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Hossain A, Joti FT, Hossain MS, Al-Noman A, Thowing C, Mursona M, Islam MR, Rahman ME, Matin MN, Haque MA. Identification of Potential Inhibitors Targeting Non-Structural Proteins NS3 and NS5 of Dengue Virus Using Docking and Deep Learning Approaches. Pharmaceuticals (Basel) 2025; 18:566. [PMID: 40284001 PMCID: PMC12030398 DOI: 10.3390/ph18040566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 03/21/2025] [Accepted: 04/11/2025] [Indexed: 04/29/2025] Open
Abstract
Background: Dengue virus (DENV) is the fatal pathogenic arthropod-borne virus (arboviruses) that belongs to the Flaviviridae family, which transmits to humans through mosquito bites from infected Aedes aegypti and Aedes albopictus mosquitoes or maternal-fetal transmission. Despite antigenic differences, the four serotypes of DENV (DENV-1 to DENV-4) share 65-78% of their genome. Non-structural (NS) proteins amongst serotypes show analogous functions. Among NS proteins, NS3 and NS5 are frequently used as targets for antiviral drugs due to their multifunctional roles. Methods: To identify potential inhibitors of DENV, we created a phytochemical library of 898 compounds derived from 17 medicinal plants recognized for their medicinal and antiviral properties. The phytochemicals library has been docked against the target proteins. Phytochemicals with a docking score greater than -8.0 kcal/mol were selected for further evaluation using a machine learning approach. Further, molecular dynamics (MD) simulations were conducted to evaluate the root mean square deviation, root mean square fluctuation, solvent-accessible surface area, radius of gyration, and hydrogen bond count of the compounds. Results: From the docking results, Silibinin, Rubiadin, and Ellagic acid showed binding affinities of -8.5, -8.3, and -8.2 kcal/mol, respectively, for NS3, and NSC 640467, Bisandrographolide A, and Andrographidin A showed binding affinities of -9.3, -10.1, and -9.3 kcal/mol, respectively, for NS5 target proteins. These compounds exhibited strong interactions with target proteins. MD simulation results confirmed the stable formation of protein-ligand complexes. Further, absorption, distribution, metabolism, excretion, and toxicity (ADMET) and bioactivity predictions confirmed their pharmacological safety. Conclusions: Despite global public health concerns, DENV still lacks specific drug treatments. Our identified new drug candidates might help for developing effective antiviral inhibitors against the DENV. However, further confirmation is needed through in vivo and in vitro research.
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Affiliation(s)
- Alomgir Hossain
- Computational Biosciences and Chemistry Research Organization, Rajshahi 6205, Bangladesh; (A.H.); (F.T.J.); (M.S.H.); (A.A.-N.); (C.T.); (M.M.); (M.R.I.); (M.E.R.)
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh
| | - Faria Tasnin Joti
- Computational Biosciences and Chemistry Research Organization, Rajshahi 6205, Bangladesh; (A.H.); (F.T.J.); (M.S.H.); (A.A.-N.); (C.T.); (M.M.); (M.R.I.); (M.E.R.)
| | - Md. Shohag Hossain
- Computational Biosciences and Chemistry Research Organization, Rajshahi 6205, Bangladesh; (A.H.); (F.T.J.); (M.S.H.); (A.A.-N.); (C.T.); (M.M.); (M.R.I.); (M.E.R.)
| | - Abdullah Al-Noman
- Computational Biosciences and Chemistry Research Organization, Rajshahi 6205, Bangladesh; (A.H.); (F.T.J.); (M.S.H.); (A.A.-N.); (C.T.); (M.M.); (M.R.I.); (M.E.R.)
| | - Chomong Thowing
- Computational Biosciences and Chemistry Research Organization, Rajshahi 6205, Bangladesh; (A.H.); (F.T.J.); (M.S.H.); (A.A.-N.); (C.T.); (M.M.); (M.R.I.); (M.E.R.)
| | - Mehjabin Mursona
- Computational Biosciences and Chemistry Research Organization, Rajshahi 6205, Bangladesh; (A.H.); (F.T.J.); (M.S.H.); (A.A.-N.); (C.T.); (M.M.); (M.R.I.); (M.E.R.)
| | - Md. Robiul Islam
- Computational Biosciences and Chemistry Research Organization, Rajshahi 6205, Bangladesh; (A.H.); (F.T.J.); (M.S.H.); (A.A.-N.); (C.T.); (M.M.); (M.R.I.); (M.E.R.)
| | - Md. Ekhtiar Rahman
- Computational Biosciences and Chemistry Research Organization, Rajshahi 6205, Bangladesh; (A.H.); (F.T.J.); (M.S.H.); (A.A.-N.); (C.T.); (M.M.); (M.R.I.); (M.E.R.)
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh
| | - Mohammad Nurul Matin
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh
- Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Md Azizul Haque
- Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea
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Lee H, Srikiatkhachorn A, Kalayanarooj S, Farmer AR, Park S. Comparison of Predictive Models for Severe Dengue: Logistic Regression, Classification Tree, and the Structural Equation Model. J Infect Dis 2025; 231:241-250. [PMID: 39078272 PMCID: PMC11793037 DOI: 10.1093/infdis/jiae366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 07/01/2024] [Accepted: 07/18/2024] [Indexed: 07/31/2024] Open
Abstract
BACKGROUND This study aimed to compare the predictive performance of 3 statistical models-logistic regression, classification tree, and structural equation model (SEM)-in predicting severe dengue illness. METHODS We adopted a modified classification of dengue illness severity based on the World Health Organization's 1997 guideline. We constructed predictive models using demographic factors and laboratory indicators on the day of fever occurrence, with data from 2 hospital cohorts in Thailand (257 Thai children). Different predictive models for each category of severe dengue illness were developed employing logistic regression, classification tree, and SEM. The model's discrimination abilties were analyzed with external validation data sets from 55 and 700 patients not used in model development. RESULTS From external validation based on predictors on the day of presentation to the hospital, the area under the receiver operating characteristic curve was from 0.65 to 0.84 for the regression models from 0.73 to 0.85 for SEMs. Classification tree models showed good results of sensitivity (0.95 to 0.99) but poor specificity (0.10 to 0.44). CONCLUSIONS Our study showed that SEM is comparable to logistic regression or classification tree, which was widely used for predicting severe forms of dengue.
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Affiliation(s)
- Hyelan Lee
- Graduate School of Urban Public Health, University of Seoul, Republic of Korea
- Department of Urban Big Data Convergence, University of Seoul, Republic of Korea
| | - Anon Srikiatkhachorn
- Department of Cell and Molecular Biology, Institute for Immunology and Informatics, University of Rhode Island, Providence
- Faculty of Medicine, King Mongkut Institute of Technology Lardkrabang, Bangkok, Thailand
| | - Siripen Kalayanarooj
- Department of Pediatrics, Queen Sirikit National Institute of Child Health, Bangkok, Thailand
| | - Aaron R Farmer
- Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand
| | - Sangshin Park
- Graduate School of Urban Public Health, University of Seoul, Republic of Korea
- Department of Urban Big Data Convergence, University of Seoul, Republic of Korea
- Department of Pathology and Laboratory Medicine, Brown University Medical School, Providence, Rhode Island
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Khalid M, Khan MS, Siddiqui E, Waafira A. Exploring the potential of Carica Papaya Leaf Extract: a perspective on its effectiveness in ameliorating thrombocytopenia in dengue patients. Infect Ecol Epidemiol 2025; 15:2456055. [PMID: 39867637 PMCID: PMC11758791 DOI: 10.1080/20008686.2025.2456055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2025] Open
Abstract
BACKGROUND Dengue fever (DF) is endemic in Pakistan, posing health risks. Recent flooding in 2022 and strong monsoon rains in 2024 have increased the possibility of an epidemic. It is an infectious disease having potentially severe outcomes including thrombocytopenia. DISCUSSION Carica Papaya Leaf Extract (CPLE) has emerged as an off-label treatment option, showing promising results in increasing platelet counts and reducing hospital stays. However, a critical assessment of existing research reveals methodological flaws, hindering specific recommendations. CONCLUSION This perspective advocates for comprehensive research to evaluate the risks and benefits of CPLE as a potential remedy for thrombocytopenia associated with dengue fever. A robust investigation will inform clinical practice and guide healthcare decisions, contributing to improved patient outcomes in dengue-endemic areas.
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Affiliation(s)
- Maliha Khalid
- Department of Medicine, Jinnah Sindh Medical University, Karachi, Pakistan
| | - Muhammad Saad Khan
- Department of Medicine, Jinnah Sindh Medical University, Karachi, Pakistan
| | - Erum Siddiqui
- Department of Medicine, Jinnah Sindh Medical University, Karachi, Pakistan
| | - Aminath Waafira
- School of Medicine, The Maldives National University, Malé, Maldives
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Dwivedi M, Pawar A, Kori M, Yadav H, Dwivedi M. A Review on the Epidemiology and Clinical Management of Neglected Tropical Diseases. Infect Disord Drug Targets 2025; 25:e18715265305007. [PMID: 39185648 DOI: 10.2174/0118715265305007240718081727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 05/13/2024] [Accepted: 06/13/2024] [Indexed: 08/27/2024]
Abstract
Infectious disorders known as Neglected Tropical Diseases (NTDs) initially affect the world's underprivileged citizens. They have been disregarded for many years, first as a result of a general indifference to such a developing world and, more recently, as an outcome of the intense attention on AIDS, TB, and malaria. Tropical diseases mostly affect the region where health and hygiene are sacrificed, and most of the population lacks access to sufficient food and living resources. WHO has drafted and released the directions for regulation, prevention, and successful eradication of NTDs as per the revised roadmap of 2021-2030. This shifts from vertical disease programs to integrated cross-cutting methods. In the current work, we have provided comprehensive information on various aspects of neglected tropical diseases, including the clinical management of NTDs. This encompasses the causative agent of the diseases, their symptoms, pathogenesis, diagnosis, treatment, prognosis, and epidemiological perspective of major NTDs. This review will shed light on several perspectives of NTDs having influential roles in proposing strategies to control and treat them around the world.
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Affiliation(s)
- Medha Dwivedi
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Gomtinagar Extension, Lucknow, 226028, India
| | | | - Mahima Kori
- Prescience Insilico Private Limited, Bangalore, India
| | - Hitendra Yadav
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Gomtinagar Extension, Lucknow, 226028, India
| | - Manish Dwivedi
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Gomtinagar Extension, Lucknow, 226028, India
- Research Cell, Amity University Uttar Pradesh, Lucknow Campus, India
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Bur R, Suwarto S, Pohan HT, Prihartono J, Harahap AR, Dewi BE, Sadikin M, Rachman A, Yusuf H. Early intervention of 5% albumin shown superior control of vascular integrity and function compared to ringer's lactatein hospitalized adult with grade I & II Dengue hemorrhagic fever: a multicenter randomized controlled trial in Indonesia. Trop Dis Travel Med Vaccines 2024; 10:20. [PMID: 39350232 PMCID: PMC11443621 DOI: 10.1186/s40794-024-00230-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 07/17/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND Dengue virus remains a major public health problem with one of the hallmark pathologies is the vascular leakage caused by endothelial dysfunction which can lead to Dengue Hemorrhagic Fever (DHF) manifestation. In the status quo, no specific therapy has been discovered but rather heavily relies on judicious and frequent monitoring of intravenous fluids administration. The current guideline has discussed the roles of fluid therapy during the Dengue Shock Syndrome (DSS) stage, however, administration of early fluid intervention for DHF grade I and II remains uncharted territory. In addition, the choice and timing of colloid administration remains underexplored. As one of the widely available colloids, 5% albumin has known physiological properties that potentially minimize plasma leakage. Therefore, this study aimed to evaluate the benefit of early intervention of 5% albumin in adults with DHF in the hope of preventing the lethal progression to DSS and further, shorten the length of stay (LOS) for patients. METHODS We conducted a multicenter, open-labeled, randomized controlled trial in Jakarta and Banten to compare the effect of early intervention with 5% albumin in adult patients with DHF compared to Ringer's Lactate (RL). Statistical analyses were conducted using unpaired t-test and Mann-Whitney for normally and abnormally distributed data respectively. RESULTS Adult patients with a diagnosis of DHF grade I and II that being hospitalized to receive the early intervention of 5% albumin had significantly lower levels of hemoconcentration 4, 12, and 24 h (p = 0.002, 0.001, 0.003, respectively), higher platelet counts 4 h (p = 0.036), higher serum albumin levels 48 h (p = 0.036), lower proteinuria 24 and 48 h post-albumin administration (p < 0.001, < 0.001, respectively), and shorter LOS (p < 0.001) when compared to the RL group. CONCLUSION Early intervention of 5% albumin showed better control on vascular integrity and function compared to ringer lactate in hospitalized adults with grade I & II DHF, thus halting the progression of DHF into DSS and other related complications which leads to faster recovery and shorter length of stay. TRIAL REGISTRATION The study was registered to www. CLINICALTRIAL gov with trial registration number NCT04076254, and registration date October 31st 2016.
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Affiliation(s)
- Rika Bur
- Division of Tropical and Infectious Diseases, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Harapan Kita National Women and Children Health Center, Jakarta, 11420, Indonesia.
| | - Suhendro Suwarto
- Division of Tropical and Infectious Diseases, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, 10430, Indonesia
| | - Herdiman Theodorus Pohan
- Division of Tropical and Infectious Diseases, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, 10430, Indonesia
| | - Joedo Prihartono
- Department of Community Medicine, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo National Hospital, Jakarta, 10430, Indonesia
| | | | - Beti Ernawati Dewi
- Microbiology Department, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo National Hospital, Jakarta, 10430, Indonesia
| | - Mohamad Sadikin
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo National Hospital, Jakarta, 10430, Indonesia
| | - Andhika Rachman
- Division of Hematology and Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo National Hospital, Jakarta, 10430, Indonesia
| | - Hadi Yusuf
- Division of Tropical and Infectious Diseases, Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran, Hasan Sadikin Hospital, Bandung, 40161, West Java, Indonesia
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Tejo AM, Hamasaki DT, Menezes LM, Ho YL. Severe dengue in the intensive care unit. JOURNAL OF INTENSIVE MEDICINE 2024; 4:16-33. [PMID: 38263966 PMCID: PMC10800775 DOI: 10.1016/j.jointm.2023.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 06/19/2023] [Accepted: 07/24/2023] [Indexed: 01/25/2024]
Abstract
Dengue fever is considered the most prolific vector-borne disease in the world, with its transmission rate increasing more than eight times in the last two decades. While most cases present mild to moderate symptoms, 5% of patients can develop severe disease. Although the mechanisms are yet not fully comprehended, immune-mediated activation leading to excessive cytokine expression is suggested as a cause of the two main findings in critical patients: increased vascular permeability that may shock and thrombocytopenia, and coagulopathy that can induce hemorrhage. The risk factors of severe disease include previous infection by a different serotype, specific genotypes associated with more efficient replication, certain genetic polymorphisms, and comorbidities such as diabetes, obesity, and cardiovascular disease. The World Health Organization recommends careful monitoring and prompt hospitalization of patients with warning signs or propensity for severe disease to reduce mortality. This review aims to update the diagnosis and management of patients with severe dengue in the intensive care unit.
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Affiliation(s)
- Alexandre Mestre Tejo
- Intensive Care Unit, Department of Intensive Medicine of the Cancer Institute of the State of São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Debora Toshie Hamasaki
- Transfusion Medicine and Cell Therapy Department, A.C. Camargo Cancer Center, São Paulo, Brazil
| | - Letícia Mattos Menezes
- Intensive Care Unit of Infectious Disease Department, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Yeh-Li Ho
- Intensive Care Unit of Infectious Disease Department, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
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Yang J, Mosabbir AA, Raheem E, Hu W, Hossain MS. Demographic characteristics, clinical symptoms, biochemical markers and probability of occurrence of severe dengue: A multicenter hospital-based study in Bangladesh. PLoS Negl Trop Dis 2023; 17:e0011161. [PMID: 36921001 PMCID: PMC10042364 DOI: 10.1371/journal.pntd.0011161] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 03/27/2023] [Accepted: 02/10/2023] [Indexed: 03/16/2023] Open
Abstract
Establishing reliable early warning models for severe dengue cases is a high priority to facilitate triage in dengue-endemic areas and optimal use of limited resources. However, few studies have identified the complex interactive relationship between potential risk factors and severe dengue. This research aimed to assess the potential risk factors and detect their high-order combinative effects on severe dengue. A structured questionnaire was used to collect detailed dengue outbreak data from eight representative hospitals in Dhaka, Bangladesh, in 2019. Logistic regression and machine learning models were used to examine the complex effects of demographic characteristics, clinical symptoms, and biochemical markers on severe dengue. A total of 1,090 dengue cases (158 severe and 932 non-severe) were included in this study. Dyspnoea (Odds Ratio [OR] = 2.87, 95% Confidence Interval [CI]: 1.72 to 4.77), plasma leakage (OR = 3.61, 95% CI: 2.12 to 6.15), and hemorrhage (OR = 2.33, 95% CI: 1.46 to 3.73) were positively and significantly associated with the occurrence of severe dengue. Classification and regression tree models showed that the probability of occurrence of severe dengue cases ranged from 7% (age >12.5 years without plasma leakage) to 92.9% (age ≤12.5 years with dyspnoea and plasma leakage). The random forest model indicated that age was the most important factor in predicting severe dengue, followed by education, plasma leakage, platelet, and dyspnoea. The research provides new evidence to identify key risk factors contributing to severe dengue cases, which could be beneficial to clinical doctors to identify and predict the severity of dengue early.
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Affiliation(s)
- Jingli Yang
- Ecosystem Change and Population Health Research Group, School of Public Health and Social Work, Queensland University of Technology, Brisbane, Australia
- College of Earth and Environmental Sciences, Lanzhou University, Lanzhou, China
| | - Abdullah Al Mosabbir
- Department of Emerging and Neglected Diseases, Biomedical Research Foundation, Dhaka, Bangladesh
| | - Enayetur Raheem
- Department of Emerging and Neglected Diseases, Biomedical Research Foundation, Dhaka, Bangladesh
| | - Wenbiao Hu
- Ecosystem Change and Population Health Research Group, School of Public Health and Social Work, Queensland University of Technology, Brisbane, Australia
- * E-mail: (WH); (MSH)
| | - Mohammad Sorowar Hossain
- Department of Emerging and Neglected Diseases, Biomedical Research Foundation, Dhaka, Bangladesh
- School of Environment and Life Sciences, Independent University, Dhaka, Bangladesh
- * E-mail: (WH); (MSH)
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Lee MF, Anasir MI, Poh CL. Development of novel antiviral peptides against dengue serotypes 1-4. Virology 2023; 580:10-27. [PMID: 36739680 DOI: 10.1016/j.virol.2023.01.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/25/2023] [Accepted: 01/29/2023] [Indexed: 02/03/2023]
Abstract
Dengue infections pose a critical threat to public health worldwide. Since there are no clinically approved antiviral drugs to treat dengue infections caused by the four dengue virus (DENV) serotypes, there is an urgent need to develop effective antivirals. Peptides are promising antiviral candidates due to their specificity and non-toxic properties. The DENV envelope (E) protein was selected for the design of antiviral peptides due to its importance in receptor binding and viral fusion to the host cell membrane. Twelve novel peptides were designed to mimic regions containing critical amino acid residues of the DENV E protein required for interaction with the host. A total of four peptides were identified to exhibit potent inhibitory effects against at least three or all four DENV serotypes. Peptide 3 demonstrated all three modes of action: cell protection and inhibition of post-infection against all four DENV serotypes, whereas direct virus-inactivating effects were only observed against DENV-2, 3, and 4. Peptide 4 showed good direct virus-inactivating effects against DENV-2 (74.26%) as well as good inhibitions of DENV-1 (80.37%) and DENV-4 (72.22%) during the post-infection stage. Peptide 5 exhibited direct virus-inactivating effects against all four DENV serotypes, albeit at lower inhibition levels against DENV-1 and DENV-3. It also exhibited highly significant inhibition of DENV-4 (89.31%) during post-infection. Truncated peptide 5F which was derived from peptide 5 showed more significant inhibition of DENV-4 (91.58%) during post-infection and good direct virus-inactivating effects against DENV-2 (77.55%) at a lower concentration of 100 μM. Peptide 3 could be considered as the best antiviral candidate for pre- and post-infection treatments of DENV infections in regions with four circulating dengue serotypes. However, if the most predominant dengue serotype for a particular region could be identified, peptides with significantly high antiviral activities against that particular dengue serotype could serve as more suitable antiviral candidates. Thus, peptide 5F serves as a more suitable antiviral candidate for post-infection treatment against DENV-4.
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Affiliation(s)
- Michelle Felicia Lee
- Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, 5, Jalan Universiti, Bandar Sunway, Selangor, 47500, Malaysia
| | - Mohd Ishtiaq Anasir
- Virology Unit, Infectious Disease Research Centre, Institute for Medical Research, National Institutes of Health, Setia Alam, Shah Alam, Selangor, Malaysia
| | - Chit Laa Poh
- Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, 5, Jalan Universiti, Bandar Sunway, Selangor, 47500, Malaysia.
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Preeprem N, Phumeetham S. Paediatric dengue shock syndrome and acute respiratory failure: a single-centre retrospective study. BMJ Paediatr Open 2022; 6:10.1136/bmjpo-2022-001578. [PMID: 36645744 PMCID: PMC9668030 DOI: 10.1136/bmjpo-2022-001578] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 09/29/2022] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVE Dengue shock syndrome (DSS) is a serious health condition leading to paediatric intensive care unit (PICU) admissions and deaths in tropical countries. Acute respiratory failure (ARF) is associated with DSS and is a major cause of dengue deaths. We aimed to identify risk factors associated with ARF in children with DSS. METHODS We retrospectively reviewed children with DSS admitted to a PICU from 2010 to 2020 at a tertiary level hospital in Bangkok, Thailand. Patient characteristics, clinical parameters and laboratory data were collected. Multivariable logistic regression analysis was used to identify factors associated with ARF. RESULTS Twenty-six (43.3%) of 60 children with DSS developed ARF and 6 did not survive to day 28. The median (IQR) age was 8.1 years (IQR 4.0-11.0). Fluid accumulation during the first 72 hours of PICU admission was greater in the ARF group compared with the non-ARF group (12.2% (IQR 7.6-21.7) vs 8.3% (IQR 4.4-13.3), p=0.009). In a multivariate analysis at 72 hours post PICU admission, the presence of ˃15% fluid accumulation was independently associated with ARF (adjusted OR 5.67, 95% CI 1.24 to 25.89, p=0.025). CONCLUSION ARF is an important complication in children with DSS. A close assessment of patient fluid status is essential to identify patients at risk of ARF. Once the patient is haemodynamically stable and leakage slows, judicious fluid management is required to prevent ARF.
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Affiliation(s)
- Nutnicha Preeprem
- Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Suwannee Phumeetham
- Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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Foucambert P, Esbrand FD, Zafar S, Panthangi V, Cyril Kurupp AR, Raju A, Luthra G, Shahbaz M, Almatooq H, Khan S. Efficacy of Dengue Vaccines in the Prevention of Severe Dengue in Children: A Systematic Review. Cureus 2022; 14:e28916. [PMID: 36225478 PMCID: PMC9542041 DOI: 10.7759/cureus.28916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 09/07/2022] [Indexed: 11/25/2022] Open
Abstract
Dengue is a vector-borne disease caused by the dengue virus (DENV) and is a major health concern worldwide, particularly in regions of endemic disease. Dengue usually presents as a self-limited febrile illness. In some cases, more severe forms with hemorrhage and shock can occur, and children are especially prone to develop it. These forms can be lethal without appropriate management, and no antiviral treatment exists today. In the absence of a curative treatment for dengue, its clinical prevention remains essential. One vaccine - the chimeric yellow fever-dengue-tetravalent dengue vaccine (CYD-TDV) - has been approved for use in some populations, and several others are currently in development, including Takeda's tetravalent dengue vaccine candidate (TAK-003). This study is a systematic review of the current literature realized to evaluate the efficacy of the dengue vaccines in preventing severe dengue in children. This review focuses on the vaccines CYD-TDV and TAK-003. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, PubMed Central (PMC), Medical Literature Analysis and Retrieval System Online (MEDLINE), Cochrane Library, and Google Scholar were the databases used to find the relevant data. The articles were selected using specific inclusion and exclusion criteria, and quality appraisal was realized with standardized quality assessment tools. Overall, our study shows that the dengue vaccines CYD-TDV and TAK-003 confer protection against severe dengue in children. Some distinctions exist depending on the vaccine type, the age, and the dengue serostatus of patients. While demonstrating encouraging results, this review also emphasizes the need for more in-depth studies about the safety and efficacy of dengue vaccines.
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Affiliation(s)
- Paul Foucambert
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Faith D Esbrand
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Sana Zafar
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Venkatesh Panthangi
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | | | - Anjumol Raju
- Pediatrics, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Gaurav Luthra
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Mahrukh Shahbaz
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Halah Almatooq
- Dermatology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Safeera Khan
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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11
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Ni N, Wang W, Sun Y, Sun X, Leong DT. Inducible endothelial leakiness in nanotherapeutic applications. Biomaterials 2022; 287:121640. [PMID: 35772348 DOI: 10.1016/j.biomaterials.2022.121640] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 05/23/2022] [Accepted: 06/14/2022] [Indexed: 11/02/2022]
Abstract
All intravenous delivered nanomedicine needs to escape from the blood vessel to exert their therapeutic efficacy at their designated site of action. Failure to do so increases the possibility of detrimental side effects and negates their therapeutic intent. Many powerful anticancer nanomedicine strategies rely solely on the tumor derived enhanced permeability and retention (EPR) effect for the only mode of escaping from the tumor vasculature. However, not all tumors have the EPR effect nor can the EPR effect be induced or controlled for its location and timeliness. In recent years, there have been exciting developments along the lines of inducing endothelial leakiness at the tumor to decrease the dependence of EPR. Physical disruption of the endothelial-endothelial cell junctions with coordinated biological intrinsic pathways have been proposed that includes various modalities like ultrasound, radiotherapy, heat and even nanoparticles, appear to show good progress towards the goal of inducing endothelial leakiness. This review explains the intricate and complex biological background behind the endothelial cells with linkages on how updated reported nanomedicine strategies managed to induce endothelial leakiness. This review will also end off with fresh insights on where the future of inducible endothelial leakiness holds.
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Affiliation(s)
- Nengyi Ni
- Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore, 117585, Singapore
| | - Weiyi Wang
- School of Chemistry and Pharmaceutical Engineering, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250000, China
| | - Yu Sun
- Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore, 117585, Singapore; Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, No.88 Jiefang Road, Shangcheng District, Hangzhou, 310009, PR China
| | - Xiao Sun
- School of Chemistry and Pharmaceutical Engineering, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250000, China.
| | - David Tai Leong
- Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore, 117585, Singapore.
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12
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Arshad H, Bashir M, Mushtaq US, Imtiaz H, Rajpar R, Alam MF, Fatima S, Rehman A, Abbas K, Talpur AS. Clinical Characteristics and Symptomatology Associated With Dengue Fever. Cureus 2022; 14:e26677. [PMID: 35949791 PMCID: PMC9358055 DOI: 10.7759/cureus.26677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/08/2022] [Indexed: 11/13/2022] Open
Abstract
Background Early diagnosis and prompt treatment are critical to reducing overall morbidity and mortality associated with dengue fever. Thus, to better understand the condition, the present study was conducted to assess the clinical signs and symptomatology associated with dengue fever in patients in a tertiary care hospital. Methods This prospective observational study was conducted at a tertiary care hospital in Karachi, Pakistan between July and December 2021. All patients who tested positive for the dengue virus either based on antigen or antibodies were included in the study. Convenient sampling was used. A structured proforma was used for data collection. Microsoft Excel (Microsoft Corporation, Redmond, WA) and Statistical Package for the Social Sciences (SPSS, IBM Corp., Armonk, NY) were used for the entry and analysis of data, respectively. Results More than half of the patients were suffering from fever (82.5%), headache/body ache/joint pain (80.5%), and vomiting (55%). Bleeding was observed in 16 (8%) patients and was directly related to platelet count (OR: 0.981; 95% CI: 0.971-0.992), and more than half of the patients (56%) required platelet transfusion. Laboratory values included a mean platelet count of 145.22 ± 90.36 thousand, a mean total leukocyte count (TLC) of 6.87 ± 5.76 thousand, and a mean hemoglobin level of 13.71 ± 2.11 g/dl. Of the patients, 171 (85.5%) individuals tested positive for antigen nonstructural protein 1 (Ns1Ag), and 68 (34%) tested positive for either immunoglobulin G (IgG) or immunoglobulin M (IgM), or both dengue-specific antibodies. Those with dengue-specific antibodies were less likely to bleed as 6.2% were IgG and IgM positive and 31.2% were positive for both antibodies. The regression model showed a significant relationship between bleeding and platelet transfusion (p < 0.001), hospital stay (p < 0.005), and diarrhea (p < 0.001). Conclusion In conclusion, the study revealed that males were more frequently infected with the virus as compared to females. Furthermore, fever, headache/joint pain/body aches, diarrhea, and low platelet count are the major clinical and laboratory outcomes. Patients with a low level of platelets are more prone to bleeding, and platelet transfusion increased survival chances in such patients.
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13
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Wong JM, Adams LE, Durbin AP, Muñoz-Jordán JL, Poehling KA, Sánchez-González LM, Volkman HR, Paz-Bailey G. Dengue: A Growing Problem With New Interventions. Pediatrics 2022; 149:187012. [PMID: 35543085 DOI: 10.1542/peds.2021-055522] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/11/2022] [Indexed: 12/12/2022] Open
Abstract
Dengue is the disease caused by 1 of 4 distinct, but closely related dengue viruses (DENV-1-4) that are transmitted by Aedes spp. mosquito vectors. It is the most common arboviral disease worldwide, with the greatest burden in tropical and sub-tropical regions. In the absence of effective prevention and control measures, dengue is projected to increase in both disease burden and geographic range. Given its increasing importance as an etiology of fever in the returning traveler or the possibility of local transmission in regions in the United States with competent vectors, as well as the risk for large outbreaks in endemic US territories and associated states, clinicians should understand its clinical presentation and be familiar with appropriate testing, triage, and management of patients with dengue. Control and prevention efforts reached a milestone in June 2021 when the Advisory Committee on Immunization Practices (ACIP) recommended Dengvaxia for routine use in children aged 9 to 16 years living in endemic areas with laboratory confirmation of previous dengue virus infection. Dengvaxia is the first vaccine against dengue to be recommended for use in the United States and one of the first to require laboratory testing of potential recipients to be eligible for vaccination. In this review, we outline dengue pathogenesis, epidemiology, and key clinical features for front-line clinicians evaluating patients presenting with dengue. We also provide a summary of Dengvaxia efficacy, safety, and considerations for use as well as an overview of other potential new tools to control and prevent the growing threat of dengue .
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Affiliation(s)
- Joshua M Wong
- Epidemic Intelligence Service, Center for Surveillance, Epidemiology, and Laboratory Services, Centers for Disease Control and Prevention, Atlanta, Georgia.,Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, San Juan, Puerto Rico
| | - Laura E Adams
- Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, San Juan, Puerto Rico
| | - Anna P Durbin
- Center for Immunization Research, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Jorge L Muñoz-Jordán
- Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, San Juan, Puerto Rico
| | | | - Liliana M Sánchez-González
- Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, San Juan, Puerto Rico
| | - Hannah R Volkman
- Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, San Juan, Puerto Rico
| | - Gabriela Paz-Bailey
- Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, San Juan, Puerto Rico
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14
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Yang X, Quam MBM, Zhang T, Sang S. Global burden for dengue and the evolving pattern in the past 30 years. J Travel Med 2021; 28:6368502. [PMID: 34510205 DOI: 10.1093/jtm/taab146] [Citation(s) in RCA: 143] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 09/05/2021] [Accepted: 09/07/2021] [Indexed: 11/15/2022]
Abstract
BACKGROUND Dengue is the most prevalent and rapidly spreading mosquito-borne viral disease. We present the global, regional and national burden of dengue from 1990 to 2019 based on the findings from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019). METHODS Based upon GBD 2019 dengue data on age-standardized incidence rate (ASIR), age-standardized death rate (ASDR) and age-standardized disability-adjusted life years (DALYs) rate, this study estimates and presents annual percentage change (EAPC) to quantify trends over time to assess potential correlates of increased dengue activity, such as global travel and warming. RESULTS Globally from 1990 to 2019, dengue incident cases, deaths and DALYs gradually increased. Those under 5 years of age, once accounting for the largest portion of deaths and DALYs in 1990, were eclipsed by those who were 15-49 years old in 2019. Age standardized incidence [ASIR: EAPC: 3.16, 95% confidence interval (CI): 2.90-3.43], death (ASDR: EAPC: 5.42, 95% CI: 2.64-8.28) and DALY rates (EAPC: 2.31, 95% CI: 2.00-2.62) accelerated most among high-middle and high sociodemographic index (SDI) regions. South-East Asia and South Asia had most of the dengue incident cases, deaths and DALYs, but East Asia had the fastest rise in ASIR (EAPC: 4.57, 95% CI: 4.31, 4.82), while Tropical Latin America led in ASDR (EAPC: 11.32, 95% CI: 9.11, 13.58) and age-standardized DALYs rate (EAPC: 4.13, 95% CI: 2.98, 5.29). SDI showed consistent bell-shaped relationship with ASIR, ASDR and age-standardized DALYs rate. Global land-ocean temperature index and air passenger travel metrics were found to be remarkably positively correlated with dengue burden. CONCLUSIONS The burden of dengue has become heavier from 1990 to 2019, amidst the three decades of urbanization, warming climates and increased human mobility in much of the world. South-East Asia and South Asia remain as regions of concern, especially in conjunction with the Americas' swift rise in dengue burden.
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Affiliation(s)
- Xiaorong Yang
- Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, Shandong 250012, People's Republic of China.,Clinical Research Center, Shandong University, Jinan, Shandong 250012, People's Republic of China
| | - Mikkel B M Quam
- Section on Sustainable Health, Department of Public Health and Clinical Medicine, Umeå University, 90187, Sweden.,Division of Epidemiology, College of Public Health, The Ohio State University, 43210, USA
| | - Tongchao Zhang
- Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, Shandong 250012, People's Republic of China.,Clinical Research Center, Shandong University, Jinan, Shandong 250012, People's Republic of China
| | - Shaowei Sang
- Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, Shandong 250012, People's Republic of China.,Clinical Research Center, Shandong University, Jinan, Shandong 250012, People's Republic of China.,Department of Epidemiology and Health Statistics, School of Public Health, Shandong University, Jinan, Shandong 250012, People's Republic of China
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15
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Leowattana W, Leowattana T. Dengue hemorrhagic fever and the liver. World J Hepatol 2021; 13:1968-1976. [PMID: 35070001 PMCID: PMC8727196 DOI: 10.4254/wjh.v13.i12.1968] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 03/30/2021] [Accepted: 11/13/2021] [Indexed: 02/06/2023] Open
Abstract
Dengue hemorrhagic fever (DHF) is one of the most rapidly emerging infections of tropical and subtropical regions worldwide. It affects more rural and urban areas due to many factors, including climate change. Although most people with dengue viral infection are asymptomatic, approximately 25% experience a self-limited febrile illness with mild to moderate biochemical abnormalities. Severe dengue diseases develop in a small proportion of these patients, and the common organ involvement is the liver. The hepatocellular injury was found in 60%-90% of DHF patients manifested as hepatomegaly, jaundice, elevated aminotransferase enzymes, and critical condition as an acute liver failure (ALF). Even the incidence of ALF in DHF is very low (0.31%-1.1%), but it is associated with a relatively high mortality rate (20%-68.3%). The pathophysiology of liver injury in DHF included the direct cytopathic effect of the DENV causing hepatocytes apoptosis, immune-mediated hepatocyte injury induced hepatitis, and cytokine storm. Hepatic hypoperfusion is another contributing factor in dengue shock syndrome. The reduction of morbidity and mortality in DHF with liver involvement is dependent on the early detection of warning signs before the development of ALF.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Bangkok, Thailand.
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Bangkok, Thailand
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16
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Paz-Bailey G, Adams L, Wong JM, Poehling KA, Chen WH, McNally V, Atmar RL, Waterman SH. Dengue Vaccine: Recommendations of the Advisory Committee on Immunization Practices, United States, 2021. MMWR Recomm Rep 2021; 70:1-16. [PMID: 34978547 PMCID: PMC8694708 DOI: 10.15585/mmwr.rr7006a1] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Dengue is a vectorborne infectious disease caused by dengue viruses (DENVs), which are predominantly transmitted by Aedes aegypti and Aedes albopictus mosquitos. Dengue is caused by four closely related viruses (DENV-1–4), and a person can be infected with each serotype for a total of four infections during their lifetime. Areas where dengue is endemic in the United States and its territories and freely associated states include Puerto Rico, American Samoa, the U.S. Virgin Islands, the Federated States of Micronesia, the Republic of Marshall Islands, and the Republic of Palau. This report summarizes the recommendations of the Advisory Committee on Immunization Practices (ACIP) for use of the Dengvaxia vaccine in the United States. The vaccine is a live-attenuated, chimeric tetravalent dengue vaccine built on a yellow fever 17D backbone. Dengvaxia is safe and effective in reducing dengue-related hospitalizations and severe dengue among persons who have had dengue infection in the past. Previous natural infection is important because Dengvaxia is associated with an increased risk for severe dengue in those who experience their first natural infection (i.e., primary infection) after vaccination. Dengvaxia was licensed by the Food and Drug Administration for use among children and adolescents aged 9–16 years (referred to in this report as children). ACIP recommends vaccination with Dengvaxia for children aged 9–16 having evidence of a previous dengue infection and living in areas where dengue is endemic. Evidence of previous dengue infection, such as detection of anti-DENV immunoglobulin G with a highly specific serodiagnostic test, will be required for eligible children before vaccination.
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17
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Dayarathna S, Jeewandara C, Gomes L, Somathilaka G, Jayathilaka D, Vimalachandran V, Wijewickrama A, Narangoda E, Idampitiya D, Ogg GS, Malavige GN. Similarities and differences between the 'cytokine storms' in acute dengue and COVID-19. Sci Rep 2020; 10:19839. [PMID: 33199778 PMCID: PMC7670444 DOI: 10.1038/s41598-020-76836-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 10/20/2020] [Indexed: 01/08/2023] Open
Abstract
Severe pneumonia and multiorgan dysfunction in COVID-19 and dengue haemorrhagic fever (DHF) are two diseases that can associate with an altered immune response to the infecting virus. To determine the similarities and differences in the cytokine and chemokine responses in these two infections, we compared responses in patients with varying severity of COVID-19 and acute dengue at different time points of illness. During early disease, patients who proceeded to develop COVID-19 severe pneumonia (SP) and DHF had significantly higher levels of IL-6, IL-10 and MIP3α than those who developed mild illness. The lowest levels of IFNγ in early illness were seen in those who succumbed to their illness due to COVID-19. Levels of serum IL-10 (p = 0.0001), IL-6 (p = 0.002), MIP-3α (p = 0.02) and CD40-L levels (p = 0.002) significantly increased from 5 to 9 day of illness to 10-21 day of illness in patients with moderate-to-severe COVID-19, but not in those with mild illness. In contrast, these cytokine/chemokine levels remained unchanged in those with DHF or dengue fever (DF) during febrile and critical phases. Although IL-10 levels were significantly higher in COVID-19 patients with SP, patients with DHF had 25-fold higher levels, whereas IL-6 levels were 11-fold higher in those with COVID-19 SP. IL-10 and other cytokines were evaluated in a larger cohort of patients during early illness (≤ 4 days) who proceeded to develop DF (n = 71) or DHF (n = 64). Of the cytokines evaluated, IL-10 was significantly higher (p < 0.0001) in those who went on to develop DHF compared to DF. Low IFNγ response to the SARS-CoV2 and high levels of immunosuppressive IL-10 in both COVID-19 and dengue during early illness are indicators of an altered antiviral response potentially contributing to disease severity.
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Affiliation(s)
- Shashika Dayarathna
- Centre for Dengue Research, Faculty of Medical Sciences, University of Sri Jayawardenapura, Nugegoda, Sri Lanka
| | - Chandima Jeewandara
- Centre for Dengue Research, Faculty of Medical Sciences, University of Sri Jayawardenapura, Nugegoda, Sri Lanka
- Allergy, Immunology and Cell Biology Unit, University of Sri Jayewardenepura, Nugegoda, Sri Lanka
| | - Laksiri Gomes
- Centre for Dengue Research, Faculty of Medical Sciences, University of Sri Jayawardenapura, Nugegoda, Sri Lanka
| | - Gayasha Somathilaka
- Allergy, Immunology and Cell Biology Unit, University of Sri Jayewardenepura, Nugegoda, Sri Lanka
| | - Deshni Jayathilaka
- Centre for Dengue Research, Faculty of Medical Sciences, University of Sri Jayawardenapura, Nugegoda, Sri Lanka
| | - Vimalahan Vimalachandran
- Centre for Dengue Research, Faculty of Medical Sciences, University of Sri Jayawardenapura, Nugegoda, Sri Lanka
| | | | | | | | - Graham S Ogg
- Centre for Dengue Research, Faculty of Medical Sciences, University of Sri Jayawardenapura, Nugegoda, Sri Lanka
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Gathsaurie Neelika Malavige
- Centre for Dengue Research, Faculty of Medical Sciences, University of Sri Jayawardenapura, Nugegoda, Sri Lanka.
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
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18
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Shyamali NLA, Mahapatuna SD, Gomes L, Wijewickrama A, Ogg GS, Malavige GN. Risk Factors for Elevated Serum Lipopolysaccharide in Acute Dengue and Association with Clinical Disease Severity. Trop Med Infect Dis 2020; 5:tropicalmed5040170. [PMID: 33207759 PMCID: PMC7709576 DOI: 10.3390/tropicalmed5040170] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 10/24/2020] [Accepted: 10/30/2020] [Indexed: 11/17/2022] Open
Abstract
Although serum lipopolysaccharide (LPS) was shown to associate with development of severe dengue, the reasons for high LPS and its subsequent involvement in disease pathogenesis are not known. We assessed serum LPS, C-reactive protein (CRP), and procalcitonin in patients with acute dengue fever (DF = 129) and dengue haemorrhagic fever (DHF = 64) and correlated these observations with the presence of comorbid illnesses, and clinical disease severity. Serum LPS levels were significantly (p = 0.01) higher in patients with DHF, compared to those with DF. In total, 45 (70%) of those with DHF and 63 (49%) of those with DF had detectable LPS and therefore, the presence of LPS was significantly associated with DHF (p = 0.005, OR = 2.48, 95% CI: 1.29 to 4.64). Those with metabolic diseases, 22/29 (75.9%) and those with atopic diseases 17/22 (77.3%) were significantly more likely to have detectable LPS levels (p = 0.025, OR = 2.9, 95% CI-1.17 to 7.59 and p = 0.039, OR = 3.06, 95% CI-1.07 to 7.81 respectively). Those with detectable LPS levels were also more likely to develop shock and severe thrombocytopenia. Patients with detectable LPS were more likely to have elevated CRP levels and were more likely to develop DHF. Procalcitonin levels too were significantly (p = 0.009) higher in those with DHF compared to those with DF and were more likely to be high in those with detectable serum LPS. Since serum LPS levels were higher in patients with DHF and significantly more likely to be present in those with comorbid illnesses, the possible role of LPS in disease pathogenesis should be further investigated.
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Affiliation(s)
- N. L. Ajantha Shyamali
- Centre for Dengue Research, University of Sri Jayewardenepura, Nugegoda 10250, Sri Lanka; (N.L.A.S.); (S.D.M.); (L.G.); (G.S.O.)
| | - Sameera D. Mahapatuna
- Centre for Dengue Research, University of Sri Jayewardenepura, Nugegoda 10250, Sri Lanka; (N.L.A.S.); (S.D.M.); (L.G.); (G.S.O.)
| | - Laksiri Gomes
- Centre for Dengue Research, University of Sri Jayewardenepura, Nugegoda 10250, Sri Lanka; (N.L.A.S.); (S.D.M.); (L.G.); (G.S.O.)
| | | | - Graham S. Ogg
- Centre for Dengue Research, University of Sri Jayewardenepura, Nugegoda 10250, Sri Lanka; (N.L.A.S.); (S.D.M.); (L.G.); (G.S.O.)
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Biomedical Research Centre, Oxford OX3 9DS, UK
| | - Gathsaurie Neelika Malavige
- Centre for Dengue Research, University of Sri Jayewardenepura, Nugegoda 10250, Sri Lanka; (N.L.A.S.); (S.D.M.); (L.G.); (G.S.O.)
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Biomedical Research Centre, Oxford OX3 9DS, UK
- Correspondence: ; Tel.: +94-(0)-772443193
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19
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Tafere GG, Wondafrash DZ, Demoz FB. <p>Repurposing of N-Acetylcysteine for the Treatment of Dengue Virus-Induced Acute Liver Failure</p>. Hepat Med 2020; 12:173-178. [PMID: 33177895 PMCID: PMC7650016 DOI: 10.2147/hmer.s263840] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 08/25/2020] [Indexed: 11/23/2022] Open
Abstract
The prevalence of dengue infection-induced acute liver damage is increasing from time to time. Since it has no specific antiviral treatment in the world, people in endemic areas suffer more from dengue disorders. Thus, there is a need for searching options for the treatment of dengue-induced acute liver failure. N-acetylcysteine, which is used for the treatment of nasal congestion disorder and paracetamol overdose toxicity, could be used as a definitive therapy for dengue virus-induced acute liver disease. Therefore, this review discusses the therapeutic use of N-acetylcysteine for dengue-induced acute liver disease. Various case reports and case series showed that patients received NAC recovered from their clinical status. Additionally, a preclinical study showed that N-acetylcysteine has anti-dengue virus activity. Thus, N-acetylcysteine could be used as a definitive therapy in dengue virus-induced hepatitis. This might encourage researchers to further investigate the importance of N-acetylcysteine for dengue virus-induced hepatitis.
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Affiliation(s)
- Gebrehiwot Gebremedhin Tafere
- Department of Pharmacology and Toxicology, School of Pharmacy, Mekelle University, Mekelle, Ethiopia
- Correspondence: Gebrehiwot Gebremedhin Tafere P.O. Box: 1871, Mekelle, EthiopiaTel +251-908822323 Email
| | - Dawit Zewdu Wondafrash
- Department of Pharmacology and Toxicology, School of Pharmacy, Mekelle University, Mekelle, Ethiopia
| | - Filmon Beyenne Demoz
- Department of Pharmacology and Toxicology, School of Pharmacy, Mekelle University, Mekelle, Ethiopia
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20
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Raza MA, Khan MA, Ejaz K, Haider MA, Rasheed F. A Case of Dengue Fever With Hemorrhagic Manifestations. Cureus 2020; 12:e8581. [PMID: 32670716 PMCID: PMC7358921 DOI: 10.7759/cureus.8581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
Dengue fever is an arboviral infection spread by the Aedes mosquito with a wide spectrum of presentations encompassing simple flu-like illness to hemorrhagic manifestations. Hemorrhagic complications range from simple petechiae and purpura to gastrointestinal bleeding, hematuria, and severe central nervous system (CNS) bleeds. Herein we present a case of a 38-year-old male with dengue fever along with its hemorrhagic manifestations. Additionally, we conducted an extensive review of the literature to elucidate pathophysiology, diagnosis, and management of hemorrhagic manifestations in dengue fever.
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21
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De Hayr L, Asad S, Hussain M, Asgari S. RNA activation in insects: The targeted activation of endogenous and exogenous genes. INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY 2020; 119:103325. [PMID: 31978586 DOI: 10.1016/j.ibmb.2020.103325] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 12/10/2019] [Accepted: 01/15/2020] [Indexed: 06/10/2023]
Abstract
RNA activation (RNAa) is a newly emerging area of research in which dsRNA targeting promoter regions can induce the expression of the target gene. Although still in its infancy, it is already having significant impacts in several research areas in particular as cancer therapeutics. So far, the scope of RNAa has been limited to mammals and Caenorhabditis elegans with no indication of its prevalence in insects. In this study, we aimed to demonstrate the presence of RNAa in the insect dengue vector Aedes aegypti. Furthermore, we looked to uncover some details surrounding the involvement of host factors in order to present this as a new technique for insect research. The outcomes of this study provide new opportunities to further research into arthropod-borne diseases and insect biology in the same way as RNA interference.
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Affiliation(s)
- Lachlan De Hayr
- Australian Infectious Disease Research Centre, School of Biological Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Sultan Asad
- Australian Infectious Disease Research Centre, School of Biological Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Mazhar Hussain
- Australian Infectious Disease Research Centre, School of Biological Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Sassan Asgari
- Australian Infectious Disease Research Centre, School of Biological Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia.
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22
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Coudeville L, Baurin N, Shepard DS. The potential impact of dengue vaccination with, and without, pre-vaccination screening. Vaccine 2019; 38:1363-1369. [PMID: 31879126 DOI: 10.1016/j.vaccine.2019.12.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 12/04/2019] [Accepted: 12/06/2019] [Indexed: 11/29/2022]
Abstract
BACKGROUND The World Health Organization defined a 'screen and vaccinate' strategy as its recommended policy for the licensed dengue vaccine (Dengvaxia, Sanofi Pasteur), so that only individuals with previous dengue infection are vaccinated. The objectives of the present study were to build upon a recently published analysis of the benefits and risks associated with dengue vaccination to evaluate the public health impact and cost-effectiveness of a screen and vaccinate strategy. METHODS The current analysis was based on a previously reported transmission model and added, for the screening part, three rapid diagnostic tests with identical specificity (99%) but alternative sensitivities (50-70-90%) in the detection of prior dengue infection. The impact of a screen-and-vaccinate strategy considered nine settings representing different levels of transmission intensity. Outcomes (dengue-related hospitalizations, severe dengue, and symptomatic dengue) were assessed according to the level of transmission setting. The cost-effectiveness of vaccination in 10 endemic countries was also assessed. RESULTS Although associated, in most cases, with a lower population impact than a 'no-screening' approach, a screen and vaccinate strategy is more effective in reducing the number of hospitalized and severe cases prevented per vaccination performed and generates positive health benefits for individuals screened and subsequently vaccinated. As a result, this intervention is cost-effective in all countries considered except for very low transmission settings. The overall population impact of a screen and vaccinate approach is also likely to be improved by the use of several rounds of screening (up to 48% reduction in dengue hospitalization over 10 years with 5 rounds). CONCLUSIONS WHO recommended option of a screen and vaccinate policy is likely to have a positive impact both at the individual and population level across a wide range of transmission settings and has the potential to be as, if not more, cost-effective than a no screening strategy.
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Affiliation(s)
| | - Nicolas Baurin
- Vaccination Value Modelling, Sanofi Pasteur, Lyon, France
| | - Donald S Shepard
- Heller School for Social Policy and Management, Brandeis University, Waltham, MA, USA
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Ramesh K, Walvekar VA, Wong B, Sayed AMM, Missé D, Kini RM, Mok YK, Pompon J. Increased Mosquito Midgut Infection by Dengue Virus Recruitment of Plasmin Is Blocked by an Endogenous Kazal-type Inhibitor. iScience 2019; 21:564-576. [PMID: 31726374 PMCID: PMC6854080 DOI: 10.1016/j.isci.2019.10.056] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 10/20/2019] [Accepted: 10/25/2019] [Indexed: 12/17/2022] Open
Abstract
Dengue symptoms include alteration of blood coagulation and fibrinolysis, causing severe hemorrhage and death. Here, we demonstrate that higher concentration of plasmin, the human fibrinolytic factor, in blood meal enhances dengue virus (DENV) infection in mosquito midgut and dissemination in mosquitoes. We also show that mosquitoes express a plasmin-selective Kazal-type inhibitor (AaTI) in the midgut to inhibit plasmin proteolysis and revert the enhanced infection. Using bio-layer interferometry, we show that DENV, plasmin, and AaTI interact to form a tripartite complex. Eventually, plasmin increases midgut internalization of dextran molecules and this is reverted by AaTI. Our study demonstrates that (1) DENV recruits plasmin to increase local proteolytic activity in the midgut, thus degrading the glycocalyx and enhancing DENV internalization and (2) AaTI can act as a transmission-blocking agent by inhibiting plasmin proteolysis. Our results indicate that dengue pathogenesis enhances DENV fitness by increasing its infectivity to mosquitoes.
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Affiliation(s)
- Karthik Ramesh
- Department of Biological Sciences, National University of Singapore, 16 Science Drive 4, Singapore 117558, Singapore
| | - Varsha A Walvekar
- Department of Biological Sciences, National University of Singapore, 16 Science Drive 4, Singapore 117558, Singapore
| | - Benjamin Wong
- Program in Emerging Infectious Disease, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
| | - Ahmed Mahmoud Mohammed Sayed
- Department of Biological Sciences, National University of Singapore, 16 Science Drive 4, Singapore 117558, Singapore; Assiut University, Department of Chemistry, Faculty of Science, Assiut 71516, Egypt
| | - Dorothée Missé
- MIVEGEC, UMR IRD 224-CNRS5290-Université de Montpellier, Montpellier, France
| | - R Manjunatha Kini
- Department of Biological Sciences, National University of Singapore, 16 Science Drive 4, Singapore 117558, Singapore
| | - Yu Keung Mok
- Department of Biological Sciences, National University of Singapore, 16 Science Drive 4, Singapore 117558, Singapore.
| | - Julien Pompon
- Program in Emerging Infectious Disease, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore; MIVEGEC, UMR IRD 224-CNRS5290-Université de Montpellier, Montpellier, France.
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24
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Rajapakse S, de Silva NL, Weeratunga P, Rodrigo C, Sigera C, Fernando SD. Carica papaya extract in dengue: a systematic review and meta-analysis. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 19:265. [PMID: 31601215 PMCID: PMC6788024 DOI: 10.1186/s12906-019-2678-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 09/09/2019] [Indexed: 12/18/2022]
Abstract
Background Carica papaya (CP) extract is becoming popular as an unlicensed herbal remedy purported to hasten recovery in dengue infection, mostly based on observations that it may increase platelet counts. This systematic review and meta-analysis aims to critically analyze the evidence from controlled clinical trials on the efficacy and safety of CP extract in the treatment of dengue infection. Methods PubMed, LILACS and Google Scholar were searched for randomized or non-randomized trials enrolling patients with suspected or confirmed dengue where CP extract was compared, as a treatment measure, against standard treatment. Recovery of platelet counts as well as other clinical indicators of favourable outcome (duration of hospital stay, prevention of plasma leakage, life threatening complications, and mortality) were assessed. Results Nine studies (India-6, Pakistan-1, Indonesia-1, Malaysia-1) met the inclusion criteria. Seven studies showed an increase in platelet counts in patients receiving CP extract, while one study showed no significant difference between the two groups, and direct comparison was not possible in the remaining study. Serious adverse events were not reported. CP extract may reduce the duration of hospital stay (mean difference − 1.98 days, 95% confidence interval − 1.83 to − 2.12, 3 studies, 580 participants, low quality evidence), and cause improvement in mean platelet counts between the first and fifth day of treatment (mean difference 35.45, 95% confidence interval 23.74 to 47.15, 3 studies, 129 participants, low quality evidence). No evidence was available regarding other clinical outcomes. Conclusions The clinical value of improvement in platelet count or early discharge is unclear in the absence of more robust indicators of favourable clinical outcome. Current evidence is insufficient to comment on the role of CP extract in dengue. There is a need for further well designed clinical trials examining the effect of CP on platelet counts, plasma leakage, other serious manifestations of dengue, and mortality, with clearly defined outcome measures.
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25
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Pillai AB, Muthuraman KR, Mariappan V, Belur SS, Lokesh S, Rajendiran S. Oxidative stress response in the pathogenesis of dengue virus virulence, disease prognosis and therapeutics: an update. Arch Virol 2019; 164:2895-2908. [PMID: 31531742 DOI: 10.1007/s00705-019-04406-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 08/09/2019] [Indexed: 12/26/2022]
Abstract
Dengue virus (DENV) is a mosquito-borne arbovirus that causes febrile illness and can lead to a potentially lethal disease. The mechanism of disease pathogenesis is not completely understood, and there are currently no vaccines or therapeutic drugs available to protect against all four serotypes of DENV. Although many reasons have been suggested for the development of the disease, dengue studies have shown that, during DENV infection, there is an imbalance between oxidants and antioxidants that disrupts homeostasis. An increase in reactive oxygen species (ROS) levels triggers the sudden release of cytokines, which can lead to plasma leakage and other severe symptoms. In the present review, we give an overview of the oxidative stress response and its effect on the progression of dengue disease. We also discuss the role of oxidative-stress-associated molecules in disease prognostic and therapeutics.
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Affiliation(s)
- Agieshkumar Balakrishna Pillai
- Central Inter-Disciplinary Research Facility (CIDRF), Sri Balaji Vidyapeeth (Deemed to be University), Puducherry, 607 402, India.
| | | | - Vignesh Mariappan
- Central Inter-Disciplinary Research Facility (CIDRF), Sri Balaji Vidyapeeth (Deemed to be University), Puducherry, 607 402, India
| | | | - S Lokesh
- Department of General Medicine, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth (Deemed to be University), Puducherry, 607 402, India
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Abstract
Chikungunya and Zika virus infections are emerging diseases in the Americas, and dengue continues to be the most prevalent arthropod-borne virus in the world. These arbovirus diseases may spread by endemic transmission or as travel-related infections and have rapidly expanded their geographic distribution secondary to vector spread. All 3 share a similar clinical picture that includes a maculopapular rash. Zika is characterized by pruritic rash, low-grade fever, and arthralgia. Congenital nervous system malformations are a growing public-health concern. Chikungunya distinctive dermatologic manifestations include facial melanosis and bullous eruption. Dengue bleeding complications may be life-threatening and require inpatient management.
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Affiliation(s)
- Jose Dario Martinez
- Department of Internal Medicine, University Hospital "Dr. José E. González", UANL, Mitras Centro, Avenida Gonzalitos y Madero S/N, Monterrey 64460, Mexico.
| | - Jesus Alberto Cardenas-de la Garza
- Department of Dermatology, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Mitras Centro, Avenida Gonzalitos y Madero S/N, Monterrey 64460, Mexico
| | - Adrian Cuellar-Barboza
- Department of Dermatology, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Mitras Centro, Avenida Gonzalitos y Madero S/N, Monterrey 64460, Mexico
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27
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Mishra R, Lata S, Ali A, Banerjea AC. Dengue haemorrhagic fever: a job done via exosomes? Emerg Microbes Infect 2019; 8:1626-1635. [PMID: 31711408 PMCID: PMC6853225 DOI: 10.1080/22221751.2019.1685913] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 10/23/2019] [Indexed: 12/18/2022]
Abstract
Dengue fever is one of those unique diseases where host immune responses largely determine the pathogenesis and its severity. Earlier studies have established the fact that dengue virus (DENV) infection causes haemorrhagic fever and shock syndrome, but it is not directly responsible for exhibiting these clinical symptoms. It is noteworthy that clinically, vascular leakage syndrome does not develop for several days after infection despite a robust innate immune response that elicits the production of proinflammatory and proangiogenic cytokines. The onset of hyperpermeability in severe cases of dengue disease takes place around the time of defervescence and after clearance of viraemia. Extracellular vesicles are known to carry biological information (mRNA, miRNA, transcription factors) from their cells of origin and have emerged as a significant vehicle for horizontal transfer of stress signals. In dengue virus infection, the relevance of exosomes can be instrumental since the majority of the immune responses in severe dengue involve heavy secretion and circulation of pro-inflammatory cytokines and chemokines. Here, we present an updated review which will address the unique and puzzling features of hyperpermeability associated with DENV infection with a special focus on the role of secreted extracellular vesicles.
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Affiliation(s)
- Ritu Mishra
- Laboratory of Virology, National Institute of Immunology, New Delhi, India
| | - Sneh Lata
- Laboratory of Virology, National Institute of Immunology, New Delhi, India
| | - Amjad Ali
- Jamia Millia Islamia, Okhla, New Delhi, India
| | - Akhil C. Banerjea
- Laboratory of Virology, National Institute of Immunology, New Delhi, India
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28
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Cardenas JC, Drame PM, Luque-Burgos KA, Berrio JD, Entrena-Mutis E, González MU, Carvajal DJ, Gutiérrez-Silva LY, Cardenas LD, Colpitts TM, Mores CN, Londono-Renteria B. IgG1 and IgG4 antibodies against Aedes aegypti salivary proteins and risk for dengue infections. PLoS One 2019; 14:e0208455. [PMID: 30601814 PMCID: PMC6314615 DOI: 10.1371/journal.pone.0208455] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 11/16/2018] [Indexed: 12/22/2022] Open
Abstract
Dengue virus (DENV) is an arbovirus responsible for a significant number of deaths in Latin America. This virus is transmitted through the bite of Aedes aegypti, the main mosquito vector, and Ae. albopictus. During blood uptake, the mosquito injects its saliva into the host to facilitate the feeding process. Mosquito saliva contains potent immunogens capable of inducing antibody production directly related to mosquito bite exposure intensity and disease risk. In this study, we first determined the DENV infection status by two different DENV non-structural protein 1 (NS1) based rapid tests and qRT-PCR, then measured the levels of IgG1 and IgG4 antibodies against salivary proteins of Ae. aegypti female mosquitoes in volunteers living in a dengue endemic area. Our results show that people with a positive DENV diagnosis present higher levels of IgG4 antibodies than people with a negative diagnostic test, and that these antibody levels were higher in people with secondary DENV infections. With this study, we show that detection of IgG4 antibodies against mosquito saliva may be a reliable method to evaluate the risk of dengue infection.
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Affiliation(s)
- Jenny C. Cardenas
- Laboratorio Clínico, Hospital Local Los Patios, Norte de Santander, Colombia
- Department of Entomology, Kansas State University, Manhattan, Kansas, United States of America
| | - Papa M. Drame
- Department of Entomology, Kansas State University, Manhattan, Kansas, United States of America
| | | | - Juan D. Berrio
- Laboratorio Clínico, Hospital Erasmo Meoz de Cúcuta, Norte de Santander, Colombia
| | - Elsi Entrena-Mutis
- Laboratorio Clínico, Hospital Erasmo Meoz de Cúcuta, Norte de Santander, Colombia
| | - María U. González
- Laboratorio Clínico, Hospital Erasmo Meoz de Cúcuta, Norte de Santander, Colombia
| | - Daisy J. Carvajal
- Grupo Investigaciones en Enfermedades Parasitarias e Infecciosas, Universidad de Pamplona, Pamplona, Norte de Santander, Colombia
| | - Lady Y. Gutiérrez-Silva
- Laboratorio Clinico, E.S.E Hospital Emiro Quintero Cañizares, Ocaña, Norte de Santander, Colombia
| | - Lucio D. Cardenas
- Grupo Investigaciones en Enfermedades Parasitarias e Infecciosas, Universidad de Pamplona, Pamplona, Norte de Santander, Colombia
| | - Tonya M. Colpitts
- National Emerging Infectious Diseases Laboratories (NEIDL), Department of Microbiology, Boston University School of Medicine, Boston, MA, United States of America
| | - Christopher N. Mores
- Department of Global Health, Milken Institute School of Public Health, The George Washington University, Washington DC, United States of America
| | - Berlin Londono-Renteria
- Department of Entomology, Kansas State University, Manhattan, Kansas, United States of America
- * E-mail:
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Hwang J, Jiang A, Fikrig E. A potent prolyl tRNA synthetase inhibitor antagonizes Chikungunya and Dengue viruses. Antiviral Res 2018; 161:163-168. [PMID: 30521835 DOI: 10.1016/j.antiviral.2018.11.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 11/26/2018] [Accepted: 11/30/2018] [Indexed: 12/31/2022]
Abstract
Arboviruses represent a group of pathogens that can spread efficiently throughout human populations by hematophagous arthropod vectors. The mosquito-borne (re)emerging Chikungunya and Dengue viruses belong to the alphavirus and flavivirus genus, respectively, with no approved therapeutics or safe vaccines for humans. Transmitted by the same vector Aedes spp., these viruses cause significant morbidity and mortality in endemic areas. Due to the increasing likelihood of co-circulation and co-infection with viruses, we aimed to identify a pharmacologically targetable host factor that can inhibit multiple viruses and show that a potent antagonist of prolyl tRNA synthetase (halofuginone) suppresses both Chikungunya and Dengue viruses. Host tRNA synthetase inhibition may signify an additional approach to combat present and future epidemic pathogens.
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Affiliation(s)
- Jesse Hwang
- Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
| | - Alfred Jiang
- Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Erol Fikrig
- Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA
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30
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Jairaj A, Shirisha P, Abdul MSM, Fatima U, Tiwari RVC, Moothedath M. Adult Immunization - Need of the Hour. J Int Soc Prev Community Dent 2018; 8:475-481. [PMID: 30596036 PMCID: PMC6280562 DOI: 10.4103/jispcd.jispcd_347_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 10/16/2018] [Indexed: 11/15/2022] Open
Abstract
Immunization is the process of making individuals immune. Childhood immunization is a common process for various aliments, but adult immunization in the Indian scenario is obscure. Officially, India has been declared polio-free, which is an achievement despite cultural, political, economic, geographic, and so many other factors. The changing demographics of adult, geriatric population and growing cost of health-care maintenance are a concern in developing countries like India. Thus, promoting healthy lifestyle needs prevention, early detection, and management of various diseases and disorders. Certainly, prevention in adults is yet to be tapped completely, so that goal of 100% prevention can be achieved. Various fraternities of medical association have come up with guidelines for adult immunization schedules in India. The present paper reviews infectious diseases such as anthrax, chikungunya, cholera, dengue, influenza, and malaria in this section of the review. We humbly request all health-care professionals and educators to educate the mass for adult immunization. So that, cost involved for treatment and workforce for the management of diseases can be better utilized in some other needed areas.
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Affiliation(s)
| | - P Shirisha
- Department of Humanities and Social Sciences, IIT Madras, Chennai, Tamil Nadu, India
| | | | - Urooj Fatima
- Skin and Laser Care Centre, Dr. Sulaiman Al Habib Hospital, Riyadh, Saudi Arabia
| | - Rahul Vinay Chandra Tiwari
- Department of Oral and Maxillofacial Surgery and Dentistry, Jubilee Mission Medical College Hospital and Research Center, Thrissur, Kerala, India
| | - Muhamood Moothedath
- Department of Public Health Dentistry, College of Applied Health Sciences in Ar Rass, Qassim University, Buraydah, Saudi Arabia
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31
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Norazharuddin H, Lai NS. Roles and Prospects of Dengue Virus Non-structural Proteins as Antiviral Targets: An Easy Digest. Malays J Med Sci 2018; 25:6-15. [PMID: 30914859 PMCID: PMC6419879 DOI: 10.21315/mjms2018.25.5.2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Accepted: 03/21/2018] [Indexed: 12/13/2022] Open
Abstract
Dengue is a neglected disease caused by the infection of dengue virus which is transmitted by Aedes mosquitoes and to some, it could be fatal. Regardless of the enormous work devoted to research for the treatment of dengue, to this day there is no cure, and treatment is solely limited to supportive care by treating the symptoms. The inhibition of the viral RNA non-structural enzymes has been the most popular approach amongst the strategies applied to the search and development of dengue antivirals. This review is a compact digest of what is already known of the roles and the prospects of the dengue virus non-structural proteins NS1, NS2BNS3, NS4A, NS4B and NS5 as the targets for antiviral studies including the recent progress that has been published regarding their roles.
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Affiliation(s)
- Hannah Norazharuddin
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, 11800 USM, Pulau Pinang, Malaysia
| | - Ngit Shin Lai
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, 11800 USM, Pulau Pinang, Malaysia
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32
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Coudeville L, Baurin N, Olivera-Botello G. Assessment of benefits and risks associated with dengue vaccination at the individual and population levels: a dynamic modeling approach. Expert Rev Vaccines 2018; 17:753-763. [PMID: 30063839 DOI: 10.1080/14760584.2018.1503955] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND A case-cohort study, using a novel assay and data from three dengue vaccine efficacy trials, highlighted differences in vaccination outcomes according to baseline serostatus. Based on these results, we explored, with a model, the benefits and risks associated with vaccination. RESEARCH DESIGN AND METHODS Parameters of a previously developed transmission model were estimated with subject-level data from a case-cohort study. The model was used to assess vaccination outcomes for a range of transmission settings over 5-30 years, with or without indirect protection. MAIN OUTCOME MEASURES Symptomatic dengue cases, dengue hospitalizations, and severe dengue cases. RESULTS The model is consistent with previous results indicating a transitory period at increased risk for dengue-seronegative vaccine recipients (setting-dependent duration) and long-term benefits for dengue-seropositive recipients. At the population level, benefits to seropositive individuals over 10 years outweighed the risk to those seronegative in moderate to high transmission settings (≥50% seropositivity at age 9), especially in high transmission settings (no excess hospitalizations in dengue-seronegative for ≥80% seropositivity at age 9). Results were more favorable when longer time horizons or indirect protection were considered. CONCLUSIONS Results indicate a public health benefit associated with dengue vaccination especially in high-transmission settings, even with the initial excess risks to dengue-seronegative patients which diminish over time.
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Affiliation(s)
| | - Nicolas Baurin
- a Vaccination Value Modelling , Sanofi Pasteur , Lyon , France
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33
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Oliveira ES, Colombarolli SG, Nascimento CS, Batista ICA, Ferreira JGG, Alvarenga DLR, de Sousa LOB, Assis RR, Rocha MN, Alves ÉAR, Calzavara-Silva CE. Increased Levels of Txa₂ Induced by Dengue Virus Infection in IgM Positive Individuals Is Related to the Mild Symptoms of Dengue. Viruses 2018; 10:v10030104. [PMID: 29495587 PMCID: PMC5869497 DOI: 10.3390/v10030104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 02/23/2018] [Accepted: 02/25/2018] [Indexed: 11/16/2022] Open
Abstract
The inflammatory process plays a major role in the prognosis of dengue. In this context, the eicosanoids may have considerable influence on the regulation of the Dengue virus-induced inflammatory process. To quantify the molecules involved in the cyclooxygenase and lipoxygenase pathways during Dengue virus infection, plasma levels of thromboxane A2, prostaglandin E2 and leukotriene B4; mRNA levels of thromboxane A2 synthase, prostaglandin E2 synthase, leukotriene A4 hydrolase, cyclooxygenase-2 and 5-lipoxygenase; and the levels of lipid bodies in peripheral blood leukocytes collected from IgM-positive and IgM-negative volunteers with mild dengue, and non-infected volunteers, were evaluated. Dengue virus infection increases the levels of thromboxane A2 in IgM-positive individuals as well as the amount of lipid bodies in monocytes in IgM-negative individuals. We suggest that increased levels of thromboxane A2 in IgM-positive individuals plays a protective role against the development of severe symptoms of dengue, such as vascular leakage.
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Affiliation(s)
- Eneida S Oliveira
- Imunologia Celular e Molecular, Instituto René Rachou, Avenida Augusto de Lima, 1715, sala 406, Belo Horizonte 30190-002, Brazil.
| | - Stella G Colombarolli
- Imunologia Celular e Molecular, Instituto René Rachou, Avenida Augusto de Lima, 1715, sala 406, Belo Horizonte 30190-002, Brazil.
| | - Camila S Nascimento
- Imunologia Celular e Molecular, Instituto René Rachou, Avenida Augusto de Lima, 1715, sala 406, Belo Horizonte 30190-002, Brazil.
| | - Izabella C A Batista
- Imunologia Celular e Molecular, Instituto René Rachou, Avenida Augusto de Lima, 1715, sala 406, Belo Horizonte 30190-002, Brazil.
| | - Jorge G G Ferreira
- Imunologia Celular e Molecular, Instituto René Rachou, Avenida Augusto de Lima, 1715, sala 406, Belo Horizonte 30190-002, Brazil.
| | - Daniele L R Alvarenga
- Imunologia Celular e Molecular, Instituto René Rachou, Avenida Augusto de Lima, 1715, sala 406, Belo Horizonte 30190-002, Brazil.
| | - Laís O B de Sousa
- Santa Casa de Misericórdia de Santo Antônio do Monte, Santo Antônio do Monte 35560-000, Brazil.
| | - Rafael R Assis
- Imunologia Celular e Molecular, Instituto René Rachou, Avenida Augusto de Lima, 1715, sala 406, Belo Horizonte 30190-002, Brazil.
| | - Marcele N Rocha
- Mosquitos Vetores: Endossimbiontes e Interação Patógeno-Vetor, Instituto René Rachou, Belo Horizonte 30190-002, Brazil.
| | - Érica A R Alves
- Imunologia Celular e Molecular, Instituto René Rachou, Avenida Augusto de Lima, 1715, sala 406, Belo Horizonte 30190-002, Brazil.
| | - Carlos E Calzavara-Silva
- Imunologia Celular e Molecular, Instituto René Rachou, Avenida Augusto de Lima, 1715, sala 406, Belo Horizonte 30190-002, Brazil.
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IL-10 and socs3 Are Predictive Biomarkers of Dengue Hemorrhagic Fever. Mediators Inflamm 2017; 2017:5197592. [PMID: 28827898 PMCID: PMC5554562 DOI: 10.1155/2017/5197592] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Revised: 06/03/2017] [Accepted: 06/27/2017] [Indexed: 12/30/2022] Open
Abstract
Background Cytokines play important roles in the physiopathology of dengue infection; therefore, the suppressors of cytokine signaling (socs) that control the type and timing of cytokine functions could be involved in the origin of immune alterations in dengue. Objective To explore the association of cytokine and socs levels with disease severity in dengue patients. Methods Blood samples of 48 patients with confirmed dengue infection were analyzed. Amounts of interleukins IL-2, IL-4, IL-6, and IL-10, interferon- (IFN-) γ, and tumor necrosis factor- (TNF-) α were quantified by flow cytometry, and the relative expression of socs1 and socs3 mRNA was quantified by real-time RT-PCR. Results Increased levels of IL-10 and socs3 and lower expression of socs1 were found in patients with dengue hemorrhagic fever (DHF) with respect to those with dengue fever (DF) (p < 0.05). Negative correlations were found between socs1 and both IL-10 and socs3 (p < 0.01). The cutoff values of socs3 (>199.8-fold), socs1 (<1.94-fold), and IL-10 (>134 pg/ml) have the highest sensitivity and specificity to discriminate between DF and DHF. Conclusion Simultaneous changes in IL-10 and socs1/socs3 could be used as prognostic biomarkers of dengue severity.
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Abstract
INTRODUCTION Changing dengue epidemiological trends have resulted in a shift in the disease burden to the adult population. Older adults suffer from poorer outcomes as compared to their younger counterparts, making clinical management of this sub-population particularly challenging. Areas covered: We present a review of the current literature on the changing epidemiology of dengue in the elderly, the atypical features of the clinical disease in this population with emphasis on severe disease presentations and challenges in the current management strategies. Expert commentary: Dengue in the elderly is an increasingly important yet greatly understudied area. There is an urgent need to refine the current diagnostic criteria to improve diagnosis, classification of disease severity and identify individuals in this population who are likely to progress to severe disease. Management strategies in this population would have to be adjusted to account for the increased number of co-morbidities. The role of the available dengue vaccines in this group is uncertain, and more studies into their safety and efficacy are critically needed.
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Affiliation(s)
- Ray Junhao Lin
- a Department of Infectious Diseases, Institute of Infectious Diseases and Epidemiology , Tan Tock Seng Hospital , Singapore
| | - Tau Hong Lee
- a Department of Infectious Diseases, Institute of Infectious Diseases and Epidemiology , Tan Tock Seng Hospital , Singapore
| | - Yee Sin Leo
- a Department of Infectious Diseases, Institute of Infectious Diseases and Epidemiology , Tan Tock Seng Hospital , Singapore.,b Saw Swee Hock School of Public Health , National University of Singapore , Singapore.,c Lee Kong Chian School of Medicine , Nanyang Technological University , Singapore
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36
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Malavige GN, Ogg GS. Pathogenesis of vascular leak in dengue virus infection. Immunology 2017; 151:261-269. [PMID: 28437586 DOI: 10.1111/imm.12748] [Citation(s) in RCA: 175] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Revised: 03/26/2017] [Accepted: 04/17/2017] [Indexed: 12/31/2022] Open
Abstract
Endothelial dysfunction leading to vascular leak is the hallmark of severe dengue. Vascular leak typically becomes clinically evident 3-6 days after the onset of illness, which is known as the critical phase. This critical phase follows the period of peak viraemia, and lasts for 24-48 hr and usually shows rapid and complete reversal, suggesting that it is likely to occur as a result of inflammatory mediators, rather than infection of the endothelium. Cytokines such as tumour necrosis factor-α, which are known to be elevated in the critical phase of dengue, are likely to be contributing factors. Dengue NS1, a soluble viral protein, has also been shown to disrupt the endothelial glycocalyx and thus contribute to vascular leak, although there appears to be a discordance between the timing of NS1 antigenaemia and occurrence of vascular leak. In addition, many inflammatory lipid mediators are elevated in acute dengue viral infection such as platelet activating factor (PAF) and leukotrienes. Furthermore, many other inflammatory mediators such as vascular endothelial growth factor and angiopoietin-2 have been shown to be elevated in patients with dengue haemorrhagic fever, exerting their action in part by inducing the activity of phospholipases, which have diverse inflammatory effects including generation of PAF. Platelets have also been shown to significantly contribute to endothelial dysfunction by production of interleukin-1β through activation of the NLRP3 inflammasome and also by inducing production of inflammatory cytokines by monocytes. Drugs that block down-stream immunological mediator pathways such as PAF may also be beneficial in the treatment of severe disease.
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Affiliation(s)
- Gathsaurie Neelika Malavige
- Centre for Dengue Research, University of Sri Jayewardenepura, Nugegoda, Sri Lanka.,MRC Human Immunology Unit, Radcliffe Department of Medicine, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Graham S Ogg
- MRC Human Immunology Unit, Radcliffe Department of Medicine, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
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Londono-Renteria B, Marinez-Angarita JC, Troupin A, Colpitts TM. Role of Mast Cells in Dengue Virus Pathogenesis. DNA Cell Biol 2017; 36:423-427. [PMID: 28486041 DOI: 10.1089/dna.2017.3765] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Dengue is currently regarded as the most common arthropod-borne viral disease in tropical and subtropical areas, with an estimated 50-100 million infections occurring each year. Nearly all patients experience a self-limiting clinical course; however, the illness ranges from undifferentiated fever to severe hemorrhagic fever with or without shock syndrome complications. There are several immune cells associated with the pathogenesis of dengue virus (DENV) infection and systemic spread, including dendritic cells, macrophages, and mast cells (MCs). MCs are widely recognized for their immune functions and as cellular regulators of vascular integrity in human skin. Furthermore, these cells are able to detect DENV, which results in activation and degranulation of potent vasoactive mediators prestored in the granules. These mediators can act directly on vascular endothelium, increasing permeability and inducing vascular leakage. This review is designed to present an insight into the role of MCs during DENV infection and the dual functions in immune protection and contribution to the most severe forms of dengue.
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Affiliation(s)
| | | | - Andrea Troupin
- 3 Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine , Columbia, South Carolina
| | - Tonya M Colpitts
- 3 Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine , Columbia, South Carolina
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38
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Bedin F, Boulet L, Voilin E, Theillet G, Rubens A, Rozand C. Paper-based point-of-care testing for cost-effective diagnosis of acute flavivirus infections. J Med Virol 2017; 89:1520-1527. [DOI: 10.1002/jmv.24806] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Accepted: 02/23/2017] [Indexed: 12/28/2022]
Affiliation(s)
- Frederic Bedin
- Innovation, BioMerieux SA; Chemin de l'Orme; Marcy l'Etoile France
| | - Laurent Boulet
- Innovation, BioMerieux SA; Chemin de l'Orme; Marcy l'Etoile France
| | - Elodie Voilin
- Innovation, BioMerieux SA; Chemin de l'Orme; Marcy l'Etoile France
| | - Gerald Theillet
- Innovation, BioMerieux SA; Chemin de l'Orme; Marcy l'Etoile France
| | - Agnes Rubens
- Innovation, BioMerieux SA; Chemin de l'Orme; Marcy l'Etoile France
| | - Christine Rozand
- Innovation, BioMerieux SA; Chemin de l'Orme; Marcy l'Etoile France
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