Changing clinical and biological manifestations of dengue during the dengue-2 epidemic in French Polynesia in 1996/97 – description and analysis in a prospective study

In August 1996 dengue-2 virus was detected in French Polynesia for the first time since 1976. A prospective study was conducted from November 1996 to April 1997. Each time one of 7 physicians suspected dengue, the patient was enrolled and epidemiological, clinical and biological data were recorded. Dengue diagnosis was confirmed by virus isolation and IgM detection. The aims of this study were to find clinical and biological predictive factors constituting a specific profile of dengue (DF) and dengue haemorrhagic fever (DHF/DSS) and to assess the possibility of diagnosing dengue at primary health care level using clinical criteria and basic laboratory parameters. Of 298 clinically suspect cases, 196 (66%) were confirmed as dengue. The association of macular rash, pruritis, low platelet count and leukopenia was statistically predictive of dengue but not clinically, since these four signs occur in many other viral infections. As the prevalence of clinical and biological manifestations varied over time in our study, a specific profile useful for dengue diagnosis cannot be defined. With six cases of DHF, the morbidity of this dengue-2 outbreak was very low despite the sequential infection scheme DEN-3/DEN-2. The clinical expression of dengue could depend on a specific virus strain circulating in a specific population in a particular place, with varying virulence over time.     

Prolonged viremia in dengue virus infection in hematopoietic stem cell transplant recipients and patients with hematological malignancies

Fever, skin rash, headache, and thrombocytopenia are considered hallmarks of dengue infection. However, these symptoms are frequently observed in infectious and non‐infectious complications of hematopoietic stem cell transplant recipients and oncohematological patients. Thus, laboratory confirmation of dengue is relevant for prompt intervention and proper management of dengue in endemic and non‐endemic regions. Because no prospective study of dengue has been conducted in these populations, the actual morbidity and mortality of dengue is unknown. In the present series, we describe five cases of dengue in patients living in endemic areas, emphasizing the prolonged course of the disease and the occurrence of prolonged viremia.     

Multicentre prospective study on dengue classification in four South-east Asian and three Latin American countries

Objective To evaluate the existing WHO dengue classification across all age groups and a wide geographical range and to develop a revised evidence‐based classification that would better reflect clinical severity. Methods We followed suspected dengue cases daily in seven countries across South‐east Asia and Latin America and then categorised them into one of three intervention groups describing disease severity according to the overall level of medical and nursing support required. Using a pre‐defined analysis plan, we explored the clinical and laboratory profiles characteristic of these intervention categories and presented the most promising options for a revised classification scheme to an independent group of WHO dengue experts for consideration. Potential warning signs were also evaluated by comparing contemporaneous data of patients who progressed to severe disease with the data of those who did not. Results A total of 2259 patients were recruited during 2006–2007 and 230 (13%) of the 1734 laboratory‐confirmed patients required major intervention. Applying the existing WHO system, 47/210 (22%) of patients with shock did not fulfil all the criteria for dengue haemorrhagic fever. However, no three‐tier revision adequately described the different severity groups either. Inclusion of readily discernible complications (shock/severe vascular leakage and/or severe bleeding and/or severe organ dysfunction) was necessary to devise a system that identified patients requiring major intervention with sufficient sensitivity and specificity to be practically useful. Only a small number of subjects (5%) progressed to severe disease while under observation; several warning signs were identified, but much larger studies are necessary to fully characterize features associated with disease progression. Conclusions Based on these results, a revised classification system comprised of two entities, ‘Dengue’ and ‘Severe Dengue’, was proposed and has now been incorporated into the new WHO guidelines.     

Dengue transmission in the Asia-Pacific region: impact of climate change and socio-environmental factors

Objective To review the scientific evidence about the impact of climate change and socio‐environmental factors on dengue transmission, particularly in the Asia‐Pacific region. Methods Search of the published literature on PubMed, ISI web of Knowledge and Google Scholar. Articles were included if an association between climate or socio‐environmental factors and dengue transmission was assessed in any country of the Asia‐Pacific region. Results Twenty‐two studies met the inclusion criteria. The weight of the evidence indicates that global climate change is likely to affect the seasonal and geographical distribution of dengue fever (DF) in the Asia‐Pacific region. However, empirical evidence linking DF to climate change is inconsistent across geographical locations and absent in some countries where dengue is endemic. Conclusion Even though climate change may play an increasing role in the transmission of DF, no clear evidence shows that such impact has already occurred. More research is needed across countries to better understand the relationship between climate change and dengue transmission. Future research should also consider and adjust for the influence of important socio‐environmental factors in the assessment of the climate change‐related effects on dengue transmission.     

我国登革热病例临床特征研究进展

登革热是由登革病毒感染引起经蚊虫叮咬传播的一种虫媒病毒性疾病。广泛流行于全球热带和亚热带地区,人对登革病毒普遍易感,登革热临床症状、体征主要包括高热、全身肌肉关节痛、皮疹等,实验室生化检查指标主要有白细胞和血小板减少等。登革热重症病例救治不及时,死亡率较高,早期临床诊断登革热病例对于降低患者死亡率和防止登革热疫情暴发或扩散具有重要价值。登革热临床病例特征主要包括症状、体征和实验室生化检查,本文就登革热上述临床特征研究进展进行综述。     

Isolation and partial characterization of dengue virus type 2 and 4 strains from dengue fever and dengue haemorrhagic fever patients from Mindanao, Republic of the Philippines

OBJECTIVE: Isolation of dengue virus from dengue fever and dengue haemorrhagic fever cases from Mindanao, Republic of the Philippines. METHODS: 12 patients with clinically suspected dengue fever (DF) or dengue haemorrhagic fever (DHF) presenting in four regional hospitals between August and September 1995 on Minadano were enrolled in the study. Dengue virus was isolated by inoculation of Vero/E6 or C6/36 cells with patient serum. IgM antibodies were measured using a commercial test system. Up to 454 bp of the capsid region and 240 bp of the E/NS1 gene junction of different viral isolates were sequenced and phylogenetically analyzed. RESULTS: Virus could be isolated from seven patients, five isolates were typed as dengue virus type 2 and two as dengue virus type 4 by immunostaining with monoclonal antibodies or by RT/PCR. Phylogenetic analysis confirmed a close relationship of the dengue virus type 2 isolates with viruses isolated in the Philippines in 1983 and 1988. CONCLUSION: As observed in studies from other parts of South East Asia, dengue virus type 2 was readily isolated from dengue haemorrhagic fever cases. Dengue virus type 2 and 4 circulate in Mindanao, Philippines, with dengue type 2 being responsible for most of our severe DF or DHF cases.     

Evaluation of the World Health Organization standard tourniquet test and a modified tourniquet test in the diagnosis of dengue infection in Viet Nam

OBJECTIVES: A positive tourniquet test is one of several clinical parameters considered by the World Health Organization to be important in the diagnosis of dengue haemorrhagic fever, but no formal evaluation of the test has been undertaken. As many doctors remain unconvinced of its usefulness, this study was designed to assess the diagnostic utility of both the standard test and a commonly employed modified test. METHODS: A prospective evaluation of the standard sphygmomanometer cuff tourniquet test, compared with a simple elastic cuff tourniquet test, was carried out in 1136 children with suspected dengue infection admitted to a provincial paediatric hospital in southern Viet Nam. RESULTS: There was good agreement between independent observers for both techniques, but the sphygmomanometer method resulted in consistently greater numbers of petechiae. This standard method had a sensitivity of 41.6% for dengue infection, with a specificity of 94.4%, positive predictive value of 98.3% and negative predictive value of 17.3%. The test differentiated poorly between dengue haemorrhagic fever (45% positive) and dengue fever (38% positive). The simple elastic tourniquet was less sensitive than the sphygmomanometer cuff, but at a threshold of 10 petechiae (compared with the WHO recommendation of 20) per 2.5 cm2 the sensitivity for the elastic tourniquet rose to 45% (specificity 85%). Other evidence of bleeding was frequently present and the tourniquet test provided additional information to aid diagnosis in only 5% of cases. CONCLUSION: The conventional tourniquet test adds little to the diagnosis of dengue in hospitalized children. The simple, cheap elastic tourniquet may be useful in diagnosing dengue infection in busy rural health stations in dengue endemic areas of the tropics. A positive test should prompt close observation or early hospital referral, but a negative test does not exclude dengue infection.     

Classification of dengue illness based on readily available laboratory data

The aim of this study was to examine retrospective dengue-illness classification using only clinical laboratory data, without relying on X-ray, ultrasound, or percent hemoconcentration. We analyzed data from a study of children who presented with acute febrile illness to two hospitals in Thailand. Multivariable logistic regression models were used to distinguish: (1) dengue hemorrhagic fever (DHF) versus dengue fever (DF), (2) DHF versus DF + other febrile illness (OFI), (3) dengue versus OFI, and (4) severe dengue versus non-severe dengue + OFI. Data from the second hospital served as a validation set. There were 1,227 patients in the analysis. The sensitivity of the models ranged from 89.2% (dengue versus OFI) to 79.6% (DHF versus DF). The models showed high sensitivity in the validation dataset. These models could be used to calculate a probability and classify patients based on readily available clinical laboratory data, and they will need to be validated in other dengue-endemic regions.     

Detection and subtyping of dengue 1-4 and yellow fever viruses by means of a multiplex RT-nested-PCR using degenerated primers

OBJECTIVE: Differential diagnosis of infections that cause similar diseases and may be active simultaneously in the same geographical areas is greatly needed. Dengue and yellow fever viruses (DENV and YFV) are transmitted by the same species of mosquito and both can cause haemorrhagic fever symptoms. These viruses are active mainly in regions where expensive and sophisticated technologies are not available. Our objective was to develop a simple, reliable and easy-to-perform method to detect and identify these viruses. METHODS: We slightly modified a generic RT-PCR able to detect the mentioned viruses and other members of this genus: specific primers for each one of these viruses were designed and included in the nested reaction instead of one of the generic ones. The reaction was optimized and viruses are amplified giving rise to bands of different sizes distinguishable in agarose gels. RESULTS: This test is able to detect and identify the four DENVs and YFV to a high level of sensitivity and specificity and can be used with clinical samples. This simple, reliable and easy-to-perform method able to detect and identify dengue 1-4 and YFV can be used in poor endemic countries.     

Dengue: an evaluation of dengue severity in French Polynesia based on an analysis of 403 laboratory-confirmed cases

We conducted a retrospective study of 403 laboratory-confirmed dengue cases hospitalized in Tahiti between August 1989 and March 1997. According to standard WHO criteria, 337 of these cases were dengue fever (DF) and 64 were dengue haemorrhagic fever (DHF). Of the 10 fatal cases, 6 were DF and 4 were DHF. As an alternative, we used a correspondence analysis procedure to define dengue severity based on basic clinical and biological criteria for which we assigned a severity score, and then selected the 50 most severe cases from this analysis. Of the latter, 17 patients had been classified as DF and 33 as DHF by the WHO criteria. From this analysis, haemorrhages and decreased platelets counts associated with hepatic disorders are the main criteria associated with the severe dengue cases. Thus in our study population, the WHO classification does not account for the overall severity of dengue; hepatic failure should be considered as a specific severe form of dengue since plasma leakage, which is the pathophysiological hallmark of DHF, is only one of the pathogenic mechanisms leading to severity.     

Decision tree algorithm in deciding hospitalization for adult patients with dengue haemorrhagic fever in Singapore

Objectives  To develop a simple decision tree for clinicians to decide between hospitalization and outpatient monitoring of adult dengue patients.
Method  Retrospective cohort study on all laboratory-diagnosed dengue patients admitted in 2004 to Tan Tock Seng Hospital, Singapore. Demographic, clinical, laboratory and radiological data were collected, and cases classified as dengue fever (DF) or dengue haemorrhagic fever (DHF) using World Health Organization criteria. To develop the decision tree, we used chi-squared automatic interaction detector (CHAID) with bi-way and multi-way splitting. The resulting trees were pruned to achieve the highest sensitivity with the shortest tree.
Results  In 2004, 1973 probable and confirmed adult dengue patients were admitted; DF comprised 1855 (94.0%) and DHF 118 (6.0%) of the cases. The best decision tree prediction had three branches, consisting of a history of clinical bleeding, serum urea, and serum total protein. This decision tree had a sensitivity of 1.00, specificity of 0.46, positive predictive value of 7.5%, and negative predictive value of 100%. The overall accuracy of the decision tree was 48.1%. The test sensitivity and specificity compared favourably with other predictive probability equations and sophisticated laboratory tests, and would prevent 43.9% of mild DF cases from hospitalization.
Conclusions  A simple decision tree is effective in predicting DHF in the clinical setting for adult dengue infection.     

3 dengue fever cases,infected during a group tour to the Philippines

We report three dengue fever cases, infected during a group tour to the Philippines. A 58-year old male experienced sudden onset of high fever 5 days after returning to Japan, followed by rash and thrombocytopenia. The other 2 cases experienced similar symptoms. Clinically suspected from the travel history, incubation time and the state of dengue fever epidemic in the Philippines, dengue virus infection was confirmed by the laboratory tests. The incidence and geographical distribution of dengue virus infection have greatly increased in recent years. There have been reports of Japanese travelers who visited dengue endemic countries, infected and developed symptoms after returning home. Dengue virus infection should be included in the differential diagnosis of the patients who develop high fever and rash after returning from tropical areas.     

Clinical and laboratory features of dengue virus-infected travellers previously vaccinated against yellow fever

Dengue is a mosquito-borne viral infection endemic throughout the tropics and subtropics. The global prevalence of dengue has grown dramatically in recent years and it has become a major international public health concern. The close taxonomic relationships between yellow fever and dengue viruses gave rise to concerns that previous vaccination against yellow fever could modify the course of dengue infection and contribute to the development of dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS). This study reports the clinical and laboratory features of dengue virus-infected travellers previously vaccinated against yellow fever.     

The Incidence, Characteristics, and Presentation of Dengue Virus Infections during Infancy

Infants are a vulnerable and unique population at risk for dengue in endemic areas. This report describes the incidence and presenting clinical features of infant dengue virus (DENV) infections from a prospective community-based study performed between January 2007 and May 2009 in the Philippines. DENV3 was the predominant infecting serotype over a wide spectrum of disease severity, ranging from inapparent infection to dengue hemorrhagic fever (DHF). In 2007, the incidence of inapparent DENV infections during infancy was 103 per 1,000 persons person-years and 6-fold higher than symptomatic dengue. The age-specific incidence of infant DHF was 0.5 per 1,000 persons over the age of 3–8 months, and it disappeared by age 9 months. A febrile seizure, macular rash, petechiae, and lower platelet count were presenting clinical features associated with DENV infection among infants with acute undifferentiated febrile illnesses. Community-based studies can help to delineate the incidence rates, disease spectrum, and clinical features of DENV infections during infancy.     

Dengue virus infection in travellers returning to Berlin, Germany: clinical, laboratory, and diagnostic aspects

BACKGROUND: Dengue is a mosquito-borne viral infection endemic throughout the tropics and subtropics. The global prevalence of dengue has grown dramatically in recent years and it has been recognized as a potential hazard to tourists. OBJECTIVE: In this study, we analyzed the epidemiology, clinical manifestations, laboratory features and serological/virological results in a series of German travellers returning to Berlin with acute dengue virus infection. STUDY DESIGN: Laboratory-confirmed dengue virus infections among German travellers returning to Berlin were studied retrospectively during the period of 1993-2001. Seventy-one patients tested positive for dengue fever and were included in this study. RESULTS: The majority of patients (77.5%) contracted the disease in South Central and South East Asia. The most important clinical characteristics were fever and prostration (100%), headache, predominantly frontal or retroorbital (86%), arthralgia (79%), morbilliform rash (66%) and myalgia (48%). The most meaningful laboratory results were: marked leucopenia (72%), thrombocytopenia (70-89%), hyponatremia (41%) and increased hepatic enzymes ALAT (41%), ASAT (45%) and LDH (62%). Dengue virus infection was diagnosed by means of a matching clinico-epidemiological history and positivity of specific serology and/or virus isolation. Hemorrhagic phenomena appeared in 10 of the 71 patients (14%), out of which one was diagnosed with DHF according to WHO criteria. All patients recovered fully. CONCLUSION: Pretravel advice should be given to all travellers to dengue-endemic areas. DF must be included in the differential diagnosis of patients returning febrile from tropical areas.     

Incidence and risk factors of probable dengue virus infection among Dutch travellers to Asia

We studied the incidence of dengue virus (DEN) infections in a cohort of Dutch short-term travellers to endemic areas in Asia during 1991-92. Sera were collected before and after travel. All post-travel sera were tested for DEN immunoglobulin M (IgM) [IgM capture (MAC)-enzyme-linked immunosorbent assay (ELISA)] and IgG (indirect ELISA). Probable DEN infection was defined as IgM seroconversion or a fourfold rise in IgG ratio in the absence of cross-reaction with antibody to Japanese encephalitis virus (JEV). Infections were considered clinically apparent in case of febrile illness (> 24 H) with headache, myalgia, arthralgia or rash. Probable DEN infection was found in 13 of 447 travellers (incidence rate 30/1000 person-months, 95% CI 17.4-51.6). One infection was considered secondary; no haemorrhagic fever occurred. The clinical-to-subclinical infection rate was 1 : 3.3. The risk of infection showed marked seasonal variation. DEN infections are frequent in travellers to endemic areas in Asia; most remain subclinical.     

Risk factors and clinical features associated with severe dengue infection in adults and children during the 2001 epidemic in Chonburi, Thailand

OBJECTIVES: Dengue haemorrhagic fever (DHF) is an important cause of morbidity in South-east Asia and used to occur almost exclusively in young children. In recent years, there has been a progressive shift in age-distribution towards older children and adults. We investigated an outbreak in 2001 in both children and adults, in an endemic area of Thailand. METHODS: Retrospective study of 347 patients with serologically confirmed dengue infection admitted to Chonburi Hospital during an epidemic in 2001. RESULTS: A total of 128 (37%) patients had dengue fever (DF) and 219 (63%) had DHF. Patients with DHF were significantly older than patients with DF (11 years vs. 8 years). Clinical bleeding was noted in 124 individuals, both with DF (n = 24) and DHF (n = 100), and significantly more frequently in adults. Twenty-nine (13.2%) of all DHF cases were caused by primary infection. Secondary dengue infection was associated significantly with the development of DHF in children, OR (95% CI) = 3.63 (1.94-6.82), P < 0.0001, but not in adults, OR (95% CI) = 0.6 (0.02-6.04), P = 1. Unusual clinical manifestations were observed in 23 patients: three presented with encephalopathy and 20 with highly elevated liver-enzymes. In the latter group, four patients were icteric and nine had gastrointestinal bleeding. CONCLUSION: These results indicate that DHF in South-east Asia is common in both children and adults. In dengue-endemic countries, dengue should be considered as a differential diagnosis in patients with clinical gastrointestinal bleeding in association with increased liver enzymes.     

First Isolation of Dengue Virus from the 2010 Epidemic in Nepal

Dengue is an emerging disease in Nepal and was first observed as an outbreak in nine lowland districts in 2006. In 2010, however, a large epidemic of dengue occurred with 4,529 suspected and 917 serologically-confirmed cases and five deaths reported in government hospitals in Nepal. The collection of demographic information was performed along with an entomological survey and clinical evaluation of the patients. A total of 280 serum samples were collected from suspected dengue patients. These samples were subjected to routine laboratory investigations and IgM-capture ELISA for dengue serological identification, and 160 acute serum samples were used for virus isolation, RT-PCR, sequencing and phylogenetic analysis. The results showed that affected patients were predominately adults, and that 10% of the cases were classified as dengue haemorrhagic fever/ dengue shock syndrome. The genetic characterization of dengue viruses isolated from patients in four major outbreak areas of Nepal suggests that the DENV-1 strain was responsible for the 2010 epidemic. Entomological studies identified Aedes aegypti in all epidemic areas. All viruses belonged to a monophyletic single clade which is phylogenetically close to Indian viruses. The dengue epidemic started in the lowlands and expanded to the highland areas. To our knowledge, this is the first dengue isolation and genetic characterization reported from Nepal.