A 23bp Indel Polymorphism in TLR2 Gene Enhances Inflammation and Disease Severity in Dengue

AbstractBackgroundDengue is the most rapidly spreading viral disease transmitted by the bite of infectedAedesmosquitos. Pathogenesis of dengue is still unclear; although host genetic factors, immune responses and virus serotypes have been proposed to contribute to disease severity. The development of high-throughput methods have allowed to scale up capabilities of identifying the key markers of inflammation. Since NS1 protein of dengue virus has been reported to activate immune cells towards enhanced inflammation through TLR2, we examined the role of a polymorphism, a 23bp deletion in 5’UTR region of TLR2 gene in patients with dengue (with and without warning signs) and correlated with plasma levels of inflammatory mediators with disease severity and viral serotypes.MethodsEighty nine patients classified as per WHO 2009 criteria during dengue outbreak in Odisha, India in 2016 were included in the current study. Presence of dengue virus (DENV) was demonstrated by detecting NS1 antigen, IgM capture ELISA and serotypes in circulation were discriminated by type-specific RT-PCR and/or sequencing. Sixty-one confirmed dengue cases were typed for TLR2 indel polymorphism and compared with 485 disease free controls. Plasma samples were assayed for 41-plex cytokine/ chemokines using Luminex bead based immunoassay.ResultsPresence of 23bp deletion allele of TLR2 gene was significantly more in patients with severe dengue in comparison to dengue fever cases (p= 0.03; Odds ratio 4.05) although the frequency of insertion (Ins) allele of TLR2 was comparable in healthy controls and dengue cases (82.4 and 87.9 % respectively). Seventy-three (82%) samples were found to be positive by NS1/IgM capture ELISA/ RT-PCR. DENV-2 was predominant (58%) during the outbreak. Among the host inflammatory biomarkers 9 molecules were significantly altered in dengue patients when compared to healthy controls. The increased levels of IFN-γ, GM-CSF, IL-10, IL-1Rα and MIP-1β correlated significantly with severe dengue.ConclusionsThe frequency of 23bp Indel mutation of TLR2 was comparable between healthy controls and dengue fever (with and without warning signs), suggesting that this indel mutation does not contribute significantly to susceptibility/ resistance to dengue; however, del allele of TLR2 gene was significantly more associated in patients with severe dengue symptoms when compared to dengue fever cases.

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Cytokine Signature Associated with Disease Severity in Dengue

Viruses ◽

10.3390/v11010034 ◽

2019 ◽

Vol 11 (1) ◽

pp. 34 ◽

Cited By ~ 17

Author(s):

A. Raj Kumar Patro ◽

Sriprasad Mohanty ◽

Birendra K. Prusty ◽

Diwakar K. Singh ◽

Sagar Gaikwad ◽

...

Keyword(s):

Disease Severity ◽

Viral Disease ◽

Warning Signs ◽

Severe Dengue ◽

Rt Pcr ◽

Capture Elisa ◽

Gm Csf ◽

Host Immune Responses ◽

Luminex Assay ◽

Ifn Γ

Dengue is the most rapidly spreading viral disease transmitted by the bite of infected Aedes mosquitos. The pathogenesis of dengue is still unclear; although host immune responses and virus serotypes have been proposed to contribute to disease severity. In this study, we examined the circulating dengue virus (DENV) and measured plasma levels of inflammatory mediators. Ninety-eight patients during a dengue outbreak in eastern India in 2016 were included in the study. The presence of DENV was demonstrated by detecting NS1 antigen; IgM capture ELISA and serotypes were discriminated by type-specific RT-PCR and/or sequencing. Plasma samples were assayed for 41-plex cytokine/chemokines using multiplex Luminex assay. Eighty-five (87%) samples were positive by NS1/IgM capture ELISA/RT-PCR. All four serotypes of DENV were detected in this outbreak, with DENV-2 as the predominant type, seen in 55% of cases. Mixed infections were seen in 39% of subjects. Among the host inflammatory biomarkers, GM-CSF, IFN-γ, IL-10, IL-15, IL-8, MCP-1, IL-6, MIP-1β, and TNF-α levels were significantly increased in dengue with and without warning signs, in severe dengue patients in comparison to healthy controls. Four cytokines IFN-γ, GM-CSF, IL-10, and MIP-1β correlated significantly with disease severity and could serve as potential predictor for disease severity. Information on the host biomarkers and the dengue serotype may help guide in optimizing effective intervention strategies.

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All four dengue virus serotypes co-circulate in concurrent dengue infections in a single dengue session in Chittagong, Bangladesh

Bioresearch Communications ◽

10.3329/brc.v8i1.57042 ◽

2021 ◽

Vol 8 (1) ◽

pp. 1042-1048

Author(s):

Moushumi Ghosh Roy ◽

Kutub Uddin ◽

Din Islam ◽

Anjuvan Singh ◽

Mohammad Monirul Islam

Keyword(s):

Dengue Virus ◽

Dengue Fever ◽

Disease Severity ◽

Clinical Symptoms ◽

Global Public Health ◽

Rt Pcr ◽

Serum Samples ◽

Dengue Disease ◽

Denv Serotypes ◽

Public Health Burden

Purposes: Dengue fever, a mosquito-borne viral disease, is a global public health burden affecting millions of people each year and over 40% of world populations are at risk of dengue. Therefore, prompt and accurate dengue diagnosis is inevitable for disease surveillance and for aiding disease management. In this study we report dengue virus (DENV) seroprevalence in Chittagong, Bangladesh along with clinical manifestation of dengue infections. Methods: All samples included in this study were selected based on dengue NS1-based diagnosis, clinical sign and symptoms were judged by expert clinical physicians and infecting DENV serotyping was done by RT-PCR. The blood cells (Platelet, Haematocrit, WBC etc) were analyzed using Haematology cell counter. Results: First, among the 112 DENV infected serum samples tested by RT-PCR, 42 were DENV positive where 76% samples had single DENV serotype infection and 24% were concurrently infected with two or more DENV serotypes, indicating that all four DENVs were present in a single dengue session in Chittagong, Bangladesh. Then, DENV4 was the most prevailed serotype, followed by DENV2, DENV1 and DENV3 in single DENV serotype infections. However, in almost 90% cases of concurrent multiple DENV infections DENV1 serotype was present. A detail analysis of clinical data clearly indicated that DENV1 and DENV2 resulted very similar patterns of clinical symptoms which were quite different from those caused by DENV3 and DENV4. For example, ache and pain were absent in DENV3 infection and diarrhea was absent in DENV4 infections. Furthermore, DENV3, both in single and concurrent multiple DENV infections, might increase dengue disease severity as observed highly reduced platelet counts along with increased WBC in patients infected with DENV3 serotype. Conclusion: All four DENV serotypes, both as single and concurrent multiple DENV infections, were present in single dengue session in Bangladesh. Despite having very similar sequences and structures all four DENVs might produce different disease spectra, ranging from classical dengue fever to dengue hemorrhagic fever. Concurrent multiple DENV infections could contribute increased dengue disease severity in dengue outbreaks in Bangladesh. Bioresearch Commu. 8(1): 1042-1048, 2022 (January)

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Patterns of Gall Bladder Wall Thickening in Dengue Fever: A Mirror of the Severity of Disease

Ultrasound International Open ◽

10.1055/s-0043-105262 ◽

2017 ◽

Vol 03 (02) ◽

pp. E76-E81 ◽

Cited By ~ 5

Author(s):

Jitendra Parmar ◽

Chander Mohan ◽

Maulik Vora

Keyword(s):

Gall Bladder ◽

Dengue Fever ◽

Bladder Wall ◽

Warning Signs ◽

Severe Dengue ◽

Wall Thickening ◽

Severity Of Disease ◽

Gall Bladder Wall ◽

Track Pattern ◽

Honeycomb Pattern

Abstract Background Dengue fever is a major public health problem with an increased incidence in recent years. Gall bladder wall thickening has been reported as one of the most common findings in dengue fever. There is a paucity of literature regarding the various patterns of gall bladder wall thickening in dengue fever and their significance in predicting the severity of disease. Methodology and Significant Findings Out of 93 seropositive patients included in the study, 54 patients with dengue fever had gall bladder wall thickening. 4 patterns of gall bladder wall thickening are demonstrated in this study. A uniform echogenic pattern in 20 patients, striated or tram track pattern in 11 patients, an asymmetric pattern in 2 patients and a honeycombing pattern in 21 patients. The range of patterns of wall thickening included normal wall thickening or uniform echogenic wall thickening in DF without warning signs, a striated or tram track pattern, and a honeycomb pattern in severe DF. Serial ultrasound done on consecutive alternate days revealed a change in the pattern of gall bladder wall thickening according to the severity of disease. Conclusion The present study revealed 4 distinct patterns of gall bladder wall thickening. The uniform echogenic pattern was found to be more prevalent in dengue fever without warning signs, while the honeycomb pattern was found to be more prevalent in severe dengue fever. A change in the pattern of gall bladder wall thickening on subsequent serial ultrasound can predict the severity of the disease.

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Clinical profile of dengue fever in children: analysis of 2017 outbreak from Central Kerala, India

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20184293 ◽

2018 ◽

Vol 5 (6) ◽

pp. 2265 ◽

Cited By ~ 1

Author(s):

Senthil Kumar K. ◽

Rajendran N. K. ◽

Ajith Brabhukumar C.

Keyword(s):

Dengue Fever ◽

Dengue Infection ◽

Tertiary Care ◽

Hemorrhagic Fever ◽

Warning Signs ◽

Clinical Profile ◽

Severe Dengue ◽

High Morbidity ◽

Care Hospital ◽

High Grade Fever

Background: In India, dengue epidemics are becoming more frequent (WHO, 2008). The majority of dengue viral infections are self-limiting, but complications may cause high morbidity and mortality. The objective of this study is to assess the clinical profile of the dengue infection in children less than 15 years of age and to evaluate the outcomes of dengue fever from March 2017 to July 2017 at the Pediatric Department of Karuna Medical College, the tertiary care hospital in Palakkad.Methods: In this retrospective study, medical records were reviewed and analyzed. Patients with suspected dengue infection were classified further into 2 groups, Dengue fever (probable dengue, dengue with warning signs) and ‘Severe Dengue’ (dengue hemorrhagic fever and/or dengue shock syndrome (DHF/DSS) according to WHO.Results: A total of 77 cases were classified into 67 (87%) non-severe and 10 (13%) severe dengue cases. The most common age of presentation was above 10 yrs. The mean age of admission was 8.9 yrs. The most common presenting symptom was fever seen in 93% followed by vomiting in 68%. Elevation in Aspartate transaminase (SGOT) and thrombocytopenia were found in 32.4 %.Conclusions: High grade fever, vomiting, abdominal pain and skin rash with normal or low platelet count were the presenting features. Early diagnosis, monitoring and prompt supportive management can reduce mortality.

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Dengue Fever and Severe Dengue in Barbados, 2008–2016

Tropical Medicine and Infectious Disease ◽

10.3390/tropicalmed5020068 ◽

2020 ◽

Vol 5 (2) ◽

pp. 68

Author(s):

Kirk Osmond Douglas ◽

Sudip Kumar Dutta ◽

Byron Martina ◽

Fatih Anfasa ◽

T. Alafia Samuels ◽

...

Keyword(s):

Dengue Virus ◽

Dengue Fever ◽

Small Sample Size ◽

Health Planning ◽

Case Fatality ◽

Small Sample ◽

Severe Dengue ◽

Medical Attention ◽

Enzyme Linked Immunosorbent Assay ◽

Virus Serotype

Analysis of the temporal, seasonal and demographic distribution of dengue virus (DENV) infections in Barbados was conducted using national surveillance data from a total of 3994 confirmed dengue cases. Diagnosis was confirmed either by DENV–specific real time reverse transcriptase polymerase chain reaction (rRT–PCR), or non–structural protein 1 (NS1) antigen or enzyme linked immunosorbent assay (ELISA) tests; a case fatality rate of 0.4% (10/3994) was observed. The dengue fever (DF) prevalence varied from 27.5 to 453.9 cases per 100,000 population among febrile patients who sought medical attention annually. DF cases occurred throughout the year with low level of transmission observed during the dry season (December to June), then increased transmission during rainy season (July to November) peaking in October. Three major dengue epidemics occurred in Barbados during 2010, 2013 and possibly 2016 with an emerging three–year interval. DF prevalence among febrile patients who sought medical attention overall was highest among the 10–19 years old age group. The highest DF hospitalisation prevalence was observed in 2013. Multiple serotypes circulated during the study period and Dengue virus serotype 2 (DENV–2) was the most prevalent serotype during 2010, whilst DENV–1 was the most prevalent serotype in 2013. Two DENV–1 strains from the 2013 DENV epidemic were genetically more closely related to South East Asian strains, than Caribbean or South American strains, and represent the first ever sequencing of DENV strains in Barbados. However, the small sample size (n = 2) limits any meaningful conclusions. DF prevalence was not significantly different between females and males. Public health planning should consider DENV inter–epidemic periodicity, the current COVID–19 pandemic and similar clinical symptomology between DF and COVID–19. The implementation of routine sequencing of DENV strains to obtain critical data can aid in battling DENV epidemics in Barbados.

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Epidemiological and Clinical Features of Dengue Infection in Adults in the 2017 Outbreak in Vietnam

BioMed Research International ◽

10.1155/2019/3085827 ◽

2019 ◽

Vol 2019 ◽

pp. 1-6 ◽

Cited By ~ 5

Author(s):

Bui Vu Huy ◽

Le Nguyen Minh Hoa ◽

Dang Thi Thuy ◽

Nguyen Van Kinh ◽

Ta Thi Dieu Ngan ◽

...

Keyword(s):

Elderly Patients ◽

Dengue Fever ◽

Clinical Features ◽

Dengue Infection ◽

Clinical Manifestations ◽

Warning Signs ◽

Severe Dengue ◽

Severe Bleeding ◽

Cross Sectional ◽

Number Of Patients

Purpose. The clinical features and laboratory results of dengue-infected adult patients admitted to the hospital during the 2017 outbreak were analyzed in this study. Method. This is a cross-sectional study. 2922 patients aged 18 years or more with dengue fever in National Hospital for Tropical Diseases (NHTD) in the North and Hospital for Tropical Disease (HTD) in the South of Vietnam were recruited in this study. Result. Patients were admitted in the hospital around the year and concentrated from August to December, in 53/63 (84.0%) provinces in Vietnam, and patients in all ages were affected. The number of patients with dengue fever was 1675 (57.3%), dengue with warning signs 914 (31.3%), and severe dengue 333 (11.4%), respectively. Among patients with severe dengue, severe plasma leakage and dengue shock account for 238 (8.1%), severe organ impairment 73 (2.5%), and severe bleeding 22 (0.75%). The rate of mortality was 0.8%, and the outcome of dengue patients is worse in the elderly and people with underlying diseases. Conclusion. The 2017 dengue outbreak occurred in a larger scale than in the previous years in terms of time, location, and number of patients. More elderly patients were infected by dengue in this outbreak, and this may contribute to the mortality rate. Clinical manifestations of dengue patients in Southern Vietnam are more typical than the northern, but the rate of severe dengue is not different. The mortality risk and underlying conditions associated with dengue-infected elderly patients are worthy of further investigations in the future.

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Complement protein levels and MBL2 polymorphisms are associated with dengue and disease severity

Scientific Reports ◽

10.1038/s41598-020-71947-2 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Ngo Truong Giang ◽

Hoang van Tong ◽

Do Quyet ◽

Nghiem Xuan Hoan ◽

Trinh Huu Nghia ◽

...

Keyword(s):

Warning Signs ◽

Severe Dengue ◽

Healthy Controls ◽

Complement Protein ◽

Complement Proteins ◽

Protein Levels ◽

Study Population ◽

Dengue With Warning Signs ◽

The Complement System

Abstract The complement system may be crucial during dengue virus infection and progression to severe dengue. This study investigates the role of MBL2 genetic variants and levels of MBL in serum and complement proteins in Vietnamese dengue patients. MBL2 genotypes (− 550L/H, MBL2 codon 54), MBL2 diplotypes (XA/XO, YA/XO) and MBL2 haplotypes (LXPB, HXPA, XO) were associated with dengue in the study population. The levels of complement factors C2, C5, and C5a were higher in dengue and dengue with warning signs (DWS) patients compared to those in healthy controls, while factor D levels were decreased in dengue and DWS patients compared to the levels determined in healthy controls. C2 and C5a levels were associated with the levels of AST and ALT and with WBC counts. C9 levels were negatively correlated with ALT levels and WBC counts, and factor D levels were associated with AST and ALT levels and with platelet counts. In conclusions, MBL2 polymorphisms are associated with dengue in the Vietnamese study population. The levels of the complement proteins C2, C4b, C5, C5a, C9, factor D and factor I are modulated in dengue patients during the clinical course of dengue.

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Dengue fever in travellers: are we missing warning signs of severe dengue in a non‐endemic setting?

The Medical Journal of Australia ◽

10.5694/mja15.01183 ◽

2016 ◽

Vol 204 (7) ◽

pp. 267-267 ◽

Cited By ~ 3

Author(s):

Alex Tai ◽

Roselle Robosa ◽

Alexander A Padiglione ◽

Chamila Dalpatadu ◽

Tony M Korman

Keyword(s):

Dengue Fever ◽

Warning Signs ◽

Severe Dengue ◽

Endemic Setting

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Biochemical parameters (lactate dehydrogenase, serum albumin) as early predictor of severe dengue

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20170690 ◽

2017 ◽

Vol 4 (2) ◽

pp. 464

Author(s):

Poornima Shankar ◽

Prarthana B.

Keyword(s):

Lactate Dehydrogenase ◽

Dengue Virus ◽

Serum Albumin ◽

Dengue Fever ◽

Tertiary Care Hospital ◽

Tertiary Care ◽

Severe Dengue ◽

P Value ◽

Care Hospital ◽

Biochemical Tests

Background: Dengue fever (DF) is the arboviral infection with the largest incidence worldwide. Clinical expression of dengue virus infection varies from no symptoms to severe dengue with shock. It is the most rapidly spreading vector borne disease in the world. Nearly 100 million cases of Dengue fever and between 250,000 and 500,000 cases of severe dengue are annually reported to the WHO. The objective of this study was to study aims at determining the LDH and serum albumin levels as early parameter to predict the severity of Dengue illness.Methods: A observational clinical study conducted at K.I.M.S hospital, Bangalore, Karnataka, a tertiary care hospital. Children admitted in KIMS Hospital, Bangalore, Karnataka, a tertiary care hospital, Serum LDH and serum albumin levels are measured using the blood sample taken on the 3rd day of fever after confirmation of dengue fever (NS1 Ag- positive).Results: Study enrolled 150 patients with confirmed infection of Dengue virus who were admitted to paediatric unit between July 2014 and December 2016. Serum samples taken 72-96 hours within onset of fever were used for biochemical tests. Of 150 patients, 40 developed Severe Dengue (SD). Cases of SD had higher levels of lactate dehydrogenase (LDH) and low levels of serum albumin. Multivariate analysis showed that early alterations of LDH levels i.e. Out of 40 patients who developed severe dengue, 37 patients i.e. 92.7% had raised levels of LDH with levels more than >600 IU and<3 levels of serum albumin 13 patients i.e 32.5% of severe dengue cases with P value of < 0.001, which showed significant association.Conclusions: Early alterations of biochemical parameter like LDH and serum albumin can predict Severe Dengue in patients with acute dengue illness.

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Retrospective study of clinical profile and outcome of pediatric dengue cases in a teaching hospital

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20164609 ◽

2016 ◽

Vol 4 (1) ◽

pp. 226

Author(s):

Alok Kumar M. K. ◽

Timmangouda R. Patil ◽

Santhosh Veerabadhraiah

Keyword(s):

Retrospective Study ◽

Respiratory Distress ◽

Dengue Fever ◽

Clinical Symptoms ◽

Fluid Management ◽

Clinical Manifestations ◽

Warning Signs ◽

Severe Dengue ◽

Study Results ◽

Wide Range

Background: Dengue fever is an acute febrile illness caused by 4 closely related viral serotypes of the genus Flavivirus. Dengue has a broad range of clinical manifestations and often with unpredictable clinical evaluation and outcome. So this study has been done to see the wide range of clinical presentation of dengue and its outcome.Methods: It is a retrospective study done in tertiary hospital during the period of 8 months. Study was done by collecting the previous records from hospital record section. There were 48 cases of serologically confirmed cases of dengue which satisfied the inclusion and exclusion criteria were included in the study. Results: In our study there were 52% of the cases of dengue fever, 16.6% of cases were dengue fever with warning signs and remaining 31.4% of patients were severe dengue. Common Clinical symptoms at admission were fever (100%), vomiting (77%), respiratory distress (56.25%), generalised weakness (54.1%) and pain abdomen (33.3%). Less common symptoms were loose stools (6.25%), periorbital puffiness (6.25%), altered sensorium (4.1%), oliguria (2%) and bleeding manifestations (2%). Out of these dengue children 70.8% of these children improved without complication, 20.8 % of children improved with complication, in the form of ARDS, acute liver failure, DSS, meningitis, 6.25 % of these children went DAMA and 2 % of children expired.Conclusions: In our study atypical presentations like respiratory distress, loose stools meningitis were commonly noted and bleeding manifestation at admission was rare in our study. Platelet transfusions have little role in management of dengue patients. Early diagnosis, careful monitoring and proper fluid management goes a long way in reducing the mortality due to dengue hemorrhagic fever and shock syndrome.

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