Utility of the WHO dengue guidelines in pediatric immunological studies.

Dengue is a significant health problem due to the high burden of critical infections during outbreaks. In 1997, the World Health Organization (WHO) classified dengue as dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). It was revised in 2009 (updated in 2015), and the new guidelines recommended classifying patients as dengue without warning signs (DNS), dengue with warning signs (DWS), and severe dengue (SD). Although the utility of the revised 2009 classification for clinical studies is accepted, for immunological studies it needs to be clarified. We determined the usefulness of the 2009 classification for pediatric studies that analyze the circulating interleukin (IL)-6 and IL-8, two inflammatory cytokines. Plasma levels of IL-6 and IL-8 were evaluated in the acute and convalescent phases by flow cytometry in children with dengue classified using the 1997 and 2009 WHO guidelines. The plasma levels of IL-6 and IL-8 were elevated during the acute and decreased during convalescence, and both cytokines served as a good marker of acute dengue illness compared to convalescence. There were no differences in the plasma level of the evaluated cytokines among children with different clinical severity with any classification, except for the IL-8, which was higher in DWS than DNS. Based on the levels of IL-8, the 2009 classification identified DWS plus SD (hospital-treated children) compared to the DNS group [area under the curve (AUC): 0.7, p = 0.028]. These results support the utility of the revised 2009 (updated in 2015) classification in studies of immune markers in pediatric dengue.

Leptospirosis and Dengue Coinfection-Associated Multi-Organ Dysfunction Syndrome: A Case Report.

Dengue and leptospirosis are frequently discussed separately, with dengue causing rash and leptospirosis causing jaundice. Currently, there are more and more reports of coinfections. The comparable clinical symptoms of both infections make it challenging to distinguish between leptospirosis and dengue. Differentiating between leptospirosis and dengue is crucial since leptospirosis has a more favorable prognosis with early antibiotic therapy, whereas dengue does not have a specific treatment, although early detection is essential for close monitoring and cautious fluid management. Here, we highlight a case of dengue virus and leptospirosis coinfection in a female who presented with acute febrile illness, dyspnea, and altered sensorium, which progressed to multiorgan dysfunction syndrome, involving the neurological, respiratory, hepatic, and hematological systems.

Oro-Pharyngeal Candidiasis in Two Dengue Patients.

Dengue, a prevalent arboviral disease, has witnessed a resurgence in India, with outbreaks frequently reported. However, dengue-associated oral (oro-pharyngeal) candidiasis (DAOC) was never reported. We present two severe dengue cases with oral/oro-pharyngeal pseudomembranous candidiasis. Case 1 of a young man without any comorbidities or abuse or immunosuppression presented with fever, headache, altered sensorium, throat pain on recovery, and laboratory reports confirmed dengue with leukopenia, thrombocytopenia, and severe hepatic involvement with oro-pharyngeal candidiasis. Similarly, case 2 of a middle-aged man with a history of smoking and diabetes presented with fever, gum bleeding, and throat pain, later confirmed to be dengue NS1 positive with thrombocytopenia, and mild-moderate hepatic involvement along with oral-oro-pharyngeal candidiasis. Both cases showed improvement with conservative management and oral nystatin suspension. These cases prompt consideration of superadded candida infections in dengue patients, emphasizing the need for further study and clinical vigilance.

Dengue, Chikungunya, and Zika: The Causes and Threats of Emerging and Re-emerging Arboviral Diseases.

The recent emergence and re-emergence of viral infections transmitted by vectors, Zika, chikungunya, dengue, and others, is a cause for international concern. Here, we provide a summary of the current understanding of the transmission, clinical features, diagnosis, global burden, and the likelihood of future epidemics by these viruses. Arboviruses transmitted by mosquitoes are challenging to diagnose and can have surprising clinical complications. Dengue, chikungunya, and Zika are the most important diseases caused by arboviruses worldwide, especially in tropical and subtropical regions. These are transmitted to humans by day-biting Aedes aegypti and Aedes albopictus mosquitoes. In India, the increase in the incidence of dengue and chikungunya cases is primarily linked to the dissemination of Aedes aegypti. A rapid and accurate diagnosis is paramount for effectively controlling dengue outbreaks. As there is no vaccination or specific treatment available for these viruses, vector control is the only comprehensive solution available.

Uncovering the Hidden Threat: A Case Report of Suspected Dengue Fever in Armenia.

Dengue is a viral infection transmitted by mosquitoes that causes fever, headache, joint pain, nausea, vomiting, and pain behind the eyes. In severe cases, it can progress to dengue hemorrhagic fever and dengue shock syndrome, which can be life-threatening. Armenia has not reported a single case of dengue to date and is non-endemic for this disease. However, it has been found that the vector of the disease, Aedes albopictus, is present in Armenia since 2016. The aim of this report is to present the imported case of suspected dengue hemorrhagic fever. A 23-year-old female who was admitted to the University Hospital experienced symptoms of general weakness, fever, joint pain, and chills after her return from Bali and had a three-day febrile period. A thorough examination revealed mosquito bites on her skin. On the fourth day of hospitalization, the patient's condition deteriorated. She started experiencing vaginal bleeding. On the same day, the patient noted a small petechiae rash sized 1-2 mm in diameter in the upper and lower extremities. The patient deteriorated, with progressive leukopenia and thrombocytopenia, and hypertransaminasemia. Screening tests for HIV and hepatitis A, B, C, and E were performed, and the results showed that the anti-hepatitis C antibody was positive, while the hepatitis C virus polymerase chain reaction was negative. The case was reported to the National Center for Disease Control and Prevention as an imported case of hemorrhagic fever. Unfortunately, no lab test was available there for confirmation of the diagnosis. The patient received IV infusion and symptomatic treatment. Her condition improved, and upon discharge, she was in a state of recovery. This case report highlights the importance of early diagnosis and appropriate treatment for hemorrhagic fevers, particularly dengue fever. The unavailability of diagnostic kits for dengue in Armenia highlights the need to invest in improving their availability. It also emphasizes the importance of maintaining dengue surveillance in non-endemic nations and carefully evaluating and monitoring febrile patients who have returned from dengue-endemic countries.

A short communication of 2022 dengue outbreak in Bangladesh: a continuous public health threat.

Dengue virus infection, a highly prominent health concern, has caused many health complications, positive cases, and deaths in Bangladesh in previous years. However, the prevalence of this infection and fatality rates in 2022 has shattered all prior records. The dengue virus vector, mosquitoes, found a high prevalence of infection due to the weather's favorable conditions for breeding in the months of June and July. While there is presently no particular vaccination for dengue infection, awareness of its epidemiology, pathogenesis, signs, and symptoms may aid in the development of improved diagnostic and treatment strategies. The government should also improve the infrastructure of cities to make prevent mosquito breeding and the spread of dengue infection.

Aminotransferases in Relation to the Severity of Dengue: A Systematic Review.

A systematic review was conducted to investigate the relationship between aminotransferases and the severity of dengue infection, which is a prevalent and significant infection in tropical and subtropical regions. Aminotransferases are enzymes that are often elevated in dengue due to the liver's physiological and immunological response to the infection. This review focused on analyzing various studies that examined the correlation between aminotransferase levels and the severity of dengue. Extensive literature searches were performed using ("dengue*" OR "dengue fever*" OR "dengue haemorrhagic fever*" OR "dengue shock syndrome*") AND ("alanine aminotransferase*" OR "aspartate aminotransferase*") on PubMed. The selected articles were thoroughly reviewed, encompassing epidemiology, pathogenesis, and clinical manifestations of dengue. The consistent findings across the studies indicated that aminotransferases can serve as predictive markers for dengue severity. Therefore, early assessment of liver enzyme levels is crucial in dengue cases, and elevated levels should be closely monitored to prevent adverse outcomes.

A Case Report on CNS Hemophagocytic Lymphohistiocytosis in an Infant With Dengue Hemorrhagic Fever.

India is an endemic country for dengue. The incidence of hemophagocytic lymphohistiocytosis (HLH) with dengue in children has been well-reported. However, central nervous system (CNS) HLH associated with dengue has not been described in the literature yet. We hereby report a novel case of CNS HLH triggered by dengue infection. An eight-month-old, well-grown male infant with uneventful antenatal, perinatal, and neonatal history was admitted with a history of febrile illness associated with cough, cold, vomiting, and loose motions and one episode of hematochezia and hepatosplenomegaly on examination. Investigations revealed bi-cytopenia, hyper-ferritinemia, deranged coagulation profile, liver function test, and hypo-fibrinogenemia. Dengue non-structural protein 1 ( NS1) antigen was positive. The child was given dexamethasone and continued supportive care with a diagnosis of dengue shock syndrome. The child showed an overall transient improvement, however, he had rebound fever followed by right focal convulsion on Day 9 of steroids. MRI brain revealed areas of diffusion-restricted embolic infarcts with diffuse leptomeningeal enhancement and mild cerebral edema, and CSF showed a total leukocyte count of 80 cells with 75% lymphocytic picture, histiocytes with hemophagocytosis, confirmatory of CNS HLH. Intrathecal methotrexate, hydrocortisone, and intravenous (IV) etoposide were started. However, the child succumbed to his illness. CNS involvement in dengue-triggered HLH needs to be suspected despite subtle neurological signs and aggressively managed following a multi-departmental approach to ensure the best clinical and neuro-developmental outcomes.

Dengue and Chikungunya Co-Infection-Associated Multi-Organ Dysfunction Syndrome: A Case Report.

Dengue and chikungunya infections are increasing globally, especially in India. While the majority of patients settle with symptomatic management, some develop life-threatening complications. Here we discuss a case of co-infection between dengue virus (DENV-2) and chikungunya virus (CHIKV) in a young Indian male who presented with an acute febrile illness that progressed to multi-organ dysfunction involving the hepatic, nervous, respiratory, and hematological systems. We discuss the management of this complicated case and attempt to generate awareness regarding the severity of co-infection by these viruses.

Predictive Factors for the Complications of Dengue Fever in Children: A Retrospective Analysis.

Background and objective Dengue fever (DF) and its complications - dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) - are major public health problems in Southeast Asia. Predicting the development of DHF and DSS using hematological parameters and ultrasonic signs of vascular leakage will help in reducing morbidity and mortality associated with these diseases. Hence, this study aimed to test the association of platelets and packed cell volume (PCV) on day one (D1) of admission with gallbladder wall thickness (GWT) and ascites, which herald the onset of DHF and DSS. Methods The electronic health records of 52 pediatric patients admitted during a mini-outbreak were analyzed to assess platelets and PCV on D1, laboratory and ultrasonography findings, and outcomes. Correlations between D1 hematological parameters and GWT and ascites were tested. Results There was a positive correlation between GWT of more than 5 mm and ascites. However, there was no significant correlation of platelets and PCV on D1 with either GWT or ascites and consequently DHF or DSS. All the patients responded to fluid, blood, and supportive therapy. There were no mortalities. Conclusion Patients who develop GWT after DF are at an increased risk of developing ascites that deteriorate to DHF and DSS. D1 platelets and PCV are not reliable indicators for predicting the progression or worsening of the disease in the pediatric population.

Association Between Soluble Notch Ligand Delta-like Ligand 1 and Bleeding Complications in Patients With Dengue Fever Infection.

Bleeding associated with endothelial damage is a key feature of severe dengue fever. In the current study, we investigated whether Notch ligands were associated with bleeding in 115 patients with confirmed dengue infection in Vietnam. Soluble Notch ligands were determined by means of enzyme-linked immunosorbent assay. Seventeen of 115 patients (14.8%) experienced bleeding manifestations. High soluble delta-like ligand 1 (sDLL1) plasma levels was associated with bleeding (median, 15 674 vs 7117 pg/mL; P < .001). Receiver operating characteristic (ROC) curve analysis demonstrated that sDLL1 had the best test performance (area under the ROC curve, 0.852), with 88% sensitivity and 84% specificity. The combination with alanine aminotransferase and aspartate aminotransferase slightly increased sDLL1 performance. sDLL1 may be useful to guide clinical management of patients with patients in endemic settings.

Modeling the Relationship Between Antibody-Dependent Enhancement and Disease Severity in Secondary Dengue Infection.

Sequential infections with different dengue serotypes (DENV-1, 4) significantly increase the risk of a severe disease outcome (fever, shock, and hemorrhagic disorders). Two hypotheses have been proposed to explain the severity of the disease: (1) antibody-dependent enhancement (ADE) and (2) original T cell antigenic sin. In this work, we explored the first hypothesis through mathematical modeling. The proposed model reproduces the dynamic of susceptible and infected target cells and dengue virus in scenarios of infection-neutralizing and infection-enhancing antibody competition induced by two distinct serotypes of the dengue virus during secondary infection. The enhancement and neutralization functions are derived from basic concepts of chemical reactions and used to mimic binding to the virus by two distinct populations of antibodies. The analytic study of the model showed the existence of two equilibriums: a disease-free equilibrium and an endemic one. Using the concept of the basic reproduction number [Formula: see text], we performed the asymptotic stability analysis for the two equilibriums. To measure the severity of the disease, we considered the maximum value of infected cells as well as the time when this maximum is reached. We observed that it corresponds to the time when the maximum enhancing activity for the infection occurs. This critical time was calculated from the model to be a few days after the occurrence of the infection, which corresponds to what is observed in the literature. Finally, using as output [Formula: see text], we were able to rank the contribution of each parameter of the model. In particular, we highlighted that the cross-reactive antibody responses may be responsible for the disease enhancement during secondary heterologous dengue infection.

A novel anti-NS2BNS3pro antibody-based indirect ELISA test for the diagnosis of dengue virus infections.

Dengue virus reportedly circulates as four genetically distinct serotypes for which there is no widely accepted vaccine or drug at present. Morbidity and mortality caused by this virus are alarming for the possible increased threat to human health. A suitable diagnostic test is the prerequisite for designing and developing control measures. But, the tests being employed at present possess one or the other drawback for this disease diagnosis. During the dengue virus infections, NS2B is essential for the stability and catalytic activity of the NS3 protease. N-terminal 185 amino acids of NS3 protease domain along with hydrophilic portion of NS2B (NS2BNS3pro) is being used to screen dengue inhibitors but not for diagnosis until now. In the present study, we have used purified NS2BNS3pro as an antigen to trap anti-NS2BNS3pro antibodies of the clinical samples. Antibodies were detected successfully in both Western blot analysis and enzyme-linked immunosorbent assay (ELISA) tests. In ELISA, antibodies were detected in both primary and secondary infections of all serotypes. Interestingly, 17 samples declared as other febrile infections by NS1 and IgM/IgG tests were found to be positive in present test, which were further confirmed by reverse-transcription polymerase chain reaction. In silico studies suggested the absence of conserved epitopes between NS2BNS3pro and the counterpart in JEV, Zika, and CHIKV, indicating less possibility of crossreaction, which was in turn confirmed by using synthetic peptides representing the above epitopes. Statistical analysis with 76% specificity, 87% sensitivity, and 95% concordance also supported the present test as a suitable test for large scale diagnosis of dengue virus infections.

Infection severity across scales in multi-strain immuno-epidemiological Dengue model structured by host antibody level.

Infection by distinct Dengue virus serotypes and host immunity are intricately linked. In particular, certain levels of cross-reactive antibodies in the host may actually enhance infection severity leading to Dengue hemorrhagic fever (DHF). The coupled immunological and epidemiological dynamics of Dengue calls for a multi-scale modeling approach. In this work, we formulate a within-host model which mechanistically recapitulates characteristics of antibody dependent enhancement in Dengue infection. The within-host scale is then linked to epidemiological spread by a vector-host partial differential equation model structured by host antibody level. The coupling allows for dynamic population-wide antibody levels to be tracked through primary and secondary infections by distinct Dengue strains, along with waning of cross-protective immunity after primary infection. Analysis of both the within-host and between-host systems are conducted. Stability results in the epidemic model are formulated via basic and invasion reproduction numbers as a function of immunological variables. Additionally, we develop numerical methods in order to simulate the multi-scale model and assess the influence of parameters on disease spread and DHF prevalence in the population.

The Difference of sVE-Cadherin Levels between Dengue Hemorrhagic Fever Patients with Shock and without Shock.

BACKGROUND: Dengue virus infection is an infectious disease caused by the dengue virus and transmitted by the Aedes aegypti mosquito. Dengue virus (DEN-V) consists of 4 serotypes, namely DEN-1, DEN-2, DEN-3, and DEN-4. The most feared result of DHF is death. Death in children is caused by hypovolemic shock due to plasma leakage from intravascular to extravascular space due to endothelial dysfunction. AIM: This study aims to analyse difference in sVE-Cadherin levels in Dengue Hemorrhagic Fever (DHF) with and without shock. MATERIAL AND METHODS: The method of taking samples is consecutive sampling, namely the research subjects obtained based on the order of entry in the hospital with a comparative cross-sectional design. From the results of the calculation using the sample formula, the sample size for each group is set at 32 people. So that the total sample size used for both groups is 64 people. The serum sVE-Cadherin levels using the ELISA method. The statistical test used is the independent t-test. The value of p < 0.05 was said to be statistically significant. RESULTS: The result showed that there was no difference in mean sVE-Cadherin levels between DHF patients with shock and without shock (p > 0.05). CONCLUSION: This study concluded that there was no difference in mean of sVE-Cadherin level in DHF patients with shock and without shock.

The Difference of Angiopoietin-2 Levels between Dengue Hemorrhagic Fever Patients with Shock and without Shock.

BACKGROUND: Dengue infection is one of the problems in the national health sector in Indonesia because the incidence and mortality in Indonesia due to dengue infection is still very high. In 2005 Indonesia became the highest contributor to dengue infection in Southeast Asia (53%) with 95.270 people and 1.298 deaths. AIM: This study aims to analyse differences in angiopoietin-2 levels in dengue hemorrhagic fever (DHF) with and without shock. METHODS: This study was a consecutive sampling design with the research subject was obtained based on the order of admission to the hospital - the serum Angiopoietin-2 levels using the ELISA method. The statistical test used is the independent t-test. The value of p < 0.05 was said to be statistically significant. RESULT: The result showed that the mean of Angiopoietin-2 levels in DHF patients with shock was higher than in DHF (p < 0.05). CONCLUSION: This study concluded that there was a difference in the average level of Angiopoietin-2 among DHF patients with shock compared to without shock.

Online Advanced Analytical Service: Profiles for Dengue Hemorrhagic Fever Transmission in Southern Thailand.

BACKGROUND: Southern Thailand has the highest Dengue Hemorrhagic Fever (DHF) incidence and fatality rate in Thailand. Geographic Information Systems (GIS) technology and spatial analysis techniques are powerful tools to describe epidemiological patterns. The aim of this study was to develop an Online Advanced Analytical Service: Profiles for Dengue Hemorrhagic Fever Transmission (OSD) in Southern Thailand. METHODS: The system was developed using JavaServer Pages (JSP) and Database Management System (DBMS) with Structured Query Language (SQL) technology as the web database tool for data entry and data access, web Mathematica technology for data analysis and Google Maps™ API technology for online data display as the map service implementing GIS technology. RESULTS: The OSD system has been available online at URL http://www.s-cm.co/dengue . Users performed data entry using the web-service with login by social network (i.e. Facebook) account, used data analysis tools with online real-time statistical analysis and data display with transparent color circles overlaid on Google Maps™. CONCLUSION: The OSD system display represents the distribution of DHF cases with spatial information. This system enables health planners to provide interventions for DHF focusing on prevention, control, and strategic planning.

Co-circulation and co-infections of all dengue virus serotypes in Hyderabad, India 2014.

The burden of dengue virus infections increased globally during recent years. Though India is considered as dengue hyper-endemic country, limited data are available on disease epidemiology. The present study includes molecular characterization of dengue virus strains occurred in Hyderabad, India, during the year 2014. A total of 120 febrile cases were recruited for this study, which includes only children and 41 were serologically confirmed for dengue positive infections using non-structural (NS1) and/or IgG/IgM ELISA tests. RT-PCR, nucleotide sequencing and evolutionary analyses were carried out to identify the circulating serotypes/genotypes. The data indicated a high percent of severe dengue (63%) in primary infections. Simultaneous circulation of all four serotypes and co-infections were observed for the first time in Hyderabad, India. In total, 15 patients were co-infected with more than one dengue serotype and 12 (80%) of them had severe dengue. One of the striking findings of the present study is the identification of serotype Den-1 as the first report from this region and this strain showed close relatedness to the Thailand 1980 strains but not to any of the strains reported from India until now. Phylogenetically, all four strains of the present study showed close relatedness to the strains, which are reported to be high virulent.

Complete genome characterization and evolutionary analysis of serotype-4 associated with severe dengue.

Dengue virus circulates as four independent serotypes posing a major public health threat around the globe. In the recent years, frequent dengue outbreaks are being reported in many parts of the world including India. Among four serotypes, Den-4 is the least sampled and studied serotype until recent times, but the reported cases with Den-4 infections were mostly known to associate with severe dengue. In the past three decades, only one complete genome sequence of Den-4 has been published from India. Hence there is a deficit in information with reference to this serotype which would be required in deciphering its association with severe dengue. In this study, we have carried out the complete genome characterization of Den-4 virus, isolated from a dengue shock syndrome patient during the 2015 outbreak from Hyderabad, South India. Phylogenetic analysis revealed the circulation of genotype I (lineage C) which showed close relatedness to the reported virulent strains. The data also indicated few unique amino acid substitutions which are known to be important in virus replication and epitope presentation. This is the first report of complete genome characterization of Den-4 from South India, which may assist in shaping the genetic diversity of circulating strains in India.

Progress towards understanding the pathogenesis of dengue hemorrhagic fever.

Dengue virus (DENV) is a mosquito-borne virus belonging to the Flaviviridae family. There are 4 serotypes of DENV that cause human disease through transmission by mosquito vectors. DENV infection results in a broad spectrum of clinical symptoms, ranging from mild fever to dengue hemorrhagic fever (DHF), the latter of which can progress to dengue shock syndrome (DSS) and death. Researchers have made unremitting efforts over the last half-century to understand DHF pathogenesis. DHF is probably caused by multiple factors, such as virus-specific antibodies, viral antigens and host immune responses. This review summarizes the current progress of studies on DHF pathogenesis, which may provide important information for achieving effective control of dengue in the future.