Dengue Haemorrhagic Fever

Synonyms: Breakbone fever, Dengue Shock Syndrome, Dandy fever, Seven-day fever, Duengero, Ki denga pepo (Swahili - sudden overtaking by a spirit)

See also viral haemorrhagic fevers.

In all types of viral haemorrhagic fevers there are vascular abnormalities with loss of vascular integrity. This leads to increased vascular permeability and local haemorrhage.

Dengue Haemorrhagic Fever is a mosquito-borne (Aedes genus) viral infection endemic in the tropical and sub-tropical regions. The female Ae.aegypti (the most important vector) mosquito is semi-domesticated, preferring to lay its eggs in man-made water containers, resting indoors and feeding in the early morning or late afternoon (unlike the malaria mosquito). They are thus relatively immune to outdoor public health spraying. They are easily disturbed during feeding (and infected mosquitoes are slower feeders) but will return to the same subject or others to complete a meal, thus potentially infecting several people during one feed. Transmission may occur transovarially, potentially acting as a reservoir between epidemics. There are 4 subtypes of the single-stranded RNA virus (flaviviridae).¹

Infection syndromes comprise

1. Asymptomatic infection
2. Dengue fever (DF)
3. Dengue haemorrhagic fever (DHF)
4. Dengue shock syndrome (DSS)

The following table illustrates the WHO classification of dengue:

However, there are concerns regarding how practical this classification is and it may need revision.²

A endemic disease in the tropics and subtropics mainly affecting children. Most prevalent in tropical Asia, Latin America and the Caribbean.² It is the commonest of the flaviviruses with an estimated 100 million cases of dengue fever, and 0.5 million of DHF worldwide annually.³ 90% of DHF cases occur in children aged <15. Recent pandemics in 1998 and 2001 are thought to be due to the emergence of a new subtype of the DEN-3 virus. Infection provides life-long immunity but only against the infecting viral serotype. Travellers can also become infected.⁴ WHO recognises dengue as a major concern due to an increased frequency of epidemics of late and an ever expanding distribution.⁴

• High population density
• Urban living
• Poor public hygiene
• Exposure to mosquitoes in endemic areas
• Lack of immunity in children/travellers

Patients become infected once bitten by mosquitos. The virus passes to lymph nodes and replicates which is followed by spread to the circulation and other tissues. It is thought that infection with a secondary serotype is what leads to severe haemorrhagic disease.⁴

Symptoms

• Enquire about travel to tropical or sub-tropical areas.
• Incubation period is 2-7 days.
• All haemorrhagic fever syndromes begin with abrupt onset of fever (39.5–41ºC) and myalgia.
• Fever is often biphasic with two peaks.
• Fever is associated with frontal or retro-orbital headache lasting 1–7 days, accompanied by generalised macular, blanching rash.
• Initial rash usually fades after 1–2 days.
• Symptoms regress for a day or two then rash reappears in maculopapular, morbilliform pattern, sparing palms and soles of feet. Fever recurs but not as high. There may be desquamation.
• 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.

Signs

• High fever, rash, hypotension and narrow pulse pressure, poor capillary refill.
• There may be hepatomegaly and lymphadenopathy.
• A tourniquet placed on an arm may induce petechiae in early DHF cases. DHF sufferers exhibit a bleeding tendency as evidenced by petechiae, purpura, epistaxis, gum bleeding, GI haemorrhage and menorrhagia. There may be pleural effusion, ascites and pericarditis due to plasma leakage.
• Petechiae are best visualized in the axillae.
• Flushing of head and neck.
• Tender muscles on palpation.
• Periorbital oedema and proteinuria may be present.
• Maculopathy and retinal haemorrhages may also occur.⁵
• DSS pattern cases progress through DHF until profound shock due to severe hypotension is present.
• CNS involvement e.g. encephalopathy, coma, convulsions.

Also see Dengue haemorrhagic fever: diagnosis, treatment, prevention and control from WHO (chapter two).⁶

DF

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

DHF

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

DSS

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

• FBC may show low platelets and high packed cell volume if haemoconcentrated. There may be a paradoxical lymphocytosis (>15% circulating white cells) in context of overall leukopenia. Patients with platelets less than 100,000 per cubic millimeter have highest risk of developing DHF.⁴
• 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.
• Infection may be confirmed by isolation of virus in serum and detection of IgM and IgG antibodies by ELISA, monoclonal antibody or haemagglutination.⁷
• Molecular diagnostic methods such as reverse-transcriptase-PCR are increasingly being used.
• Severe cases may show reduced venous bicarbonate due to acidosis.
• X-rays 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.⁸
• Blood cultures and repeated malaria films should be checked in the traveller returning with a high fever.

• Fever control with paracetamol, tepid sponging and fans.
• Intravenous fluid resuscitation with close monitoring especially in DHF. Need to remember that there may be increased capillary permeability. Thus monitor CVP and urine output and 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 be required as may renal support.
• Secondary bacterial infections may occur and require treatment.
• Haemorrhage and shock will require FFP, platelets and intensive management of the shock syndrome may be required in severe DHF/DSS cases.

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

• Hepatic failure
• Encephalopathy
• Myocarditis
• Disseminated intravascular coagulation

• Vaccines are being researched but are as yet insufficiently protective against all four subtypes to be used routinely. Research with live vaccines has raised the possibility of recombination of flaviviruses with the potential to produce a new virus, thus there are safety issues.⁹
• 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 nonexistent in most endemic countries.
• Mosquito nets are unhelpful as the Aedes mosquitoes 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 is unique in that it cannot be aerosolised, and therefore is unlikely to be an agent of bioterrorism.

• 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 dengue 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 that it could be transmitted by mosquito in 1906.
• 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 WWII, Sabin (of polio vaccine fame) and Schlesinger the DEN-1 a few months later, and DEN-2 shortly after.
• 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.