Synonyms: breakbone fever, dengue shock syndrome, dandy fever, seven-day fever, duengero, ki denga pepo (Swahili, meaning 'sudden overtaking by a spirit')

See also separate article Viral Haemorrhagic Fevers.

Epidemiology

• Dengue is an endemic disease in the tropics and subtropics and is found in the Caribbean, South and Central America, Mexico, Africa, the Pacific Islands, South East Asia, the Indian sub-continent, Hawaii, and Australia.⁵
• During the eighteenth and nineteenth century, epidemic outbreaks of dengue would occur, mainly centred on seaports with mosquitoes introducing the virus or bringing novel serotypes by boat. During the twentieth century, increasing urbanisation and air transportation has allowed the disease to gather pandemic status with 40% of the global population currently living at risk of the disease.⁵
• WHO recognises dengue as a major and emergent concern due both to its expanding distribution and also to an increased frequency of epidemics.⁶
• It is the most common of the flaviviruses with an estimated 100 million cases of dengue fever (DF), and 0.5 million of DHF worldwide annually.⁷
• 90% of DHF cases occur in children aged <15 and DHF is a leading cause of death and serious illness in children in some Asian countries.
• Infection provides lifelong immunity but only against the infecting viral serotype. There is evidence that secondary infection with another serotype increases the risk of developing DHF. Recent pandemics in 1998 and 2001 are thought to be due to the emergence of a new subtype of the DEN-3 virus.
• Travellers can also become infected.⁶

Risk factors

For contracting dengue:

• High population density
• Urban living
• Poor public hygiene
• Exposure to mosquitoes in endemic areas

For developing severe DHF:²

• Age - 95% of DHF/dengue shock syndrome (DSS) occurs in the under 15s and physiological changes in capillary permeability may be important.
• Repeat dengue infections - infection with a secondary serotype is thought to be important in the development of severe haemorrhagic disease.⁶ Memory T cells may inappropriately activate when exposed to a different serotype of the disease.⁸
• Genetic factors - disease severity and outcome unsurprisingly appear to be associated with allelic variation at multiple gene loci involved in acquired and innate immune response⁹
• Viral genotypes - some strains may be more virulent and produce higher rates of DHF.
• Nutritional status - malnourished children are less likely to develop DHF than well nourished children due to impaired cellular immunity but, where they do, the disease is more likely to be severe.

Presentation

Patients become infected once bitten by mosquitoes. The virus passes to lymph nodes and replicates, which is followed by spread to the circulation and other tissues. Incubation period is 2-7 days. Take a full travel history, including stop-overs, and always consider the diagnosis in a febrile patient returning from the tropics or subtropics.

Symptoms

• All haemorrhagic fever syndromes begin with abrupt onset of fever and myalgia.
• Fever is associated with frontal or retro-orbital headache accompanied by onset of a generalised rash.
• Symptoms regress for a day or two but may recur, although fever is rarely as high as at the onset.
• DF cases experience severe bony and myalgic pain in legs, joints and lower back which may last for weeks (hence breakbone fever).
• Nausea, vomiting, cutaneous hyperaesthesia, taste disturbance and anorexia are common.
• Abdominal pain may occur and, if severe, suggests DHF pattern.¹⁰

Signs

• High fever - usually between 39.5–41ºC - persisting for 1-7 days only. Fever is often biphasic with two peaks.
• Cardiovascular signs include hypotension and narrow pulse pressure, poor capillary refill and relative bradycardia.
• Rash is initially generalised, macular and blanching and fades after 1-2 days and may then reappear as a maculopapular, morbilliform rash with sparing of palms and soles. Desquamation may follow.
• Tender muscles on palpation.
• There may be hepatomegaly and lymphadenopathy.
• A tourniquet placed on an arm may induce petechiae. Other haemorrhagic manifestations include spontaneous petechiae (best visualised in the axillae), purpura, epistaxis, gum bleeding, gastrointestinal haemorrhage and menorrhagia.
• With DHF, there may be pleural effusion, ascites and pericarditis due to plasma leakage.
• Periorbital oedema and proteinuria may be present.
• Maculopathy and retinal haemorrhages may also occur.¹¹
• DSS occurs with the development of profound hypotensive shock.
• Central nervous system involvement, e.g. encephalopathy, coma, convulsions.

Differential diagnosis

Dengue fever

• Malaria
• Typhoid fever
• HIV seroconversion
• Infectious mononucleosis
• Coxsackie and other enteroviruses
• Rickettsial infections
• Measles
• Rubella
• Parvovirus B19
• Weil's disease (leptospirosis)
• Influenza
• Scrub typhus
• Chikungunya viral infections

Dengue haemorrhagic fever

• Weil's disease (leptospirosis)
• Chikungunya viral infections
• Kawasaki disease
• Yellow fever
• Hantavirus/other viral haemorrhagic infections
• Meningococcal septicaemia
• Encephalitic viruses, e.g. West Nile virus

Dengue shock syndrome

As DHF, plus any cause of shock, particularly septic shock and toxic shock syndrome caused by occult staphylococcal infection (check for tampon use).

Investigations

• FBC may show high packed cell volume if haemoconcentrated and low platelets. There may be a paradoxical lymphocytosis (>15% circulating white cells) in context of overall leucopenia.
• Clotting studies can reveal prolongation of APTT and PT. Fibrin degradation products may be elevated.
• U&E may show electrolyte disturbance and LFTs can be elevated - especially AST.
• Severe cases may show reduced venous bicarbonate due to acidosis.
• Infection may be confirmed by isolation of virus in serum and detection of IgM and IgG antibodies by ELISA, monoclonal antibody or haemagglutination.¹² PCR-based techniques are increasingly being used.
• X-rays are often used to exclude other sources of sepsis/assess complications, although in dengue infection, CXR may show abnormalities in the first week, e.g. pleural effusion.¹³
• Blood cultures and repeated malaria films should be checked in the traveller returning with a high fever.

Management⁷

Whilst there is no specific treatment for DF, medical care by teams experienced with the effects and progression of complicated DHF frequently saves lives:

• Fever control with paracetamol, tepid sponging and fans.
• Intravenous fluid resuscitation with close monitoring, remembering the risk of increased capillary permeability. Monitor CVP and urine output and pay close attention to electrolytes, packed cell volume, platelets and LFTs. High volume and aggressive colloid/crystalloid infusion under expert guidance may be needed. Inotropes may also be required, as may renal support.
• Secondary bacterial infections may occur and require treatment.
• Haemorrhage and shock will require FFP and platelets.
• Those with DHF/DSS are likely to require intensive care, where available.

Prognosis

• Severe infections probably only account for 2–4% of cases.⁷
• The vast majority have no serious sequelae and the return of appetite is a good marker of recovery.⁷ However, recovery can be associated with prolonged fatigue and depression.
• Background mortality rate in treated cases in Asia is about 0.5–3%.⁷
• If severe and untreated or with complications, as listed below, then mortality is high - up to 50%.

Complications

• Hepatic failure
• Encephalopathy
• Myocarditis
• Disseminated intravascular coagulation

Prevention

• Any potential vaccine must be protective against all the subtypes of the disease. A number of different candidate vaccines are under development. A live attenuated tetravalent vaccine is at Phase 2 clinical testing.¹⁴ There are safety concerns including the potential of live vaccines to undergo recombination with flaviviruses.¹⁵
• Anti-mosquito public health measures, such as reducing breeding sites, good sewage management, house design and use of insecticides, may help. Effective mosquito control is virtually non-existent in most endemic countries.
• Mosquito nets are unhelpful as the Aedes mosquito is day-biting.
• Repellents may reduce the risk by reducing the overall number of bites, especially those containing N,N-diethyl-3-methylbenzamide (DEET - use during the day).
• Unlike the other viral haemorrhagic fevers, dengue cannot be aerosolised and thus is an unattractive potential agent of bioterrorism.

Historical aspects

• Dr Benjamin Rush (a signer of the American Declaration of Independence) in Philadelphia coined the name 'breakbone fever' in 1780, the first clear description of DF in English, during the first simultaneous reported epidemics in Asia, Africa, and North America of 1779-1780.
• Ashburn and Craig showed that the agent responsible was ultramicroscopic and non-filterable, and confirmed in 1906 that it could be transmitted by mosquito.
• The first epidemic in Europe was thought to have occurred in 1928 in Greece.
• Hotta and Kimura isolated the DEN-1 virus in 1943 in Japan, and independently, due to World War II, Sabin (of polio vaccine fame) and Schlesinger the DEN-1 a few months later, and DEN-2 shortly afterwards.
• In 1956, Philippine and Thai haemorrhagic fevers were shown to be caused by dengue viruses, by Dr Bill Hammond, who later isolated DEN-3 and DEN-4.

Document references

1. Dengue haemorrhagic fever; diagnosis, treatment, prevention and control. 2nd edition. Geneva : World Health Organization.
2. Senanayake S; Dengue fever and dengue haemorrhagic fever--a diagnostic challenge. Aust Fam Physician. 2006 Aug;35(8):609-12. [abstract]
3. Deen JL, Harris E, Wills B, et al; The WHO dengue classification and case definitions: time for a reassessment. Lancet. 2006 Jul 8;368(9530):170-3.
4. Gibbons RV, Vaughn DW; Dengue: an escalating problem. BMJ. 2002 Jun 29;324(7353):1563-6.
5. NaTHNaC Dengue fever information sheet for professionals, Jan 2007.
6. Wilder-Smith A, Schwartz E; Dengue in travelers. N Engl J Med. 2005 Sep 1;353(9):924-32.
7. Malavige GN, Fernando S, Fernando DJ, et al; Dengue viral infections. Postgrad Med J. 2004 Oct;80(948):588-601. [abstract]
8. Rothman AL; Cellular immunology of sequential dengue virus infection and its role in disease pathogenesis. Curr Top Microbiol Immunol. 2010;338:83-98. [abstract]
9. Stephens HA; HLA and Other Gene Associations with Dengue Disease Severity. Curr Top Microbiol Immunol. 2010;338:99-114. [abstract]
10. Ooi ET, Ganesananthan S, Anil R, et al; Gastrointestinal manifestations of dengue infection in adults. Med J Malaysia. 2008 Dec;63(5):401-5. [abstract]
11. Bacsal KE, Chee SP, Cheng CL, et al; Dengue-associated maculopathy. Arch Ophthalmol. 2007 Apr;125(4):501-10. [abstract]
12. Rigau-Perez JG, Clark GG, Gubler DJ, et al; Dengue and dengue haemorrhagic fever. Lancet. 1998 Sep 19;352(9132):971-7. [abstract]
13. Wang CC, Wu CC, Liu JW, et al; Chest radiographic presentation in patients with dengue hemorrhagic Fever. Am J Trop Med Hyg. 2007 Aug;77(2):291-6. [abstract]
14. Durbin AP, Whitehead SS; Dengue vaccine candidates in development. Curr Top Microbiol Immunol. 2010;338:129-43. [abstract]
15. Seligman SJ, Gould EA; Live flavivirus vaccines: reasons for caution. Lancet. 2004 Jun 19;363(9426):2073-5. [abstract]

Internet and further reading

• Dengue haemorrhagic fever; diagnosis, treatment, prevention and control. 2nd edition. Geneva : World Health Organization.
• Piggot DC; CBRNE - Viral Hemorrhagic Fevers, eMedicine, May 2009
• Teixeira MG, Barreto ML; Diagnosis and management of dengue. BMJ. 2009 Nov 18;339:b4338. doi: 10.1136/bmj.b4338.

Acknowledgements