Dengue

Dengue

Dengue is the most important mosquito-borne viral infection of humans. It represents a major problem for public health services around the world, with recent estimates indicating that 390 million infections occur each year, of which almost 100 million are symptomatic. Infection can be caused by any one of four closely related dengue viral (DENV) serotypes, transmitted between people by Aedes mosquitoes. The disease is endemic across much of Asia and Latin America, and the global footprint is expanding rapidly in parallel with the dispersal of efficient mosquito vectors across tropical and subtropical regions of the world.

Although most DENV infections are asymptomatic, a wide variety of clinical manifestations may occur, ranging from mild febrile illness to severe and fatal disease. Symptoms of dengue include fever, headache, muscle and joint pains, and gastrointestinal symptoms; in most cases these symptoms resolve within one week. However a small proportion of patients develop complications that may include bleeding, organ dysfunction and a capillary leak syndrome that progresses to hypovolaemic shock in severe cases, i.e. dengue shock syndrome. Typically these complications become apparent rather late in the illness course when the fever is settling and the virus is already disappearing from the body. Currently no antivirals or other therapeutic agents have been shown to be effective and careful supportive care, with a particular focus on judicious fluid management, remains the cornerstone of good case-management. Major efforts are being directed towards developing a safe and effective vaccine but as yet no suitable candidate is available. Deployment of effective vector control strategies remains an important approach in global disease prevention efforts.

 

Dengue in Viet Nam

In Viet Nam, 85% of dengue cases occur in the southern regions of the country. Case numbers peak between June and November each year, during the wet season. The dengue case burden has increased progressively in recent years; in southern Viet Nam approximately 19,000 cases were reported in 2000 and 68,000 in 2012. In epidemic years more than 80,000 dengue cases may be admitted to hospital in a single season. Approximately two thirds of the cases are children under 16 years of age, with most of the severe disease also occurring in this age group. All four DENV serotypes co-circulate in Viet Nam, with periodic changes in the dominant serotype every few years.

 

What we’re doing to improve outcomes for dengue patients

One of the most important aims of the research carried out by the Dengue Group is to improve diagnosis and clinical management of patients. One notable achievement has been leadership of a body of work that culminated in revision of the WHO Dengue Guidelines in 2009, incorporating of a new simpler disease classification scheme, and publication of a new WHO handbook for clinical management in 2012. We are also world leaders in the conduct of therapeutic intervention trials for dengue.

Intervention studies

There are two main approaches to dengue therapeutic interventions. The first is to target the virus through the use of an antiviral, and the second is to target the immune response to the virus since this is thought to be partly responsible for the development of severe disease. In partnership with the Hospital of Tropical Diseases we have tried both of these approaches, and have completed blinded randomized controlled clinical trials of chloroquine, balapiravir (an antiviral) and corticosteroids in dengue. We are currently conducting a trial of lovastatin which has both antiviral and immunomodulatory activities. We have published recommendations for the conduct of early phase clinical trials in dengue. In the past, we have also conducted trials of intravenous fluid therapy for resuscitation in dengue shock syndrome.

Clinical management

Differentiating dengue from other common viral illnesses during the initial febrile phase, and identifying patients at risk of disease progression, are key questions for dengue case-management. We are conducting several large observational studies, both across Viet Nam and at a number of international sites (IDAMS Study), that we hope will help us answer these questions. We are carrying out serial assessments of a number of clinical, immunological and virological markers during the different phases of the illness course, in order to create diagnostic and prognostic algorithms suitable for clinical application in the communities in which we work, and hopefully also in the global context.

What we’re doing to understand dengue better

Our research on entomology and the epidemiology of disease has aided understanding of dengue transmission, and our work on host susceptibility and pathogenesis has the potential to inform the design of future vaccine and therapeutic candidates.

Pathogenesis

One of the group’s main aims is to try to understand the reasons why some people get severe disease and to work out what the pathological processes are that cause these severe manifestations. One area of special interest focuses on identifying structural and/or functional changes in the microcirculation, so that we can understand how dengue infection causes blood vessels to become ‘leaky’, and also identify the mechanisms underlying the coagulation abnormalities that contribute to bleeding. We are using a number of non-invasive methods to assess microvascular function in patients of different severity at different time-points during the evolution of their illness, and in doing so we hope we may identify early markers that could be useful in predicting which patients will go on to develop DSS or severe bleeding. We are also using histological techniques, including electron microscopy, to look in great detail at blood vessel structure in skin biopsies taken from DSS patients compared to healthy volunteers.

Host susceptibility

Together with colleagues in Singapore our group was involved with the first genome-wide association study in dengue. This study, published in Nature Genetics, identified susceptibility loci for severe dengue in the MICB and PLCE1 genes. Our group is involved in further studies to explore the role of these genes in dengue pathogenesis and hopefully extend our understanding of the disease.

Epidemiology

We are studying the spatial and temporal patterns of dengue in the community, by analysing time series of dengue surveillance data and investigating clustering of dengue cases in and around households. A large prospective birth cohort study has been running since 2009 to investigate dengue immunity and pathogenesis in infants, as well as the epidemiology of other viral infections in infancy.

Entomology

Recently we have defined the infectious dose of dengue virus required to infect Aedes aegypti mosquitoes. In addition we are currently doing studies to compare the vector competence of different mosquitoes such as Aedes aegypti and Aedes albopictus. Wolbachia are intracellular bacteria that infect many arthropod species and have been shown to confer resistance to dengue infection in mosquitoes. Members of our group are involved with the release of Wolbachia-infected mosquitoes in Viet Nam as part of the Eliminate Dengue project and are assessing the vector competence of Aedes aegypti mosquitoes infected with a number of Wolbachia strains for their suitability for release into the community. We are also assessing the attractiveness of mosquitoes to febrile dengue patients, and whether mosquito repellent works as effectively on dengue patients as on healthy control volunteers.

 

Dengue research locations in Viet Nam

  • Hospital for Tropical Diseases, Ho Chi Minh City
  • National Hospital for Tropical Diseases, Hanoi
  • Children Hospitals No.1 and No. 2, Ho Chi Minh City
  • Huong Vuong Hospital, Ho Chi Minh City
  • Tien Giang Hospital
  • Dong Thap Hospital
  • Binh Duong Hospital
  • Dong Nai Paediatric Hospital
  • Long An Hospital
  • Tri Nguyen Island (Eliminate Dengue Wolbachia projects)

Dengue research locations internationally (IDAMS Study)

  • University of Malaya Medical Centre, Kuala Lumpur, Malaysia
  • The Gadjah Mada University, Yoygakarta, Indonesia
  • Angkor Hospital for Children, Phnom Penh, Cambodia
  • Hospital Nacional de Ninos Benjamin Bloom, San Salvador, El Salvador
  • Universidade Estadual Do Ceara, Fortaleza, Brazil
  • University of Carabobo, Valencia, Venezuela

Dengue collaborations/partnerships

  • Imperial College, London, UK
  • London School of Hygiene and Tropical Medicine, UK
  • University of Melbourne, Nossal Institute of Global Health, Australia
  • Monash University, Australia
  • Eliminate Dengue (http://www.eliminatedengue.com)
  • IDAMS (http://www.idams.eu)
  • Heidelberg University Hospital, Germany
  • The Special Programme for Research and Training in Tropical Diseases of the World Health Organization (WHO/TDR), Geneva, Sitzerland
  • Pedro Kouri Tropical Medicine Institute, Havana, Cuba
  • The Institute for Research in Biomedicine, Bellinzona, Switzerland
  • Genome Institute Singapore
  • Singapore Immunology Network
  • Sasisekharan Laboratory, Harvard-MIT, USA
  • Liverpool John Moores University, UK
  • University of Bristol Microvascular Research Laboratories, UK

 

Our research team

  • Bridget Wills – Senior Clinical Research Fellow & Group Head
  • Tran Nguyen Bich Chau – Wellcome Trust Training Fellow & Deputy Group Head
  • Cameron Simmons – NHMRC Senior Research Fellow
  • Dinh The Trung – Research Physician
  • Dong Thi Hoai Tam – Senior Clinical Consultant
  • Duong Thi Hue Kien – Lead, Molecular Diagnostics Group
  • Hoang Quoc Cuong – PhD Student
  • James Whitehorn – Wellcome Trust Clinical Research Fellow
  • Katie Anders – Epidemiologist & PhD Student
  • Lauren Carrington – Postdoctoral Scientist, Entomology
  • Nguyen Minh Nguyet – PhD Student
  • Nguyen Minh Tuan – PhD Student
  • Nguyen Thi Hanh Tien – PhD Student
  • Nguyen Thi Lan Hoa – Senior Scientific Consultant
  • Nguyen Than Ha Quyen – Postdoctoral Scientist & Lead, Immunology Group
  • Phung Khanh Lam – PhD Student (Biostatistics, OUCRU)
  • Sophie Yacoub – Wellcome Trust Clinical Research Fellow (OUCRU-Hanoi)
  • Vo Thi Long – Lead, Entomology Group

 

Selected Publications

  1. Lam PK, Tam DT, Diet TV, Tam CT, Tien NT, Kieu NT, Simmons C, Farrar J, Nga NT, Qui PT, Dung NM, Wolbers M, Wills B. Clinical characteristics of dengue shock syndrome in vietnamese children: a 10-year prospective study in a single hospital. Clin Infect Dis. 2013 Dec; 57(11):1577-86.
  2. Cuong HQ, Vu NT, Cazelles B, Boni MF, Thai KDT, Rabaa MA, et al. Spatiotemporal dynamics of dengue epidemics, southern Vietnam. Emerg Inf Dis. 2013 Jun; 19(6):945:53.
  3. Nguyen NM, Thi Hue Kien D, Tuan TV, Quyen NT, Tran CN, Vo Thi L, et al. Host and viral features of human dengue cases shape the population of infected and infectious Aedes aegypti mosquitoes. Proc Natl Acad Sci U S A. 2013 May; 110(22):9072-7.
  4. Nguyen NM, Tran CN, Phung LK, Duong KT, Huynh HL, Farrar J, et al. A Randomized, Double-Blind Placebo Controlled Trial of Balapiravir, a Polymerase Inhibitor, in Adult Dengue Patients. J Infect Dis. 2013 May; 207(9):1442-50.
  5. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. The global distribution and burden of dengue. Nature. 2013 Apr; 496(7446):504-7.
  6. Tam DT, Ngoc TV, Tien NT, Kieu NT, Thuy TT, Thanh LT, et al. Effects of Short-Course Oral Corticosteroid Therapy in Early Dengue Infection in Vietnamese Patients: A Randomized, Placebo-Controlled Trial. Clin Infect Dis. 2012 Nov; 55(9):1216-24.
  7. Simmons CP, Farrar JJ, Nguyen v V, Wills B. Dengue. N Engl J Med. 2012 Apr; 366(15):1423-32.
  8. Yacoub S, Griffiths A, Chau TT, Simmons CP, Wills B, Hien TT, Henein M, Farrar J. Cardiac function in Vietnamese patients with different dengue severity grades. Crit Care Med. 2012 Feb; 40(2):477-83
  9. Khor CC, Chau TN, Pang J, Davila S, Long HT, Ong RT, et al. Genome-wide association study identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1. Nat Genet. 2011 Oct; 43(11):1139-41
  10. Raghwani J, Rambaut A, Holmes EC, Hang VT, Hien TT, Farrar J, Wills B, Lennon NJ, Birren BW, Henn MR, Simmons CP. Endemic dengue associated with the co-circulation of multiple viral lineages and localized density-dependent transmission. PLoS Pathog. 2011 Jun;7(6): e1002064
  11. Tuan NM, Nhan HT, Chau NV, Hung NT, Tuan HM, Tram TV, Ha Nle D, Loi P, Quang HK, Kien DT, Hubbard S, Chau TN, Wills B, Wolbers M,Simmons CP. Sensitivity and specificity of a novel classifier for the early diagnosis of dengue. PLoS Negl Trop Dis. 2015 Apr 2;9(4):e0003638. doi: 10.1371/journal.pntd.0003638. eCollection 2015 Apr. PMID: 25836753
  12. Ferguson NM, Hue Kien DT, Clapham H, Aguas R, Trung VT, Bich Chau TN, Popovici J, Ryan PA, O’Neill SL, McGraw EA, Long VT, Dui le T, Nguyen HL, Vinh Chau NV, Wills B, Simmons CP. Modeling the impact on virus transmission of Wolbachia-mediated blocking of dengue virus infection of Aedes aegypti.Sci Transl Med. 2015 Mar 18;7(279):279ra37. doi: 10.1126/scitranslmed.3010370. PMID: 25787763
  13. Whitehorn J, Kien DT, Nguyen NM, Nguyen HL, Kyrylos PP, Carrington LB, Bich Tran CN, Quyen NT, Thi LV, Thi DL, Truong NT, Luong TT, Nguyen CV, Wills B, Wolbers M, Simmons CP. Comparative susceptibility of Aedes albopictus and Aedes aegypti to dengue virus infection following human viremic blood-feeding: implications for public health. J Infect Dis. 2015 Mar 17. pii: jiv173. PMID: 25784733
  14. Anders KL, Nga le H, Thuy NT, Ngoc TV, Tam CT, Tai LT, Truong NT, Duyen HT, Trung VT, Kien DT, Wolbers M, Wills B, Chau NV, Tho ND, Simmons CP. Households as foci for dengue transmission in highly urban Vietnam. PLoS Negl Trop Dis. 2015 Feb 13;9(2):e0003528. doi: 10.1371/journal.pntd.0003528. eCollection 2015 Feb. PMID: 25680106
  15. Carrington LB, Nguyen HL, Nguyen NM, Duong TH, Tuan TV, Giang NT, Tuyet NV, Thi DL, Thi LV, Tran CN, Simmons CP. Naturally-Acquired Dengue Virus Infections Do Not Reduce Short-Term Survival of Infected Aedes aegypti from Ho Chi Minh City, Vietnam. Am J Trop Med Hyg. 2015 Mar 4;92(3):492-6. doi: 10.4269/ajtmh.14-0499. Epub 2015 Jan 5. PMID: 25561566
  16. Dejnirattisai W, Wongwiwat W, Supasa S, Zhang X, Dai X, Rouvinsky A, Jumnainsong A, Edwards C, Quyen NT, Duangchinda T, Grimes JM, Tsai WY, Lai CY, Wang WK, Malasit P, Farrar J, Simmons CP, Zhou ZH, Rey FA, Mongkolsapaya J, Screaton GR. A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus. Nat Immunol. 2015 Feb;16(2):170-7. doi: 10.1038/ni.3058. Epub 2014 Dec 15.PMID: 25501631

 

Contributions to WHO Guidelines

  • WHO. Dengue: guidelines for diagnosis, treatment, prevention and control – New edition. Geneva: World Health Organisation, 2009
  • WHO. Handbook for clinical mangement of dengue. Geneva: World Health Organisation, 2012