Dengue

THIS PAGE IS UNDER DEVELOPMENT – The content has been produced by WHO, in collaboration with SPC and other PPHSN members
Dengue is a viral disease caused by infection with dengue virus (DENV), transmitted to humans through the bite of infected mosquitoes.
All individuals, regardless of age or sex, are at risk of contracting dengue virus if exposed to infected mosquitoes.
Individuals at increased risk of developing severe dengue include infants, older adults, pregnant women, and those with underlying health conditions such as diabetes or hypertension. People experiencing a second dengue infection or presenting with warning sign are also at higher risk of severe disease and complications
About half of the world’s population is now at risk of dengue, with an estimated 100–400 million infections occurring each year. Dengue is endemic in many Pacific Island countries and territories. Sporadic and/or continuous transmission occurs during periods of heavy rainfall. More than 50 outbreaks have occurred in the Pacific in the last 3 decades.

Epidemiology

Infectious Cause(s)

Four distinct serotypes of dengue virus (DENV-1, DENV-2, DENV-3, and DENV-4)

Source of infection

Humans are primary reservoirs.
Mosquitoes of the Aedes genus are vectors. Aedes aegypti, Aedes albopictus and Aedes polynesiensis are the major vectors in the Pacific. However, there are nine other Aedes species present in certain areas of the Pacific that are known to play a role in transmission.

Transmission

The dengue virus is transmitted to humans through the bites of infected Aedes mosquitoes. After a mosquito blood-feeds on an infected person, the virus replicates in the mosquito, reaching the salivary glands to be injected when the mosquito feeds on the next human.
Aedes mosquitoes are daytime feeders, biting mostly during the early morning and the late afternoon.

Incubation Period

Usually 5-7 days. From 4 to 10 days

Infectious Period

Not directly transmitted from person to person, but a person can infect a mosquito while they have symptoms, usually within a week of an infectious bite.
Infected mosquitoes can transmit the virus for the rest of their life.

Symptoms

Most people experiencing dengue infection for the first time have no symptoms. When symptoms occur, patients develop a high fever that mimics other febrile illnesses, lasting more than two days.
Symptoms may include high fever (40°C/104°F), severe headache, pain behind eyes, muscle and joint pains, nausea, vomiting, swollen glands, and rash. See details in the section of case definition.
Subsequent infections with a different serotype can result in more severe symptoms. Clinicians must be aware of the warning signs (see case definition) and should suspect dengue if there is no clinical improvement or if the patient’s condition worsens just before or during the transition to the afebrile phase.
Severe dengue symptoms often appear after the fever subsides. After the third to fourth day of fever, patients may enter the critical phase, characterized by severe plasma leakage leading to shock and/or fluid accumulation causing respiratory distress, severe bleeding, and severe organ impairment.
Since dengue virus, leptospirosis and chikungunya infections can present with similar prodromal symptoms, it is important for clinicians to be able to distinguish between chikungunya and dengue fever in a patient because the latter can quickly progress to severe, life-threatening complications, and death.

Differential Diagnosis

Arboviruses: Chikungunya (this has often been mistaken for dengue in South-East Asia), Zika.
Other viral diseases: Measles, rubella and other viral exanthems, Epstein-Barr Virus (EBV), enteroviruses, influenza, hepatitis A, Hantavirus
Bacterial diseases: Meningococcemia, leptospirosis, typhoid, rickettsia diseases, scarlet fever.
Parasitic diseases: Malaria.

Public health measures

Surveillance Case Definition

A suspected case is defined as:

A person with an acute febrile illness that lasts more than 2 days with TWO OR MORE of the following:
- Nausea and vomiting
- Headache and retro-orbital pain
- Aches and pains
- Rash
- Low white blood cell count (leukopenia)
- Petechiae OR positive tourniquet test
  * With or without warning signs
Warning signs:
- Abdominal pain or tenderness
- Mucosal bleeding
- Lethargy, restlessness
- Persistent vomiting
- Clinical fluid accumulation
- Increase in hematocrit with rapid decrease in platelet count
A confirmed case is:
- A suspected case with laboratory confirmation by
- - Detection of DENV RNA by polymerase chain reaction (PCR); OR
  - Detection of NS1 antigen

Threshold

Alert threshold can be defined as:

Non-endemic areas: one suspected case regardless of travel history.
Endemic areas: twice the average of suspected cases in the previous three weeks or an unusual clustering of suspected cases.

Action threshold can be defined as:

Non-endemic areas: two confirmed cases without travel history to an endemic area in a week.
Endemic areas: consider one of the following :

twice the average of suspected cases in the previous three weeks or an unusual clustering of suspected cases, in which dengue is confirmed.
+2 standard deviation (SD) of historical data
Increasing positivity rate
New serotypes identified

End of outbreak can be declared when:

there is a sustained decline in the weekly incidence of cases to pre-epidemic levels (i.e., below epidemic and alert thresholds) for four consecutive weeks (i.e., twice the longest incubation period).

Notification

Clinicians should report any suspected or confirmed cases to public health officials according to national disease guidelines.

Investigation

It is important for the response team to be multidisciplinary (i.e. environmental health officers, entomologists, epidemiologist, risk communication, clusters from health facilities, laboratories, and community).
Conduct active surveillance to identify new cases from health facilities, laboratories, and the community.
Complete case investigation forms for any suspected/confirmed cases. Minimum information needed includes demographic, clinical (symptoms and date of onset of first symptoms), history of exposure, travel history, laboratory (if any), and other relevant epidemiological and entomological information to identify likely location of infection (i.e., at work, school, other public place, or home).
Collect clinical samples for testing and confirmation. Note both date of symptom onset and date of sample collection. Blood/serum samples collected during the first 6 days post-symptom onset that test positive using PCR or NS1 antigen should be forwarded onto serotyping to identify circulating dengue virus serotype(s).
Use a line list when investigating clusters or outbreaks to track individual cases, identify epidemiologic patterns, and support early response efforts, especially in the initial stages.
Implement control measures to reduce the mosquito population in collaboration with environmental health teams (see below). Prioritise rapid adult control for containment but also undertake larval control. Encourage use of personal protection measures to prevent mosquito bites.
In order to optimize resource management, particularly in the face of potential stockouts, de-escalation of testing should be considered once the pathogen causing the outbreak has been confirmed and is included in a robust case definition to reliably identify new cases moving forward. This will allow laboratory capacity to be prioritized for high priority testing such as for severe cases. The same applies for serotyping.

Management of cases & contact

1. Dengue is not transmitted from person to person so contact tracing in not necessary.
2. However, case investigations are required for suspected cases to determine travel and exposure history and assess potential mosquito sources because other household or community members are still at risk of getting infected from the bites of mosquitoes that have fed on positive cases, especially during the first week of symptoms.
3. Testing of household or community members is not recommended.
4. Personal protection against mosquito bites through use of insecticide-treated nets (ITNs) and/or topical repellents should be encouraged for confirmed cases to prevent onwards transmission.

Laboratory

The following laboratory tests are available for the diagnosis of dengue fever:
- Viral nucleic acid detection: PCR
- Viral antigen (NS1) detection: rapid test or ELISA
- Antibody tests: IgM and IgG antibody in either a rapid test or ELISA
- Dengue duo NS1/IgM/IgG rapid test
The selection of appropriate tests and interpretation of results depends on the date of onset of symptoms and the date of sample collection.

Specimen collection

Testing is based on the use of whole blood or serum. Upon collecting samples, the date of symptom onset and the date of sample collection should be recorded.
Serum should be stored at 2-8°C and tested within 48 hours. If testing cannot be performed within 48 hours, serum can be separated and stored at -20°C for up to 7 days, otherwise stored at -70°C until sent for testing.
If a prior sample has been collected for other arboviruses such as Zika or chikungunya, the same sample can be used for dengue testing.

Results & interpretation

Type of Test	Sample	Results and Interpretation
PCR	Whole blood/ serum collected during Days 0-5 after symptom onset (Single acute sample)	1. A positive PCR in a single diagnostic specimen is considered CONFIRMED dengue. 2. A negative PCR does not rule out the virus if sampling exceeds the first six days of symptom onset.
Viral antigen (NS1) detection	Whole blood/ serum collected during Days 0-5 after symptom onset (Single acute sample)	1. A positive NS1 antigen in a single diagnostic specimen is considered CONFIRMED dengue. 2. A negative NS1 antigen does not rule out the virus if sampling exceeds the first six days of symptoms.
Serology	Serum collected 6 days or more after symptom onset	IgM A positive IgM from a single sample is considered PROBABLE dengue. In addition, it is recommended that additional steps be taken to assess if the person has had other exposures to rule out a false-positive test, such as recent dengue vaccination, or cross-reactive antibodies from Zika or other flaviviruses. A negative IgM does not rule out dengue if sampling was taken in the first week after the onset of symptom.

*Note:

NS1 may be detected by rapid diagnostic test or plate-based ELISA. These kits detect all four serotypes but do not differentiate between them.
Serology results should be interpreted with caution due to the likelihood of cross-reactivity of virus-specific antibodies. A good understanding of the patient’s current and previous Flavivirus exposure is required; otherwise, a lot of false positives can be reported. Hence, testing for antibodies to ZIKV and DENV should be done with careful consideration of epidemiologic and clinical context.
IgG testing should not be used with suspected cases when only a single sample can be collected, such as when RDTs are used in the field or outpatient clinics. The disease state cannot be properly determined from single sample IgG RDT tests. IgG can be considered for inpatient settings where serial samples can be collected using a IgG ELISA test; a 4-fold increase in IgG indicates a probable case.

Referral

Please see the PPHSN LabNet catalogue to determine country-specific referral lab information for dengue.
Please schedule a consultation with the referral laboratory BEFORE sending samples.
Only laboratory personnel trained and certified in infectious substance shipment training (in accordance with IATA Dangerous Goods regulations) should package and ship referral samples.

Infection prevention control

Standard Precautions should be taken to provide care.
Patients do not need to be isolated, but mosquito nets should be used during the early symptomatic stage in healthcare facilities where there is a risk of mosquito presence during the daytime.
Physicians or health care workers who visit zika virus -infected patients at home should take care to avoid being bitten by mosquitoes by using insect repellent and wearing long sleeves and pants.

Clinical care & treatment

Treatment of dengue is symptomatic or supportive. Patients without warning signs and who can tolerate adequate volumes of oral fluid and pass urine at least once every 6 hours may be sent home.
The patients are advised to have bed rest, adequate fluid intake, and paracetamol for pain and fever. Aspirin (acetylsalicylic acid) and other nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided due to the risk of bleeding.
Patients with underlying conditions, including social circumstances or existing warning signs, should be referred for in-hospital care.
Clinicians consider advanced management with IV fluid resuscitation and correction of metabolic imbalances, including hypoglycemia, hypocalcemia, and metabolic acidosis.
Severe dengue cases require emergency treatment. Refer to WHO Dengue Guidelines for diagnosis, treatment, prevention, and control for details.

Control measures

Environmental health measures

Effective mosquito control includes:

Personal protection measures: insecticide-treated nets (ITN) and/or topical repellents issued to confirmed cases to prevent onwards transmission. Note that these are not currently recommended by WHO for widespread deployment for community protection against dengue.
Adult control: targeted residual spraying with an effective insecticide indoors and/or outdoors (depending on the Aedes species) in likely infection locations and surrounds, such as within a 50-100 meter radius. NOTE: indoor space spraying (fogging) is useful only for emergency response if done during mosquito flying times, and if implemented repeatedly and at high coverage.
Larval control: container management (e.g., covering, cleaning, removing), clean-up campaigns (i.e., waste management), and where appropriate, application of larvicides, or introduction of biological agents that feed on larvae. Select larvicides based on local regulations, especially for use in drinking/household water.
Routine dengue mosquito surveillance should be carried out continually in endemic areas, and both before and after outbreaks in non-endemic areas. Information can guide selection of interventions and priorities for response, such as areas with high Aedes vector densities.

Immunization

Two dengue vaccines have been licensed: Dengvaxia® (CYD-TDV), developed by Sanofi Pasteur, and Qdenga® (TAK-003), developed by Takeda
WHO recommends the use of TAK-003 in children aged 6–16 years in settings with high dengue transmission intensity.

Risk communication & community engagement

Share timely and accurate information on dengue risks, symptoms, and prevention measures, including what it is, how it spreads, the role of mosquitoes, where and how they breed/rest, how they can be controlled, and how to prevent mosquito bites. In addition, information about how and where to seek medical care before severe dengue develops should be clearly communicated to the public.
Communication must be targeted at changing behaviours related to water storage, waste management, environmental cleanliness, and personal protection from mosquito bites to reduce dengue transmission.
Mobilise and engage communities to sustain mosquito control efforts.
Work with community leaders to provide reassurance about the disease being preventable and encouragement to cooperate during the implementation of control measures like residual spraying, clean-up campaigns, and application of larvicides.
Use simple, culturally appropriate language in multiple formats (such as radio, social media, posters, SMS) to reach diverse populations, including those in remote areas, people with disabilities, and non-digital users. Combat misinformation by proactively identifying and addressing rumours about dengue transmission, symptoms, and prevention.

End of outbreak response

Conduct a post-outbreak evaluation and review the outbreak response plan.
Moving from emergency outbreak response to standard mosquito surveillance and control

IHR reporting

Under IHR, countries should report to WHO if a new serotype is detected.