Dengue is responsible for upwards of 50 million infections per year worldwide; however, given that asymptomatic infection is possible, the true incidence is thought to be far higher. The virus is emerging or re-emerging in many regions of the world, including Australia, where episodic outbreaks occur in North Queensland. With a changing future climate, household water storage and mosquito distribution could affect outbreak frequency and the geographic distribution of this virus.

Virology

Dengue viruses (DENV) are enveloped viruses in the family Flaviviridae; genus Flavivirus. The genome is positive-sense, single-stranded RNA, which encodes seven non-structural proteins (including NS1, which is used for laboratory testing – see below) and three structural proteins.^{1 2} There are four DENV serotypes (DENV-1, DENV-2, DENV-3 and DENV-4).³ A fifth DENV type was discovered in samples collected during a dengue outbreak in Sarawak, Malaysia, in 2007; however, its transmission cycle is not believed to be sustained in humans.⁴

Transmission

DENV is transmitted via the bite of infected mosquitoes, predominantly  Aedes aegypti, although Aedes albopictus also has the potential to carry DENV. The virus is maintained in a human- mosquito-human (urban) transmission cycle.^{1 2} There is the chance of non-vector modes of transmission, including through needle-stick injury⁵, transplantation 6.and transfusion of blood components.7 Vertical transmission may also be possible during pregnancy or at birth; infection via such routes does not appear to result in long-term sequelae and there appears to be no association between the severity of disease in the mother and disease in the newborn.^{6 7 8 9} DENV has been detected in the breastmilk of an acutely infected mother, suggesting that this may be a possible additional route of DENV transmission from mother to child.¹⁰

Epidemiology

According to the World Health Organization (WHO), more than 40 per cent of the world’s population are at risk of dengue fever, with 50–100 million dengue infections occurring worldwide each year. A recent study re-evaluating the global impact of dengue estimated there to be 390 million infections per year (more than three times the WHO estimate).¹¹ Although dengue infection is traditionally more common in children, increasing numbers of cases in adults have resulted in more pregnant women being infected.¹² Dengue is endemic in tropical and sub-tropical countries, owing to continual circulation of the virus within an established mosquito population. More than 100 countries are endemic for dengue, including those in Africa, the Americas, the Eastern Mediterranean, South-East Asia and the Western Pacific. In Australia, dengue is not considered endemic; rather, it is episodic in North Queensland, owing to the presence of the primary vector: Ae. aegypti. Regular outbreaks occur seasonally in North Queensland.^{13 15 16} and, in 2013, this region experienced another outbreak, with approximately 200 confirmed cases.¹⁷ There are a number of factors, such as changes in climate and human behaviour, that suggest that DENV might spread farther in Queensland and indeed to other parts of Australia.^{18 19 20}

Clinical features

Infection can result in dengue fever (DF), dengue haemorrhagic fever (DHF), dengue shock syndrome (DSS), a range of intermediate responses or no clinical response at all.³ Symptoms may include severe headache, severe joint and muscle pain, retro-orbital pain, nausea and vomiting.³ Life-long immunity to infection occurs, but it is specific for the DENV serotype (cross protection between types persists only for several months). More severe symptoms (DHF, DSS) have been associated with secondary infection with a differing DENV serotype, which can be fatal.³ In pregnant women, dengue infection may result in an acute febrile illness and there is a greater risk of pre-eclampsia, preterm labour and a low birthweight baby.²¹ Most cases of DF infection in pregnancy result in no serious harm to the mother or baby; however, women who contract DF in early or late pregnancy tend to have a poorer prognosis.14 Severe thrombocytopenia (platelet count of <50 000 cell/mm3) was observed in 79 per cent of a cohort of pregnant women with dengue in India, which included women in the second trimester.¹² However, many of these women had an uneventful course of infection, were treated conservatively and discharged.¹² Dengue infection in the neonate can range from an asymptomatic or mild disease, to DHF or DSS.²² and passively transferred antibodies, such as in breastmilk from an infected mother, may influence the clinical picture.

Case definition

In Australia, dengue is nationally notifiable, with both confirmed and probable cases requiring notification. A confirmed case requires laboratory definitive evidence (isolation of virus; detection through nucleic acid testing; or detection of DENV NS1 antigen in blood; DENV IgG seroconversion; an increase in DENV antibody level; or the detection of DENV IgM in cerebrospinal fluid, in the absence of IgM to other flaviviruses) and clinical evidence (a clinically compatible illness for example, fever, headache, arthralgia, myalgia, rash, nausea, vomiting and so forth).²³ A probable case requires laboratory suggestive evidence (detection of DENV IgM in blood) and clinical evidence as well as epidemiological evidence (a plausible explanation, for instance travel to an area endemic for dengue or exposure in Australia where local transmission has occurred).²⁴ Delay in notification is an important factor influencing outbreak duration in Australia15, highlighting the importance of a timely diagnosis and of our notification system.

Treatment and prevention

There are no specific antiviral drugs available for the treatment of dengue infection. Treatment is dependent on symptoms and involves their management. For DF, this usually involves hydration and pain control (paracetamol, codeine or other agents that are not nonsteroidal anti-inflammatory agents). Hospitalisation and additional treatments are often required for DHF or DSS, including IV hydration, blood and/or platelet transfusions, blood pressure support and other intensive-care measures. Studies suggest that during pregnancy most cases require only conservative treatment unless there are complications^{12 25}, and platelet transfusion is only needed for women in labour or with a bleeding disorder.²⁵ There is no vaccine available, despite work in the area for a number of years. There are a number of candidate vaccines in the preclinical or clinical states of evaluation, with additional candidates in the research phase of development.²⁶ Some challenges faced by vaccine developers include the need to protect against all serotypes in naïve as well as previously immune individuals as well as the requirement to induce life-long protection against infection with all serotypes.²⁶ Prevention therefore currently relies on preventing mosquito bites and/or the control of the mosquito vector itself.

1. Henchal EA, Putnak JR. The Dengue Viruses. Clin Microbiol Rev. 1990 Oct;3(4):376-96. PMID: ISI:A1990EF54800005.
2. Mackenzie JS, Gubler DJ, Petersen LR. Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses. Nature Medicine. 2004 Dec;10(12):S98-S109. PMID: ISI:000225733900006.
3. Gubler DJ. Dengue and dengue hemorrhagic fever. Clin Microbiol Rev. 1998 Jul;11(3):480-96. PMID: ISI:000074714500006.
4. Mustafa MS, Rasotgi V, Jain S, Gupta V. Discovery of fifth serotype of dengue virus (DENV-5): A new public health dilemma in dengue control. Medical Journal, Armed Forces India. 2015 Jan;71(1):67-70. PMID: 25609867. Epub 2015/01/23.
5. Langgartner J, Audebert F, Scholmerich J, Gluck T. Dengue virus infection transmitted by needle stick injury. The Journal of Infection. 2002 May;44(4):269-70. PMID: 12099738. Epub 2002/07/09.
6. Boussemart T, Babe P, Sibille G, Neyret C, Berchel C. Prenatal transmission of dengue: two new cases. Journal of Perinatology. 2001 Jun;21(4):255-7. PubMed PMID: 11533844. Epub 2001/09/05.
7. Chye JK, Lim CT, Ng KB, Lim JM, George R, Lam SK. Vertical transmission of dengue. Clinical Infectious Diseases. 1997 Dec;25(6):1374-7. PMID: 9431381. Epub 1998/02/07.
8. Phongsamart W, Yoksan S, Vanaprapa N, Chokephaibulkit K. Dengue virus infection in late pregnancy and transmission to the infants. The Pediatric Infectious Disease Journal. 2008 Jun;27(6):500-4. PMID: 18434933. Epub 2008/04/25.
9. Ribeiro CF, Lopes VG, Brasil P, Coelho J, Muniz AG, Nogueira RM. Perinatal transmission of dengue: a report of 7 cases. The Journal of Pediatrics. 2013 Nov;163(5):1514-6. PMID: 23916226. Epub 2013/08/07.
10. Barthel A, Gourinat AC, Cazorla C, Joubert C, Dupont-Rouzeyrol M, Descloux E.Breast milk as a possible route of vertical transmission of dengue virus? Clinical Infectious Diseases. 2013 Aug;57(3):415- 7. PMID: 23575200. Epub 2013/04/12.
11. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. The global distribution and burden of dengue. Nature- Letter Research 2013:5.
12. Chitra TV, Panicker S. Maternal and fetal outcome of dengue fever in pregnancy. Journal of Vector Borne Diseases. 2011 Dec;48(4):210-3. PMID: 22297282. Epub 2012/02/03.
13. Viennet E, Ritchie SA, Faddy HM, Williams CR, Harley D. Epidemiology of dengue in a high-income country: a case study in Queensland, Australia. Parasites & Vectors. 2014;7(1):379. PMID: 25138897. Epub 2014/08/21.
15. McBride WJ. Dengue fever: is it endemic in Australia? Internal Medicine Journal. 2010 Apr;40(4):247-9. PMID: 20529038. Epub 2010/06/10.[/note[ One of the largest epidemics in at least 50 years occurred in 2008–09, affecting a significant proportion of North Queensland, totalling more than 1000 clinical cases¹⁴Viennet E, Ritchie SA, Faddy HM, Williams CR, Harley D. Epidemiology of dengue in a high-income country: a case study in Queensland, Australia. Parasites & Vectors. 2014;7(1):379. PMID: 25138897. Epub 2014/08/21.
16. Ritchie SA, Pyke AT, Hall-Mendelin S, Day A, Mores CN, Christofferson RC, et al. An explosive epidemic of DENV-3 in Cairns, Australia. PloS One. 2013;8(7):e68137. PMID: 23874522. Epub 2013/07/23.
17. Health Q. Current dengue outbreaks 2013 [updated 24th July 2013; cited 2013 September 23]. Available from: www.health. qld.gov.au/dengue/outbreaks/current.asp .
18. Beebe NW, Cooper RD, Mottram P, Sweeney AW. Australia’s dengue risk driven by human adaptation to climate change. PLoS Neglected Tropical Diseases. 2009;3(5):e429. PMID: 19415109. Epub 2009/05/06.
19. Potter S. The Sting of Climate Change: Malaria and Dengue Fever in Maritime Southeast Asia and the Pacific Islands. Policy Brief: Lowy Institute for International Policy; 2008.
20. Russell RC, Currie BJ, Lindsay MD, Mackenzie JS, Ritchie SA, Whelan PI. Dengue and climate change in Australia: predictions for the future should incorporate knowledge from the past. Med J Aust. 2009 Mar 2;190(5):265-8. PMID: ISI:000265400000015.
21. Pouliot SH, Xiong X, Harville E, Paz- Soldan V, Tomashek KM, Breart G, et al. Maternal dengue and pregnancy outcomes: a systematic review. Obstetrical & Gynecological Survey. 2010 Feb;65(2):107-18. PMID: 20100360. Epub 2010/01/27.
22. 11 Ribeiro CF, Lopes VG, Brasil P, Coelho J, Muniz AG, Nogueira RM. Perinatal transmission of dengue: a report of 7 cases. The Journal of Pediatrics. 2013 Nov;163(5):1514-6. PMID: 23916226.Epub 2013/08/07.
23. Dengue virus case definition: Australian Government; Department of Health; 2013 [08/04/2015]. Available from: www.health.gov.au/internet/main/publishing. nsf/Content/cda-surveil-nndss-casedefs- cd_dengue.htm
24. Dengue virus case definition: Australian Government; Department of Health; 2013 [08/04/2015]. Available from: www.health.gov.au/internet/main/publishing. nsf/Content/cda-surveil-nndss-casedefs- cd_dengue.htm .
25. Phupong V. Dengue fever in pregnancy: a case report. BMC Pregnancy and Childbirth. 2001;1(1):7. PMID: 11747474. Epub 2001/12/19.
26. Ramakrishnan L, Pillai MR, Nair RR. Dengue vaccine development: strategies and challenges. Viral Immunology. 2015 Mar;28(2):76-84. PMID: 25494228. Epub 2014/12/11.