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1.  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
2.  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
3.  The exanthem of dengue fever: Clinical features of two US tourists traveling abroad 
Background
Dengue fever is the most common identifiable cause of acute febrile illness among travelers returning from South America, South Central Asia, Southeast Asia, and the Caribbean. Although the characteristic exanthem of dengue fever occurs in up to 50% of patients, few descriptions of it are found in the dermatology literature, and discussions of how to distinguish the dengue exanthem from other infectious disease entities are rare. Chikungunya fever is an emerging infectious disease now seen in returning US tourists and should be considered in the differential diagnosis of dengue fever in the appropriate patient.
Objective
The purpose of our study was to report two cases of dengue fever among returning US tourists, provide a review of dengue fever, offer an extensive differential diagnosis of dengue fever, and raise awareness among dermatologists of chikungunya fever.
Methods
This study includes clinical findings of two returning travelers, one who traveled to Mexico and the other to Thailand, complemented by a discussion of both dengue fever and its differential diagnosis.
Limitations
Limited to 2 case reports.
Conclusion
Dengue fever should be considered in the differential diagnosis of fever and rash in the returning traveler. Dermatologists should be aware of the distinctive exanthem of dengue fever. Recognition of the dengue fever rash permits a rapid and early diagnosis, which is critical, as dengue fever can progress to life-threatening dengue hemorrhagic fever or dengue shock syndrome.
doi:10.1016/j.jaad.2007.08.042
PMCID: PMC4061973  PMID: 17959270
4.  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
5.  Dengue Incidence in Urban and Rural Cambodia: Results from Population-Based Active Fever Surveillance, 2006–2008 
Background
Dengue vaccines are now in late-stage development, and evaluation and robust estimates of dengue disease burden are needed to facilitate further development and introduction. In Cambodia, the national dengue case-definition only allows reporting of children less than 16 years of age, and little is known about dengue burden in rural areas and among older persons. To estimate the true burden of dengue in the largest province of Cambodia, Kampong Cham, we conducted community-based active dengue fever surveillance among the 0-to-19–year age group in rural villages and urban areas during 2006–2008.
Methods and Findings
Active surveillance for febrile illness was conducted in 32 villages and 10 urban areas by mothers trained to use digital thermometers combined with weekly home visits to identify persons with fever. An investigation team visited families with febrile persons to obtain informed consent for participation in the follow-up study, which included collection of personal data and blood specimens. Dengue-related febrile illness was defined using molecular and serological testing of paired acute and convalescent blood samples. Over the three years of surveillance, 6,121 fever episodes were identified with 736 laboratory-confirmed dengue virus (DENV) infections for incidences of 13.4–57.8/1,000 person-seasons. Average incidence was highest among children less than 7 years of age (41.1/1,000 person-seasons) and lowest among the 16-to-19–year age group (11.3/1,000 person-seasons). The distribution of dengue was highly focal, with incidence rates in villages and urban areas ranging from 1.5–211.5/1,000 person-seasons (median 36.5). During a DENV-3 outbreak in 2007, rural areas were affected more than urban areas (incidence 71 vs. 17/1,000 person-seasons, p<0.001).
Conclusion
The large-scale active surveillance study for dengue fever in Cambodia found a higher disease incidence than reported to the national surveillance system, particularly in preschool children and that disease incidence was high in both rural and urban areas. It also confirmed the previously observed focal nature of dengue virus transmission.
Author Summary
Dengue is a major public health problem in South-East Asia. Several dengue vaccine candidates are now in late-stage development and are being evaluated in clinical trials. Accurate estimates of true dengue disease burden will become an important factor in the public-health decision-making process for endemic countries once safe and effective vaccines become available. However, estimates of the true disease incidence are difficult to make, because national surveillance systems suffer from disease under-recognition and reporting. Dengue is mainly reported among children, and in some countries, such as Cambodia, the national case definition only includes hospitalized children. This study used active, community-based surveillance of febrile illness coupled with laboratory testing for DENV infection to identify cases of dengue fever in rural and urban populations. We found a high burden of dengue in young children and late adolescents in both rural and urban communities at a magnitude greater than previously described. The study also confirmed the previously observed focal nature of dengue virus transmission.
doi:10.1371/journal.pntd.0000903
PMCID: PMC2994922  PMID: 21152061
6.  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
7.  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
8.  Incidence of dengue virus infection among Japanese travellers, 2006 to 2010 
Introduction
Dengue continues to be a global public health concern. In Japan, although dengue cases are currently seen only among travellers returning from endemic areas, the number of reported cases is rising according to the national case-based surveillance system. We evaluated the characteristics of dengue cases imported into Japan and the relationship between the incidence of infection and season of travel to popular destinations.
Methods
Dengue cases reported to the national surveillance system were retrospectively examined. The number of reported cases per number of Japanese travellers to a dengue-endemic country was calculated to estimate the country-specific incidence of imported dengue virus infection. The incidence of dengue infection among Japanese travellers was compared between dengue high season and low season in each country using relative risk (RR) and associated 95% confidence intervals (CI).
Results
Among 540 Japanese residents who were reported as dengue cases from 2006 to 2010, the majority had travelled to Indonesia, India, the Philippines and Thailand. The RR of dengue infection among Japanese travellers during dengue high season versus low season was 4.92 (95% CI: 3.01–8.04) for the Philippines, 2.76 (95% CI: 1.67–4.54) for Thailand and 0.37 (95% CI: 0.15–0.92) for Indonesia.
Discussion
Overall, higher incidence of imported cases appeared to be related to historic dengue high seasons. Travellers planning to visit dengue-endemic countries should be aware of historic dengue seasonality and the current dengue situation.
doi:10.5365/WPSAR.2011.2.3.002
PMCID: PMC3729080  PMID: 23908911
9.  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
10.  Dengue and Other Common Causes of Acute Febrile Illness in Asia: An Active Surveillance Study in Children 
Background
Common causes of acute febrile illness in tropical countries have similar symptoms, which often mimic those of dengue. Accurate clinical diagnosis can be difficult without laboratory confirmation and disease burden is generally under-reported. Accurate, population-based, laboratory-confirmed incidence data on dengue and other causes of acute fever in dengue-endemic Asian countries are needed.
Methods and principal findings
This prospective, multicenter, active fever surveillance, cohort study was conducted in selected centers in Indonesia, Malaysia, Philippines, Thailand and Vietnam to determine the incidence density of acute febrile episodes (≥38°C for ≥2 days) in 1,500 healthy children aged 2–14 years, followed for a mean 237 days. Causes of fever were assessed by testing acute and convalescent sera from febrile participants for dengue, chikungunya, hepatitis A, influenza A, leptospirosis, rickettsia, and Salmonella Typhi. Overall, 289 participants had acute fever, an incidence density of 33.6 per 100 person-years (95% CI: 30.0; 37.8); 57% were IgM-positive for at least one of these diseases. The most common causes of fever by IgM ELISA were chikungunya (in 35.0% of in febrile participants) and S. Typhi (in 29.4%). The overall incidence density of dengue per 100 person-years was 3.4 by nonstructural protein 1 (NS1) antigen positivity (95% CI: 2.4; 4.8) and 7.3 (95% CI: 5.7; 9.2) by serology. Dengue was diagnosed in 11.4% (95% CI: 8.0; 15.7) and 23.9% (95% CI: 19.1; 29.2) of febrile participants by NS1 positivity and serology, respectively. Of the febrile episodes not clinically diagnosed as dengue, 5.3% were dengue-positive by NS1 antigen testing and 16.0% were dengue-positive by serology.
Conclusions
During the study period, the most common identified causes of pediatric acute febrile illness among the seven tested for were chikungunya, S. Typhi and dengue. Not all dengue cases were clinically diagnosed; laboratory confirmation is essential to refine disease burden estimates.
Author Summary
Acute febrile episodes are common in children living in tropical countries. Diagnosis can be challenging because symptoms of the more common infectious causes are similar and often mimic those of dengue. Asia Pacific has over 70% of the worldwide dengue disease burden, although dengue incidence is generally underestimated because most surveillance systems are passive or based on clinical diagnosis without laboratory confirmation. Understanding the local etiology of febrile illness and the incidence of dengue is important when planning large-scale vaccine trials. This prospective, active fever surveillance, cohort study was carried out in children in five dengue-endemic Asian countries – Indonesia, Malaysia, Philippines, Thailand and Vietnam – during 2010–2011. Acute febrile episodes occurred in 289 (19.3%) of the cohort of 1,500 children. Among the diseases for which antibodies were tested using commercial kits, the top three causes of acute fever were chikungunya, Salmonella Typhi and dengue, followed by influenza A, rickettsia and hepatitis A. Dengue was confirmed in 11.4% of the febrile children by viral protein detection and in 23.9% by serology. Clinical diagnosis was not sufficient to detect all dengue cases. These findings are of relevance to those planning clinical studies of vaccines against these infectious agents in Southeast Asia.
doi:10.1371/journal.pntd.0002331
PMCID: PMC3723539  PMID: 23936565
11.  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
12.  Clinical and Virological Study of Dengue Cases and the Members of Their Households: The Multinational DENFRAME Project 
Background
Dengue has emerged as the most important vector-borne viral disease in tropical areas. Evaluations of the burden and severity of dengue disease have been hindered by the frequent lack of laboratory confirmation and strong selection bias toward more severe cases.
Methodology
A multinational, prospective clinical study was carried out in South-East Asia (SEA) and Latin America (LA), to ascertain the proportion of inapparent dengue infections in households of febrile dengue cases, and to compare clinical data and biological markers from subjects with various dengue disease patterns. Dengue infection was laboratory-confirmed during the acute phase, by virus isolation and detection of the genome. The four participating reference laboratories used standardized methods.
Principal Findings
Among 215 febrile dengue subjects—114 in SEA and 101 in LA—28 (13.0%) were diagnosed with severe dengue (from SEA only) using the WHO definition. Household investigations were carried out for 177 febrile subjects. Among household members at the time of the first home visit, 39 acute dengue infections were detected of which 29 were inapparent. A further 62 dengue cases were classified at early convalescent phase. Therefore, 101 dengue infections were found among the 408 household members. Adding these together with the 177 Dengue Index Cases, the overall proportion of dengue infections among the study participants was estimated at 47.5% (278/585; 95% CI 43.5–51.6). Lymphocyte counts and detection of the NS1 antigen differed significantly between inapparent and symptomatic dengue subjects; among inapparent cases lymphocyte counts were normal and only 20% were positive for NS1 antigen. Primary dengue infection and a specific dengue virus serotype were not associated with symptomatic dengue infection.
Conclusion
Household investigation demonstrated a high proportion of household members positive for dengue infection, including a number of inapparent cases, the frequency of which was higher in SEA than in LA.
Author Summary
Dengue is the most important mosquito-borne viral disease in humans. This disease is now endemic in more than 100 countries and threatens more than 2.5 billion people living in tropical countries. It currently affects about 50 to 100 million people each year. It causes a wide range of symptoms, from an inapparent to mild dengue fever, to severe forms, including dengue hemorrhagic fever. Currently no specific vaccine or antiviral drugs are available. We carried out a prospective clinical study in South-East Asia and Latin America, of virologically confirmed dengue-infected patients attending the hospital, and members of their households. Among 215 febrile dengue subjects, 177 agreed to household investigation. Based on our data, we estimated the proportion of dengue-infected household members to be about 45%. At the time of the home visit, almost three quarters of (29/39) presented an inapparent dengue infection. The proportion of inapparent dengue infection was higher in South-East Asia than in Latin America. These findings confirm the complexity of dengue disease in humans and the need to strengthen multidisciplinary research efforts to improve our understanding of virus transmission and host responses to dengue virus in various human populations.
doi:10.1371/journal.pntd.0001482
PMCID: PMC3265457  PMID: 22292098
13.  Clinical and laboratory features that discriminate dengue from other febrile illnesses: a diagnostic accuracy study in Rio de Janeiro, Brazil 
Background
Dengue is an acute febrile illness caused by an arbovirus that is endemic in more than 100 countries. Early diagnosis and adequate management are critical to reduce mortality. This study aims to identify clinical and hematological features that could be useful to discriminate dengue from other febrile illnesses (OFI) up to the third day of disease.
Methods
We conducted a sectional diagnostic study with patients aged 12 years or older who reported fever lasting up to three days, without any evident focus of infection, attending an outpatient clinic in the city of Rio de Janeiro, Brazil, between the years 2005 and 2008. Logistic regression analysis was used to identify symptoms, physical signs, and hematological features valid for dengue diagnosis. Receiver-operating characteristic (ROC) curve analyses were used to define the best cut-off and to compare the accuracy of generated models with the World Health Organization (WHO) criteria for probable dengue.
Results
Based on serological tests and virus genome detection by polymerase chain reaction (PCR), 69 patients were classified as dengue and 73 as non-dengue. Among clinical features, conjunctival redness and history of rash were independent predictors of dengue infection. A model including clinical and laboratory features (conjunctival redness and leukocyte counts) achieved a sensitivity of 81% and specificity of 71% and showed greater accuracy than the WHO criteria for probable dengue.
Conclusions
We constructed a predictive model for early dengue diagnosis that was moderately accurate and performed better than the current WHO criteria for suspected dengue. Validation of this model in larger samples and in other sites should be attempted before it can be applied in endemic areas.
doi:10.1186/1471-2334-13-77
PMCID: PMC3574824  PMID: 23394216
Dengue/diagnosis; Signs and symptoms; Sensitivity and specificity; Fever/diagnosis
14.  Dengue infections in travellers 
Dengue has been designated a major international public health problem by the World Health Organization (WHO). It is endemic in most tropical and sub-tropical countries, which are also popular tourist destinations. Travellers are not only at significant risk of acquiring dengue but they also contribute to its spread to non-endemic regions. Furthermore, they may serve as sentinels to alert the international community to epidemics in dengue-endemic regions. GeoSentinel, a global surveillance network, monitors all travel-related illnesses and estimates that dengue accounts for 2% of all illness in travellers returning from dengue-endemic regions. In fact, in travellers returning from South-east Asia, dengue is now a more frequent cause of febrile illness than malaria. Dengue-infected travellers returning home to countries where the vector exists can place the local population at risk of further spread of the disease with subsequent autochthonous cycles of infection. The true incidence of dengue amongst travellers may be underestimated because of variability in reporting requirements in different countries and under-diagnosis owing to the non-specific clinical presentation of the disease. Risk factors for acquiring dengue include duration of stay, season of travel and epidemic activity at the destination. Any pre-travel advice on the risks of developing dengue infections should consider these factors.
doi:10.1179/2046904712Z.00000000050
PMCID: PMC3381444  PMID: 22668447
Dengue; Travellers; GeoSentinel; Autochthonous spread; Sentinel surveillance
15.  Yellow Fever in Africa: Estimating the Burden of Disease and Impact of Mass Vaccination from Outbreak and Serological Data 
PLoS Medicine  2014;11(5):e1001638.
Neil Ferguson and colleagues estimate the disease burden of yellow fever in Africa, as well as the impact of mass vaccination campaigns.
Please see later in the article for the Editors' Summary
Background
Yellow fever is a vector-borne disease affecting humans and non-human primates in tropical areas of Africa and South America. While eradication is not feasible due to the wildlife reservoir, large scale vaccination activities in Africa during the 1940s to 1960s reduced yellow fever incidence for several decades. However, after a period of low vaccination coverage, yellow fever has resurged in the continent. Since 2006 there has been substantial funding for large preventive mass vaccination campaigns in the most affected countries in Africa to curb the rising burden of disease and control future outbreaks. Contemporary estimates of the yellow fever disease burden are lacking, and the present study aimed to update the previous estimates on the basis of more recent yellow fever occurrence data and improved estimation methods.
Methods and Findings
Generalised linear regression models were fitted to a dataset of the locations of yellow fever outbreaks within the last 25 years to estimate the probability of outbreak reports across the endemic zone. Environmental variables and indicators for the surveillance quality in the affected countries were used as covariates. By comparing probabilities of outbreak reports estimated in the regression with the force of infection estimated for a limited set of locations for which serological surveys were available, the detection probability per case and the force of infection were estimated across the endemic zone.
The yellow fever burden in Africa was estimated for the year 2013 as 130,000 (95% CI 51,000–380,000) cases with fever and jaundice or haemorrhage including 78,000 (95% CI 19,000–180,000) deaths, taking into account the current level of vaccination coverage. The impact of the recent mass vaccination campaigns was assessed by evaluating the difference between the estimates obtained for the current vaccination coverage and for a hypothetical scenario excluding these vaccination campaigns. Vaccination campaigns were estimated to have reduced the number of cases and deaths by 27% (95% CI 22%–31%) across the region, achieving up to an 82% reduction in countries targeted by these campaigns. A limitation of our study is the high level of uncertainty in our estimates arising from the sparseness of data available from both surveillance and serological surveys.
Conclusions
With the estimation method presented here, spatial estimates of transmission intensity can be combined with vaccination coverage levels to evaluate the impact of past or proposed vaccination campaigns, thereby helping to allocate resources efficiently for yellow fever control. This method has been used by the Global Alliance for Vaccines and Immunization (GAVI Alliance) to estimate the potential impact of future vaccination campaigns.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Yellow fever is a flavivirus infection that is transmitted to people and to non-human primates through the bites of infected mosquitoes. This serious viral disease affects people living in and visiting tropical regions of Africa and Central and South America. In rural areas next to forests, the virus typically causes sporadic cases or even small-scale epidemics (outbreaks) but, if it is introduced into urban areas, it can cause large explosive epidemics that are hard to control. Although many people who contract yellow fever do not develop any symptoms, some have mild flu-like symptoms, and others develop a high fever with jaundice (yellowing of the skin and eyes) or hemorrhaging (bleeding) from the mouth, nose, eyes, or stomach. Half of patients who develop these severe symptoms die. Because of this wide spectrum of symptoms, which overlap with those of other tropical diseases, it is hard to diagnose yellow fever from symptoms alone. However, serological tests that detect antibodies to the virus in the blood can help in diagnosis. There is no specific antiviral treatment for yellow fever but its symptoms can be treated.
Why Was This Study Done?
Eradication of yellow fever is not feasible because of the wildlife reservoir for the virus but there is a safe, affordable, and highly effective vaccine against the disease. Large-scale vaccination efforts during the 1940s, 1950s, and 1960s reduced the yellow fever burden for several decades but, after a period of low vaccination coverage, the number of cases rebounded. In 2005, the Yellow Fever Initiative—a collaboration between the World Health Organization (WHO) and the United Nations Children Fund supported by the Global Alliance for Vaccines and Immunization (GAVI Alliance)—was launched to create a vaccine stockpile for use in epidemics and to implement preventive mass vaccination campaigns in the 12 most affected countries in West Africa. Campaigns have now been implemented in all these countries except Nigeria. However, without an estimate of the current yellow fever burden, it is hard to determine the impact of these campaigns. Here, the researchers use recent yellow fever occurrence data, serological survey data, and improved estimation methods to update estimates of the yellow fever burden and to determine the impact of mass vaccination on this burden.
What Did the Researchers Do and Find?
The researchers developed a generalized linear statistical model and used data on the locations where yellow fever was reported between 1987 and 2011 in Africa, force of infection estimates for a limited set of locations where serological surveys were available (the force of infection is the rate at which susceptible individuals acquire a disease), data on vaccination coverage, and demographic and environmental data for their calculations. They estimate that about 130,000 yellow fever cases with fever and jaundice or hemorrhage occurred in Africa in 2013 and that about 78,000 people died from the disease. By evaluating the difference between this estimate, which takes into account the current vaccination coverage, and a hypothetical scenario that excluded the mass vaccination campaigns, the researchers estimate that these campaigns have reduced the burden of disease by 27% across Africa and by up to 82% in the countries targeted by the campaigns (an overall reduction of 57% in the 12 targeted countries).
What Do These Findings Mean?
These findings provide a contemporary estimate of the burden of yellow fever in Africa. This estimate is broadly similar to the historic estimate of 200,000 cases and 30,000 deaths annually, which was based on serological survey data obtained from children in Nigeria between 1945 and 1971. Notably, both disease burden estimates are several hundred-fold higher than the average number of yellow fever cases reported annually to WHO, which reflects the difficulties associated with the diagnosis of yellow fever. Importantly, these findings also provide an estimate of the impact of recent mass vaccination campaigns. All these findings have a high level of uncertainty, however, because of the lack of data from both surveillance and serological surveys. Other assumptions incorporated in the researchers' model may also affect the accuracy of these findings. Nevertheless, the framework for burden estimation developed here provides essential new information about the yellow fever burden and the impact of vaccination campaigns and should help the partners of the Yellow Fever Initiative estimate the potential impact of future vaccination campaigns and ensure the efficient allocation of resources for yellow fever control.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001638.
The World Health Organization provides detailed information about yellow fever (in several languages), including photo stories about vaccination campaigns in the Sudan and Mali; it also provides information about the Yellow Fever Initiative (in English and French)
The GAVI Alliance website includes detailed of its support for yellow fever vaccination
The US Centers for Disease Control and Prevention provides information about yellow fever for the public, travelers, and health care providers
The UK National Health Service Choices website also has information about yellow fever
Wikipedia has a page on yellow fever that includes information about the history of the disease (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001638
PMCID: PMC4011853  PMID: 24800812
16.  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
17.  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
18.  The Role of Imported Cases and Favorable Meteorological Conditions in the Onset of Dengue Epidemics 
Background
Travelers who acquire dengue infection are often routes for virus transmission to other regions. Nevertheless, the interplay between infected travelers, climate, vectors, and indigenous dengue incidence remains unclear. The role of foreign-origin cases on local dengue epidemics thus has been largely neglected by research. This study investigated the effect of both imported dengue and local meteorological factors on the occurrence of indigenous dengue in Taiwan.
Methods and Principal Findings
Using logistic and Poisson regression models, we analyzed bi-weekly, laboratory-confirmed dengue cases at their onset dates of illness from 1998 to 2007 to identify correlations between indigenous dengue and imported dengue cases (in the context of local meteorological factors) across different time lags. Our results revealed that the occurrence of indigenous dengue was significantly correlated with temporally-lagged cases of imported dengue (2–14 weeks), higher temperatures (6–14 weeks), and lower relative humidity (6–20 weeks). In addition, imported and indigenous dengue cases had a significant quantitative relationship in the onset of local epidemics. However, this relationship became less significant once indigenous epidemics progressed past the initial stage.
Conclusions
These findings imply that imported dengue cases are able to initiate indigenous epidemics when appropriate weather conditions are present. Early detection and case management of imported cases through rapid diagnosis may avert large-scale epidemics of dengue/dengue hemorrhagic fever. The deployment of an early-warning surveillance system, with the capacity to integrate meteorological data, will be an invaluable tool for successful prevention and control of dengue, particularly in non-endemic countries.
Author Summary
Dengue/dengue hemorrhagic fever is the world's most widely spread mosquito-borne arboviral disease and threatens more than two-thirds of the world's population. Cases are mainly distributed in tropical and subtropical areas in accordance with vector habitats for Aedes aegypti and Ae. albopictus. However, the role of imported cases and favorable meteorological conditions has not yet been quantitatively assessed. This study verified the correlation between the occurrence of indigenous dengue and imported cases in the context of weather variables (temperature, rainfall, relative humidity, etc.) for different time lags in southern Taiwan. Our findings imply that imported cases have a role in igniting indigenous outbreaks, in non-endemics areas, when favorable weather conditions are present. This relationship becomes insignificant in the late phase of local dengue epidemics. Therefore, early detection and case management of imported cases through timely surveillance and rapid laboratory-diagnosis may avert large scale epidemics of dengue/dengue hemorrhagic fever. An early-warning surveillance system integrating meteorological data will be an invaluable tool for successful prevention and control of dengue, particularly in non-endemic countries.
doi:10.1371/journal.pntd.0000775
PMCID: PMC2914757  PMID: 20689820
19.  Managing patients with dengue fever during an epidemic: the importance of a hydration tent and of a multidisciplinary approach 
BMC Research Notes  2011;4:335.
Background
Dengue fever is one of the most common tropical diseases worldwide. Early detection of the disease, followed by intravenous fluid therapy in patients with dengue hemorrhagic fever (DHF) or with warning signs of dengue has a major impact on the prognosis. The purpose of this study is to describe the care provided in a hydration tent, including early detection, treatment, and serial follow-up of patients with dengue fever.
Findings
The analysis included all patients treated in the hydration tent from April 8 to May 9, 2008. The tent was set up inside the premises of the 2nd Military Firemen Group, located in Meier, a neighborhood in Rio de Janeiro, Brazil. The case form data were stored in a computerized database for subsequent assessment. Patients were referred to the tent from primary care units and from secondary city and state hospitals. The routine procedure consisted of an initial screening including vital signs (temperature, blood pressure, heart rate, and respiratory rate), tourniquet test and blood sampling for complete blood count. Over a 31-day period, 3,393 case recordings were seen at the hydration tent. The mean was 109 patients per day. A total of 2,102 initial visits and 1,291 return visits were conducted. Of the patients who returned to the hydration tent for reevaluation, 850 returned once, 230 returned twice, 114 returned three times, and 97 returned four times or more. Overall, 93 (5.3%) patients with DHF seen at the tent were transferred to a tertiary hospital. There were no deaths among these patients.
Discussion
As the epidemics were already widespread and there were no technical conditions for routine serology, all cases of suspected dengue fever were treated as such. Implementing hydration tents decrease the number of dengue fever hospitalizations.
doi:10.1186/1756-0500-4-335
PMCID: PMC3180466  PMID: 21902823
20.  Travel and migration associated infectious diseases morbidity in Europe, 2008 
BMC Infectious Diseases  2010;10:330.
Background
Europeans represent the majority of international travellers and clinicians encountering returned patients have an essential role in recognizing, and communicating travel-associated public health risks.
Methods
To investigate the morbidity of travel associated infectious diseases in European travellers, we analysed diagnoses with demographic, clinical and travel-related predictors of disease, in 6957 ill returned travellers who presented in 2008 to EuroTravNet centres with a presumed travel associated condition.
Results
Gastro-intestinal (GI) diseases accounted for 33% of illnesses, followed by febrile systemic illnesses (20%), dermatological conditions (12%) and respiratory illnesses (8%). There were 3 deaths recorded; a sepsis caused by Escherichia coli pyelonephritis, a dengue shock syndrome and a Plasmodium falciparum malaria.
GI conditions included bacterial acute diarrhea (6.9%), as well as giardiasis and amebasis (2.3%). Among febrile systemic illnesses with identified pathogens, malaria (5.4%) accounted for most cases followed by dengue (1.9%) and others including chikungunya, rickettsial diseases, leptospirosis, brucellosis, Epstein Barr virus infections, tick-borne encephalitis (TBE) and viral hepatitis. Dermatological conditions were dominated by bacterial infections, arthropod bites, cutaneous larva migrans and animal bites requiring rabies post-exposure prophylaxis and also leishmaniasis, myasis, tungiasis and one case of leprosy. Respiratory illness included 112 cases of tuberculosis including cases of multi-drug resistant or extensively drug resistant tuberculosis, 104 cases of influenza like illness, and 5 cases of Legionnaires disease. Sexually transmitted infections (STI) accounted for 0.6% of total diagnoses and included HIV infection and syphilis. A total of 165 cases of potentially vaccine preventable diseases were reported. Purpose of travel and destination specific risk factors was identified for several diagnoses such as Chagas disease in immigrant travellers from South America and P. falciparum malaria in immigrants from sub-Saharan Africa. Travel within Europe was also associated with health risks with distinctive profiles for Eastern and Western Europe.
Conclusions
In 2008, a broad spectrum of travel associated diseases were diagnosed at EuroTravNet core sites. Diagnoses varied according to regions visited by ill travellers. The spectrum of travel associated morbidity also shows that there is a need to dispel the misconception that travel, close to home, in Europe, is without significant health risk.
doi:10.1186/1471-2334-10-330
PMCID: PMC3001727  PMID: 21083874
21.  Acute renal failure due to rhabdomyolysis following dengue viral infection: a case report 
Introduction
With more than one-third of the world’s population living in areas at risk for transmission, dengue fever is a leading cause of illness and death in the tropics and subtropics. Despite the high incidence of dengue fever, rhabdomyolysis leading to acute renal failure is an extremely rare complication of dengue fever. Only a few such cases have been reported in the literature.
Case presentation
We describe the case of a 42-year-old, previously healthy Sri Lankan Sinhalese man who developed acute renal failure due to rhabdomyolysis following dengue virus infection. He was transferred to our institution with a five-day history of fever, headache, myalgia, impaired level of consciousness, and reduced urinary output. He was hemodynamically stable and did not have evidence of plasma leakage. His serology for dengue immunoglobulin M and immunoglobulin G was positive, and biochemical investigations disclosed evidence of rhabdomyolysis and acute renal failure. He was treated with induced alkaline diuresis and hemodialysis, and he experienced an uncomplicated recovery.
Conclusion
The occurrence of acute renal failure significantly increases the mortality of patients with dengue fever. Therefore, early diagnosis and early management are crucial in rhabdomyolysis complicating dengue fever to prevent established acute renal failure. It should be kept in mind that the threshold for suspecting rhabdomyolysis is very low in dengue fever. Creatinine phosphokinase levels should routinely be measured in all patients with severe dengue fever for early detection of rhabdomyolysis to prevent acute renal failure.
doi:10.1186/1752-1947-7-195
PMCID: PMC3750229  PMID: 23889764
Dengue fever; Myositis; Rhabdomyolysis; Acute renal failure
22.  Human and entomological surveillance of West Nile fever, dengue and chikungunya in Veneto Region, Italy, 2010-2012 
Background
Since 2010 Veneto region (North-Eastern Italy) planned a special integrated surveillance of summer fevers to promptly identify cases of West Nile Fever (WNF), dengue (DENV) and chikungunya (CHIKV). The objectives of this study were (i) To increase the detection rate of imported CHIKV and DENV cases in travellers from endemic areas and promptly identify potential autochthonous cases.(ii) To detect autochthonous cases of WNF, besides those of West Nile Neuroinvasive Disease (WNND) that were already included in a national surveillance.
Methods
Human surveillance: a traveler who had returned within the previous 15 days from endemic countries, with fever >38°C, absence of leucocytosis (leukocyte count <10,000 μL), and absence of other obvious causes of fever, after ruling out malaria, was considered a possible case of CHIKV or DENV. A possible autochthonous case of WNF was defined as a patient with fever >38°C for <7 days, no recent travel history and absence of other obvious causes of fever. Entomologic surveillance: for West Nile (WNV) it was carried out from May through November placing CDC-CO2 traps in five provinces of Veneto Region, while for DENV and CHIKV it was also performed around residences of viremic cases.
Results
Human surveillance: between 2010 and 2012, 234 patients with fever after travelling were screened, of which 27 (11,5%) were found infected (24 with DENV and 3 with CHIKV). No autochthonous case of DENV or CHIKV was detected. Autochthonous patients screened for WNF were 408, and 24 (5,9%) were confirmed cases. Entomologic surveillance: the WNV was found in 10, 2 and 11 pools of Culex pipiens from 2010 to 2012 respectively, in sites of Rovigo, Verona, Venezia and Treviso provinces). No infected Aedes albopictus with DENV or CHIKV was found.
Conclusions
Veneto is the only Italian region reporting WNV human cases every year since 2008. WNV is likely to cause sporadic cases and unforeseeable outbreaks for decades. Including WNF in surveillance provides additional information and possibly an early alert system. Timely detection of DENV and CHIKV should prompt vector control measures to prevent local outbreaks.
doi:10.1186/1471-2334-14-60
PMCID: PMC3922982  PMID: 24499011
Dengue; Chikungunya; West Nile; Surveillance
23.  Identification of Dengue Type 1 Virus (DENV-1) in Koreans Traveling Abroad 
Objectives
To date, no indigenous dengue virus (DENV) transmissions have been reported in Korea. However, imported dengue infections have been diagnosed in travelers returning from endemic areas. This study presents the first virological evidence of travel-associated DENV importation into South Korea.
Methods
From January 2004 to June 2006, a total of 278 serum samples from 245 patients with suspected dengue fever were tested using the Panbio Dengue Duo IgM/IgG Rapid Strip Test. We selected 11 of the early symptomatic-phase sera that were negative for IgM and retrospectively studied them by virus isolation and reverse transcription-polymerase chain reaction.
Results
All 11 serum samples were found to be DENV positive by reverse transcription-polymerase chain reaction and viruses were successfully isolated from seven of the 11 serum samples. All the isolates were identified as DENV serotype-1.
Conclusion
We successfully isolated seven DENV serotype-1 strains for the first time in South Korea from imported infections. Considering that the vector mosquito, Aedes albopictus, already exists in South Korea, we propose that a vector surveillance program for dengue is urgently needed.
doi:10.1016/j.phrp.2011.04.002
PMCID: PMC3766905  PMID: 24159448
Dengue virus; diagnosis; Korea; reverse transcriptase polymerase chain reaction
24.  Dengue Hemorrhagic Fever: the sensitivity and specificity of the WHO definition in identifying severe dengue cases in Thailand, 1994-2005 
Summary
Background
Dengue virus infection causes a spectrum of clinical manifestations, usually classified according to the World Health Organization (WHO) guidelines into dengue fever (DF) and dengue hemorrhagic fever (DHF). Its ability to categorize severe dengue illness has recently been questioned.
Methods
We evaluated dengue case definitions in a prospective study at a pediatric hospital in Bangkok from 1994-2005. One thousand and thirteen children were enrolled within the first three days of fever and followed with standardized data collection. Cases were classified based on application of the strict WHO criteria. All dengue virus infections were laboratory confirmed. We retrospectively grouped patients based on whether they received significant intervention based on the fluid replacement and/or requirements for blood transfusion.
Results
Fifty eight percent (85/150), 15% (40/264), and 12% (73/599) of DHF, DF and other febrile illnesses (OFI) cases, respectively, received significant intervention. Sixty-eight percent of dengue cases requiring intervention met strict WHO criteria for DHF. In contrast, only 1% of OFI cases met WHO criteria for DHF. Plasma leakage and thrombocytopenia were the two components contributing to the specificity of the WHO case definition and identified dengue cases that required intervention. Hemorrhagic tendency did not reliably differentiate DF and DHF. In DF cases, thrombocytopenia and bleeding were associated with severity.
Conclusions
Dengue illness is heterogeneous in severity, and severe clinical features occurred in patients that were not characterized as DHF. The WHO case definition of DHF demonstrates 62% sensitivity and 92% specificity in identifying dengue illness requiring intervention without the need for laboratory confirmation of dengue virus infection in endemic areas.
doi:10.1086/651268
PMCID: PMC2853952  PMID: 20205587
dengue hemorrhagic fever; dengue fever; WHO clinical guidelines; plasma leakage; clinical severity
25.  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

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