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1.  Spatial and Temporal Clustering of Dengue Virus Transmission in Thai Villages 
PLoS Medicine  2008;5(11):e205.
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.
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
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
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)
PMCID: PMC2577695  PMID: 18986209
2.  The exanthem of dengue fever: Clinical features of two US tourists traveling abroad 
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.
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.
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.
Limited to 2 case reports.
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.
PMCID: PMC4061973  PMID: 17959270
3.  The re-emergence of dengue virus in non-endemic countries: a case series 
BMC Research Notes  2014;7(1):596.
Dengue has been designated a major international public health problem by the World Health Organization. It is endemic in most tropical and sub-tropical countries, which are also popular tourist destinations. Travelers are at significant risk of acquiring the disease and also contribute to its spread to non-endemic countries where the vector is present. Children represent a particular susceptible category, since they have a higher risk than adults of developing severe dengue.
Case presentation
We describe 3 cases of imported dengue fever in Italy in three children (two born in the Philippines and one of Bangladeshi ethnicity) who acquired dengue fever during a recent travel to Southeast Asia, initially not-recognized because of the low index of suspicion of physicians not working in dengue endemic areas. Clinical presentations, differential diagnosis and management of these children are presented and discussed.
Due to global urbanization and increased air travel, it is nowadays important that physicians who practice outside of traditionally dengue endemic areas are adept at the recognition of potentially fatal reemerging infectious diseases such as dengue.
Electronic supplementary material
The online version of this article (doi:10.1186/1756-0500-7-596) contains supplementary material, which is available to authorized users.
PMCID: PMC4174650  PMID: 25186647
Dengue; Children; Travel; Imported dengue; Vaccine
4.  Dengue Infection in Children in Ratchaburi, Thailand: A Cohort Study. II. Clinical Manifestations 
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.
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.
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.
PMCID: PMC3289597  PMID: 22389735
5.  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.
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.
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
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
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
PMCID: PMC3168879  PMID: 21918642
6.  Dengue haemorrhagic fever presenting with cholestatic hepatitis: two case reports and a review of literature 
BMC Research Notes  2014;7(1):568.
Dengue fever is a common mosquito borne viral fever in South Asia, which causes significant morbidity and mortality. Dengue fever is well known to involve the liver, especially in dengue hemorrhagic fever. The hepatic involvement is usually that of a mild hepatitis with transaminase derangement without jaundice. In cases of dengue hemorrhagic fever where shock has ensued, a severe hepatitis with gross derangements of transaminases and bilirubin may occur. These are two rare cases of adult patients with dengue hemorrhagic fever presenting with a cholestatic type of jaundice.
Case presentation
This case report describes two female patients aged 30 and 46 years who presented with fever, icterus and biochemical analysis revealed cholestatic jaundice. Evolution of the clinical picture and dropping platelets prompted serological investigations in the form of dengue non-structural protein 1 antigen and dengue immunoglobulin M which confirmed acute dengue infection.
These cases highlight the importance of considering dengue fever as a differential diagnosis even in the presence of a cholestatic jaundice, especially in countries where dengue fever is endemic, and in travelers returning from dengue endemic countries. The early diagnosis of dengue fever and timely institution of supportive fluid management is essential to prevent morbidity and mortality.
PMCID: PMC4152580  PMID: 25159536
Dengue fever; Hepatitis; Cholestasis; Cholestatic jaundice
7.  Prediction of Dengue Disease Severity among Pediatric Thai Patients Using Early Clinical Laboratory Indicators 
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.
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.
PMCID: PMC2914746  PMID: 20689812
8.  Dengue and Other Common Causes of Acute Febrile Illness in Asia: An Active Surveillance Study in Children 
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.
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.
PMCID: PMC3723539  PMID: 23936565
9.  Early Clinical Features of Dengue Virus Infection in Nicaraguan Children: A Longitudinal Analysis 
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.
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.
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.
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.
PMCID: PMC3295819  PMID: 22413033
10.  Emergence of travel: Associated dengue fever in a non-endemic, hilly state 
We assessed the occurrence of dengue fever in association with travel in a non-endemic hilly region. The clinical presentation and laboratory parameters of febrile patients with a travel history to an endemic region were studied, and the role of the laboratory in the diagnosis was affirmed.
Materials and Methods:
Febrile patients presenting with clinical features defining dengue with a history of travel to an endemic area constituted the study group. Serum samples were tested for dengue-specific NS1 antigen and IgM, IgG antibodies. The demographic data were retrieved from the hospital information system. A hematological and biochemical workup was done and the results analyzed using percentage, proportion, mean, and median.
Out of 189 febrile patients, 58 were reactive to serological tests for dengue, with 47 (81%) males. The presenting features were chills and rigors, myalgia, cough, sweating, and vomiting. Thrombocytopenia (74.35%), lymphopenia (52.94%), and leucopenia (47.05%) were present in early disease, with AST >34 IU/L in 58.97% of the patients. The NS1 antigen was detectable between three and seven days of fever and the IgM antibodies after five days. The positivities to only NS1, both NS1 and IgM, and IgM alone were 60.34, 27.58, and 10.34%, respectively, and the median duration of fever was five, seven, and ten days, respectively. One case of dengue hemorrhagic fever and one of probable secondary dengue infection with detectable IgG were encountered.
Dengue fever remains unsuspected in febrile cases in non-endemic regions. History of travel is an essential criterion to suspect dengue. A non-specific clinical presentation eludes diagnosis. Serological tests for antigen and antibodies, and hematological and biochemical markers are vital for distinguishing the diagnosis.
PMCID: PMC4260275  PMID: 25538925
Dengue; dengue fever; IgM; IgM/IgG antibody; lymphopenia; neutrophilia; NS1 antigen; thrombocytopenia
11.  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.
PMCID: PMC3381444  PMID: 22668447
Dengue; Travellers; GeoSentinel; Autochthonous spread; Sentinel surveillance
12.  Emergence of a New Lineage of Dengue Virus Type 2 Identified in Travelers Entering Western Australia from Indonesia, 2010-2012 
PLoS Neglected Tropical Diseases  2015;9(1):e0003442.
Dengue virus (DENV) transmission is ubiquitous throughout the tropics. More than 70% of the current global dengue disease burden is borne by people who live in the Asia-Pacific region. We sequenced the E gene of DENV isolated from travellers entering Western Australia between 2010–2012, most of whom visited Indonesia, and identified a diverse array of DENV1-4, including multiple co-circulating viral lineages. Most viruses were closely related to lineages known to have circulated in Indonesia for some time, indicating that this geographic region serves as a major hub for dengue genetic diversity. Most notably, we identified a new lineage of DENV-2 (Cosmopolitan genotype) that emerged in Bali in 2011–2012. The spread of this lineage should clearly be monitored. Surveillance of symptomatic returned travellers provides important and timely information on circulating DENV serotypes and genotypes, and can reveal the herald wave of dengue and other emerging infectious diseases.
Author Summary
Dengue is currently the most rapidly spreading mosquito-borne viral disease of humans, and is endemic in most tropical and sub-tropical countries. An estimated 390 million infections occur annually, and over 70% of the current global dengue disease burden is borne by people who live in Southeast Asia and the Western Pacific region. DENV serotype and genotype data is lacking in many parts of this region, limiting our attempts to understand the observed patterns of hyperendemicity and disease severity. Many countries in the Southeast Asia and Western Pacific region are popular tourist destinations, and dengue has been identified as a cause of travel-related illness in people returning from endemic countries. We sequenced the E gene of DENV isolated from travellers returning to Western Australia from 7 countries throughout Asia between 2010 and 2012. The majority of DENV originated in Indonesia, predominantly Bali, a popular travel destination for Australians. We identified hyperendemic transmission of all four DENV serotypes in Bali in 2010; circulating DENV included dominant local strains which had circulated for several years in Indonesia and Singapore, as well as strains more recently introduced into Bali from other countries in the region. Finally, we show the emergence of a new lineage of DENV2 (Cosmopolitan genotype) in 2011–2012, which should be monitored. Travellers may act as sentinels and provide important information on DENV genotypes and linages circulating in countries where locally generated detailed genetic data may not be available.
PMCID: PMC4311992  PMID: 25635775
13.  Dengue Incidence in Urban and Rural Cambodia: Results from Population-Based Active Fever Surveillance, 2006–2008 
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).
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.
PMCID: PMC2994922  PMID: 21152061
14.  Dengue Deaths in Puerto Rico: Lessons Learned from the 2007 Epidemic 
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.
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.
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.
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.
PMCID: PMC3328431  PMID: 22530072
15.  Incidence of dengue virus infection among Japanese travellers, 2006 to 2010 
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.
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).
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.
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.
PMCID: PMC3729080  PMID: 23908911
16.  Best Practices in Dengue Surveillance: A Report from the Asia-Pacific and Americas Dengue Prevention Boards 
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.
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.
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.
PMCID: PMC2982842  PMID: 21103381
17.  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.
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.
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
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
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)
PMCID: PMC2726436  PMID: 19721696
18.  Clinical and laboratory features that discriminate dengue from other febrile illnesses: a diagnostic accuracy study in Rio de Janeiro, Brazil 
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.
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.
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.
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.
PMCID: PMC3574824  PMID: 23394216
Dengue/diagnosis; Signs and symptoms; Sensitivity and specificity; Fever/diagnosis
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.
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.
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.
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.
PMCID: PMC3180466  PMID: 21902823
20.  Travel and migration associated infectious diseases morbidity in Europe, 2008 
BMC Infectious Diseases  2010;10:330.
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.
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.
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.
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.
PMCID: PMC3001727  PMID: 21083874
21.  Clinical and Virological Study of Dengue Cases and the Members of Their Households: The Multinational DENFRAME Project 
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.
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.
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.
PMCID: PMC3265457  PMID: 22292098
22.  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
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.
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
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
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)
PMCID: PMC4011853  PMID: 24800812
23.  High Dengue Case Capture Rate in Four Years of a Cohort Study in Nicaragua Compared to National Surveillance Data 
Dengue is a major public health problem in tropical and subtropical regions; however, under-reporting of cases to national surveillance systems hinders accurate knowledge of disease burden and costs. Laboratory-confirmed dengue cases identified through the Nicaraguan Pediatric Dengue Cohort Study (PDCS) were compared to those reported from other health facilities in Managua to the National Epidemiologic Surveillance (NES) program of the Nicaraguan Ministry of Health. Compared to reporting among similar pediatric populations in Managua, the PDCS identified 14 to 28 (average 21.3) times more dengue cases each year per 100,000 persons than were reported to the NES. Applying these annual expansion factors to national-level data, we estimate that the incidence of confirmed pediatric dengue throughout Nicaragua ranged from 300 to 1000 cases per 100,000 persons. We have estimated a much higher incidence of dengue than reported by the Ministry of Health. A country-specific expansion factor for dengue that allows for a more accurate estimate of incidence may aid governments and other institutions calculating disease burden, costs, resource needs for prevention and treatment, and the economic benefits of drug and vaccine development.
Author Summary
National public health and epidemiology programs are often tasked with tracking certain infectious diseases, but many barriers lead to under-reporting. In tropical and subtropical countries where dengue fever is endemic, under-reporting may be due to misdiagnosis, limitations of the WHO case classification, and lack of laboratory infrastructure or resources, among other issues. In Nicaragua's capital, Managua, we compared the number of dengue cases identified in a cohort study of 2- to 12-year-old children in one health center to the number of pediatric cases reported from all other municipal health centers in Managua to the National Epidemiologic Surveillance (NES) program. In the years 2004–2008, between 13 and 65 dengue cases were identified in the cohort (approximately 3,700 participants), and between 0 and 51 cases were reported by individual health centers in Managua. When the incidence per 100,000 people was calculated and compared, an average of 21 times more dengue cases were identified in the cohort study compared to the number reported to NES. Application of such an expansion factor may help governments and other health institutions to estimate the actual number of dengue cases in a population and therefore better allocate resources for prevention, treatment, and drug and vaccine development.
PMCID: PMC2838781  PMID: 20300515
24.  Immunologic hypo- or non-responder in natural dengue virus infection 
Serologically defined primary dengue virus infection and/or subsequent homologous serotype infection is known to be associated with less severe disease as compared with secondary subsequent heterologous serotype infection. In geographical locales of high dengue endemicity, almost all individuals in the population are infected at some point in time and should therefore are at high risk of secondary infection. Interestingly, dengue viremia in healthy blood donors whose sera apparently lack detectable levels of specific antibody to dengue viral antigens has been reported. The incidence rate of potential immunologic hypo- or non-responders following natural primary dengue virus infection in dengue endemic regions, who do become immune responders only after repeated exposure, has not been described. These are the patients who may be diagnosed as primary infection in the subsequent infection, but actually are secondary infection. This concept has important implications with regards to the hypothesis of immunological enhancement of dengue pathogenesis, which has largely been advanced based on empirical observations and/or from in vitro experimental assays. The fact that dengue naïve travelers can suffer from severe dengue upon primary exposure while visiting dengue endemic countries underscores one of the major problems in explaining the role of immune enhancement in the pathogenesis of severe dengue virus infection. This evidence suggests that the mechanism(s) leading to severe dengue may not be associated with pre-existing enhancing antibody. Consequently, we propose a new paradigm for dengue virus infection classification. These include a) patients with naïve primary infection, b) those that are serologically defined primary in dengue endemic zones and c) those who are serologically defined secondary dengue virus infection. We submit that clarity with regards to such definitions may help facilitate the delineation of the potential mechanisms of severe dengue virus infection.
PMCID: PMC3680176  PMID: 23725050
Nonresponder; Naïve; Flavivirus; Dengue fever; DHF
25.  A Hospital Based Serosurveillance Study of Dengue Infection in Jaipur (Rajasthan) , India 
Background: Dengue has been known to be endemic in India for over two centuries. There is a need to assess the magnitude of dengue virus establishment in the state of Rajasthan. A surveillance study was conducted to analyze dengue seropositivity among patients with clinical suspicion of dengue fever like illness, who presented to or were admitted at a tertiary care private hospital at Jaipur.
Methods: Serum samples from 2169 suspected dengue cases (1356 males and 813 females) were received in the Serology lab over the four year study period (2008-2011). The samples were subjected to a rapid immuno-chromatography assay with differential detection of IgM and IgG antibodies. A primary dengue infection was defined by a positive IgM band and a negative IgG band, whereas a secondary infection was defined by a positive Ig G band with or without an IgM band.
Result: Among the 2169 patients who were screened; 18.99% (412) were dengue specific IgM positive cases. 64. 49% (1399) cases were negative for dengue specific antibodies, 5.67% (123) were primary dengue cases, and 23.51% (510) were total secondary dengue cases. During the study period, the Dengue IgM seropositivity was highest in the year 2009 and was lowest in the year 2011. Most of the cases occurred in the post-monsoon season, with a peak in the month of October, each year.
Conclusion: A detailed and continuous epidemiological surveillance is required, for monitoring the incrusion and spread of dengue viruses. This will help in undertaking and implementing effective control and management strategies.
PMCID: PMC3809636  PMID: 24179897
Dengue; Serosurveillance; Jaipur

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