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.     

Studies on dengue and dengue haemorrhagic fever (DHF) in West Bengal State, India

A large outbreak of dengue and dengue haemorrhagic fever (DHF) occurred from August to November 2005 involving all districts of West Bengal. Altogether 6293 persons were serologically diagnosed to be suffering from dengue through detection of IgM antibodies, with 27 (0.42%) seropositive deaths. In Kolkata alone 3967 persons were affected with 14 deaths. A total of 874 sera samples from febrile patients were quantitatively analysed for IgG and IgM antibodies using the IVD microwell ELISA dengue fever test kit. In 21.6%, no antibody was detected and 52.6% had only IgG antibodies. In 8.9% only IgM antibodies and in 16.8% both IgG, IgM antibodies were present, suggesting primary and secondary dengue respectively. About 10% of secondary dengue would develop DHF. As in this outbreak secondary dengue was 65.3% of total dengue cases, so of the 6293 dengue victims presumably, 3998 had secondary dengue, thus having risk of DHF in about 400 persons. Case fatality rate amongst DHF patients was 8.5%. This study also indicated that DHF would be a nagging problem in coming days. Age-group analysis of primary and secondary dengue cases revealed that although secondary cases occurred in all ages, more of primary cases belonged to younger ages (1-10) years and more of secondary cases in middle to older ages. Prevailing type during this outbreak was DEN3. This epidemiological study of an outbreak categorized prevalence of primary and secondary dengue, calculated risk factors for precipitation of DHF, model of which could be utilized to compare and evaluate future epidemiological pattern, where-ever and whenever applicable.     

Neurological manifestations in dengue patients

To determine the frequency and the natural history of neurological manifestations of dengue infection in Thai children, 1,493 children diagnosed with dengue infection by serology and admitted to the Department of Pediatrics, Chulalongkorn Hospital, Bangkok, Thailand from 1987 to 1998 were reviewed from prospectively recorded medical charts. There were 80 children identified with neurological manifestations, an incidence of 5.4% of all dengue patients. Of these, there were 41 males and 39 females, with ages ranging from 3 months to 14 years. They were categorized into 20 cases of dengue fever, 26 cases of dengue hemorrhagic fever and 34 cases of dengue shock syndrome. All cases experienced the neurological manifestations during the febrile stage of the illness. The patients were classified into an encephalitic group (called "dengue encephalopathy") (42), a seizure group (35) and a miscellaneous group (3). Encephalitic patients presented with alteration of consciousness (83.3%), seizure (45.2%), mental confusion (23.8%), nuchal rigidity (21.4%), spasticity of limbs (9.5%), positive clonus (4.8%), hemiplegia (2.4%) and positive kernig (2.4%), and were older than those in the other groups. Patients in the seizure group presented with seizure (100%) and positive clonus (2.9%). Abnormal laboratory findings included hyponatremia, abnormal liver enzymes and CSF pleocytosis. Dengue IgM and dengue PCR were not demonstrated in 16 CSF specimens. An autopsy finding of a child in the encephalitic group showed histologic evidence of encephalitis, the only case of confirmed dengue encephalitis in this study. One patient with encephalitic symptoms suffered from long-term neurological sequelae. The overall mortality rate was 5%. In conclusion, neurological manifestations including seizure and encephalopathy in children with dengue are not uncommon whereas dengue encephalitis is a rare entity.     

Validation of probability equation and decision tree in predicting subsequent dengue hemorrhagic fever in adult dengue inpatients in Singapore

We developed a probability equation and a decision tree from 1,973 predominantly dengue serotype 1 hospitalized adult dengue patients in 2004 to predict progression to dengue hemorrhagic fever (DHF), applied in our clinic since March 2007. The parameters predicting DHF were clinical bleeding, high serum urea, low serum protein, and low lymphocyte proportion. This study validated these in a predominantly dengue serotype 2 cohort in 2007. The 1,017 adult dengue patients admitted to Tan Tock Seng Hospital, Singapore had a median age of 35 years. Of 933 patients without DHF on admission, 131 progressed to DHF. The probability equation predicted DHF with a sensitivity (Sn) of 94%, specificity (Sp) 17%, positive predictive value (PPV) 16%, and negative predictive value (NPV) 94%. The decision tree predicted DHF with a Sn of 99%, Sp 12%, PPV 16%, and NPV 99%. Both tools performed well despite a switch in predominant dengue serotypes.     

Dengue hemorrhagic fever in infants: a study of clinical and cytokine profiles

A prospective study of clinical and cytokine profiles of 107 infants with dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS) was conducted. Fever, petechiae on the skin, and hepatomegaly were the most common clinical findings associated with DHF/DSS in infants. DSS occurred in 20.5% of the patients. Hemoconcentration and thrombocytopenia were observed in 91.5% and 92.5% of the patients, respectively. Serologic testing revealed that almost all of the patients (95.3%) had primary dengue virus infections. These data demonstrate that clinical and laboratory findings of DHF/DSS in infants are compatible with the World Health Organization's clinical diagnostic criteria for pediatric DHF. The present study is the first to report evidence of production of cytokines in infants with DHF/DSS and to describe the difference between the cytokine profile of infants with primary dengue virus infections and children with secondary infections. Overproduction of both proinflammatory cytokines (interferon-gamma and tumor necrosis factor-alpha) and anti-inflammatory cytokines (interleukin-10 and -6) may play a role in the pathogenesis of DHF/DSS in infants.     

Is dengue severity related to nutritional status?

A retrospective review of dengue patients admitted to Queen Sirikit National Institute of Child Health (previously known as Children's Hospital) from 1995 to 1999 revealed 4,532 confirmed cases of dengue infection; 80.9% were dengue hemorrhagic fever (DHF) and 19.1% were dengue fever cases (DF). Among the DHF patients; 30.6% had shock. The majority of them, 66.6%, had a normal nutritional status, while 9.3% were malnourished and 24.2% had obesity as classified by weight for age. Compared with control patients with other diagnoses (excluding HIV/AIDS patients), malnourished children had a lower risk of contracting dengue infection (odds ratio = 0.48, 95% Cl = 0.39-0.60, p = 0.000) while obese children had a greater risk of infection with dengue viruses (odds ratio = 1.96, 95% Cl = 1.55-2.5, p = 0.000). The clinical signs, symptoms and laboratory findings of dengue were almost the same among the 3 groups of malnourished, normal, and obese patients. The minor differences observed were that in obese children liver enlargement was found less often; maculopapular/convalescence rash and elevations of alanine aminotransferase were found more often. Malnourished patients had a higher risk of developing shock (37.8%) than normal (29.9%) and obese patients (30.2%) (p = 0.000). Obese patients had more unusual presentations: encephalopathy (1.3%) and associated infections (4.8%), than normal (0.5% and 2.7%) and malnourished patients (1.2% and 3.1%). Complications of fluid overload were found more in obese patients (6.5%) compared to normal (3.2%) and malnourished patients (2.1%) (p = 0.000). The case-fatality rates (CFR) in malnourished patients and obese patients were 0.5% and 0.4%, respectively, while in normal patients the CFR was 0.07%. Under and over nutrition DHF patients had either a greater risk of shock or unusual presentations and complications, which can lead to severe disease or complications and probably a higher CFR.     

Quantitation of T lymphocyte subsets helps to distinguish dengue hemorrhagic fever from classic dengue fever during the acute febrile stage

Activation of immunoregulatory T lymphocyte subsets has been observed in dengue viral infection, being more evident in dengue hemorrhagic fever (DHF) than in classical dengue fever (DF). There are, however, as yet no well-defined host markers to determine which patients with dengue viral infection will develop severe complications during the acute febrile stage of the disease. A study was performed to compare the cellular immune status in DHF, DF and non-dengue viral infections (NDF) in order to determine the value of these parameters in distinguishing DHF from classic DF and other viral infections during the acute febrile stage of the disease. This study involved 109 febrile patients admitted because of suspected DHF. Fifty patients were serologically confirmed cases of dengue infection, of which 25 had grade 1 or 2 DHF. There was a reduction in total T (CD3), CD4 and CD8 cells in DHF and demonstrated that a low level of CD3, CD4, CD8 and CD5 cells discriminated DHF from DF patients during the febrile stage of the illness. In contrast, B (CD19) cells and natural killer (NK) cells did not appear to be discriminatory in this study. Receiver operating characteristic (ROC) curve analysis showed that a combination of CD3 cell of < or = 45% and CD5 cell of < or = 55% was the best marker to identify DHF patients (sensitivity = 84% and specificity = 52% for CD3 cell of < or = 45%; sensitivity = 92% and specificity = 71% for CD5 cell of < or = 55%). CD4 cell of < or = 25% and CD8 cell < or = 30% were equally good in discriminating DHF from DF patients. On the other hand, the ROC curves indicated no clear difference between the immunoregulatory cell counts in DF from NDF Lymphopenia, atypical lymphocytosis and thrombocytopenia were significantly more evident in dengue compared to non-dengue infection but did not appear to be discriminatory among DHF and DF patients. The reduction in CD3, CD4, CD8, CD5 cells correlated with the degree of thrombocytopenia in DHF (p < 0.05) which suggests that these cells probably participate in a common pathogenetic mechanism.     

Influence of the dengue serotype, previous dengue infection, and plasma viral load on clinical presentation and outcome during a dengue-2 and dengue-4 co-epidemic

Martinique experienced a dengue outbreak with co-circulation of DENV-2 and DENV-4. In an emergency department-based study, we analyzed whether the clinical presentation and outcome of adult patients were related to serotype, immune status, or plasma viral load. Of the 146 adult patients who had confirmed dengue infection, 91 (62.3%) were classified as having classic dengue fever, 11 (7.5%) fulfilled World Health Organization criteria for dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), 21 other patients (14.4%) presented with at least one typical feature of DHF/DSS [i.e., internal hemorrhage, plasma leakage, marked thrombocytopenia (platelet count < or = 50,000 platelets/mm(3)) and/or shock], and 23 further patients (15.8%) had unusual manifestations. Four patients died. Severe illness was more frequent in patients with secondary dengue infection (odds ratio, 7.18; 95% confidence interval, 3.1-16.7; P < 0.001). Multivariate regression analysis showed that gastrointestinal symptoms and other unusual manifestations were independently associated with DENV-2 infection, whereas cough and DHF/DSS features were independently associated with secondary immune response. A high plasma viral load was associated with DENV-2 infection, increased serum liver enzymes, and with DHF/DSS features in patients presenting after the third day of illness. The most severe cases of dengue resulted from the combined effects of DENV-2 and secondary infection.     

Clinical and biochemical profile of dengue haemorrhagic fever in children in Delhi

The clinical and biochemical profile of dengue haemorrhagic fever (DHF) varies from epidemic to epidemic. We studied children hospitalized with DHF from September 2003 to December 2003. All were diagnosed, managed and monitored according to a standard protocol. Of the 34 who fulfilled the World Health Organization criteria of DHF, 22 (64.6%) were male. All patients presented with fever and hepatomegaly. Examination also revealed splenomegaly in 11 (32.4%), ascites in 6 (17.6%) and pleural effusion in 3 (8.8%). Common bleeding manifestations were positive tourniquet test in 22 (64.7%) and epistaxis in eight (23.5%). Most children had a platelet count of between 20,000/mm(3) and 50,000/mm(3) (56%). Bleeding manifestations were not related to platelet count (P > 0.05). Serum glutamic pyruvic transaminase (SGPT) >40 IU/L was seen in 22 (64.6%) patients, alkaline phosphate (ALP) >400 IU/L in 12 (35.3%) and serum bilirubin >1 mg% in 3 (8.8%). IgM dengue serology was positive in 68.5% cases. There was no significant difference in liver function tests with age or sex (P > 0.05). Clinical features of DHF varied from the previous epidemic. Hepatic dysfunction with increased levels of serum enzymes was common in DHF.     

Dengue hemorrhagic fever: knowledge,attitude and practice in Ang Thong Province,Thailand

A cross-sectional study was carried out between July 1998 and June 1999 to identify dengue virus-infected patients under age 15 admitted to seven government hospitals in Ang Thong Province, a central region of Thailand, and to assess the knowledge, attitude, and practice (KAP) of their care takers. To differentiate dengue cases, clinical evaluation and laboratory diagnosis were used. Serum samples were collected from 90 admitted children and also from 80 healthy students. The dengue cases were classified as dengue fever (9 cases, 12.2%) and dengue hemorrhagic fever (DHF: 65 cases, 87.8%). Nine patients had dengue shock syndrome, but no death occurred. With serological confirmation, primary antibody response was observed in 8 (11.3%) and definite secondary infection in 49 (69%). Out of 41 serum samples, 14 (34.1%) were positive for dengue virus isolation: dengue serotypes 1, 2 or 3. A total of 131 care takers of enrolled children were interviewed in the context of KAP in DHF. The majority of them were mothers with primary school education level. Half of the care takers were workers. DHF knowledge of the care takers of the dengue cases, non-cases, and healthy students was almost the same. However, the care takers of dengue cases recognized petechiae as a danger sign, p-value of 0.006. They had a higher response in prevention, control and treatment of DHF than the other two groups after their children were admitted to hospital, p-value of 0.000. The results indicated that DHF remains a public health problem in this area and the people need more understanding of the disease. Continuous campaigns are required for community participation so as to prevent and control DHF successfully.     

An evidence of intestinal mucosal injury in dengue infection

The aim of this study was to determine whether there is an association between dengue infection and intestinal mucosal injury. Serum levels of intestinal fatty acid binding protein (I-FABP) were used as a specific marker for mucosal injury. The diagnosis of all patients was serologically confirmed by anti-dengue IgG or IgM. Serum I-FABP levels of 120 patients were determined and compared to those of 25 controls using ELISA. In order to investigate serum I-FABP among dengue patients, they were categorized into 5 groups according to disease severity: dengue fever (DF), dengue hemorrhagic fever (DHF) grade I through DHF grade IV. The dengue patients had higher levels of serum I-FABP compared to 25 controls (408.0 +/- 499.3 vs 124.72 +/- 147.81 pg/ml, p=0.006). The patients with DHF grade IV had the highest levels of serum I-FABP, ALT, and AST compared to the other groups. However, there were no differences in serum I-FABP, ALT, and AST levels among patients with DF, DHF grade I, grade II, and grade III. Evidence of intestinal mucosal injury in patients with dengue infection was demonstrated. Patients with DHF grade IV had high serum I-FABP levels and had associated liver injury.     

The impact of a program for strengthening dengue hemorrhagic fever case management on the clinical outcome of dengue hemorrhagic fever patients

This study compared the case fatality ratio (CFR) of dengue shock syndrome (DSS) patients admitted to Buri Ram Hospital, an area with CFR of 0.11, 0.43 and 0.23% in 2002, 2003 and 2004, respectively, to obtain a provincial model for dengue case management using the I. development of a special program for strengthening dengue hemorrhagic fever (DHF) case management (No deaths in DSS patients), II. a retrospective review of the medical records of dengue fever (DF), DHF and DSS patients referred to Buri Ram Hospital. We compared the data during the 3 periods of the implementation of this program. Data was statistically analyzed using chi2 or Fisher's exact test for categorical variables, one-way ANOVA for continuous data with normal distribution and Kruskal-Wallis test for nonparametric variables. The numbers of DF, DHF and DSS cases in Buri Ram were 1332, 1700 and 1630 person, respectively, during 2006-2008. The number of DSS patients increased after implementation of the program: 12.2, 51.2 and 47.22 for 2006, 2007 and 2008, respectively, but the complications of the disease decreased. The CFR during 2006, 2007 and 2008 were 0.15, 0 and 0.06% (p > 0.05). The program for strengthening DHF case management did improve clinical outcomes in dengue patients after the implementation. The CFR in 2008 was only 0.06%, lower than the goal of the Ministry of Public Health (<0.13%). This program is still running, sustaining low CFR in dengue patients. It may be used as a model for other provinces in Thailand that have high dengue deaths.     

Dengue and dengue hemorrhagic fever among adults: clinical outcomes related to viremia, serotypes, and antibody response

BACKGROUND: Clinical manifestations of dengue vary in different areas of endemicity and between specific age groups, whereas predictors of outcome have remained controversial. In Brazil, the disease burden predominantly affects adults, with an increasing trend toward progression to dengue hemorrhagic fever (DHF) noted. METHODS: A cohort of adults with confirmed cases of dengue was recruited in central Brazil in 2005. Patients were classified according to the severity of their disease. Associations of antibody responses, viremia levels (as determined by real-time polymerase chain reaction [PCR]), and serotypes (as determined by multiplex PCR) with disease severity were evaluated. RESULTS: Of the 185 symptomatic patients >14 years of age who had a confirmed case of dengue, 26.5% and 23.2% were classified as having intermediate dengue fever (DF)/DHF (defined as internal hemorrhage, plasma leakage, manifested signs of shock, and/or thrombocytopenia [platelet count, < or =50,000 platelets/mm3]) and DHF, respectively. The onset of intermediate DF/DHF and DHF occurred at a late stage of disease, around the period of defervescence. Patients with DHF had abnormal liver enzyme levels, with a >3-fold increase in aspartate aminotransferase level, compared with the range of values considered to be normal. Overall, 65% of patients presented with secondary infections with dengue virus, with such infection occurring in similar proportions of patients in each of the 3 disease category groups. Dengue virus serotype 3 (DV3) was the predominant serotype, and viremia was detected during and after defervescence among patients with DHF or intermediate DF/DHF. CONCLUSIONS: Viremia was detected after defervescence in adult patients classified as having DHF or intermediate DF/DHF. Secondary infection was not a predictor of severe clinical manifestation in adults with infected with the DV3 serotype.     

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.     

Dengue Serotype-Specific Differences in Clinical Manifestation,Laboratory Parameters and Risk of Severe Disease in Adults,Singapore

Studies on serotype-specific features of dengue and disease severity on adults are limited. We prospectively recruited adult febrile patients without alternate diagnosis to dengue from April 2005 to December 2011. Outcomes were defined using both the World Health Organization (WHO) 1997 and 2009 criteria; Dengue hemorrhagic fever (DHF) and severe dengue (SD). Infecting serotype was identified in 469 dengue-confirmed patients comprising 22.0% dengue virus serotype 1 (DENV-1), 57.1% DENV-2, 17.1% DENV-3, and 3.8% DENV-4. Cases infected with DENV-1 were more likely to present with red eyes whereas presence of joint pain and lower platelet count was associated with DENV-2 cases. After adjusting for potential confounders, DENV-1 was associated with both DHF (adjusted Relative Risk [aRR] = 1.74) and SD (aRR = 2.1) whereas DENV-2 had a lower risk of DHF (aRR = 0.5). DENV-1 genotype 1 and DENV-2 cosmopolitan were the predominant genotypes identified. Infecting dengue serotype and possibly genotype may play an important role in disease severity among adult dengue patients in Singapore.     

Comparison of clinical features and hematologic abnormalities between dengue fever and dengue hemorrhagic fever among children in the Philippines

To demonstrate the differences of clinical features and hematologic abnormalities between dengue fever (DF) and dengue hemorrhagic fever (DHF), 359 pediatric patients admitted St. Luke's Medical Center in Quezon City, between 1999 and 2001 in Metro Manila, and adjoining provinces the Philippines, with a laboratory-confirmed dengue virus infection were evaluated. One third of the patients had DHF, and most of these patients were without shock. Restlessness, epistaxis, and abdominal pain were more associated with DHF. The platelet count was significantly lower in the DHF group than in the DF group before and after defervescence. In the DHF patients, the hematocrit was significantly increased before defervescence, and decreased the day after due to administration of intravenous fluid. Coagulation abnormalities associated with most DHF patients were thrombocytopenia and an increased fibrinolysis, but not disseminated intravascular coagulation. We present recent data on readily obtained clinical and laboratory data that can be used for early diagnosis and consequently earlier appropriate treatment of dengue virus infections.     

Dengue hemorrhagic fever in infancy at Petchabun Hospital, Thailand

Prospective study of dengue hemorrhagic fever in infancy at the Pediatric Department, Petchabun Hospital during May 1997 to April 1999 is reported. There were 31 patients (2.9%) from total DHF cases of 1,044. Ten patients from 31 (32.2%) were referred from district hospitals. Male to female ratio was 17:14 (1.2:1). Maximal, minimal and median ages were 11.5 months, 22 days and 8 months, respectively. All patients had signs, symptoms and laboratory results compatible with dengue hemorrhagic fever. Serologic response was primary dengue infection. Five patients (16.1%) had gastrointestinal hemorrhage, all of them needed blood transfusion. Crystalline solution was fluid of choice given to all patients. Three patients were complicated with febrile convulsions. All patients had rapid and uneventful recovery.     

Application of revised dengue classification criteria as a severity marker of dengue viral infection in Indonesia

A prospective study of dengue infected patients at Dr.Soetomo Hospital pediatric ward was carried out from October 2008 to April 2009 to evaluate the revised dengue classification system proposed by the Dengue Control (DENCO), for early detection of severe dengue infected patients using the WHO classification system for comparison, with the addition of clinical interventions as a tool to grade for severity. One hundred forty-five patients were included in the study. Using the WHO classification system, 122 cases (84.1%) were classified as having non-severe dengue, of which 70 (48.3%) were classified as having dengue fever (DF), 39 (26.9%) as having dengue hemorrhagic fever (DHF) grade I, and 13 (9%) as having DHF grade II. Twenty-three (15.9%) were classified as having severe dengue, of which 16 (11%) were classified as having DHF grade III and 7 (4.8%) as having DHF grade IV. With clinical interventions included, 8 cases (6.6%) originally classified as having non-severe dengue infection were reclassified as having severe infection (sensitivity = 74%, specificity = 100%, likelihood ratio (-) = 0.26). Using the new dengue classification system, 117 cases (80.7%) were classified as having non-severe dengue infection, of which 79 (54.5%) were classified as having dengue without warning signs and 38 (26.2%) were classified as having dengue with warning signs, while 28 (19.3%) were classified as having severe dengue infection. Using clinical intervention, 4 cases (3.4%) which were originally classified as having non-severe dengue infection were reclassified as having severe dengue infection (sensitivity = 88%, specificity = 99%, likelihood ratio (+) = 98.88, likelihood ratio (-) = 0.13). Binary logistic regression showed the revised dengue classification system (p = 0.000, Wald:22.446) was better in detecting severe dengue infections than the WHO classification system (p = 0.175, Wald:6.339).