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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: Dengue Virus/classification*; Dengue Virus/genetics; Dengue Virus/immunology
Anti-dengue virus serotype 2 activity and mode of action of a novel peptide

Chew MF, Tham HW, Rajik M, Sharifah SH

J Appl Microbiol, 2015 Oct;119(4):1170-80.
PMID: 26248692 DOI: 10.1111/jam.12921

To identify a novel antiviral peptide against dengue virus serotype 2 (DENV-2) by screening a phage display peptide library and to evaluate its in vitro antiviral activity and mode of action.

Matched MeSH terms: Dengue Virus/classification; Dengue Virus/drug effects*; Dengue Virus/isolation & purification; Dengue Virus/physiology
Opsoclonus-myoclonus-ataxia syndrome associated with dengue virus infection

Tan AH, Linn K, Sam IC, Tan CT, Lim SY

Parkinsonism Relat Disord, 2015 Feb;21(2):160-1.
PMID: 25443556 DOI: 10.1016/j.parkreldis.2014.11.009
Matched MeSH terms: Dengue Virus/isolation & purification*
DENVirDB: a web portal of dengue virus sequence information on Asian isolates

Asnet MJ, Rubia AG, Ramya G, Nagalakshmi RN, Shenbagarathai R

J Vector Borne Dis, 2014 Jun;51(2):82-5.
PMID: 24947213

DENVirDB is a web portal that provides the sequence information and computationally curated information of dengue viral proteins. The advent of genomic technology has increased the sequences available in the public databases. In order to create relevant concise information on Dengue Virus (DENV), the genomic sequences were collected, analysed with the bioinformatics tools and presented as DENVirDB. It provides the comprehensive information of complete genome sequences of dengue virus isolates of Southeast Asia, viz. India, Bangladesh, Sri Lanka, East Timor, Philippines, Malaysia, Papua New Guinea, Brunei and China. DENVirDB also includes the structural and non-structural protein sequences of DENV. It intends to provide the integrated information on the physicochemical properties, topology, secondary structure, domain and structural properties for each protein sequences. It contains over 99 entries in complete genome sequences and 990 entries in protein sequences, respectively. Therefore, DENVirDB could serve as a user friendly database for researchers in acquiring sequences and proteomic information in one platform.

Matched MeSH terms: Dengue Virus/genetics*
The effect of extrinsic incubation temperature on development of dengue serotype 2 and 4 viruses in Aedes aegypti (L.)

Rohani A, Wong YC, Zamre I, Lee HL, Zurainee MN

Southeast Asian J. Trop. Med. Public Health, 2009 Sep;40(5):942-50.
PMID: 19842378

Dengue 2 and 4 viruses obtained from dengue-infected patients were maintained in a C6/36 Aedes albopictus Skuse cell line and used to infect adult female Aedes aegypti mosquitoes. Each serotype was mixed separately with fresh human erythrocytes and fed to adult female mosquitoes using an artificial membrane feeding technique. Fully engorged mosquitoes were selected and retained at 26 degrees C, 28 degrees C and 30 degrees C to observe dengue virus development in Aedes vectors. Virus detection was carried out by reverse-transcriptase polymerase chain reaction (RT-PCR). The virus was first detected on Day 9 at 26 degrees C and 28 degrees C and on Day 5 at 30 degrees C for both dengue 2 and 4. The study shows the incubation period of the viruses decreased when the extrinsic incubation temperature increases.

Matched MeSH terms: Dengue Virus/growth & development*
Fulltext Co-infection of dengue virus and chikungunya virus in two patients with acute febrile illness

Nayar SK, Noridah O, Paranthaman V, Ranjit K, Norizah I, Chem YK, et al.

Med J Malaysia, 2007 Oct;62(4):335-6.
PMID: 18551940 MyJurnal

During an outbreak of chikungunya in a dengue hyperendemic area within the Kinta district of Perak, two patients with acute febrile illness were laboratory confirmed to have co-infection of both dengue and chikungunya viruses in their blood. The concomitant presence of two types of viruses transmitted by the same vector in a susceptible population contributed to the resultant event. A good understanding of virus vector ecology in association with population dynamics and wider application of improved laboratory techniques by using different cell-lines suited for optimal replication of each type of virus and the correct utilization of powerful molecular techniques will enhance accurate diagnosis of these infectious diseases.

Matched MeSH terms: Dengue Virus*
Zinc accelerates dengue virus type 2-induced apoptosis in Vero cells

Shafee N, AbuBakar S

FEBS Lett., 2002 Jul 31;524(1-3):20-4.
PMID: 12135735

Dengue virus type 2 (DENV-2) infection induced apoptotic cellular DNA fragmentation in Vero cells within 8 days of infection. The addition of high concentrations of extracellular Zn(2+) but not Ca(2+), Mg(2+) or Mn(2+) to the cell culture medium hastened the detection of apoptosis to within 4 h after infection. No apoptotic cellular DNA fragmentation was detected in the cell culture treated with Zn(2+) alone or infected with heat- or ultraviolet light-inactivated DENV-2 in the presence of Zn(2+). These results suggest that (i) apoptosis is induced in African green monkey kidney cells infected with live DENV-2 and (ii) the addition of high extracellular Zn(2+) accelerates detection of apoptosis in the DENV-2-infected cells.

Matched MeSH terms: Dengue Virus/physiology*
Fulltext Dot enzyme immunoassay: an alternative diagnostic aid for dengue fever and dengue haemorrhagic fever

Cardosa MJ, Tio PH

Bull World Health Organ, 1991;69(6):741-5.
PMID: 1786623

A dot enzyme immunoassay (DEIA) for the detection of antibodies to dengue virus was tested for use as a tool in the presumptive diagnosis of dengue fever and dengue haemorrhagic fever. Paired sera from the following groups of patients were tested using the DEIA and the haemagglutination inhibition (HI) test: those with primary dengue fever; those experiencing a second dengue infection; and febrile patients who did not have dengue. The data obtained show that the DEIA can be effectively used at a serum dilution of 1:1000 to confirm presumptive recent dengue in patients with a second dengue infection. However, demonstration of seroconversion proved necessary for patients with primary dengue. At a serum dilution of 1:1000 the DEIA has a specificity of 97.3%. The role of this simple and rapid test in improving the effectivity of programmes for the control of dengue virus infection is discussed.

Matched MeSH terms: Dengue Virus/immunology*
Fulltext Dengue haemorrhagic fever and dengue shock syndrome: are they tumour necrosis factor-mediated disorders?

Yadav M, Kamath KR, Iyngkaran N, Sinniah M

FEMS Microbiol Immunol, 1991 Dec;4(1):45-9.
PMID: 1815710 DOI: 10.1111/j.1574-6968.1991.tb04969.x

A consecutive series of 24 patients with clinical features of primary dengue infection and 22 controls (14 patients with viral fever of unknown origin and 8 healthy subjects) were assayed for serum levels of tumour necrosis factor (TNF). The acute sera of the 24 patients with clinical dengue infection were positive for dengue virus-specific IgM antibody. Clinically, 8 had dengue fever (DF), 14 dengue haemorrhagic fever (DHF) and 2 dengue shock syndrome (DSS). All 16 patients with DHF/DSS had significantly elevated serum TNF levels but the 8 DF patients had TNF levels equivalent to that in the 22 controls. A case is made for augmented TNF production having a role for the pathophysiological changes observed in DHF/DSS and mediator modulation as a possible therapeutic approach to treatment.

Matched MeSH terms: Dengue Virus/immunology
Nucleotide sequence of the envelope protein gene of a Malaysian dengue-2 virus isolated from a patient with dengue haemorrhagic fever

Samuel S, Koh CL, Blok J, Pang T, Lam SK

Nucleic Acids Res, 1989 Nov 11;17(21):8875.
PMID: 2587234
Matched MeSH terms: Dengue Virus/genetics*
Nucleotide sequence of the envelope protein gene of a Malaysian dengue-2 virus isolated from a patient with dengue shock syndrome

Samuel S, Koh CL, Blok J, Pang T, Lam SK

Nucleic Acids Res, 1989 Nov 11;17(21):8888.
PMID: 2587243
Matched MeSH terms: Dengue Virus/genetics*
Nucleotide sequence of the envelope protein gene of a Malaysian dengue-2 virus isolated from a patient with dengue fever

Samuel S, Koh CL, Blok J, Pang T, Lam SK

Nucleic Acids Res, 1989 Nov 11;17(21):8887.
PMID: 2587242
Matched MeSH terms: Dengue Virus/genetics*
A dot enzyme immunoassay for dengue 3 virus: comparison with the haemagglutination inhibition test

Cardosa MJ, Noor Sham S, Tio PH, Lim SS

Southeast Asian J. Trop. Med. Public Health, 1988 Dec;19(4):591-4.
PMID: 3238470

A dot enzyme immunoassay (DEIA) was used to determine the levels of antibody to dengue 3 virus in the acute and convalescent sera of febrile patients with a clinical diagnosis of dengue fever or dengue haemorrhagic fever. The antibody titres were compared with titres determined by the haemagglutination inhibition (HI) test. The results of the study showed that, besides being more simple to perform, the DEIA is in order of magnitude more sensitive than the HI test. Furthermore, the data suggest that it is possible to use a single dilution as a cutoff point to predict with reasonable accuracy, if a patient has had a recent dengue infection. The DEIA test for antibodies to dengue virus is an appropriate technology highly suitable for rapid diagnosis and surveillance in developing countries.

Matched MeSH terms: Dengue Virus/isolation & purification*
Highly sensitive and specific graphene/TiO2 impedimetric immunosensor based on plant-derived tetravalent envelope glycoprotein domain III (EDIII) probe antigen for dengue diagnosis

Siew QY, Pang EL, Loh HS, Tan MTT

Biosens Bioelectron, 2021 Mar 15;176:112895.
PMID: 33358432 DOI: 10.1016/j.bios.2020.112895

This study reports on the development of a novel impedimetric immunosensor design using plant-derived antigenic glycoprotein for the detection of dengue virus (DENV) IgG antibodies. The electrochemical immunosensor platform was constructed using screen-printed carbon electrode (SPCE) modified with graphene/titanium dioxide (G/TiO2) nanocomposite to improve the electrode in terms electrochemical performance and specific surface area. A plant-derived dengue envelope domain III (EDIII) protein was used as the antigenic probe protein in this immunosensing strategy. Under optimised sensing conditions, the immunosensor demonstrated high sensitivity towards DENV IgG in a wide linear working range (62.5-2000 ng/mL), with a limit of detection of 2.81 ng/mL. The immunosensor showed high specificity for discriminating DENV IgG against antibodies of other infectious disease, including the closely related Zika virus (ZIKV). The reliability of the immunosensor in serological diagnosis was verified by challenging the immunosensor against serum samples, compared to conventional enzyme-linked immunosorbent assay (ELISA). As shown by its remarkable performance throughout the study, the devised immunosensor is proposed as a reliable and practical diagnostic tool for the serological detection of dengue in realistic applications.

Matched MeSH terms: Dengue Virus*
Dengue epidemic in Malaysia: urban versus rural comparison of dengue immunoglobulin G seroprevalence among Malaysian adults aged 35-74 years

Azami NAM, Moi ML, Salleh SA, Neoh HM, Kamaruddin MA, Jalal NA, et al.

Trans R Soc Trop Med Hyg, 2020 11 06;114(11):798-811.
PMID: 32735681 DOI: 10.1093/trstmh/traa056

BACKGROUND: A periodic serosurvey of dengue seroprevalence is vital to determine the prevalence of dengue in countries where this disease is endemic. This study aimed to determine the prevalence of dengue immunoglobulin G (IgG) seropositivity among healthy Malaysian adults living in urban and rural areas.
METHODS: A total of 2598 serum samples (1417 urban samples, 1181 rural samples) were randomly collected from adults ages 35-74 y. The presence of the dengue IgG antibody and neutralising antibodies to dengue virus (DENV) 1-4 was determined using enzyme-linked immunosorbent assay and the plaque reduction neutralisation test assay, respectively.
RESULTS: The prevalence of dengue IgG seropositivity was 85.39% in urban areas and 83.48% in rural areas. The seropositivity increased with every 10-y increase in age. Ethnicity was associated with dengue seropositivity in urban areas but not in rural areas. The factors associated with dengue seropositivity were sex and working outdoors. In dengue IgG-positive serum samples, 98.39% of the samples had neutralising antibodies against DENV3, but only 70.97% of them had neutralising antibodies against DENV4.
CONCLUSION: The high seroprevalence of dengue found in urban and rural areas suggests that both urban and rural communities are vital for establishing and sustaining DENV transmission in Malaysia.

Matched MeSH terms: Dengue Virus*
Micro-anatomical changes in major blood vessel caused by dengue virus (serotype 2) infection

Priya SP, Sakinah S, Ling MP, Chee HY, Higuchi A, Hamat RA, et al.

Acta Trop, 2017 Jul;171:213-219.
PMID: 28427958 DOI: 10.1016/j.actatropica.2017.04.010

Dengue virus (DENV) has emerged as a major economic concern in developing countries, with 2.5 billion people believed to be at risk. Vascular endothelial cells (ECs) lining the circulatory system from heart to end vessels perform crucial functions in the human body, by aiding gas exchange in lungs, gaseous, nutritional and its waste exchange in all tissues, including the blood brain barrier, filtration of fluid in the glomeruli, neutrophil recruitment, hormone trafficking, as well as maintenance of blood vessel tone and hemostasis. These functions can be deregulated during DENV infection. In this study, BALB/c mice infected with DENV serotype 2 were analyzed histologically for changes in major blood vessels in response to DENV infection. In the uninfected mouse model, blood vessels showed normal architecture with intact endothelial monolayer, tunica media, and tunica adventitia. In the infected mouse model, DENV distorted the endothelium lining and disturbed the smooth muscle, elastic laminae and their supporting tissues causing vascular structural disarrangement. This may explain the severe pathological illness in DENV-infected individuals. The overall DENV-induced damages on the endothelial and it's supporting tissues and the dysregulated immune reactions initiated by the host were discussed.

Matched MeSH terms: Dengue Virus/classification*
Autochthonous spread of DENV-3 genotype III in Malaysia mitigated by pre-existing homotypic and heterotypic immunity

Tan KK, Nellis S, Zulkifle NI, Sulaiman S, AbuBakar S

Epidemiol Infect, 2018 10;146(13):1635-1641.
PMID: 29860959 DOI: 10.1017/S0950268818001425

Dengue virus type 3 genotype III (DENV-3/III) is widely distributed in most dengue-endemic regions. It emerged in Malaysia in 2008 and autochthonously spread in the midst of endemic DENV-3/I circulation. The spread, however, was limited and the virus did not cause any major outbreak. Spatiotemporal distribution study of DENV-3 over the period between 2005 and 2011 revealed that dengue cases involving DENV-3/III occurred mostly in areas without pre-existing circulating DENV-3. Neutralisation assays performed using sera of patients with the respective infection showed that the DENV-3/III viruses can be effectively neutralised by sera of patients with DENV-3 infection (50% foci reduction neutralisation titres (FRNT50) > 1300). Sera of patients with DENV-1 infection (FRNT50 ⩾ 190), but not sera of patients with DENV-2 infection (FRNT50 ⩽ 50), were also able to neutralise the virus. These findings highlight the possibility that the pre-existing homotypic DENV-3 and the cross-reacting heterotypic DENV-1 antibody responses could play a role in mitigating a major outbreak involving DENV-3/III in the Klang Valley, Malaysia.

Matched MeSH terms: Dengue Virus/genetics*
Fulltext The association between obesity and dengue virus (DENV) infection in hospitalised patients

Tan VPK, Ngim CF, Lee EZ, Ramadas A, Pong LY, Ng JI, et al.

PLoS One, 2018;13(7):e0200698.
PMID: 30016369 DOI: 10.1371/journal.pone.0200698

Both obesity and DENV infections are growing public health concerns that have far-ranging socioeconomic effects, especially in developing countries. Despite the increasing prevalence of these conditions, there is a scarcity of data investigating the potential relationships between these two entities. Our study aims to examine the influence of obesity on various clinical and laboratory parameters amongst patients with DENV infections. A total of 335 hospitalized patients aged >12 years who were DENV non-structural protein 1 (NS1) antigen-positive were enrolled in this study. Clinical and laboratory variables were compared between patients with and without obesity. Multivariate analysis showed that the following admission clinical findings and laboratory results were independently associated with obesity; chills and rigors (AOR:2.653, 95% CI: 1.286-5.474), higher temperature (AOR:1.485, 95% CI: 1.080-2.042), higher systolic BP (AOR:1.057, 95% CI:1.037-1.078), raised haematocrit (AOR: 1.953, 95% CI: 1.010-3.778), elevated creatinine (AOR:3.504, 95% CI:1.351-9.008) and elevated ALT (AOR: 4.146, 95% CI:1.878-9.154). Obesity was found to be significantly associated with hospitalization >3 days (AOR: 1.990, 95% CI: 1.134-3.494) and the presence of increasing haematocrit with decreasing platelets (AOR: 2.134, 95% CI = 1.235-3.688). Serial assessment of laboratory data revealed that peak haematocrit was significantly higher and nadir platelets levels were significantly lower in obese patients. Both peak and admission levels of leukocyte counts, AST, ALT and creatinine were significantly higher in the obese group. Conversely, both admission and nadir albumin levels were lower for the obese group, although only nadir albumin levels achieved statistical significance. These findings support closer clinical monitoring of obese patients who present with DENV infections, as this patient cohort may possess an increased tendency towards developing more severe clinical manifestations of DENV infections as compared to non-obese patients.

Matched MeSH terms: Dengue Virus*
Acrylic-based genosensor utilizing metal salphen labeling approach for reflectometric dengue virus detection

Mazlan NF, Tan LL, Karim NHA, Heng LY, Jamaluddin ND, Yusof NYM, et al.

Talanta, 2019 Jun 01;198:358-370.
PMID: 30876573 DOI: 10.1016/j.talanta.2019.02.036

An optical genosensor based on Schiff base complex (Zn2+ salphen) DNA label and acrylic microspheres (AMs) as polymer support of the capturing DNA probe (cpDNA) was developed for dengue virus serotype 2 (DEN-2) detection via reflectance spectrophotometric method. The solid-state optical DNA biosensor showed high selectivity and specificity up to one-base mismatch in the target DNA sequence owing to the salphen chemical structure that is rich in localized electrons, and allowed π-π stacking interaction between stacked base pairs of double-stranded DNA (dsDNA). The reflectometric DNA microsensor demonstrated a broad linear detection range towards DEN-2 DNA from 1 × 10-15 M to 1 × 10-3 M with a low limit of detection (LOD) obtained at 1.21 × 10-16 M. The DNA biosensor gave reproducible optical response with a satisfactory relative standard deviation (RSD) at 3.1%, (n = 3), and the reflectance response was stable even after four regeneration cycles of the DNA biosensor. The optical genosensor was proven comparable with standard reverse transcription polymerase chain reaction (RT-PCR) in detecting DEN-2 genome acquired from clinical samples of serum, urine and saliva of dengue virus infected patients under informed consent. The developed reflectometric DNA biosensor is advantageous in offering an early DEN-2 diagnosis, when fever symptom started to manifest in patient.

Matched MeSH terms: Dengue Virus/isolation & purification*
Fulltext Factors determining dengue outbreak in Malaysia

Ahmad R, Suzilah I, Wan Najdah WMA, Topek O, Mustafakamal I, Lee HL

PLoS One, 2018;13(2):e0193326.
PMID: 29474401 DOI: 10.1371/journal.pone.0193326

A large scale study was conducted to elucidate the true relationship among entomological, epidemiological and environmental factors that contributed to dengue outbreak in Malaysia. Two large areas (Selayang and Bandar Baru Bangi) were selected in this study based on five consecutive years of high dengue cases. Entomological data were collected using ovitraps where the number of larvae was used to reflect Aedes mosquito population size; followed by RT-PCR screening to detect and serotype dengue virus in mosquitoes. Notified cases, date of disease onset, and number and type of the interventions were used as epidemiological endpoint, while rainfall, temperature, relative humidity and air pollution index (API) were indicators for environmental data. The field study was conducted during 81 weeks of data collection. Correlation and Autoregressive Distributed Lag Model were used to determine the relationship. The study showed that, notified cases were indirectly related with the environmental data, but shifted one week, i.e. last 3 weeks positive PCR; last 4 weeks rainfall; last 3 weeks maximum relative humidity; last 3 weeks minimum and maximum temperature; and last 4 weeks air pollution index (API), respectively. Notified cases were also related with next week intervention, while conventional intervention only happened 4 weeks after larvae were found, indicating ample time for dengue transmission. Based on a significant relationship among the three factors (epidemiological, entomological and environmental), estimated Autoregressive Distributed Lag (ADL) model for both locations produced high accuracy 84.9% for Selayang and 84.1% for Bandar Baru Bangi in predicting the actual notified cases. Hence, such model can be used in forestalling dengue outbreak and acts as an early warning system. The existence of relationships among the entomological, epidemiological and environmental factors can be used to build an early warning system for the prediction of dengue outbreak so that preventive interventions can be taken early to avert the outbreaks.

Matched MeSH terms: Dengue Virus*

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