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Fulltext Prediction of mortality in severe dengue cases

Md-Sani SS, Md-Noor J, Han WH, Gan SP, Rani NS, Tan HL, et al.

BMC Infect Dis, 2018 05 21;18(1):232.
PMID: 29783955 DOI: 10.1186/s12879-018-3141-6

BACKGROUND: Increasing incidence of dengue cases in Malaysia over the last few years has been paralleled by increased deaths. Mortality prediction models will therefore be useful in clinical management. The aim of this study is to identify factors at diagnosis of severe dengue that predicts mortality and assess predictive models based on these identified factors.
METHOD: This is a retrospective cohort study of confirmed severe dengue patients that were admitted in 2014 to Hospital Kuala Lumpur. Data on baseline characteristics, clinical parameters, and laboratory findings at diagnosis of severe dengue were collected. The outcome of interest is death among patients diagnosed with severe dengue.
RESULTS: There were 199 patients with severe dengue included in the study. Multivariate analysis found lethargy, OR 3.84 (95% CI 1.23-12.03); bleeding, OR 8.88 (95% CI 2.91-27.15); pulse rate, OR 1.04 (95% CI 1.01-1.07); serum bicarbonate, OR 0.79 (95% CI 0.70-0.89) and serum lactate OR 1.27 (95% CI 1.09-1.47), to be statistically significant predictors of death. The regression equation to our model with the highest AUROC, 83.5 (95% CI 72.4-94.6), is: Log odds of death amongst severe dengue cases = - 1.021 - 0.220(Serum bicarbonate) + 0.001(ALT) + 0.067(Age) - 0.190(Gender).
CONCLUSION: This study showed that a large proportion of severe dengue occurred early, whilst patients were still febrile. The best prediction model to predict death at recognition of severe dengue is a model that incorporates serum bicarbonate and ALT levels.

Matched MeSH terms: Severe Dengue/diagnosis; Severe Dengue/mortality*
Fulltext Dengue virus serotype 2 from a sylvatic lineage isolated from a patient with dengue hemorrhagic fever

Cardosa J, Ooi MH, Tio PH, Perera D, Holmes EC, Bibi K, et al.

PLoS Negl Trop Dis, 2009;3(4):e423.
PMID: 19399166 DOI: 10.1371/journal.pntd.0000423

Dengue viruses circulate in both human and sylvatic cycles. Although dengue viruses (DENV) infecting humans can cause major epidemics and severe disease, relatively little is known about the epidemiology and etiology of sylvatic dengue viruses. A 20-year-old male developed dengue hemorrhagic fever (DHF) with thrombocytopenia (12,000/ul) and a raised hematocrit (29.5% above baseline) in January 2008 in Malaysia. Dengue virus serotype 2 was isolated from his blood on day 4 of fever. A phylogenetic analysis of the complete genome sequence revealed that this virus was a member of a sylvatic lineage of DENV-2 and most closely related to a virus isolated from a sentinel monkey in Malaysia in 1970. This is the first identification of a sylvatic DENV circulating in Asia since 1975.

Matched MeSH terms: Severe Dengue/pathology; Severe Dengue/virology*
Fulltext High producing tumor necrosis factor alpha gene alleles in protection against severe manifestations of dengue

Sam SS, Teoh BT, Chinna K, AbuBakar S

Int J Med Sci, 2015;12(2):177-86.
PMID: 25589894 DOI: 10.7150/ijms.8988

Dengue virus (DENV) infection usually presents with mild self-limiting dengue fever (DF). Few however, would present with the more severe form of the disease, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). In the present study, the association between IL-12B, IL-10 and TNF-α gene polymorphisms and dengue severity was investigated.
METHODS: A case-control study was performed on a total of 120 unrelated controls, 86 DF patients and 196 DHF/DSS patients. The polymorphisms in IL-12B, IL-10 and TNF-α genes were genotyped using PCR-RFLP and PCR-sequencing methods.
RESULTS: A protective association of TNF-α -308A allele and -308GA genotype against DHF/DSS was observed, while TNF-α -238A allele and -238GA genotype were associated with DHF/DSS. A combination of TNF-α -308GA+AA genotype and IL-10 non-GCC haplotypes, IL-12B pro homozygotes (pro1/pro1, pro2/pro2) and IL-12B 3'UTR AC were significantly correlated with protective effects against DHF/DSS. An association between the cytokine gene polymorphisms and protection against the clinical features of severe dengue including thrombocytopenia and increased liver enzymes was observed in this study.
CONCLUSION: The overall findings of the study support the correlation of high-producer TNF-α genotypes combined with low-producer IL-10 haplotypes and IL-12B genotypes in reduced risk of DHF/DSS.
KEYWORDS: Infectious disease; cytokine; dengue; genetics; polymorphism.; tropical

Matched MeSH terms: Severe Dengue/virology
Fulltext Review of Dengue hemorrhagic fever fatal cases seen among adults: a retrospective study

Sam SS, Omar SF, Teoh BT, Abd-Jamil J, AbuBakar S

PLoS Negl Trop Dis, 2013;7(5):e2194.
PMID: 23658849 DOI: 10.1371/journal.pntd.0002194

Dengue is a mosquito-borne viral disease endemic in many countries in the tropics and sub-tropics. The disease affects mainly children, but in recent years it is becoming more of an adult disease. Malaysia experienced a large dengue outbreak in 2006 to 2007, involving mostly adults, with a high number of deaths.

Matched MeSH terms: Severe Dengue/mortality*; Severe Dengue/epidemiology*
Fulltext Dengue death with evidence of hemophagocytic syndrome and dengue virus infection in the bone marrow

Ab-Rahman HA, Wong PF, Rahim H, Abd-Jamil J, Tan KK, Sulaiman S, et al.

Springerplus, 2015;4:665.
PMID: 26558168 DOI: 10.1186/s40064-015-1463-z

INTRODUCTION: HPS is a potentially life-threatening histiocytic disorder that has been described in various viral infections including dengue. Its involvement in severe and fatal dengue is probably more common but is presently under recognized.
CASE DESCRIPTION: A 38-year-old female was admitted after 5 days of fever. She was deeply jaundiced, leukopenic and thrombocytopenic. Marked elevation of transaminases, hyperbilirubinemia and hypoalbuminemia were observed. She had deranged INR values and prolonged aPTT accompanied with hypofibrinogenemia. She also had splenomegaly. She was positive for dengue IgM. Five days later she became polyuric and CT brain image showed gross generalized cerebral edema. Her conditions deteriorated by day 9, became confused with GCS of 9/15. Her BMAT showed minimal histiocytes. Her serum ferritin level peaked at 13,670.00 µg/mL and her sCD163 and sCD25 values were markedly elevated at 4750.00 ng/mL and 4191.00 pg/mL, respectively. She succumbed to the disease on day 10 and examination of her tissues showed the presence of dengue virus genome in the bone marrow.
DISCUSSION AND EVALUATION: It is described here, a case of fatal dengue with clinical features of HPS. Though BMAT results did not show the presence of macrophage hemophagocytosis, other laboratory features were consistent with HPS especially marked elevation of ferritin, sCD163 and sCD25. Detection of dengue virus in the patient's bone marrow, fifteen days after the onset of fever was also consistent with the suggestion that the HPS is associated with dengue virus infection.
CONCLUSIONS: The findings highlight HPS as a possible complication leading to severe dengue and revealed persistent dengue virus infection of the bone marrow. Detection of HPS markers; ferritin, sCD163 and sCD25, therefore, should be considered for early recognition of HPS-associated dengue.
KEYWORDS: Bone marrow; Dengue; Ferritin; Hemophagocytic syndrome; MAS; Macrophage
Study site: University Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia

Matched MeSH terms: Severe Dengue*
Fulltext Diagnosis of severe dengue: Challenges, needs and opportunities

Wong PF, Wong LP, AbuBakar S

J Infect Public Health, 2020 Feb;13(2):193-198.
PMID: 31405788 DOI: 10.1016/j.jiph.2019.07.012

BACKGROUND: Delayed diagnosis of dengue cases with increased risk for severe disease could lead to poor disease outcome. To date there is no specific laboratory diagnostic test for severe dengue. This qualitative study explored expert views regarding current issues in diagnosing severe dengue, rationale for severe dengue-specific diagnostics, future prospects and features of potential diagnostics for severe dengue.
METHODS: In-depth individual interviews with thematic saturation were conducted between May and July 2018. The data was analyzed using thematic analysis.
RESULTS: Based on expert opinion, diagnosis of severe dengue is challenging as it depends on astute clinical interpretation of non-dengue-specific clinical and laboratory findings. A specific test that detects impending manifestation of severe dengue could 1) overcome failure in identifying severe disease for referral or admission, 2) facilitate timely and appropriate management of plasma leakage and bleeding, 3) overcome the lack of clinical expertise and laboratory diagnosis in rural health settings. The most important feature of any diagnostics for severe dengue is the point-of-care (POC) format where it can be performed at or near the bedside.
CONCLUSION: The development of diagnostics to detect impending severe dengue is warranted to reduce the morbidity and mortality rates of dengue infection and it should be prioritized.

Matched MeSH terms: Severe Dengue/diagnosis*
Fulltext The east coast districts are the possible epicenter of severe dengue in Sabah

Kaur N, Rahim SSSA, Jaimin JJ, Dony JJF, Khoon KT, Ahmed K

J Physiol Anthropol, 2020 Aug 14;39(1):19.
PMID: 32795350 DOI: 10.1186/s40101-020-00230-0

BACKGROUND: Malaysia recorded the highest number of dengue cases between 2014 and 2017. There are 13 states and three federal territories in Malaysia, and each area varies in their prevalence of dengue. Sabah is one of the states situated in Borneo, Malaysia. Although dengue has been increasing for the last several years, no study was being done to understand the burden and serotype distribution of the dengue virus (DENV) in Sabah. Therefore, the present study was carried out to understand the epidemiology of the dengue infection and the factors responsible for severe dengue in Sabah.
METHODS: Data on dengue infection were extracted from the dengue database of the state of Sabah from 2013 through 2018. DENV NS-1-positive serum samples from multiple sites throughout Sabah were sent to the state public health laboratory, Kota Kinabalu Public Health Laboratory, for serotype determination. The analysis of factors associated with severe dengue was determined from the data of 2018 only.
RESULTS: In 2013, there were 724 dengue cases; however, from 2014, dengue cases increased exponentially and resulted in 3423 cases in 2018. Increasing dengue cases also led to increased dengue mortality. The number of dengue deaths in 2013 was only five which then gradually increased, and in 2018, 29 patients died. This is an increase of 580% from 2013 to 2018. Deaths were considerably more in the districts of the east coast of Sabah compared with districts in the west coast. During the study period, all DENV serotypes could be identified as serotypes circulating in Sabah. In 2018, the predominant serotype was DENV-3. The monthly peak of dengue infection varied in different years. In the logistic regression analysis, it was identified that children were 6.5 times, patients infected with mixed serotype of DENV were 13 times, and cases from the districts of the east coast were 5.2 times more likely to develop severe dengue.
CONCLUSIONS: An increasing trend of dengue infection has been observed in Sabah. The burden of dengue, severe dengue, and mortality was noted especially in the districts of the east coast of Sabah. Severe dengue was most likely developed in children, cases from the east coast, and patients infected with mixed serotype of DENV.

Matched MeSH terms: Severe Dengue/epidemiology*; Severe Dengue/virology*
A comparison of the pattern of liver involvement in dengue hemorrhagic fever with classic dengue fever

Wahid SF, Sanusi S, Zawawi MM, Ali RA

Southeast Asian J. Trop. Med. Public Health, 2000 Jun;31(2):259-63.
PMID: 11127322

The impact of dengue on liver function was studied on fifty serologically confirmed dengue cases admitted to Hospital Universiti Kebangsaan Malaysia (HUKM). Twenty-five of these patients had classic dengue fever (DF) and 25 had grade 1 or 2 dengue hemorrhagic fever (DHF). There were more (60%) DHF patients with hepatomegaly compared to DF (40%) but the difference was not statistically significant. Analysis of the liver profile showed that liver dysfunction was commoner in DHF compared to DF, indicating that the degree of liver impairment may be related to the severity of DHF. Hyperbilirubinemia was noted in 3 (12%) DHF and 2 (8%) DF patients. The mean (range) serum bilirubin was higher in DHF [14.2(5-50) micromol/l] compared to DF [10.9(5-30) micromol/l)] (p > 0.05). Elevated levels of serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were observed more frequently in DHF (20 and 12 patients respectively) compared to DF (16 and 8 patients respectively). Nine (36%) DHF and 6 (24%) DF patients had concomitant elevation of ALT and ALP levels. The mean (range) serum ALT levels were 109.3(23-325) U/l in DHF and 90.8(13-352) U/l in DF (p > 0.05). The mean (range) serum ALP levels were 102.2(15-319) U/l in DHF and 93.3(34-258) U/l in DF (p > 0.05). The ALT and ALP levels were significantly higher in DHF patients with spontaneous bleeding than those without bleeding (p < 0.05) None of the patients developed fulminant hepatitis. The immunoregulatory cells, which include the T (CD3), B (CD 19), CD4, CD8, CD5 and natural killer (NK) cells were significantly lower in DHF compared to DF patients (p < 0.05). However, the reduction in these cell counts did not correlate with the liver dysfunction seen in DHF patients. In conclusion, hepatomegaly and liver dysfunction were commoner in DHF compared to DF.

Matched MeSH terms: Severe Dengue/immunology; Severe Dengue/pathology*; Severe Dengue/physiopathology*
Fulltext Evaluation of creatine kinase and liver enzymes in identification of severe dengue

Md Sani SS, Han WH, Bujang MA, Ding HJ, Ng KL, Amir Shariffuddin MA

BMC Infect Dis, 2017 07 21;17(1):505.
PMID: 28732476 DOI: 10.1186/s12879-017-2601-8

BACKGROUND: Existing biomarkers such as AST, ALT and hematocrit have been associated with severe dengue but evidence are mixed. Recently, interests in creatine kinase as a dengue biomarker have risen. These biomarkers represent several underlying pathophysiological processes in dengue. Hence, we aimed to assess AST, ALT, CK and hematocrit in identification of severe dengue and to assess the correlational relationship amongst common biomarkers of dengue.
METHODS: This was a retrospective cohort study of confirmed dengue patients who were warded in Kuala Lumpur Hospital between December 2014 and January 2015. CK, AST, ALT, hematocrit, platelet count, WBC and serum albumin were taken upon ward admission and repeated at timed intervals. Composite indices based on admission AST and ALT were analyzed. Correlation coefficients and coefficients of determination were computed.
RESULTS: Among the 365 cases reviewed, twenty-two (6%) patients had severe dengue. AST and ALT were found to be good at identification of severe dengue. The AST2/ALT composite index was the most accurate (AUC 0.83; 95% CI 0.73 - 0.93). Optimal cutoff was 402 with a sensitivity of 59.1% (95% CI: 36.4 - 79.3%) and specificity of 92.4% (95% CI: 89.1 - 95.0%). Modified cutoff of 653 had a sensitivity of 40.9% (95% CI: 20.7 - 63.7%) and specificity of 97.4% (95% CI: 95.1 - 98.8%). Our analyses also suggested that several underlying biological processes represented by biomarkers tested were unrelated despite occurring in the same disease entity. Also, markers of plasma leakage were discordant and AST was likely hepatic in origin.
CONCLUSIONS: The composite index AST2/ALT may be used as a marker for identification of severe dengue based on admission AST and ALT, with two choices of cutoff values, 402 and 653. AST is most likely of liver origin and CK does not provide additional value.

Matched MeSH terms: Severe Dengue/diagnosis*; Severe Dengue/enzymology*
Evaluation of the spatial risk factors for high incidence of dengue fever and dengue hemorrhagic fever using GIS application

Aziz Shafie

Sains Malaysiana, 2011;40:1179-1186.

In Malaysia, the incidence of Dengue Fever (DF) and Dengue Hemorrhagic Fever (DHF) have risen dramatically in the last twenty years. With the use of Geographical Information System an explanation for the spread and control of these diseases can be obtained. This study aims to develop a spatial modeling that can predict the risks for DF and DHF based on environmental factors such as physical surroundings, land use, rainfall, temperature and GIS application using logistic regression. A total of 16 variables were used in the process of spatial modeling development. At the significant level of 0.05, the results of logistic regression showed that only 10 out of 16 significant variables in the modeling process. The accuracy of the resulting model is 70.3%. A crucial feature of this study is a risk area map for incidence of DF and DHF in the study area. This study also highlights the application of spatial analysis in planning and implementing the process for the prevention and control activities of DF and DHF in Malaysia.

Matched MeSH terms: Severe Dengue
Fulltext A case series of secondary Hemophagocytic Lymphohistiocytosis (HLH) secondary to dengue infection receiving dexamethasone in a tertiary centre

Liew Kean Yew, Suraya Hanim Abdullah, Beh Ting Yuen

Malaysian Journal of Medicine and Health Sciences, 2019;15(106):41-41.
MyJurnal

Introduction: Secondary Hemophagocytic Lymphohistiocytosis (HLH) is a condition seen in severe dengue that can be potentially fatal. Timely management using HLH-directed treatment such as steroids or etoposide have been seen to improve the outcome of patients however there is no protocol on how to manage the disease. Two criteria commonly used to guide the direction of treatment are namely the HLH-2004 criteria and the Hscore; with the latter being used more often. The best cut-off H score is 169 corresponding to a sensitivity of 93%, specificity of 86% and accurate classification of 90% of the patients. We described of five patients diagnosed with severe dengue compli-cated with HLH. Methods: 5 cases that were diagnosed with severe dengue with secondary HLH and received dexa-methasone were reviewed retrospectively and clinical data extracted. Results: All patients had fever beyond critical or leaking phase. Four out of five cases had Hscore higher than 169 and had a mean score of 181 with only one bone marrow performed. Three patients had concurrent leaking and bleeding and three patients had fast progression of se-vere transaminitis during the critical phase. The mean peak ferritin level was 21077 micro/L. The only bone marrow aspiration done revealed increased macrophages and hemophagocytic activity. All patients received a short course of dexamethasone and discharged well. Conclusion: Short course dexamethasone is effective in treatment of HLH in dengue despite the concerns of administration of steroids in bleeding dengue patient. Secondary HLH in dengue remains a clinical diagnosis with no conclusive diagnostic criteria. It should be suspected in a severe dengue patient with hyperferritinemia and persistent fever. Technical difficulty of performing bone marrow during severe dengue makes conclusive diagnosis remains elusive.

Matched MeSH terms: Severe Dengue
Fulltext Serotype-specific host responses in rhesus macaques after primary dengue challenge

Hickey AC, Koster JA, Thalmann CM, Hardcastle K, Tio PH, Cardosa MJ, et al.

Am J Trop Med Hyg, 2013 Dec;89(6):1043-57.
PMID: 24062475 DOI: 10.4269/ajtmh.13-0145

Dengue virus (DENV) is considered to be the most important arthropod-borne viral disease and causes more than 100 million human infections annually. To further characterize primary DENV infection in vivo, rhesus macaques were infected with DENV-1, DENV-2, DENV-3, or DENV-4 and clinical parameters, as well as specificity and longevity of serologic responses, were assessed. Overt clinical symptoms were not present after infection. However, abnormalities in blood biochemical parameters consistent with heart, kidney, and liver damage were observed, and changes in plasma fibrinogen, D-dimers, and protein C indicated systemic activation of the blood coagulation pathway. Significant homotypic and heterotypic serum immunoglobulins were present in all animals, and IgG persisted for at least 390 days. Serum neutralizing antibody responses were highly serotype specific by day 120. However, some heterotypic neutralizing activity was noted in infected animals. Identification of serotype-specific host responses may help elucidate mechanisms that mediate severe DENV disease after reinfection.

Matched MeSH terms: Severe Dengue/immunology; Severe Dengue/virology
Fulltext Symptomatic Dengue Disease in Five Southeast Asian Countries: Epidemiological Evidence from a Dengue Vaccine Trial

Nealon J, Taurel AF, Capeding MR, Tran NH, Hadinegoro SR, Chotpitayasunondh T, et al.

PLoS Negl Trop Dis, 2016 Aug;10(8):e0004918.
PMID: 27532617 DOI: 10.1371/journal.pntd.0004918

Dengue incidence has increased globally, but empirical burden estimates are scarce. Prospective methods are best-able to capture all severities of disease. CYD14 was an observer-blinded dengue vaccine study conducted in children 2-14 years of age in Indonesia, Malaysia, Thailand, the Philippines, and Vietnam. The control group received no vaccine and resembled a prospective, observational study. We calculated the rates of dengue according to different laboratory or clinical criteria to make inferences about dengue burden, and compared with rates reported in the passive surveillance systems to calculate expansion factors which describe under-reporting. Over 6,933 person-years of observation in the control group there were 319 virologically confirmed dengue cases, a crude attack rate of 4.6%/year. Of these, 92 cases (28.8%) were clinically diagnosed as dengue fever or dengue hemorrhagic fever by investigators and 227 were not, indicating that most symptomatic disease fails to satisfy existing case definitions. When examining different case definitions, there was an inverse relationship between clinical severity and observed incidence rates. CYD14's active surveillance system captured a greater proportion of symptomatic dengue than national passive surveillance systems, giving rise to expansion factors ranging from 0.5 to 31.7. This analysis showed substantial, unpredictable and variable under-reporting of symptomatic dengue, even within a controlled clinical trial environment, and emphasizes that burden estimates are highly sensitive to case definitions. These data will assist in generating disease burden estimates and have important policy implications when considering the introduction and health economics of dengue prevention and control interventions.

Matched MeSH terms: Severe Dengue/epidemiology*; Severe Dengue/prevention & control*; Severe Dengue/virology
Fulltext Dengue vaccine design: issues and challenges

Cardosa MJ

Br Med Bull, 1998;54(2):395-405.
PMID: 9830205 DOI: 10.1093/oxfordjournals.bmb.a011696

Dengue virus infection is now a global problem affecting tens of millions of people. The spread of the four dengue virus serotypes had led to increased incidence of dengue haemorrhagic fever (DHF) reported and with 2.5 billion people at risk, efforts towards the development of safe and effective vaccines against dengue must be accelerated. This chapter reviews some of the important lessons of pathogenesis which may be learnt from classical studies in the field and place these in the context of current knowledge about the molecular biology of the virus. The issues which have to be addressed in designing a safe vaccine against dengue are raised and the problems of designing subunit as well as whole virus vaccines are pointed out, particularly with regard to the phenomenon of antibody dependent enhancement and, more generally, the problem of immune potentiation of disease. More efforts must be made to understand the basis of pathogenesis in DHF and in finding out what nature has to teach about protection against and recovery from dengue virus infection.

Matched MeSH terms: Severe Dengue/immunology; Severe Dengue/prevention & control
Fulltext A two-year review on epidemiology and clinical characteristics of dengue deaths in Malaysia, 2013-2014

Woon YL, Hor CP, Hussin N, Zakaria A, Goh PP, Cheah WK

PLoS Negl Trop Dis, 2016 05;10(5):e0004575.
PMID: 27203726 DOI: 10.1371/journal.pntd.0004575

BACKGROUND: Dengue infection is the fastest spreading mosquito-borne viral disease, which affects people living in the tropical and subtropical countries. Malaysia had large dengue outbreaks in recent years. We aimed to study the demographics and clinical characteristics associated with dengue deaths in Malaysia.

METHODS: We conducted a retrospective review on all dengue deaths that occurred nationwide between 1st January 2013 and 31st December 2014. Relevant data were extracted from mortality review reports and investigational forms. These cases were categorized into children (<15 years), adults (15-59 years) and elderly (≥60 years) to compare their clinical characteristics.

RESULTS: A total of 322 dengue deaths were reviewed. Their mean age was 40.7±19.30 years, half were females and 72.5% were adults. The median durations of first medical contact, and hospitalization were 1 and 3 days, respectively. Diabetes and hypertension were common co-morbidities among adults and elderly. The most common warning signs reported were lethargy and vomiting, with lethargy (p = 0.038) being more common in children, while abdominal pain was observed more often in the adults (p = 0.040). But 22.4% did not have any warning signs. Only 34% were suspected of dengue illness at their initial presentation. More adults developed severe plasma leakage (p = 0.018). More than half (54%) suffered from multi-organ involvement, and 20.2% were free from any organ involvement. Dengue deaths occurred at the median of 3 days post-admission. Dengue shock syndrome (DSS) contributed to more than 70% of dengue deaths, followed by severe organ involvement (69%) and severe bleeding (29.7%).

CONCLUSION: In Malaysia, dengue deaths occurred primarily in adult patients. DSS was the leading cause of death, regardless of age groups. The atypical presentation and dynamic progression of severe dengue in this cohort prompts early recognition and aggressive intervention to prevent deaths.

TRIAL REGISTRATION: National Medical Research Registry (NMRR, NMRR-14-1374-23352).

Matched MeSH terms: Severe Dengue/diagnosis; Severe Dengue/mortality*; Severe Dengue/epidemiology*; Severe Dengue/virology
Fulltext Meta-analysis of biomarkers for severe dengue infections

Soo KM, Khalid B, Ching SM, Tham CL, Basir R, Chee HY

PeerJ, 2017;5:e3589.
PMID: 28929009 DOI: 10.7717/peerj.3589

BACKGROUND: Dengue viral infection is an acute infection that has the potential to have severe complications as its major sequela. Currently, there is no routine laboratory biomarker with which to predict the severity of dengue infection or monitor the effectiveness of standard management. Hence, this meta-analysis compared biomarker levels between dengue fever (DF) and severe dengue infections (SDI) to identify potential biomarkers for SDI.

METHODS: Data concerning levels of cytokines, chemokines, and other potential biomarkers of DF, dengue hemorrhagic fever, dengue shock syndrome, and severe dengue were obtained for patients of all ages and populations using the Scopus, PubMed, and Ovid search engines. The keywords "(IL1* or IL-1*) AND (dengue*)" were used and the same process was repeated for other potential biomarkers, according to Medical Subject Headings terms suggested by PubMed and Ovid. Meta-analysis of the mean difference in plasma or serum level of biomarkers between DF and SDI patients was performed, separated by different periods of time (days) since fever onset. Subgroup analyses comparing biomarker levels of healthy plasma and sera controls, biomarker levels of primary and secondary infection samples were also performed, as well as analyses of different levels of severity and biomarker levels upon infection by different dengue serotypes.

RESULTS: Fifty-six studies of 53 biomarkers from 3,739 dengue cases (2,021 DF and 1,728 SDI) were included in this meta-analysis. Results showed that RANTES, IL-7, IL-8, IL-10, IL-18, TGF-b, and VEGFR2 levels were significantly different between DF and SDI. IL-8, IL-10, and IL-18 levels increased during SDI (95% CI, 18.1-253.2 pg/mL, 3-13 studies, n = 177-1,909, I(2) = 98.86%-99.75%). In contrast, RANTES, IL-7, TGF-b, and VEGFR2 showed a decrease in levels during SDI (95% CI, -3238.7 to -3.2 pg/mL, 1-3 studies, n = 95-418, I(2) = 97.59%-99.99%). Levels of these biomarkers were also found to correlate with the severity of the dengue infection, in comparison to healthy controls. Furthermore, the results showed that IL-7, IL-8, IL-10, TGF-b, and VEGFR2 display peak differences between DF and SDI during or before the critical phase (day 4-5) of SDI.

DISCUSSION: This meta-analysis suggests that IL-7, IL-8, IL-10, TGF-b, and VEGFR2 may be used as potential early laboratory biomarkers in the diagnosis of SDI. This can be used to predict the severity of dengue infection and to monitor the effectiveness of treatment. Nevertheless, methodological and reporting limitations must be overcome in future research to minimize variables that affect the results and to confirm the findings.

Matched MeSH terms: Severe Dengue*
Fulltext Meta-Analysis of Dengue Severity during Infection by Different Dengue Virus Serotypes in Primary and Secondary Infections

Soo KM, Khalid B, Ching SM, Chee HY

PLoS One, 2016;11(5):e0154760.
PMID: 27213782 DOI: 10.1371/journal.pone.0154760

INTRODUCTION: Dengue virus (DENV) infection is currently a major cause of morbidity and mortality in the world; it has become more common and virulent over the past half-century and has gained much attention. Thus, this review compared the percentage of severe cases of both primary and secondary infections with different serotypes of dengue virus.
METHODS: Data related to the number of cases involving dengue fever (DF), dengue hemorrhagic fever (DHF), dengue shock syndrome (DSS) or severe dengue infections caused by different serotypes of dengue virus were obtained by using the SCOPUS, the PUBMED and the OVID search engines with the keywords "(dengue* OR dengue virus*) AND (severe dengue* OR severity of illness index* OR severity* OR DF* OR DHF* OR DSS*) AND (serotypes* OR serogroup*)", according to the MESH terms suggested by PUBMED and OVID.
RESULTS: Approximately 31 studies encompassing 15,741 cases reporting on the dengue serotypes together with their severity were obtained, and meta-analysis was carried out to analyze the data. This study found that DENV-3 from the Southeast Asia (SEA) region displayed the greatest percentage of severe cases in primary infection (95% confidence interval (CI), 31.22-53.67, 9 studies, n = 598, I2 = 71.53%), whereas DENV-2, DENV-3, and DENV-4 from the SEA region, as well as DENV-2 and DENV-3 from non-SEA regions, exhibited the greatest percentage of severe cases in secondary infection (95% CI, 11.64-80.89, 4-14 studies, n = 668-3,149, I2 = 14.77-96.20%). Moreover, DENV-2 and DENV-4 from the SEA region had been found to be more highly associated with dengue shock syndrome (DSS) (95% CI, 10.47-40.24, 5-8 studies, n = 642-2,530, I2 = 76.93-97.70%), while DENV-3 and DENV-4 from the SEA region were found to be more highly associated with dengue hemorrhagic fever (DHF) (95% CI, 31.86-54.58, 9 studies, n = 674-2,278, I2 = 55.74-88.47%), according to the 1997 WHO dengue classification. Finally, DENV-2 and DENV-4 from the SEA region were discovered to be more highly associated with secondary infection compared to other serotypes (95% CI, 72.01-96.32, 9-12 studies, n = 671-2,863, I2 = 25.01-96.75%).
CONCLUSION: This study provides evidence that the presence of certain serotypes, including primary infection with DENV-3 from the SEA region and secondary infection with DENV-2, DENV-3, and DENV-4 also from the SEA region, as well as DENV-2 and DENV-3 from non SEA regions, increased the risk of severe dengue infections. Thus, these serotypes are worthy of special consideration when making clinical predictions upon the severity of the infection.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015026093 (http://www.crd.york.ac.uk/PROSPERO).

Matched MeSH terms: Severe Dengue/virology*
Fulltext Isolation of monoclonal antibodies-escape variant of dengue virus serotype 1

Chua SK, Selvanesan S, Sivalingam B, Chem YK, Norizah I, Zuridah H, et al.

Singapore Med J, 2006 Nov;47(11):940-6.
PMID: 17075660

During an outbreak from December 2004 to March 2005, 138 isolates of dengue virus were prospectively obtained from acute-phase serum samples of 1,067 patients with the provisional clinical diagnosis of acute dengue illness admitted to the adult wards of Hospital Tengku Ampuan Rahimah, Klang, Malaysia. Of the 138 dengue virus isolates, 87, 11, 24 and 3 were typed as dengue serotypes 1, 2, 3 and 4, respectively, by a commercial dengue virus typing kit using monoclonal antibodies (Mab). 13 dengue virus isolates could not be assigned to any specific serotype by serotyping Mab and molecular typing using dengue-type specific molecular typing primer pairs. We report the associated clinical features and limited molecular genetics of this Mab-escape dengue virus variant.

Matched MeSH terms: Severe Dengue/epidemiology; Severe Dengue/virology
Fulltext Evaluating the sensitivity of a commercial dengue NS1 antigen-capture ELISA for early diagnosis of acute dengue virus infection

Kumarasamy V, Chua SK, Hassan Z, Wahab AH, Chem YK, Mohamad M, et al.

Singapore Med J, 2007 Jul;48(7):669-73.
PMID: 17609831

INTRODUCTION: The aim of this report is to establish an accurate diagnosis of acute dengue virus infection early, in order to provide timely information for the management of patients and early public health control of dengue outbreak.
METHODS: 224 serum samples from patients with a clinical diagnosis of acute dengue infection, which were subsequently confirmed by laboratory tests, were used to evaluate the performance of a commercially-available dengue NS1 antigen-capture ELISA kit.
RESULTS: The dengue NS1 antigen-capture ELISA gave an overall sensitivity rate of 93.3 percent (209/224). The sensitivity rate was significantly higher in acute primary dengue (97.4 percent) than in acute secondary dengue (68.8 percent). In comparison, the virus isolation gave an overall positive isolation rate of 64.7 percent, with a positive rate of 70.8 percent and 28.1 percent, for acute primary dengue and acute secondary dengue, respectively. Molecular detection of dengue RNA by RT-PCR gave an overall positive detection rate of 63.4 percent, with a positive rate of 62.5 percent and 68.8 percent, for acute primary dengue and acute secondary dengue, respectively. Of the 224 acute serum samples from patients with laboratory-confirmed acute dengue infection, dengue IgM was detected in 88 specimens, comprising 68 acute primary dengue specimens and 20 acute secondary dengue specimens. NS1 antigen-capture ELISA kit gave an overall sensitivity rate of 88.6 percent in the presence of anti-dengue IgM and 96.3 percent in the absence of anti-dengue IgM.
CONCLUSION: Of the 224 acute serum samples, the sample ages of 166 acute serum samples are known. The positive detection rate of dengue NS1 antigen-capture ELISA, on the whole, was higher than the other three established diagnostic test methods for laboratory diagnosis of acute dengue infection.

Matched MeSH terms: Severe Dengue/diagnosis*; Severe Dengue/immunology
Fulltext Effect of chemical fogging on immature Aedes mosquitoes in natural field conditions

Chua KB, Chua IL, Chua IE, Chua KH

Singapore Med J, 2005 Nov;46(11):639-44.
PMID: 16228097

Dengue and dengue haemorrhagic fever are common and serious arboviral diseases endemic in a number of countries situated in both the tropical and subtropical belts.

Matched MeSH terms: Severe Dengue/prevention & control

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