy.
Author Summary
Dengue disease has become a major global public health concern, but an ideal diagnostic test that permits early and rapid diagnosis is not yet available. Improving diagnostic performance in this area is a major challenge and necessitates the development and evaluation of new efficient, accurate methods. According to the kinetics of dengue infection in serum, virus isolation and nucleic acid or antigen detection are the most specific diagnostic methods during the early acute stage of disease; serology is often used for diagnosis later in the course of infection. In order to provide an earlier and reliable dating of the dengue infection, few recent studies showed that the detection of specific IgA in the serum is a useful diagnostic parameter. Exploring that new approach, this study was carried out to assess the performance of a Platelia Dengue IgA Capture assay for dengue infection detection, newly developed by Bio-Rad, using 184 well-characterized samples provided by the French Guiana NRC sera collection of the Institut Pasteur in French Guiana. This study revealed good overall performances of this test, constituting promising assistance in dengue diagnosis, especially in hyper-endemic countries.
doi:10.1371/journal.pntd.0003596
PMCID: PMC4372552  PMID: 25803718
23.  Clinical Manifestations and Trend of Dengue Cases Admitted in a Tertiary Care Hospital, Udupi District, Karnataka 
Background:
India is one of the seven identified countries in the South-East Asia region regularly reporting dengue fever (DF)/dengue hemorrhagic fever (DHF) outbreaks and may soon transform into a major niche for dengue infection in the future with more and more new areas being struck by dengue epidemics
Objective:
To study the clinical manifestations, trend and outcome of all confirmed dengue cases admitted in a tertiary care hospital.
Study Design:
Record-based study conducted in a coastal district of Karnataka. Required data from all the laboratory confirmed cases from 2002 to 2008 were collected from Medical Records Department (MRD) and analyzed using SPSS 13.5 version.
Results:
Study included 466 patients. Majority were males, 301(64.6%) and in the and in the age group of 15-44 years, 267 (57.5%). Maximum number of cases were seen in 2007, 219 (47%) and in the month of September, 89 (19.1%). The most common presentation was fever 462 (99.1%), followed by myalgia 301 (64.6%), vomiting 222 (47.6%), headache 222 (47.6%) and abdominal pain 175 (37.6%). The most common hemorrhagic manifestation was petechiae 84 (67.2%). 391 (83.9%) cases presented with dengue fever, 41 (8.8%) dengue hemorrhagic fever, and 34 (7.3%) with dengue shock syndrome. Out of 66 (14.1%) patients who developed clinical complications, 22 (33.3%) had ARDS and 20 (30.3%) had pleural effusion. Deaths reported were 11(2.4%).
Conclusion:
Community awareness, early diagnosis and management and vector control measures need to be strengthened, during peri-monsoon period, in order to curb the increasing number of dengue cases.
doi:10.4103/0970-0218.69253
PMCID: PMC2963875  PMID: 21031102
Dengue; dengue hemorrhagic fever; dengue shock syndrome
24.  Challenges in Dengue Fever in the Elderly: Atypical Presentation and Risk of Severe Dengue and Hospita-Acquired Infection 
Background/methods
To better understand dengue fever in the elderly, we compared clinical features, World Health Organization (WHO) dengue classification and outcomes between adult (<60) and elderly (≥60) dengue patients. We explored the impact of co-morbidity and hospital-acquired infection (HAI) on clinical outcomes in the elderly. All patients managed at the Communicable Disease Centre, Singapore, between 2005 and 2008 with positive dengue polymerase chain reaction (PCR) or who fulfilled WHO 1997 or 2009 probable dengue criteria with positive dengue IgM were included.
Results
Of the 6989 cases, 295 (4.4%) were elderly. PCR was positive in 29%. The elderly suffered more severe disease with more dengue haemorrhagic fever (DHF) (29.2% vs. 21.4%) and severe dengue (SD) (20.3% vs. 14.6%) (p<0.05). Classic dengue symptoms were more common in the adult group. The elderly were less likely to fulfill WHO 1997 (93.6% vs. 96.4%) (p = 0.014), but not WHO 2009 probable dengue (75.3% vs. 71.5%). Time to dengue diagnosis was similar. There was no significant difference in the frequency of warning signs between the two groups, but the elderly were more likely to have hepatomegaly (p = 0.006) and malaise/lethargy (p = 0.033) while the adults had significantly more mucosal bleeding (p<0.001). Intensive care admission occurred in 15 and death in three, with no age difference. Notably, the elderly stayed in hospital longer (median 5 vs. 4 days), and suffered more pneumonia (3.8% vs. 0.7%) and urinary infection (1.9% vs. 0.3%) (p = 0.003). Predictors of excess length of stay were age (adjusted odds ratio [aOR] 2.01, 95% confidence interval [CI] 1.37–2.88), critical illness (aOR 5.13, 95%CI 2.59–9.75), HAI (aOR 12.06, 95%CI 7.39–19.9), Charlson score (aOR 6.9, 95%CI 2.02–22.56) and severe dengue (DHF/dengue shock syndrome/SD) (aOR 2.24, 95%CI 1.83–2.74).
Conclusion
Elderly dengue patients present atypically and are at higher risk of DHF, SD and HAI. Aside from dengue severity, age, co-morbidity and HAI were associated with longer hospital stay.
Author Summary
Dengue is a neglected tropical disease that is increasingly affecting elderly patients; however, there is a paucity of data on clinical presentation and outcomes in this group. The limited data suggests that elderly dengue patients have the highest case-fatality rate but the pathogenesis of mortality in elderly dengue patients remains unclear. To better understand dengue fever in the elderly we compared clinical features, WHO dengue classification and outcomes between adult (<60) and elderly (≥60) dengue patients and explored the impact of co-morbidity and HAI on clinical outcomes in the elderly. We found that diagnosis in the elderly may be challenging due to atypical presentation. Elderly patients have worse outcomes compared with their younger counterparts with increased rates of DHF and SD. Elderly patients have higher rates of HAI placing them at risk of infection-related mortality. Aside from dengue severity, age, co-morbidity and HAI were associated with longer hospital stay. This will place further burden on already stretched hospital systems.
doi:10.1371/journal.pntd.0002777
PMCID: PMC3974675  PMID: 24699282
25.  Utilities and Limitations of the World Health Organization 2009 Warning Signs for Adult Dengue Severity 
Background
In 2009, the World Health Organization (WHO) proposed seven warning signs (WS) as criteria for hospitalization and predictors of severe dengue (SD). We assessed their performance for predicting dengue hemorrhagic fever (DHF) and SD in adult dengue.
Method
DHF, WS and SD were defined according to the WHO 1997 and 2009 dengue guidelines. We analyzed the prevalence, sensitivity (Sn), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of WS before DHF and SD onset.
Results
Of 1507 cases, median age was 35 years (5th–95th percentile, 17–60), illness duration on admission 4 days (5th–95th percentile, 2–6) and length of hospitalization 5 days (5th–95th percentile, 3–7). DHF occurred in 298 (19.5%) and SD in 248 (16.5%). Of these, WS occurred before DHF in 124 and SD in 65 at median of two days before DHF or SD. Three commonest warning signs were lethargy, abdominal pain/tenderness and mucosal bleeding. No single WS alone or combined had Sn >64% in predicting severe disease. Specificity was >90% for both DHF and SD with persistent vomiting, hepatomegaly, hematocrit rise and rapid platelet drop, clinical fluid accumulation, and any 3 or 4 WS. Any one of seven WS had 96% Sn but only 18% Sp for SD.
Conclusions
No WS was highly sensitive in predicting subsequent DHF or SD in our confirmed adult dengue cohort. Persistent vomiting, hepatomegaly, hematocrit rise and rapid platelet drop, and clinical fluid accumulation, as well as any 3 or 4 WS were highly specific for DHF or SD.
Author Summary
Dengue is a mosquito-borne infection with significant public health burden in tropical and subtropical regions. Clinical presentations may vary from self-limiting fever to severe dengue including death. The World Health Organization 2009 dengue guidelines classified dengue into dengue with and without warning signs, and severe dengue. In our adult dengue cohort, we found that lethargy, abdominal pain/tenderness, and mucosal bleeding occurred commonly. As predictors of severe dengue, these were not as specific as persistent vomiting, hepatomegaly, hematocrit rise and rapid platelet drop, and clinical fluid accumulation which occurred infrequently. Presence of any one warning sign had high sensitivity, but low specificity for severe dengue. Removal of lethargy from the list increased the specificity of any one warning sign, but sensitivity decreased. Consideration of these findings may avoid over hospitalization of potentially non-severe dengue patients and reduce burden on the healthcare system.
doi:10.1371/journal.pntd.0002023
PMCID: PMC3547865  PMID: 23350013

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