Dengue

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

See also the separate Viral Haemorrhagic Fevers article.

What is dengue?^{1 2}

Dengue is a highly infectious disease of tropical countries and is rapidly becoming a global burden.

Dengue is a viral infection transmitted to humans through the bite of infected mosquitoes. Dengue virus is transmitted by female mosquitoes mainly of the species Aedes aegypti and, to a lesser extent, Ae. albopictus. These mosquitoes are also vectors of chikungunya, yellow fever and Zika viruses. Human-to-human direct spread of dengue fever does not occur.

In order for transmission to occur, the mosquito must feed on a person during the five-day period when large amounts of virus are in the blood; this period usually begins before the person becomes symptomatic. After entering the mosquito, the virus will require an additional 8-12 days of incubation before it can then be transmitted to another human. The mosquito remains infected for the remainder of its life, which might be days or a few weeks.³

Dengue is caused by a virus of the Flaviviridae family. The virus responsible for causing dengue, is called dengue virus (DENV). There are four distinct serotypes of the virus that cause dengue (DENV-1, DENV-2, DENV-3 and DENV-4).

Infection by any of the four serotypes may range from asymptomatic to life-threatening. The pathological effects are immune-mediated. The development of severe disease seems to involve a complex interplay of host immunity and genetic predisposition combined with certain viral virulence factors.⁴

Recovery from infection provides lifelong immunity against that serotype. However, cross-immunity to the other serotypes after recovery is only partial, and temporary. Subsequent infections (secondary infection) by other serotypes increase the risk of developing severe dengue.

Dengue is rarely diagnosed in the UK. However, Dengue is an important cause of fever in returning travellers. It should be on the differential diagnosis of travellers with unexplained pyrexia returning from an affected area. It should rise higher on the list of differential diagnosis if there are features suggesting bleeding, hypovolaemia, increased vascular permeability, or organ failure.

The global impact of dengue has markedly increased over the last few decades and about half the world's population is now at risk. Dengue is considered a major and emergent concern.

Classification of dengue⁵

Dengue is a single disease with several different clinical presentations. In 2009 the World Health Organization (WHO) revised the classification according to levels of severity:

Dengue without warning signs
Fever and two of the following:

• Nausea, vomiting.

• Rash.

• Aches and pains.

• Leukopenia.

• Positive tourniquet test.

• Laboratory-confirmed dengue.

With ability:

• To tolerate adequate volumes of oral fluid replacement.

• To pass urine at least once every six hours.

Dengue with warning signs
Patients with at least one of the following warning signs:

• Abdominal pain or tenderness.

• Persistent vomiting.

• Clinical fluid accumulation.

• Mucosal bleed (gingival bleeding, epistaxis, conjunctival bleeding, haematemesis, melaena, fresh blood per rectum, haematuria, or vaginal bleeding).

• Lethargy/restlessness.

• Liver enlargement >2 cm.

• Increased haematocrit with concurrent decrease in platelet count (100,000 platelets/mm³ or less).

OR: at least one comorbid condition such as pregnancy, infancy, old age, diabetes mellitus, renal failure.
OR: social circumstances such as living alone or living far from hospital.

Severe dengue fever
Patients with any of the following features:

• Severe plasma leakage leading to:

  • Shock.

  • Fluid accumulation leading to respiratory distress.

• Severe bleeding as evaluated by the clinician.

• Severe organ involvement:

  • Liver: AST or ALT above 1000 IU/L.

  • Impaired consciousness.

  • • Heart and other organs.

Some argue that the definitions need to be more specific, so classification may evolve further.

Dengue epidemiology²

• The global incidence of dengue has grown dramatically with about half of the world's population now at risk.

• At least one half of the global population is estimated at risk of infection and an estimated 390 million people are infected each year.⁶ However, over 80% are generally mild and asymptomatic.

• Dengue is endemic in more than 100 countries in Africa, the Americas, the Eastern Mediterranean, Southeast Asia and the Western Pacific. The Americas, Southeast Asia and the Western Pacific regions are the most seriously affected. There have been outbreaks in the Southern States of the USA.

• In endemic areas dengue occurs annually when rainfall is optimal for mosquito breeding. These areas are additionally at periodic risk for epidemic dengue. Dengue epidemics require the coincidence of large numbers of vector mosquitoes and large numbers of people with no immunity.

• Local pockets of increased risk are related to rainfall, temperature and rapid urbanisation.

• Between 2010 and 2014, there were an average of 350-400 imported cases of dengue fever in England, Wales and Northern Ireland each year.⁷

Risk factors²

For contracting dengue virus

• High population density.

• Urban living.

• Poor public hygiene.

• Exposure to mosquitoes in endemic areas.

For developing severe dengue⁸

• Age - 95% of severe dengue occurs in the those aged under 15 years.

• Repeated dengue infections - infection with a secondary serotype is a risk factor for the development of severe disease.⁹

• Genetic factors - disease severity and outcome appear related to variation at multiple gene loci involved in immune response.¹⁰

• Viral genotypes - some strains may be more virulent.

• Nutritional status - malnourished children are less likely to develop severe dengue than well nourished children, due to impaired cellular immunity but, where they do, the disease is more likely to be severe.

Dengue symptoms ^{2 11 12}

Although many DENV infections are asymptomatic or produce only mild illness, DENV can cause an acute flu-like illness. Occasionally this develops into severe dengue, which is a leading cause of serious illness and death in some Asian and Latin American countries.

In symptomatic presentations, following an incubation period of 4-10 days, the illness begins abruptly, going through three phases - febrile, critical and recovery:

Febrile phase

Initial symptoms consist of a high fever (39.5-41°C/104°F), which may be biphasic and which is accompanied by two or more of:

• Severe headache.

• Pain behind the eyes.

• Muscle and joint pains, which are typically severe.

• Nausea, vomiting.

• Swollen glands.

• Rash (typically morbilliform or confluent, although there may also be petechiae).

Symptoms usually last for 2-7 days. In non-severe dengue the illness does not enter a critical phase beyond this, and recovery occurs. This is often characterised by return of appetite and by profound itching. There is commonly peeling of the skin, giving rise to potential confusion with Kawasaki disease.

Signs

• Rash is initially generalised, macular and blanching, fading after 1-2 days. It may return as a maculopapular, morbilliform rash with sparing of palms and soles. Desquamation may follow.

• Tender muscles.

• Positive tourniquet test. This can be performed by inflating a blood pressure cuff on the upper arm to a pressure midway between the systolic and diastolic pressures, for five minutes. The test is considered positive when ≥20 petechiae per 2.5 cm²are seen. Even in profound shock it can be negative or just mildly positive.

Critical phase

Some patients move into a critical phase in which warning symptoms appear and there is a risk of progression to severe dengue. During this phase increased vascular permeability may develop, heralding the onset of severe dengue.

Warning signs may develop 3-7 days after the first symptoms in conjunction with a sudden decrease in temperature (below 38°C/100°F) and include:

• Severe abdominal pain.

• Persistent vomiting.

• Rapid breathing.

• Bleeding gums.

• Fatigue.

• Restlessness.

• Blood in vomit.

• If severe dengue develops, patients may become profoundly shocked and may also become encephalopathic.

Signs

Non-severe dengue

• Rash is initially generalised, macular and blanching, fading after 1-2 days. It may return as a maculopapular, morbilliform rash with sparing of palms and soles. Desquamation may follow.

• Tender muscles.

• Positive tourniquet test. This can be performed by inflating a blood pressure cuff on the upper arm to a pressure midway between the systolic and diastolic pressures, for five minutes. The test is considered positive when ≥20 petechiae per 2.5 cm² are seen. Even in profound shock it can be negative or just mildly positive.

Non-severe dengue with warning signs
This may also include:

• Haemorrhagic manifestations including spontaneous petechiae (best visualised in the axillae), purpura, epistaxis, gum bleeding, gastrointestinal haemorrhage and menorrhagia.

• Cardiovascular signs include hypotension, narrow pulse pressure, poor capillary refill and relative bradycardia.

• Hepatomegaly and lymphadenopathy may occur.

Severe dengue
This may also include:

• Pleural effusion, ascites and pericarditis due to plasma leakage.

• Periorbital oedema and proteinuria.

• Maculopathy and retinal haemorrhage.¹³

• Progress, in severe cases, to profound hypovolaemic shock.

• Central nervous system involvement, in severe cases - eg, encephalopathy.

• Hepatitis with altered liver function.

• Myocarditis with impairment of cardiac function.

• Severe bleeding, especially from the gastrointestinal tract (previously referred to as 'dengue haemorrhagic fever').

• Hypovolaemic shock.

Recovery phase

Fatigue and depression may last for weeks, particularly in adults. Where there has been plasma leakage, the recovery phase involves rapid fluid resorption over 2-3 days, and fluid overload may occur; this may result in cerebral oedema. Severe itching and a slow heart rate are common during recovery. There may be another rash which may be maculopapular or vasculitic, followed by peeling of the skin.

Differential diagnosis

There is a long list of differential diagnoses, including many causes of febrile illness, of flu-like illness and of shock. A careful history will rule some conditions out.

• Malaria.

• Typhoid fever.

• Typhus.

• Scrub typhus.

• HIV seroconversion.

• Infectious mononucleosis.

• Coxsackievirus and other enteroviruses.

• Rickettsial infections.

• Measles.

• Rubella.

• Parvovirus B19.

• Weil's disease (leptospirosis).

• Influenza.

• Chikungunya viral infection.

• Kawasaki disease.

• Yellow fever.

• Hantavirus.

• Other viral haemorrhagic infections.

• Meningococcal septicaemia.

• Encephalitic viruses - eg, West Nile virus.

Severe dengue

As above, plus any cause of shock, including sepsis and toxic shock syndrome.

Investigations²

General

• FBC may show high PCV with low platelets. There may be paradoxical lymphocytosis (>15% circulating white cells) but overall leukopenia.

• Clotting studies can reveal prolongation of APTT and PT. Fibrin degradation products may be elevated.

• U&E may show electrolyte disturbance. LFTs can be elevated - especially AST.

• Severe cases may show reduced bicarbonate due to acidosis.

• Blood cultures and repeated malaria films should be checked in the traveller returning with a high fever.

Specific

Several methods can be used for diagnosis of DENV infection.

The virus may be isolated from the blood during the first few days of infection. Reverse transcriptase-polymerase chain reaction (RT-PCR) methods are considered the gold standard. However, they require specialised equipment and training.

The virus may also be detected by testing for a virus-produced protein, called NS1. There are commercially produced rapid diagnostic tests available and it takes only about 20 minutes to determine the result. The test does not require specialised laboratory techniques or equipment.

Serological methods for anti-dengue antibodies - eg, enzyme-linked immunosorbent assays (ELISA) - may confirm the presence of a recent or past infection.

• IgM antibodies are detectable about one week after infection and remain detectable for about three months. IgM is indicative of a recent DENV infection.

• IgG antibody levels take longer to develop and remain in the body for years. IgG is indicative of a past infection.

Dengue fever treatment and management^{2 14 15 16}

There is no specific treatment for dengue fever. Patients should rest, stay hydrated and seek medical advice. Depending on the clinical manifestations and other circumstances, patients may be sent home, be referred for in-hospital management, or require emergency treatment and urgent referral. Supportive care such as fever reducers and painkillers can be taken to control the symptoms of muscle aches and pains, and fever. The best option to treat these symptoms is paracetamol. NSAIDs should be avoided in view of the risk of haemorrhage.

Therefore management principles include:

• Fever control with paracetamol, tepid sponging and fans.

• Intravenous fluid resuscitation with close monitoring, observing for increased capillary permeability. Monitor CVP and urine output, electrolytes, packed cell volume, platelets and LFTs.

• High-volume and aggressive colloid/crystalloid infusion under expert guidance may be needed. Inotropes and renal support may be necessary.

• Secondary bacterial infections may occur and require treatment.

• Haemorrhage and shock require FFP and platelets.

• Effective management of severe dengue requires early detection with urgent and often intensive care in hospital, where available.

Prognosis²

• Dengue is typically a self-limiting flu-like disease. The vast majority have no serious sequelae. However, recovery can be associated with prolonged fatigue and depression.

• Severe dengue has a mortality rate of 50% if untreated; however, this is reduced to less than 5% if appropriately treated. Medical care by experienced teams decreases mortality rates to less than 1% in majority of the countries.

• Most severe dengue and most deaths occur in children aged under 15 years.

Complications

• Hepatic failure.

• Encephalopathy.

• Myocarditis.

• Disseminated intravascular coagulation.

• Septicaemia.

Prevention of dengue fever²

There is an ongoing need to adhere to other disease preventative measures such as well-executed and sustained vector control. Individuals, whether vaccinated or not, should seek prompt medical care if dengue-like symptoms occur.

Risk factors

Further mosquito bites should be particularly avoided during the first week of illness. Virus may be circulating in the blood during this time, and there may be transmission of the virus to new uninfected mosquitoes, who may in turn infect other people.

The main method to control or prevent the transmission of dengue virus is to combat the mosquito vectors by:

Individual

• Disposing of solid waste properly and removing artificial man-made habitats that can hold water.

• Covering, emptying and cleaning of domestic water storage containers on a weekly basis.

• Applying appropriate insecticides to water storage outdoor containers.

• Use of personal household protection measures, such as window screens, repellents, coils and vaporisers. These measures must be observed during the day both inside and outside of the home (including at work/school) because the primary mosquito vectors bite throughout the day.

• Wearing clothing that minimises skin exposure to mosquitoes.

Community

• Preventing mosquitoes from accessing egg-laying habitats by environmental management and modification.

• Educating the community on the risks of mosquito-borne diseases.

• Engaging with the community to improve participation and mobilisation for sustained vector control.

• Active monitoring and surveillance of vector abundance and species composition should be carried out to determine effectiveness of control interventions.

• Prospectively monitoring prevalence of virus in the mosquito population, with active screening of sentinel mosquito collections.

• Vector surveillance can be combined with clinical and environment surveillance.

Vaccination against dengue

Vaccination is part of an integrated dengue prevention and control strategy.

• In late 2015 the first dengue vaccine, Dengvaxia® (CYD-TDV) by Sanofi Pasteur, was registered in several countries for use in individuals aged 9-45 years living in endemic areas.^{2 16}

• The WHO recommends that countries should consider introduction of the dengue vaccine CYD-TDV for people living in endemic areas, 9-45 years of age, and who have had at least one episode of dengue virus infection in the past.¹⁷ .

Dr Mary Lowth is an author or the original author of this leaflet.